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TEXT-BOOK

OF

PHYSIOLOGICAL AND PATHOLOGICAL

CHEMISTRY

BUNGE

FIFTH EDITION

BARTLEY^S

Medical and Pharmaceutical
Chemistry

A Text-book for Medical and Pharma-
ceutical Students. By E. H. Baetley,
M. D. , Professor of Chemistry and Toxi-
cology at the Long Island College Hos-
pital ; Dean and Professor of Chemistry,
Brooklyn College of Pharmacy ; Presi-
dent of the American Society of Public
Analysis; Chief Chemist, Board of Health
of Brooklyn, N. Y. Ee vised and Im-
proved. With Illustrations, Glossary,
and Complete Index. 12mo.

Cloth, netp.OO; Leather, net p. 50

* * * In this book the author has not only
demonstrated his thorough knowledge of the
subject, but has written in a manner which
clearly shows him to be a teacher as well as a
writer, by placing that which is essential in such
a manner as to at once arrest the attention of
the student. ** * —Therapeutic Gazette.

P» Blakiston's Son & Co.

PUBLISHERS

TEXT-BOOK

OP

PHYSIOLOGICAL AND PATHOLOGICAL

CHEMISTKY

BY

G. BUNGE

PKOFESSOE OP PHYSIOLOGICAL CHEMISTRY AT BALE

SECOND ENGLISH EDITION

TEANSLATED FROM THE FOURTH GERMAN EDITION

BY'

FLORENCE A. STAELING

AND EDITED BY

ERNEST H. STARLING, M.D., F.R.S.

PROFESSOK OP PHYSIOLOGY IN UNIVERSITY COLLEGE, LONDON

PHILADELPHIA

P. BLAKISTON'S SON & CO.

1012 WALNUT STREET

1902

Copyright, 1902, by
P. Blakiston's Son & Co.

EDITOR'S PREFACE

Professor Bunge's Lectures on Physiological Chemistry
have had a great influence on physiological thought both here
and abroad. Representing as they do the ideas which have
produced throughout many years discoveries of fundamental
importance in the school of Schmiedeberg, they have served
to spread the method of thought of that school and to render
more effective the work of men in other laboratories. Among
these researches, I might especially mention those of Schmiede-
berg alone or in conjunction with his pupils on the mechanism
of oxidation in the body, on the occurrence of synthetic proc-
esses in the body [e. g., the synthesis of hippuric acid in the
kidney, worked out by Bunge and Schmiedeberg), Schroder's
work on the formation of urea, Minkowski and J^aunyn on
uric acid, Minkowski on the production of diabetes by extir-
pation of the pancreas, besides researches into the chemistry
of nucleins, of chondrin, the mucins (Leathes), and many other
subjects of bio-chemical interest.

These Lectures have also the merit of being written by a
man who was philosopher, mathematician and chemist before
he was a physiologist, and who, being thus in a position to
grasp the general bearings of his subject, has succeeded in
making the dry bones of physiological chemistry interesting
even to the beginner.

It was with great pleasure that I undertook to edit a new
. translation by my wife of the latest German Edition, as I con-

sider it eminently desirable that these suggestive Lectures should

be available for those students and medical men who are not
X~y familiar with German.

I would here especially endorse the author's recommenda-
tion to students to go back whenever possible to the original

vi editor's preface

papers, copious references to which form a prominent feature
of these Lectures. A careful study of a few of the classic
researches in their original form will do more to acquaint a
man with the spirit of physiology than the most arduous
perusal of text -books. It is essential to the healthy develop-
ment of the thinking powers that they should have some work
to do, and not be nourished solely on a diet of already digested
material.

Although the conclusions drawn by the author are occa-
sionally not those which would commend themselves to the
majority of physiologists, I have thought it better to indicate
in a footnote the existence of other opinions rather than inter-
fere in any way with the vitalistic mode of thought which
gives these Lectures much of their interest and individuality.
Such additions are distinguished by square brackets.

ERNEST H. STARLING.

London, March, 1902.

PREFACE TO THE FIRST EDITION

It has not been my intention to enlarge the present volume
beyond the scope of a text-book ; all disconnected facts and
mere descriptive matter have therefore been omitted. In
original research, every fact, however isolated it may at first
seem, may prove of inestimable value as a starting-point for
fresh ideas and inquiries. For this reason, an exhaustive
account of all facts is both valuable and necessary in a hand-
book. But a text-book should merely seek to initiate and
interest the student, and to acquaint him with the principal
achievements of investigation in biological sequence. A mass
of statements and details would weary and disgust the begiuner,
and might deter him from pursuing the subject altogether.
But if interest once be awakened by a suggestive though inade-
quate treatment of the subject, the deficiencies may readily be
supplied by recourse to the hand-books, or, better still, by a
careful perusal of the original works.

Descriptions of analytic methods have also for the most part
been avoided, as they would have interrupted the main narra-
tive, and as we already possess numerous standard works on
chemical analysis in physiology and pathology, such as those
by Hoppe-Seyler, Leube and Salkowski, Neubauer and Vogel.
With the aid of such teachers as these, analysis should be learnt
and practised in the laboratory.

On the other hand, I have endeavored to introduce every-
thing that is at present ripe for a connected account. Especial
care has been bestowed on the references. The original
memoirs quoted have been so chosen that, with them as a
basis, the reader who is desirous of pursuing the study of
physiological chemistry will readily be able to find his way
through its remaining literature, and will also have his atten-

VUl PREFACE TO THE FIRST EDITION

tion drawn to those works which were beyond the scope of my
subject.

If my lectures succeed in inducing the study of the original
sources, my aim will have been attained. Of what use would
it be to the medical student to learn up an exhaustive treatise
on physiology? In a few years he would be no wiser than
before. In science, it is imperative that all academic teaching
should be so directed as to render the student capable of fol-
lowing its progress. For this, a thorough knowledge of the
exact sciences, physics and chemistry, is requisite ; he will
then be in a position to read physiological works, which he
should be led to weigh and discuss critically. No one will
ever regret time and trouble spent in this way. Later in life,
he will find that he can always increase his knowledge, and
that all medical work will be the easier for it. An intimate
acquaintance with the exact natural sciences would shorten and
simplify medical study.

The object I have kept in view throughout these lectures has
been to enable the beginner to refer at once to the most valuable
passages in the original works, whenever his interest has been
excited in any question of physiological chemistry.

G. BUNGE.

CONTENTS

LECTURE I

PAGE

Vitalism and Mechanism , 1

LECTURE II

The Circulation of the Chemical Elements 13

LECTURE III
Conservation of Energy 27

LECTURE IV

The Food of Man — Definition and Classification op Food-
stuffs— The Organic Food-stuffs: Proteid and Gelatin 41

LECTURE V

The Organic Food-stuffs (continued) — Carbohydrates and Fats
— Significance of the Three Main Groups of Organic
Food-stuffs 60

LECTURE VI

The Organic Food-stuffs (conclusion) — The Organic Compounds
of Phosphorus — Cholesterin 75

LECTURE VII
The Inorganic Food-stuffs 82

LECTURE VIII
Milk and the Food of Infants 104

LECTURE IX

Subsidiary Articles of Diet 115

CONTENTS

LECTUEE X

PAGE

Saliva and Gastric Juice 129

LECTURE XI

The Processes of Digestion in the Intestine — The Pancreatic
Juice and its Fermentative Action — Ferments In General,
— The Action op the Pancreatic Juice on Carbohydrates,
Fats, and Proteids — The Nature and Significance of
Peptones 151

LECTURE XII
Intestinal Juice and Bile 172

LECTURE XIII

The Paths of Absorption, and the Immediate Destination op
the Absorbed Food-stuffs 187

LECTURE XIV
The Blood 200

LECTURE XV
Lymph 218

LECTURE XVI
The Spleen 229

LECTURE XVII

The Gases of the Blood and Respiration— Behavior of
Oxygen in the Processes of External and Internal
Respiration 237

LECTURE XVIII

The Gases op the Blood and Respiration (continued) — Be-
havior OP Carbonic Acid in the Processes op Internal
AND External Respiration — Cutaneous Respiration —
Intestinal Gases 261

LECTURE XIX

The Nitrogenous End-products op Metabolism — Hippuric
Acid, Urea, Creatin 281

CONTENTS XI

LECTUEE XX

PAGE

The Niteogenous End-products of Metabolism (continued) — Uric
Acid and the Xanthin Group 299

LECTURE XXI

The Functions of the Kidneys and the Composition of the

Urine 816

LECTURE XXII
Metabolism in the Liver — Formation of Glycogen 334

LECTURE XXIII
The Source op Muscular Energy 348

LECTURE XXIV
Formation of Fat in the Animal Body 358

LECTURE XXV
Iron 370

LECTURE XXVI
Diabetes Mellitus 386

LECTURE XXVII
Infection 408

LECTURE XXVIII
Fever , 420

LECTURE XXIX

The Ductless Glands 428

INDICES 449

LECTURE I

INTRODUCTION VITALISM AND MECHANISM

By way of introduction, I may be allowed to lay before my
readers the views I hold on the aims and prospects of modern
physiological research. We read in numberless physiological
papers, and in the introduction to almost every text-book of
physiology, that the object of physiological inquiry is to explain
the phenomena of life by physical and chemical, and therefore
ultimately by mechanical laws. A physiologist of the present
day would be regarded as lacking both in intelligence and
industry, were he to take refuge, as at one time the ' vitalists '
did, in the assumption of a special ' vital force ' as a means of
explaining biological problems. I can only accept this view in
a modified form, and with the understanding that no explana-
tion is offered by a mere term. I regard ' vital force ' as a
convenient resting-place where, to quote Kant, " reason can
repose on the pillow of obscure qualities."

But I cannot assent to the doctrine which some opponents
of vitalism maintain, and which would have us believe that
in living beings there are no other factors at work than simply
the forces and matter of inorganic nature. We certainly
cannot recognize more than these forces, owing to the limita-
tion of our powers, since in the observation of both organic
and inorganic nature we always make use of the same organs
of sense, which react only to certain forms of motion. A form
of motion transmitted to the brain by the fibers of the oj)tic
nerves arouses in us the consciousness of light and color ; the
consciousness of sound is due to another form of motion trans-
mitted by the auditory nerve ; all our sensations of taste and
smell, of temperature and touch, are due to forms of motion.
At least this is what physics teaches us ; these appear to be at
present the most fruitful hypotheses. It would indeed be a
lack of intelligence to expect, with the same senses, to make
discoveries in living nature of a difiPerent order to those revealed
to us in inorganic nature.

But for the study of organic nature we possess one addi-
tional sense, our 'internal sense': the power of studymg and

1 1

Z LECTURE I

observing the conditions and processes of our own conscious-
ness. To hold that this also is a variety of motion is, in my
opinion, an untenable doctrine. The simple fact that many
conditions of consciousness have no relation to space is opposed
to such a view. Only what consciousness has acquired by
certain senses, sight, touch, muscular sense,^ is related to space.
All other sensations, emotions, passions, and an unlimited
number of ideas have no relation to space, but only to time.
We cannot here, then, speak of a mechanism. It might be
suggested that this is only an apparent difference — that in
reality these also have spatial qualities. But such an opinion
cannot be sustained. We suppose that objects which we per-
ceive with our senses have spatial qualities simply on the
ground that, so far as we can observe them by means of our
senses, touch and sight, they seem to possess them. But for
the whole world of our internal sense, we have not even this
apparent reason, so that we cannot admit that there is any
ground for such a supposition.

Therefore the deepest insight we can gain into the most
essential part of our nature shows us something quite different,
shows us things which are without spatial qualities, and proc-
esses which can have nothing to do with mechanism.

The opponents of vitalism, those who support the mechanical
explanation of life, usually seek to justify their views by saying
that the further physiology advances, the more does it become
possible to explain, on physical and chemical grounds, phenom-
ena which have hitherto been regarded as associated with a
special vital force ; that it is only a question of time ; that it
will finally be shown that the whole process of life is only a
more complicated form of motion regulated solely by the laws
which govern inorganic nature.

But to me the history of physiology teaches the exact
opposite. I think the more thoroughly and conscientiously
we endeavor to study biological problems, the more are we
convinced that even those processes which we have already
regarded as explicable by chemical and physical laws, are in
reality infinitely more complex, and at present defy any attempt
at a mechanical explanation.

1 The ideas of space, which are connected with the sensations of sight and
touch, are possibly only brought about by the complex muscular apparatus, which
plays a part in all the functions of the organs of sight and touch. This is also
true of the so-called ' common sensations.' The ideas of space may be due to
the sensory fibers of the muscular nerves only. This view was first upheld by
Steinbach (" Beiträge zur Physiologie der Sinne," Nürnberg, 1811), and contested
by Joh. Müller ("Zur vergleichenden Physiologie des Gesichtssinnes," p. 52:
Leipzig, 1826), but, in my opinion, on unsatisfactory grounds. Joh. Müller was
a supporter of Kant's doctrine of space, which likewise appears to me untenable.

INTRODUCTION VITALISM AND MECHANISM Ö

Thus we- have been satisfied to account for the absorption
of food from the alimentary canal by the laws of diffusion and
osmosis. But we now know that, as regards osmosis, the wall
of the intestine does not behave like a dead membrane. We
know that the intestinal wall is covered with epithelium, and
that every epithelial cell is in itself an organism, a living being
with the most complex functions ; we know that it takes up
food by the active contraction of its protoplasm in the same
way as observed in independent naked animal cells, such as
amebae and rhizopods. Observations on the intestinal epithe-
lium of cold-blooded animals have made it obvious that the
cells grasp the particles of fat contained in the food by means
of protoplasmic processes which they send out ; that they in-
corporate the fat-globules with the protoplasm of the cell,
which finally passes them on to the commencement of the
lacteals.^ As long as this active intervention of cells was un-
known, it was impossible to understand the remarkable fact
that, although the minute drops of fat were able to pass
through the intestinal wall, yet finely divided pigments, in-
tentionally introduced into the intestine, remained quite un-
absorbed. At the present time we know that all unicellular
organisms possess the power of selecting their food, of taking
up the useful and rejecting the useless substances. In this
connection, I may relate an interesting observation made by
Cienkowski ^ on an ameba, called the Vampyrella.

The Vampyrella Spirogyroe is a minute red-tinged cell
devoid of any special limiting membrane, and apparently
quite structureless. Cienkowski could find no nucleus in the
cell, and the small granules observed in the protoplasm were
probably only residues of nutrient matter. This minute mass
of protoplasm will take but one form of food, a particular
variety of algae, the Spirogyra. It can be observed to send
out pseudopodia and to creep along the Confervse until it
meets with a Spirogyra ; then it affixes itself to the cellulose
coat enclosing one of the cells of the latter, dissolves the coat
at the point of contact, sucks in the contents of the cell, and
travels to the next to repeat the process. Cienkowski never
saw the Vampyrella attack any other class of algse, or even

^ R. Wiedersheim, has given an account of the older literature, together with
his own investigations on this subject in the " Festschrift der 56. Versammlung-
deutscher Naturforscher und Aerzte, gewidmet von der naturforschenden
Gesellschaft zu Freiburg i. B." Freiburg und Tübingen : 1883 ; and G. H.
Theodor Eimer, Biolog. Centralbl., vol. iv. p. 580: 1884; and Heidenhain,
Pflüger's Arch., vol. xliii., Suppl. : 1888.

^L. Cienkowski, "Beiträge zurKenntniss der Monaden," Arch. f. niikrosk,
Anatomie, vol. i. p. 203 : 1865.

4 LECTURE I

take up any other substance ; Vaucherise, CEdogonise, purposely
placed before it, were always rejected.

Another monad, the Colpodella jiugnax, was observed by
Cienkowski to feed exclusively on Chlamydomonas : " it punc-
tures, as it were, the latter, absorbs the escaping chlorophyl,
and departs." " The behavior of these monads," says Cien-
kowski, " in their search after food and in their method of
absorbing it, is so remarkable, that one can hardly avoid the
conclusion that the acts are those of conscious beings."

If this power of selecting food is possessed by the structure-
less mass of protoplasm, why should it not also be a function of
the epithelium of our intestine ? Just as the Vampyrella picks
out the Spirogyra from amongst all other algae, so do the epi-
thelial cells of our intestines select the fat-drops and reject the
pigment-granules. We know that the epithelium of the in-
testine prevents the absorption of a whole series of poisons, in
sjDite of the fact that the latter are easily soluble in the gastric
and intestinal juices. Indeed, we know that these poisons when
injected into the blood, are excreted by the intestine.

It was likewise once thought that the activit}^ of glands
and the processes of secretion were in the main explicable by
osmosis. But we now know that here too the epithelial cells
play an active part. Here again we find the same mysterious
power of selection, of picking out certain constituents of the
blood, of altering them by processes of synthesis and decom-
position, of sending some into the ducts of the glands, and
others back mto the lymph and blood. The epithelial cells of
the mammary gland collect all the inorganic salts from the
blood — which has a totally diiferent constitution — in the exact
proportion required by the infant, that its growth and devel-
opment may assimilate it to its parents. These phenomena
cannot at present be explained by the laws of diffusion and
osmosis.

All the cells of our tissues possess the same wonderful
powers as the epithelial cells of the alimentary canal and of
glands. Consider the mode of development of our organism :
all tissue elements are produced from a single ovum, and in
proportion as the cells increase by segmentation, they become
differentiated on the principle of the division of labor ; every
cell acquires the faculty of rejecting some substances, of attract-
ing others and storing them up, thereby attaining the composi-
tion necessary for the due fulfilment of the functions it has to
perform. But it is hopeless to offer a chemical explanation of
this process.

Just as little has it been possible, in other branches of

i INTEODUCTIOX VITALISM AND MECHANISM 5

physiology besides that of uutrition, to refer any single vital
process to the laws of chemistry and physics.

We have sought to explain the functions of nerve and
muscle by the laws of electricity, and must now admit that
electrical processes have been demonstrated with certainty to
occur in the living organism only in a few fishes ; or even if we
grant that electrical currents have been decisively proved to
exist in muscles and nerves, we are bound to confess that the
explanation of the functions of nerve and muscle is but
slightly advanced thereby.

It may be suggested that the physiology of the special
senses offers a field for precise physical explanations. It is
true that the eye is a physical apparatus, an optical apparatus,
a camera obscura. The image on the retina is formed by
the same unchanging laws of refraction as the image on the
sensitive plate of a photographer. But it is not a vital process.
The eye is absolutely passive in the matter. The image on
the retina is formed in an eye separated from the body and
dead. The development of the eye is a vital process. How is
this complex optical apparatus formed? Why do the cells
arrange themselves so as to produce this wonderful structure ?
This is the great problem towards the solution of which
nothing has yet been done. The succession of events in de-
velopment may indeed be observed and described, but of the
wherefore, the causal connection, we know absolutely nothing.
The process of accommodation is a vital process. Here again
we have to deal with the old unsolved question of muscle and
nerve. The same is true of the other organs of sense. We
can explain physically nothing but those processes in which the
organ is quite passively set in vibration by external impulses.

The same is true of all other branches of physiology. We
have endeavored to explain the phenomena of the circulation
of the blood on a physical basis. The blood is certainly subject
to the laws of hydrostatics and hydrodynamics, but it is per-
fectly passive as regards circulation. No one has hitherto been
able to explain the active functions of the heart and muscular
wall by a reference to physical laws. An attempt has been
made to explain the gaseous interchange which occurs in the
lungs, by the laws of aerodynamics, of absorption and diffusion,
and it is possible that the attempt may be successful. Here
again, however, we are not dealing with a vital phenom-
enon. The respiratory bellows being set into motion, the
gases move in and out according to the unchangeable laws
of dynamics, but we have to inquire how the respiratory bellows
are formed and maintained, and how they are able to carry out

b LECTURE I

their movements. Throughout the whole process the gases
play only a passive part.

I maintain that all the processes of our organism capable of
explanation on mechanical principles are as little to be regarded
as vital phenomena as the rustling of leaves on a tree, or as the
movement of the pollen when blown from stamen to pistil.
Here we have a form of motion essential to the phenomenon
of life, and yet no one would consider it a vital act, simply
because the pollen is quite passive under it. It does not in the
least alter the main point at issue, whether the source of motion
is formed by the kinetic energy of the wind, or by the sunlight
which induces the wind, or by the latent chemical energy into
which the sunlight has been converted.

The mystery of life lies hidden — in activity.^ But the con-
ception of activity has come to us, not as the result of sensory
perceptions, but from the study of our own internal conscious-
ness. We transfer to the objects of our sensory perception,
to the organs, to the tissue-elements and to every minute cell,
something which we have acquired from our own consciousness.
This is the first attempt towards a psychological explanation of
all vital phenomena.

If, as it thus appears, it is impossible to explain vital
phenomena by the help of physics and chemistry alone, we
must inquire what the other auxiliaries to the science of physi-
ology— the morphological sciences, anatomy and histology —
can do for us.

I hold that there is at present but little likelihood of attain-
ing our aim by their means. For when we have, with the aid
of scalpel and microscope, carried our anatomical analysis to its
utmost limit, to the simple cell, we still have the great prob-
lem to face. The most simple cell — a formless, structureless,
minute mass of protoplasm — exhibits all the essential processes
of life, as nutrition, growth, reproduction, movement, reaction
to stimulation ; it even displays functions which act at least as
a substitute for the psychical powers of higher organisms.
You will remember that it is so in the case of the Vampyrella,
and I should like to call your attention to the still more re-
markable observations which Engelmann has made on the
Arcellse.^

^ Activity and life are perhaps two words for the same idea, or rather two
words to which no definite idea is attached. And yet these vague terms are all
that we have at our command. Here we approach the most difiicult problems,
which have foiled all attempts at solution.

2 Th. W. Engelmann, " Beiträge zur Physiologie des Protoplasmas," Pflüger's
Arch., vol. ii. p. 307 : 1869. Compare also vol. xxv. p. 288, Note I. 1881 ; vol.
xxvi. p. 544, 1881; vol. xxx. pp. 96, 97, 1883; and Max Verworn, Pflüger's
Arch., vol. liii. p. 140, 1893.

INTRODUCTION VITALISM AND MECHANISM 7

The Arcellse are also unicellular organisms, but they are more
complex than the Vampyrella, because they have a nucleus and
a shell. This shell has a convex-concave form. In the middle
of the concave side of the shell is an opening from which the
pseudopodia project, appearing as clear protuberances at the
edge of the shell. If a drop of water containing Arcellse be
placed under the microscope, it often occurs that one of them
falls on its back as it were, i. e., with the convex side downwards
on the slide, so that the pseudopodia which appear at the edge
of the shell cannot reach any support. It is then observed
that, near the edge on one side, minute bubbles of gas make
their appearance in the protoplasm ; this side consequently
becomes lighter and floats up, so that the animal now rests
upon the opposite sharp edge. It is now able, by means of its
pseudopodia, to grasp the slide and thus completely to turn
over, so that all the pseudopodia are downwards. The gas-
bubbles now disappear, and the animal crawls away. If a little
water containing Arcellse be dropped on the under side of a
cover-glass, and the latter be placed in a small gas-chamber, it
is observed that the animalcules at first sink to the bottom of
the drops. If they find nothing to lay hold of, large bubbles
of gas are developed in the protoplasm, and as they are thus
rendered specifically lighter than the water, they rise in the
drops. If they reach the surface of the glass in such a position
that they cannot attach themselves to it by their pseudopodia,
the gas-bubbles are diminished on one side or increased on the
other (sometimes simultaneously on both), until a tilting takes
place and the edge of the shell comes in contact with the glass,
and they are thus enabled to turn over. When once this is
accomplished, the bubbles again disappear, and the animal can
now crawl freely about the glass. If the Arcellse are carefully
detached by means of a needle, they at first fall to the bottom,
and then go through the same proceedings anew. Whatever
attempt may be made to put them into an inconvenient position,
they are always able, by the development of gas-bubbles of
appropriate size and at the proper spot, to right themselves, so
that they acquire a position favorable to locomotion ; and the
attainment of this object is always followed by the disappear-
ance of the bubbles. " It cannot be denied," says Engelmann,
"that these facts point to psychical processes in the proto-
plasm."

Whether this view of Engelmann's is justified or not, I do
not venture to decide. I will even unreservedly admit that
these remarkable phenomena may find a mechanical expla-
nation. I have brought these facts to your notice merely in

8 LECTURE I

order to show you what complex manifestations of life we meet
with, in cases where microscopical investigation has already
reached its limit, and how little it has at present been possi-
ble to explain any single vital process on purely mechanical
grounds. For the cells of which our body is composed exhibit
processes which are at least as complicated as those of the
simple organisms. Every one of the innumerable microscopic
cells of which our body is made up is a microcosm, a world in
itself.

It is a well-known fact that through one single spermato-
zoon, through this minute cell, five hundred millions of which
would hardly occupy one cubic millimeter, all the physical and
intellectual peculiarities may be transmitted from father to son,
or, even skipping the son, may again, by the agency of one
single minute cell, reappear in the grandson. If this is really
a mechanical process, how wonderful must be the molecular
structure, how complicated the interchange of forces, how in-
tricate the forms of motion, in this small cell which shall direct
all subsequent forms of motion, and the mode of development
for generations ! And how shall this minute structure transmit
mental qualities ? Here we are utterly abandoned by physics,
chemistry, and anatomy.

Many centuries may pass over the human race, many a
thinker's brow be furrowed, and many a giant worker be worn
out, ere even the first step be taken towards the solution of this
problem. And yet it is quite conceivable that a sudden flash
of light may illumine the darkness. You would misunder-
stand me, were you to take my exposition as a confession that I
imagine that science has impassable boundaries. Science will
continue to ask and to answer even bolder questions. Nothing
can stop its victorious career, not even the limitations of our
intellect. This too is capable of being made more perfect.
There is no rational ground for thinking that the continuous
progression, development, and ennoblement of type which
has been going on for centuries on this planet, should come
to an end with us. There was a time when the only living
creatures were the infusoria floating in the primeval sea, and
the time may come when a race may dominate the globe as
superior to ourselves in intellectual faculties as we are to the
infusoria.

We must therefore unreservedly admit that the stupendous
difficulties which at present beset physiological investiga-
tions may finally be overcome. But for the moment it
is not apparent how any further progress of importance can
be made with the help of chemistry, physics, and anatomy

IXTRODUCTIOX VITALISM AXD MECHANISM 9

only. The smallest cell exhibits all the mysteries of life,
and our present methods of its investigation have reached
their limit.

But we may improve our methods, we may acquire micro-
scopes of still higher power than those we now possess. The
cell which at present appears to be without structure, may
show a nucleus when treated with some new stain. And the
nucleus itself displays a structure so complex that it will soon
require the entire attention of numerous observers for its
adequate investigation and description. But unfortimately a
complex structure is no explanation ; it only offers a new prob-
lem as to its mode of origin. And moreover how little does
our knowledge of this structure help us to understand even
the simple processes observable in the A'^ampyrell and the
Arcella !

For all this, physiological inquiry must commence with the
study of the most complicated organism, that of man. Apart
from the requirements of practical medicine, this is justified by
the following reason, which leads us back to the starting-point
of our remarks : that in researches upon the human organism
we are not limited to our physical senses, but also possess the
advantage afforded by the ' internal sense,' or self-observation.
In fact we may in this way approach the problems of physiology
from two sides, just as in mining or tunnelling the workmen
excavate from two directions, until those on one side hear
through the intervening stone the strokes of the hammers of
those on the other.

To the clear recognition of the value of this method, which
enables us to attack the problem from two sides, is due
Johannes Müller's great discovery of the law of the " specific
energy of the senses," which is without doubt the greatest
achievement both of physiology and psychology, and the exact
basis of all idealistic philosophy.^ I mean the simple law, that
the same stimulus, the same external phenomenon, acting on
different organs of sense, always produces different sensations ;
and that different stimuli acting on the same organ of sense
always produce the same sensation. The phenomena of the
outer world therefore have nothing in common with the sen-
sation and ideas they call forth in us, and the states and proc-
esses of our own consciousness are alone immediately subject
to our observation and recognition.

This simple truth is the greatest and deepest ever thought

^ In the disputation for liis doctorate, Joh. Müller maintained the thesis :
"Psychologus nemo nisi Physiologus." The time will come when the converse
thesis : " Physiologus nemo nisi Psychologus " will stand in no need of defence.

10 LEcrruRE I

out by the human intellect, and leads us at once to a complete
understanding of what constitutes the essence of vitalism.
The essence of vitalism does not lie in being content with a
term and abandoning reflection, but in adopting the only right
path of obtaining knowledge which is possible, in starting from
what we know, the internal world, to explain what we do not
know, the external world.

The opposite and erroneous view is adopted by mechanism,
which is no other than materialism ; it starts from the un-
known, the external world, to explain the known, the internal
world.

The physiologist is continually being driven back to
materialism by the fact that in psychology no attempt has
yet been made to attain an exactness to which the studies of
physics and chemistry have accustomed us. It cannot be
denied that, although nothing is so immediately under observa-
tion as the conditions and processes of our own consciousness,
it is precisely on this subject that our knowledge is most
vague and uncertain. There are numerous reasons for this.
The object is more complicated, the qualities are much
more numerous, than in the outer world; moreover, the
states and processes in our consciousness are ever undergoing
rapid variations ; and, finally, we possess at present no
means of quantitatively estimating the objects of our internal
sense.

So long as psychology remains in this condition, we cannot
arrive at satisfactory explanations of vital processes. In most
branches of physiology, there is nothing to be done but to
proceed along the same mechanical lines. This method is
undoubtedly valuable ; we must endeavor to advance as far
as possible by the sole help of chemistry and physics. What
these sciences fail to achieve will stand out more prominently,
and thus the mechanical theories of the present will assuredly
carry us eventually to the vitalism of the future.

The views put forward here have been attacked from various
quarters, e. g.^ by R. Heidenhain,^ E. du Bois-Reymond,^ Max
Verworn,^ A. Mosso,* &c.

All the objections raised by these authors can be summed
up in the single sentence with which I began my discussion of
the subject, viz., " It would indeed be a lack of intelligence to

^ Heidenhain, Pflüger's Archiv., vol. xliii. ; Suppl., pp. 61-64, 1888. See also
my reply to the same, Pflüger's Archiv., vol. xliv. p. 270, 1889.

2 E. du Bois-Reymond, Sitzungsb. d. k. preuss. Akad. d. Wiss. z. Berlin,
June 28, 1894.

3 M. Verworn, " Allgemeine Physiologie," p. 50, Jena, 1895.

* A. Mosso, Revue Scientifique, 4th series, vol. v. p. 1, Jan. 4, 1896.

INTEODUCTION VITALISM AND MECHANISM 11

expect, with the same senses, to make discoveries in living
nature of a different order to those revealed to us in inorganic
nature " (vide p. 2).

These authors have left untouched the central point of the
whole question, viz., the impossibility of giving a mechanistic
explanation of psychical processes, and have forgotten that these
processes form the immediate object of our experience, the
most real of the real.

It is quite open to any one who objects to the term vitalism
to replace it by another, such as idealism, scepticism, empiri-
cism ; but that will not alter my contention. I have only
shown how the metaphysical speculations and dogmas are in
direct variance with the immediate results of observation and
experience, i. e., empirical psychology. The hypotheses on which
the mechanistic explanation of natural phenomena is based,
such as the atomic theory, the wave theory of light, the mecha-
nical theory of heat, are all of them purely metaphysical
speculations, i. e., attempts to gain an insight into the essential
nature of things as they are, in contradistinction to that which
they appear to us to be. Such hypotheses can only be arrived
at by projecting certain conceptions of our inner consciousness
into the outside world — conceptions such as those of space,
time, quantity, number, force. So far we have not found it
any advantage to project in this way other of our conceptions,
although some philosophers have made such an attempt. The
physicist wisely limits himself to measuring the quantity of
objects, and does not attempt to form a judgment as to their
quality.

Now however the mechanists come and, crab-like, reverse
the whole process. Having begun by ascribing certain quali-
ties, which were a pure product of their inner consciousness, to
external things, they proceed to use the same conceptions to
explain all vital phenomena, and imagine that by help of these
threadbare and scanty conceptions they have explained the
manifold activities of the inner world of consciousness.

In fact we have no grounds for assuming that our internal
world, the world of consciousness, is necessarily and entirely
bound up with certain parts of the brain. For we must re-
member that our consciousness arises by inheritance through
a simple cell, from which, by repeated division, all the cells
and tissues of our body are derived, including those of the
brain and cerebral hemispheres, and other parts of the nervous
system. Now the history of the evolution of function must
run parallel with that of the evolution of structure. We cannot
indeed suppose that, as we trace the animal kingdom down-

12 LECTURE I

wards to the unicellular organisms, the conscious life of the
individual ceases at that exact point where a brain is no longer
present, or even where Ave can no longer make out a specially
differentiated nervous system. May it not be possible that
every cell and every atom is really a conscious being, and that
all life is conscious life ?

LECTURE II

THE CIRCULATION OF THE CHEMICAL, ELEMENTS^

The object of physiological chemistry is to investigate the
chemical processes of the living organism, and to consider the
relation of these processes to vital phenomena. We shall con-
fine ourselves to a consideration of these processes as they occur
in man and the higher animals. It may appear erroneous to
commence the study of the most complex organisms before
obtaining a general knowledge of the chemical processes of the
more simple ; but since no physiological chemistry of the latter
as yet exists, there is no choice left to us. The little that is
known on this subject will be introduced, as occasion offers,
when we come to discuss the metabolism of the higher animals.

Before we approach our subject, we must consider the
various chemical elements and forces concerned in vital mani-
festations, as they present themselves in organic and inorganic
nature. Nature must be considered as a whole if she is to be
understood in detail ; there must be a clear comprehension of
the great unchanging laws which are equally applicable to liv-
ing and inanimate things.

Twelve chemical elements enter into the composition of all
living beings without exception : carbon, hydrogen, oxygen,
nitrogen, sulphur, phosphorus, chlorin, potassium, sodium,
calcium, magnesium, and iron.

Carbojst occurs, on the surface of our planet, chiefly united
with oxygen in the form of carbonic acid. Of this only a small
part exists free in the atmosphere, or absorbed in water. The
greater part is united with such bases as lime and magnesia,
and forms gigantic strata of the earth's crust. Only a com-
paratively small amount of carbon occurs in a free state as

^The beginner who desires to make himself more fully acquainted with the
subject of the pi'esent chapter is particularly recommended to study Liebig's great
work, " Chemistry in its Applications to Agriculture and Physiology," 1840, 8th
edit., 1865. The scientific enthusiasm which our great teacher imparted during
his life to all who came into contact with him still speaks from every page of
this work. Those who wish to familiarize themselves with more modem achieve-
ments should read Adolf Meyer's "Text-book of Agricultural Chemistry"
(Heidelberg, 1886) , in which will be found a full account of the original literature
on the subject.

13

14 LECTUEE II

coal, and a still smaller quantity as graphite and diamond.
Coal is, as we well know, the residue of plants, and plants
derive their carbon from the carbonic acid of the atmosphere.
Apart then from graphite and diamond, the mode of formation
of which is still unknown, it may be said that all the carbon
on the earth is or has been in the form of carbonic acid, and
that carbonic acid is the compound through which carbon must
always pass in its innumerable metamorphoses. It is in this
form that carbon appears in the cycle of life ; in this form
alone it is taken up by plants and converted into the numerous
combinations of which they are composed. Carbon is intro-
duced into the animal organism as vegetable food, and is
excreted either as carbonic acid or in the form of compounds,
such as urea, which very rapidly decompose outside the
organism, and yield carbonic acid. Carbon then leaves the
cycle of life in the same form in which it entered, and returns
to the atmosphere to repeat the process anew.

Hydeogen is found only in traces as a free gas. In in-
organic nature it occurs almost exclusively in the form of
water, but a minute quantity appears as ammonia. Hydrogen
is taken up by plants in the form of water and ammonia only ;
it enters into the constitution of the organic compounds of the
plants which serve as food for animals ; it leaves the animal
organism again in the form of water and ammonia, or in the
shape of compounds which rapidly split up into these two
bodies.

Oxygen is the most widely distributed of all elements on
the surface of the globe ; it forms nearly one-fourth by weight
of the atmosphere, eight-ninths of the weight of water, and
about half the weight of the earth's crust, which is made up
almost exclusively of oxygen-compounds. Oxygen is the only
element which enters the living organism in a free state, but
it does so only in part, and in the case of plants only to a very
small extent. The chief bulk of the oxygen enters the organi-
zation of plants as water and as carbonic acid. By the aid of
sunlight, the plants split off from these combinations a part of
the oxygen, and form compounds richer in carbon and hydro-
gen, which as food-stuffs are taken into the animal body, where
they again unite with oxygen, and are returned as carbonic acid
and water to the air.

By this antagonism between the animal and vegetable king-
doms, the balance of carbonic acid and oxygen is maintained in
the atmosphere : the plant yielding the oxygen which the animal
requires, while the animal in its turn gives out the carbonic acid
needed by the plant.

THE CIRCULATION OF THE CHEMICAL ELEMENTS 15

We may now ask whether this balance will always be
maintained. Even should it not be disturbed by vital proc-
esses, may there not be agents at work in inorganic nature,
which, by their action on the atmosphere, may increase or
diminish those of its constituents necessary to existence ?

As regards carbonic acid, the geologists are of opinion that
there was formerly a larger amount in the atmosphere. What
are the causes of this diminution ? are they still at work ? and
have we to look forward to a continuous decrease in the bulk of
this gas ?

One of the causes of the diminution of carbonic acid is not
far to seek, i. e., the formation of coal strata from plants which
in their turn have derived their carbon from the carbonic acid
of the atmosphere. At the same time, the amount of carbon
taken up in this way appears to be comparatively small. And
even if the formation of coal is still going on under the sea,
on the other hand carbonic acid is being unceasingly returned
to the atmosphere from thousands of chimneys. We need
scarcely fear a diminution of carbonic acid from this cause.
But there is another one of far greater importance : I mean
the displacement of the silicic acid from the stone of the earth's
crust by the carbonic acid of the atmosphere — the union of
carbonic acid with the bases previously existing as silicates.
The rocks, which form the solid crust, consist principally of
silicates and carbonates — of compounds of silicic and carbonic
acids with lime, magnesium, oxid of iron, and alkalies. Now
each acid is always trying to prevent the other from combining,
and to unite itself with the basic constituents. Silicic acid and
carbonic acid are "the two great powers in the construction
of the earth," and are always at war with each other, with
alternate victory and defeat on each side. As soon as the car-
bonic acid succeeds in obtaining complete mastery over the
silicic acid, all organic life must cease on our planet.

The chemical affinity of carbonic acid to the basic con-
stituents of the rocks is closer than that of the silicic acid, in
the cold and in presence of water ; the carbonic is the more
powerful acid on the earth's surface, where it is obtaining a
slow but sure victory. Every wave breaking against the cliffs,
every ripple which washes the flinty bed of the river, every
drop of rain which falls to the ground contains carbonic acid in
solution, and slowly but surely destroys the hardest rock ; the
carbonic acid unites with the basic constituents, and the dis-
placed silicic acid, combined with the residue of the bases,
sinks to the bottom of the water, where as clay or sandstone
it gradually forms massive strata of the earth's surface. But

16 LECTURE II

the carbonic acid, united with lime or magnesium, is likewise
precipitated, mixed either with part of the decomposed silicates
in the form of marl, or in separate strata as limestone and
dolomite. Half the entire weight of the thick calcareous strata,
which compose a very large part of the earth's crust, consists of
carbonic acid, derived from the atmosphere, and which has
apparently been withdrawn for ever from the cycle of life.

But the struggle between the two acids wears another
aspect in the interior of the earth. At the higher temperature
which prevails there, the silicic acid is the more powerful. In
the depths of the earth it attacks the carbonates, and the
carbonic acid which is driven off escapes into, the atmosphere.
This carbonic acid is continually issuing from all active vol-
canoes, and also from other cracks and fissures in various parts
of the earth. The quantity which is thus returned to the
atmosphere cannot be determined, but it seems probable that
it is much less than what is constantly being removed in the
form of chalk and carbonate of magnesia. If it is true that
our planet is steadily becomiug cooler and its crust thicker, the
factor which aids the silicic acid, the warmth of the earth itself,
must continually decrease, and thus leave nothing to dispute
the rule of carbonic acid ; hence organic life must terminate.

In like manner as carbonic acid, a second constituent of the
atmosphere, oxygen, is constantly becoming fixed in the crust
of the earth, and thus removed from the cycle of vital phe-
nomena. The constituent of the earth's crust which binds it
is the ferrous oxid resulting from the decomposition of certain
silicates. This becomes oxidized to ferric oxid, which, as is
well known, forms by itself considerable strata, and occurs in
still larger quantities mixed with other materials, as clay, loam,
sandstone, and shale. One-third of the oxygen in these huge
masses of ferric oxid is derived from the atmosphere. A part
of this oxygen may return to the atmosphere, for, when the
oxid of iron comes into contact with decomposing organic
substances, the latter abstract part of its oxygen. As a result
of the oxidation of the organic substances, carbonic acid is
returned to the atmosphere, where it may again be decomposed
by plants, thus liberating oxygen. But this activity of plants
is the only process by which oxygen is set free on the earth's
surface, and it is very questionable whether it is of itself
sufficient to counterbalance the consumption of oxygen in
respiration, putrefaction, combustion, and oxidation of the
compounds of iron and sulphur.

It thus appears that a substance of great importance in the
nutrition of plants, free carbonic acid, and a substance essential

THE CIECULATIOX OF THE CHEMICAL ELEMENTS 17

to the maintenance of all organic life, free oxygen, are contin-
ually diminishing, and that the time is slowly but surely ap-
proaching when the conditions necessary for our existence will
no longer prevail, and when all life will become extinct on this
planet.

We will now turn our attention to the niteogex, the fourth
and last of the elements which organic nature derives from the
atmosphere directly or indirectly. Nitrogen is characterized
by its small affinity for other elements. For this reason the
greater part of the nitrogen is found in a free state ; it forms
four-fifths of the atmosphere. Only a minute portion is found
in inorganic nature in the form of compounds : this is the
nitrogen of ammonia, and of its products of oxidation, nitrous
and nitric acids. Nitrogen enters organic nature in the form of
these compounds only. The great bulk of free nitrogen has
no part in vital processes, for the plant cannot assimilate it.
So far the assimilation of atmospheric nitrogen has been proved
to occur only in certain bacteria.

Now, since the quantity of fixed nitrogen existing in nature
is very small, and since plants cannot utilize the other constit-
uents of their food unless an appropriate quantity' of fixed
nitrogen be taken up at the same time, it is obvious that the
total number of organic beings which can simultaneously exist
on the earth must depend in the first instance on the amount of
fixed nitrogen available. It is therefore a question of the great-
est interest to know by what means the amount of fixed nitrogen
is increased or diminished.

The process of life itself does not alter the sum total of fixed
nitrogen. Nitrogen is taken up by the plants as ammonia, ni-
trites, and nitrates, and is converted into and forms part of nu-
merous and most complicated substances, chiefly proteids. In
the latter form it enters the animal economy, where the proteid
breaks do^vn into urea, uric acid, and other compounds, which
rapidly decompose outside the organism and yield ammonia.

The bacteria mentioned above form an exception to this rule.
On the roots of leguminosse we may find small nodules, which
are produced by an infection with certain bacteria, the two
organisms, plant and bacteria, being symbiotic. If the legu-
minosas are grown on a sterilized soil these nodules are not
formed, and the plants attain only a slow and imperfect de-
velopment, the amount of proteid formed in them being
abnormally small. If however the soil be inoculated with
the proper species of bacterium, the nodules soon make their
appearance ; the plants grow luxuriantly, and form large
quantities of proteid out of the combined nitrogen of the

2

18 LECTURE II

soil.^ It might have been expected that other microorganisms
might have been found to possess the same properties. Up to
the present, however, only one other species of bacterium, the
Clostridium pasteurianum, has been found to possess the capacity
of fixing free nitrogen.^

But in inorganic nature there must be factors at work
which produce fixed nitrogen. Such a process has been rec-
ognized in atmospheric electrical discharges. It has been
established by numerous experiments that, by means of electric
discharges, nitrogen is united with oxygen to form nitric acid,
and that, by sending electric sparks through a damp atmos-
phere, nitrogen and aqueous vapour combine to form nitrate of
ammonia.^

2N4-2H20 = NH4NOi,

This process occurs on a large scale in every thunderstorm,
the products being conveyed to the ground by the rain.
Schönbein has pointed out a second process, viz., that wherever
evaporation occurs, minute traces of nitrite of ammonia are
formed in the air. The evaporation which is constantly going
on from the surface of the plants themselves, may therefore be
a source of combined nitrogen for them.

It follows that the whole store of fixed nitrogen is con-
stantly increasing from various sources. Organic life would
therefore develop with ever greater luxuriance were it not
for the operation of other causes, by means of which combined
nitrogen is again set free. This is efiected by combustion.
The burning up of vast forests of wood by man, which has
been going on for thousands of years, detracts from the store of
fixed nitrogen, to which animals and plants owe their exist-
ence ; the total of life is no doubt diminished thereby, and the
fertility of the soil must decrease. For this reason the pro-
ject of cremation, recently introduced, should be abandoned,
although the amount of fixed nitrogen destroyed in this manner
would be much less than it is in consuming forests as fuel.
Combined nitrogen is further destroyed by igniting gunpowder
or other explosives, which are all derivatives of nitric acid. In
this sense it may be affirmed that every shot from a fire-

^ W. O. Atwater and C. D. Woods, Amer. Chem. Journ., vol. vi. p. 365, 1884
vol. xii. p. 256, 1890; vol. xiii. p. 42, 1891. H. Hellriegel and H. Willfarth
"Unters, üb. d. Stickstoffnahrung d. Gramineen u. Leguminosen." Berlin,
1888. This discovery has been repeatedly confirmed by experiments of Beyer-
ink, B. Frank, Breal, Berthelot, Nobbe, and others.

2 S. Winogradsky, Arch. d. Sei. Mol., St. Petersburg, vol. iii. p. 297, 1895.

'Berthelot, Bull. Soc. Chim. (2), t. xxvii. p. 338; Ann. Chim. Phys. (5), t.
xii. p. 445, 1877.

THE CIECULATION OF THE CHEMICAL ELEMENTS 19

arm kills, that it destroys life whether the ball strikes a living
being or not. For no life is lost by the death of the individual ;
from the decay of the body equivalent new life arises. But
the destruction of combined nitrogen means the definite dimi-
nution of the capital, upon the amount of which the total num-
ber of living beings depends.

These views of mine have been objected to on the grounds
that certain bacteria have the power of fixing nitrogen, so that
the burning of forests and dead bodies cannot be regarded as a
spoliation of the capital of life. This is analogous to saying
that a man may be robbed if he is going to inherit property.
The formation and the destruction of fixed nitrogen are not
mutually dependent processes. An increase in destruction
does not imply an increase in formation, and the sum of life is
therefore diminished. So long as there are fields where the
ammonia of the soil is at a minimum, so long must the burn-
ing of plants and animals be regarded as a spoliation of living
nature.

In the world about twenty men per thousand die every year,
so that in fifty years the total number of deaths corresponds
approximately to the total number of inhabitants on the globe,
i. e., about ten human beings to every square kilometer of land.
(The total area of land on the earth's surface is 135 million
square kilometers, and the total number of inhabitants about
1500 millions.) Thus if all dead bodies were burnt, they
would amount in fifty years to ten per square kilometer, and
in 5000 years to 1000 corpses. Can it be imagined that such
a process would have no eifect on the fertility of the soil?
Adolf Meyer, in his " Text-book of Agricultural Chemistry "
(part ii. p. 303, 1886), states that already it is no longer
possible to obtain a proper yield from our cultivated lands with-
out recourse to artificial manures containing combined nitrogen.

All the arguments which have been brought forward
against burial are really only applicable to the interment of
a number of bodies in a confined space, such as a churchyard,
and have no weight against the only rational mode of disposal
of the dead, viz., their distribution as widely as possible over
the woods and fields. With all our improved means of com-
munication this should be an easy task. The contamination of
our water by dead bodies is negligible compared with that
from sewage. It is absurd to cremate only the smaller part,
and if we begin to destroy by combustion our excreta as well
as our dead bodies, there will soon be a perceptible loss of fer-
ility to the soil.

The remaining eight elements are derived by the plant

20 LECTURE II

from the soil. Sulphur is widely distributed in inorganic
nature as sulphates of the alkalies and alkaline earths. It
enters the vegetable organism in this form, and takes part in
the building up of the proteid molecule, in which it amounts
to about 0.3 to 2 per cent, of the weight. It is chiefly taken
up by the animal organism in the form of proteid, and is
excreted for the most part in the highest oxidized condition as
sulphuric acid, derived from the splitting up and oxidation
of the proteid molecule. In this form, united with alkalies,
it is again ready to repeat the cycle of life.

The course of phosphorus is very similar. It occurs in the
inorganic world only in a high state of oxidation as phosphoric
acid united with bases, esj)ecially with alkalies and alkaline
earths, and enters the plant only in this form.

Although phosphoric acid is widely distributed over the
whole surface of the globe, its amount in most soils is very
small. As in the case of nitrogen, the quantity present in a
field may be so little that vegetable life is unable to convert
all the other elements into food. In rare cases this is also
true of potassium ; but there is never a lack of the remaining
nutrient substance. In agriculture it is therefore of the greatest
importance to determine which of these three elements is most
deficient in any given soil. The fertility of the land will
depend on the quantity of the substance of which there is
a minimum. This is the important law which agricultural
chemistry designates as the " Law of the Minimum." The
element which is present in the smallest quantity must be
supplied to the soil by artificial manuring. It is generally
phosphoric acid ; hence the use of bone-dust, apatite, and the
like.

In the plant, phosphoric acid takes part in the formation
of very complicated combinations — of the various forms of
lecithin and nuclein, which are integral constituents of every
vegetable and animal cell. It is chiefly in these combinations,
and only to a small extent as salts, that phosphorus enters the
animal body, which it leaves in the same form that it entered
the plant — as a phosphate.

The circulation of chlorin is very simple ; it occurs in
nature only in the form of salts, chiefly united with sodium and
potassium. In this form it enters and leaves the cycle of life.
It takes no part in the formation of organic compounds.

The same is true of sodium, potassium, calcium, and
magnesium. They occur in the inorganic world only as salts,
enter plants as such, combine very loosely with organic matter,
and are excreted from the animal body also in the form of salts.

THE CIRCULATION OF THE CHEMICAL ELEMENTS 21

Iron never occurs on the surface of the globe as a free
metal, but chiefly in union with oxygen as ferrous and ferric
oxides. The former is a strong base, and forms neutral salts
with all acids. Ferric oxid is only a weak base, and is unable
to fix carbonic acid. Ferrous silicates, when decomposed by
atmospheric carbonic acid, yield ferrous carbonate, which is
soluble in water containing carbonic acid, and is distributed by
water all over the earth. But as soon as it comes in contact
with the atmosphere, it is oxidized to ferric oxid, and the
carbonic acid, being set free, is returned to the atmosphere.
The ferric oxid, when it comes in contact with decomposing
organic matter, is reduced, and ferrous carbonate is again
formed and carried oif by water, until it again comes in
contact with air, and again aids in the oxidation of vegetable
and animal refuse. Iron is therefore an indefatigable oxidizing
agent. The iron prevents the retention of carbon in the soil,
and enables it to return to the atmosphere, and thus to reenter
the cycle of life.

The process of oxidation is rather more complicated when
sulphur is present. Sulphur also acts as a carrier of oxygen.
If decomposing organic substances meet simultaneously with
oxids of iron and sulphates, e. g., gypsum, not only is the
oxygen of the oxids completely taken up, but that also of the
sulphuric acid, sulphid of iron being formed. The latter, in
the presence of air, may again be oxidized to sulphuric acid
and ferric oxid, and then again act as an oxidizing agent. The
sulphur required for the formation of sulphid of iron after the
reduction of ferric oxid, may be yielded by decomposing
organic matter itself, since this always contains proteid and
consequently sulphur. In fact the organic sulphur compounds
have themselves been formed in plants by the reduction of
sulphates.

Iron plays the same part m our organism as it does in the
earth's crust, the part of oxygen-carrier. Only the iron in our
organism does not occur as ferric and ferrous oxids, but as a
complex organic compound, the most complicated body wliich
has hitherto been investigated with precision, and which con-
tains at least seven hundred atoms of carbon in its molecule.
This is the red coloring matter of the blood, hemoglobin,
which, as oxy-hemoglobin, a loose compound with oxygen,
corresponds to the ferric oxid, and, as reduced hemoglobin, to
ferrous oxid. Hemoglobin also contains sulphur, and it may
be that the sulphur of hemoglobin, and of all other proteid
bodies, still retains its function as an oxidizing agent. At any
rate, it cannot be to the iron alone that this property is due,

22 LECTURE II

since, as we shall see in the seventeenth lecture, the amount of
loosely combined oxygen is much too large.

The enormous size of the hemoglobin molecule finds a teleo-
logical explanation if we consider that iron is eight times as
heavy as water. A compound of iron which would float easily
along with the blood-current through the vessels could only
be secured by the iron being taken up by so large an organic
molecule.

Hemoglobin first makes its appearance in the animal
organism. It does not exist in plants. The plant has the
power of assimilating inorganic compounds of iron, and of
using them for building up complex organic compounds, which
have not yet been sufficiently investigated. From these
bodies the hemoglobin is produced in the animal economy
(vide Lecture XXV.).

Iron likewise plays an important part in vegetable life ;^
we know that chlorophyl granules cannot be formed without
it. If plants are allowed to grow in nutritive solutions free
from iron, the leaves are colorless, but become green as soon
as an iron salt is added to the fluid in which the roots are im-
mersed. It is even sufficient merely to brush the surface of
the colorless leaf with a solution of an iron salt to cause the
appearance of the green color in the part thus painted.
Chlorophyl itself contains no iron, and we do not know in
what way the iron is concerned in its production. It seems
however that there is a proportionality between the amount
of iron and that of chlorophyl in any given part of the plant.
Thus Boussingault ^ found .0039 per cent. Fe in the green
leaves of a cabbage, while the inner etiolated leaves contained
only 0.0009 per cent. Fe.

It is not yet known in what form and by what path iron
leaves the animal body. Urine contains scarcely perceptible
traces of iron, probably as an organic compound. The feces
always contain a considerable quantity of sulphid of iron.
But it cannot be determined how much of this is derived from
the food, and how much from the digestive secretions. Outside
the body, the sulphid of iron is converted by the atmospheric
oxygen into sulphuric acid and oxid of iron, and the cycle is
complete.

In addition to the twelve elements alluded to, the follow-
ing elements are met with in certain organisms, though they

^ Molisch (" Die Pflanze in ihren Beziehungen zum Eisen ") gives an account
of the botanical literature on the relations of iron in plants.

2 Boussingault, CorniH. rend., vol. Ixxiv. p. 1356: 1872; E. Häusermann,
Zeitschr. f. 2)hysiolog. C'hem., vol. xxiii. p. 587: 1897.

THE CIRCULATION OF THE CHEMICAL ELEMENTS 23

are not always an integral part of their composition : silicon,
fluorin, bromin, iodin, aluminium, manganese, and copper.

Silicon does not occur in the free state, but only as silicic
acid. This compound, as already mentioned, is amongst the
most widely distributed bodies in the earth's crust. The alkaline
salts of silicic acid are soluble in water, and the free acid, when
liberated by carbonic acid from certain silicates, at first appears
as a hydrated acid apparently in a state of solution, in what is
known as a colloid condition (see Lecture IV.). Probably
plants absorb silicic acid in both these forms. All the higher
plants seem to contain silicic acid. Among cryptogamic plants,
the reeds and grasses are distinguished by the large amount of
silicic acid they contain. Certain unicellular algse (the Dia-
tomacese) cover themselves with a shell of silica. Silicic acid
is said to be absent from the ash of certain fungi.

But it would not appear that silicic acid plays any im-
portant part in the economy of the higher plants. This is
shown by the following experiments on the graminacese, which
are rich in silicon, as wheat, oats, maize, barley. When these
plants are allowed to germinate in nutrient fluids free from
silica, so that they can only obtain mere traces of silicic acid
from the glass vessel containing the solution, they develop
completely, and pass through a perfectly normal course of life.
In the ash of maize grown in this way, only 0.7 per cent, of
silicic acid was found, whilst, under ordinary conditions of
growth, 20 per cent, is the average quantity.^

Whether silicon exists in plants only as silicic acid, or
whether it forms more complex compounds, has not been
ascertained. Silicon is a tetravalent element, like carbon.
Silicic acid is quite analogous in its composition to carbonic
acid. Hence a probability that silicon could form numerous
compounds which would bear the same relation to silicic acid
as the organic compounds do to carbonic acid ; and, as a matter
of fact, Friedel and Ladenburg ^ have succeeded in preparing a
series of such compounds. But their existence in plants has,
up to the present time, not been detected.^

Silicic acid is taken up by animals in the form of vegetable
food. It is absorbed by the alimentary canal, and passes
through all the tissues ; hence minute traces can be demon-

1 Sachs, " Flora," p. 52 : 1862 ; and Wochenblatt der Annalen der Landioirth-
Schaft, p. 184 : 1862.

2 C. Friedel and A. Ladenburg, Compt. rend., vol. Ixvi. p. 816 : 1868 ; and
vol. Ixviii. p. 920 : 1869. Ber. d. deutsch, ehem. Ges., p. 901 : 1871 ; and pp.
319, 1081 : 1872.

3 Ladenburg, £er. d. deutsch, ehem. Ges., vol. v. p. 568 : 1872 ; W. Lange,
ibid., vol. xi. p. 822: 1878.

24 LECTURE II

strated in every organ. It is contained in considerable quantity
in the urine of herbivorous animals, and in sheep sometimes
occasions stone in the bladder. It appears however to be of
importance only in the development of hairs and feathers/ the
asb of which is always rich in silicic acid. The constant pres-
ence of silicic acid in eggs points to its being essential in the
development of birds.

Fluorin has been found in very small quantity in some
plants and anhnals. It is difficult to detect/ and it may
possibly be more widely existent in organic nature than has
been suspected. It is invariably found in the bones and teeth
of men and mammals, although Ave have not yet succeeded in
ascertaining the exact amount by our present methods. It is
also said to have been detected in the blood of mammals and
of birds. ^ Recently, G. Tammann,"* by means of careful deter-
minations, has found .001 per cent, fluorin in the yolk of eggs,
.0007 per cent, in calves' brains, and .0003 grms. in one liter
of cow's milk. In 3000 ccm. of cow's blood, the presence of
fluorin could be qualitatively detected. Small quantities of
fluorin are distributed everywhere in the earth, in the form
of fluorspar and apatite ; therefore plants are never without it.
It acts perhaps differently in the nutrition of men and animals.
It would be very interesting to have the exact amount of
fluorin in our food determined, and also the quantity we really
need of it. At any rate, the above-mentioned " law of the
minimum " holds good for animal as well as for vegetable
growth. It is conceivable that milk, although rich in the most
important substances of nutrition, might yet be useless for
the growth of the infant, for want of the necessary trace of
fluorin.

Bromin and lODiisr are present in many kinds of sea-
weed, and thus pass into the system of marine animals. A
collected account of the organisms containing iodin, which
have been utilized for therapeutic purposes, has recently been
published by E. Harnack.^ The horny axial skeleton of a

^ [It is interesting to note that Drechsel, in his last published paper, has
described an organic silicon compound, viz., a cliolesterin ester of silicic acid, as
occurring in birds' feathers. This is the first organic silicon compound which
has, so far, been found to occur in nature. Centralbl. f. Physiol., vol. xi. pp.
361-363: 1897.]

^See G. Tammann, Zeitschr. f, analyt. Chem., vol. xxiv. p. 328: 1885, where
an account of the literature on the methods of detecting fluorin will also be
found.

^G. Wilson, Trans, of the Brit. Ass. for the Adv. of Sei., p. 67: 1851;
and J. Nicies, Compt. rend., vol. xliii. p. 885 : 1856.

*G. Tammann, Zeitschr. f. physiol. Chem., vol. xii. p. 322: 1888.

^E. Harnack, Munch, med. Wochenschr., No. 9: 1896.

THE CIRCULATION OF THE CHEMICAL ELEMENTS 25

species of coral ( Gorgonia ^ ) is rich in iodin, part of which
at any rate is in organic combination. Iodin is however also
contained in small quantities in many land plants as well as
in fresh-water animals, such as the fresh-water sponges (Spongia
*fluviatiUs).

Universal attention has recently been attracted by Baumann's,
discovery of iodin in the thyroid gland of men, sheep, pig,,
and apparently many other mammals.^ Further investiga-
tions have shown that iodin is also contained in the thymus,^;
the spleen, and the pituitary body of man,^ and in the ovaries ^•
of the cow and pig. In all the animal and vegetable organisms-
just mentioned, the iodin is present for the greater part as an,
organic compound, although only the iodin compound of
Gorgonia has been hitherto isolated as a chemical individual in,
a crystalline form.'' This compound is an acid of the compo-
sition C^H-,]S[IO,. Drechsel suggests that it is an amido-iodo-
butyric acid, and has proposed to call it, for the present, iodo-
gorgonic acid.

We know absolutely nothing as to the significance of iodin
for any vital functions.

Aluminium is one of the elements most frequently met
with. Its sesquioxide, alumina, is found, united with silicic
acid, in almost all crystalline rocks which form the larger
portion of the great mountain ranges. Mixed with the prod-
ucts of disintegration of these rocks it is found everywhere
in ample quantity in the soil. It is therefore very remarkable
that alumina takes little or no part in the metabolism of living
beings. It has been shown positively to exist in any noticeable
quantity only in a few plants, especially in a few kinds of
lycopodium, in the ash of which it amounts to over 57 percent.
We do not know whether it is essential for these plants, nor of
what use it is to them ; no experiments have yet been made to
decide this question. Alumina has not yet been detected in the
animal body.

Manganese is found in considerable quantity in the ash of
a few plants, although nothing is known concerning its sig-
nificance in vital processes. Traces of this metal are found all
through the vegetable kingdom, and occasionally in the animal
body.

IE. Drechsel, Centralbl. f. Physiol., vol. ix. p. 704; 1895; and Zeitschr. f.
Biolog., vol. xxxiii, p. 96 : 1896.

2 Compare Lecture XXIX.

* Baumann, Munch, med. Wochenschr., No. 14 : 1896.

*Schnitzleru. Ewald, Wien. klin. Wochenschr., l^o. 29: 1896.

^Schaerges, Pharm. Zeitg., No. 71: 1896; and E. Barell, idem, No. 15:
1897.

^ Drechsel, loc. cit.

26 LECTURE II

Minute traces of most of the other metals are occasionally
fomid in plants and animals. They should not on that account
be considered as essential constituents.

The presence of copper in the blood of certain cephalopods
and Crustacea is noteworthy. This metal appears to be present '
in the form of an organic compound, and to serve as oxygen-
carrier, thus playing a part similar to that of the iron in hemo-
globin. The blood of these animals is blue, but loses its color
as soon as the oxygen is withdrawn either by pumping, by. the
passage of a stream of an indifferent gas, or by the action of re-
ducing agents. When shaken up with air the blood again be-
comes blue. The latest experiments on this subject have been
carried out by Fr6d§ricq,^ whose essay also contains an account
of the work done by his predecessors.

1 Leon Fredericq, Bulletins de Vac. roy. de Belgique, ser. ii. t. xlvi. No. 11 :
1878; Comp«. re?id., t. Ixxxvii, p. 996: 1878.

LECTURE III

CONSERVATION OF ENERGY

Most intimately connected with the circulation of the ele-
ments is the circulation of energy. The latter is not however
limited to this earth ; it streams on to our planet with the
sunlight, and, having run its course through plant and animal
life, streams back again into illimitable space.

It is as impossible to destroy energy as matter. Energy
itself cannot be directly observed and pursued. We can say
nothing more definite about it than that it is the cause of
motion. But we can prove that motion is never annihilated,
for whenever motion ceases, its cessation is only apparent.
The movement of masses of matter, visible to us, has either
changed into a movement of the smallest particles of matter,
of the atoms, or into ' latent motion,' into so-called ^ potential
energy,' from which, at any time under appropriate conditions,
the same amount of motion can again arise.

If a stone fall to the ground and remain lying there, motion
has not ceased. The place on the ground where it fell, and
the stone itself, have become warmed, and heat is well known
to be a mode of motion. If a stone is thrown straight up in
the air, it rises with decreasing rapidity and comes at last to
rest. At that moment its movement is latent, and is stored
up in it as potential energy. By virtue of this potential
energy it now comes down again, and reaches the ground at
the same velocity with which its ascent began. In rising,
the energy of movement, the so-called ^kinetic energy,' is
converted into potential energy ; in falling, the potential
into kinetic energy. The conversion of kinetic into poten-
tial energy is called ' work,' and the science of mechanics
teaches the well-known fact that work is measured by the
product of the weight raised into the height to which it is
raised, and that it is always the same as the kinetic energy,

^ Physiology cannot be studied to any advantage without a thorough knowl-
edge of the law of the conservation of energy, which can only be acquired by
advanced mathematical and physical studies. This lecture may serve the be-
ginner, who has hitherto neglected these subjects, as a slight preliminary account.

27

28 LECTURE III

which is measured by the product of half the mass into the
square of the velocity. If the stone that is thrown up be
supported at the moment it has reached the highest point and
comes to rest, the energy can remain stored up in it for an
unlimited period. But as soon as the support is removed,
potential is again converted into kinetic energy ; it falls with
increasing rapidity, and reaches the ground at the same speed
with which its ascent began. Hence none of the kinetic energy
has been lost. If it strikes the ground, an amount of heat is
generated, which under appropriate conditions — for instance,
by means of a steam-engine — would exactly suffice to raise the
stone to the same height from which it fell. Thus no energy
is lost in the conversion of the kinetic energy of moving masses
into the kinetic energy of moving atoms, and vice versa. As is
well known, it has been proved by numerous experiments, made
by different observers and conducted upon various methods, that
425 kilogrammeters of work produce one unit of heat (i. e., the
amount of heat required to raise the temperature of one kilo-
gramme of water by 1° C), and that the unit of heat exactly
suffices to accomplish work equal to 425 kilogrammeters.

Let us imagine a tube to be laid through the globe and
its center of gravity, from us to our antipodes, and let us
further imagine a stone brought to rest in this tube, so that
the center of gravity of the stone coincides with the center
of gravity of the earth ; in this case the stone would remain
motionless and free, suspended in the air. But if the stone, by
virtue of any kinetic energy, were raised to our end of the tube,
a reserve of potential energy would now be stored up in it, by
means of which the stone, as soon as it is left to itself, returns
with increasing rapidity to the middle of the tube. At the
moment when its center of gravity coincides with that of the
earth, all potential energy is used up and converted into kinetic
energy, and has attained its greatest velocity. This kinetic
energy cannot be lost ; it drives the stone further on, it is re-
converted into potential energy, work is accomplished, the stone
is driven to the other end of the tube, to the antipodes. By
this time the kinetic energy is used up, and is contained in the
stone as potential energy, by means of which the stone again
falls with increasing speed to the earth's center of gravity, and
rises with diminishing velocity to us. And if the tube be free
from air, the stone must thus swing backwards and forwards to
all eternity, none of its movement being lost. But if there is
air in the tube, a part of the kinetic energy of the stone will
be continually given over to the individual molecules of air ;
the stone will swing backwards and forwards at constantly

CONSERVATION OF ENERGY 29

decreasing dfstances from the center of gravity, where it finally
comes to rest. At this moment, the whole kinetic energy of
the stone's moving bulk is converted into the kinetic energy of
moving molecules, which we call heat. But nothing is lost ;
precisely as many units of heat are produced as correspond
to the kilogrammeters of work performed by the rise of the
stone from the earth's center of gravity to the end of the
tube.

The same principle seen in this imaginary and impracticable
experiment may be observed, only in a more complicated form,
in every swinging pendulum. The pendulum would also
oscillate to all eternity, if the kinetic energy of the moving
mass were not converted into heat by the friction at the point
of attachment and with the air.

If we make use of that form of kinetic energy which we
call the electric current, to split up a chemical compound (for
instance, to resolve water into its elements, hydrogen and
oxygen), a part of the kinetic energy disappears, but only
apparently so ; it is converted into that form of latent move-
ment which we term chemical potential energy, and which is
entirely analogous to the force with which the stone falls when
raised. Chemical potential energy is stored up in the sepa-
rate atoms. If they again unite, the potential energy they
contain is again converted into kinetic energy, which appears
to us as light and heat ; as, for instance, when a flame is
produced by the combination of oxygen and hydrogen. By
means of a thermopile, the heat produced might be reconverted
into electrical movement, which would be found exactly equal
to the amount originally required to split up the water.
Nothing would be lost.

We thus see that nature possesses a certain store of kinetic
energy, which can in no way be either increased or diminished.
If one part of matter comes to rest, another part is set in
motion. Movement of masses is converted into movement of
molecules, molecular movement into movement of masses ;
kinetic into potential energy, and potential into kinetic energy.
The sum total of all potential energy and of all kinetic energy
always remains the same. This law is called the Law of the
Conservation of Energy.

All movements on the surface of the earth (with the single
exception of the tides, which are connected with the rotation
of the earth on its axis) may be traced back to one common
source, to the sun's rays of light and heat. The varying degree
of heat of the different layers in air and water is the cause of
all currents of sea and air, the storms and winds. Sailing;

30 LECTURE III

vessels and windmills are moved by sunbeams. By using up
the kinetic energy of the sun's heat, vapor arises from the
surface of water, and is raised to the higher layers of the
atmosphere. If the vapor is condensed in the colder upper
regions, the kinetic energy of the waves of ether reappears as
the kinetic energy of the falling raindrops, or, when the rain-
drops collect, as the kinetic energy of flowing brooks and rivers.
It is sunlight that reappears in the sparks from the millstone ;
it is the sun's heat which issues from the glowing hammers and
saws, wheels, axles, and rollers of all machiues set in motion
by water.

We now come to the question of the forms of energy and
motion which are met with in vital processes. We have seen
that the plant is always taking up carbonic acid and water,
separating the oxygen from these compounds, and thereby
forming other compounds poorer in oxygen and with a great
affinity for oxygen. There is thus a large reserve of chemical
potential energy stored up in the plant. By combustion of the
plant by reunion of its constituents with oxygen, we can
convert this potential energy into heat, and the heat, by means
of steam engines, into mechanical work. Now, what is the
source of this chemical potential energy ? It cannot have
originated from nothing. Energy is eternal. But no potential
energy is conveyed to the plant by its food. Carbonic acid
and water are fully oxidized compounds ; they cannot produce
movement, any more than the stone lying on the ground. Not
till the stone is raised by the employment of kinetic energy,
can it fall down ; and not till the oxygen is separated from the
carbon and hydrogen in the plant by the employment of kinetic
energy, can chemical potential energy arise in it, to be con-
verted into light and heat and mechanical work. The force
which effects the separation of the oxygen in the plant is again
nothing but sunlight. We know that the plant liberates
oxygen only so long as sunshine reaches it, and that the amount
of oxygen set free varies in proportion to the intensity of the
light. This maintenance of the proportion was proved by
Wolkoff ^ by the following simple experiment.

Wolkoff counted the gas-bubbles which arose from water-
plants when the rays of the sun, conducted through a flat piece
of ground glass, were allowed to fall upon them. The water-
plants were in a glass vessel, which could be moved to any
distance from the light as required. The intensity of the light
is well known to be in inverse proportion to the square of the
distance from the point of light. Wolkoif found that the
^ Al. von Wolkoff, Jahrb. f. wissensch. Botanik., vol. v. p. 1 : 1866.

CONSERVATION OF ENERGY 31

number of oxygen-bubbles was increased and diminished in
simple proportion to the intensity of the light.

Van Tieghem ^ obtained the same result when he tried the
experiment with artificial light. The number of gas-bubbles
from the water-plants diminished as the square of the distance
from the candle.

Hence there can be no doubt that all the potential
energy of vegetable substances is converted sunlight. It is
sunlight that reappears in the fire of burning wood. It is sun-
light that gives us light in the form of gas-jets and petroleum
flames. The gaslight which at this moment illuminates us,
has shone on our earth before, millions and millions of years
ago ; it has lain dormant in our earth for millions of years, and
reappears again at this moment. The whole immense store of
energy which lies in the vast coal strata, which sets all machines
and locomotives in motion, is only the fixed kinetic energy of
sunlight which was once shining upon the luxuriant vegetation
of the prehistoric world.

The substances formed by plants serve as food for animals.
The oxygen which is liberated from the water and carbonic
acid in the plant by the kinetic energy of sunlight, is in the
animal body again united with compounds that are deficient in
oxygen, and the ultimate products of this combination are
again given off as carbonic acid and water, the same simple
substances which serve the plant as food. The chemical
potential energy of food is thus used up. But, as no energy
can perish, we must expect to find an equivalent amount of
other forms of energy appearing in the animal body. And
indeed we know that, firstly, all animals have a temperature
higher than that of their surroundings, that they are thus con-
tinually producing heat; and that, secondly, they carry out
movements, or perform work.

The sum of the work executed by an animal, and of the
heat which it gives out, must therefore be exactly equivalent
to the chemical potential energy taken in with its food, and
to the kinetic energy of sunlight used up in the production of
this potential energy in the plant.

The difficulties of obtaining precise experimental proof of
this equivalence are very great. So far as the precision
hitherto attained allows us to judge, direct experiments prove
that such equivalence does exist : that the amount of heat and
work produced by an animal, expressed in units of heat, is
equal to the amount of heat generated by the food-stuff of the
animal when burnt outside the organism.

^ Van Tieghem, Compt. rend., vol. Ixix. p. 482 : 1869.

32 LECTURE III

The first experiment of this kind was carried out by
Lavoisier ^ as early as the year 1780. The object was to prove
that combustion is the sole source of animal heat. A guinea-
pig was placed in an ice-calorimeter, and the quantity of water
produced in ten hours by the melting of the ice was measured.
It amounted to 341.08 grms. The same guinea-pig was then
put under a bell-jar over mercury. A current of air was
passed through the bell-jar and then conducted through caustic
potash, which retained the carbonic acid. The amount of- the
latter was quantitatively determined. The mean of several ex-
periments showed that the guinea-pig in ten hours gave out
3.333 grms. of carbon in the form of carbonic acid. Lavoisier
and Laplace had previously, by means of the calorimeter,
determined the heat of combustion of carbon, and found that
the heat produced by the combustion of 3.333 grms. of carbon
melted 326.75 grms. of ice. Were Lavoisier's hypothesis, that
animal-heat arises from the combustion of the carbon in the
food-stuffs, correct, the amount of heat or of ice-water found in
the above experiment on an animal would necessarily be pre-
cisely as great as in the combustion of the carbon, provided
the production of carbonic acid were the same in both instances.
As a matter of fact, it was found thus —

326^ _
341:Ö8~^'^^-

It was a mere chance that the numbers approximated each
other so closely. Any one with our present knowledge, who
criticised the experiment, would easily discover numerous
sources of error. Indeed its chief defects did not escape
Lavoisier's penetration. He had already discovered that the
whole of the oxygen inspired did not reappear in the carbonic
acid exhaled, and he therefore assumed that the oxygen which
had disappeared went to form water. Lavoisier had further
observed that the temperature of the animal in the calorimeter
was lower at the conclusion of the experiment than at the
commencement ; that the animal therefore, during the progress
of the experiment, partially lost its heat, which arose from
combustion that took place before the experiment began, and
which did not therefore correspond to the amount of carbonic
acid exhaled during the experiment. For both reasons, the
quantity of water produced in the calorimeter must be greater
than what would correspond to the carbonic acid produced.
The necessity for a more exact repetition of Lavoisier's

^ Lavoisier et de la Place, Memoircs de I' Acad, royale des Sciences, p. 355 :
1780.

CONSERVATION OF ENERGY 33

experiments 'was soon afterwards recognized by the French
Academy ; and in 1822 they offered a prize on the subject
of the source of animal heat. There were two competitors,
Despretz and Dulong. The prize was awarded to Despretz
and his work appeared in the year 1824.^ Dulong's work,
which was carried out on the same principle, was not printed
till after his death.^

Both experimenters made use of a water-calorimeter. The
animal being in the calorimeter, atmospheric air was passed
from one gasometer through the air chamber immediately
around the animal, and collected in another gasometer. In
this way the quantity of the oxygen used up, and carbonic
acid formed, was determined. The latter did not correspond
to all the oxygen consumed ; the excess of oxygen was sup-
posed to have united with hydrogen to form water. The heat
of combustion of hydrogen and carbon was calculated from
the figures given by Lavoisier and Laplace. The amount of
heat estimated in this way was compared with the amount
of heat produced in the calorimeter. Both Despretz and
Dulong found the amount of the former smaller than of the
latter. In the experiments of Dulong, the number calculated
amounted from 68.8 to 83.3 per cent, of the number found ; in
those of Despretz, from 74.0 to 90.4 per cent.

Among the numerous sources of error in this calculation,
the following may be specially noticed : 1. The numbers given
by Lavoisier and Laplace, which form the basis of the com-
parison, are, as subsequent and more exact investigation has
shown, too low. 2. The heat of combustion of the food-stuffs
is not equivalent to that of their component elements, but a
little less, since a certain amount of kinetic energy is used up
in effecting their dissociation. 3. The quantity of carbonic acid
in the expired air must be too small, since the gas in the gaso-
meter was confined over water, which would absorb some of
the carbonic acid. 4. The time occupied by the experiment
was much too short ; it was only two hours. The processes of
combustion and the taking up of oxygen or elimination of
carbonic acid are not proportional in every short interval ; only
during longer periods is there an approximate correspondence.
The quantities of oxygen and carbonic acid, and of the inter-
mediate products of combustion contained in the tissues of the
body, vary greatly at different times.

1 Despretz, " Recherches experimentales sur les causes de la chaleur ani-
male": Paris, 1824 ; also Ann. de chim. et dephys., vol. xxvi. p. 337 : 1824.

2 Dulong," Memoire sur la chaleur animale," Ann. de chim. et dephys., ser.
iii. vol. i. p. 440: 1841. See also " Recherches sur la chaleur, trouvees dans les
papiers de M. Dulong," Ann. de chim. et de phys., ser. iii. vol. viii. p. 180 : 1843.

3

34 LECTURE III

At a later period Gavarret ^ calculated the numbers obtained
by Dulong and Despretz, and, by correcting certain errors,
found the values 84.7 to 101.8 per cent., as a mean 92.3 per
cent.; instead of the proportion of 74.0 to 90.4 per cent., as
found by Dulong and Despretz.

The movements of the animal while confined in the calori-
meter must have been almost entirely converted into heat " and
observed as such ; they must have produced heat by the mutual
friction of the parts moved, by the rubbing of the animal
against the walls of its cage, and by the shaking of the water
in the calorimeter thus set up.

In recent years M. Rubner ^ has taken up the same subject
with all the aids afforded by modern apparatus and technique,
and has succeeded in demonstrating the exact equivalents be-
tween the chemical potential energy taken up by the body in
the form of food and the kinetic energy given out by the
animal. In Rubner's experiments on dogs these amounts, as a
matter of fact, differed only by about |^ to 1|^ per cent.

We thus see that the law of the conservation of energy rules
in the department of animal life. The body-heat, our move-
ments, all our vital functions — so far as they are perceptible to
our senses — are transmuted sunlight.

We may now inquire into the relation borne by our psychical
processes to the conservation of energy. Are all our feelings,
emotions, instincts, ideas only converted sunlight, or must we
assume that the world of the internal sense does not obey the
great uniform law to which the whole world of the external
senses yields constant and unwavering allegiance ?

It is beyond doubt that there is a certain causal connection
between psychical processes and certain material modes of motion
in our bodies. Sensation is excited by a process of movement in
the nervous system. A muscular contraction is the result of an
impulse of the will. But the question arises as to the nature of
this causal connection. Is it really a causal connection of the
same kind as the law of the conservation of energy demands,
that proportion should exist between cause and effect? Or
have we to deal with other kinds of causal connection ?

Above all things, we must sharply distinguish between an
immediate cause and an ultimate cause, a distinction so neces-
sary for the comprehension of physiological processes that I
may be permitted to give one or two illustrations. It is usual
to define the cutting through of a string by which a weight is
held up as the cause of falling. But the real cause is the

' Gavarret, " De la chaleur produite par les etres vivants ": 1855.
^M. Rubner, Zeitschr. f. Biol., vol. xxx. p. 73: 1894.

CONSEEVATION OF ENEEQY 35

work which has been performed in raising the weight. This is
proportional to the kinetic energy of the falling weight. If
the lifting is efPected by muscular force, the latter owes its
origin to the chemical potential energy of food, which was
originally derived from the kinetic energy of sunlight in
the plant. If the falling weight strikes the ground, the
energy of sunlight again makes its appearance as heat.
All these forces, the kinetic energy of the sunlight, the
chemical potential energy of food, the kinetic energy of
muscular movement, the potential energy of the lifted weight,
the heat produced by the falling weight, &c., are related as
cause and effect ; they are proportional and equivalent — the
same thing appearing in different shapes. The effect is the
cause itself in a changed form. Cutting the string is only the
immediate or exciting cause, the impetus which starts the con-
version of cause into effect, of potential into kinetic energy.
Between the exciting cause or ' liberating force,' as it is also
called, and the effect, there is no sort of proportion. The
weight may be hung up by a string and the latter cut through
with a razor, or the same weight may be hung up by a rope
and the latter shot through by a cannon-ball — the kinetic
energy of the falling stone remains the same.

The movement of a locomotive is transmuted heat ; the
heat is produced by chemical potential energy, by the affinity
of the fuel for oxygen ; the chemical potential energy is the
converted energy of sunlight. The kinetic energy of the
moving engine is completely used up in overcoming friction.
The heat which causes the movement of the locomotive appears
again in the heated rails, wheels, and axles. It is the same
heat which, as the heat of the sun, produced the chemical
potential energy in the plant. The energy of the sunlight, the
potential energy of the fuel, the heat of the furnace, the kinetic
energy of the engine, the heat produced by friction, are all
proportional and equivalent ; they are identical. The flame,
which was used to light the fire in the furnace, is merely the
exciting cause of the conversion of chemical energy into heat ;
the amount of heat produced is totally independent of it. A
single lucifer match may set fire to one pound or a thousand
pounds of wood, or even to a whole forest ; but the heat pro-
duced is in proportion to the amount of chemical energy used
up, and is entirely independent of the liberating force.

In the case of a rifle, the pulling of the trigger constitutes
the liberating force for converting the potential energy of the
spring into the kinetic energy of the falling hammer. The
energy of the hammer is converted into molecular movement,

36 LECTURE III

which again acts as a liberating force in causing the explosion
of the percussion-cap ; this explosion acts as the exciting cause
for the conversion of the chemical potential energy of the
powder into the kinetic energy of the ball.

In addition to the ultimate cause, and the exciting cause, a
third factor is generally required in the production of a definite
result, which I will call the determining factor. In the last
illustration, the determining factor for the projection of the
bullet is to be found in the fact that the latter is contained in
the barrel of the rifle, and thus only able to pass in one direction.
For the production of a definite movement, a certain arrange-
ment of surrounding objects is a necessary determining factor.
We can thus distinguish between three sorts of causes : the
ultimate cause, the exciting cause, and the determining cause.

It must be observed that in certain exceptional cases
there is a proportion between the effect and the exciting
cause. A well-known instance of this is seen in the drawing
up of a sluice. The work performed in raising it is in pro-
portion to the cross section of the falling current of water, and
to the kinetic energy of the water. Nevertheless, the drawing
up of the sluice is only the exciting cause which converts the
potential energy of the dammed up water into the kinetic
energy of water in motion.

Similarly, if we have a number of weights hung up by
strings of uniform size, the work done in cutting through the
strings will be in proportion to their number, and consequently
in proportion to the kinetic energy of the falling weights.
And yet the cutting is only the exciting cause.

We may now return to the question as to the relation
between psychical and physical processes.

The impulse of the will and muscular contraction certainly
do not stand to each other in the relation of cause and effect in
the limited sense. The impulse of the will is merely the
exciting cause. The ultimate cause is the chemical potential
energy of the food which is used up in the muscle, and is
therefore converted sunlight. But the impulse of the will
does not even afford the direct impetus for the conversion of
chemical energy into the kinetic energy of muscle. There is
probably a long chain of causes, such as processes in the brain,
nervous system, and muscle, analogous to those shown to exist
in the illustration of the rifle.

The question as to the nature of the causal connection be-
tween stimulation of the senses and the sensations themselves,
is much more difiicult to decide. Here there is undoubtedly
quantitative proportion. The intensity of the sensation in-

CONSERVATION OF ENERGY 37

creases with the strength of the stimulation ; but is there any-
proportionate relation between the two ?

We shall not be able to decide this question, so long as we
possess no means of measuring the intensity of sensations, or of
any other psychical conditions and processes ; in the present
state of human knowledge and of human intellect, it appears
quite inconceivable that such means should ever be discovered.^
We are therefore unable to answer the question whether the
phenomena of consciousness follow the law of the conservation
of energy, and whether they are transmuted sunlight,

I must note that there is probably, in the afferent and
central organs, a chain of processes intervening between
stimulation and sensations, as there is between will and
muscular action. We are quite unable to decide whether
the last form of motion, which reaches the brain as the result
of stimulation, is converted into sensation, or only serves as an
impulse originating sensation, possibly from chemical potential
energy. It is conceivable that an entirely new and particular
kind of causal connection may be at work in this case.

The theory has nevertheless often been advanced that
there is an exhaustion of chemical potential energy, of food-
substances, corresponding to the performance of psychical
functions. People have even tried to prove experimentally
that intellectual exertion has an influence on metabolism, as
shown by the amount of excretions. All these experiments
fail on account of the impossibility of measuring intellectual
exertion, of even deciding whether it was greater or less. A
man who shuts himself up in a dark room, with the intention
of keeping his mind a blank, may involuntarily exercise it more
than if he were to sit down to his books with the intention of
exerting all his intellectual faculties ; besides, we ought to take
into consideration the emotions, which probably far exceed all
mental exertions in the expenditure of energy, and which we
cannot call into play or dismiss at will.

We must consider moreover that the weight of the brain
is less than 2 per cent, of the weight of the body, and that
only a portion of the brain is employed in mental functions.
Even if the metabolism of this organ were, by higher psychical

^ Fechner (" Elemente der Psychophysik " : Leipzig, 1860), taking Weber's
law as his starting-point (viz., that the increase of stimulation must grow in
proportion to the stimulation already existing, in order to produce a minimal
increase in sensation), arrives at the conclusion that sensations are proportionate
to the logarithm of the stimuli. Attention has frequently been drawn to the
fact that the assumed equality of the minimal increments of sensation, upon
which the computation is founded, is purely arbitrary. This is not the place to
enter more fully into this subject.

38 LECTimE III

activity, promoted to the utmost, we could not expect to recog-
nize this fact in an increase of the total metabolism. Even if
it could be distinguished, we should not be justified in conclud-
ing that the work of the mind was converted potential energy.
The connection might be an indirect one.

With a knowledge of this point of view, the beginner will
be in a position to peruse critically the works ^ that have
appeared concerning the influence of mental work on meta-
bolism.

In recapitulating the main features of our previous remarks
the following contrasts strike us in the changes that animal
and vegetable substances undergo : —

1. The plant forms organic substances ; the animal destroys
organic substances. The vital process in the plant is synthetic,
in the animal anahi:ic.

2. The life of the plant is a process of reduction ; the life of
the animal a process of oxidation.

3. The plant uses up kinetic energy and produces potential
energy ; the animal uses up potential energy and produces
kinetic energy.

But " nature takes no leaps." In morphology no definite
demarcation can be dra^vn between plants and animals ; in the
same way the contrast between them disappears when we
examine the two kingdoms in relation to the conversion of
energy and metabolic processes which they exhibit.

There are unicellular beings without chlorophyl, such as
fungi and bacteria, which are incapable of assimilating the
carbon of carbonic acid. It must be brought to them as an
organic compound, as sugar, tartaric acid, &c. Here they
resemble animals. But they can assimilate nitrogen in inor-
ganic compounds, as ammonia and nitric acid ; here they
resemble plants. The fungi and bacteria, which cause fermen-
tation and processes of decomposition (see Lecture XL), use up
chemical potential energy and develop kinetic energy, heat,
and movement ; again behaving like animals. But by synthesis
they form proteid from ammonia and sugar, thus again behav-
ing like plants. In our future observations we shall see that
in every cell, even of the most highly organized animal, synthetic
processes occur side by side with processes of decomposition, as
they do in the cells of plants. Within the rigid cellulose-wall
of every vegetable cell is a contractile protoplasmic body which

^ Bcecker, Beitr. z. Heilkutidt: 1849 ; Hammond, Amer. Journal of 3Iedical
Sciences, p. 330: 1856; Sam. Haughton, Dublin Quarterly Journal of 3Iedical
Science, p. 1 : 1860; J. W. Paton, Journal of Anatomy and Physiol., vol. v. p.
296 : 1871 ; Liebermeister, Uandb. d. Pathol, u. Therap. des Fiebers, p. 196 :
Leipzig, 1875 ; Speck, Arch. f. exper. Path. u. Pharm., vol. xv. p. 81 : 1882.

CONSERVATION OF ENERGY 39

breathes and performs ' active ' movements like every animal.
In every part of a plant oxygen is used up and carbonic acid
produced, as in every animal; only that, in the parts of the
plant which have chlorophyl, this process of oxidation is hidden
by the more powerful process of reduction. But even this only
takes place so long as sunlight shines upon those particular
parts. In the dark, the parts of the plant containing chloro-
phyl breathe like animals ; the parts without chlorophyl do
so iu the sunlight as well.

The contrast disappears however still more completely
in certain highly organized phanerogams, so-called parasites,
which do not possess chlorophyl, and which derive their
nourishment from the organic substances formed by other
plants. The Monotropa, for instance, is in morphological
structure a Pyrolacea, but in its metabolism it is an animal.

On the other hand, there are animals which contain
chlorophyl. Certain worms (Planarise) and Celenteratse [Hydra
viridis) have chlorophyl-granules, seek sunlight, and give off
oxygen in the light, but soon die if kept in the dark.^ It has
however been more recently shown by Geza Entz^ and Karl
Brandt ^ that the chlorophyl-granules are not free in the tissues
of the above-mentioned animals, but are enclosed in unicellular
algse, which live in these animals as ' symbionta.' * But the
chlorophyl-granules in plants may be likewise only symbionta.
So far it is certain that they never arise in the tissues of plants
in any other way than by division of other chlorophyl-granules
already there.^ Besides this. Engelmann ^ has shown that

^ P. Geddes, Compt. rend., vol. Ixxxvii. p. 1095: 1878; and Proc. Roy. Soc,
vol. xxviii. p. 449 : 1879.

2 Geza Entz, Ueber die Natur der ' Chlorophyllkörperchen ' niederer Thiere,
Biolog. Centralblatt, vol. i. No. 21, p. 646 : January 20, 1882.

^ Karl Brandt, Verh. d. physiol. Gesellsch.: Berlin, November 11, 1881 ;
Biolog. Centralblatt, vol. i. No. 17, p. 524; Arch. f. Änat. ii. Physiol., p. 125 :
1882 ; Mittheilungen a. d. zoolog. Station zu Neapel., vol. iv. p. 191 : 1883.

^ The term .' symbionta ' is applied to those parasites which do no harm to
their hosts, each being of mutual assistance to the other. A known instance of
symbiosis occurs in the relationship between algse and fungi in the thallus of
herpes (Flechtea thallus), discovered by Schwendener (Nägeli's Beitr. z. wissensch.
Bot., Heft ii., iii., and iv.: Leipzig, 1860-68). The more recent discovery of
numerous examples of symbiosis is undoubtedly an acquisition of the greatest
importance in every branch of physiology. The name " Symbiosis " was intro-
duced by De Bary, "Die Erscheinung der Symbiose," Vortrag, Strasbourg:
Trübner, 1879. An interesting account of the literature of this subject will be
found in O. Hertwig's " Die Symbiose oder das Genossenschaftsleben im Thier-
reich," Vortrag: Jena, 1883.

5 Arthur Meyer, "Das Chlorophyllkorn," p. 55: Leipzig, 1883; A. F. W.
Schimper, Jahrbücher für wissensch. Botanik, vol. vi. p. 188 : 1885. An account
of the earlier literatui'e of the subject will be found here.

= Th. W. Engelmann, Pfliiger's Arch., vol. xxxii. p. 80: 1883. The method
employed by Engelmann to prove the occurrence of oxygen was peculiar. It was

40 LECTURE III

certain infusoria, Vorticellse, contain chlorophyl diffused in
their plasma, which likewise gives off oxygen in sunshine.

It follows that a complete antithesis between interchange of
force and matter in animals and plants does not exist ; ^ and
it will be henceforward impossible to separate the physiological
chemistry of the vegetable from that of the animal world. The
more our knowledge of each section of science advances, the
more the two become fused together.

based on the fact that certain bacteria, eager for oxygen, swarm round the cells
containing chlorophyl. Compare the earlier and highly interesting treatises of
Engelmann in Pfliiger's Arch., vol. xxv. p. 285 : 1881 ; vol. xxvi. p. 537 : 1881 ;
vol. xxvii. p. 485 : 1882 ; and vol. xxx. p. 95 : 1883.

^ Comp. CI. Bernard, " Lecons sur les phenomenes de la vie, communs aux
animaux et aux vegetaux ": Paris, 1878.

LECTURE IV

THE FOOD OF MAN DEFINITION AND CLASSIFICATION OF

FOOD-STUFFS THE ORGANIC FOOD-STUFFS PROTEID

AND GELATIN

Our observations up to this point have shown us that the
constituents of our body are subject to a constant circulation,
to uninterrupted change. The materials, which we take into
our body to replace the loss which is always going on in this
circulation, are called food-stuifs. This is the definition of the
term food-stuifs which is still met with in most text-books.
But this definition is incomplete ; it does not cover the whole
meaning of food-stuffs ; it dates from the time before the law
of the conservation of energy was discovered. According to
this definition, water would be the most important food-stuff,
for our body contains 63 per cent, of water, which is constantly
being given off by the lungs, the skin, and the kidneys ; and
this loss can only be replaced by the introduction of a fresh
supply. The rudest form of empiricism, untutored common
sense, is opposed to this interpretation, as no one would think
of calling water ' nutritious.' Now, why is water not nutritious ?
For the simple reason that no potential energy is conveyed to
the body by water. Water is a saturated compound ; it as
little produces movement as a stone lying on the ground. The
stone cannot fall till it has been raised from the ground by the
employment of kinetic energy ; and not until the atoms of
oxygen have been separated from the atoms of hydrogen and
carbon by the kinetic energy of sunlight, is the plant enabled
to store up that potential energy which gives rise to all the
forms of kinetic energy contributing to animal life.

We shall therefore include under the term ' food-stuffs '
those substances, which are a source of energy in the body, as
well as those which replace the lost constituents of the body.
There are substances in our food which never become integral
constituents of our tissues, but which go to form a source of
kinetic energy. To these belong the organic acids so widely

41

42 LECTUEE IV

diffused in vegetable food, such as tartaric acid, citric acid, and
malic acid, which are never concerned in the formation of the
tissues, but are burnt up to form carbonic acid and water, with
the liberation of kinetic energy, which could be utilized for the
performance of normal functions. To these we may perhaps
add the carbohydrates, which likewise do not appear to be
employed in the building up of tissues, although we know for
a fact that they are the principal source of muscular work.
Hence they are always circulating through all the organs of the
body in the plasma of blood and lymph. They are indeed
also found deposited in the tissues in the form of glycogen, but
these deposits cannot be regarded as integral constituents of
the living tissues ; they are only stores of potential energy
which disappear during muscular work ;, they are as little parts
of our organism as coal is a part of the steam-engine.^ The
gelatin-yielding substances in our food, glutin, chondrin, ossein,
likewise serve only as sources of energy, and never assist in
repairing the waste of tissue. The collagenous substances of
our tissues are not formed from the collagenous but from the
proteid constituents of food. But the gelatins in food are, as
a matter of fact, split up and oxidized ; they produce kinetic
energy.

Inspired oxygen must also be reckoned among the food-stuffs.
It is the only one which enters our tissues as a free element.
It never becomes an integral constituent of our tissues, unless
the loosely combined oxygen in the oxyhemoglobin of the
blood-corpuscles may be considered so, but it is the most pro-
ductive source of energy.

We have therefore to distinguish three classes of food-
stuffs : —

1. Those which serve as sources of energy, and which can
replace the exhausted constituents of the body. To this class
belong proteids and fats.

2. Those which serve only as sources of energy. To this
class belong carbohydrates, gelatins, oxygen.

3. Those which serve only to repair the waste of tissue, and

^ [This opinion must be received with some reserve, since it has been shown
that the proximate constituents of all cells are the very complex bodies, tissue-
fiVjrinogens, nucleo-albumins, &c., classed together under the term conjugated
proteids. In nearly all cases, these substances yield a carbohydrate as one of the
products of their decomposition, and we must therefore assume that carbohydrate
forms a necessary integral constituent of the molecule. Even egg-albumin, one
of the commonest of the so-called proteids, contains a carbohydrate moiety. In
light of these results, it becomes doubtful whether any tissue, even muscle, can
utilize carbohydrates directly for the production of energy, or whether these
substances must not first be built up to form part of the living material of the
cell.]

THE FOOD OF MAN 43

not as sources of energy. To this class belong water and the
inorganic salts.

Our knowledge is at present too limited to permit of our
giving a satisfactory and sharply defined classification of food-
stuffs.

When a substance is split up and oxidized in our body, we
do not know whether the kinetic energy thereby set free is
really used up in the performance of normal functions, or
whether it is given out as superfluous heat. In the latter
case, the substance could not be regarded as a nutrient material,
as it would be of no possible service to our organism. Alcohol
may perhaps be cited as an example. In order to be of use
in the performance of a normal function, a substance must
split up and be consumed at the right time, at the right
place, in a definite tissue. But we are not yet in a position to
follow out the course of the substances taken up so closely as
this.

It must moreover be borne in mind that certain substances,
belonging to the second division, may indirectly assist in the
building up of cells, by protecting the substances of the first
class from decomposition and oxidation. Fats sometimes come
under the first, and sometimes under the second heading ; for,
besides serving as stores of energy in the tissues, they are of
great use in another way. The carbohydrates have, as we
shall see, the power of changing into fats in the animal body,
thus coming into the first instead of the second class. In
short, the division is merely provisional.

We will now consider the separate group of food-stuffs in
somewhat greater detail, beginning with proteids.

Proteids may be regarded as the most important food-
stuffs, in so far as they are the only organic food-stuffs of which
it can with certainty be affirmed that they are indispensable,
and that they cannot be replaced by any other nutrient material.
They are to be found in every animal and vegetable tissue ; they
form the chief part of every cell ; they are never absent from
any vegetable or animal food.

The various kinds of proteid which occur in the different
animal and vegetable tissues present great differences in their
chemical and physical properties. The question is therefore :
What is included under the name proteid ? Does it correspond
to a clearly defined group of bodies? What have all varieties
of proteid in common, and what distinguishes them from all
other organic substances?

First, all proteids resemble one another in being composed
of the same five elements, in proportions of weight not very

44 LECTURE IV

remote from each other, and which vary within the following
limits, according to the analyses hitherto made of the different
proteids : —

Carbon , 50.0 to 55.0 per cent.

Hydrogen 6.6 " 7.3 "

Nitrogen 15.0 " 19.0 "

Sulphur 0.3 " 2.4 "

Oxygen 19.0 " 24.0 "

Secondly, all proteids are alike in never occurring in true
solution. Numerous clear liquids, containing proteids, are
found in plants and animals, or may be artificially produced.
But the fact that the proteid does not diffuse through animal
membranes proves that it is not really dissolved in these liquids.
The substances that are thus only apparently soluble have been
termed " colloids " by Graham.^

If a solution of sodium silicate be poured into a vessel con-
taining a large excess of dilute hydrochloric acid, the silicic
acid thus set free remains apparently dissolved. By dialysis,
the sodium chlorid thus formed and the excess hydrochloric
acid may be got rid of, when a clear solution of pure silicic
acid will remain in the dialyzer. The silicic acid may amount
to 14 per cent, of the solution without its becoming thick and
turbid ; it is readily poured out. But a few bubbles of carbonic
acid passed through this solution suffice to coagulate the silicic
acid, which is precipitated in the form of a jelly.^ Grimaux^
prepared a 2.26 per cent, solution of silicic acid, which was
more stable, and which did not clot either in cold or upon
warming when carbonic acid was passed through, but did so
when heated, after the addition of common salt or of Glauber's
salt.

The hydrate of alumina is soluble in a watery solution of
aluminium sesquichlorid. If such a solution be placed in the
dialyzer, the chlorid diffuses out, and the solution of pure
alumina remains in the dialyzer as a clear, readily transferable
fluid. This solution coagulates as soon as a small quantity of
any salt is added. A 2 or 3 per cent, solution of alumina can
be made to clot by the addition of a few drops of spring water ;
it coagulates when poured from one glass into another, unless
the glass has immediately before been washed out with distilled
water.*

In a similar way as with the alumina, oxid of iron may be

^Th. Graham, Phil. Trans., vol. cli. part i. p. 183 : 1861.

2 Graham, loc. cit., p. 204.

3 Grimaux, Gompt. rend., vol. xcviii. p. 1437 : 1884.
■* Graham, loc. cit., p. 207.

THE FOOD OF MAN 45

obtained as a ölear blood-red apparent solution which is also
very prone to coagulate/

Grimaux found that an ammoniacal solution of oxid of
copper also behaves like a colloidal substance, that it does not
diffuse, and that it coagulates on dilution with water, on the
addition of magnesium sulphate or of dilute acetic acid, or
when exposed to a temperature of from 40° to 50° C.^

Many organic, as well as these inorganic colloidal substances,
and all proteids, have the property of appearing in two forms,
in apparent solution or in a coagulated form. The conditions,
under which the proteids pass from one modification to the other,
are very varying, and offer a method of classifying and dis-
tinguishing the many different kinds of proteid.^ Some of
them may, under appropriate conditions, be kept in solution
by water alone ; to these proteids belong serum-albumin and
egg-albumin. Other kinds of proteid require the addition of
alkaline chlorids in order to dissolve them ; such are the
globulins which are found in the blood, in muscle, in the white
and yolk of egg, and probably in the protoplasm of every cell.
If blood-serum be put in a dialyzer, the salts which hold
the serum-globulins in solution diffuse out, and the globulins
separate on the dialyzer as finely flocculent coagula, but the
serum-albumin remains dissolved in the pure water.* There
are other varieties of proteid which cannot be held in solution
by alkaline chlorids, but only by basic alkaline salts, in which
case neutralization of the alkalies with acids causes precipita-
tion. The casein of milk and the artificial alkali-albumins
belong to this category. Lastly, we come to the proteids
which are so prone to coagulate, that they do so as soon as life
is extinct in the tissues to which they belong. The coagulation
of the blood and the phenomenon of muscular rigidity after
death are connected with this fact. It even appears that these
kinds of spontaneously coagulable albumin exist in every
animal and vegetable cell. All proteids, without exception,
pass from the soluble into the coagulated modification by

* Graham, loc. cit., p. 208.

2 Grimaux, loc. cit., p. 1435.

3 A complete enumeration of all kinds of proteid and their distinguishing
reactions would, I fear, weary the beginner, so I will refer him to the article
" Eiweisskörper " (Proteids), in Ladenburg's " Handwörterbuch der Chemie." In
this article E. Drechsel has given a very complete description and classification
of the varieties of proteid, with a careful account of the literature of the subject
(249 treatises).

■* Aronstein, " Ueber die Darstellung salzfreier Albuminlösungen," Dissert. :
Dorpat, 1873; and Pfliiger's Arch., vol. viii. p. 75: 1873. See also A. E. Biirck-
hardt, Arch. f. exper. Path. u. Pharm., vol. xvi. p. 322 : 1883 ; and G. Kauder
ibid., vol. XX. p. 411 : 1886.

46 LECTUßE IV

exposure to the boiling-point, provided they have a neutral or
weakly acid reaction, and if neutral alkaline salts be present in
considerable quantities. Silicic acid and many other colloids,
as already stated, act in the same manner.

Concerning the inorganic colloidal substances, we know
that besides occurring in these two modifications they also
appear in nature in a third, viz., the crystalline form : silicic
acid as rock-crystal, alumina as ruby, oxid of iron as specular
iron ore.

This fact justifies us in hoping to obtain proteids likewise
in a crystalline state. Not until we succeed in so doing, shall
we be certain of having chemical individuals to deal with, and
in a position to ascertain and compare their composition. The
analysis and examination of pure proteid crystals and of all
their products of decomposition would form the keynote of
physiological chemistry.

Histologists have long been on the track of crystalline
proteid. Under the microscope may be seen embedded in the
seeds and glands of certain plants, little granules which have
the appearance of incompletely formed crystals, and are there-
fore termed crystalloids, or aleuron-crystals. Similar structures '
may be seen in the yolk of egg of many animals, the so-called
yolk-plates. By mechanical means, such as shaking the finely
chopped materials with ether and other liquids, by washing,
filtering, etc., these crystalloids may be isolated and obtained in
considerable quantities. They give the proteid reactions and
behave like globulins ; they are soluble in a solution of
common salt.^ Maschke^ has succeeded in recrystallizing the
crystalloids of the para nut (Bertholletia excelsd). They dis-
solved in water at from 40° to 50° C, and the albumin separated
out into crystals upon concentration of the solution. Schmiede-
berg ^ obtained crystalline compounds of the same proteid with
alkaline earths, the crystalloids being mostly soluble in distilled
water at from 30° to 35° C. When a stream of carbonic acid
is passed through the clear filtered solution, globulin is precip-
itated. If this precipitate is treated with magnesia and water,
the magnesia compound of the globulin is dissolved. From
this solution, when concentrated at from 30° to 35° C, the
magnesia compound of the globulin is separated out as well-
formed peculiarly glistening polyhedral crystals, of the size of
poppy-seeds. If a little calcium chlorid or barium chlorid be

^Th. Weyl, Zeitschr. f. physiol. Chem., vol. i. p. 84: 1877; containing also
an account of the earlier literature of the subject.
2 O. Maschke, Botan. Zeitg., p. 411 : 1859.
^O. Schmiedeberg, Zeitschr. f. physiol. Chem., vol. i. p. 205: 1877.

THE FOOD OF MAN 47

added to the solution before concentration, we obtain the
calcium and barium salts of the globulin in fine crystals.

The fact that these crystals are not free proteid, but com-
pounds of proteid with substances of known atomic weight,
presents a great advantage, in that it enables us to make an
exact analysis of this compound, and thus determine the molec-
ular weight of the proteid.

DrechseP found 1.40 per cent. MgO in the crystals of the
magnesia compound, which he obtained according to Schmiede-
berg's method, drying them at 110° C. From this, the molec-
ular weight of the proteid has been reckoned —

. 100-1.40 ^^23^^_

40 1.4

By the following alteration in Schmiedeberg's method,
Drechsel succeeded in more perfectly crystallizing the magnesia
compound. Instead of concentrating the solution, he intro-
duced it into a dialyzer, which he placed in absolute alcohol.
In proportion as the alcohol took the place of the water,
crystalline granules continued separating out of the solution.
The determination of the magnesia in the crystals dried at
110° C. gave 1.4f3 per cent. MgO, or nearly the same as in the
first preparation. The molecular weight of the proteid thus
calculated is 2757. On the other hand, the amount of water
varied in each preparation, the first yielding 7.7 per cent., the
second 13.8 per cent, of water, both at 110° C.

By a similar method, with the alcohol dialyzer, Drechsel
succeeded in producing a sodium compound of the same glob-
ulin. At 110° C. this yielded 15.5 per cent, of water, and
contained in a dry state 3.98 per cent. Na20. From this the
proteid molecule is found to be equal to 1496, or nearly half as
great as in the calculation from the magnesia compound. If
the smaller molecular weight be accepted, we must conceive
that a bi-valent atom of magnesium links two molecules of
proteid. If we accept the double weight, the molecule must
contain two hydrogen atoms, which are replaced by sodium
atoms. The amount of incinerated proteid was moreover
much too small to allow of an exact estimate of the molecular
weight. The absolute amount of the MgO weighed 0.0050 and
0.0065 grm.; that of the NagCOg weighed 0.0773 grm. It would
be of great interest to determine with accuracy the relation of
sulphur to sodium by a series of careful analyses, in which large
quantities of proteid were incinerated. Supposing that no
whole number of sulphur atoms went to one atom of sodium,

^E. Drechsel, Journ. f, prakt. Cliem. N.F., vol. xix. p. 331 : 1879.

48

LECTURE IV

but a whole number and a fraction, then the denominator of
the fraction would have to be multiplied by the equivalent of
the albumin molecule, calculated from the proportion of sodium.
No one has hitherto been found to undertake such a trouble-
some experiment, and we therefore know nothing concerning
the size of proteid-molecules.

The most thorough investigations upon proteid-crystals have
been carried out by G. Grübler,^ under Drechsel's guidance.
They succeeded in recrystallizing the crystalloids of pumpkin-
seeds by preparing at 40° C saturated solutions of globulin in
salt solutions, such as sodium chlorid, ammonium chlorid,
magnesium sulphate, from which the albumin separated out in
crystals on very slow cooling. These crystals were regular
octahedra, and when incinerated left only 0.11 to 0.18 per
cent, of ash, which consisted of alkalies, lime, magnesia, iron,
and phosphoric acid. When incinerated with potash, 0.23 per
cent. PjO, was obtained.

The elementary analysis of Griibler's proteid-crystals gave '
the following mean, obtained from a series of analyses which
agreed well with each other : —

Carbon . .
Hydrogen
Nitrogen .
Sulphur
Oxygen . .
Ash ...

Proteid-crystals from

sodium chlorid

solution.

53.21
7.22

19.22
1.07

19.10
0.18

Proteid-crystals from

ammonium chlorid

solution.

53.55
7.31

19.17
1.16

18.70
0.11

Proteid-crystals from

magnesium sulphate

solution.

53.29
6.99

18.99
1.13

19.47
0.13

Grübler has also produced a crystalline combination of the
same proteid with magnesia : the crystals separating out on
slow cooling of a solution (obtained at 40° C.) of the proteid
and magnesia in water. The crystals showed the following
composition : —

Dry matter. Matter free from ash.

Carbon 52.66 52.98

Hydrogen 7.20 7.25

Nitrogen 18.92 18.99

Sulphur 0.96 0.97

Oxygen 19.74 19.81

Ash 0.52

MgO 0.45

1 G. Grübler, " Ueber ein krystallinisches Eiweiss der Kürbissamen," Journ,
f.prakt. Chem., vol. xxiii. p. 97: 1881.

THE FOOD OF MAN 49

The following formula for the magnesium compound of globulin
may be made out from the percentage composition : —

^1170^1920^3600332^8^^ Sa-
lt is to be regretted in this analysis that the quantity of in-
cinerated proteid was again far too small for an exact estimate
of the magnesium and sulphur. The absolute weight of the
barium sulphate was 0.0521 grm., that of the pyrophosphate of
magnesia 0.0166 grm.

If we assume the presence of only one atom of magnesium
in the magnesium compound, as Grübler did in his computa-
tion, then the size of the molecule would be 8848. But our
calculation shows that for each atom of magnesium we must
claim 2f atoms of sulphur.

40 "~0.45' ^"~3*

The molecule of the magnesium compound must therefore be
taken as three times larger. It is conceivable that the three
bivalent magnesium atoms may link four proteid molecules,
and that only two atoms of sulphur are contained in each.
Every proteid molecule would then have the following com-
position : —

^292^481-'-^ 9o'-'83^2"

From this point of view, we attain to the smallest molecular
weight of which analysis admits. But this supposition is quite
arbitrary, and the molecular weight probably a multiple of that
calculated.

Ritthausen,^ adopting the methods of Drechsel and Grübler,
produced crystalline proteid from hemp and castor-oil seeds.
The elementary analysis gave the following percentage com-
position : —

Globulin from Globulin from

hemp seed. castor-oil seed.

Carbon 50.92 50.85

Hydrogen 6.91 6.97

Nitrogen 18.71 18.55

Sulphur 0.82 0.77

Ash 0.11 0.057

Oxygen 22.53 22.80

Hemoglobin,^ the red coloring matter of the blood, also
belongs to the proteid compounds capable of crystallization.

1 Ritthausen, Journ.f.prakt. Chem., N. F., vol. xxv. p. 130 : 1882.

* The discoverer of the hemoglobin crystals was A. Boettcher, and the first
analyses of them were carried out by my revered teacher, Carl Schmidt, in
Dorpat. See A. Boettcher, " Ueb. Blutkrystalle " : Dorpat, 1862.
4

50 LECTURE IV

This substance forms the chief constituent of the red blood-
corpuscles, and is the compound of a proteid with a body of
known composition containing iron, called hematin. An exact
analysis of completely pure hemoglobin crystals has been
carried out by Zinoflfsky,^ who went on recrystallizing the
hemoglobin crystals obtained from horse's blood, until the dry
residue of the solution showed the same amount of iron as the
dry crystals. The elementary analysis of these crystals yielded
the following results : —

Carbon 51.15

Hydrogen . . . . . • 6.76

Nitrogen • 17.96

Sulphur 0.389

Iron 0.336

Oxygen 24.425

The relation of the sulphur atom to the iron atom may,
from Zinoffsky's analysis, be calculated thus —

x.32_ 0.3890 _ono

""56^-073358' ^-^•"^•

Exactly two atoms of sulphur combine with one atom of iron,
and the formula of the hemoglobin is found to be —

If the molecule of the hematin, C^gHajN^O^Fe, be subtracted,
the formula of the proteid is obtained —

A. Jaquet^ found that exactly three atoms of sulphur go to
one atom of iron in the hemoglobin of dog's blood. The
analysis gave the formula : —

After subtraction of the hematin it is : —

*-'726H]i71^ 194S30214'

The calculation is not quite exact, because the splitting up
of the hemoglobin into proteid and hematin occurs only by

^O. Zinoffsky (Bunge's laboratory), " Ueber die Grösse des Hämoglobin-
moleküls," Dissert. : Dorpat, 1885; reprinted in the Zeitschr. f. physiol. Chem.,
vol. X. p. 16: 1885.

2 Alfred Jaquet (Bunge's laboratory), " Beitr. z. Kenntniss des Blutfarb-
stoflfes," Dissert.: Basel, 1889; or the Zeitschr. f. physiol. Chem., vol. xii. p.
285: 1888.

THE FOOD OF MAN 51

the absorption of water and oxygen.^ A few hydrogen and
oxygen atoms must therefore be added to the above proteid for-
mulae. Nevertheless they are perhaps the most exact that have
been computed from the proteid analyses hitherto made, and
may serve for present guidance.

Harnack ^ has produced and analyzed a proteid compound
which, though amorphous, is probably pure. Harnack precipi-
tated neutral solutions of egg-albumin with solutions of cop-
per, and obtained the noteworthy result that, although the
quantitative relation of the albumin and of the copper salt
varied greatly, yet in the precipitates the albumin combined
with the oxid of copper was only found in two perfectly
definite proportions. The precipitates contained either from
1.34 to 1.37, a mean of 1.35 per cent. Cu, or from 2.56 to
2.68, a mean of 2.64 per cent. Cu ; in one case therefore ex-
actly twice as many copper atoms as in the other.

The complete elementary analysis gave a mean from a
series of estimates agreeing well with each other : —

I. II.

Carbon 52.50 51.43

Hydrogen 7.00 6.84

Nitrogen 15.32 15.34

Sulphur 1.23 1.25

Copper 1.35 2.64

According to the first analysis, the relation of the sulphur atom
to the copper atom may be calculated as —

X.32 1.23 ^ _

6374= 1:36 ■ " = ^-^^^-

The second analysis makes x= 0.938. In these analyses also,
the incinerated residue was much too small to allow a determi-
nation of the copper and sulphur.^ A more exact determina-
tion of these elements is urgently required. From his analyses,
Harnack reckons the formula for the first compound :

Loew* has produced two silver compounds of egg-albumin,
which correspond to Harnack's copper compounds ; one con-

1 Concerning this, see Max Lebensbaum, Wien. Sitzungsher., vol. xcv. part
ii., March, 1887. In this vrork, carried out in Berne under Nencki's direction,
there is also an account of the earlier literature on the splitting up of hemo-
globin. Compare also Hoppe-Seyler, Zeitschr.f. physiol. Chem., vol. xiii. p. 477:
1889.

^ E. Harnack, Zeitschr. f. physiol. Chem., vol. v. p. 198 : 1881.

^ Compare O. Loew, Pfliiger's Arch., vol. xxxi. p. 393 : 1883.

^ O. Loew, loc. cit., p. 402.

52 LECTURE IV

tained from 2.2 to 2.4 per cent. Ag, the other a mean of 4.3
per cent. Ag. Taking Harnack's figures for the amount of
copper, the silver equivalent may be computed = 2.3 per cent,
and 4.5 per cent. These facts go to prove that Harnack's and
Loew's preparations were true chemical entities. It is to be
regretted that Loew has not made any elementary analysis of
his preparations.

Finally Franz Hofmeister^ has succeeded in crystallizing
egg-albumin itself. The white of the hen's egg contains two
kinds of proteid substances, one belonging to the albumin and
the other to the globulin group. If the globulins are precipi-
tated by a concentrated solution of ammonium sulphate, and
the filtrate from this precipitate be allowed to stand for some
days exposed to slow evaporation, small spheroids separate out,
which are composed of incompletely formed crystals. By dis-
solving and recrystallizing these spheroids, albumin is obtained
in well-formed, needle-shaped crystals. Analysis of these crys-
tals gave the following composition : —

C 53.3

H 7.3

N 15.0

S 1.1

O 23.3

Using Hofmeister's method, Bondzynski and Zoja ^ prepared
albumin crystals from white of egg, and succeeded, by frac-
tional crystallization, in demonstrating the existence in white of
egg of several distinct albumins, differing by their solubilities
in ammonium sulphate solutions as well as by their coagula-
tion temperatures and their rotatory power on polarized light.
On the other hand, the elementary composition was identical in
all the fractions. In one preparation the lime and phosphoric
acid were also determined, and the following composition was
arrived at : —

C 52.3

H 71

N 15.5

S 1.6

O 23.5

PA 0.29

CaO 0.26

The ash forms part of the constitution of the proteid molecule.
Proteid free from ash never occurs in nature. Although it

■■ Franz Hofmeister, Zeitschr. f. physiol. Chem., vol. xiv. p. 165 : 1889, and
vol. xvi. p. 187 : 1892. Compare also S. Gabriel, idem, vol. xv. p. 456 : 1891.

2 St. Bondynski and L. Zoja, Zeitschr. f. physiol. Chem., vol. xix. p. 1 : 1894.

THE FOOD OF MAN 53

can be prepared artificially/ we have not yet succeeded in crys-
tallizing it.

Bondzynski and Zoja could not obtain the globulins of
white of egg in a crystalline form ; the only precipitates they
obtained were in the form of the spheroids, which are the first
stage in the crystallization of albumin.

In blood-serum, as in the white of egg, we also find albu-
mins and globulins (compare Lect. XIV.). In albuminuria both
escape into the urine, but in very varying proportions. Until
quite recently no spontaneous crystallization of the proteids in
the urine had ever been observed. It seems however that the
presence of one kind of proteid hinders the crystallization of the
other, since in a recent case of marked albuminuria, published
by Byrom Bramwell and Noel Paton,^ where almost only glob-
ulin was present, this globulin could be easily crystallized by
Hofmeister's method. Indeed at times it was sufficient to
allow the urine to stand for one or two days to obtain a crystal-
line silky precipitate, which under the microscope was seen
to consist of beautiful rhombic prisms. The analysis of these
globulin crystals gave the following results : —

C 51.9

H 6.9

N 16.1

S 1.2

O 33.9

Finally, we may mention that Gürber ^ and Michel * have
succeeded in preparing beautiful crystals of the albumin of
blood-serum. [The technique of the crystallization of proteids
has been much simplified by the discovery of Hopkins that the
addition of a trace of acid much favors the ease of crystalliza-
tion. Full details of the method will be found in the original
paper.^ By this method it is possible to prepare crystals, in
any quantity and within a few hours, both of egg- and serum-
albumin. By washing these crystals with an acid solution of
sodium chlorid, the whole of the ammonium sulphate may be
removed, showing that the presence of this salt is not necessary
to the integrity of the crystalline form.]

' See letter written by Liebig to Wöhler, Not. 16, 1848 (Aus J. Liebig's u.
Fr. Wöhler's Briefwechsel, vol. i. p. 323 ; Braunschweig, Vieweg u. Sohn, 1888) ;
E. Hamack, Ber. d. deut. chem. Ges., vol. xxiii. p. 40 : 1890, and vol. xxv. p. 204 :
1892; K. Bülow, Pflüger's Arch., vol. Iviii. p. 207: 1894.

2 Byrom Bramwell and D. Noel Baton, Reports fr. the Lab. of Roy. Coll. of
Physicians, Edin., vol. iv. p. 47 : 1892.

^ A. Gürber, Sitzungsber. d. phys.-med. Ges. zu Würsburg, p. 143 : 1894.

* A. Michel, Verh. d. phys.-med. Ges. zu Würzburg, vol. xxix. No. 3 : 1895.

^ F. Gowland Hopkins and S. N. Pinkus, "Crystallization of Proteids,"
Joum. of Physiol., vol. xxiii. p. 130 : 1898.

54 LECTURE IV

The formulae of the proteids already quoted are : —

Egg-albumin, C^^^ü^^^l^^p^ß^.
Proteid in hemoglobin of horse, CggpHj^ggMg^oOg^^Sg.
Proteid in hemoglobin of dog, C!y26-'^ii7i-^i94^2u^3*
Globulin from pumpkin-seeds, CgggH^g^lSTg^OggSg.

Thus if we select the most careful and exact of all the analyses
hitherto made of the purest preparations of different proteids,
we find that they give very varying quantitative compositions,
and that they particularly differ in the amount of sulphur.

So far as they have been investigated, proteids show a
certain agreement in their products of decomposition. It ap-
pears that the different proteids are composed of the same
proximate constituents combined in varying proportions.
On heating the proteids with baryta water, they break up
under hydration into numerous compounds, which are
almost all of known constitution. The principal are car-
bonic acid, oxalic acid, acetic acid, ammonia, sulphuretted
hydrogen, sulphuric acid, and a number of amido-acids, such as
aspartic acid, leucin, tyrosin, as well as lysin, lysatin, &c. The
same amido-acids, as well as ammonia and the bases lysin,
lysatin, azginin, and histidin,^ also present themselves on boil-
ing the proteids with acids and under the influence of fer-
ments. We shall have to discuss the products produced by
the splitting up of proteids more fully when we come to treat
of the chemistry of the urine ; we shall then also consider the
decomposition of the nitrogen compounds in the organism (vide
Lecture XIX.).

Another group of food-stuffs, the gelatiniferous or col-
lagenous SUBSTANCES, are closely related to the proteids in
chemical qualities ; but their physiological import is quite dif-
ferent.

Gelatiniferous substances are the chief constituents of con-
nective tissue, of bone and cartilage, and therefore form an
important part of the food of carnivorous and omnivorous ani-
mals.

Gelatins, like proteids, are colloids containing nitrogen and
sulphur, and may likewise occur in two modifications — one
apparently dissolved but not diffusible ; the other coagulated.
But the conditions of the transit from one modification to
another are exactly the reverse. All proteids coagulate, as

1 Kossel, Sitzungsber. d. Ges. z. Bef'drd. d. ges. Naturwiasensch., Marburg, p.
56 : July, 1897. Here also references will be found to the earlier authors wh<v
have dealt with these bases.

THE POOD OF MAN 55

already described, at boiling-point, with neutral or weakly acid
reaction, and in the presence of salts ; the gelatins, on the con-
trary, become soluble under these circumstances,^ and on cool-
ing the solution of gelatin thus formed again coagulates. Solu-
tions of proteid are precipitated by mineral acids, but not so
solutions of gelatin. The gelatin of cartilage is certainly pre-
cipitated by very dilute mineral acids, but dissolved by an ex-
cess, thus behaving in the opposite manner to the globulins,
which are soluble in very dilute (1 per 1000) hydrochloric acid,
but are again precipitated by an excess of it.

If therefore varieties of proteid or gelatin are soluble or
coagulable under opposite conditions, we need not be surprised
to find that, under similar conditions in the organism, the one
occurs invariably in the soluble, the other only in the solid,
modification. Proteids are found in our bodies only in a liquid
state. In this form they are the main constituents of the
blood-plasma and of lymph, or they occur in that peculiar
semi-liquid modification common to all those tissues which
play an active part in the functions of our bodies : the con-
tractile contents of muscle-fibers, the axis-cylinders of nerve-
fibers, the protoplasm of all cells which we must not conceive
as rigid structures, but as engaged in a constant state of active
ameboid movement.^ The collagenous substances, on the
contrary, are found in our tissues only in the rigid modifica-
tion ; they form the supports and the framework of our bodies,
viz., bone, cartilage, ligaments, and connective tissue of all
kinds.

But here I must guard against a misunderstanding, lest it
should appear that I am identifying the gelatiniferous constit-
uents of the tissues with coagulated gelatin. In the conversion
of collagenous tissues into solutions of gelatin, a fundamental
change takes place, possibly a decomposition accompanied by
hydration, and the gelatin is not reconverted into the collage-
nous substances on coagulation.

The percentage composition of the varieties of gelatin is
nearly the same as that of the proteids. At the same time, it
is characteristic of the former that they are somewhat poorer in

^ It is not until after the phosphates and carbonates of lime and magnesia
have been extracted with dilute hydrochloric acid at a low temperature, that the
gelatin of bone is dissolved in boiling water, and especially under increased pres-
sure. The salts of lime and magnesia appear to be chemically united with the
collagenous substance.

2 As already mentioned, proteid is found in the solid form, deposited in crys-
tals, only in the yolk of egg and in the seeds and bulbs of plants. These crystal-
loids are however not integral constituents of the living tissue, but dead material,
the store of nutriment for the future development of the germ.

56

LECTURE IV

carbon and richer in oxygen ; they are products of the initia-
tion of the breaking up and oxidation of the proteids in the
animal body. According to the analyses ' hitherto made, the
percentage composition of the gelatins varies within the follow-
ing limits : —

Carbon ,
Hydrogen.
Nitrogen .
Sulphur. .
Oxygen .

Gelatin from bone
or connective tissue.

49.3—50.8

6.5— 6.6

17.5—18.4

— 0.56(?)
24.9—26.0

Chondrin.

47.7—50.2
6.6— 6.8

13.9—14.1
0.4— 0.6(?)

29.0—31.0

Albumin.

50.0—55.0
6.6— 7.3

15.0—19.0
0.3— 2.4

19.0—24.0

We know for a fact that certain compounds of the aromatic
class, rich in carbon and which issue in the form of tyrosin
and indol from the decomposition of proteids, are absent in the
gelatiniferous substances.^ It is moreover a fact that the heat-
equivalent of gelatin is lower than that of the proteids f that
therefore a part of the potential energy introduced into the
animal body by proteid is already consumed during its conver-
sion into gelatin-yielding substances. We should therefore, ä
priori, expect to find that the gelatins do not replace the pro-
teids of the food, and that they cannot form the proteids of

^ Fr. Hofmeister, Zeitschr. f. physiol. Chem., vol. ii. p. 299: 1878.

2 The absence of tyrosin explains the fact that gelatin does not give Millon's
reaction, which is common to all proteids (red coloration on boiling with nitrate
of mercury, with the addition of fuming nitric acid). All aromatic oxy-acids
and their derivatives, to which tyrosin belongs, give this reaction. On the other
hand, compounds which are wanting in proteids occur among the decomposition-
products of gelatins. Amido-acetic acid (glycin, glycocoll), which has hitherto
not been shown to exist among the decomposition-products of any proteid, is ob-
tained from the gelatin of bones and connective tissue, on boiling with alkalies and
acids, and in putrefaction. From cartilage Schmiedeberg {Arch. f. exp. Path. u.
Pharm., vol. xxviii.p. 355 : 1891) isolated small quantities of a compound, which
on boiling with dilute acids was dissociated with the formation of sulphuric acid,
acetic acid, glycuronic acid, and glycosamin. These results explain the older
statements as to the occurrence of sugar or ' reducing substances ' among the de-
composition-products of chondrin. On the products of the decomposition of pro-
teids and gelatin, see further, M. Nencki, " Ueber die Zersetzung der Gelatine
und des Eiweisses bei der Fäulniss mit Pankreas," Bern., 1876 ; and Sitzungsher.
d. Akad. d. Wissensch. in Wien, Math.-natur. Klasse, vol. xcviii. Pt. 2, May 9,
1889 ; Jules Jeanneret, Journ. f. prakt. Chem., N. F., vol. xv. p. 353 : 1877 ; Leon
Selitrenny, Sitzungsber. d. Akad. d. Wissensch. in Wien, Math.-natur. Klasse, vol.
xcviii. Pt. 2, b. Dec. 12, 1889 (from Neucki's laboratory) ; Ed. Buchner und Th.
Curtius, Ber. de deutsch, chem. Ges., vol. xix. p. 850 : 1886 ; and R. Maly, Sit-
zungsher, d. Kais. Akad. d. Wissensch. in Wien, Math.-natur. Klasse, vol. xcviii.
Jan. 6, 1889.

* Danilewsky, Centralblatt f. d. med. Wissensch., Nos. 26 and 27: 1881.

THE FOOD OF MAN 57

the tissues. Such a conversion would be opposed to the whole
tendency of animal metabolism, which is essentially a process
of decomposition and of oxidation. The conversion of gelatin
into albumin would be one of synthesis and reduction. The
results of Voit's experiments/ showing that gelatin cannot
replace proteid in the food, are in agreement with the ä •priori
deduction. When Voit fed dogs exclusively on gelatin, or on
gelatin and fat, they excreted more nitrogen than they took in
with their food ; they therefore used up the proteids of their
tissues. But if to a small amount of the proteid in the food,
which was not by itself sufficient to prevent a loss of tissue-pro-
teid, gelatin was added, the nitrogenous equilibrium was re-
stored. The gelatin therefore had preserved the proteid of the
tissues from decomposition ; it acts as a ' proteid sparer.' This
proteid-sparing action is also shared by fats and carbohydrates ;
but, as Voit's experiments have shown, not in the same degree
as by gelatin.

It has recently been supposed that the gelatin might
perhaps replace the proteid if tyrosin were at the same time ad-
ministered. We now know that the contrast in the metabo-
lism of animals and plants is not so complete as was formerly
supposed. Hence there was the d priori possibility that pro-
teid might be formed by synthesis from gelatin and tyrosin.
The first experiments ^ appeared even to favor this supposition;
but on careful repetition, a negative result was obtained.
Lehmann ^ fed two rats on a mixed diet of gelatin, rice-starch,
butter, meat-extract, and bone-ash ; and six rats on the same
diet with the addition of tyrosin. They all died at about the
same time, from forty-seven to seventy days afterwards. Thus
these experiments also tend to show that no proteid can be

1 Voit, Zeitschr. /. Biolog., vol. viii. p. 297 : 1872. The historical introduction
to this treatise, showing the numerous errors into which any one would neces-
sarily fall from the experiments, formerly made to decide the question concerning
the nutritive value of gelatin, is highly instructive and interesting. Compare
also the more recent paper on this subject : Zeitschr. f. Biolog., vol. x. p. 203 :
1874. We cannot attain to a complete understanding of the significance of
food-stuffs until we get to know all the processes of metabolism. We ought
therefore properly to leave the consideration of the import of the various food-
stuffs to the last chapter of physiological chemistry. But this diiSculty can in
no way be surmounted, for every chapter of physiology presupposes other chap-
ters. It appears to me advisable to arouse the reader's interest at the start by
pointing out the importance in vital processes of those substances whose gradual
changes and ultimate destination in the animal body must be the foundation of
all future study.

^L. Hermann und Th. Escher, Vierteljahr sehr, der naturforsch. Ges. in
Zürich, p. 36 : 1876.

^ Karl B. Lehmann, Sitzungsber. d. Ges. f. Morphol. u. Physiol, in Jlünchen :
1885.

58 LECTURE IV

produced from gelatin, although we know, on the other hand,
that all gelatin-yielding tissues of the body are formed from
proteid. This is seen in the growth of the herbivora, and of
the young animal in its suckling stage, since their food contains
proteids but no gelatin.

Gelatin, as such, is to be found only in cooked food. Of
the gelatin-yielding tissues, connective tissue is easily digested,
and is therefore an important element of food. Meat, which
consists to a great extent of connective tissue, disappears
almost entirely in the alimentary canal of man. The digesti-
bility of cartilage and bone was long doubted, until it was
proved, by experiments in Voit's laboratory,^ that dogs fed on
cartilage ejected but a very inconsiderable amount in the feces.
A large part (as much as 53 per cent.) of the collagenous
substance of the bones did not reappear in the feces. We do
not know how far the digestive organs of man are capable of
dealing with cartilage and bone, as no experiments have been
made to ascertain this.

Keratin, the chief constituent of the epidermis, of hair,
nails, claws, hoofs, horns, and feathers, was formerly classed
with the collagenous substances. But keratin is distinguish-
able from the gelatins, as well as from the proteids, by its high
percentage of sulphur (from 4 to 5 per cent.) but more
especially from the gelatins by the fact that tyrosin makes its
appearance among its products of decomposition. According
to this last property keratin should be classed among the pro-
teids. The keratins of the various tissues are probably not
identical and not chemical entities, but mixtures of different
substances. Keratin does not come under our consideration
as a food ; according to previous experiments it appears in-
capable of being digested by the mammal.^ Certain insects
can digest keratin. The caterpillar of the clothes-moth
apparently feeds almost entirely upon keratin. Wherever
therefore keratin is rendered soluble, it can take the place of
proteid. The chief constituent of elastic tissue, ' elastin,' which
was likewise formerly classified under the same heading as
gelatin, now stands by itself: on decomposition, it yields a
small amount of tyrosin.^ Elastic tissue is almost completely

1 J. Etzinger, Zeitschr.f. Biolog., vol. x. p. 84 : 1874.

^ Knieriem, "On the Value of Cellulose in the Animal Organism," p. 6,
Jubilee Essay: Riga, 1884. Reprinted in the Zeitschr. f. Biolog., vol. xxi. p.
67: 1885.

ä For the composition and properties of elastin, vide R. H. Chittenden und
A. S. Hart, Zeitschr. /. Biolog., vol. xxv. 368: 1889. The earlier literature is
here quoted.

THE FOOD OF MAN 59

digested by dogs.^ As regards human beings, we must mention
an experiment made by Horbaczewski ^ on a patient with
gastric fistula. Powdered elastin in a small bag was introduced
through the fistula, and was found to be partly dissolved in
twenty-four hours.

1 Etzinger, loc. cit. Compare also L. Morochowetz, St. FetersMirger med.
Wochenschr. : No. xv., 1886; A. Ewald und "W. Kühne, Verhandlungen des

natur.-histor. med. Vereins zu Seidelberg, N. F., vol. i. p. 441 : 1877 ; and Chit-
tenden und Hart, loc. cit.

2 J. Horbaczewski, Zeitschr. f. physiol. Chem., vol. vi. p. 330: 1882.

LECTURE V

THE ORGANIC FOOD-STUFFS (continued) CARBOHYDRATES

AND FATS SIGNIFICANCE OF THE THREE MAIN

GROUPS OF ORGANIC FOOD-STUFFS

We will now turn our attention to two main groups of food-
stuifs which oifer a contrast to the two last mentioned, in being
free from nitrogen and sulphur — the fats and the carbohy-
drates.^ They agree with one another in being made up of the
same three elements : carbon, hydrogen, and oxygen. But the
quantitative composition is well known to be quite diiferent ; the
fats are much poorer in oxygen, and richer in carbon and hydro-
gen. Therefore the heat-equivalent of the fats is much greater.

The heat-equivalent of the organic substances can not be
exactly computed from the known heat-equivalents of carbon
and hydrogen, because, of the amount of heat which is set free
by the union of the oxygen with the carbon and hydrogen, a
part which is used up in the separation of the hydrogen atoms
from the carbon atoms, and of the carbon atoms from each
other. This amount of heat may vary greatly in different com-
pounds, because the atoms are more or less firmly combined
with each other, and varying amounts of heat are set free by
their union. Metameric compounds are known to produce dif-
ferent heat-equivalents. Hence the heat-equivalents of food
stuffs have been determined by direct calorimetric methods,
first by Frankland,^ then by an improved method by Stoh-
mann ^ and his pupil Rechenberg,* lastly by Danilewsky ^ and
by Rubner.^ In the following table I give the values ascertained

1 Both here and in all subsequent remarks, a knowledge of the chemical
properties of the carbohydrates and fats is presupposed, as these compounds are
usually described at sufficient length in the text-books of organic chemistry.

2 Frankland, Philos. Mag., vol. xxxii. p. 182 : 1866.

^Stohmann, Journ.f. prakt. Chem., N. F., vol. xix. pp. 115-142: 1879; and
Landwirthschaftl. Jahrb., pp. 531-581 : 1884; Zeitschr. f. Biolog., vol. xxxi. p.
364: 1895.

*von Eechenberg, Journ.f.prakt. Chem., N. F., vol. xxii. pp. 1-45, 223-250:
1880.

5 Danilewsky, Pfliiger's Arch., vol. xxxvi. p. 237 : 1885.

« Rubner, Zeitschr. f. Biolog., vol. xxi. pp. 250, 337 : 1885.

60

THE ORGANIC FOOD-STUFFS 61

by the above-mentioned authors. By the side of each figure
will be found the first letters of the author's name. The heat-
equivalents of carbon, hydrogen, and of a few decomposition-
products of food-stuffs, are also added to the table for reference in
future remarks. The unit of heat (calorie) is that quantity of heat
required to raise the temperature of one gramme of water 1 ° C.

Heat-Equivalents of One Gramme of Substance Expressed
IN Calories.

Hydrogen F. andS.» 34,462

Stearic acid, CigHjgOj Ech 9886

Rub 9745

«' F. and S 9717

Beef fat D 9686

Olive oil St 9455

Pig's fat Rub 9423

Stearic acid . . St 9412

Fat (human and animal), the aver-
age of a number of approximate

figures, 9319-9429 St 9372

Butter St 9179

Charcoal F. and S 8080

Ethylalcohol F. and S 7184

" Berthelot 6980

Leucin . . St. and h.^ 6525

B. and A. 3 6537

Fibrin (vegetable) D. 6231

Elastin . . St. and L 5961

Hemoglobin (from horse) D. 5949

Vegetable fibrin St. and L 5942

Serum-albumin St. and L 5918

Tyrosin B. and A 5916

Hemoglobin (from horse) ..... B. and A 5915

Syntonin St. and L 5908

Hemoglobin St. and L 5885

Casein St. and L 5858

" D 5855

Legumin St. and L 5793

Blood fibrin D 5772

Vitellin St. and L 5745

Egg-albumin St. and L 5735

Milk -casein (three preparations

5754-5693), average ... St 5715

Egg-albumin B. and A 5690

Crystallized albumin (from pump-
kin-seeds) St. and L 5672

Hippuric acid St. and L 5668

" " B. and A 5659

Butyric acid F. and S 5647

1 Favre and Silbermann, Ann. d. Chim. et d. Phys., vol. xxxiv. p. 357 : 1852.

2 F. Strohmann and H. Langbein, Joum. f. prakt. Chem., N. F., vol. xliv. p.
336: 1891.

3 Berthelot and A. Andre, Ann. d. Chim. et d. Phys., series vi. vol. xxii. pp.
5 and 25: 1891.

62 LECTURE V

Heat-Eqtjivaients of One Gramme of Substance Expressed
IN CaI/ORIEs {continued).

Paraglobulin (from horse's serum) 5634

Casein . B. and A 5629

Crystallized proteid (prepared by

Grübler from pumpkin seeds) . . St 5595

Egg-albumin ( two preparations,

5556 and 5597), mean . . .St 5577

Blood fibrin (three preparations,

5487-5536), average .... St 5508

Gelatin (from isinglass) . . . D 5493

Ossein B. and A 5414

Chrondrin B. and A 5346

Peptone St. and L 5299

Caffein St. and L 5231

Chondrin St. and L 5131

Ossein . . St. and^L 5040

Peptone ( prepared by Drechsel ) . . D 4914

Chondrin D 4909

Peptone D 4876

Sarcosin St. and L 4506

Starch Ech 4479

Erythrodextrin Ech 4325

Glycerin St 4305

Creatin (anhydrous) St. and L 4275

Cane sugar D. 4176

" " Ech 4173

Maltose anhydride Ech 4163

Lactose anhydride Ech 4162

Cellulose (from Swedish filter-paper) St . 4146

Starch St 4116

Cane sugar . . .... St 3959

Lactose hydrate, C12H22O11, HjO . . Ech 3945

Dextrose anhydride . . .... Ech 3939

Maltose hydrate, C^^K^fin, H2O . . Ech 3932

Guanin
Lactose anhydride
Creatin -|- HjO
Dextrose anhydride
Lactose hvdrate

St. and L 3892

St 3877

St. and L 3714

St. 3692

St 3667

Dextrose hydrate, CgHijOg, HjO Ech 3567

Acetic acid . F. and S 3505

Aspartic acid St 3423

Glycocoll = ... St 3050

Succinic acid Ech 2996

" " St. 2937

Aspartic acid B. and A 2911

" " St. and L 2899

Uric acid St. and L 2750

" " Frankl 2645

" " St. 2620

Urea St. and L. ... 2542

" D 2537

" St 2465

Frankl 2121

Tartaric acid St 1744

" " Ech 1407

Oxalic acid . . . • Ech 659

" " St 569

THE ORGANIC FOOD-STUFFS 63

In the case' of non-nitrogenous food-stuifs, the same amounts
of heat are produced in our bodies as in the calorimeter, be-
cause the ultimate products are the same ; but it is different
in the case of food-stuffs containing nitrogen. Nitrogen
is liberated in a free state from combustion in the calorim-
eter ; on the other hand, it issues from the decomposition
and oxidation of the body as an organic compound, in union
with a part of the carbon and hydrogen, and, in the case ot
man, principally as urea. The amount of urea which can be
formed from the proteid is about one-third of the weight of
the proteid. In order therefore to ascertain the heat-equiva-
lent of the proteid in our organism, we must deduct one-third
of the heat-equivalent of urea from that of the proteid. But
this figure would come out rather too high, because the nitrogen
leaves our body not only as urea, but partly as a compound
containing both more carbon and more hydrogen. We must
therefore subtract at least 800 units of heat from the heat-
equivalent of the proteids in the above table, and we then ob-
tain figures which are only a little higher than those of the car-
bohydrates. As a store of energy in our bodies therefore, the
carbohydrates are, in a quantitative respect, about equivalent
to the proteids. The heat-equivalent of fats, on the other hand,
is twice as great.

Little has as yet been ascertained as to the manner in which
the organs, in the performance of their various functions, util-
ize the potential energy acquired with the food. As muscle
consists chiefly of proteid, it was a plausible supposition that
this substance was the source of muscular work. This view
was maintained by Liebig, who contrasted the food-stuffs con-
taining no nitrogen — the fats and carbohydrates — as " respira-
tory foods" with the proteids as "plastic foods." He taught
that the former served mainly to generate heat. At the present
time we know that, in muscular work, the excretion of nitrogen
is increased only in a slight degree, but that the excretion of
carbonic acid and the absorption of oxygen is notably increased;
that therefore muscle works principally with material free from
nitrogen. We know that a store of carbohydrates is to be
found in the muscles in the form of glycogen, and that this
store disappears during work. It thus appears that the carbo-
hydrates serve as the chief sources of energy in muscle.^ The
fats and the carbohydrates may replace each other, but only
within certain limits ; they do not appear to play exactly the
same part. This is proved by their simultaneous appearance

^ The question as to the source of muscular energy will be fully treated in
Lecture XXIII.

64 LECTURE V

in the milk of all Carnivora, omnivora, and herbivora. It is
farther proved by the instinctive desire for the addition of fat
to a diet, however abundant in carbohydrates it may be, and
the desire, on the other hand, for the addition of carbohydrates
to the richest fat-diet.

The fats are, at any rate, the most fertile sources of heat.
Concerning the importance of animal heat in vital functions,
we know, so far, that all chemical processes, as well as the
interchange of energy connected with them, and the functions
of the body dependent upon them, are more intense at a higher
temperature. The fact that the functions of the nervous system,
and of the muscles especially, are performed more rapidly at a
higher temperature, may be easily demonstrated, as is well
known, on Poikilothermie animals.

It has not yet been ascertained which functions of the body
are aided by the decomposition and oxidation of the large
amount of proteid, which no other food-substance can replace.
It is a matter of experience, that each person must be daily
supplied with at least 100 grms. of proteid in one form or
another. If he eats less than this amount, he must use part
of the proteid of his tissues, however large a quantity of fat
and carbohydrates he takes as well.^ The fats and carbohy-
drates can only act in a certain degree as substitutes for the
proteids.

We know indeed that the elements of our tissues which are
rich in proteids undergo, like all unicellular organisms, a rapid
change of generations ; that increase, death of one part, growth
and division of another, follow each other in uninterrupted
succession. In the epidermis (the tissue most convenient for
observation), we see the older cells continually dying off and
being replaced by the proliferation of under layers. The same
process has been traced in the epithelial cells of the intestine
and of certain glands. A glance at a section of bone shows
that newly-formed concentric lamellae are continually growing
into the older system as it becomes absorbed. We shall see,
when we come to consider the processes of absorption in the
intestine (Lectures XIII. and XV.), that the leucocytes also
undergo rapid growth and destruction. Why should not the

1 From numerous experiments recently communicated, it appears that when
a large amount of carbohydrates is taken, much less than 100 grms. of proteid is
almost, if not quite, sufficient to maintain nitrogenous equilibrium. It is open
to question however whether it would be so over a long period of laborious work
and normal sexual life. Vide C. Voit, E. Voit und Constantinidi, Zeitschr. /.
Biolog., vol. XXV. p. 232 : 1888; Hirschfeld, Virchow's Arch., vol. cxiv. p. 301 :
1888 ; and Pfliiger's Arch., vol. xlix. p. 428 : 1889 ; and Muneo Kumagawa, Vir-
chow's Arch., vol. cxvi. p. 370 : 1889. Compare also end of Lect. VIII.

THE OEGANIC FOOD-STUFFS 65

same thing b'e taking place in the tissues hidden from our
observation ?

But the material of the dying cells may be used up in the
growth of the surviving ones. The necessity for a daily con-
sumption of 100 grms. of proteid is incomprehensible, so long
as we do not know of any function of the body in the per-
formance of which the chemical potential energies of the de-
stroyed proteid are used up.

As we know for a fact that proteid is the only one of the
three main groups of food that cannot be replaced by any other,
our choice and combination of the articles of diet [must be
regulated by the amount of proteid they contain. In the fol-
lowing table ^ may be seen the average composition of the most
important articles of diet, arranged according to the quantity
of proteid found in them : —

TABLE I.

One Hundred Grms. of Food in a Natueax, State Contain—

Proteid. Fats. Carbohydrates.

Apples 0.4 — 13

Carrots 1.1 0.2 9

Potatoes 2.0 0.1 20

Human milk 2.4 4.0 .. . 6

Cabbage (various) ... 3.3 -0.7 7

Cow's milk 3.4 4.0 .. . 5

Eice 8.0 0.9 77

Maize 10.0 4.6 71

Wheat 12.0 1.7 70

Egg-albumin 13.0 0.3 —

Fat fish (eel) 13.0 28.0 —

Fat pork 15.0 37.0 —

Yolk of egg . . - . 16.0 . . . 32.0 —

Fat beef 17.0 26.0 —

Lean fish (pike) . . 18.0 0.5 —

Lean beef 21.0 1.5 —

Peas 23.0 1.8 58

TABLE II.
One Hundred Gems, of Dried Substances Contain-

Apples .....

Proteid.
... 2.4 .. .

Fats.

Carbohydrates.
79

Potatoes ....
Rice

... 8.0
... 9.0 .. .

. . 0.6 .
... 1.0 . .

... 87
89

Carrots

. . , 10.0 . . .

. 2.0 . ,

82

Maize

. . . 11.0 . . .

. . . 5.0

81

Wheat

. . . 14.0 . . .

... 2.0 . .

... 81

Human milk . .

. . . 18.0 . . .

. . . 30.0 . .

. ... 48

1 The numbers are taken from the work of J. König, " Chemie der menschli-
chen Nahrungs- und Genussmittel," 2d edit. (Berlin, 1882), in which will be
found an exhaustive collection of all former analyses.

5

66

LECTUEE V

TABLE II. (continued).

Cabbage

Proteid.
. . . 26.0 . . .

Fats
... 5.0 . .

Carbohydrates
. ... 56

. . . 27.0 . . .

. 2.0 . .

. ... 62

Cow's milk . . .

. . . 27.0 . . .

. . . 29.0 . .

. , . 38

Fat pork ....

. . . 28.0 . . .

. . . 71.0 . .

Fat fish

. . . 30.0 . . .

. . . 67.0 . .

Yolk of egg . . .
Fat beef . .

. . . 33.0 . . .
. . . 39.0 . . .

. . 65.0 . .
. . . 59.0 . .

. . . —

Lean beef ....

. . . 89.0 . . .

... 6.0 .

Egg-albumin . .
Lean fish ....

. . . 89.0 . . .
. . . 90.0 . . .

. . 2.0 , .
... 2.5 . .

. . . . —

In the following table we give the amount which it is
necessary to eat of the various articles of diet in their natural
undried condition, in order to convey 100 grms. of proteid into
our bodies : —

TABLE III.

One Hundred Gems, op Peoteid aee Contained in —

25,000 grms. apples.

9000
5000
4200
3000
3000
1250
1000
800

carrots,
potatoes,
human milk,
cabbage,
cow's milk,
rice,
maize,
wheat.

750 grms

egg-albumin

750 "

fat fish (eel).

650 "

fat pork.

620 "

yolk of egg.

600 "

fat beef.

550 "

lean fish.

480 "

lean beef.

430 "

peas.

In the following table we give the amount of dried articles of
food which contain 100 grms. of proteid : —

TABLE IV.

One Hundeed Gems, op Peoteid aee Contained in —

4200 grms. dried apples.

1250
1100
1000
900
700
550
440
370

potatoes.

rice.

carrots.

maize.

wheat.

human milk.

cabbage.

peas.

370 grms. dried cow's milk.

360
330
300
250
112
112
110

fat pork.

fat fish.

yolk of egg.

fat beef.

lean beef.

egg-albumin.

lean fish (pike).

If we subtract 100 from the numbers given, we learn from
this last table how much of the other solid constituents, espe-
cially carbohydrates and fats, we must consume in order to ob-
tain 100 grms. of proteid. In the following two tables these
quantities are divided into carbohydrates and fats ; in Table V.
they are arranged according to increase of carbohydrates, and
in Table VI. according to increase of fats.

THE ORGANIC FOOD-STUFFS 67

TABLE V.
With One Hundred Grms. of Proteid we Take up in —

Carbohydrates. Fats.

Cow's milk 140 107

Cabbage 220 21

Peas 230 7

Human milk 270 170

Wheat 580 14

Maize 740 46

Carrots 820 20

Eice 990 11

Potatoes 1000 8

Apples 3300 0

TABLE VI.
With One Hundred Grms. of Proteid we Take up in —

Fats. Carbohydrates.

Apples — 3300

Egg-albumin 2 — -

Pike 3 —

Lean beef 7 —

Peas 7 230

Potatoes 8 1090

Eice 11 990

Corn 14 580

Carrots . . . , 20 . 820

Cabbage 21 220

Maize 46 740

Cow's milk 107 140

Fat beef 150 —

Human milk 170 270

Yolk of egg 200 —

Eel 220 —

Fat Pork 250 —

In forming an opinion from these tables concerning the
value of the different animal and vegetable foods, the follow-
ing must also be taken into consideration. The amount of
proteid in most articles of food has not been accurately deter-
mined. The amount of nitrogen only has been ascertained, and
from this the amount of proteid has been calculated under the
supposition that no other nitrogen- compounds exist in food, and
that all kinds of proteids contain 16 per cent, of nitrogen.
Both assumptions are wanting in precision. The amount of
nitrogen in the various proteids varies, as we have seen, from
15 to 19 per cent. The other assumption, that foods contain
no other nitrogen-compound, holds good in the case of the
grains of cereals and leguminosse. But in most of the other
vegetable food-stuflFs, ammonia, nitric acid, amides, amido-acids,
&c., are found in considerable quantities. In certain kinds of

68 LECTURE V

vegetables the nitrogen of these compounds amounts to more '
than one-third of the total nitrogen. ^!^

It would also be a serious mistake to calculate the amount
of proteid from the amount of nitrogen in meat. This contains
a considerable quantity of gelatin-yielding substances which, as
I have already pointed out, have a totally different action in
nutrition to that of proteid. The collagenous substances of
animal food may be regarded as more analogous to the carbohy-
drates of vegetable food than to the proteids. If therefore the
nutrient value of meat and vegetables be judged from the above
tables according to their relative amount of proteid, the value
of the meat Avill be rated too highly, and that of the vegetables
not highly enough.

On the other hand it must be remembered that animal food
is much more completely absorbed than vegetable food. The
capability of absorption of the proteid in different foods has of
late been accurately tested by a careful comparison of the amount
of nitrogen in the nutriment taken with that in the feces. It
has thus been ascertained that the proteid of the meat almost
entirely disappears. A considerable part of the proteid in
milk reappears in the feces, and a still larger proportion is un-
absorbed from vegetables. The table on p. 69 gives the results
of these experiments on the absorption of proteid ; they have all
been carried out on human beings.

If the following table be compared with Tables III. and
IV., it appears scarcely possible that a man could take up, in
the form of vegetables, the daily amount of at least 100 grms.
of proteid necessary to maintain nitrogenous equilibrium. The
potato appears especially unsuited for this purpose ; 5 kgrms.
must be eaten in order to introduce 100 grms. of proteid into
the stomach, but 7 kgrms. must be consumed to allow of the
absorption of 100 grms. of proteid. English statisticians do in
fact show that Irish workmen, who live chiefly on potatoes, eat
on an average 4 to 6.5 kgrms. each daily. This appears
scarcely credible. The person experimented on by Rubner,^
a powerful soldier, who was accustomed to take large quantities
of potato when at home in the Bavarian Alps, could not
manage more than from 3 to 3.5 kgrms., although this monot-
onous form of food was prepared in various ways, with salt or
with butter, with vinegar and oil as a salad, in the form of
chips, or baked ; and although the man was eating all day
long. The potatoes he ate contained only 71.5 grms. of pro-
teid, of which 23.1 grms. remained unabsorbed. He could not
therefore maintain his nitrogenous equilibrium, as he gave out

^ Rubner, loc. cit., vol. xv. p. 146.

THE ORGANIC FOOD-STUFFS

69

Food.

Beef (the same person being experi-\

mented on) j

Eggs

Milk and cheese (the same person) .

Milk 3 ( four experiments on four dif- \
ferent people) J

"Leguminose" (flour from legumi-")
nosse and cereals) .... J

Macaroni

Maize

Peas and bread

Vermicelli

Savoy cabbage

Wheat bread .

Rice

Kye bread

White bread (the same person) . ,

Peas, shelled and well boiled (the\

same person) . J

Broad beans, well cooked

Whole wheat-meal bread

Black break (rye bread)

Potatoes

Harsford-Liebig bread

Carrots (boiled)

Lentils

Bran bread

Kye-bran bread

Lentils, potatoes, and bread ....

Percentage of un-
absorbed proteid.'

2.51
2.8/

1.9 [
5.7)

2.9

2.9

4.

3.

6.5
7.0

7.7
12.0

iio'.ö}

11.2

15.5
12.0-20.0

17.1

18.5

19.9

20.4

22.2

18.7-

20.7

24.6

25.7.
f 17.51
\27.8/

30.25

30.5

32.0

32.2

32.4

39.0

40.0

42.3

45.4
53.5

Author.

Kubner ^
Kubner

Eubner

Eubner

Strümpell *

Rubner

Eubner

Woroschiloflf^

flubner

Eubner

Meyer ^

Eubner

Meyer

Eubner

Eubner

Prausnitz '

Eubner

Eubner

Eubner

Meyer

Eubner

Strümpell

Meyer
/ Huldgren and
1 Landergren ^

Hofmann ^

1 These figures are rather too high, because the nitrogen in the feces is con-
tained, not only in the unabsorbed food, but also in the products of metabolism,
which are eliminated in the intestine. According to Rieder's experiments with
non-nitrogenous food, the nitrogen eliminated in the intestine amounts to 8 per
cent, of the total nitrogen excreted under these circumstances. Zeitschr. f.
Biolog., vol. XX. p. 478 : 1884.

2 Max Eubner, Zeitschr. f. Biolog., vol. xiv. p. 115 : 1879 ; vol. xvi. p. 119
1880; vol. xix. p. 45: 1883.

' Concerning the absorbability of milk, see W. Prausnitz, Zeitschr. f. Biolog.,
vol. XXV. p. 533 : 1889.

4 A. Strümpell, Deutsch. Arch. f. Min. Med., vol. xvii. p. 108: 1876.

^ WoroschilofiF, Botkin's Arch., vol. iv. p. 1 : 1872 (Russian). Unfortunately
a very inaccurate account of this useful work is to be found in the Berl. klin.
Wochenschr., p. 90 : 1873.

* G. Meyer, Zeitschr. f. Biolog., vol. vii. p. 1 : 1871.

'W. Prausnitz, Zeitschr. f. Biolog., vol. xxvi. p. 227: 1890.

* E. Huldgren and E. Landergren, JYord. Med. Arkiv, p. 21 : 1890.

^ Fr. Hofmann, " Die Bedeutung der Fleischnahrung und Fleiachconserven,"
pp. 11, 44 : Leipzig, 1880.

70 LECTUEE V

more nitrogen through the kidneys than he absorbed from the
intestines, thus using up the store of proteid in his tissues, i. e.,
he was gradually dying of hunger. A sceptical observer must,
however, concede the possibility that many Irish laborers may
consume 5 kgrms. of potatoes and maintain their nitrogenous
equilibrium. The difference in individuals is of course very great.

I wish further to point out that such a diet can be better
borne by adults than by children. Children have to build up
an organism rich in proteid ; adults have only to maintain the
previous store, performing their muscular work with the carbo-
hydrates, of which a superfluity is introduced with a potato-
diet. The frightful mortality among children of the lower
classes is perhaps largely due to the want of proteid in their food.

Among the more important articles of vegetable food, the
leguminosse contain the largest amount of proteid. A diet of
these, if properly prepared, maintains nitrogenous equilibrium.
This is shown by the experiments Woroschiloff^ made upon
himself. He lived for thirty days entirely upon peas, bread,
and sugar, while at the same time he performed 8528 kilogram-
meters of work per hour, for the space of one to three hours a
day, and yet he showed no loss of proteid. The person whom
Rubner ^ experimented upon, also kept his nitrogenous equilib-
rium on a diet of peas.

If an exclusively vegetable diet proves insufficient, it is
perhaps caused less by the want of proteid than by the want
of fat. If we glance at Table V. (p. 67), we see that the
relation of carbohydrates to proteid is the same in a diet of
leguminosse and cereals as in milk, with the diflPerence that
the former contain much less fat than milk does. We should
hence ä priori expect to find that a man could exist very well
upon cereals and leguminosse, with the addition of fat, or per-
haps even upon cereals and fat only. Milk is the normal food
of the infant, not of the adult. The adult requires, as I have
just explained, relatively less proteid and more carbohydrates.
We might, therefore, conclude that the normal food of the
adult would be furnished by the proteid and carbohydrates, in
the proportion met with in the cereals, and that this diet
would only require the addition of fat. This theory appears
to be confirmed by experience. The laborers in some districts
of Bavaria, who do the hardest work, are said to live upon a
diet prepared from flour and lard.^ This mode of living would

' WoroschilofF, loc. cit. "^TiAihneY, loc. cit., vol. xvi. p. 125 : 1880.

^H. Ranke, "Die bayr. Landwirthschaft in den letzten 10 Jahren." Fest-
gabe, &c., p. 160: München, 1872; Liebig, Sitzungsber. d. bayr. Akad., vol. ii.
p. 463: 1869; " Reden und Abhand.,"p. 121. Compare also Ohlmüller, ZeiiscAr.
/. Biolog., vol. XX. p. 393 : 1884.

THE ORGANIC FOOD-STUFFS 71

be the ideal of vegetarians ^ if the fat were likewise obtained
from the vegetable kingdom, in the form of oil, olives, nuts,
cocoa. From investigations made by Panum and Buntzen, it
appears that even a carnivorous animal can be nourished on
cereals and fat ; a dog which was fed exclusively on groats and
butter could be kept in good health for two months without
loss of weight.^ Unfortunately this experiment lasted much too
short a time.

The fat of all food is very completely absorbed,^ far more
so than the proteids. The same is true of all carbohydrates,^
with the single exception of cellulose. This was held to be
totally indigestible until quite recently, when it was proved
by experiments on ruminants^ at the farm-stations kept for
investigations, that from 60 to 70 per cent, of the woody fibers
disappear from the digestive canal. At the experimental farm
of Tharand,*' it was even found that from 30 to 40 per cent, of
the cellulose of sawdust and paper was absorbed by sheep when
mixed and eaten with hay. Weiske^ was the first to make
experiments on human beings, which he carried out on himself
and on another person. He found that one of them digested
62.7 per cent., the other 47.3 per cent., of the woody fibers
in the food, which consisted of carrots, cabbage, and celery.
Later on Knieriem ^ made experiments on himself, and found
that he digested 25.3 per cent, of the tender woody fibers oi
lettuce, but only 4.4 per cent, of the tougher fibers of Scor-
zonera. The latter figure is within the limits of unavoidable
error. How cellulose undergoes solution in the intestines, we
shall explain further on, when we come to the consideration of
the digestive processes.

Cellulose can scarcely be classed among the food-substances
of human beings. On the other hand it is of great importance
in acting as a mechanical stimulus to promote the peristalsis of
the intestine. For this reason cellulose is absolutely essential
to animals with a long intestinal tract. If rabbits are fed on a

1 T have published a detailed criticism of vegetarianism in a small pamphlet,
" Der Vegetarianismus " (Berlin, Hirsch wald : 1885).

^Jahresbericht über die Fortschritte der TMerchemie, vol. iv., of the year
1874, p. 365 : Wiesbaden, 1875.

^Rubner, loc. cit., vol. xv. p. 189.

*Rubner, loc. cit., p. 192.

^Haubner, Zeitschr. für Landwirthschaft, p. 177: 1855; Henneberg and
Stohmann, "Beiträge zur Begründung einer rationellen Fütterung der Wieder-
käuer," Heft i. : 1860; Heftii. : 1863.

^ " Der chemische Ackersmann," pp. 51, 118 : 1860.

' H. Weiske, Zeitschr. f. Biolog., vol. vi. p. 456 : 1870.

* V. Knieriem, " Ueber die Verwerthung der Cellulose im thierischen Organ-
ismus," Festschrift : Riga, 1884. Also printed in the Zeitschrift f. Biolog., vol.
xxi. p. 67 : 1885.

72 LECTURE V

diet containing no cellulose, the onward movement of the in-
testinal contents ceases, inflammation in the intestines ensues,
and the animals rapidly die. But if horn-parings be added to
the same food, nutrition is normal.^ These horn-parings are, as
Knieriem proved by experiments devoted to that purpose, abso-
lutely undigested, and can therefore only have taken the place
of woody fiber in so far as its mechanical properties were con-
cerned. Of three mice, fed entirely on milk, one died after
forty-seven days of intussusception, as dissection showed.^

The following are the details of a post-mortem examination
of a rabbit which had died for lack of cellulose : " The stomach
only contained mucus, and showed signs of incipient inflamma-
tion in the region of the pylorus ; the small intestine, full of
mucus, was much inflamed throughout its whole length, as was
also the cecum. The latter was largely filled with excrement of
the consistency of putty, which adhered firmly to the wall? and
folds of the cecum. The diiference between these contents and
those of the cecum of a normally fed rabbit is very noticeable,
for here the mass in the cecum is pretty loose, falling almost
completely away if the intestine be bent backwards, and this
loose consistency is caused only by the tough fibers, by means of
which the communication between the anus and the stomach is
kept open. This could hardly have been the case in the animal
which died." ^

The short intestine of Carnivora does not require a mechan-
ical stimulus to produce peristaltic action. The intestine of
human beings is well known to be of medium length ; a man's
life therefore is not endangered by deprivation of cellulose,
although the normal movement of the intestine might be thereby
impeded. The muscular wall of the intestine becomes atrophied
like every other muscle, if it has no work to do. We must
therefore see that the diet of human beings does not lack woody
fibers. The excessive fear of indigestible food which prevails
among the wealthier classes may lead to universal debility of
the intestinal muscular walls. Habitual constipation would
perhaps not be such a common trouble if we were accustomed
from our childhood to a dietary containing a sufficient supply
of woody fiber. Of late years whole-meal bread, which is rich
in cellulose, has been a successful remedy for chronic constipa-
tion. It is well known that an exclusive milk diet may occa-
sion constipation.

^Knieriem, loc. cit., pp. 6, 17-19.

^N. Lunin (Bunge's laboratory), " Ueber die Bedeutung der anorganischen
Salze für die Ernährung des Thieres," p. 15, Dissert. : Dorpat, 1880. Also printed
in the Zeitschr. f. physiol. Chem., vol. v. p. 37 : 1881.

3 Knieriem, loc. cit., p. 17.

THE OEGANIC FOOD-STUFFS 73

On the other hand it is urged that the rapid and continual
movement of the intestinal contents in consequence of the irri-
tating action of the woody fibers has one drawback — the in-
complete utilization of the food. In fact, Meyer ^ has already
shown, by direct experiment, that it is more economical to feed
on the dearer bread of fine flour than on the cheaper bran
bread. Fr. Hofmann showed that the addition of cellulose
diminishes the nutritive value of meat.^ At the same time, it
appears to me that the advantages of food containing cellulose
far outweigh the drawbacks.

The following table shows the amount of cellulose contained
in the most important vegetables used as food by man ; from a
dietetic, point of view this is not without interest.

Pebcentage of Cellulose in various Articles of Diet in a
Natural State.''

Cellulose. Water.

Eice flour 0.2 13.0

Wheat flour (fine) 0.3 13.0

Cucumber 0.6 96.0

Eice 0.6 ..... . 13.0

Onion 0.7 86.0

Potato 0.8 7o.O

Cauliflower 0.9 91.0

Asparagus 1-0 94.0

Carrots 1-0 89.0

Melon 1.1 90.0

Mushroom 1-4 91.0

Apple (including pips) 1-5 85.0

Eye meal 1-6 14.0

Eadish 1.6 87.0

Cabbage 1-8 90.0

Green peas 1-9 "8.0

Eye 2.0 15.0

Strawberries 2.3 88.0

Maize 2.5 13.0

Wheat 2.5 14.0

Peas ^ 2.6 15.0

Horseradish. . 2.8 ...... 77.0

Lentils 3.0 . . . 12.0

Hazel-nut 3.3 3.8

Beans 3.6 14.0

Grapes (including pips) 3.6 78.0

Pears (including pips) .... . 4.3 83.0

Barlev 5.3 14.0

Walnut 6.2 4.7

Almonds 6.6 5.4

Easpberries .... 6.7 86.0

1 G. Meyer, ZeitscJir. f. Biolog., vol. vii. pp. 32 and 33 : 1871 ; compare also
Eubner, Zeitschr. f. Biolog., vol. xix. p. 45 : 1883.

2 Volt, Sitzungsber. der bayr. Akad. : December, 1869.

3 The average figure, taken from König's work previously quoted.

74

LECTURE V

Percentage of Cellulose in Dried Articles of Diet.

Cellulose.

Rice flour 0.2

Wheat flour (fine) . . . 0.4

Eice 0.7

Eye meal 1.8

Eye 2.4

"Wheat 2.9

Maize 2.9

Potato 3.1

Hazel-nut 3.4

Lentils 4.1

Beans 4.1

Onion 5.0

Barley 6.2

Peas 6.4

Walnut 6.5

Almond 6.9

Cellulose.

Spinach 8.1

Green peas 8.7

Carrot 8.8

Apples 10.0

Eadish 12.0

Horseradish 12.0

Cauliflower 13.0

Cucumber ...... 14.0

Mushroom 16.0

Asparagus 17.0

Cabbage 18.0

Strawberries 19.0

Melon 22.0

Pears. 25.0

Easpberries 47.0

The amount of carbohydrates and fats required for our daily
nutrition cannot be determined, as they may either replace
each other or be replaced by proteid. Experience has taught
us that workingmen, who are able to obtain sufficient food, eat
daily from 50 to 200 grms. of fat, and from 300 to 800 grms.
of carbohydrates, besides from 100 to 150 grms. of proteid.
Tables V. and VI. (p. 67) show us how we can combine such
articles of nutrition in the most varied ways. The food must
be more abundant in carbohydrates in proportion to the work
performed by the muscles, and more abundant in fat according
to the lowering of the surrounding temperature. Travellers in
the far north relate that they were glad to adopt the habit, prev-
alent among the natives in those regions, of eating a pound of
butter or oil in the day, and that the distaste for large quanti-
ties of fat returned as soon as they reached warmer climates.
On the other hand the negroes in the plantations of the tropics,
while doing the hardest muscular work, thrive on a dietary
poor in fat, but very rich in carbohydrates.

LECTURE VI

THE ORGANIC FOOD-STUFFS (conclusion) THE ORGANIC COM-
POUNDS OF PHOSPHORUS CHOLESTERIN

In the previous chapters we have become acquainted with
those organic substances which, according to the doctrines of
physiology now prevailing, are requisite for the nutrition of man.
But they are probably much more numerous.

Certain phosphorus compounds should also probably be
regarded as essential organic food-substances of man. In all
animal and vegetable tissues, in every cell we find two complex
organic compounds, which are very rich in phosphorus, the
LECITHINS and the nucleins.

The LECITHINS are compounds which we may regard as
having been formed from the union of one molecule of glycerin
with two molecules of a fatty acid (stearic acid, palmitic acid,
or oleic acid) one molecule of phosphoric acid and one molecule
of cholin, with the loss of four molecules of water.^

Cholin is an ammonium base, the composition of which is
accurately known. When heated, it splits up into glycol (ethy-
lene alcohol) and trimethylamin. Its synthesis corresponds with
this decomposition : Wurtz ^ produced it by the action of ethy-
lene oxide and water on trimethylamin. The formula of cholin
is therefore —

N^

CH3

CH3

CH3

CH2CH2OH

OH

In the animal kingdom cholin has, up to the present time,

1 Vide Diakonow, Centralbl. f. d. med. Wissensch., Nos. 1, 7, 28 : 1868. Hoppe-
Seyler, Med. chem. Unters., Ueü ii. p. 221: 1867; and Heft iii. p. 405: 1868;
Strecker, Ann. Chem. Pharm., vol. cxlviii. p. 77: 1868; Hundeshagen, "Zur
Synthese des Lecithins," Inaug. Dissert. : Leipzig, 1883; E. Gilson, Zeitschr. f.
physiol. Chem., vol. xii. p. 585 : 1888.

2 Wurtz, Ann. Chem. Pharm., Suppl. vi. pp. 116, 197: 1868. Compt. rend.,
vol. Ixv. p. 1015: 1867; and vol. Ixvi. p. 772: 1868. Compare Baeyer, ^nn.
Chem. Pharm., vol. cxl. p. 306 : 1866 ; and vol. cxlii. p. 322 : 1867.

75

76 LECTUßE VI

been found only in lecithin. It was first obtained by Strecker ^
from the bile, which contains lecithin, and hence it was called
cholin. Liebreich ^ found it among the products of decomposi-
tion of phosphorus compounds from nerve substance (brain).
Diakonow showed that it was a product of decomposition of
lecithin. In the tissues of plants cholin is found in other com-
binations as well as in lecithin. In mustard seed there is an
alkaloid (sinapin) which, on boiling with alkalies, is resolved into
smapic acid and cholin. Two alkaloids have been obtained by
Schmiedeberg and his pupils^ from the fly-fungus {Amanita
muscaria) — amanitin and muscarin, the former of which was
found to be identical with cholin. The latter, a violent poison,
differs from amanitin only in possessing one more atom of
oxygen. In fact, by the action of boiling nitric acid on cholin
(the cholin being taken indifferently from amanita, from the
lecithin of the brain or of yolk of egg, as well as that syn-
thetically produced), an alkaloid containing one more atom
of oxygen was successfully obtained, which acted poisonously
in a similar manner to muscarin ; the action on the heart in
particular being alike in both cases. This intimate connection
between a substance contained in every animal and vegetable
cell and a powerful poison, is a fact of great interest. Accord-
ing to the more recent researches of Boehm,^ however, the mus-
carin artificially produced by oxidation of cholin is not identical
with the muscarin from the fly-fungus, but is isomeric ; the
pharmacological action is different. Boehm found cholin in
other fungi, and obtained it in large quantities from the residue
of crushed cotton seeds and beech-nuts.

Lecithins have, in common with fats to which they are so
nearly allied in composition, the property of solubility in alco-
hol and ether ; they are also miscible in every proportion with
fats ; but at the same time they have the power of swelling and
becoming slimy in water. For this reason they appear pecu-
liarly adapted to aid in the interaction of watery solutions and
substances not soluble in water, and to take part in the most
various chemical processes in the tissues. But at present we
know absolutely nothing about the part which the lecithins may
play in any of the vital functions.

''■ Strecker, Ann. Chem. Pharm., vol. cxxiii, p. 353 : 1862 : vol. cxlviii. p. 76 :
1868.

* Liebreich, ibid., vol. cxxxiv. p. 29 : 1865.

^ Schmiedeberg a,nd Koppe, " Das Muskarin, das giftige Alkaloid des Fliegen-
pilzes": Leipzig, 1869 ; E. Harnack, Arch. f. exper. Path. u. Pharm., vol. iv. p.
168 : 1875 ; Schmiedeberg and Harnack, Arch. f. exper. Path. u. Pharm., vol. vi.
p. 101 : 1876.

* Boehm, Arch.f. exper. Path. u. Pharm., vol. six. p. 87 : 1885.

THE ORGANIC FOOD-STUFFS 77

The next.question which must occupy our attention is whether
the lecithins of our tissues are produced from the lecithins of
food, or by synthesis from other materials such as fat, proteid,
and phosphoric acid. It has been ascertained from experi-
ments in Hoppe-Seyler's laboratory ^ that, in artificial pan-
creatic digestion, the lecithins take up water and readily split
up into glycerin-phosphoric acid, fatty acids, and cholin. It is
not yet known whether this decomposition is complete in the
case of normal digestion, or whether a portion is absorbed
undecomposed, and if so how large a portion ; whether only
the undecomposed part, when absorbed, can be utilized in the
building up of the tissues, or whether the products of decom-
position which are absorbed again become united ; whether
finally lecithin may also be formed from other material. The
absorption of lecithin or of its products of decomposition is in
any case complete ; neither lecithin nor glycerin-phosphoric acid
can ever be found in the feces. The presence of lecithin in
milk ^ seems to show how essential that substance is in nutrition.

The generic name of nuclein ^ has been bestowed upon a
large number of very different organic phosphorus compounds,
which are to be found in all animal and vegetable tissues,
being especially abundant in the nuclei of cells. The nucleins
have as yet been little investigated, and we have no proof that
the pure substances hitherto isolated are chemical individuals.
All are alike in being insoluble in alcohol, ether, water, and
dilute mineral acids, and in being soluble in alkalies. The
nucleins are acids. The phosphorus is given oif from them all
as phosphoric acid on boiling with water, and more rapidly so
on boiling with alkalies or acids. But the organic substances
which are combined with the phosphoric acid appear to be of
very varying character, and have been but little investigated.
Most nucleins are proteid compounds, although a few do not
contain proteid. Many, on splitting up, produce xanthin,
hypoxanthin, guanin, and adenin ^ — crystalline compounds rich

^S. Bokay, Zeitschr. f. physiol. Chem., vol. i. p. 157: 1877.

2 TolmatschefF, Hoppe-Seyler's 3Ied. chem. Unters., Heft ii. p. 272 : 1867.

^ The Eucleins were first discovered and investigated by Miescher in the
nuclei of pus-corpuscles, and subsequently in the yolk of egg and salmon-sperm
(Hoppe-Seyler's 3Ied.. chevi. Unters., Heft iv. pp. 441, 502 : 1871 ; Verhand-
lungen der naturforschenden Gesellschaft zu. Bo.sel, vol. vi. p. 138: 1874). The
most recent and complete experiments on nucleins were made by Kossel
Zeitschr. f. physiol. Chem., vol. iii. p. 284: 1879; vol. iv. p. 290: 1880; vol. v'
pp. 152, 267: 1881; "Untersuchungen über die Nucleine": Strassburg, 1881;
Zeitschr. f. physiol. Chem., vol. vi. p. 422 : 1882 ; vol. vii. p. 7 : 1882; vol.
x.p. 250: 1886; vol. xii. p. 241 : 1888; Arch. f. Anat. u. Physiol., p. 181 :
1891.

* Piccard, Ber. d. deutsch, chem. Ges., vol. vii. p. 1714 : 1874.

78

LECTURE VI

in nitrogen, which we shall describe more at length when we
consider the chemistry of urine. The preparations of nuclein,
hitherto analyzed, contained from 3.2 .to 9.6 per cent, of
phosphorus.

The nucleins have much the same solubilities as proteids,
and are found united with these in the same morphological
structures, but they can be separated by artificial gastric
digestion (Lectures X. and XL) : the proteids are peptonized ;
the nucleins on the other hand are little affected by the gastric
juice. It appears that the nucleins mostly occur in the tissues,
not in a free state, but as compounds with proteid (nucleo-
albumins), and perhaps also with lecithin, and that gastric
digestion separates them from these bodies.

As an example of the percentage composition of nucleins,
I may give the following analyses of preparations, which were
to some extent pure. Since the nucleins have not yet been
prepared in a crystalline state, we have no adequate guarantee
of their chemical individuality or of the purity of the prepara-
tions.

Nucleins prepared from—

Carp-Roe.^

Yeast ^

Yolk of Egg. 2

I.

II.

c

40.8

42.1

48.0

47.8

H

5.4

6.1

7.2

7.2

N

16.0

14.7

14.7

12.7

S

0.4

0.55

0.3

—

P

6.2

5.19

2.4

2.9

Fe

—

0.29

—

0.25

0

31.3

31.05

—

—

From some of the nucleins the phosphoric acid may be split
off in combination with part of the organic radical as an acid
containing nitrogen, but free from sulphur, which, following
Altmann's suggestion,^ we may designate nucleic acid. As
example of such an acid may be cited the nucleic acid split off
from the nuclein of yeast, to which the formula C^gHggN^gOgg,
2P O^ has been given.^

* Kossel, Zeitschr. f. physiol. Chem., vol. iii. p. 284 : 1879.

'^ Bunge, ibid., vol. ix. p. 56 : 1885.

3 G. Walter, ibid., vol. xv. p. 489 : 1891.

4R. Altmann, Du Bois' Arch., p. 524 : 1889.

^ Altmann, loc. cit.

THE ORGANIC FOOD-STUFFS 79

In certain cells nucleic acid appears to occur in a free state.
Thus Miescher ^ has prepared a nucleic acid from salmon-sperm,
to which he has assigned the formula C^'^^J^^JJ^^, 2P2O.. In
the heads of the spermatozoa this acid is combined with the
organic base, protamin (see Lecture XIX.), to form a salt. In
the dried heads of the spermatozoa the nucleic acid amounts to
60.7 per cent, and the protamin to 19.8 per cent.

Whether the nucleins of our tissues arise from the nucleins
of food (in which case the nucleins would rank among the
number of essential food-substances), or whether the nucleins
are formed in the body by synthesis, is a question of great im-
portance, about which as little is known as concerning the
mode in which the lecithins originate. The occurrence of
nucleins in milk ^ seems to point to the former supposition as
the correct one, whereas the slight digestibility of the nucleins
would lead us to the latter conclusion. The experiments car-
ried out in Hoppe-Seyler's laboratory ^ showed that nuclein is
as little aifected by artificial pancreatic, as by artificial gastric,
digestion. Nuclein was found in abundance in the feces of
dogs. A quantitative determination of the comparative amounts
of nuclein in food and in the feces has not yet been made,
and it is therefore not yet known whether the nucleins are
absolutely indigestible, or whether a part, and if so how much,
is absorbed.

The following observation, made by Miescher* on Rhine
salmon, seems to show that the nucleins as well as the lecithins
arise in the animal body by synthesis. The salmon travel up
the river every year from the sea to spawn in the Upper
Rhine. During the journey, the ovary grows from 0.4 to
19.27 per cent, of the salmon's entire weight. These journey-
ings last from four to fourteen weeks. During the whole of
this time they take no food ; the intestinal canal is always
found empty. The material which goes to form the ovaries
can only be produced by the muscles, which constitute the
bulk of the fish's weight. Miescher showed by comparative
determinations, made on fish of equal size, that the muscles

1 Miescher, Arch. f. exp. Path. ii. Pharm., vol. xxxvii. p. 100 : 1896.

2 Nuclein was proved to be a constitiient of milk by Lubavin (Hoppe-Seyler's
Med. chem. Unters., Heft iv. p. 463 : 1871 ; Per. d. deutsch, ehem. Ges., vol. x. p.
2237 : 1877 ; and vol. xii. p. 1021 : 1879). Hammarsten showed that nuclein is
contained in milk as nucleo-albumin {Zeitschr.f.physiol. Chem., vol. vii. p. 227 :
1883).

* Bokay, Zeitschr. f. physiol. Chem,, vol. i. p. 157 : 1877.

•* Miescher, " Statistische u. biologische Beiträge zur Kenntniss vom Leben
des Rheinlachses," Separatabdruck aus der schweizerischen Literatursammlung
zur internationalen Fischerei-Ausstellung in Berlin, p. 183 : 1880 ; and Arch. f.
Anat. u. Physiol., Anat. Abth., p. 193 : 1881.

80 LECTURE VI

disappear in proportion as the ovaries develop, and that the
loss in weight of the large lateral trunk-muscles is sufficient to
cover the increase in weight of the ovaries. Now the ova are
very rich in lecithin and nuclein ; the muscles however are
poor in these compounds. But the muscles contain phosphoric
acid in abundance in another form, probably as potassium salts,
loosely united with proteids. Miescher therefore concludes that
the new compounds characteristic of the egg are formed from
the proteid, the fat, and the phosphates of the muscles, a pro-
found chemical rearrangement taking place.

Perhaps Cholesterin also belongs to the organic food-stuffs
essential to man. Like the lecithins and nucleins, it is a
normal constituent of all vegetable and animal tissues and of
milk.^ Here also we do not know whether Cholesterin is formed
only in the plant, and enters the animal body either directly in
the form of vegetable food (in the case of herbivora), or indi-
rectly (in the case of Carnivora), or whether it is formed from
other material in the animal body. Cholesterin is, like lecithins
and fats, insoluble in water, and soluble in ether and alcohol,
but is distinguished from them by its insolubility in boiling
potash ; it cannot be saponified, as it is not an ethereal salt, but
a monatomic alcohol with the composition Cg^H^^OH. The
chemical constitution of this compound is not known.

We are still in complete ignorance concerning the fate of
Cholesterin in the organism. Considerable quantities of Choles-
terin are being continually turned out into the intestine along
with the bile, but we do not know whether this Cholesterin is
taken up preformed in the food or whether it is formed from
other substances by the organism itself. In huuaan feces
Cholesterin occurs modified as dihydrocholesterin, formed by
the addition of two atoms of hydrogen to the unsaturated
Cholesterin molecule. This reduction product was named by
its discoverer, Bondzynski,^ koprosterin, and assigned the
formula Cj^H^^OH. That this process of reduction takes place
in the intestine is rendered probable by the fact that in dogs,
with their short gut, the Cholesterin of the food and of the bile
is passed unchanged, whereas in the long intestine of the
horse, Cholesterin undergoes a still further reduction, appearing
in the feces as C27H,30H. It has not yet proved possible,
outside the body, by means of reducing or putrefactive proc-
esses, to prepare the koprosterin from Cholesterin. Koprosterin

^ Tolmatscheff, Hoppe-Seyler's Med. chem. Unters., Heft ii. p. 272: 1867;
and Schmidt-Mülheim, Pfliiger's Arch., vol. xxx. p. 384 : 1883.

2 St. Bondzynski, Ber. d. deutsch, chem. Ges., p. 476 : 1896 ; Bondzynski and
Humnicki, Zeitschr. f. physiol. Chem., vol. xxii. p. 396 : 1896.

THE ORGANIC FOOD-STUFFS 81

differs from . Cholesterin both in its melting-point and in its
action on polarized light, being dextro-rotatory, while Choles-
terin is levo-rotatory. Moreover the color-reactions of kopros-
terin differ from those of Cholesterin.

We know nothing as yet concerning the significance of
Cholesterin for any vital functions.

LECTURE VII

THE IjSTOEGANIC FOOD-STUFFS

In our previous remarks on alimentary substances we have
not given any account of the inorganic materials, salts and
water.

In deciding the question of man's need for inorganic salts,
we must clearly distinguish between the growing and the adult
body. It is evident that the former requires a considerable
amount of inorganic salts for its development. The quality
and quantity needed may be best seen from the composition of
milk. An infant weighing 6 or 7 kgrms.^ takes about a liter
of milk daily. This contains — ^

KjO 0.78 grm.

NajO 0.23 "

CaO , 0.33

MgO 0.06

FejOj 0.004 "

PA 0.47 "

CI 0.44 "

It would be very interesting to compare the composition
of the ash of milk with that of the total ash of the infant. But
unfortunately no analysis of the total ash of an infant has ever
been made. A comparative analysis of the ash of dog's
milk and the total ash of a sucking puppy resulted in the
following figures,'^ which I give together with the analysis of
the ash of blood, and another of the total ash of a young rabbit
and a kitten while being suckled : —

^ This is what an infant usually weighs in the sixth month. I choose this
stage for the above table, because the numbers are of a suitable size. Assuming
that the need for inorganic salts is in proportion to the body-weight, the decimal
point has only to be moved one figure to the right, in order to ascertain the
amount required by an adult. But these figures can only be taken as a maximal
value. As we shall see it is probable that the adult does not require nearly so
large an amount of inorganic salts.

2 G. Bunge, Zeitschr. f. Biolog., vol. x. p. 316 : 1874.

3 Bunge, loc. cit., p. 326; and Du Bois' Arch., p. 539: 1886.

82

THE INORaANIC FOOD-STUFFS.

83

One hundred parts of

Sucking young of animals.

Dog's
milk.

Dog's
blood.

Dog's
blood

ash contain.

Babbit.

Dog.

Cat.

KjO

10.8

8.5

10.1

10.7

3.1

2.4

NajO

6.0

8.2

8.3

6.1

45.6

52.1

CaO

35.0

35.8

34.1

34.4

0.9

2.1

MgO

2.2

1.6

1.5

1.5

0.4

0.5

FeA

0.23

0.34

0.24

0.14

9.4

0.12

P2O5

41.9

39.8

40.2

37.5

13.3

5.9

CI

4.9

7.3

7.1

12.4

35.6

47.6

This table shows the remarkable fact that the proportion
of the various inorganic substances to each other in milk, is
almost the same as it is in the whole body of animals while
they are being suckled. This correspondence is the more
remarkable as the quantitative composition of the inorganic
residue of blood is completely different. But the epithelial
cells of the mammary gland do not derive their nourishment
directly from the blood, but from the lymph which has tran-
suded from the latter ; and the composition of the ash of lymph
differs much more. The fact that the ash of milk contains
more potassium and less sodium than the total ash of the
suckling may be teleologically explained by the fact that, as I
have proved by a series of analyses,^ the animal as it grows
always becomes richer in potassium and poorer in sodium ;
this probably depends on the relative increase of the muscles
which contain an abundance of potassium, and the relative
diminution of the cartilage which is rich in sodium. The
larger amount of chlorin in milk may perhaps be explained by
the fact that the chlorids are useful, not only in the construc-
tion of the organs, but also in the preparation of the digestive
secretions, and that those chlorids which have reached the in-
testine with the digestive secretions do not again become com-
pletely absorbed. It appears also that the chlorids are impor-
tant for renal secretion. The nitrogenous products of metabolism
cannot be eliminated simply in the form of aqueous solutions ;
the presence of chlorids is also necessary.^ This is shown by
the fact, among others, that diuretics also increase the excretion
of chlorin.

It follows that the inorganic constituents are all appropri-
ated by the epithelial cells of the mammary gland from the

^ Bunge, loc. cit., p. 324.

^ The chlorids are occasionally absent from the urine in certain febrile
diseases, especially in pneumonia. See Lecture XXVIII.

84

LECTÜEE VII

blood-plasma (which is of a totally different composition), in the
exact proportion required by the young animal for its develop-
ment into an organism like that of the parent.

This fact alone refutes all previous attempts at a mechanical
explanation of the activity of the glands. It cannot be objected
that the secretion of milk does not correspond with the compo-
sition of the sucking animal, but, on the contrary, that the tis-
sues of the latter are built up in accordance with the composition
of the milk ; for the incinerated puppies were only four days
old, and were therefore born with an ash of a composition cor-
responding to that of the ash of the milk. We also find a simi-
lar composition of the total ash as far down as the lower verte-
brates, which have no mammary glands.

We now know exactly what salts are required by the grow-
ing animal, and in what proportion each must be introduced.
We may now therefore ask whether the child, in passing from
milk to another form of diet, will continue to obtain these inor-
ganic salts in sufficient quantities. In answer to this question,
I give the following table containing the most reliable determi-
nations of the constituents of the ash of the most important
articles of diet, together with analyses of the ash of milk.
The articles of diet are arranged according to the ratio of lime
contained : —

In One Hundeed Pakts of Deied Substance the Peopoetions aee —

K^O.

Na^O.

CaO.

MgO.

Fe,03.

P.O..

01. 1

Beef

1.66

0.32

0.029

0.152

0.02

1.83

0.28

Wheat . . .

0.62

0.06

0.065

0.24

0.026

0.94

(?)

Potato . . .

2.28

0.11

0.100

0.19

0.042

0.64

0.13

Egg-albumin . .

1.44

1.45

0.130

0.13

0.026

0.20

1.32

Peas . .

1.13

0.03

0.137

0.22

0.024

0.99

(?)

Human milk .

0.58

0.17

0.243

0.05

0.003

0.35

0.32

Yolk of egg . .

0.27

0.17

0.380

0.06

0.040

1.90

0.35

Cow's milk . .

1.67

1.05

1.51

0.20

0.003

1.86

1.60

The above table shows that the other articles of food possess
all the inorganic constituents in as large or in a larger quan-
tity than milk. Lime is the only inorganic material which we
have to provide for in the choice of a child's food. If brought
up on meat and bread a child would probably not obtain the
lime requisite for the growth of its frame. The leguminosae
contain more ; but the only food which has the same amount

' The amount of chlorin in cereals and leguminosse has never yet been cor-
rectly determined, too low an estimate having been formed. Concerning this,
see Behaghel von Adlerskron, Zeitschr.f. analyt. Chem., vol. xii.: 1873.

THE INORGANIC FOOD-STUFFS 85

as milk is the yolk of egg, which should therefore always be
given to children when milk is either not procurable or cannot
be digested. Considerable quantities of lime occur in spring-
water, but it is not known whether these are assimilated. Lime
is found combined with organic substances in food ; it is there-
fore irrational to prescribe lime for children in the form of in-
organic compounds. In medical practice, rickety children are
constantly being ordered a couple of teaspoonfuls of lime-water.
This is useless, because the amount ordered is far too small. A
saturated solution of lime contains less lime than cow's milk.
In a pint of cow's milk I found 1.7 grm. CaO ; a pint of lime-
water contains only 1.3 grm. CaO.

The nature and causes of rickets are still quite unknown.
It is a fact that artificial feeding of growing animals on a diet
containing a little lime can produce a diminution of the salts of
lime in the bones, rendering them abnormally pliable and
brittle. It is also affirmed that in several experiments of this
nature true rickets has been produced with all the characteristics
of this disease.^ But it is equally a fact that children become
rickety who have never suffered from want of lime in their
food. In these cases it seems obvious to suppose that, owing
to disturbed digestion, the lime salts have not been adequately
absorbed ; ^ or that, in spite of adequate absorption, they
have not been assimilated owing to abnormal processes in
the bone-forming tissues. All speculation on the truth of
either theory is quite useless, until we have careful and reli-
able experiments on the metabolism of rickety children com-
pared with that of healthy ones of the same age, and brought up
on the same food. In spite of much experimental work on the
subject, all attempts to give a satisfactory explanation of the
causation of osteomalacia have been as unsuccessful as in the
case of rickets.^

Finally, the above table shows that cow's milk, compared
with organic food-stuffs, is much richer in inorganic salts than

^ Erwin Voit, Zeitschr. f. Biolog., vol. xvi. p. 55 : 1880. An account of the
previous literature will also be found here. See further, A. Baginsky, Virchow's
Arch., vol. Ixxxvii. p. 301 : 1882; and Seemann, Zeitschr. f. klin. Med., vol. v.
pp. 1, 152 : 1882.

2 In the researches on the absorbability of calcium compounds we meet with
the same difficulty as in the case of the iron compounds (see Lect. XXV.): the
greater part of the lime is excreted through the intestines, only a small propor-
tion finding its way into the urine. On this point compare Fr. Voit, Zeitschr. f.
Biolog., vol. xxix. p. 325 : 1893. Here also will be found an account of the
earlier work on the subject. Compare also Rudel, Arch. f. exper. Path. u. Pharm.,
vol. xxxiii., pp. 80 and 90, 1893.

^ H. Stilling and J. v. Mering, Centralbl. f. d. med. Wissensch., p. 803 :
1889 ; L. Gelpke, " Die Osteomalacic im Ergolzthale " : Basel, 1891.

86 LECTURE VII

human milk. This may be teleologically explained by the fact
that the calf grows much more rapidly than the infant. It is
therefore probable that the adult organism could exist with a
very small amount of salts ; m fact, it is ä priori difficult to
see what the constant addition of salts is required for. In-
organic salts serve a totally different purpose to the organic
food-stuffs. The latter act as sources of energy ; chemical
potential energy is introduced with them into our tissues, and
is converted by the decomposition and oxidation of these or-
ganic substances into all those forms of kinetic energy which
make up life as understood by our senses. They serve us by
the very fact of their decomposition. The necessity for their
constant renewal is not only a matter of experience ; it is also
at once apparent on ä j)riori grounds. Inorganic salts must be
regarded from a different point of view. These are already
saturated compounds of oxygen, or chlorids, which likewise
have no affinity for oxygen. No energy is set free in the
body by their decomposition and oxidation ; they can in no
way become used up and useless. Why therefore are they
renewed ? Even water behaves differently to the salts ; it as-
sists in the elimination of the waste products of metabolism.
The kidneys can only separate the nitrogenous substances
when in a watery solution. The diffusion of gases in the
lungs is only possible while the surface of the lungs is moist.
The expired air is saturated with watery vapor. The evapo-
ration of water from the surface of the skin plays a most im-
portant part in regulating the heat of the body. The ä priori
necessity for a constant supply of water is thus likewise evi-
dent. But it is otherwise with the salts. It is conceivable
that if only the organic aliments and water always entered the
organism in sufficient quantity, the inorganic salts arising from
the decay of the tissues might again be used in the reconstruc-
tion of the tissues. Even if a little waste were unavoidable, as
by excretion with the feces in consequence of incomplete ab-
sorption of the gastric juices, by the scaling off of the epidermis,
the loss of hair, &c., yet we might expect that the full-grown
organism would cling firmly to its store of salts, and would re-
quire but a very small additional supply. The constant supply
of salts in considerable quantities is not an ä priori necessity
for the adult.

We must therefore determine the question by experiment.
We might feed a full-grown animal for a long period exclu-
sively on organic food-stuffs and water, and ascertain the dis-
turbances that would occur, and the length of time it would live
on such a diet. This fundamental experiment in metabolism had,

THE INORGANIC FOOD-STUFFS 87

until quite recently, only once been made by Forster, Voit's
assistant in Munich.^

Forster met with insuperable difficulties when he tried to
obtain food free from ash. It is possible to get carbohydrates
and fats free from ash, but no one has yet succeeded in
separating proteid from all inorganic matter. Even crystal-
line proteid contains all the constituents of ash in small
quantity. Forster, in his experiments, employed the residue
of the meat left from the preparation of Liebig's extract of
meat. After boiling it repeatedly with distilled water and
drying, it still contained 0.8 per cent, of ash. Forster fed two
dogs on this proteid containing this small amount of salts, as
well as on fat, sugar, and starch-flour. He also fed three
pigeons on starch-flour and casein, which likewise contained
very little saline ingredient.

Forster observed that the animals died remarkably quickly
when fed on this diet. The three pigeons lived thirteen,
twenty-five, and twenty-nine days. One of the dogs was " so
ill at the end of thirty-six days that he would certainly have
died in a short time if the experiment had been continued,
while the other was dying at the end of twenty-six days."
When completely deprived of food, dogs live from forty to
sixty days. Food from which the organic salts have been re-
moved appears to be more rapidly fatal than the deprivation of
all food.

Forster concludes, from these experiments, that the full-
grown animal requires considerable quantities of inorganic
salts. An objection may however be raised to this conclusion,
for there is one condition to which Forster has omitted to draw
attention — I mean the formation of free sulphuric acid from
the sulphur of the proteid.

Proteid contains from J to 1 J per cent, of sulphur which,
in the decomposition and oxidation of proteid, is converted into
sulphuric acid. Eighty per cent, of the sulphur taken in food
appears in this form in the urine. Under normal conditions
this sulphuric acid is united with the bases which are taken up
with every form of animal and vegetable food. Animal food
contains basic phosphates of the alkalies, carbonates of the
alkalies, and alkali-albuminates ; vegetable food yields in addi-
tion the alkaline salts of vegetable acids, such as tartaric,,
citric, malic, &c., which in the organism are converted into
carbonates by oxidation. These bases saturate the sulphuric
acid formed from proteid. If the basic salts are removed from
the food, this powerful acid finds no bases at hand to neutralize

■'J. Forster, Zeitschr.f. Biolog., vol. is. p. 297: 1873.

88 LECTURE VII

it, and consequently attacks those bases which are integral
constituents of the living tissues ; figuratively, it may be said
to wrench individual bricks out of their places, and thus to
induce the destruction of the edifice,^ This appears to me to
be the cause of the rapid death in the animals experimented
upon by Forster. The remarkable fact that the dogs died in a
shorter time than when simply starved, would be explicable on
this ground.^ The correctness of this reasoning has been tested
experimentally by Lunin.^

Lunin fed a certain number of his animals with food de-
prived of its mineral constituents ; the others were treated in a
similar way, but with an addition of carbonate of soda which
was just sufficient to neutralize the sulphuric acid formed from
the sulphur of the proteid.

It was important to use as large a number of animals as
possible, in order to eliminate the influence of accidental
factors and thus arrive at a reliable result. Mice were there-
fore chosen for the purpose, since it would have been almost
impossible to obtain food free from mineral constituents in the
quantity requisite for a number of large animals.

The food was prepared in the following manner. By pre-
cipitating diluted milk with acetic acid, and washing the finely
flocculent coagulum with water acidified with acetic acid, a
mixture of fat and casein was obtained, which only contained
from .05 to .08 of ash in 100 parts of dry matter, therefore ten
times less salts than in the experiments of Forster. To this
mixture, cane sugar deprived of its ash was added as a repre-
sentative of the third group of food-stuffs.

On this food and distilled water, five mice lived eleven,
thirteen, fourteen, fifteen, and twenty-one days. Two mice
that were completely starved, lived four days : two more only
three days.

Again, six mice were fed upon the same food with the
addition of carbonate of soda. These lived sixteen, twenty-
three, twenty-four, twenty-six, twenty-seven, and thirty days,
therefore twice as long as the animals which had no base to
saturate the sulphuric acid formed.

^ As we shall see later on {vide Lecture XIX.), the organism of the dog is
able to protect itself against the injurious action of free acids, by splitting off
ammonia from the nitrogenous organic compounds. But this power is not
unlimited, and it is doubtful whether the ammonia is invariably present in the
particular cells in which the sulphuric acid thus liberated begins its work of
destruction.

2 G. Bunge, Zeitschr. f. Biolog., vol. x. p. 130: 1874.

3 N. Lunin (Bunge's laboratory), " Ueber die Bedeutung der anorganischen
Salze für die Ernährung des Thieres," Dissert.: Dorpat, 1880. Reprinted in
Zeitschr. f. physiol. Chem., vol. v. p. 31 : 1881.

THE INORGANIC FOOD-STUFFS 89

It might be objected that the animals lived longer, not be-
cause of the neutralization of the sulphuric acid, but because
they obtained at least one inorganic ingredient. This objection
is answered by the following experiment, in which seven mice
were given, ceteris paribus, instead of the carbonate of soda, an
equivalent quantity of chlorid of sodium — that is, a neutral
salt incapable of neutralizing the sulphuric acid. The seven
mice expired after six, ten, eleven, fifteen, sixteen, seventeen,
and twenty days. In this case, although they received two in-
organic substances, sodium and chlorin, they lived only half as
long as the animals which received but one, sodium, and in fact
no longer than the animals which had no inorganic addition at
all. The experiments were in complete accordance with my
deductions. As a control, two parallel series of experiments
with potassium chlorid and potassium carbonate were carried
out, and gave precisely the same results.

By preventing the formation of free sulphuric acid, the
animals lived twice as long, but still for a very short period. As
the action of the acid could not have caused their death, what
made the mice die ? Was the composition of the organic food-
stuffs insufficient? In order to decide this question, all the
inorganic salts of milk were added to the same artificial mixture
of organic food, in the exact proportions in which they exist
in the ash of milk, and in the same relation to the amount of
organic matter as in milk. Six mice lived twenty, twenty-three,
twenty-three, twenty-nine, thirty, and thirty-one days upon this
mixture — no longer than they did with the carbonate of soda
only. Of three mice which were fed exclusively on cow's milk,
one died after forty-seven days, and, as dissection showed, of in-
tussusception (compare p. 72) ; the two others lived in their
cage for two and a half months, grew considerably fatter, and
were in capital condition when the experiment ceased.

It is a noteworthy fact that, although animals can live on
milk alone, yet if all the constituents of milk which according
to the present teaching of physiology are necessary for the
maintenance of the organism be mixed together, the animals
rapidly die. Cannot cane sugar take the place of sugar of
milk ? Or are the inorganic and organic constituents of milk
chemically combined, and only assimilable in this combination ?
On precipitation of the casein by acetic acid, the small amount
of proteid in the milk remained in solution. Cannot this
proteid be replaced by the casein ? Or does milk contain, in
addition to proteid, fat, and carbohydrates, other organic sub-
stances, which are also indispensable to the maintenance of life?
It would be worth while to continue the experiments.

90 LECTURE VII

The question as to the need of adult anunals for inorganic
salts cannot be considered as settled. Before it can be decided,
we must become intimately acquainted with all the organic
food-stuffs Avhich are indispensable ; we must also manage to
combine them in such a way that they may be palatable to the
animals during lengthened experiments. Finally, we must be
able to saturate the sulphuric acid resulting from the proteid —
by means of a harmless organic base, such as cholin — without
the addition of inorganic bases. But even then it would prob-
ably be impossible to come to a decision, because it is beyond
our power to ensure the presence of the base at the spot where
the sulphuric acid is set free, or because the sulphates, formed
with the base thus artificially introduced, expel the normal salts
from the tissues. The difficulty appears for the present to be
insuperable.

There is only one inorganic salt about which I must add a
few words, because it holds a rather exceptional position — com-
mon salt.

It is a very remarkable fact that of all the inorganic salts
in our bodies we only take one with our organic food-stuffs,
and that is common salt. We obtain enough of all the other
salts from the amount contained in our food, and we never
think of providing ourselves with them separately. Common
salt forms the only exception, which is the more remarkable as
our diet is by no means deficient in it. All vegetable and
animal food contains considerable quantities of chlorin and
sodium. Why do these quantities not suffice, and why do we
add common salt?

In the earlier experiments made to decide this point, one
fact was quite overlooked, which appears to me likely to lead
to a correct solution of the difficulty. I mean the fact that
the desire for salt in the food was only observed in the case
of herbivora, and never in the case of Carnivora. Our car-
nivorous domestic animals, the dog and the cat, prefer unsalted
to salted food, and show great dislike to very salt food, while
the domesticated herbivora are well known to be very fond of
salt. The same thing has been observed in wild animals. It
is a known fact that wild ruminants and hoofed animals seek
out salt-rocks and pools, and places where salt effloresces, to lick
the salt, and that hunters watch for them at such places, or
expose salt as a bait. This has been noticed by numerous
travellers to hold good for herbivora of all countries and climates,
but it has never been observed in the case of beasts of prey.

The difference is the more striking as the amount of salt
which herbivorous animals take in with their food is, compared

THE INOEGANIC FOOD-STUFFS 91

with the weight of the body, generally not much less than that
consumed by carnivorous animals. On the other hand there is
a considerable difference in another constituent of the ash of
their food, in the potassium. Herbivorous animals take at
least three or four times as much of salts of potassium as the
Carnivora. This fact leads me to imagine that the abundance
of potassium in vegetable food is the cause of the need for salt
in the herbivora.

If, for instance, a salt of potassium, such as potassium
carbonate, meets with common salt or chlorid of sodium in
solution, a partial exchange takes place ; chlorid of potassium
and carbonate of sodium are formed. Now chlorid of sodium
is well known to be the chief constituent among the inorganic
salts of blood-plasma. When, therefore, salts of potassium
reach the blood by the absorption of food, an exchange takes
place. Chlorid of potassium and the sodium salt of the acid
which was combined with the potassium are formed. Instead
of the chlorid of sodium, therefore, the blood now contains
another sodium salt, which did not form part of the normal com-
position of the blood, or at any rate not in so large a proportion.
A foreign constituent or an excess of a normal constituent, i. e.,
sodium carbonate, has arisen in the blood. But the kidneys
possess the function of maintaining the same composition of the
blood, and of thus eliminating every abnormal constituent and
any excess of a normal constituent. The sodium salt formed is
therefore ejected by the kidneys, together with the chlorid of
potassium, and the blood becomes poorer in chlorin and
sodium. Common salt is therefore withdrawn from the or-
ganism by the ingestion of potassium salts. This loss can only be
made up from without, and this explains the fact that animals,
which live on a diet rich in potassium, have a longing for salt.

I have proved the correctness of this deduction by experi-
ment. To a diet of uniform character salts of potassium were
one day added, the consequence being a striking increase in
the excretion of chlorin and sodium. I have tried this experi-
ment on myself with all the salts of potassium which are
concerned in human nutrition. Eighteen grammes K,0, as
phosphate or citrate, divided into three doses during the day,
caused a loss to the body of 6 grms. of common salt, besides 2
grms. of sodium ; for the potassium salts effect an exchange,
not only with the chlorid, but also with other compounds of
sodium, as albuminate, carbonate, and phosphate.

The amount of potassium taken in these experiments was
not large — in fact, much less than that introduced with the
most important vegetable articles of diet ; and yet 6 grms. of

92 LECTURE VII

salt were withdrawn from the organism by it. This is about
one-half of the common salt which is contained in the 5 liters
of a man's blood. That other tissues likewise suffer by this
loss is undoubted. But in the first instance the"! blood is
chiefly affected, and I think that if this loss in the blood was
covered by a comparatively small loss in the other tissues, a
fresh addition of potassium must have the effect of producing
a fresh loss of sodium. Experiments of this kind have not
so far been made. It has not yet been ascertained up to
what point the body will continue to give up sodium, when
potassium is constantly taken. There is no doubt that a
point would soon be reached at which the body would stoutly
retain its remaining sodium.

But even those quantities of chlorin and sodium, the
loss of which I have specially investigated, appear to me
sufficiently large to account for the need to replace them
caused by eating vegetables containing an abundance of potas-
sium. Having regard to the important part which salt plays
in the organism (as in the formation of the digestive secretion,
or in dissolving the globulins), even a small diminution may be
prejudicial to certain functions, and may give rise to the need of
recovering the loss.

As already mentioned, the amount of potassium taken in
my experiments was not more than 18 grms. A man who
lives chiefly on potatoes takes, in the course of the day, up
to 40 grms. of potassium. This shows why potatoes are so
unpalatable without salt, and are eaten everywhere with well-
salted adjuncts. Like potatoes, all the other important vege-
table articles of diet, the cereals and leguminosse, are very rich
in potassium, and this explains the fact that country people, liv-
ing mainly on a vegetable diet, use more salt than the inhabi-
tants of towns, who eat a great deal of animal food. It has
been statistically shown in France that people living in the
country eat three times as much salt per head as those in towns.

We may now ask what the people do who take no vegetable
food at all. There are whole tribes of hunters, fishermen, and
other nomads, who live entirely on animal food. We might
expect that these people would, like the carnivorous animals,
have a disinclination for salt. This is in fact the case. In
order to ascertain this, I have gone through a very large
number of works of travel, and have obtained a great deal of
information from recent travellers, either personally or by
letter. From all this it appears to be a universal rule that in
all times and in all lands those people who live entirely upon
animal food either have never heard of salt, or, if they possess

THE INOEGANIC FOOD-STUFFS 93

it, avoid it ; . whereas the people whose staple food is vegetable
have the greatest desire for it, and regard it as an indispensable
article of diet.

This difference was manifested as far back as the ancient
Greek and Roman times, when the sacrificial animals were
always offered to the gods without salt, but the fruits of the
earth with salt. The Mosaic law expressly commanded the
Jews to present their vegetable offerings accompanied by salt
to their Deity.^

The Indo-Germanic languages have no common word for
salt, just as they have none for farming industries, whereas
the terms used in cattle-breeding may mostly be traced back
to common roots. This probably shows that the Indo-Ger-
manic tribes knew nothing about salt so long as they were
wandering about — an undifferentiated nation — pasturing their
flocks on the summit and slopes of the mighty Bulur-Tagh.
They first became acquainted with it after their dispersion,
when they began farming and took to vegetable food. In
the time depicted by Tacitus, we find the Germans just
adopting fixed places of abode, and beginning to devote
themselves to agriculture. But at this time they did not
know how to obtain a regular supply of salt, although the
desire for it was already awakened in them, since Tacitus gives
accounts of raging and decimating wars, which were carried on
by different tribes for the possession of the salt-mines on the
frontiers.

The Finnish languages have up to the present day no word
for salt. The western Finlanders, who are now engaged in
farming, use salt and call it by the German name. On the
other hand the eastern Finlanders, who still lead hunters' and
nomads' lives, use no salt whatever, and this is the case with
all the other hunting, fishing, and nomadic tribes in the north
of Eussia and in Siberia. It is not because they are un-
acquainted with salt, or cannot procure it, but because they
have a decided dislike to it. In all parts of Siberia there
are rock-salt strata, salt lakes, and salt efilorescences. The
Siberian hunters are only interested in these salt strata be-
cause the flocks of reindeer assemble in these places to lick the
salt ; the hunters themselves devour their meat without it. A
large number of Siberian travellers have informed me, both
personally and by letter, that such is the case with all
the Siberian tribes. The mineralogist, C. von Ditmar, who

^ The sources of these and all following statements concerning the use of
salt among different nations are quoted in my work, " Ethnologischer Nachtrag
zur Abhandlung über die Bedeutung des Kochsalzes, u. s. w.," Zeitschr. f. Biolog. ,
vol. X. p. 111 : 1874.

94 LECTURE VI!

travelled over the whole of Siberia between 1851 and 1856,
and lived for a long time among the Kamtschadales, writes to
me as follows : " I have frequently in my travels, given those
people (Kamtschadales, Korachs, Tschuktsches, Ainos, Tun-
guses) some of my salted viands to taste, and have noticed the
grimaces they made, showing how much they disliked it."
Ditmar relates how the Kamtschadales live chiefly on fish,
which they throw into large holes dug in the ground, where
the whole mass is soon turned into a " stinking jelly." The
Russian Government, disapproving of the Kamtschadales'
favorite food, which is certainly disgusting to any European
and must be unwholesome, endeavored to introduce the salt-
ing of fish by stringent regulations. Arrangements were made
at Petropaulowski for obtaining salt from sea-water, and the
salt was sold to the Kamtschadales at a nominal price. The
Kamtschadales, who are an uncommonly docile race, obeyed
orders, and the fish was conscientiously salted. But they did
not eat it. They kept to their decomposing fish ; and at the
time that Ditmar was in Kamschatka, the Russian Govern-
ment had relinquished the task of persuading them as hopeless.
Only the old people still spoke of that period as of a time of
plague. Ditmar relates that the descendants of the Russians
in Kamschatka do cultivate European vegetables, but only in
small quantities, that they prefer the Kamtschadales' bill of
fare, and accordingly their use of salt has gradually diminished.
Vegetables and cereals are only eaten in any quantity in Petro-
paulowski, and here, on the other hand, the salt-cellar is always
on the table.

The astronomer, L. Schwarz, informed me that on his
travels in the country of the Tunguses, he lived exclusively on
reindeer-flesh and game. This diet agreed perfectly with him,
and he never experienced any wish for salt.

But as it might be thought that the disinclination of the
Siberian tribes for salt might be due, not to the animal food,
but to the northern climate, I will refer to the accounts of the
inhabitants of warm countries who live on an animal diet, and
yet take no salt.

In the Neilgherry Hills in India, a pastoral tribe, the Tudas,
was first discovered during the present century. Owing to
their being surrounded by fever marshes, the English had al-
ways been prevented reaching them. They were totally unac-
quainted with vegetable food, and lived on milk and bufiFalo-
meat, knowing nothing of salt.

The Kirghese also live on meat and milk, and never use
salt, although they are inhabitants of the salt steppes. I was

THE lis ORGANIC FOOD-STUFFS 95

informed of .this by Baron Maydell, who travelled through the
Kirghese Steppes in 1845 and in 1847.

Sallust relates the same thing of the Numidians : " Numidse
plerumque lacte et ferina carne vescebantur et neque salem
neque alia irritamenta gulae quserebant." There is an abun-
dance of salt on the north coast of Africa.

At present there are certain tribes of Bedouins in Arabia
who live under conditions similar to those of the Numidians in
the time of Sallust. In Wrede's Travels it is stated that the
Bedouins eat meat without salt, and appear to consider the use
of salt as altogether ridiculous.

The Bushmen in the south of Africa live by the chase, and
do not use any salt.

The negro races on the contrary are agriculturists. The
interior of Africa contains but little salt. At the present time
the negroes are plentifully supplied with salt, both by importa-
tion and by salt-boiling on the coast. Among the older trav-
ellers, Mungo Park gives the following description of the
longing of the negroes for salt : " In the districts of the in-
terior, salt is the greatest of all delicacies. It strikes a Euro-
pean very strangely to observe a child sucking a piece of rock-
salt as if it were sugar. I have frequently seen this done,
although the poorer class of inhabitants in the interior are so
badly provided with this costly article, that to say that a man eats
salt with his meal is equivalent to saying that he is rich. I my-
self have found the scarcity of this natural product very trying.
Constant vegetable food causes a painful longing for salt that
is quite indescribable. On the coast of Sierra Leone the desire
for salt was so keen among the negroes that they gave away
wives, children, and everything that was dear to them, in return
for it."

The Indians of North America are well known to have been
hunters and fishermen at the time of their discovery ; they did
not use salt, although the North American prairies are full of it.
Only a few tribes on the lower course of the Mississippi were
diligent tillers of the soil at the time of the first invasion of the
Spaniards. It is related of these tribes that they waged wars
about the salt-springs.

The Mexicans were farmers, and understood the methods of
obtaining salt. The same account is given of the natives whom
Columbus met with in the West Indian Islands.

The shepherds of the South American pampas, who live
entirely on meat and regard vegetable food as fit only for
animals, do not use any salt, although the pampas abound in
numberless salt-lakes and incrustations. The neighboring

96 . LECTURE vn

Araucanians, on the other hand, who were farmers at the time
of the discovery of America, made use both of sea-salt and rock-
salt. The inhabitants of New Holland were hunters, and em-
ployed no salt.

Most of the tribes of Australia and of the East Indian
Archipelago live on a mixed diet, and get enough salt from the
marine animals that they eat. But there is an account of one
purely agricultural tribe in the tropical islands, where the
people live almost exclusively on the produce of the field, which
is rich in potassium. They are the Battas in Sumatra. We
should expect that these people would have a great desire for
salt. For a long time I was unable to find any account about
it in any books of travel, till at last I lighted upon a passage in
a chapter describing then" modes of legal procedure, in which it
said that the solemn form of oath in use among them ran as fol-
lows : " May my harvest fail, my cattle die, and may I never
taste salt again, if I do not speak the truth."

From the above facts we see that at every period, in
every part of the world, and in every climate, there are
people who use salt as well as those who do not. The
people who take salt, though differing from each other in
every other respect, are all characterized by a vegetable diet ;
in the same way, those who do not use any salt are all alike
in taking animal food. We see that whole tribes, when
forsaking their nomadic life for an agricultural one, begin the
use of salt ; and that, vice versa, people who have been
accustomed to take salt, cease to do so when they emigrate
and settle down among a flesh-eating population. We see
that European travellers, if their supply of salt fails them in
foreign countries, do not feel any want of it if they are living
on animal food ; but that, on the other hand, they experience
" a painful longing " for it if they adopt a vegetarian mode of
diet. The causal connection between vegetable food and the
need for salt is undeniable. It might be still doubted whether
it is really the abundance of potassium in the vegetables which
causes this need. The occurrence of potassium in considerable
quantity is not the only difference between vegetable and ani-
mal food. The following facts may serve to confirm my view
of the matter : —

One important article of vegetable diet, rice, is very poor in
potassium salts. Rice contains six times less potassium than
the European cereals (wheat, rye, barley), from ten to twenty
times less than the leguminosse, and from twenty to thirty
times less than the potato. If we consume enough rice to
yield 100 grms. of proteid, we only take in 1 grm. K2O from

THE INORGANIC FOOD-STUFFS

97

the same source. But if we consume 100 grms. of proteid in
the form of potatoes, we should at the same time obtain above
40 grms. K^O. We should therefore expect people who only
take rice and no other vegetable with their meat to have no
desire for salt. This is in fact the case, and is universally re-
corded of certain tribes of Bedouins on the Arabian Peninsula,
and of a few races in the East Indian Islands.

L. Lapicque has objected to my hypothesis on the grounds
that certain negro races, who can obtain no common salt, use
instead as an adjunct to their vegetable food the ashes of a
plant consisting chiefly of potassium salts. I cannot regard my
hypothesis as controverted by this fact, unless it were shown
that these negroes had a choice between common salt and salts
of potash and gave the preference to the latter. If however
they are driven by need to the potash salts, it is possible that
we have here merely an example of disordered instinct, for
which we have other analogies. A man who has always taken
alcohol instead of water to quench his thirst prefers the former
to the latter, although the alcohol has the effect of increasing
rather than of diminishing his thirst.

The amount of potassium and sodium in the different articles
of vegetable and animal food eaten by man and animals may be
gathered from the following tables :

TABLE I.
In 1000 Pakts of Dried Stjbstakces the Proportions are —

Arranged according to increasing amount
of potassium.

Arranged according to increasing
amountj,of sodium.

Kice .

Bullock's blood .
Oats )
Wheat I

Eye • • • •

Barley i

Dog's milk . . .
Human milk . .

Apples

Peas . . . .
Milk of herbivora

Hay

Beef

Beans

Strawberries . .

Clover

Potatoes ....

K,0.

1

2

5-6

5-6
5-6
11
12

9-17
6-18
19
21
22
23
20-28

Na,0.

0.03
19.0

0.1- 0.4

2.0- 3.0
1.0- 2.0

0.1

0.2
1.0-10.0
0.3- 1.5

3.0

0.1

0.2

0.1
0.3- 0.6

Rice

Apples . . . . .

Beans

Peas

Clover

Oats "I
Wheat I

Barley ( • • ■ •
Eye J

Potatoes

Hay . . . . .
Human milk . . .
Dog's milk . . ,
Milk of herbivora

Beef

Bullock's blood .

Na,0.

0.03
0.07
0.13
0.17
0.17

0.1- 0.4

0.3-
0.3- 1.5
1.0- 2.0
2.0- 3.0
1.0-10.0
3.0

19.0

98

LECTTJEE VII

We see from the second table that the beast of prey, which
devours every part of an animal, obtains potassium and so-
dium in almost equal quantity. This is the case, not only with
mammals, but with the whole class of vertebrates.^ On the
other hand, four equivalents of potassium are present for every
equivalent of sodium in the bloodless meat of slaughtered ani-
mals. It is therefore noteworthy that the people who live on
an animal diet without salt, carefully avoid loss of blood when
they slaughter the animals. This was told me by four dif-
ferent naturalists, who have lived among flesh-eaters in various
parts of northern Russia and Siberia. The Samoyedes, when
dining off reindeer-flesh, dip every mouthful in blood be-
fore eating it. The Esquimaux, in Greenland, are said to
plug the wound as soon as they have killed a seal.^ Among
the Masai, a tribe of eastern equatorial Africa, who during
their period as warriors from seventeen to twenty-four years
of age, live exclusively on an animal diet without salt, blood is
regarded as the choicest and most desirable of all articles of
food.^

TABLE II.
Foe One EquivAiiENT NAjO the Equivalents of KjO are

Bullock's blood
Egg-albumin . . .
Yolk of egg . . .
The wbole body of mam

mals . . .

Milk of Carnivora .
Mangel-wurzel . .
Human milk
Milk of herbivora .

Beef

Wheat

Equivalent
K,0

0.07

0.7
1.0

0.7- 1.3
0.8- 1.6

2.0
1.0- 4.0
0.8- 6.0

4.0
12.0-23.0

Barley . .

Oats . . .

Rice . . .

Eye

Hay

Potatoes

Peas

Strawberries

Clover

Apples . .

Beans . . .

Equivalent
K,0

14-21

15-21

24

9-57

3-57

31-42

44-50

71

90

100

110

The two bases are also contained in the milk of Carnivora
in equal proportions, whereas potassium generally preponde-
rates largely in the milk of herbivora and in human milk, as

1 A. von Bezold, "Das chemische Skelett der Wirbelthiere," Zcitschr. für
wissenschaftl. Zoologie, vol. ix. p. 241 : 1858 ; G. Bunge, Zeitschr. f. Biolog., vol.
X. p. .318 : 1874.

2 The exact source of these facts is given in the Zeitschr. f. Biolog., vol. x. p.
11.5 (note) : 1874.

3 Vide H. H. Johnston, " Kilimandjaro."

THE INOEGANIC FOOD-STUFFS 99

may be seen by a reference to Table II. This shows that man
and herbivora can do very well on a diet, in which the relation
is from four to six equivalents of potassium to one equivalent
of sodium, without any addition of salt. And there are many
vegetables in which the proportion is no higher. In hay,
which is a mixture of all kinds of herbage, the proportion is
sometimes, as the above table shows, only as three to one. It
is a fact that many wild herbivorous mammals, such as hares
and rabbits, never eat salt, and in many places it is not offered
to herbivorous domestic mammals. A keen desire for salt would
only be awakened in these animals if they were exclusively fed
on one of the varieties of herbage containing both the most
potassium and the least sodium, such as clover. The wild
herbivora perhaps instinctively avoid browsing only on the
herbage that contains the largest proportion of potassium.
But the domesticated animals would suffer if they were given
food that was very rich in potassium, without salt. I will not
affirm that they could not exist under this treatment, although
farmers have found by experience that the animals eat more
and thrive better if they are allowed to have salt, and even
that obvious ill-effects follow a complete abstinence from this
article.^ Nor do I maintain that human beings cannot exist
without salt on a diet almost entirely vegetarian. But if we
had no salt, we should have a strong disinclination to eat large
quantities of a vegetable rich in potassium, such as potatoes.
The use of salt enables us to employ a larger variety of the
earth's products as food than we could without it.

It is particularly worthy of note that those articles of diet
in which, according to Table II., the proportion of potassium
to sodium is the highest, such as rye, potatoes, peas, and beans,
are the very ones that form the staple food of the lower classes
in Europe. The injustice of a salt-tax is therefore apparent,
for the poorer a man is the more he is forced to live on the
vegetables containing the largest amount of potassium, and the
greater his consumption of salt in consequence.

In passing, I must call attention to the fact that we are
accustomed to take far too much salt with our viands. Salt is
not only an aliment, it is also a condiment, and easily lends
itself, as all such things do, to abuse. A glance at Table III.
shows us how little salt need be added to most articles of diet

1 Barral, " Statique chimique des animaux, appliquee speeialement ä la
question de I'emploi agricole du sei " : Paris, 1850 ; Boussingault, Ann. de Chim.
et de Phys., ser. Ill, vol. xxii. p. 116: 1848. Demesmay, Journal des J^cono-
mistes, vol. xxv. pp. 7, 251: 1849; Desaive, " Ueber den vielseitigen Nutzen
des Salzes in der Landwirthschaft," Deutsch von Protz : Leipzig, 1852.

100

LECTUEE VII

in order to preserve the same proportion of the alkalies as ia
milk. For instance, from 1 to 2 grms. of salt in the day
would be sufficient to add to a diet of cereals and legumiaosse,
or a few decigrammes to a diet of rice. Instead of this, most
people take from 20 to 30 grms. daily, and frequently even
more.

TABLE III.

Fob evilry One Hundred Gems, op Proteid we get —

•

K.O.

Na„0.

Bullock's blood

Eice

Beef. ...

Wheat )

Eye [

0.2 grms.
1.0 "
2.0 "

2.0-5.0 "

5.0-6.0 "
42 "

2.0 grms.
0.03 "
0.3

0.05-0.3 "

Peas J

Human milk

1.0 -2.4 "

Potatoes

0.7 "

We must ask whether our kidneys are really able to
eleminate such large quantities of salt ? Do we not impose too
great a task upon them, and may it not be fraught with
serious consequences ? When on a diet of meat and bread,
without salt, we excrete not more than from 6 to 8 grms. of
alkaline salts in twenty-four hours. With a diet of potatoes,
and a corresponding addition of salt, over 100 grms. of
alkaline salts pass through the kidneys in the day. May not
there be danger in this ? The habit of drinking spirituous
liquors, which moreover is reckoned one of the causes of
chronic nephritis, also brings about the immoderate use of
salt,^ and thus one sin against nature leads to another. These
are questions to which I would direct the attention of practi-
tioners.

There is no organ in our body so mercilessly ill treated as
the kidneys. The stomach reacts against overloading. The
kidneys are obliged to let everything pass through them, and
the harm done to them is not felt till it is too late to avoid the
evil consequences.

I would further call attention to the slight amount of
work that devolves upon the kidneys when rice is the staple
food. Only 2 grms. of alkaline salts are excreted in twenty-

1 Compare H. Keller (Bunge's laboratory), ^ez^scAr. f.physiol. Chem., vol.
xiii. pp. 130 and 134 : 1889.

THE INOBGANIC FOOD-STUFFS 101

four hours. . The superiority of rice (which has for centuries
been the food of the majority of mankind — Persians, Indians,
Chinese, Japanese) over potato is evident. Should not rice
be employed as a chief article of diet in patients with renal
disease? The same with affections of the stomach, for the
potassium salts act as a powerful irritant to the gastric mucous
membrane,' and rice contains less of these than any other article
of food.

I cannot leave this subject without, in conclusion, giving
expression to one other theory which is becoming more and
more a conviction with me, and in proof of which I have car-
ried out a series of troublesome experiments. I have not
hitherto ventured to publish them, because I was well aware
that the theory might be thought very fanciful while the
grounds upon which it was built were still so scanty. I am
however convinced that the remarkably high percentage of
salt in vertebrate animals, as well as the desire to take salt
with our food, can only be satisfactorily explained by the theory
of evolution.

Let us glance at the distribution of the two alkalies, po-
tassium and sodium, over the whole surface of the globe. In
our introductory remarks on the circulation of the elements, I
mentioned the struggle that went on between the carbonic acid
and the silicic acid for the possession of the bases (see p. 15).
In this conflict the carbonic acid shows a greater affinity for
sodium, and the silicic acid for potassium. By the action of
the weather on silicic rocks, the sodium, after decomposition,
is dissolved in water as a carbonate, and trickles with the
water into the ground. The potassium on the contrary, with
other bases, especially alumina, remains combined with the
silicic acid, and continues to lie on the surface as an insoluble
double salt. When the sodium carbonate reaches the sea by
means of springs, streams, and rivers, it is converted by the
chlorids of the alkaline earths into common salt, the insoluble
carbonates of the alkaline earths are formed, which sink to
the bottom, and are continually building up whole mountain
ranges in the shape of lime, chalk, and dolomite. Sea- water is
thus rich in common salt, poor in potassium salts, while the
surface of dry land is rich in potassium salts and poor in
common salt.

The amount of common salt in the organism corresponds
with the amount in the environment. Sodium differs in this
respect from potassium, which is an integral, indispensable

^G. Bunge, Zeitschr.f. Biolog., vol. ix. p. 130: 1873; and Pfliiger's Arch.,
vol. iv. pp. 277, 280: 1871.

102 LECTURE VII

constituent of every vegetable and animal cell. Every cell
has the power of withdrawing and of assimilating the requisite
amount of this base, even from the most scantily supplied soil.
All sea and land plants therefore contain an abundance of
potassium. Sodium on the other hand does not appear to play
such an important part. Many plants contain only traces of
sodium ; those which are rich in it are only the sea-weeds and
the plants which grow on the sea-shore, and on the salt steppes
which are dried-up sea-basins. There are only a few apparent
exceptions to this rule, as for instance in the classes of Cheno-
podium and Atriplex. But these species thrive only in a
saline soil ; they are closely allied to the denizens of the salt
steppes, and have probably migrated from there. Among cul-
tivated plants, the Beta altissima, which also belongs to the
Chenopodiacese, is the only one rich in sodium, and this was
originally indigenous on the sea-coast.

This is also the case with invertebrate animals ; only those
which live in the sea, and those nearest allied to them on land,
contain much salt. The typical representatives of land inverte-
brates, the insects, have very little salt in them. I have myself
made an analysis which proves that they do not contain more
sodium than the plants from which they derive their nourish-
ment.

The land vertebrates are all remarkably rich in salt, in spite
of the scanty supply around them. But even these are only
apparent exceptions. We need but remember the fact that the
first vertebrates on our planet all lived in the sea. Is not the
large amount of chlorid of sodium found in the present inhabi-
tants of dry land another proof of the genealogical connection
which we are forced to accept from morphological facts ? There
is no doubt that each of us in his individual development has
gone through a stage in which he still possessed the chorda
dorsalis and the branchial arches of his sea-dwelling ancestors.
Why may not the high average of salt in our tissues be also in-
herited from them ?

If this interpretation be correct, we should expect that the
younger the vertebrates are in their individual development,
the more salt they would possess. This is in fact the case. I
have convinced myself by numerous experiments that an
embryo of a mammal contains more salt than a new-bom
animal, and that it gradually becomes, after birth, poorer in
chlorin and sodium as it develops. Cartilage contains the
most sodium of any tissue in our bodies, besides being also the
tissue of greatest antiquity. It is histologically identical
with the tissue which still survives in the skeleton of the

THE INOEGAJSriC FOOD-STUFFS 103

Selachians, -a salt-water animal, during its whole life. The
human skeleton, as every one knows, is originally also composed
of cartilage, and even before birth much of this is replaced by
bone. This phenomenon cannot be understood on teleological
grounds; it can only be explained by the theory of evolution.
We cannot assume that the cartilage period must be passed
through in order that the bone may develop from the cartilage.
This is not the fact. Bone does not arise from cartilage.
The cartilage is entirely absorbed, and the bone grows from
the perichondrium to take the place of the cartilage. And
moreover the oldest formation, the cartilage, also contains the
largest proportion of sodium.

These are facts which lead most readily to the interpreta-
tion that the vertebrates living on dry land originally came
from the sea, and are still continuing to adapt themselves to
their present surroundings, where they can get but little salt.
We prolong this process of acclimatization by taking advantage
of the salt strata which have been left on the land by our
primeval element, the salt flood.

LECTURE VIII

MILK AND THE FOOD OF INFANTS

We have already had occasion in considering food-stuffs to
make frequent mention of milk, the nourishment which nature
provides for the growing organism, and we may now consider
this subject more in detail.

In the following table I give the results of the analyses of
milk/ so far as they have been carried out up to the present
time : —

One Hundred Parts of Mix,k Contain —

HumaQ.

Dog.

Cat

Rabbit

Guinea-

Sow

Elephant.

I.

II.

III.

pig-

Casein

_

1.2

_

5.2

3.1

_

_

_

_

Albumin .

—

0.5

—

1.9

6.4

—

—

—

—

Total Proteids . . .

1.7

1.7

1.5

7.1

9.5

15.5

11.2

5.9

3.1

Fat . .

3.1

3.8

3.3

12.5

3.3

10.5

45.8

6.9

19.6

Sugar of milk

5.9

6.0

6.5

3.5

4.9

2.0

1.3

3.8

8.8

Ash

0.2

0.2

0.3

1.3

0.6

2.6

0.6

1.1

0.7

' In the cases of mare's, cow's, goat's, and sheep's milk, I have taken the
average figures as calculated by J. König in his "Chemistry of Human Food-
stuffs," 3d edition, Berlin, 1889. The few older and less reliable analyses have
been superseded by the numerous later ones carried out according to accurate
methods. For sow's milk I have, in calculating the average composition, adopted
only the last four of König's nine analyses since the earlier analyses, in con-
sequence of the incomplete extraction of the casein precipitate with ether,
obviously give too small an amount of fat and too large a one of casein. For the
same reason I have only employed for dog's milk two analyses of my pupil Fr.
Pröscher, in which the fat was completely extracted by means of the Soxhlet
apparatus {Zeitschr. f. physiol. Chem., vol. xxiv. p. 290: 1897). The analysis
of rabbit's milk is by A. Pizzi {Le staz. sperim. agric. ital., vol. xxvi. p. 615 :
1894) ; that of reindeer milk by Fr. Werenskiold {Chemikerzeitung, vol. xix.,
1895) ; that of porpoise milk by Frankland {The Chemical News, vol. Ixi. p.
63: 1890). The mean figures for the milk of the remaining animals are
reckoned from the small number of analyses which have so far been made and
are to be found in König's work. Finally, as regards human milk, nearly all
the analyses have been carried out by inaccurate methods. After close in-
vestigation, it seems to me that the analyses of the following authors are the
most worthy of confidence : (1) Emil Pfeiffer, Jahrb. f. Kinderheilkunde, vol. xx.
p. 389: 1883; (2) .lulius Lehmann, Pflüger's Arch., vol. Ivi. p. 577: 1894; (3)
Söldner, Zeitschr. f. Biolog., vol. xxxiii. p. 66 : 1896. The average compositions
obtained by these three authors are given separately in the following tables as

104

MILK AND THE FOOD OF INFANTS

105

One Hundred Pakts of Milk Contain (continued)-

Horse.

Don-
key.

Cow.

Goat.

Sheep.

Rein-
deer.

Camel.

Llama.

Porpoise.

( Glohiocephalus

melas.)

Casein ....

1.2

0.7

3.0

3.2

5.0

8.4

3.0

Albumin . . .

0.8

1.6

0.5

1.1

1.6

2.0

—

0.9

—

Total Proteids .

2.0

2.2

3.5

4.3

6.5

10.4

4.0

3.9

7.61

Fat.

1.2

1.6

3.7

4.8

6.9

17.1

3.1

3.2

43.8

Sugar of milk .

5.7

6.0

4.9

4.5

4.9

2.8

5.6

5.6

—

Ash

0.4

0.5

0.7

0.8

0.9

1.5

0.8

0.8

0.5

ANALYSES OF ASH.
One Thousand Parts of Milk Contain-

Man.

Dog.

Horse.

Cow.

Goat.

Sheep.

KjO

0.780

1.41

1.05

1.77

2.35

1.17

Na^O

0.232

0.81

0.14

1.11

0.52

1.08

CaO

0.328

4.53

1.24

1.60

2.10

2.72

MgO .......

0.064

0.20

0.13

0.21

0.36

0.50

FejOs

0.004

0.02

0.02

0.004

0.015

0.04

P2O5

0.473

4.93

1.31

1.97

3.22

4.12

CI

0.438

1.63

0.31

1.70

2.04

1.34

The composition of the milk in various mammals is thus very-
striking in its variability. So far as I know, no attempt has
been made to explain this diflPerence. It appears to me that a
teleological explanation may be found in the diiferent rate of
growth of the sucklings. It is a plausible conjecture that a
more rapidly growing animal needs a milk richer in those con-
stituents which serve particularly to build up tissue — proteid
and inorganic salts. This connection appeared in the analyses
of milk ^ which I published in 1874.

One Hundred Parts of Milk Contained —

Proteid.

Ash.

Human

1.4

1.8
4.0
9.9

0.22

Horse ....

0.41

Cow

0.80

Doff

1.31

Nos. I., II., and III. It speaks well for these figures that, although obtained by
very different methods, they all agree well with each other. The analyses of
the ash are obtained from G. Bunge, Zeitschr. f. Biolog., vol. x. p. 295: 1874;
and from Fr. Pröscher, loc. cit.

^ Proteids and sugar of milk.

2 G. Bunge, Zeitschr. f. Biolog., vol. x. p. 295: 1874.

106

LECTUEE VIII

Now it is well known that the infant grows more slowly than
the foal, the foal than the calf, the calf than the dog. In order
to see whether this theory held good universally I suggested
to Mr. Pröscher that he should estimate the rapidity of growth
of the domestic animals during lactation, as so far the weights
at different periods had only been ascertained in the case of
infants, foals, and calves.^ In the following table I give the
results of these weighings as well as the most reliable average
figures of the proteid and ash of the milk. Of the constituents
of the ash, the amounts of phosphoric acid and lime are par-
ticularly mentioned, since these substances are especially con-
cerned in the building up of the tissues. The alkaline chlorids
stand in a different position, and play an important part in
excretion.^

One Hundred Parts of Milk Contain —

Time in which the body-weight

of the uew-born animal

was doubled.

Proteid.

Ash.

Lime.

Phosphoric
acid.

Man 180 days

Horse . . 60 "

Cow. . . 47 "

Goat . . 19 "

Pig. 18 "

Sheep 10 "

Dog. . . 8 "

Cat . . . 7 "

1.6
2.0
3.5
4.3
5.9
6.5
7.1
9.5

0.2
0.4
0.7
0.8

0.9
1.3

0.328
1.24
1.60
2.10

2.72
4.53

0.473
1.31
1.97
3.22

4.12
4.93

These results thus confirm in a striking manner the sug-
gestion which was put forward above. The agreement would
perhaps be still more complete if the specimens of milk
analyzed had all been taken at the time that the weight
was first doubled. A sample of the milk should be analyzed
every day from the date of birth until that on which the
weight was doubled, and the average of these analyses taken.
For instance, the amount of proteid and ash in the milk
diminishes with the duration of lactation. The suckling grows
the most rapidly directly after birth, and increases in weight
by degrees more and more slowly. The composition of the
milk varies in accordance with the growth. The same law
which we have laid down in the case of the various mammals
also holds good for the various stages of development in the
individual. My attention was directed to their connection by

iFr. Pröscher, Zeitschr. f. Biolog., vol. xxiv. p. 285: 1897.
2 Compare the agreement in the composition of the ash of milk and that of
the suckling discussed in the last chapter.

MILK AND THE FOOD OF INFANTS 107

an analysis -of milk published in 1874. Thus in one woman
during the first month after birth the milk contained 1 5 per
mille proteid, whereas in the tenth month the amount had
dropped to 9 per mille ; the proportion of ash having likewise
decreased.^ The diminution of proteid in the milk as lactation
proceeds has also been observed and tabulated by other authors
for man and animals.^

It has long been known that the proportion of proteid in
milk is very large from the first to the third day after birth,
and this may be recognized without any quantitative estimation
from the fact that this milk, to which the name of colostrum
has been given, coagulates on boiling. As a practical result of
this fact, a wet nurse can never completely replace the mother
unless her infant has been born on the same day as her foster
child.

As regards the remarkable difference in the amounts of fat
and sugar in the milk of various animals, we might anticipate
that here climate might have the same influence that we have
seen it to possess for the food of man in cold and hot coun-
tries. As already mentioned, people in cold regions instinc-
tively adopt a diet rich in fat and poor in sugar, while the
converse is the case among the inhabitants of warm countries.
Correspondingly we find the milk of animals which originally
lived in a warm climate, rich in sugar and poor in fat (camel,
llama, horse, donkeyj, while the milk of animals inhabiting
the North is rich in fat and poor in sugar (reindeer). The
composition of human milk shows that the human race was
cradled in the warmer regions of the earth and supports a
hypothesis which is based on many other grounds. The ex-
ception to this rule, e. g., the higher percentage of fat in the
milk of the elephant, a native of southern climes, may be more
apparent than real. It is possible that the elephant may be de-
scended from a northern ancestor, since the mammoth is known
to have lived during the diluvial period in the present home of
the reindeer. The elephant may therefore have emigrated
southwards and have partially preserved the original compo-
sition of the milk. A thorough comparative analysis of the
milk of all mammals may perhaps be the means in the future
of controlling all the conclusions which have been arrived at
by comparative anatomists, paleontologists, systematists, and
natural historians.

The high percentage of fat in the milk of the dolphin

1 G. Bunge, loc. cit., pp. 316 and 317.
_ ^Th. Brunner, Pfliiger's Arch., vol. vii. p. 440: 1873; Siedamgrotzky u. Hof-
meister, Mitth. a. d. chtm. physiol. Versuchsst. d. Thierarzneischule in Dresden,
1879. H. Weiske u. G. Kennepohl, Journ f. Landw., vol. xxix. p. 451 : 1881.

108 LECTURE VIII

(^Globiocephalus melas) (three times as much as in that of the
reindeer) may be explained on two grounds, firstly, that it lives
in high latitudes, and secondly, that, being an aquatic animal, it
is surrounded by a better conductor of heat than is the case with
animals that live on land, and so needs for the maintenance of
its temperature a higher proportion of the food-stuff with the
greatest potential energy, i. e., fat.

The great amount of fat in the milk of guinea-pigs cannot
be explained in this way, since these animals come originally
from a tropical country — Peru. From the first day of birth the
guinea-pig picks up its own food by the mother's side. The milk
in this case plays but a secondary part therefore in its nutrition,
and only supplies a welcome addition to the vegetable food so
deficient in fat.

These observations show how carefully nature has provided
for the supply of all necessary food-stuffs in their due propor-
tions. It is therefore not a matter of indifference whether the
young derives its nourishment from its own mother or from the
milk of another animal, or even from an artificial food. Even
were the constituents and their proportions in the milk known
to us, the preparation of such an artificial food would present
considerable difficulties. But we must acknowledge that we are
possibly not even acquainted with all the constituents. For in-
stance, the various proteids and nucleins of milk have not yet
been separated out as chemical entities, nor have their charac-
teristics in this condition been studied. And finally there is the
possibility that milk may contain small amounts of substances
not yet discovered, which may nevertheless play an important
part in nutrition.

Now in consequence of the degeneration of our race and as
a result of the indifference of many mothers, the necessity for
the artificial rearing of infants frequently arises.

A glance at the table on p. 106 shows that if cow's milk be
diluted with an equal volume of water the amount of proteid
is nearly the same as in human milk. The total ash is only
slightly higher ; the quantity of lime however is two and a half
times, that of phosphoric acid twice as great. The smaller
proportion of sugar and fat can be supplied by the addition of
sugar of milk and cream.

Instead of a solution of sugar of milk, cow's milk is some-
times diluted with solutions of other forms of sugar as well
as with starchy decoctions from all kinds of cereals.^ Which

^ An account of the comprehensive literature on the subject of the artificial
feeding of infants is given by Ph. Biedert, " Die Kinderernährung im Säuglings-
alter," 3d edit., Stuttgart, 1897, and by E, Feer, Jahrb. f. Kinderheilk., N. F.,
vol. xlii. p. 195 : 1896.

MILK AND THE FOOD OF INFANTS 109

of these is the more digestible for infants it is difficult to decide
owing to individual variations ; hence for the present no rule
can be laid down, especially as no trustworthy statistics are
available on this subject.

Experience however shows that many children are incapable
of digesting any form of diluted cow's milk, and that in no
case does it completely replace the mother's milk.

What are the reasons for this fact ?

1. The caseinogen of human milk is not identical with that
of cow's milk, as is shown by the varying proportion of phos-
phorus and sulphur. The caseinogen belongs to the so-called
nucleo-albumins, i. e., to the substances which on artificial di-
gestion split up into peptone and a substance resembling nu-
clein. The caseinogens therefore invariably contain considerable
amounts of phosphoric acid as well as some lime. According
to Lehmann and Hempel ^ the percentage of phosphate of lime
in the caseinogen of human milk is 3.2, and in cow's milk 6.6.
The proportion of sulphur in the two cases is 1.1 per cent., and
0.72 per cent.

A complete and accurate analysis of cow's caseinogen has
been made by Hammarsten.^ This may be compared wäth the
analysis of the caseinogen of human milk, which was carried
out by Wroblewski ^ under Drechsel's guidance.

Caseinogen.

From cow's milk.

From human milk.

C 52.96

52.24

H 7.05

7.32

N 15.65

14.97

S 0.74

1.11

P 0.84

0.68

0 22.78

23.66

2. By the action of rennet ferment "* in the stomach, the

1 Jul. Lehmann u. W. Hempel, Pflüger's Arch., vol. Ivi. p. 574: 1894.

2 Hammarsten, Zeitschr. f. physiol. Chem., vol. vii. p. 269: 1883; and
vol. ix. p. 296 : 1885.

^A. Wroblewski, "Beitr. zur Kenntniss des Frauenmilcheaseins u. seiner
Unterschiede vom Kuhcasein." Dissert., Bern, 1894.

* The significance of rennet ferment and of casein coagulation in the stomach
is still unexplained. For a knowledge of the experiments which have been made
with a view to the elucidation of this problem I recommend : Hammarsten,
Upsala läkareförennings Förhandlingar, 8, p. 63 : 1872 ; 9, pp. 363 and 452 :
1874 (complete account in Maly's Jahresber. f. Thier Chemie). " Zur Kenntniss
des Caseins u. der Wirkung des Labferments," Upsala, 1877. Hoppe-Seyler' s
Zeitschr., vol. xxii. p. 103: 1896. Alex. Schmidt, "Beitr. z. Kenntniss der
Milch," Dorpat, 1874. M. C. du Saar, " Melkstremmende werking van den
maaginhoad bij jonge zuigelingen.," Diss., Amsterdam, 1890. M. Arthus et C.
Pages, Arch, de Physiol., 1890, pp. 331 and 540. 3{em. soc. Mol., vol. xliii.

110 LECTURE VIII

caseinogen of human milk coagulates in fine floccula, that of
cow's milk in coarse lumps, which by many children cannot be
digested. If the cow's milk be diluted with a solution of
milk-sugar, the coarse precipitation is prevented. Although
by such means it is possible to avoid the aggregation of the
precipitate into solid lumps, this clot still remains closer,
tougher, and more indigestible than that of human milk. This
seems to depend on the greater percentage of lime and the
smaller alkalinity of cow's milk. As Soxhlet^ has clearly
pointed out, any attempt to get rid of these differences is beset
with great difficulties, which at present are in practice almost
insuperable.

It might have been anticipated that better results would be
obtained if instead of cow's milk the milk of some animal which
in its composition more closely resembled human milk were em-
ployed. A glance at the Table on p. 105 shows that this is
especially the case with mares' and asses' milk. But so far we
have too slight a practical experience to argue upon.

3. To add to the other difficulties of artificial feeding there
remains the necessity for sterilization. Milk is a most fertile
nutrient medium for all kinds of microorganisms, which in-
crease in it at an incredible rate. Fresh milk, which contained
9000* bacteria in one c.cm. when first brought into the labora-
tory, showed an hour later 31,750 ; after nine hours, 120,000 ;
and after twenty-four hours, 5,600,000.^

A short exposure to the boiling temperature does not suffice
to destroy all bacteria. If still higher temperatures be em-
ployed, the sugar is attacked and causes the milk to become
brown. For the best method of approximately sterilizing milk
without greatly impairing its nutritive value, the reader may be
referred to the latest accounts in the works of P. Cazeneuve,^ L.
Fürst,"* A. Baginsky,^ and a summary of the literature by
Biedert, loo. cit.

p. 131 : 1891. Zdzislaw Szydlowski, Prager med. Wochenschr., No. 32 : 1892.
Pages, Comptes rendus, vol. cxviii. p. 1291 : 1894. E.. Peters, " Das Lab u. die
Labähnlichen Fermente." Gekrönte Preisschrift, Rostock, 1894. M. Arthus,
Arch, de Physiol., vol. xxvi. p. 257 : 1895. A. Edmunds, Journ. of Physiol.,
vol. xix., Nos. 5 and 6: 1896. F. S. Locke, The Journ. of Experimental Med.,
vol. ii.. No. 5 : 1897.

1 F. Soxhlet, " Die ehem. Unterschiede zwischen Kuh u. Frauenmilch u. die
Mittel zu ihrer Ausgleichung." Vortrag gehalten am 11. Jan. 1893. Münch.
med. Wochenschr., 1893. Compare O. Heubner, Berliner Hin. Wochenschr.,
vol. xxxvii. pp. 841 and 870 : 1894.

2 Miquel, Journ. de Pharm, et de Chim., vol. xxi. p. 565 : 1890. Compare
E. V. Freudenreich, Milchzeitung, p. 33 : 1890.

^ P. Cazeneuve, Bull, de la Soc. chim. de Paris, vol. xiii. p. 502 : 1895.
•* L. Fürst, Deutsche Medicinalzeitung, p. 1007 : 1895.
*A. Baginsky, Berliner klin. Wochenschr., No. 18: 1895.

MILK AND THE FOOD OF INFANTS 111

4. Finally with anything but the mother's milk there is the
constant danger of over-feeding the infant. When taking the
breast, the fatigue consequent upon the effort of sucking ap-
pears to prevent the infant taking more than the proper amount,
whereas from the feeding bottle, which can be drawn without
effort, the infant takes more than it can digest, with consequent
dyspepsia.^

From these remarks it will readily be seen that artificial
feeding is fraught with grave danger.

If on the one hand we observe how carefully nature has
adapted the composition of milk to the needs of every species
of mammal, and if on the other we consider how ignorant we
are concerning the nature of the food-stuffs, the digestive proc-
esses in the infant and the disturbances which these are liable
to from the myriad microorganisms in the intestines, it is not
a matter for wonder that in spite of the greatest efforts the
natural diet for infants has not so far been successfully replaced
by any artificial food. In support of this contention we may
quote the following statistics : —

In 1890 49,362 children were born alive in Berlin. Before
the end of their first year 12,623 of these children had died.
Of these —

1588 had been fed at the breast ;
8008 had been fed with cow's milk.

The remaining infants had been brought up on'milk and arti-
ficial foods, or upon these latter alone. No deduction however
can be drawn from the influence of the food on the mortality
unless we know what proportion of the whole number of chil-
dren born were reared at the breast. The following figures
enable us to form an approximate idea. The census taken De-
cember 1, 1890, showed that there were then in Berlin 39,312
children under the age of one year. Of these —

20,812 were breast-fed ;
16,620 were reared by hand.

Therefore of the breast-fed children one in thirteen died ;
whereas of those brought up by hand the mortality rose to one
out of every two infants.

No doubt this excessively high rate of infant mortality is
due not only to the unnatural mode of diet, but partly to the
neglect which is doubtless in many cases associated therewith ;
since a mother who nurses her child would also, as a general
rule, instinctively lavish more care upon it.

1 E. Feer, loc. cit,, p. 196.

112 LECTUEE VIII

The mortality among children reared on artificial foods is
much higher even than among those fed on cow's milk.^

Heathen races have frequently sanctioned infanticide. Chris-
tian races torture their children slowly to death. Artificial feed-
ing was unknown to the ancients.^

When children are breast-fed, the condition of the mother's
health acts both on the quantity and the quality of the milk
secreted.^ But the quality of the milk seems to be but little
dependent upon the nature of the diet. Occasionally an in-
crease of fat is observed after very abundant feeding ; but
the amount of the other constituents in the milk is hardly
altered.

Taking milk as our starting point, let us now proceed to
consider the diet normally required by the adult. In the case
of the infant we are acquainted with the natural composition of
the food ; we can also ascertain the exact quantity provided by
nature by weighing the infant before being placed at the breast
and again after it has instinctively satisfied its hunger. The
difference in weight gives the amount of milk taken, and the
repetition of this process at each meal gives the total amount
for the twenty-four hours.

The most recent and exact estimates of this kind have been
carried out by E. Feer.* He determined the amount taken by
a boy from birth until the 30th week, and found that in the
last week he took 951 grms. of milk daily. At this time the
child's weight was 8226 grms. From the average composition
of human milk, viz. : —

Proteid 1.6 per cent.

Fat 3.4 "

Sugar 6.1 "

Ash 0.2 "

we can compute the absolute amount of the nutriment daily
taken in —

Proteid 15.2

Fat 32.3

Sugar 58.0

Ash 1.9

Statistisches Jahrbuch der Stadt Berlin. Doppeljahrgang xvi., xvii.
Statistik der Jahre 1889 und 1890, pp. 30 and 148 : Berlin, 1893.

2 Biedert, loc, dt., p. 155.

^ An account of the very comprehensive literature on this subject is given by
Biedert, loc. cit., chap. iii.

* The latest experiments concerning the influence of the food on the compo-
sition of human milk are those of P. Baum ("Die Frauenmilch," Sammlung
klinischer Vorträge von Volkmann, No. 105, p. 202, et seq., Leipzig, 1894). The
earlier literature is here quoted. Experiments on animals have given essentially
the same results. For the extensive literature on this subject the text-books on
agriculture should be consulted.

MILK AND THE FOOD OF INFANTS 113

According to the same proportions a man of 70 kilos, would
take in —

Proteid 129

Fat 275

Sugar 494

Ash 16

These figures agree very well with the observations which have
been made directly on the adult. I have already mentioned
that a man in full work, who can procure sufficient food for
himself, eats daily —

Proteid 100-150

Fat 50-200

Carbohydrates 300-800

It might be thought that the amount of proteid for the
adult reckoned from that required by the infant would be a
maximum value, since the young animal needs larger quantities
of proteid for the growth of its tissues, whereas the man has
only to maintain his existing store. But it must be remem-
bered that the sexual functions of the adult are likewise a form
of growth — " growth beyond the boundaries of the individual."
This growth of the tissues in man consists in the production of
spermatozoa, in woman in the development of the embryo or
the formation of menstrual fluid. The growth beyond the
boundary of the individual appears in women during the child-
bearing period to be only in abeyance during the time of
lactation, when the milk with its rich complement of proteid
is secreted. But the secretion of milk may be regarded as a
growth of tissue, since as a matter of fact the fat-laden epithelial
cells of the mammary glands either partially or completely
break up and are regenerated.^

But the amount of fat (275 grms.) calculated for the adult
from that required by the infant is certainly too high. The
infant has relatively a much larger body-surface and therefore
gives ofi* more heat ; it thus requires larger quantities of the food-
stuif that produces the greatest heat in its combustion.

The figure 494 for the carbohydrates agrees very well with
the mean numbers obtained in direct experiments on adults.
A young man eighteen years of age who took nothing but

^ The latest researches on the histological processes involved in the secretion
of milk are those of F. Nissen, Arch. f. mikr. Anat., vol. xxvi. p. 337: 1886.
E. Coen, Beitr. 2. pathol. Anat. u. Physiol, v. Ziegler u. Nauwerck, vol. ii. p.
83: 1887. P. R. Kadkin, Diss. Petersburg : 1890 (in Russian). Frommel, ^rcA.
/. Gynäk., vol. xl., Hft. ii.: 1891 ; and Centralbl. f. Gynäkol., p. 471 : 1891. J.
Steinhaus, Du Bois' Arch., Physiol. Abth. Supplementband, p. 54: 1892.

114 LECTURE VIII

cow's milk (compare the conclusion of Lecture XXV.) drank
three liters a day, containing —

Proteid 105

Fat Ill

Sugar 147

Ash 21

His state of nutrition was certainly bad and his powers of
work poor. But it cannot be decided whether this should be
referred to an insufficient income of some organic food-stuff or
merely to the absence of iron. (See Lecture XXV.)

LECTURE IX

SUBSIDIAEY ARTICLES OF DIET

Man, together with all animals, consumes certain articles
which are neither sources of energy nor possessed of reparative
power for the continual body waste. They are eaten on account
of the agreeable influence which they exert on the nerves of
taste or smell or on other parts of the nervous system. We call
these substances condiments and stimulants. They are as nec-
essary to us as the food-stuffs themselves.

It is a very noticeable fact that our most important
organic food-stuffs are absolutely without taste or odor. We
can only smell volatile matter, or taste such substances as are
soluble in water. Our organic food-stuffs have neither of these
properties. They are not in the least volatile, and are almost
all insoluble in water. Fats, as we well know, are not miscible
with water, and proteids only swell without actually dissolving
in it. Of the carbohydrates, the sugars alone are soluble, and
they taste sweet. In the case, then, in which food is possessed
of any taste at all, it is agreeable. Since the bulk of our food
can produce no effect on our organs of sense, we find our organs
of taste and smell so adapted that the volatile and soluble
matters, which are constantly associated with aliments as they
occur in nature, produce agreeable sensations when they act on
these sense-organs. These sensations not only increase our
desire for food ; they also help digestion. It is a matter of
common experience, that even the imagination of fragrant and
savory food may augment the secretion of saliva. The in-
creased secretion of gastric juice produced by the same cause
has been observed on dogs with a gastric fistula. To show
them from a long distance a piece of meat is sufficient to
excite the secretion of the gastric juice. Thus, if a gastric
fistula be established in a dog, and at the same time the
esophagus be divided, so that all food taken in by the mouth
falls out by the opening in the esophagus without reaching
the stomach, it is observed that every act of taking food by
the mouth causes a large secretion of gastric juice containing
both hydrochloric acid and pepsin, although the food does

115

116 LECTURE IX

not reach the stomach. This reflex secretion is abolished by
division of both vagi.^ It is hence probable that the ac-
tivity of all other glands associated with digestion is reflexly
aroused by agreeable tastes and smells, and that all processes
and movements which are involved in digestion and absorption
are hereby assisted. Pleasant sensory impressions produce a
cheerful frame of mind, and thus indirectly tend to act favor-
ably on all the processes of the body. On the other hand it is
a familiar fact that disagreeable smells and tastes cause a dis-
turbance of digestion which may even induce vomiting. The
necessity of these adjuncts to food is then beyond doubt ;
every effort to consume food which has neither taste nor smell
would soon fail.

Whilst animals merely take such sapid substances as occur
naturally mixed with the food they eat, man goes much further
by artificially separating the subsidiary from the necessary
aliments. He takes the former by themselves, or with only a
small proportion of the latter. Hence arises for man the
danger of excess. The regulating mechanism, which in animals
consists of the feeling of satiety which sets in as soon as they
have eaten enough, tends to be disturbed. So long as only the
senses of taste and smell are concerned, there is but little
danger of excess. The more intense the stimulation of the
organs of smell and taste, the more rapidly is the sensibility of
our nerves blunted ; we get tired of the impressions made upon
them. But besides those substances which act agreeably on
our senses, man has learnt to isolate others which produce
pleasurable sensations by their action on the functions of the
brain ; these we term narcotics. He has discovered them even
when they cannot be detected by smell or taste, and when they
occur only in plants which have no nutritive value ; such are
opium, tea, coffee, hashish, &c. Others, which nature does not
produce, he has learnt to prepare artificially from innocuous
substances, as for instance alcohol from sugar. Conscious
volition disturbs the harmonious action of the unconscious in-
stincts, and becomes the source of unlimited misery.

So long as we are unacquainted with the chemical processes
by which these subsidiary articles of diet act on the nervous
system, their special consideration is a subject rather for toxi-
cology and the physiology of the nervous system than for
physiological chemistry. I shall therefore treat of only a few
which are still often considered to be true aliments. The most
important of these are alcoholic drinks.

1 J. P. Pawlow and E. 0. Schumowa Simanowskaja, Du Bois' Arch., p. 53,
1895.

SUBSIDIARY ARTICLES OF DIET 117

We kno.w that alcohol is to a very great extent oxidized
in the body. Only a small part is excreted unchanged by the
kidneys and lungs.^ Alcohol is therefore without doubt a
source of energy when absorbed into the body. But it does
not therefore follow that it is a food. To prove this' it would
be necessary to show that the energy liberated by the oxidation
of alcohol is used to aid the performance of a normal function.
It is not enough that chemical potential energy is transformed
into kinetic energy ; the transformation must occur at the
right time, in the right place and in definite parts of the
tissues. The tissues are not so constituted that they can be
fed with any and every combustible material ; we do not know,
for instance, whether alcohol can serve as a source of the
energy by virtue of which the functions of muscle and nerve
are performed (see Lecture XXIII.).

It will be objected that the heat which is produced by the
combustion of alcohol must in any case be useful to our
organism. Even if it does not directly subserve any definite
function of a particular organ, the combustion of the alcohol
must economize the consumption of other food-stuffs. But
even this cannot be admitted. For whilst on the one hand
the alcohol increases the production, on the other it increases
the loss, of heat. Owing to the paralyzing action which it
exerts on the vasomotor system, a dilatation of the vessels,
and especially of the cutaneous vessels, occurs, and consequently
there is an increased loss of heat. The total result is a
diminution of the temperature of the body, which has been
actually proved to take place.

Alcohol has invariably a paralyzing influence. All the re-
sults which, on superficial observation, appear to show that
alcohol possesses stimulant properties, can be explained on the
ground that they are due to paralysis.^

' Vict. Subbotin, Zeitschr. f. Biolog., vol. vii. p. 361 : 1871 ; Dupre, Proc.
Roy. Soc, vol. XX. p. 268 : 1872 ; and I'he Practitioner, vol. ix. p. 28 : 1872 ;
Anstie, Practitioner, vol.lxiii. p. 15 : 1874 ; Aug. Schmidt, Centralbl. f. d. med,
Wissen^ch., No. 23, 1875 ; H. Heubach, " Ueber die Ausscheidung des Weingeistes
durch den Harn Fiebernder," Dissert.: Bonn, 1875 ; C. Binz, Ärch. f. exper. Path,
u. Pharm., vol. vi.: 1877 ; H. Heubach, " Quantitative Bestimmung des Alkohols
im Harn," Arch. f. exp. Path. u. Pharm., vol. viii. p. 446 : 1878 ; G. Bodländer,
Pflüger's Arch., vol. xxxii. p. 398 : 1883.

2 With regard to this matter, we recommend the perusal of the short and
lucid description in Schmiedeberg's "Grundriss der Arzneimittellehre," 2d
edit., pp. 25, 27: Leipzig, Vogel, 1883. Compare Zimmerberg, Dissert., Dorpat,
1869. Maki, Dissert., Strassburg, 1884. H. Dreser, "Arch. f. exper. Path. u.
Pharm.," vol. xxvii. p. 87 : 1890. P. v. d. Mühll and A. Jaquet, Correspondenz- »
hlatt f. schweizer Aerzte, No. 15, p. 457, 1891, and E. Krsepelin, " Ueb. d.
Beeinflussung einfacher psychischer Vorgänge durch einige Arzneimittel. Jena,
Fischer, 1892 ; A. Smith, Bericht üb. d. V. internat. Congress z. Bekämpfung des

118 LECTURE IX

It is a common idea that alcohol produces a warming ef-
fect in cold weather. This feeling of warmth depends, in the
first place, on the fact already noticed — that the paralysis of
the central nervous system causes an increased blood-supply to
the surface of the body ; and secondly, in all probability, on the
blunting of the sensibility of the central organs which are con-
cerned in the sensation of cold.

The stimulating action which alcohol appears to exert on the
psychical functions is also only a paralytic action. The cere-
bral functions which are first interfered with are the powers of
clear judgment and criticism. As a consequence, emotional
life comes into free play unhampered by the guiding-strings
of reason. The individual becomes confiding and communi-
cative ; he forgets his cares and becomes gay ; in fact, he no
longer clearly sees the dangers and difficulties of life. But the
most pronounced paralyzing action of alcohol is seen in the
way it allays all sorts of discomfort and pain, and, above all,
the worst sort of pain — mental suffering, anxiety, and trouble.
Hence the light-heartedness which prevails at a carouse. It is
a prejudice which depends upon self-deception, to believe that
a man ever becomes witty by aid of spirituous drinks. This
error is simply one of the results of the paralytic influence
mentioned above ; as the power of criticising one's self
diminishes, self-complacency increases. The lively gesticula-
tions and useless exertions of intoxicated people are due to
paralysis, the inhibitory influence, which prevents a sober man
from uselessly expending his strength, being removed. Asso-
ciated with this is the increased frequency of pulse, which is
commonly cited as an instance of the stimulating power of
alcohol ; it has nothing to do with the action of alcohol, but is
caused by the surroundings among which the alcoholic drinks
are generally taken. It is a consequence of the excited condi-
tion, and, according to the experiments hitherto made, does not
occur when the body remains quiet.^

A paralytic symptom, which is erroneously regarded as one
of stimulation, is also found in the deadening of the sense
of fatigue. There is a strong belief that alcohol gives new
strength and energy after fatigue has set in. The sensation of

Missbrauches geistiger Getränke, Basel, p. 341 : 1896 ; C. Fürer, ibid., p. 355 ; G.
Aschaifenburg, "Psychologische Arbeiten v. E. Krsepelin," vol. i. p. 608: 1896.
C. Binz ("Der Weingeist als Heilmittel," Sonderabdruck aus den Verhandlungen
des VII. Congresses f. innere Medicin zu Wiesbaden, 1888 : Wiesbaden, Verlag
von J. F. Bergmann, 1888) upholds the older view, according to which alcohol
•has a stimulating action when taken in small doses.

1 Schmiedeberg, loc. cit., p. 26; Zimmerberg, " Unt. üb. den Einfluss des
Alkohols auf die Thätigkeit des Herzens," Dissert., Dorpat, 1869. P. v. d.
Mühll and A. Jaquet, Gorrespondenzblatt f. schweizer Aerzte, p. 457 : 1891.

SUBSIDIARY ARTICLES OF DIET 119

fatigue is one of the safety-valves of our machine. To stifle
the feeling o'f fatigue in order to be able to work on, is like
forcibly closing the safely-valve so that the boiler may be over-
heated.

That this prejudice concerning the ' strengthening ' power of
alcohol maintains so firm a hold is to be explained by the ex-
periences of habitual drinkers. Any one who is in the regular
habit of taking a considerable quantity of alcohol is better able
to do his work while he continues it than if he were suddenly
to leave it off. We cannot at present explain this result, al-
though it is quite analogous to the effect of other narcotics on
persons who have been accustomed to their use. The opium-
eater can neither work, nor eat, nor sleep, if his opium be de-
nied him ; he is ^ strengthened ' by the opium. But a man who
is not accustomed to a narcotic is most certainly not rendered
more fit for work by taking it.

The uselessness, if not harmfulness, of even moderate doses
of alcohol rests on better evidence than scientific deductions
and experiments. In connection with the sanitation of armies,
thousands of experiments upon large bodies of men have
been made, and have led to the result that, in peace and war,
in every climate, in heat, cold, and rain, soldiers are better able
to endure the fatigues of the most exhausting marches when
they are not allowed any alcohol at all.^ A similar result is
observed in the case of the navies, and on thousands of mer-
chant vessels belonging to England and America, which put to
sea without a drop of alcohol. Most whalers are manned by
total abstainers.

That mental exertions of all kinds are better undergone
without alcohol is generally admitted by most people who have
made the trial. Alcohol then makes no one stronger ; it only
deadens the feeling of fatigue.

One of the disagreeable sensations which alcohol diminishes
is that of boredom. This feeling is, however, like the sensation
of fatigue, one of the arrangements for self-regulation which
the organism possesses. Just as the feeling of fatigue makes
us rest, so the feeling of boredom encourages us to exertion,
without which nerve and muscle atrophy. It is interesting to
observe what curious means a lazy and empty-headed man
adopts in order to be free from the demon of boredom without
making personal exertion. It drives him without rest from
place to place, to this company and that, from one distraction
to another. But all these attempts to escape from himself

^ See A. Baer, "Der Alkoholismus," pp. 103-108: Berlin, 1878. References
to the original works are given here.

120 liECTUEE IX

would be in vain, and the bulk of mankind would be driven to
exercise their brain and muscles in some way or another,
in order to obtain the feeling of rest and satisfaction and to
lose their sense of tedium, were it not for alcohol. Alcohol
frees them easily and agreeably from this demon. A drinker
is never conscious of his own emptiness. He wants no inter-
ests and ideas ; he has the comfort and satisfaction of narcosis.
There is nothing so dangerous to the development of a man,
nothing which so undermines his character, nothing which so
surely destroys the remaining energy he is capable of, as the
continual deadening of the sense of tedium by means of
alcohol.

Another point which is adduced in favor of alcoholic drinks
is that they slow metabolic processes. It is true that a slight
diminution in the excretion of nitrogen, and consequently of
proteid decomposition, is observed after moderate doses of alco-
hol.^ But it is difficult to understand why this should be made
a reason for recommending alcoholic drinks. Why should we
wish to diminish the metabolism of the body ? Is not meta-
bolism, or the breaking down of the tissues, the source of all our
energy ? The intensity of this metabolism, this conversion of
potential into kinetic energy, is constantly regulated by a com-
plicated nervous mechanism, which now acts in an inhibitory,
now in an accelerating direction, according to the requirements
of the various organs. To interfere with this self-controlling
mechanism by the action of poisonous substances can hardly be
wise, since we are almost entirely in ignorance concerning its
intimate character. What means have we of judging whether
the metabolism is too quick or too slow ?

Moreover the latest and most accurate researches on man
have failed to show any economy of proteid as the result of the
injection of alcohol.^ Among these investigations the minutely
accurate experiments of Miura upon himself are especially
worthy of mention. This observer, after bringing himself into
a condition of nitrogenous equilibrium on a diet of fat and
carbohydrate, replaced for a few days a portion of the carbo-
hydrate by an equivalent quantity of alcohol. He found that,
on these days, there was a rise in the excretion of nitrogen,
which was as great as on other days when a portion of the

' A. P. Fokker, " Nederlandsch Tijdschrift voor Geneeskunde," p. 125 : 1871 ;
Imm. Munk, Verh. der Physiol. Ges. zu Berlin: Jan. 3, 1879 ; L. Reiss, Zeitschr.
f. klin. Med., vol. ii. p. 1 : 1880.

2 Parkes, Proc. Roy. Soc, vol. xx. p. 402 : 1872. H. Keller (Bunge's labora-
tory), Zeitschr. f. physiol. CAem., vol. xiii. p. 128 : 1888. Stammreich, " Ueb. d.
Einfluss d. Alkohols auf d. Stoffwechsel d. Menschen," Dissert.: Berlin, 1891.
K. Miura, Zeitschr. f. klin. Med., vol. xx. p. 137 : 1892.

SUBSIDIARY ARTICLES OF DIET 121

'carbohydrate was omitted without any corresponding food to
take its place. He came to the conclusion therefore that alco-
hol had no influence on proteid disintegration, and that it could
not replace carbohydrate as a sparer of proteid.

In large doses alcohol increases instead of diminishing the
excretion of nitrogen.^ In this respect it resembles certain
powerful poisons, especially phosphorus and arsenic, which
cause increase in the excretion of nitrogen, but at the same
time diminish the amount of oxygen taken up and carbonic
acid excreted, and consequently produce fatty degeneration of
various organs. It appears that these poisons give rise to the
production of fat from proteid ; the nitrogen, with a small
quantity of the carbon, is separated from the proteid molecule,
and the residue, free from nitrogen, is stored up in the tissues
as fat. We shall have to consider this process in greater de-
tail in a later section (Lecture XIV.). Possibly the fatty de-
generation of the organs sometimes observed in drunkards is
to be referred to a similar action. But unfortunately the ex-
periments hitherto made have not decided whether the con-
sumption of alcohol has any influence on the elimination of
carbonic acid.^

It is commonly thought that alcoholic drinks act as aids to
digestion. In reality it would appear that the contrary is the
case. Any one may make the observation on himself, that a
meal without alcohol is more quickly followed by hunger than
when alcohol is taken. The inhibitory influence of alcohol on
digestion has been observed on a patient with a gastric fistula,^
on several other persons by the aid of the stomach-pump,* and
by means of numerous other experiments.^

Up to this point I have chiefly considered the action of
alcohol on persons who are usually called moderate drinkers.
To describe the ultimate consequences of excessive drinking
can hardly come within the scope of these lectures. It may be
mentioned, however, that the misuse of alcoholic drinks causes

^ Imm. Munk, loc. cit.

2 The oft-quoted experiments of Boeck and Bauer allow of no definite con-
clusion, as the duration of the experiments was too short {Zeitschr. f. Biolog.,
vol. X. p. 361 : 1874). The same is still more applicable to the experiments of
Wolfers {Arch. f. d. gesam. Physiol., vol. xxxii. p. 222: 1883). Zuntz and
Berdez, Du Bois' Arch., p. 178: 1887. J. Geppert, Arch. f. exper. Path. u.
Pharm., vol. xxii. p. 367 : 1887. N. Simanowski and C. Schoumoff have shown
that absorption of alcohol diminishes the oxidation of benzol into phenol
(Pfliiger's ^rcA., vol. xxxiii. p. 251 : 1884). j

3 F. Kretschy, Deutsch. Arch. f. klin. Med., vol. xviii. p. 527: 1876.

4 W. Büchner, ibid., vol. xxix. p. 537 : 1881.

^Emil Schütz, Prager med. Wochenschr., 'No. 20: 1885; Bikfalvi, Maly's
Jahresher. f. Thier Chemie, p. 273 : 1885 ; Massanori Ogata, Arch. f. Hygiene,
vol. iii. p. 204: 1885 ; Klikowiez, Virchow's Arch., vol. cii. p. 360: 1885.

122 LECTURE IX

a whole liost of diseases ; that no organ of our body remains
free from its injurious action.^ It is also apparently certain
that from 70 to 80 per cent, of crime, and from 10 to 40 per
cent, of the suicides in most civilized countries, are to be as-
cribed to alcohol.

We must however strictly discriminate between the use of
alcohol as a luxury and an article of diet, and its use as a
medicine. In the opinion of many practitioners, it is indis-
pensable as a medicine. It is precisely its paralyzing prop-
erties which render it valuable in this case. It is a mild
anesthetic, and acts as a sedative by diminishing abnormally
increased reflex irritability. Alcohol is further used as an
antipyretic ; but proof of its value in this capacity is still
lacking.

It is evident to every reasonable being that alcoholic drinks
can only be prescribed for acute diseases, and should never be
allowed in chronic disorders for the same reason that chloral
and morphia are not given in such cases, unless indeed to com-
pass euthanasia. There can be no doubt that many medical
men are guilty of much harm in recommending the use of
alcohol, and there is hardly a single drunkard who does not
adduce the authority of some medical man or other in support
of his failing. It is . in the highest degree desirable that
alcohol should be replaced by some other drug even in those
cases where its use seems to be indicated, since it is hardly
possible to get rid of the deeply rooted superstition as to the
strengthening and stimulating effect of alcohol, so long as it
continues to be constantly employed as a therapeutic agent.
We may hope that the temperance hospitals which have been
founded in England and America, and where absolutely no
alcohol is given, may soon flirnish sufficient statistics to prove
once and for all that alcohol is not indispensable in medical
practice.

Tea and coffee are much less likely to cause ill effects
than alcoholic liquors. They exert no paralytic influence ; on
the contrary, they are helpfiil in both mental and physical
exertions. In their use there is but little danger of excess.
It is true that they occasionally disagree with certain people,

^ On this point see Legrain, "Heredite et Alcoholisme," Paris, 1891;
Laurent, " Les habitues des Prisons de Paris," Paris, 1890 ; P. Garnier, "La Folie
ä Paris," Paris, 1890; Bourneville, " Progres medical," p. 21: 1897. J. Sendt-
ner, "Ueb. Lebensdauer u. Todesursache b. d. Biergerwerben. Ein Beitrag z.
jEtioIogie d. Herzerkrankungen," München, 1891 ; Demme, " Ueb. d. Einfluss
d. Alkohols auf. d. Organismus d. Kindes," Stuttgart, 1891 ; A. Strümpell, " Ueb.
d. Alkoholfrage V. serztlichen Standpunkte aus.," Berl. Hin. Woch., p. 933:
1893.

SUBSIDIARY ARTICLES OF DIET 123

especially if token in too large quantities ; and their long-con-
tinued misuse may cause illness. But in these cases there is
but little difficulty in inducing the people so affected to abstain.
A patient who is recommended seriously to refrain from taking
too much tea generally does so ; a patient who takes too much
alcohol does not easily give it up. A man rarely becomes the
slave of coffee or tea, and excessive drinking of tea and coffee
never produces a state of moral irresponsibility, nor leads to the
commission of crime.

Tea and coffee contain, as is well known, an active principle
common to both, caffein or thein, which is closely related to
xanthin, a crystalline substance rich in nitrogen, which enters
in small quantity into all our tissues. We shall study xanthin
in connection with the chemistry of the urine (Lecture XX.).
Caffein is xanthin with three methyl groups introduced into its
molecule, and it can be artificially prepared from these constit-
uents.^

It is a very remarkable and surprising fact that people of
the most different races, in all parts of the world, have
succeeded in discovering caffein in the most varied plants.
The Arabs found it in the coffee bean ; the Chinese in tea ;
the natives of Central Africa in the cola nut (^Cola acmninata) ;
those of South Africa in bush tea, the leaves of a variety of
Cyclopia ; the natives of South America in Paraguay tea [Ilex
paraguayensis), and in the seeds of Paulinia soi^bilis, a Brazilian
creeper ; the Indians of North America in Apalache tea, the
leaves of several varieties of ilex. This fact is the more
remarkable as caffein can be detected neither by its taste nor
smell. Also interesting is the close relation of this universally
prized luxury to one of the constituents of our tissues. It is
possible that the caffein molecule, in consequence of its similar
constitution, has an affinity for the same tissue-elements in
which xanthin is found, and that it plays an analogous though,
in consequence of its more complex constitution, a modified
part. This may explain the stimulating action which it pos-
sesses.

Caffein is mostly destroyed in the tissues of our body.
Experiments ^ conducted in Dragendorft's laboratory in Dorpat

■^ Emil Fischer, Liebig^'s Annal., vol. ccxv. p. 253 : 1882.

^ Rich. Schneider, " Ueber das Schicksal des Caffeins und Theobromins im
Thierkörper, nebst Untersuchungen über den Nachweis des Morphins im Harn,"
Dissert.: Dorpat, 1884. Schutzkwer ("Das CalFein u. sein Verhalten im Thier-
körper," Dissert.: Königsberg, 1883) found that, of 0.2 grm. of caffein sub-
cutaneously injected into a dog, only 0.012 reappeared in the urine. Maly and
Andreasch ("Studien über Caffein und Theobromin," 3Ionatshefte der Chem.,
May : 1883) found that, of 0.1 grm. administered internally to a small dog,
0.066 reappeared in the urine.

124 LECTUEE IX

have shown that of the amount of caffein which is absorbed as
the result of ordinary tea and coflPee drinking — a cup of coffee
contains about 0.1 grm. caffein, and the same amount is con-
tained in from 2 to 10 grms. dry tea leaves — none passes into
the urine. Caffein can be detected in the urine when 0.5 grm.
caffein has been taken. Caffein has no influence on the proteid
metabolism of the organism. Voit ^ has shown by carefal ob-
servation that the amount of nitrogen excreted is neither in-
creased or diminished by the use of caffein.

This is not the place to give a detailed account of the various
modes of action of caffein ; I must refer you to works on phar-
macology. In addition to this common constituent, tea contains
ethereal oils,^ and in coffee certain aromatic substances are
formed as the result of roasting ; hence the difference of taste
and action of these substances.

A substance chemically closely allied and of similar action
to caffein is found in the cocoa bean. This is theobromin, a
dimethyl-xanthin. In the seeds of Paulinia soi'bilis, from
which guarana paste, much liked in South America, is pre-
pared, both these substances are united. Filehne ^ has recently
studied the action of theobromin on muscle and on the central
nervous system, and compared it with the action of xanthin and
of caffein. He has arrived at the interesting result that the
chemical series, caffein (trimethyl-xanthin), theobromin (di-
methyl-xanthin), and xanthin present a corresponding series
in their pharmacological action. A monomethyl-xanthin is at
present unknown. The cocoa bean is not only a luxury, but
also very valuable as nutriment ; it contains half its weight of
fat, and in addition about 12 per cent, of proteid. Chocolate
might be very serviceable for military purposes. It is hardly
possibly to carry food in a more concentrated form than in
chocolate.

Bouillon and extract of meat, which is bouillon evapo-
rated to a semi-solid consistence, afford the most harmless sub-
sidiary aliments. The extractives of meat do not, so far as
is known, exert the slightest narcotic influence. They act
entirely on taste and smell. This agreeable effect can hardly
be overestimated, but we must guard against supposing that

^ C. Voit, " Unt. üb. d. Einfl. des Kochsalzes, des Kaffees und der Muskel-
bewegungen auf den Stoffwechsel," pp. 67-147 : München, 1860.

2 A. Koch and E. Krtepelin ("Psycholog. Arb.," vol. i. p. 378: 1895) have
investigated the effects of these ethereal oils and of the thein separately, and have
found that the pleasant results of tea drinking must be referred to both con-
stituents.

3 Wilhelm Filehne, Du Bois' Arch., p. 72 : 1886. A summary of the earlier
literature will also be found here. Comp, also Kobert, Arch, f, exper. Path. u.
Fharm., vol. xv. p. 22 : 1882.

SUBSIDIARY ARTICLES OF DIET 125

meat bouillon possesses strengthening and nourishing properties.
In regard to this, the most delusive notions are entertained, not
only by the general public, but also by medical men.

Until quite recently, the opinion was held that bouillon con-
tained the most nutritive part of meat. There was a conftised
idea that a minute quantity of material — a plateful of bouillon
can be made from a teaspoon ful of meat-extract — could yield
an effectual source of nourishment, that the extractives of meat
were synonymous with concentrated food.

Let us inquire what substances could render bouillon nu-
tritious. The only article of food which meat yields to boiling
water is gelatin. It is well known that proteid is coagulated,
on boiling, the glycogen of meat is rapidly converted into
sugar, and this again into lactic acid. The quantity of gelatin
is moreover very small ; for a watery solution which contains
only 1 per cent, of gelatin forms a jelly on cooling. This
certainly occurs in very strong soups and gravies, but never
in bouillon. Bouillon therefore contains much less than 1 per
cent, of gelatin. In preparing extract of meat, the quantity
of gelatin is reduced as much as possible, because it is in a
high degree liable to putrefactive changes, and therefore likely
to interfere with the preservation of the preparation. The
other constituents of bouillon are decomposition products of
food-stuifs — products of the oxidations and decompositions which
take place in the animal organism. They cannot be regarded
as nutritious, because they are no longer capable of yielding
any kinetic energy, or at most such a small amount that it is of
no importance whatever.

Nevertheless, until the most recent times, creatin and
Creatinin,^ which are among the chief constituents of meat-
extract, were regarded as the source of energy in muscle.
This assertion was shown to be untrue by the researches of
Meissner^ and of Voit,^ who proved conclusively that the
whole of the creatin and Creatinin taken into the body is ex-
creted unchanged in the urine twenty-four hours after its ab-
sorption. A material which is neither oxidized nor decomposed
cannot form a source of energy, apart from the fact that the
quantity of creatin and Creatinin in bouillon is so small that
it could not possibly be regarded as the source of muscular
energy.

^ For the chemical constitution and the physiological significance of these
compounds, see Lecture XIX.

2 G. Meissner, Zeitschr. /. rat. Med., vol. xxiv. p. 97 : 1865 ; vol. xxvi. p. 225 :
1866 ; and vol. xxxi. p. 283 : 1868.

3 C. Voit, Zeitschr. f. Biolog., vol. iv. p. Ill : 1868.

126 LECTUEE IX

It has fiirther been asserted that the addition of extract
of meat increases the nutritive value of vegetable food, and
gives the latter the same value as fresh meat. This assertion
has also been refuted by Voit and his pupils/ who have shown
by experiments made on man and on animals, that the un-
favorable conditions of assimilation which characterize vege-
table food are not improved by the addition of extract of
meat.

Finally, the attempt has been made to attach a value as a
food to extract of meat, in consequence of the considerable
quantity of salts, "nutritive salts," which it contains. But,
as I have already explained, there is no lack of salts in our
food, but always an excess. Even for the growing organism
there is only one inorganic constituent which could be deficient,
i. e., lime. But there is very little lime in meat-extract ; the
ash contains only 0.23 per cent. CaO.^ No one would be
likely to eat more than 30 grms. of meat-extract, which repre-
sents the amount obtained from 1 kgrm. of meat, and contains
only 0.015 grm. of lime — that is, the same quantity as is con-
tained in 10 c.cms. of cow's milk.

We must therefore conclude that meat-extract can only be
looked upon as a pleasant adjunct to food. It is asserted even
at the present time that extract of meat acts in the same stimu-
lating and refreshing manner as tea and coffee undoubtedly do ;
but up to this date no direct action of extract of meat on muscles
or nerves has been proved. The only investigation in this
direction is due to Kemmerich,^ who lays stress on the large
amount of potassium salts contained in extract of meat, and
asserts, as the result of his experiments, that they exert, in
small doses a stimulating, in large doses a depressing, effect on
the action of the heart. He therefore warns against immoderate
use of the extract of meat.

So far as the potassium salts are concerned, the following is
really the case.* The stimulating action on the heart which
Kemmerich observed was in no way due to the potassium salts,
but simply to the fact that he used rabbits for his experiments.
Being very timid animals, the injection of almost any in-
different substance, such as'a solution of sugar or of common
salt, may easily produce a decided increase in the rate of the

1 Ernst Bischoff, Zeitschr. /. Biolog., vol. v. p. 454 : 1869 ; and C. "Voit, Zeit-
achr.f. Biolog., vol. iv. pp. 359, 360: 1870.

2 G. Bunge, Pflüger's Arch., vol. iv. p. 238 : 1871.
^ Kemmerich, Pflüger's Arch., vol. ii. p. 49 : 1869.

■* G. Bunge, Pflüger's Arch., vol. iv. p. 235 : 1871 : and Zeitschr. f. Biolog.,
vol. ix. p. 130 : 1873. Lehmann has recently confirmed my results (see Arch. f.
Hygiene, vol. iii. p. 249 : 1885).

SUBSIDIARY ARTICLES OF DIET 127

pulse. The mere passage of the stomach sound is sufficient to
have this effect. By large numbers of experiments both on dogs
and on the human subject, I have convinced myself that the in-
troduction of potassium salts into the stomach is never followed
by the slightest acceleration of the pulse.

The paralyzing influence on the heart, observed by Kem-
merich, is due to his having used an amount of potash salts
quite out of proportion to the weight of the rabbit. To give a
rabbit of 1000 grms. body weight, 5 grms. of potash salts is
the same as giving a man 300 grms. An additional factor in
the case of a rabbit is that it is unable to vomit. It is im-
possible to produce any influence on the heart of the dog,
since an excessive dose of potassium salts is promptly followed
by vomiting. I have found by numerous experiments that the
maximum dose (about 12 grms.), which can be taken without
causing vomiting, is quite without influence on the action of
the heart. In cases where poisoning has actually ensued as the
result of overdoses of potassium salts, death has been due to a
gastro-enteritis, and not to any effect upon the heart. Potas-
sium salts have a local corrosive effect. The gastric mucous
membrane of animals into whom salts of potassium have been
injected, is always hyperemic, and sometimes covered with ec-
chymoses. If the potassium salts are given in a very concen-
trated form, especially in powder, gastritis, with a fatal result,
may be produced.

In all animals paralysis of the heart follows rapidly, if the
solution of potassium salts be injected directly into the blood.
As the result of my own experience, I have convinced myself
that when 0.1 grm. KCl is injected into a medium-sized dog,
an almost immediate arrest of the heart follows. Subcutaneous
injection of potassium salts also causes cessation of the cardiac
beat. But paralysis of the heart is never preceded by accelera-
tion, but always by a slowing of the pulse.

It is hardly necessary to recur to experiment in order to
show how entirely umocuous salts of potassium are when
taken by the mouth ; it has only to be borne in mind how
large a quantity is constantly consumed with vegetable food.
I have already noticed the fact that a man who lives chiefly on
potatoes absorbs over 50 grms. of potash salts in the course of
a day.

The potash salts, therefore, which occur in bouillon, cannot
produce any effect on the heart, neither small doses stimulating
it, nor large ones paralyzing it. But even if we could admit
the exciting action of potassium salts, it would be difficult to
see why we should take bouillon on account of the potash it

128 LECTUEE IX

contains, since we could get much more with almost any other
form of food. Five grammes of extract of meat will make a
plateful of bouillon, and they only contain 0.5 grm. potassium,
the same quantity as in a small potato.

We see then that the only experiment which has been
hitherto attempted to demonstrate the stimulating influence of
extract of meat has not been successful.

It has frequently been asserted that the organic constituents
of meat-extract exert an influence on the muscular nervous
system, but never on sufficient ground. As regards creatin
and Creatinin in particular, Voit^ has given details; he found
that 6.3 grms. creatin and 8.6 grms. Creatinin given to a dog
produced no symptoms whatever. More recently Kobert ^ has
endeavored to demonstrate an action of creatin on muscle.
The experiments were conducted on frogs, and excessive doses
of creatin used ; but the result was ambiguous. Human
muscle could hardly be influenced by the minute quantity
(about 0.2 grm.) of creatin contained in an ordinary plateful of
soup. This can be deduced ä priori, quite apart from the
observations of Voit. Our muscles contain about 3 per 1000
creatin.^ The whole muscular system of an adult man, which
amounts to about 30 kgrms., contains consequently about 90 grms.
It is also found in the nervous system and in the blood. With
regard to the small quantity of creatin which is taken in
bouillon, absorbed, and at the same time rapidly excreted by
the kidneys, we are uncertain whether it ever reaches the
muscles at all. And even if a small quantity should do so, it
can hardly be of any importance, when we know that the
muscles already contain 90 grms. of creatin.

That some other organic constituent of meat-extract may
produce an effect on the muscular or nervous system, must be
admitted to be remotely possible ; at present it is in no way
proved. We know, with regard to bouillon, absolutely no more
than that it tastes and smells agreeably. This fact, however,
suffices to explain all the ^ enlivening ' and ' strengthening '
virtues which common experience attributes to extract of meat
and bouillon, and to recommend them as valuable and pleasant
accessories of our food.

1 C. Voit, " Ueber die Entwicklung der Lehre von der Quelle der Muskel-
kraft," p. 39 : 1870 ; or Zeitschr. f. Biolog., vol. vi. p. 343 : 1870.

2 Arch. f. exper. Path. u. Pharm., vol. xv. p. 56 : 1882.

3 Fr. Hofmann, Zeitschr. f. Biolog., vol. iv. p. 82 : 1868 ; M. Perls, Deutsch.
Arch. f. Hin. Med., vol. vi. p. 243 : 1869.

LECTURE X

SALIVA AND GASTRIC JUICE

We have in previous chapters become acquainted with the
various food-stuifs, and we must now trace their course through
our bodies, and the gradual changes which they undergo.

The first fluid with which the food comes in contact on
being introduced into the alimentary canal, is the saliva,^
which is well known to be the secretion of three larger pairs
of glands, and of the small glands in the mucous membrane of
the mouth. The amount of saliva formed in the course of
twenty-four hours is very considerable, and according to an
approximate estimate of Bidder and Schmidt,^ is about 1500
c.cms. This secretion might therefore be expected to play an
important part in the processes of digestion, but it has not yet
been found that it does so. The saliva has no efi'ect on most
articles of diet ; starch alone is converted by its means into
dextrin and sugar. But even this action is very inconsider-
able ; it is nothing compared with the powerful action of the
pancreatic juice in breaking up starch. The period during
which the saliva acts is of very short duration. The salivary
ferment can only operate fully on starch under the faintly
alkaline reaction which belongs to normal saliva. This action
is immediately enfeebled or entirely neutralized by the acid
gastric juice.^ Thus only a very small portion of the starch
consumed is split up by the salivary ferment. But the saliva

^ The processes of secretion in the salivary glands have been more closely
investigated by Bernard, Ludwig, and Heidenhain than those in any other
glands, and the results of these investigations are among the most important
achievements of modern physiology. But these works have thrown no light
upon the chemical processes in glandular activity. I therefore think it better to
pass them over, especially as they are adequately described in all text-books of
physiology.

2 Bidder and Schmidt, " Die Verdauungssäfte und der Stoffwechsel," p. 14:
Mitau and Leipzig, 1852.

^ O. Hammarsten, Panum's Report in the Jahresbericht über die Leistungen
der ges Medicin., Jahrg. vi. vol. i.: 1871. [Cannon has shown however that at
least half an hour may elapse before the food taken in with the meal is thor-
oughly mixed with the gastric juice. During this time the food remains in the
fundus of the stomach, and in its inner portions salivary digestion can go on un-
checked. (Amer. Journ. of Physiol. , vol. i. p. 359: 1898.)]

9 129

130 liECTUEE X

of some mammals has not even this slight action, as in the case
of the Carnivora, where for teleological reasons it might be ex-
pected to be absent.

As saliva is very abundantly secreted by Carnivora, it is
apparent that the decomposition of starch is not its main func-
tion.

It was hoped that by extirpating the salivary glands of
dogs,^ and then observing what disturbances took place in con-
sequence, a conclusion might be arrived at as to the significance
of saliva. No prejudicial effects were detected, although it was
remarked that the dogs drank more water than usual with their
accustomed and carefully regulated diet.

It appears that the saliva is chiefly of importance from a
mechanical point of view. It moistens the food in the mouth
and prepares it for the act of swallowing. At the same time
the mouth is kept clean by the constant secretion. If particles
of food were allowed to remain in the mouth, the acids which
would be formed as the result of their decomposition, would
injure the teeth ; this is prevented by the mouth being continu-
ally kept moist with the alkaline saliva. If this view of the
use of saliva is correct, we should expect the salivary glands of
mammals living in water to be absent, since the food they take
is always sufficiently moist, and the cavity of the mouth is con-
stantly being washed out by water. This is in fact the case.
The Cetacea lack salivary glands entirely, and in the Pinnipedia
they are only rudimentary.

In the stomach the food meets with a second secretion, the
GASTRIC JUICE, distinguished from all the other digestive fluids
by its acid reaction. This acid reaction is due to the free hy-
drochloric acid. The proof of this was furnished by Carl
Schmidt.^ He determined the exact quantity of the chlorin
and of all the bases, potash, soda, lime, magnesia, oxid of iron,
and ammonia. The result was that, after allowing enough hy-
drochloric acid to saturate all the bases, a quantity remained
over which amounted to about 2.5 to 4 grms. in 1 liter. Carl
Schmidt determined, in addition, the amount of free acid by
means of titration, and obtained almost exactly the same num-
bers as in the case of the determination by weight.

If we now inquire into the significance of this free acid, we
find that most writers regard it as subserving the digestion of
proteids. Proteids, and gelatins, which are closely allied to

^C. Fehr, "Ueber die Exstirpation sämmtlicher Speicheldrüsen beim
Hunde," Dissert.: Giessen, 1862.

2 Bidder and Schmidt, " Die Verdauungssäfte und der Stoffwechsel," pp. 44,
45 : Mitau and Leipzig, 1852.

SALIVA AND GASTRIC JUICE 131

them, are in fact the only food-stuffs which are altered by the
gastric juice. They are changed into peptones/ which are dis-
tinguished from proteids and gelatins by the fact that they no
longer retain their colloid properties, are no longer coagulable,
are more readily diffusible through animal membranes, and con-
sequently appear particularly suited for absorption into the
blood. This peptonizing action is attributed to a ferment called
pepsin.^ Pepsin is however only effectual in the presence of a
free acid. Hence up to the present time it has been the custom
to regard free acid as being only of use in rendering the action
of pepsin possible.

But we cannot be content with this explanation ; we know
that the pancreatic ferment acts even more energetically than
the gastric juice, and that it is most efficacious when the reac-
tion is faintly alkaline. Why should the gastric glands have
the severe labor of separating free hydrochloric acid from the
alkaline blood, if the organism can effect its purpose by much
simpler means — by the secretion of an alkaline fluid? The
free acid must have some other significance. At the present
day, when our knowledge of putrid fermentation and the means
of combating it has so much increased, and when we have found
that free mineral acids are to be counted among the most effec-
tual antiseptics, it is not unreasonable to attribute this function
to the free hydrochloric acid of the gastric juice. It has the
duty of killing the microorganisms which reach the stomach
with the food. These would otherwise set up processes of de-
composition in the alimentary canal, and thus destroy a part of
the food before its absorption, whilst the products of decomposi-
tion would produce disagreeable symptoms, or even, as a cause
of disease, endanger life.

N. Sieber,^ in Nencki's laboratory in Berne, determined the
strength of the hydrochloric acid which suffices to prevent the
development of putrefactive organisms in substances capable of
putrefaction, and arrived at the following results.

If 50 grms. finely chopped meat were put into an open flask
with 300 c.cms. of a 0.1 per cent, solution of hydrochloric acid,
only a scanty development of micrococci and bacilli took place
in twenty-four hours. After forty-eight hours they had some-

^ The nature and significance of peptones will he discussed later on (see Lec-
tures XI. and XIII.).

^ See Lecture X. for the experiments on the isolation of pepsin. Besides
pepsin, another ferment, the ' rennet ferment,' is included in the gastric juice,
and this causes the coagulation of milk in the stomach. Nothing is known con-
cerning the physiological import of this coagulation. I therefore omit all account
here.

^ N. Sieber, Journ. f. prakt. Chem., vol. xix. p. 433 : 1879.

132 LECTURE X

what increased, and on the third day the fluid presented a dis-
tinctly putrefactive odor, and a weakly acid reaction.

When the experiment was made, ceteris paribus, with 0.25
per cent, hydrochloric acid, isolated non-motile organisms were
not found till the seventh day, and pronounced formation of
mould not until the ninth day.

In a third experiment carried out, ceteris paribus, with 0.5
per cent. HCl, " no trace of putrefaction " appeared until the
seventh day.

Miquel ^ attained the same result, finding that from 0.2 to
0.3 grm. mineral acid was sufficient to render 100 c.cms. of
bouillon incapable of undergoing putrefaction.

In the gastric juice of a dog — obtained from a gastric fistula,
and from which all admixture with saliva had been prevented
by previous ligature of all the salivary ducts — C. Schmidt^
found in eight analyses, from 0.25 to 0.42 per cent. HCl, the
mean of the eight analyses being 0.33 per cent. Heidenhain ^
found in the secretion of the glands of the cardiac end of the
stomach,* by means of titration in thirty-six cases, from 0.46 to
0.58, as a mean 0.52 HCl per cent.

In Hoppe-Seyler's laboratory,^ the free acid contained in the
undiluted gastric juice, obtained from a man by the aid of the
stomach-pump, was determined ; 0.3 per cent. HCl was found.

We thus arrive at the striking result that the quantity of
free hydrochloric acid in the gastric juice exactly corresponds
to the quantity which is necessary to prevent the development
of putrefactive organisms. This coincidence cannot be acci-
dental.

It might be objected to this that the gastric juice is diluted
by the saliva and the food. On the other hand it must be re-
membered that, owing to the constant peristaltic action of the
stomach, different portions of its contents are constantly being
brought into contact with the secreting wall, and consequently
into contact with hydrochloric acid of the strength requisite to
kill bacilli. In fact, under normal conditions, pronounced
putrefactive decomposition never occurs in the stomach. But
if, under pathological conditions, the secretion should be inter-
fered with, the processes of fermentation and decomposition may
reach a very high degree.

The antiseptic action of the gastric juice was noticed more

^ Miquel, Centralbl. f. allgem. Gesundheitspflege, vol. ii. p. 403 : 1884,

2 Bidder and Schmidt, loc. cit., p. 61.

3 Heidenhain, Pflüger's Arch., vol. xix. p. 153 : 1879.

■* The method of obtaining the secretion from these glands will be discussed
later on.

' Dionys Szabö, Zeitachr. f. phyaiol. Chem., vol. i. p. 155 : 1877.

SALIVA AND GASTRIC JUICE 133

than a hundred years ago by Spallanzani.^ He found that by
moistening meat with gastric juice he could prevent decomposi-
tion for many days. But when, ceteris paribus, water was used
instead of gastric juice, an unbearable putrid odor was speedily
developed. A snake had swallowed a lizard. After sixteen
days Spallanzani opened the stomach ; the lizard was half di-
gested, but gave no odor of decomposition. Spallanzani even
observed that the gastric juice not only prevented decomposi-
tion, but stopped putrefaction which had already begun. He
found that when decomposing meat was introduced into the
stomachs of various animals, it lost its putrefactive character
after a time, and particularly its putrid odor.

A strong point in favor of the view that the antiseptic ac-
tion of the gastric juice constitutes its chief importance is found
in the fact that, in a whole series of the lower animals, the
commencement of the alimentary canal secretes a fluid very rich
in mineral acid, but containing no ferment, and having no
special action on the food. This important fact was first no-
ticed by the zoologist Troschel.^ He was making a scientific
journey with his teacher, Johannes Müller, and whilst in Mes-
sina he examined a large species of mollusc, which is there
found in the sea, the Dolium galea. It so happened that one
of these creatures, whilst being examined, suddenly ejected from
its mouth a stream of clear fluid, which fell on the floor. The
latter was covered with marble, and the fluid at once caused a
violent ebullition of carbonic acid. Troschel collected a large
quantity of this secretion from a number of these molluscs.
The weight of one of the molluscs amounted to from 1 to 2
kgrms., and the two large glands which pour the acid fluid into
the mouth, and are hence designated salivary glands by zoolo-
gists, weigh together from 80 to 150 grms. On grasping the
proboscis of the animal by its trumpet-like enlarged end, the
secretion is ejected, and can be collected in a vessel. The
quantity was very small, but amounted in one case to fully 6
loth^ Prussian weight. It was therefore easy to collect a
quantity sufficient for investigation.

Troschel, on his return to Bonn, made over the whole of
the secretion to the chemist Boedeker for analysis. It struck

^ Spallanzani, " Experiences sur la digestion," Trad, par Senebier, pp. 95, 97,
145, 320, 330, nouvelle edit. : Geneve, 1784. This work is strongly to be recom-
mended to young physiologists, as an example of impartial investigation, logical
conclusions, indomitable scepticism, and the purest enjoyment of truth for its
own sake. The same qualities are visible in all Spallanzani's other works.

* Troschel, Poggendorff's Annal., vol. xciii. p. 614 : 1854 ; or Joum. f. prakt.
Chem., vol. Ixiii. p. 170 : 1854.

^ [A ' loth ' is half an ounce.]

134 LECTURE X

Boedeker at once that the fluid displayed no trace whatever of
putrefaction or fermentation, or of mouldiness, and that it had
no smell, although it had been kept for half a year in a stop-
pered bottle. The analysis yielded so large a quantity of sul-
phuric acid that, after saturation of all the bases present, pot-
ash, soda, magnesia, a little ammonia, and a trace oiP lime, there
still remained 2.7 per cent. HgSO^. In addition, the secretion
contained 0.4 per cent, of hydrochloric acid. These results of
Troschel and Boedeker were confirmed by Panceri and De
Luca.^ They found in three analyses of the saliva of Dolium
galea, 3.3, 3.4, 4.1 per cent, of free sulphuric acid. They also
proved the presence of secretions containing free sulphuric acid
in another species of mollusc.

In more recent times, the saliva of Dolium galea has been
examined by Maly.^ He has determined the sulphuric acid
by titration, and found 0.8 and 0.9 per cent. HgSO^ in two
determinations. The secretion had no digestive influence on
any article of food. Proteid and starch remained totally un-
changed.

Fr^d^ricq^ found that the salivary glands in the octopus
had an acid reaction. The extract of these glands had no
digestive influence.

We must now ask how this remarkable phenomenon, the
secretion of the strongest free mineral acids from the alkaline
tissues, is to be explained.

That the tissue of the gastric mucous membrane does as a
matter of fact give an alkaline reaction, has been shown by
Brücke* by the following experiment. He removed a strip of
the muscular coat from a rabbit recently killed, and then with
curved scissors cut out a piece of the parenchyma of the glands
without quite touching the internal surface of the mucous mem-
brane. The fragment thus obtained could be crushed between
blue litmus paper without causing a red spot, whilst this was
produced at once on contact with the internal surface.

The material for the formation of the hydrochloric acid in
the gastric glands is undoubtedly yielded by the blood in the
form of chlorid of sodium, which is the chief constituent of
the ash of the blood-plasma and of lymph. But nevertheless
carbonate of soda is contained in both blood and lymph, which
have in consequence an alkaline reaction. How then is the

^ S. de Luca and P. Panceri, Compt. rend., vol. Ixv. pp. 577, 712 : 1867.
' Maly, Sitzungsber. d. k. Akad. d. Wissensch. Math. nat. Classe, vol. Ixxii.
part 2, p. 376: Wien, 1880.

* Fredericq, Bulletins de I' Acad. Roy. de Belgique, ser. ii. vol. xlvi. No. 11 :
1878. . '

* Brücke, Sitzungsber. d. Wien. Akad., vol. xxxvii. p. 131: 1859.

SALIVA AND GASTRIC JUICE 135

hydrochloric acid set free from the sodium chlorid of the
alkaline plasma ? Two suppositions alone are possible. Either
the hydrochloric acid is separated from the sodium by the aid
of some kinetic energy, or the hydrochloric acid is driven from
its base by another acid. With regard to the first possibility,
we are only acquainted with one kind of kinetic energy which
is able, outside the organism, to separate hydrochloric acid
from an aqueous solution of chlorid of sodium, and that is the
electric current. There was a period in the development of
physiology when a tendency existed to ascribe anything which
could not be understood to electricity. It was then thought
that the appearance of free hydrochloric acid in the gastric juice
could be explained by the supposition of electrical currents
in the gastric glands. But at the present day this view is
hardly entertained ; neither are there any valid grounds for its
adoption.

With regard to the second supposition, the displacement
of the hydrochloric acid by another acid, there was till recently
a prejudice against it, since it was thought that an acid could
only be displaced by a stronger acid. The question is whether
this opinion is well founded, and what we mean by the terms
weaker and stronger acid. The most plausible definition is
obviously the following : of two acids, the one which requires
a greater expenditure of energy to separate it from the same
base, and which, on reuniting, produces more energy, is the
stronger. In this sense, as proved by calorimetric experiments,
sulphuric acid is stronger than hydrochloric acid, hydrochloric
acid than lactic acid, and the latter than carbonic acid. But it
is erroneous to suppose that the weaker acid is never able to
drive out the stronger. From the researches of Jul. Tbomsen,^
we know with certainty that every acid drives out a portion
of every other acid from its union with a base. It may even
happen that the weaker acid unites with the bulk of the bases
present. If hydrochloric acid be added to a solution of sul-
phate of soda, heat is absorbed, and the temperature of the solu-
tion falls ; more heat is used up in the separation of the soda
from the sulphuric acid than is produced by its union with
hydrochloric acid. With the aid of the calorimeter, it is pos-
sible to follow these experiments quantitatively with exactness.
From the known amount of heat produced by the union of
hydrochloric acid and sulphuric acid with sodium, and from
the diminution of temperature observed when hydrochloric acid
acts on a solution of sulphate of sodium, it can be exactly calcu-

^ Jul. Thomsen, " Thermochemische Untersuchungen," Poggendorff's Annul.,
vols, cxxxviii.-cxliii.: 1869-1871.

136 LECTUEE X

lated how much sulphuric acid is displaced by the hydrochloric
acid. Thomsen found that when equivalent quantities of hydro-
chloric acid and sulphate of soda react upon one another, the
hydrochloric acid combines with two-thirds of the sodium pres-
ent, leaving only one-third to the sulphuric acid. The weaker
acid takes up twice as much as the stronger. Strength, as defined
above, is therefore not the determining factor. We are com-
pelled to form a new idea of the different strengths of chemical
affinity, and Thomsen has introduced the term " avidity " to
express this idea. The avidity of hydrochloric acid is therefore
twice as great as that of sulphuric acid.

Thomsen found the avidity of organic acids to be much less.
The avidity of oxalic acid is four times less than that of hydro-
chloric acid ; that of tartaric acid twenty times, that of acetic
acid thirty-three times, less. If therefore equivalent quantities
of acetic acid, hydrochloric acid, and soda react upon one
another in an aqueous solution, the acetic acid takes ^^ of the
total soda ; the hydrochloric H. If, however, more than one
equivalent of acetic acid react upon one equivalent of hydro-
chloric acid and one equivalent of sodium, more than -^^ of
the sodium unites with the acetic acid, and the further in-
crease will be in proportion to the greater amount of acetic
acid present. This phenomenon is known by the name ot
the " influence of mass." By the influence of mass, acids
of the weakest avidity are able to unite with the bases and
to displace acids of the greatest avidity. No acid has an
avidity = 0. Even carbonic acid, feeble as it is, must be able,
by the influence of mass, to displace a part of the strongest
acid.

Finally, we must suppose that even the weakest acid, water,
may displace a part of the strongest from their salts. If we
dissolve neutral chlorid of sodium in water, there will be, in
addition to the chlorid of sodium, a small trace of HCl and
NaOH contained in the solution. In the case of certain
metallic salts, which form basic salts, soluble with difficulty,
the action of water in displacing the strongest mineral acids
can be easily demonstrated. If we dilute a solution of nitrate
of bismuth with water, the basic salt is precipitated, and we find
free nitric acid in solution. In this case the mass-influence of
the feeble acid is aided by the affinity of the strong acid for
water.

The displacement of strong mineral acids by weak organic
acids may be shown in other ways than the thermo-chemical.
Maly ^ introduced into the lower portion of a tall cylinder

1 Maly, Liebig's Annal., vol. clxxiii. pp. 250-257: 1874.

SALIVA AND GASTEIC JUICE 137

a solution o'f common salt and lactic acid, and carefully poured
water upon it. After a considerable time the upper stratum
was removed and analyzed. It was found to contain more
chlorin than was sufficient to saturate the sodium that was
present. It follows that free hydrochloric acid had difiiised
into the water.

If we take these facts into consideration, there is nothing
peculiar in the separation of free hydrochloric acid from alka-
line blood. We know that the blood always contains free car-
bonic acid which, by the influence of mass, has the power of
setting free a small amount of hydrochloric acid from the chlo-
rid of sodium. The amount may be almost imperceptible, but
as soon as this small quantity of free hydrochloric acid, which
corresponds to the free carbonic acid, diffuses away, the carbonic
acid, by its mass-influence, must again set free another small
amount of hydrochloric acid, and so on.

There is thus nothing extraordinary in the occurrence of
free hydrochloric acid. But what is enigmatical is the power
epithelial cells possess of directing the hydrochloric acid, liber-
ated from the chlorid of sodium, always in the one direction
towards the excretory duct of the gastric glands, and the car-
bonate of sodium, formed from the carbonic acid, always in the
opposite direction, back towards the lymph and blood-vessels.
But this enigma confronts us everywhere in living tissue. Each
cell has the power of attracting or rejecting different materials,
according to the object they are destined to fulfil, and of for-
warding them in different directions.^ It is therefore no fresh
problem that confronts us in the attempt to explain the occur-
rence of free hydrochloric acid in the gastric glands, and, in
fact, " every explanation of the phenomena of nature consists in
referring an apparently fresh difficulty back to old and well-
known problems."

The mass-action of carbonic acid appears also to liberate
the mineral acids in the salivary glands of Dolium galea.
De Luca and Panceri observed that a strong current of gas-
bubbles arose from the glands when they were cut up and im-
mersed in water. The gas, being completely absorbed by
potash, was therefore pure carbonic acid. A gland weighing
75 grms. produced, when covered with water, 200 c.cms.
of carbonic acid, or nearly three times its volume. It must
likewise be remembered that the surrounding fluid retained
a considerable quantity of carbonic acid, and that the gland
itself remained saturated with carbonic acid. Thus at least four
times its volume of carbonic acid was absorbed in the gland.

^ Compare above, p. 4, and below p. 147, and Lecture XXI.

138 LECTURE X

As water at an ordinary temperature absorbs from an atmos-
phere of pure carbonic acid its equal volume of carbonic acid,
we must conclude that the carbonic acid in the glands was under
more than fourfold atmospheric pressure ; or we must assume
that the carbonic acid was in part loosely combined. An exact
estimate of the tension of carbonic acid which would prevent
the escape of the gas from the gland, would help to decide this
question.

It is quite possible that much carbonic acid is also liber-
ated in the epithelial cells of the gastric glands, either by
a fermentative process or by the oxidation of organic com-
pounds.

At the same time we are not obliged to ascribe the dis-
placement of the strong mineral acids to the most feeble acid,
carbonic acid. It is quite conceivable that, in the epithelial
cells of the glands, organic acids may be liberated by the
action of ferments from neutral organic compounds — for in-
stance, lactic acid from neutral sugar, which is invariably a
constituent of blood-plasma and of lymph. It is even possible
that the strongest mineral acid, sulphuric acid, may be liberated
by a fermentative action directly from a neutral compound of
sulphur, as, for instance, from proteid. That this is possible
may be seen from an example in organic chemistry — I mean
the decomposition of a glucoside, myronic acid. The potassium
salt of myronic acid, a neutral compound, splits up by the
action of a ferment into sugar, oil of mustard, and bisulphate
of potash, which latter, Graham^ has shown, at once decom-
poses in an aqueous solution into free sulphuric acid and
neutral sulphate of potash. Besides this, free sulphuric acid
might also be liberated by oxidation from neutral organic sul-
phur compounds.

At present we do not know by which, of all these con-
ceivable processes, the strong mineral acids are liberated in
glandular tissue. I have called attention to these possibilities
so as not to be obliged to have recourse to electricity for an
explanation.

The secretion of the free hydrochloric acid does not occur
in all glands of the gastric mucous membrane. The mucous
membrane in the region of the pylorus which, even with the
naked eye, can be distinguished by its pale color from the
rest of the membrane, yields an alkaline secretion which only

1 Graham, Liebig's Annal., vol. Ixxvii. p. 80: 1881. In a difiiision experi-
ment with bisulphate of potassium, more sulphuric acid diffused than corre-
sponded to the acid salt, and a little neutral sulphate of potassium crystallized out
in the diffusion-cell.

SALIVA AND GASTRIC JUICE 139

contains pepsin. The glands of the rest of the membrane
yield an acid secretion which contains pepsin as well as free
acid. This was shown to be the case by Klemensiewicz ^ and
Heidenhain ^ by the following method : —

By an incision in the linea alba of a dog that has been
fasting from thirty-six to forty-eight hours, the stomach is
drawn out by two parallel incisions, avoiding the large blood-
vessels, the pyloric zone is cut out, the two edges of the re-
sected stomach are sewn together, and the organ thus reduced
in size is replaced. Then the excised pylorus is sewn together
at one end to form a sac, while the other end is sewn into the
abdominal wound. By the careful use of antiseptics in the
treatment of the wounds, and by abstinence from food during the
following days, the animals are kept alive after this severe
operation. Heidenhain was able to observe one of the dogs,
that he had experimented upon, for ten weeks. The slimy
clear fluid secreted in the isolated pylorus invariably gave an
alkaline reaction, and, on the addition of 0.1 per cent, of
hydrochloric acid, produced a peptonizing action on proteid.
As dilute hydrochloric acid by itself cannot convert proteid
into peptone at the temperature of the body, we must assume
that the pyloric secretion contains a ferment.

In a similar method to that adopted for the pylorus,
Heidenhain isolated a rhombic portion of the fundus of the
stomach, converted it into a sac, and attached the open end
to the abdominal wound. A dog thus operated upon was
kept under observation for five weeks. The secretion collected
from the abdominal wound always possessed an acid reaction,
and manifested a pronounced peptonizing influence, showing
that it also contained pepsin.

Still further progress has been made in determining exactly
where the hydrochloric acid arises, and special cells of the
gastric glands, the so-called border or oxyntic cells, are re-
garded as its place of origin. The reasons which are adduced
in favor of this conclusion are by no means convincing ; but
it would lead me too far to consider the whole question in
detail.'

Since it is possible to keep an animal alive after resection
of the pylorus, the question occurs as to whether the whole

^ Rudolf Klemensiewicz, Sitzungsberichte der Wiener Akad., Math. nat.
Classe, vol. Ixxi. part iii. p. 249 : 1875.

2 Heidenhain, Pflüger's Arch., vol. xviii. p. 169: 1878; and vol. xix. p. 148:
1879.

' An account of the literature on this question is given in the chapter, " Phy-
siologie der Absonderungsvorgänge," by Heidenhain, in Hermann's " Handbuch
der Physiologie," vol. v. part i.: Leipzig, 1883.

140 LECTURE X

stomach might not be removed without destroying life. Such
an operation would be likely to give us much information con-
cerning the true importance of the stomach.

Czerny, the eminent surgeon, and his assistants, Kaiser
and Scriba, carried out this operation on dogs. In the year
1878, Kaiser^ published the result of the operations, and com-
municated the facts that, of the dogs in which the stomach
had been almost completely removed, one had survived three
weeks, another — operated on December 22, 1876 — was still
living. At first the animals were fed only on very small
quantities of milk and minced meat, as otherwise vomiting
ensued. The second dog, after a two-months' interval, required
no further care, and ate ordinary food like the other dogs.
The weight of the dog before the operation was 5850 grms.;
after the operation it fell to 4490 grms. by January 22, but
then increased again till it amounted to 7000 grms. on Sep-
tember 10.

In Leipzig, in the year 1882, Ludwig and his pupil Ogata ^
were engaged in investigating the functions of the stomach.
It occurred to them that it would be interesting to learn what
had become of Czerny's dogs. Ludwig wrote to Czerny at
Heidelberg, who answered by sending the dog in a perfectly
healthy state to Leipzig. It was in excellent spirits, and
ate all kinds of food with a keen appetite. The feces were
normal. In consequence of the abundant food it put on
weight, and it did not appear to differ in any way from an
ordinary dog. With Czerny's consent, the dog was killed in the
spring of 1882. "The post-mortem showed that only a very
small portion of the cardiac end of the stomach remained, and
this was dilated into a small cavity filled with food." The dog
had therefore lived for more than five years without a stomach.

Ludwig and Ogata ^ adopted another way of excluding the
stomach from participation in the functions of digestion, and
of observing what variations from the normal course of events
were then produced. They introduced the food directly into
the duodenum, by means of a fistula which had been established
close to the pylorus, and then closed the pylorus by means of a
gutta-percha ball provided with a long tube which projected
from the fistula, and by means of which the ball could be so

1 F. F. Kaiser, in Czerny's " Beiträge zur operativen Chirurgie," p. 141 :
1878. These results have been confirmed by F. de Filippi, Deutsch, med.
Wochenschr., p. 780: 1894; J. Carvallo and V. Paehon, " Arch, de Physiol.,"

vol. xxvii. pp. 349 and 766 : 1896, and U. Monari, Beitr. z. klin. Chir., vol. xvi.
p. 479 : 1896.

2 M, Ogata, Du Bois' Arch., p. 89 : 1883.
'M. Ogata, loc. cit., p. 91.

SALIVA AND GASTRIC JUICE 141

filled with water that the passage from the stomach to the
duodenum was completely cut off.

In this way it was possible to introduce at one time very
large quantities of food, such as pounded egg and minced
meat, into the duodenum without causing any disturbance.
Two injections per diem were sufficient to maintain the
animal's weight. The food was almost completely used up,
and the feces exhibited normal characters, such as are ob-
served in feeding by the mouth. The only exception was that
sometimes the connective tissue of the food was not quite so
completely absorbed as is normally the case. It was however
not a matter of indifference whether the food was previously
cooked or not. For instance, minced meat was completely
absorbed only if given raw. If administered after it had been
boiled, it was ejected per anum a few hours later but little or
entirely unaltered. Minced pork behaved in an opposite way,
and was more completely digested after having been lightly
boiled than when given raw.

Ludwig and Ogata conclude from their observations that
" the stomach is not absolutely necessary to satisfy the require-
ments of digestion, either as a reservoir of food or to produce
the gastric juice."

No experiment was made in which a dog, after removal of
the stomach, was fed by the direct introduction into the intes-
tine of putrid meat, a diet which agrees very well with normal
dogs. The chief function of the stomach would at once have
been evident had this been done.

Encouraged by the success of these experiments on animals
surgeons have carried out, with more or less success, the ex-
tirpation of the stomach in man, especially in cases of cancer of
the stomach. It is advisable, when possible, to leave a portion
of the stomach, however small it may be, since this portion will
afterwards increase in size, and thus take on the chief function
of the stomach, viz., as a reservoir and protective organ for the
intestine. In 1895 Professor Schuchardt, in Stettin, excised
the whole stomach of a patient with the exception of a small
portion (about three fingers' breadth) of the cardiac end. This
patient lived two and a half years after the operation, and was
during this time perfectly well. At the autopsy a stomach
was found with a capacity of 500 cc. It was on this account
that the patient, who at first could take only a small portion of
food at a time, was later on able to take his meals like any
other person.^

^ Communicated by C. Schlatter in the Correspondenzbl. f. schweizer Äerzte,
vol. xxvii. p. 705 : 1897. Here also several other instances of almost complete
extirpation of the stomach are recorded.

142 LECTURE X

At the Congress of Swiss Physicians in Olten on October 30,
1897, the surgeon, C, Schlatter, of Zurich,^ showed a woman
in whom he had completely extirpated the stomach, on account
of a hard tumor involving the whole stomach from pylorus
to cardia. The esophagus was too far oif from the duodenum
to allow of the two being sewn together. The esophagus was
therefore made to open into a loop of the small intestine, and
the upper end of the duodenum was closed by sutures. The
bile and pancreatic juice thus poured themselves into a blmd
portion of the gut, by which they were conducted to the small
intestine, where the food entered it through the esophagus.
The patient who had undergone this operation had already sur-
vived it eight weeks when she was shown at the Meeting, and
in this time had put on 4.4 kilos, in weight. Of course the
patient could take only small quantities of fluid or of finely
minced food at a time.

The antiseptic powers of the gastric juice have, like most
things, a limit. Certain bacteria and among them pathogenic
organisms exhibit, especially in their spore stage, such a resist-
ance to chemical agents that the hydrochloric acid of the
stomach does not kill them. Thus Falk^ observed that the
tubercle bacillus was not acted upon by gastric juice. An-
thrax virus, taken from the spleen of animals which had died
of splenic fever, was rendered inert both by gastric juice and
by a 0.11 per cent, solution of hydrochloric acid. The spores
of anthrax bacilli were as a rule not affected by dilute hydro-
chloric acid or gastric juice, though they were in a few cases.
These statements have been fully confirmed by Frank.^

The comma bacillus, which is said to cause cholera, is very
easily killed by dilute hydrochloric acid. In consequence, it is
not possible to infect animals by administration of the comma
bacillus by the mouth. But it is possible sometimes to excite
attacks resembling cholera, by injecting pure cultivations of
this bacillus into the small intestine or into the stomach, after
previously washing out the organ with a solution of carbonate
of soda.* The bacteria which produce lactic and butyric fer-
mentations appear to be more resistant to hydrochloric acid ;
at any rate, they are found very frequently, probably always,
in the human intestine,^ and after eating carbohydrates, a small

^ loc. cit. 2 Falk, Virchow's Arch., vol. xciii. p. 117 : 1883.

3 Frank, Deutsche med. Wochensch., No. 24: 1884. Compare also H. Ham-
burger, " Ueber d. Wirkung des Magensates auf pathogene Bacterien," Dissert.:
Breslau, 1890. A complete account of the literature is here given.

* Nicati et Rietsch, Eev. Seien., p. 658 : 1884 ; R. Koch, Deutsch, med.
Wochensch., No. 45 : 1884.

5 H. Notlinagel, Centralbl.f. d. med. Wissensch., No. 2 : 1881.

SALIVA AND GASTRIC JUICE J 43

amount of lactic and butyric acids is probably always found in
the stomach.- It has often been asserted that this decomposition
is produced by unorganized ferments, but it has never been
strictly proved/ In the normal feces of man, other species of
bacteria are constantly found. ^

Recently, Nencki and his pupils^ have investigated the
microorganisms occurring in the intestinal contents obtained
from a fecal fistula affecting the lower end of the small in-
testine of a patient. On meat diet they found six different
kinds of bacteria, one kind of yeast, and one mould. On
vegetable diet (peas) there were also yeasts, but no mould.
There were also six kinds of bacteria, of which only one was
identical with those found on a meat diet. These microorgan-
isms were grown in pure cultures in order to determine what
part each species played in the processes of decomposition oc-
curring in the intestine.

In pathological conditions, as in so-called catarrh of the
stomach, when the secretion of free hydrochloric acid is sup-
pressed, and the amount of alkaline mucus yielded by the sur-
face of the stomach is increased, the reaction may indeed become
alkaline, and then all sorts of bacteria are able to grow lux-
uriantly.* Lactic and butyric acids especially are formed in
abundance. The presence of acetic acid has also been demon-
strated ; this is probably produced from the alcohol, owing to
the oxidizing influence of the air which has been swallowed.
Alcohol arises by fermentation from the carbohydrates. Not
only does yeast, which has actually been observed in the
stomach, produce alcohol, but certain varieties of bacteria ap-
pear also to do so.^

The gases which are formed by the processes of fermentation
in the stomach are carbonic acid gas, hydrogen, and marsh gas.^
Under pathological conditions they may be formed in consider-
able quantities, and so cause dilatation of the organ. In one
case of dilatation of the stomach Fr. Kuhn^ found that one

1 See Ferd. Hueppe, llittheil. a. d. kaiserl. Gesundheitsamte., vol. ii. p. 309 :
Berlin, 1884. Nencki u. Sieber, Journ. f. prakt. Chem., vol. xxvi. p. 40: 1882.

2 See Berthold Bienstock, Zeitschr. f. klin. Med., vol. viii. p. 1: 1884; L.
Brieger, Zeitschr. f. physiol. Chem., vol. viii. p. 306 : 1884.

ä Macfadyen, Nencki, and Sieber, Arch. f. exper. Path. u. Pharm., vol.
xxviii. p. 325: 1891.

■* An account of the microorganisms which occur in the stomach under
pathological conditions, as well as the literature of the subject will be found in
the paper by W. de Bary, "Beitr. zur Kenntniss der niederen Organismen im
Mageninhalte" (Arch. f. exp. Path., vol. xx. p. 243: 1885).

^ L. Brieger, Zeitschr. f. physiol. Chem., vol. viii. p. 308: 1884.

«G. Hoppe-Seyler, Deutsch. Arch. f. klin. 3fed., vol. 1. p. 82: 1892.

'' Fr. Kuhn, Zeitschr. f. klin. 3Ied., vol. xxi. p. 584 : 1892.

144 LECTUEE X

liter of gastric contents developed four liters of gas in four
hours when kept outside the body at the body temperature.
This gas had the following composition : —

CO2 20.0 per cent.

O 8.3 "

H 30.9 "

CH^ 0.3

N 40.5 "

CO A trace

At times sulphuretted hydrogen may also be formed in the
stomach contents.^

If the organic acids reach the esophagus, they cause heart-
burn by the irritation of the mucous membranes of the esopha-
gus and fauces. This symptom is usually treated with car-
bonate of soda or magnesia, without considering that the cause
of the disorder is thereby increased rather than diminished.
The free acids are neutralized by the drug, and the growth of
the fungi and fermentation proceed more rapidly. The only
proper treatment of heart-burn would be to recommend absti-
nence to the patient, until the stomach was empty and disin-
fected by its normal hydrochloric acid.

The contents of the stomach in a considerable number of
diseases have recently been examined by means of the stomach-
pump.^ It has been found that the free hydrochloric acid is
frequently absent in the gastric juice of the patients, whilst
pepsin is always present.^ For this reason, dilute hydrochloric
acid is frequently prescribed as a remedy in dyspepsia. Many
practitioners assert that they have obtained a favorable result
with it. I would however warn against a too energetic
treatment with free hydrochloric acid, especially a very pro-
longed use in chronic gastric trouble. Hydrochloric acid is
partly excreted in a free state by the kidneys. We are

1 J. Boas, Deutsch, med. Wochenschr., No. 49, p. 1110 : 1892.

2 O. Minkowski, Mittheilungen aus der med. Klinik zu Königsberg i. Pr., p..
148 : 1888. The earlier literature is discussed here.

^ It has frequently been asserted that free hydrochloric acid is partly or
completely replaced by lactic acid, even in the normal gastric juice, but espe-
cially in certain diseases. It has even been asserted that the absence of free
hydrochloric acid might serve for diagnostic purposes, its absence having been
regarded as indicative of carcinoma of the pylorus. A whole series of convenient
reactions for the demonstration of free hydrochloric acid have also been devised.
But these tests have not proved reliable, nor has the absence of free hydrochloric
acid as a sign of a definite malady been found to be trustworthy. Just as little
has the presence of lactic acid as a constituent of normal gastric juice been
proved. It would appear that the lactic acid found in the stomach never comes
from the gastric glands, but always from the carbohydrates of the food. An
account of the extensive literature on this subject will be found in Deutsch. Arch,
f. klin. Med., vol. xxxix. p. 233 : 1886, by J. von Mering and A. Cahn, entitled
" Die Säuren des gesunden und kranken Magens."

SALIVA AND GASTEIC JUICE 145

ignorant whether we should not be throwing too much work
upon these organs, and whether we should not injure their tis-
sue by a too prolonged use of it. We are also unaware what
other tissues are affected by the hydrochloric acid on its way
from the stomach to the kidney, and what variations from their
normal chemical processes it causes. A diminution of their
alkalescence can never be a matter of indifference, since the in-
tensity of the processes of oxidation and disintegration must be
intimately bound up with the reaction of the tissue, judging at
any rate from analogous chemical processes that we are familiar
with outside the body. So long as we are ignorant on these
points, we must be cautious in the use of powerful remedies
like free mineral acids. In most cases, the best advice would
perhaps be that of abstinence, until the whole lining of the
stomach has become disinfected by normal undiluted gastric
juice. Even in weakened and anemic individuals abstinence is
perhaps more effectual than hydrochloric acid and pepsin, ac-
companied by more food than their instinct tells them they can
dispose of. The administration of preparations of pepsin and
pancreatin is a useless measure.

It should also be noted that to begin a meal with soup, and
to drink much during a meal, are not rational proceedings ; be-
cause the gastric juice becomes too much diluted, and loses its
disinfectant properties. There is an ancient and good dietetic
rule, not to drink for an hour or two after eating, when thirst
is actually felt. It is noticeable that to the healthy instinct of
children soup is repugnant. At periods when cholera is preva-
lent, it is advisable to avoid all voluminous foods and to reduce
liquids to a minimum, so that the whole contents of the stomach
may be impregnated with hydrochloric acid of the necessary
concentration.

The question as to why the stomach does not digest itself is
one which has caused much discussion. The tissues of the
stomach consist entirely of digestible matter — proteid and gela-
tin. In fact, as soon as life ceases, self-digestion of the stomach
takes place. In post-mortem examinations, it is common to
find a part of the mucous membrane of the stomach softened
or dissolved, and this phenomenon is especially marked in the
bodies of healthy and powerful individuals who have met with
a sudden death in the midst of full digestion. The old doc-
trine, that the ' softening of the stomach ' was a pathological
process going on during life, is now definitely rejected.^ The
reason why the process of digestion does not proceed further in

■^ Elsässer's " Die Magenerweichung der Säuglinge " (Stuttgart and Tübingen,
1846), should be read in this connection. The earlier literature is also critically

10

146 LECTURE X

the dead body is due to the process of cooling down which
takes place.

If a dog be killed during digestion and the body be kept
warm, we find, after two or three hours, not only a self-diges-
tion of the stomach, but also of the neighboring parts, liver
and spleen. Why does this solution not take place in the liv-
ing animal ? This question was taken up by John Hunter,^
who supposed that " the living principle " hindered self-diges-
tion. CI. Bernard ^ thought to refute this view by the follow-
ing experiment. He placed the leg of a living frog into the
gastric fistula of a living dog. The leg was soon digested,
and the frog remained alive. The living principle had not
therefore protected the frog. Pavy^ introduced the ear of a
live rabbit into the gastric fistula of a dog. A large part of
the ear was digested in a few hours, the tip being entirely
dissolved.

Pavy* thought that an explanation of the power of resist-
ance possessed by the living gastric mucous membrane was to
be found in the quantity of blood contained in it. He sup-
posed that the constant rapid rush of alkaline blood and alka-
line lymph through the tissues did not allow the pepsin, which
can only peptonize in acid solution, to do its work. If the
circulation were arrested, self-digestion began. Pavy showed
that, after tying the blood-vessels of the stomach in dogs, a
part of the mucous membrane was digested ; in rabbits, even
perforation of the stomach set in. He opened a dog's stom-
ach and ligatured a portion of the opposite wall so that the
piece that was tied hung into the stomach, and the piece was
digested as if it had been swallowed. Pavy concludes from
these experiments that the alkalies in the blood prevented
self-digestion ; and this interpretation has been commonly ac-
cepted. But the conclusion is not correct. The alkalies are
not the only things carried to the epithelial cells by the blood.

treated here. The most prominent pathological anatomists and medical men
have adopted Elsässer's view, that the softening of ,the stomach is a post-mortem
process. It is only in very rare and exceptional instances that softening and
perforation of the stomach set in before death. See W. Mayer, " Gastromalacia
ante mortem," Dissert, inaug. Erlang : Leipzig, 1871.

^ J. Hunter, " On the Digestion of the Stomach after Death," Phil. Trans. :
June 18, 1772; and "Observations on Certain Parts of the Animal Economy " :
London, 1786.

2 CI. Bernard, " Le5ons de physiologic experim.," &c., II. p. 406: Paris,
1856.

' F. W. Pavy, " On the Gastric Juice," &c., Guy's Hospital Reports, vol. ii.
p. 265 : 1856.

* F. W. Pavy, " On the Immunity enjoyed by the Stomach from being digested
by its own Secretion during Life," Phil. Trans., vol. cliii. part. i. p. 161 : 1863 ;
and " On Gastric Erosion," Guy's Hospital Reports, vol. xiii. p. 494 : 1868.

SALIVA AND GASTßlC JUICE 147

The blood brings to the glandular cells everything which is
necessary to fulfil their functions. If the supply of blood be
cut off, those vital functions which resist the action of the
pepsin ferment must also cease. Why does not the pancreas
digest itself, as pancreatic ferment is effective in a neutral and
alkaline solution?

Here we are face to face with an unsolved problem. But it
is not a new one ; as the epithelial cells of the gastric glands
liberate free hydrochloric acid and still remain alkaline, so the
epithelial cells of the pancreatic gland secrete the ferment and
themselves remain free from ferment. We see the same thing
going on in every vegetable cell. The cell sap which fills up
cavities in the protoplasm of the cell is acid, the cell itself,
like all contractile protoplasm, is alkaline. The cell sap is
frequently brilliantly colored, while the cell itself, which
produces the coloring matter, is colorless. But as soon as
life ceases, as soon as the vital phenomena, the visible ameboid
movements, stop, the incomprehensible power of selecting
substances likewise disappears ; the laws of diffusion are in no
way interfered with, and the protoplasm becomes tinged with
coloring matter. This inexplicable power of separating and
distributing the substances according to the object in view
is possessed by every cell in our bodies (compare above, p.
137).

Pavy relies upon the fact that self-digestion occurred after
the introduction of large quantities of acid into the stomach,
even when the circulation was not disturbed, to prove his view
that circulating blood prevents self - digestion only by its
alkalinity. In this case, Pavy considers the alkalies do not
sujffice to prevent the action of the acids. He injected 3 ozs.
(= 93 grms.) of dilute hydrochloric acid, which contained 3
drms. (= 12 grms.) HCl, into the stomach of a dog, and at the
same time tied the pylorus and the esophagus, avoiding the
vessels. The dog died in an hour and forty minutes, and the
post-mortem, which was immediately made, showed solution of
the gastric mucous membrane, and perforation of the wall of the
stomach at the cardiac orifice. But this experiment does not
justify any conclusion. The amount of hydrochloric acid in-
jected was much too large. Pavy might have destroyed the
wall of the stomach equally well with caustic potash.

It has often been attempted to refer the origin of the round
gastric ulcer to self-digestion. But the danger of self-digestion
is by no means so great as was formerly believed. It has been
shown, by numerous researches, that the wall of the stomach
has a decided tendency to heal rapidly after wounds of the

148 LECTURE X

most varied description. This is conclusively proved by the
favorable results of operations on the stomach in animals and
human beings. The most plausible hypothesis on the cause
of the gastric ulcer has been advanced by Virchow/ who con-
siders that some kind of disturbance in the circulation is at the
root of the disease. And, in fact, Panum ^ succeeded in pro-
ducing hemorrhagic infarctions with the subsequent formation
of ulcers in dogs, by embolic plugging of the smallest arteries
of the gastric mucous membrane. These results are quite
in harmony with Pavy's above-mentioned experiments. But
it has very rarely been found that thrombotic or embolic
plugging precedes the round gastric ulcer in human beings. It
has therefore been assumed that the round gastric ulcer
was caused by abnormal increase of acid in the gastric juice,
or in the contents of the stomach. But this supposition is
utterly unsupported by fact. It is also to be noted that the
gastric ulcer is generally situated in the pylorus and in the
small curvature, very seldom in the fundus, where the acidity
is greatest. The etiology of the Ulcus ventriculi is still in-
volved in obscurity.

I must not omit to mention that one of the functions of the
stomach consists in the absorption of nutritive substances.
The process undoubtedly commences in this section of the diges-
tive tract. The most recent and careful researches on this func-
tion we owe to J. von Mering ^ and his pupils. Mering established
duodenal fistulse in dogs and then introduced water or solutions
of food-stuifs into their stomachs. When pure water was given,
it flowed out of the fistula even while the animals were drink-
ing, but always in spurts. If the finger were introduced into
the pylorus, this intermittent flow was found to be due to
the alternate contraction and relaxation of the pyloric orifice.
Each minute the pylorus opened two to six times, each time letting
out from 2—15 cc. of water. In over 100 experiments, in which
a measured quantity of water was given by the mouth, almost the
exact amount was recovered from the duodenal fistula, and
indeed, on one or two occasions, a few cc. over and above.
Thus in one large dog, after 440 cc. water had been taken by
the mouth, 445 cc. flowed out from the fistula within the next

* Virchow in his Arch., vol. v. p. 281 : 1853.

2 Panum, Virchow's Arch., vol, xxv. : 1862.

3 J. von Mering, assisted by Dr. Aldehoff and Dr. Happel, " Ueb. die
Function des Magens." Separatabdruck a. d. Verhandlungen des III. Congresses

f. innere Med. zu Wiesbaden, 1893. For the older work see H. Tappeiner,
" lieber Resorption im Magen," Zeitschr. f. Biolog., vol. xvi. pp. 497-507 : 1880 ;
B. von Anrep, "Die Aufsaugung im Magen des Hundes," Du Bois' Arch., pp.
504-514 : 1881 ; R. Meade Smith, ibid., p. 481 : 1884 (experiments on frogs).

SALIVA AND GASTRIC JUICE 149

thirty minutes. Mering concludes from his experiments that
practically no water is absorbed from the stomach.

An obvious criticism of these experiments is that no account
has been taken of the salivary secretion. A large dog secretes
in one hour from 30—90 ccm. of saliva/ which gets into the
stomach. If, therefore, only just so much water is recovered
from a duodenal fistula as has been taken by the mouth, we
must conclude that the stomach has absorbed an amount of
water equal to the volume of saliva secreted during this time.
It is to be hoped that these experiments will be repeated in
combination with extirpation of the salivary glands or ligature
of their ducts, or that the saliva be prevented in some other
way from reaching the stomach. It must be further objected
that the stomach behaves quite differently when the fluid is
allowed to flow into the intestines instead of escaping by the
duodenal fistula. Thus Mering states that " if the duodenal
fistula be closed so that the contents of the stomach can only
be discharged into the intestine, all escape from the body being
prevented, a very much longer time elapses before the ingested
water leaves the stomach. Whereas, in a dog with open fistula
500 cc. left the stomach in less than thirty minutes, after closure
of the fistula in the same dog a considerable amount of fluid was
still found in the stomach sixty minutes after its introduction.
If 250 cc. of warm milk be introduced by means of the fistu-
lous opening into the duodenum in the course of fifteen minutes,
and then 500 cc. water be injected into the empty stomach, only
a few cc. of fluid will leave the stomach within the next half
hour ; although when the intestine is empty the stomach would
get rid of the 500 cc. by means of the fistulous opening in less
than thirty minutes. This arrangement evidently indicates that
distention of the small intestine reflexly inhibits the evacuation
of the stomach."

If the evacuation of the stomach is thus slowed under normal
conditions by this reflex mechanism, we must grant the possi-
bility that there may be a considerable absorption of water from
the stomach.

In the animals with a duodenal fistula, the absorption of
water on the other hand seemed to be extremely slight, as was
evident from the fact that "they were continually tormented
with thirst. They drank water by the liter, without assuaging
their thirst ; in fact, the more they drank, the worse grew the
thirst, because a small excess of fluid was secreted by the stomach
and lost to the body with the ingested fluids."

^ Bidder and Schmidt, "Die Verdauungssäfte u. der Stoffwechsel." Mitau
and Leipzig, pp. 12 and 13 : 1852.

150 LECTURE X

If solutions of food-stuffs — grape-sugar, maltose, cane-sugar,
milk-sugar, dextrin, or peptone — were injected into the stomach
of such animals, a portion of these substances could not be recov-
ered from the fluid flowing out by the fistula. Thus 20 per
cent, of the dextrose and 60 per cent, of the peptones disap-
peared. When 30 grms. of sodium chlorid in 400 cc. water
were introduced, 6.5 grms. of the salt were absorbed in the
stomach. The fluid however increased in amount, so that 787
cc. of fluid were collected from the fistula. Dilute solutions of
alcohol behaved like the salt solution : a portion of the alcohol
disappeared, but the total volume of fluid was largely increased.

The following experiment served also to show that an excre-
tion of water proceeds, pajn, passu, with the absorption of dis-
solved substances in the stomach. A dog weighing 7 kilos, was
morphinized and its pylorus ligatured. 100 cc. of a 66 per
cent, solution of dextrose were then injected into the empty
stomach and the esophagus ligatured. After nine hours the
stomach was found to contain 400 cc. of fluid, with 9 per cent,
of sugar.

These interesting experiments of Mering's are extremely
suggestive, especially in their bearing on the symptomatology
and therapeutics of pyloric stenosis and dilatation of the stomach.
For the many new points of view put forward by this author,
I must refer my readers to the study of the original.

LECTURE XI

THE PROCESSES OF DIGESTION IN THE INTESTINE THE PAN-
CREATIC JUICE AND ITS FERMENTATIVE ACTION FER-
MENTS IN GENERAL THE ACTION OF THE PAN-
CREATIC JUICE ON THE CARBOHYDRATES^

FATS, AND PROTEIDS THE NATURE

AND SIGNIFICANCE OF PEPTONES

The time during which different articles of diet remain in
the stomach of human beings varies very greatly. It does not
depend only on the quality of the food ; it also increases with
the quantity. The mechanical condition, the degree to which
it has been masticated, likewise affects it, as also the intensity
of the preceding hunger, and especially the state of the stomach
at that moment, a state which depends on many physical and
psychical influences. Numerous observations on people with
gastric fistulse ^ have shown that the food remains in a healthy
stomach from three to ten hours. In disease the time is often
much longer, as modern experience has discovered by means of
the stomach-pump. The emptying of the stomach goes on very
gradually in small portions at a time. Busch ^ observed this in
a woman, who, in consequence of a wound made by a bull's
horns, had an artificial anus a little below the duodenum, from
which the contents of the stomach oozed out, as they were un-
able to reach the other opening of the small intestine. The
first portions of food appeared in the fistulous opening as early
as from fifteen to thirty minutes after being swallowed.

Three new secretions, all of which yield an alkaline re-
action, act immediately upon the food when it reaches the in-
testine ; they are the pancreatic juice, the intestinal juice, and

^ W. Beaumont, "Experiments and Observations on the Gastric Juice, and
the Physiology of Digestion," reprinted from Plattsburgh edition, by Andrew
Combe, Edinburgh, 1838; O. von Griinewaldt, " Succi gastrici humani indoles
physic, et ehem.," &c.. Dissert.: Dorpati, 1853; Ann. Chem. Pharm., vol. xcii.
p. 42: 1854; E. v. Schröder, "Succi gastrici humani vis digestiva," Dissert.:
Dorpati, 1853; F. Kretschy, Deutsch. Arch. f. klin. Med., vol. xviii. p. 527:
1876; Jul. Uffelmann, Arch. f. klin. Med., vol. xx. p. 535 : 1877.

^ W. Busch, Arch. /. path. Anat. u. Physiol., vol. xiv. p. 140 : 1858.

151

152 LECTUEE XI

the bile. By their means, the chyme, which is the name given
to the acid contents of the stomach, is gradually neutralized,
and usually presents in the lower part of the intestine a reaction
which may be only slightly acid or even occasionally alkaline/
We will first consider the action of the pancreas.

The PANCREAS is the digestive gland par excellence. Its
secretion, so far as we know, has no other action than a
digestive one ; it effects chemical changes in all classes of
food, and prepares them for absorption. The proteids are pep-
tonized, starch is split up into soluble carbohydrates, the fats
into glycerin and fatty acids. There is scarcely any animal
which does not possess a secretion with an action analogous to
that of the pancreatic juice, whereas a gastric digestion is want-
ing in many vertebrates, e. g., many fishes and even the lowest
mammals, echidna and ornithorynchus.^ The invertebrates
have neither a peptic digestion nor have they bile. But a
process analogous to pancreatic action has been found wherever
it has been sought.^ It can even be recognized in the lowest
organisms, the bacteria : a fluid containing bacteria acts on the
three main classes of foods just like the pancreatic juice. The
pancreatic ferments have been found absent only in a few in-
testinal parasites.* This is perfectly clear for teleological
reasons : the organisms are always floating about in food that
has been already digested.

Before proceeding to consider the modes of action of the
pancreatic juice in mammals and in human beings, together
with the chemical changes which it causes in the three groups
of food-stuffs by its ferments, we will first state clearly what is
known concerning the nature and character of ferments. We
have already made use of the term ' ferment ' on several occasions.
It is therefore desirable that we should now consider what con-
ception we are to attach to this word.

■^ On the reaction of the intestinal contents see A. Macfadyen, M. Nencki,
and N. Sieber, Arch. f. exper. Path. u. Pharm., vol. xxviii. p. 319 : 1891. The
earlier literature will be found here. Compare also Schmidt-Mülheim, Du Bois'
Arch., p. 56 : 1879 ; and Gley and Lambling, Revue biol. du Nord de la France,
vol. i. : 1888. [Vaughan Harley, Journ. Physiol., vol. xviii. p. 2 : 1895 ; Moore
and Rockwood, ibid., vol. xxi. p. 58 : 1897.]

2 A. Oppel, Biol. Centralbl., vol. xvi. p. 406: 1896.

^ Hoppe-Seyler, " Ueber Unterschiede im chemischen Bau und der Ver-
dauung höherer und niederer Thiere," Pflüger's Arch., vol. xiv. p. 395 : 1877.
Compare also the numerous and comprehensive works on this subject by F.
Plateau in the years 1874-1877, and the works of Fred^ricq and Krukenberg of
the same time. An account of the literature on tlie digestion of the lower
animals has been given by Krukenberg, " Vergleichend physiologische Vorträge,"
II.; "Grundzüge einer vergleichenden Physiologie der Verdauung ": Heidel-
berg, 1882.

* L. Fredericq, Bulletins de l'Acad. Roy. de Belgique, ser. 2, t. xlvi. No. 8 :
1878.

DIGESTION IN THE INTESTINE 153

We will first restrict ourselves to facts derived from
observation. Probably no one has ever seen ferments. What
can be seen and observed is merely the process of which the
hypothetical ferment is the exciting cause. This process con-
sists, in all cases, in the fact that a complex compound splits
up into more simple ones, while kinetic energy in the shape of
heat is set free. Therefore in all these processes potential
energy is converted into kinetic energy. The atoms pass from
an unstable into a stable arrangement. Stronger affinities are
hereby satisfied. To adopt the terminology already defined
(pp. 34—35), the ultimate cause is the potential energy stored up
in the complex molecule, the effect is kinetic energy, and then
we have to seek the 'exciting cause,' the 'impetus,' the
'liberating force.' These are termed ferments in some cases,
but not in all. What therefore have the liberating forces in all
these various processes in common, and what distinguishes
them from each other? This can be clearly shown by a series
of examples.

Glyceryl trinitrate, so-called nitroglycerin, splits up into
carbonic acid, water, nitrogen, and oxygen : —

2[C3H5(ON02)3] = 6C0, + 5HjO + 6N + O.

A very considerable amount of heat is developed. A highly
unstable atomic arrangement is converted into a stable one.
The oxygen, which has a very slight affinity for nitrogen but
a very close affinity for carbon and hydrogen, was in the
original molecule combined with nitrogen, but in the smaller
molecules resulting from the decomposition, is united with
carbon and hydrogen. The impetus is given by mechanical
means such as a knock or a blow, therefore by motion, or by
heat such as a flame, another form of motion. Nitrogen
trichlorid splits up explosively with great development of
light and heat into nitrogen and chlorin : —

NCI3 + NCI3 = N, + Ck + CI, + C\,.

Here again the unstable atomic arrangement is converted into
a stable one. Stronger affinities are satisfied. For many
reasons we are compelled to adopt the conclusion that the
elements, in an uncombined state, do not consist of single
isolated atoms, but are united into molecules. The affinity of
nitrogen atoms to each other, and of chlorin atoms to each
other, is obviously stronger than the affinity of chlorin atoms
to nitrogen atoms. The impetus to the rearrangement of the
atoms is given by some mechanical means or by a rise of
temperature. lodid of nitrogen, the formation of which is

154 LECTÜKE XI

analogous to that of nitrogen trichlorid, explodes even more
readily, if acted upon by certain periodic movements, wave-
motions of a definite velocity and wave-length. It may be
shown that it does not explode on a low-toned, but that it
does so on a high-toned plate or string. This phenomenon is
evidently analogous to the resonance of certain elastic bodies
when struck by waves which proceed from another sounding
body. This resonance occurs as is well known only with notes
of a definite pitch. So that we may also imagine that, if the
vibrations which act upon an unstable molecule have a definite
wave-length, the atoms of this molecule are thrown into corre-
sponding vibration, and this suffices to overcome the slight
attraction of the atoms to one another, and thus to produce a
conversion into more stable compounds.

The explosion of the nitrogen trichlorid can also be
brought about by contact with various substances, such as
phosphorus, phosphorus compounds free from oxygen, selenium,
arsenic, some resins (other kinds being inert), non-volatile oils,
&c. Here too we might imagine that, from the various mole-
cular vibrations of these substances (which we call heat), we
get a certain resultant vibration which coincides in wave-
length with that of one of the constituents of the nitrogen tri-
chlorid molecule, and so occasions its decomposition.

Potassium chlorate splits up into potassium chlorid and
oxygen. The dissociation is set up by the application of heat.
But the rise of temperature need not be nearly so high when
certain substances are present, such as peroxid of manganese,
ferric oxid, or cupric oxid. The presence of these substances
probably so modifies the heat-waves, that the atoms of the
potassium chlorate are more easily thrown into responsive
vibrations, and thus decomposed.

Peroxid of hydrogen decomposes on contact with platinum,
gold, silver, peroxid of manganese, &c. In these cases
it is called an effisct of contact, or a katalytic effect. We
can form the following hypothesis of the process which goes on
here, as in the cases above cited : the substance which acts
' katalytically ' exercises an attraction on one of the atoms in
the unstable molecule. It does not unite with the atom, but
the unstable arrangement of the atoms in the molecule is
altered to a stable one.

Grape-sugar splits up into alcohol and carbonic acid : —

CeHiA = 2C02 + 2CÄO.

This change can be shown to be accompanied by a rise of tem-
perature. This is in accordance with the fact that the heat

DIGESTION IN THE INTESTINE 155

of combustion of alcohol is less than that of the grape-sugar
from which the alcohol arose. Thus a part of the potential
energy stored up in the sugar is converted through decomposi-
tion into kinetic energy, into heat. The atoms of the sugar
have passed from a less stable into a more stable arrangement.
Stronger affinities have been satisfied. The nature of the
liberating force is in this case still unknown. It is known
however that the conversion takes place only if two conditions
are fulfilled : they are, first, the presence of yeast-cells ; and
secondly, a certain temperature — from 10° to 40° C. Judging
from analogy of the examples already given, we should suppose
that here again a form of motion starts the decomposition.
The motion might proceed from the vital functions of the cell.
But it is likewise conceivable that certain substances are pro-
duced in the metabolism of the cell, and that these substances
act in a similar manner to the katalytic bodies in the ex-
amples adduced above. The yeast-cells are called a ' ferment.'
Quite recently Ed. Büchner ^ has shown that the presence of
living cells is not necessary in order that fermentation may
take place. He finely powdered the cells with quartz sand,
treated them with a little water, and then subjected them in an
hydraulic press to a pressure of 500 atmospheres. He obtained
in this way an almost clear yellow fluid which, on mixture with
a solution of cane-, grape-, fruit-, or malt-sugar, set up fermen-
tation within half an hour. When the mixtures were kept in
the ice-chest, the fermentation lasted a fortnight. It might be
thought that the expressed protoplasm still possessed some
vital properties, especially as it has often been found that frag-
ments of protoplasm may still present certain signs of vital
activity, such as contraction. In reply to this objection may be
set the fact observed by Büchner that the fermentative action
of yeast-juice is not abolished by the addition of chloroform,
which, as is well known, inhibits all the vital functions with
which we are acquainted.

Cane-sugar splits up into equivalent quantities of dextrose
and levulose. Here again there is a development of heat,^ and
again the yeast plays a part. But in this case also it is not
requisite that the cells should be living; an aqueous extract
from the yeast-cells, killed with ether, is all that is necessary.
We may assume that the atoms composing any of the molecules
in this extract are in a state of oscillation, or that different
molecules oscillate against each other, and that the resultant of

^ Ed. Büchner, Ber. d. deutsch, ehem. Ges., vol. xxx. p. 117 : 1897. Compare
J. de Rey-Pailhade, Compt. rend., vol. cxviii. p. 201 : 1894,
2 A. Kunkel, Pfliiger's Arch., vol. xx. p. 509 : 1879.

156 LECTURE XI

these motions causes the dissociation of the molecules of cane-
sugar. A theory has been advanced, but not yet verified, that
the presence of one particular chemical individual in the yeast-
extract is essential for the initiation of decomposition. This fer-
ment has been termed invertin.^ An account of the attempts
which have been made to isolate the ferments will be given later.

Starch-flour decomposes on boiling with dilute acid into
molecules of grape-sugar. In this reaction the direct proof
that heat is produced cannot be given. But we must assume
that this is the case, because the heat of combustion of the
grape-sugar is less than that of the starch. The impetus to
the change may be a special modification of the increased molec-
ular movement due to the heat in presence of the acid ; or
we must suppose that the acid attracts the sugar molecules con-
tained in the starch molecule, and possibly forms a temporary
compound which again rapidly breaks up with absorption of
water. The conversion of starch into sugar is always accom-
panied by hydration, which is the case in the decomposition of
cane-sugar, and probably in all similar decompositions. I shall
return to this point again.

Starch-flour also splits up at a moderate temperature
into maltose and dextrin, if it comes into contact with certain
substances, which are contained in germinating barley or in
saliva and in pancreatic juice. But in this case the term
ferments is used as indicating chemical individuals. But these
hypothetical substances are perhaps merely the conditions
necessary to start a definite form of motion, which acts as the
impetus in the decomposition of the starch-molecule. A de-
velopment of heat cannot be proved when starch is broken
up by ferments. Maly^ even observed an absorption of heat.
This is explicable in the following way : starch-flour is in-
soluble, whereas the products of decomposition are soluble in
water. Heat must be used up in their solution, as is always
the case in the transit from the solid to the fluid state. The
amount of heat thus fixed is greater than that liberated by
decomposition. That heat is set free when decomposition takes
place follows of necessity from the fact that the heat of com-
bustion of the maltose and dextrin is less than that of an equiva-
lent amount of starch -flour.

Hoppe-Seyler ^ and his pupils * have shown that formate of

* Eduard Donath, Ber. d. deutsch, ehem. Ges., vol. viii. p. 795 : 1875 ; vol. li.
p. 1089: 1878; M. Barth, ibid., vol. xi. p. 474: 1878.

2 Maly, Pflüger's Arch., vol. xxii. p. Ill : 1880.

^ Hoppe-Seyler, Pflüger's Arch., vol. xii. p. 4 : 1876.

* Leo Popoff, Pflüger's Arch., vol. x. p. 113 : 1875.

DIGESTION IN THE INTESTINE 157

lime, by the. action of certain bacteria, is split up into carbonate
of lime, carbonic acid, and hydrogen, with absorption of water : —

xH .OH

0=0 C==0

X

^Ca+2H0H= >Ca+2H2=CaC03+C02+H50-f 2H2.

0 .0

<>=0 C=Ü

^H "^HO

Heat is developed in this process. If the bacteria be killed by
ether, the decomposition continues. This ferment therefore be-
haves like invertin. Sainte-Claire Deville and Debray ^ have
made the important discovery that the same decomposition of
formic acid into carbonic acid and hydrogen can be also brought
about by finely divided iridium, rhodium, or ruthenium, ob-
tained in a moist condition by reduction. Platinum or palla-
dium produced in the same way had no action.

We thus see that a living cell, an organic substance, and a
metal all produce the same effect.

The decomposition of acetic acid into carbonic acid and marsh-
gas is completely analogous to the decomposition of formic acid,
and occurs under the same conditions : —

.CH3 ^OH

C=0 C=0

\Ca+2H0H= Nca+2CH4=CaC03+C02+H20+2CHi.

o o

c=o 0=0

^CHj ^OH

Heat must again be set free in this process, for the heat of com-
bustion of the marsh-gas is less than that of an equivalent
amount of acetic acid.

From all these examples it may be seen that we know
nothing further concerning the ferments than we do about the
' katalytic ' substances. Their presence is absolutely essen-
tial to bring about that form of motion which gives the im-
petus to the transition from an unstable arrangement of atoms
into a more stable one. We speak of a katalytic effect, when
the substance to which this effect is ascribed happens to be a

^ H. Sainte-Claire Deville et H. Debray, Comp, rend., vol. Ixxviii. 2, p. 1782 :
1874, •

158 LECTUEE XI

well-known inorganic compound or an element. If, on the
other hand, they are unknown organic substances, we speak
of a fermentative action. There is at present no reason for
assuming that there is any essential difference between the
mode of action of organized ferments — living unicellular
organisms — and non-organized, ' unformed ' ferments. We
may suppose that the process of fermentation is the same in
both cases ; but we know as little concerning the action of
the unformed ferments as we do concerning the organized
ferments.

The decomposition effected by the organized ferments ap-
pears to take place in the substance of the living cell, and the
energy liberated by the decomposition is utilized for the vital
processes of the cell. In favor of this view can be adduced
the fact that, in the case of alcoholic fermentation, the amount
of sugar decomposed in the unit of time is inversely propor-
tional to the supply of oxygen. With a free supply of oxygen,
there are two sources for the production of the kinetic energy
required for the vital functions : decomposition and oxidation.
When oxygen is withdrawn, one source is closed, and the other
utilized the more.^ This fact is of far-reaching importance
for the comprehension of the vital processes in the higher
animals.^

In all fermentations the decomposition is always accompa-
nied by hydration, in consequence of which these processes can
only take place in presence of water. The exceptions to this
rule are only apparent. Thus in alcoholic fermentation, grape-
sugar (CgHj20g) is decomposed iato 2C2lIgO and 2CO2, appa-
rently therefore without taking up any water. But we must
not forget that carbonic acid in watery solution must, like all
other dibasic acids, contain two HO radicals : —

.OH

Cr^^O =C02+H20.

Butyric acid fermentation (CgH.Pg = C^H^O^ +200^ + 2H2),
and lactic acid fermentation (CgH^jOg = 2C3lIg03) also appear

^ Brefeld, Landw. Jahrb. v. Nathusius u. Thiel, Heft. i. : 1874 ; Verhandl. d.
Würzburger phys. -med. Gesellsch., N. F., vol. viii. p. 96 : 1874 ; Pasteur, " Etudes
8ur la biere," chap. vi. p. 229 : Paris, 1876 ; Hoppe-Seyler, " Ueber die Einwirkung
des Sauerstoffes auf Gährungen " : Festschrift, Strassburg, 1881; Nencki, ^rcA.
/. exp. Path. u. Pharm., vol. xxi. p. 299 : 1886.

2 The fact observed by A. Fränkel (Virchow's Arch., vol. Ixvii. p. 283 : 1876),
that the decomposition by proteid goes on twice as fast in dogs when their supply
of oxygen is diminished, is perhaps of a similar nature. Compare also Herrn.
Oppenheim, Pflüger's Arch., vol. xiiii. p. 490 : 1880.

DIGESTION IN THE INTESTINE 159

to form exceptions. From analogy with other processes of fer-
mentation, we must suppose that these processes are also accom-
panied by hydration. We must refer the reader to the papers
of Hoppe-Seyler ^ and Nencki^ for further information on this
subject.

Many attempts have been made to isolate the unorganized
ferments. It is in fact possible to obtain precipitates from solu-
tions containing ferments which still retain the characteristic
fermentative properties. But we have no guarantee that these
precipitates, which are always amorphous, are chemical entities.
In the cases in which they have been analyzed, the composition
has been found closely similar to that of proteids and peptones.
But we cannot ascertain whether the ferment may not form a
fraction of the material analyzed, so small as not to influence
the result of the analysis.

All ferments are soluble in water ; all may be precipitated
from their aqueous solutions by alcohol or ammonium sul-
phate,^ and are again dissolved by water after their precipita-
tion. Most of them are also soluble in glycerin, and may be
precipitated from this solution by alcohol.^ All the previous
attempts at isolation mainly depend on these properties, which
are however common to a large number of other constituents
of the tissues ; so that other means must be found to effect a
further separation. Certain ferments — such for instance as
pepsin — do not diffuse through animal membranes,^ and all
have a great tendency to be carried down by neutral precipi-
tates.*' These properties have also been utilized for the pur-
pose of isolating ferments. It would lead us too far to give
details concerning all these procedures. I must refer you
to the observations of Brücke,^ Danilewsky,* Cohnheim,^

^ Hoppe-Seyler, Pfliiger's Arch., vol. xii. p. 14 : 1876.

* Nencki, Journ.f. prakt. Chem., vol. xvii. p. 105 : 1879.

^ [Invertin appears not to be precipitated by ammoniuni sulphate.]

* Von Wittich, Pfliiger's Arch., vol. ii. p. 193 : 1869 ; and vol. iii. p. 339 :
1870.

* Krasilnikow, Medicinisky Wjestnik : 1864. Diakonow gives a short notice
of this work in Hoppe-Seyler's Med. chem. Unters., p. 241. See also A. Schöflfer,
Centralbl. f. d. med. Wissensch., ]p. 641: 1866; von. Wittich, Pfliiger's Arch.,
vol. V. p. 443: 1872; Olof Hammarsten, " Oni pepsinets indifi"usibilitet," Upsala
läkareförennings forhandlingar, vol. yiü. p. 565: 1873.

* Brücke, Sitzungsber. d. Wiener Akad., vol. xliii. p. 601 : 1861. A. v.
Heltzl, "Beiträge zur Lehre der Verdauungsfermente des Magensaftes":
Dorpat, 1864.

'' Brücke, Sitzungsber. d. Wiener Akad., vol. xxxvii. p. 131 : 1859 ; and vol.
xliii. p. 601 : 1861.

* Danilewsky, Virchow's Arch., vol. xxv. p. 279 : 1862.

^ J. Cohnheim, Virchow's Arch., vol. xxviii. p. 241 : 1863.

160 LECTUEE XI

Aug. Schmidt/ Hüfner/ Maly,^ Kühne/ Barth/ and O.

Every ferment develops its maximum activity at a definite
temperature. This temperature must be diflFerent in the case
of the digestive ferments of cold- and warm-blooded animals ;
we should expect this on teleological grounds, and it is con-
firmed by direct observation. By treating the gastric mucous
membrane of a mammal, recently killed, with dilute HCl (from
2 to 3 per 1,000), a so-called artificial gastric juice is obtained
which rapidly peptonizes all varieties of proteid. At an ordi-
nary temperature this action is mostly very slight, and it ceases
entirely at about 10° C. At a temperature of 0° C, not the
least trace of digestion goes on. But Fick and Murisier^
found that the artificial gastric juice, prepared from the
stomach of the frog, the pike, and the trout, constantly exerted
a peptonizing influence even at 0°. Hoppe-Seyl er * confirmed
these results. He found that artificial gastric juice of the
pike digested fibrin more rapidly at 15° C. than at 40°, most
rapidly at about 20°. A little above 0° the action was slower
than at 15°, but still very marked. Fick and Hoppe-Seyler
conclude from these observations that the gastric juice of
warm-blooded contains a different ferment from that of cold-
blooded animals.

Like pepsin obtained from different sources, we find that
the so-called diastatic ferments, which decompose starch, de-
velop their maximum effects at temperatures which vary ac-
cording to the source from which these ferments are derived.
The diastatic ferments of the pancreas and saliva act most
quickly at from 37° to 40° C; that of germinating barley at
from 54° to 63° C.^

When aqueous solutions containing ferments are heated to
more than 70° C, the unorganized as well as the organized
ferments are destroyed. The solutions are found to be in-

■^ Aug. Schmidt, " Ueber Emulsin und Legumin," Dissert. : Tübingen, 1871.

*Hüfner, Journ. f. prakt. Chem., vol. v. p. 372: 1872.

3 Maly, Pflüger's Arch., vol. ix. p. 592 : 1874.

■* Kühne, Verhandl. des naturhist. med. Vereins zu Heidelberg, vol. i.: 1876 ;
and vol. iii. p. 463 : 1886 ; Kühne and Chittenden, Zeitsehr. f. Biol., vol. iv.
p. 428 : 1886.

''Barth, "Zur Kenntniss des Inverting," ^er. der deutsch, chem. Ges., vol.
xi. p. 474: 1878.

6 Low, Pflüger's Arch., vol. xxvii. p. 203 : 1882.

'' Murisier, Verhandlungen derphys. med. Gesellschaft zu Würzburg, vol. iv.
p. 120 : 1873.

* Hoppe-Seyler, Pflüger's Arch., vol. xiv. p. 395 : 1877. Compare also M.
Flaum, Zeitsehr. f. Biol., vol. xxviii. p. 433 : 1892.

^ J. Kjeldahl, " Meddelser fra Carlsberg Laboratoriet Kjöbenhaven" : 1879 ;
Maly's Jahresbericht für Thierchemie, p. 382 : 1879.

DIGESTION IN THE INTESTINE 161

operative, both at this temperature and also when they are
again cooled down. On the other hand, when in a dry state,
the ferments may be exposed to a very high temperature with-
out losing their power. Hüfner^ heated his dried pancreatic
ferment to 100° C. without causing it to become ineffectual.
Alex. Schmidt ^ and Salkowski showed that this was also the
case with pepsin. Salkowski^ heated pepsin to 150° C, and
pancreatic ferment and invertin to 160° C. for many hours, and
showed that they were still active on cooling and when mixed
with water. It was thought that this would serve as a means
of distinguishing the unorganized from the organized ferments.
But more recent investigations have shown that the spores of
certain bacteria can stand a temperature of from 110° to 140°
C without losing life or power of development.'*

The power of resisting absolute alcohol has also been
regarded as characteristic of unformed ferments, and as dis-
tinguishing them from formed ferments. But the spores of
certain bacteria possess even this power. Koch ^ showed, for
instance, that the spores of anthrax bacilli could be kept for
110 days in absolute alcohol without being killed. On the
other hand, all spores are apparently killed when subjected for
a long period, say thirty days, to ether — a treatment which has
not been found to have any effect on the unorganized ferments.
Prussic acid, chloroform, benzol, thymol, oil of turpentine, and
sodium fluorid,^ are all supposed to act like ether in killing
the organized, and in having no effect upon the unorganized,
ferments.

After these preliminary remarks on ferments in general, we
will now return to the pancreatic juice and its fermentative
actions. I have already mentioned that the pancreatic juice
acts upon all the three main groups of food-stuffs. To explain
these three actions, it has been assumed that there are three
different ferments, although there is no definite ground for
such an assumption. Hüfner,'^ in his numerous attempts to

1 Hiifner, Journ. f. prakt. Chem,., vol. v. p. 372 : 1872.

2 Alex. Schmidt, Centralbl. f. d. med. Wissensch., No. 29 : 1876.

^ Salkowski, Virchow's Arch., vol. Ixx. p. 158: 1877; and vol. Ixxxi. p.
552 : 1880. Compare also Hiippe, Mittheil. d. Kaiserl. Gesundheitsamtes, vol. i.:
1881.

*R. Koch, und Wolffhügel, Mittheil. d. Kaiserl. Gesundheitsamtes, vol. i. :
Berlin, 1881 ; Max. Wolff, Virchow's Arch., vol. cii. p. 81 : 1885.

5R. Koch, " Ueber Disinfection," Mittheil. d. Kaiserl. Gesundheittamtes,
vol. i. : 1881.

8 M. Arthus and Ad. Huber, Arch. d. Physiol., vol. xxiv. p. 651 : 1894.
Compt. rend., vol. cxvi. p. 839: 1894.

' Hufner, Journ. f. prakt. Chem., vol. v. p. 372 : 1872. For the experiments
to isolate three different ferments, see Danilewsky, Virchow's Arch., vol. xxv. p.
279: 1862; Lossnitzer, "Einige Versuche über die Verdauung der Eiweiss-
11

162 LECTURE XI

isolate the pancreatic ferments, always obtained preparations
which had the threefold fermentative action.

"With regard to the action on carbohydeates, the con-
version of the insoluble starch flour has been more particularly
studied. The process of starch digestion is by no means as
simple as it was formerly imagined. Till quite recently, it was
considered that starch flour was altered by the digestive fer-
ments of the saliva and of the pancreatic juice, and by the
ferment of the germinating barley or diastase, in the same way
as on boiling with dilute sulphuric acid, when, as is well
known, starch flour is by a process of hydration completely
converted into grape-sugar (dextrose), whilst dextrin only oc-
curs as an intermediate stage.

But more recent research has shown' that the amount of
sugar produced forms but half of the entire weight of the
starch, and that this sugar is not grape-sugar, but maltose
(0^2^22011+ H2O). The remainder is dextrin, and this dextrin
cannot be converted into sugar by further action of the fer-
ments. It has also been discovered that there are two varieties
of dextrin, of which one is colored red by iodin, while the
other remains colorless. It has been further ascertained that
a certain carbohydrate, so-called soluble starch, which also gives
a blue color with iodin, occurs as an intermediate product be-
tween ordinary starch and the dextrius. Finally, it has been
found that even the original starch flour is not a chemical entity,
but that the concentric layers of the starch granule are composed
of various carbohydrates in different proportions.

körper," Dissert.: Leipzig, 1864; Victor Paschutin, Du Bois' Arch., p. 382:
1873; Kühne, Verhandl. d. naturhist. med. Ver. zu Heidelb., N. F., vol. i. : 1876.
Heidenhain and his pupil Podolinski come to tlie conclusion that the ferment
which dissolves proteid does not exist preformed in the pancreas, but is formed
during secretion from a precursor present in the gland (Pfliiger's Arch., vol. x.
p. 557 : 1875 ; and vol. xiii. p. 422 : 1876). Compare also Giov. Weiss, Virchow's
Arch., vol. Ixviii. p. 413 : 1876.

^Musculus, Compt. rend., vol. 1. p. 785: 1860; or Ann. chim. et phys., ser.
iii. vol. Ix. p. 203: 1860; Compt. rend., vol. Ixviii. p. 1267: 1869; vol. Ixx. p.
857: 1870; vol. Ixxviii. 2, p. 1413: 1874; Ann. chim. et phys., ser. v. vol. ii. p.
385 : 1874 ; Payen, Ann. chim. et phys., ser. iv. vol. iv. p. 286 : 1865 ; L. Coutaret,
Compt. rend., vol. Ixx. p. 382: 1870; Aug. Schwarzer, Journ. f. prakt. Chem.,
N. F., vol. i. p. 212 : 1870 ; E. Schulze u. Märker, Dingler's Polytechnisches
Journ., vol. ccvi. p. 245 : 1872 ; Brücke, Sitzungsberichte d. Wiener Akad., vol.
Ixv. part iii. p. 126 : 1872 ; C. O'SulIivan, Journ. of Chem. Soc, ser. ii. vol. x. p.
579: 1872; E. Schulze, Ber. d. deutsch, chem. Ges., vol. vii. p. 1048: 1874;
Nägeli, "Beiträge zur Kenntniss der Stärkegruppe": Leipzig, 1874; O. Nasse,
Pflüger's Arch., vol. xiv. p. 473: 1877. Musculus und v. Mering, Zeitschr. f.
physiol. Chem., vol. i. p. 395: 1878; and vol. ii. p. 403: 1878; Musculus und G.
Gruber, Zeitschr. f. physiol. Chem.., vol. ii. p, 177: 1878. Compare also the re-
view of works by v. Mering, Du Bois' Arch., pp. 389-395 : 1877.

DIGESTION IN THE INTESTINE 163

The final products of the decomposition of starch are, at
any rate, different in the living organism to those produced by
artificial digestion outside the body ; the starch appears to be
completely converted into grape-sugar. Even in long-con-
tinued artificial pancreatic digestion of starch, grape-sugar
(dextrose) always occurs together with maltose.^ Maltose and
dextrin cannot be found in the blood and in the tissues,^ and in
the case of diabetic patients, who are unable to destroy the
carbohydrates, grape-sugar alone appears in the urine after
starch has been eaten.

We know as little concerning the changes that cellulose
undergoes in the intestine as we do concerning the fate of
dextrin. Outside the body, cellulose is neither altered by the
pancreatic juice nor by any other digestive secretion. But,
as a fact, a large portion, as we have already seen, disap-
pears in the intestine. I imagine that it is a fermentative
action which enables the epithelial cells of the intestine to dis-
solve the cellulose, and perhaps also to convert the dextrin into
sugar. This power has frequently been observed in unicellular
bodies. I may refer to the behavior of the Vampyrella, which
has already been described (p. 3), and which dissolves the
cellulose wall of the algge. A few authors have adopted the
view that the cellulose is not made use of in our body at all as
food, but is split up by parasitic bacteria in our intestines into
carbonic acid and marsh gas. That such a decomposition of
cellulose by bacteria does take place has been incontestably
proved by Hoppe-Seyler's experiments,^ which render it prob-
able that it also occurs in the alimentary canal. ^ But it is
doubtful whether all the cellulose that disappears in the ali-
mentary canal is split up in this manner.^

The pancreatic juice exercises a fermentative action on
FATS similar to that on carbohydrates ; decomposition takes

^ Musculus und v. Mering, Zeitschr. f. physiol. Chem., vol. ii. p. 403 : 1879 ;
Horace T. Brown and John Heron, Leibig's Annal., pp. 204, 228 : 1880.

2 Intimation of the occurrence of colloid carbohydrates in the blood of the
portal vein may be found in v. Mering's paper. Du Bois' Arch., p. 413: 1877;
and in another by A. M. Bleile, Du Bois' Arch., p. 70 : 1879. But only very
small quantities are concerned, and perhaps even these only occur occasionally.
Bleile's experiments prove that the chief part of the dextrin is converted into
sugar, as he observed that, after an exclusive diet of dextrin, the amount of sugar
in the portal blood increases.

* Hoppe-Seyler, Ber. d. deutsch, chem. Ges., vol. ivi. p. 122 : 1883 ; and
Zeitschr. f. physiol. Chem., vol. x. p. 404: 1886.

■* H. Tappeiner, Zeitschr. f. Biolog., vol. xx. p. 52 : 1884 ; and vol. xxiv. p.
105: 1888.

^ Compare H. Weiske, Chem. Centralhl., vol. xv. p. 385 : 1884 ; Henneberg
and Stohmann, Zeitschr. f. Biolog., vol. xii. p. 613 : 1885 ; F. Lehmann, Journ.
f. Landw., vol. xxxvii. p. 251 : 1889 ; Alf. Mallevre, Pfliiger's Arch., vol. xlix,
p. 460 : 1891 ; Zuntz, ihid., vol. xlix. p. 477 : 1891.

164 LECTURE XI

place with hydration. The fats are well known to be com-
pound ethers, combinations of a trivalent alcohol, glycerin,
with three molecules of monobasic acids, principally stearic
acid, palmitic acid, and oleic acid. Beside which, certain fats
contain small quantities of volatile fatty acids, such as butyric
acid in the fats of milk. By the action of the pancreatic
ferment, the fat molecule takes up three molecules of water,
and splits up into glycerin and into three molecules of fatty
acid. This action of the pancreatic juice was discovered by
Bernard.^ How large a portion of the fats is thus broken up
in the intestine cannot be stated, but it is probably a very small
one. For the decomposition of fats, at least in experiments on
artificial digestion, goes on very slowly, whereas the absorption
of fats proceeds very rapidly. But it is quite sufficient if only
a minute part of the fats is split up, for the whole amount
of fat is thereby rendered capable of being converted into a
fine emulsion, in which form it passes through the intestinal
wall.

The emulsification of fats is brought about in the following
manner. It is well known that the neutral fats can only be
saponified, i. e., split up into glycerin and salts of fatty acids to
form soaps, by free alkalies. Carbonates of the alkalies have
no action on neutral fats but only on free fatty acids ; the
carbonic acid is driven out of the salts by the stronger acid,
and a salt is formed by the combination of the fatty acid with
alkali. Fatty acids and neutral glycerides are intimately
miscible in every proportion. In such a mixture of fat and a
small quantity of fatty acid, the molecules of the fatty acid are
thus always to be found among the molecules of the neutral
glycerids. If a solution of carbonate of soda act upon this
mixture, a soapy solution is formed everywhere between the
molecules of the neutral fats. By this means the whole mass
of fat is immediately converted into a fine emulsion of micro-
scopically small drops. Perfectly fresh neutral fat cannot be
emulsified by a solution of carbonate of soda. If, on the other
hand, rancid fat be taken, i. e., fat in which a part of the fatty

^ Bernard, Ann. de Chim. et de Physique, ser. iii. t. xxv. p. 474 : 1849. Com-
pare also Ogata, Du Bois' Arch., p. 515 : 1881. According to this investigation,
which was carried out in Ludwig's laboratory, the decomposition of the fats be-
gins already in the stomach. Marcet had previously come to the same conclusion
(Medical Times and Gazette, new ser., vol. xvii. p. 210: 1858). The decomposi-
tion of fats in the stomach is probably effected, not by an unorganized ferment
of the gastric juice, but by putrefactive organisms. The cause of the decompo-
sition of fats in artificial pancreatic digestion has been so interpreted. But
Nencki's latest experiments (Arch. f. exper. Path. u. Pharm., vol. xx. p. 373:
1886) show that the pancreatic ferment decomposes as much fat if phenol be
present as if there were no antiseptic.

DIGESTION IN THE INTESTINE 165

acids has already been set free by the action of putrefactive
ferments, or if a small amount of free fatty acids be added to
the neutral fat, the emulsion is at once formed. When rancid
oil is poured on to a dilute solution of sodium carbonate, the
two layers of fluid combine directly they are gently shaken, and
the whole is converted into an opaque, uniform, and milky-
looking liquid. Under the microscope the fat is seen distributed
in minute drops.

There are other alkaline salt solutions which can, like the
carbonates of soda or of potash, combine with free fatty acids
to form soaps. Such, for instance, is the phosphate of soda
with the formula NagHPO^. This salt with fatty acids gives
soap and acid phosphate of sodium, NaHgPO^. As we shall
soon see, the bile, which contains alkaline salts, acts in a
similar manner on fatty acids.^ The emulsions, which are
formed by means of bile, are however very temporary.

Carbonate of soda is contained in the pancreatic secretion,
for the analysis ^ of the ash shows that the secretion contains
more sodium than is necessary for the saturation of the strong
mineral acids present. Two weak acids divide the remainder
among themselves : proteid and carbonic acid. The intestinal
juice is likewise very rich in carbonate of soda, as we shall soon
see. By the action of these alkaline secretions the fat is
emulsified in minute particles which, as previously described
(p. 164), are passed on to the commencement of the chyle-
vessels by the active intervention of the epithelial cells.

The mechanism of fat absorption is not however entirely
explained by the above-mentioned facts. Some other unknown
part must be played by the pancreatic juice in this process,
since after extirpation of the pancreas in dogs the absorption
of fat is entirely abolished, although the greater part is split up
into fatty acids and glycerin, probably by bacterial putrefaction.
All the fat eaten by the dogs can be recovered from the feces,
partly unchanged, but for the most part as free fatty acids and
soaps. If some pig's pancreas be given to the dogs along with

1 The emulsifying action of alkaline salt solutions has long been known to
technical chemists ; it is practically employed in dyeing articles Turkey red.
Marcet was the first to draw attention to its physiological bearing {Medical
Times and Gazette, new ser., vol. xvii. p. 209 : 1858). Also Brücke, Sitzungsber.
d. Wiener Akad. Math.-nat. Classe, vol. Ixi. part ii. p. 362 : 1870. Compare also
J. Steiner, Du Bois' Arch., p. 286 : 1874 ; Joh. Gad, ibid., p. 181 : 1878 ; Georg
Quincke, Pfliiger's Arch., vol. xix. p. 129 : 1879 ; and Max v. Frey, Du Bois'
Arch., p. 382 : 1881.

2 Bidder and Schmidt, "Die Verdauungssäfte u. der Stoffwechsel," p. 245 :
Mitau and Leipzig, 1852. The sulphuric acid given in the analysis must not be
taken into consideration, because it was produced from the sulphur of the Pro-
teids only in incineration.

166 LECTURE XI

the fat, a portion of the latter is absorbed.^ Moreover, Claude
Bernard has already shown that a pancreatic emulsion differs
from other emulsions in that it is not destroyed by a slightly
acid medium.

It now only remains to consider the action of the pancreatic
secretion on the third main group of food-stuffs, the Proteids.
By the action of the pancreatic ferment, as well as that of the
gastric ferment, the proteids lose their colloid character ; they
become diffusible," and are no longer coagulable ; they are
converted into peptones. The gelatin-yielding substances
undergo a similar alteration ; they become dissolved, and the
solutions lose the power of forming a jelly in the cold.^

The peptonizing action of the pancreatic juice was for a
long time doubted, until Corvisart * decided the matter in the
affirmative. Kühne, who was present at Corvisart's experi-
ments, afterwards carried out a series of exhaustive experi-
ments on the subject in Germany.^ Kühne obtained the
secretion from eleven dogs with a temporary pancreatic fistula,
and he found that "amazing quantities of boiled fibrin and
proteid were dissolved by the juice without any trace of putre-
faction, in from half an hour to three hours, at a temperature
of 40° C, so that the larger portion was converted into a sub-
stance not coagulable at boiling heat, which was readily dif-
fusible through vegetable parchment."

When a fresh pancreas was cut up into small pieces with
scissors, mixed with a large quantity of fibrin and water heated
to 40° C, and left to stand from three to six hours, the
gland disappeared with the fibrin, leaving but a trace behind.
The reaction after complete solution was alkaline. Only a
small portion of the decomposed proteid could be precipitated

' M. Abelmann, " Ueb. d. Ausnützung d. Nahrungsstoflfe nach Pankreas-
exstirpation." Dissert. : Dorpat, 1890. Compare also Vaughan Harley, Journ.
Physiol., vol. xviii. p. 1 : 1895 ; E. Hedon and J. Ville, Arch. d. Physiol., p.
606 : 1897 ; and Hedon, ibid., p. 622. [It should be mentioned here that, accord-
ing to most authorities at the present time, the greater proportion at any rate of
the fat is absorbed by the intestinal wall, not in a particulate condition but in so-
lution, either as fatty acid or as soap. The chief function of the bile seems to be
to act as a solvent of these two classes of bodies, and therefore as a carrier of
them into the intestinal mucous membrane, where they, with the glycerin, are
recombined to form neutral fats.]

2 The proofs of the power of ready diffusion possessed by peptones have been
disputed. See von Wittich, Berliner klin. Wochetischr., No. 37 : 1872.

^See Fr. Hofmeister, Zeitschr. f.physiol. Chem., vol. ii. p. 299: 1878. An
account of the older literature will also be found here.

* Corvisart, " Sur une fonction peu connue du pancreas ; la digestion des
aliments azotees," Gaz. hehdom., Nos. 15, 16, 19 : 1857.

^ W. Kühne, Virchow's Arch., vol. xxxix. p. 130 : 1867.

DIGESTION IN THE INTESTINE 167

by acetic acid and by boiling.^ The solution, when filtered,
was concentrated at from 60° to 70° C. to one-sixth of its
volume and mixed with 95 per cent, of alcohol. This precipi-
tated the peptones in flocculent masses. When the filtered so-
lution was concentrated and cooled down, tyrosin first separated
out in crystals; then, on further concentration, leucin crystal-
lized out, in clumps — " leucin cones."

382 parts of dried fibrin and 14.2 parts of dried pancreas
yielded —

11.0 undissolved remainder 1 co c

42.0 coagulated proteid /
211.2 peptone ")

13.3 tyrosin V 256.1

31.6 leucin j
397.2 — 53.5 — 343.7 dissolved proteid.

From this it appears that 100 parts of fibrin gave 61 of pep-
tone, 3.9 of tyrosin, 9.1 of leucin, and 26 of products that we
are at present unacquainted with.^

It might be supposed that the amido-acids, leucin and
tyrosin, are not split off from the proteid molecule by the
action of a pancreatic ferment, but by the fermentative action
of putrefactive organisms. The pancreas and its juice are
substances eminently prone to putrefaction, and the alkaline
reaction is favorable to the development of putrefactive or-
ganisms. It is this liability to putrefaction which makes it
so much more difficult to carry out experiments on artificial
pancreatic digestion that on gastric digestion. We know, in
fact, that peptones and amido-acids are formed from proteids
by the action of putrefactive organisms. But Kühne meets
this objection by experiments,^ which were carried out with

^ For an account of the globulin, acid albumin, parapeptone, propeptone,
albumoses, &c., which occur in the conversion of proteid into peptone, both in
pancreatic and gastric digestion, see Meissner, Zeitschr. f. rat. Med., III. Eeihe.
vol. vii. p. 1 : 1859 ; Brücke, Sitzungsber. der Wiener Akad., vol. xxxvii. p. 131 :
1859; Kühne and Chittenden, Zeitschr. f. Biolog.,yd\. xix. p. 159: 1883; vol.
XX. p. 11 : 1884 ; vol. xxii. p. 409 : 1886 ; R. Herth, 3fonatshefte f. CJiem., vol. v.
p. 266 : 1884; Kühne, Verhandl. d. nat. w-ed. Vereins zu Heidelb., N. F., vol. iii.
p. 286 : 1885 ; Schmidt-Mülheim, Du Bois' Arch., p. 36 : 1880 ; Hans Thierfelder,
Zeitschr. f. physiol. Chem., vol. x. p. 577: 1886; E.. Neumeister, Zeitschr. f.
Biolog., vol. xxiii. pp. 381, 402: 1887; and " Ueb. d. nächste Einwirk, ges-
pannter Wasserdämpfe auf Proteine," &c. : München, 1889; E. P. Pick, "Zur
Kenntniss d. peptischen Spaltungsprodukte des Fibrins," Zeitschr. f. physiol.
ehem., vol. xxviii. p. 219 : 1899.

2 [Among these products are to be found the same substances as those which
occur in the disintegration of proteids by strong acids, e. g., glutamic and aspartic
acids, as well as the hexone bases, argenin, lysin, and histidin.]

* Kühne, Verhandl. d. naturhistor. med. Vereins zu Heidelb., N. F., vol. i.
Heft iii.: 1876.

168 LECTURE XI

the use of salicylic acid as an antiseptic. He showed that
concentrated salicylic acid, while arresting the development of
putrefactive germs, does not inhibit the action of the pan-
creatic ferment, and that amido-acids are still formed under
these conditions.

Kühne is of opinion that amido-acids are also formed in
the intestine of living animals. He tied the intestine of a live
dog above the entrance of the pancreatic duct, and again four
feet lower down, introduced canulse at the upper and lower ex-
tremities of the intestine he had tied, and passed a stream of
water heated to 40° C. through it until it was quite clean.
Fibrin was then put in the piece of intestine, and the wound in
the abdomen was closed. The dog was killed after four hours,
and the piece of intestine cut out. Among the contents were
found peptone, tyrosin, and leucin.

It may be ä jpriori doubted on teleological grounds,
whether under normal conditions the amount of amido-acids
formed in the intestine is a large one. It would be a waste
of chemical potential energy, which would serve no purpose
when converted into kinetic energy by their decomposition,
and a reunion of the products of such a profound decomposition
outside the intestinal wall is highly improbable. And indeed
Schmidt-Mülheim,^ in numerous experiments on the intestinal
contents of dogs fed on meat, could find only traces of amido-
acids or else none at all. In the same way Nencki found
neither leucin nor tyrosin in the intestinal contents obtained
from the fistula of the lower end of the small intestine in the
case previously mentioned.^

On boiling proteids with dilute acids and alkalies, peptones
again appear at first, and amido-acids later on.

We will now inquire into the nature of the process by which
proteid is converted into peptone.

As peptone occurs as an intermediate stage in the forma-
tion of such decomposition-products as amido-acids from
proteid, it may reasonably be imagined that the peptones are
the first immediate products of decomposition. This view is
further confirmed by the analogy of fermentative action and of
the action of acids and alkalies on complex organic compounds
of known composition. In all these processes disintegration
is accompanied by hydration. The same pancreatic ferment
which, accompanied by hydration, splits up the fats into
glycerin and fatty acids, and starch flour into dextrin and

1 Schmidt-Mülheim, Du Bois' Arch., p. 39 : 1879.

^ Macfadyen, Nencki, and Sieber, Arch. f. exper. Path. u. Pharm., vol.
xxviii. p. 323 : 1891.

DIGESTION IN THE INTESTINE 169

sugar — thie same ferment also changes the proteids into pep-
tones. What is more natural than to conclude that the pep-
tones are also formed from the proteids by a process of decom-
position accompanied by hydration ?

It is a very seductive theory to assume that the colloid and
insoluble proteids are polymeric products of the soluble pep-
tones, just as the colloid and insoluble carbohydrates, such as
glycogen, gum, starch, or cellulose, are polymeric products of
the soluble sugars, and that the peptone molecules after absorp-
tion are again combined into proteid molecules, just as the sugar
molecules are united to form glycogen in animal tissues, or
starch and woody fiber in vegetable tissues. But it must be
remembered that this theory is only based upon analogy. At
present nothing certain is known about the nature of peptones.
It is not known whether the peptones are decomposition-prod-
ucts of proteid, or even whether the decomposition-products
themselves are alike or differ from each other, or whether the
peptones have arisen from proteid either by a rearrangement of
atoms without alteration of the size of the molecules, or by
hydration.

In experiments on the composition of peptones, the error
has always been made of using impure material. The proteid
chosen for the production of peptone has generally been the
fibrin of the blood (compare Lecture XIV.). We do not know
how many different proteids there are in the coagulum of
fibrin ; but we know for certain that the nuclei and remains of
the broken-up leucocytes, as well as whole leucocytes and the
stromata of red blood-corpuscles, are all contained in this coag-
ulum. This method of subjecting a conglomeration of sub-
stances and organisms to elementary analysis, and of after-
wards comparing the result of the analysis of a mixture of the
products of our experiment, can lead to no satisfactory conclu-
sions. But this is the type of some of the most exact work
on peptone.^ Now that we are in a position to produce crys-
talline proteid compounds, all experiments on the composi-
tion of peptones which are made on other material are utterly
worthless.

As it has not been found possible to crystallize the peptones
from their solutions, or to produce compounds capable of crys-
tallization, or even compounds of constant composition, Maly ^
has adopted the method of fractional precipitation, in order
to decide the question whether the peptone solution, obtained
from the blood-fibrin by artificial pepsin digestion, contains

* Compare R. Maly's critique in Pfliiger's Arch., vol. xx. p. 315 : 1879.
2 R. Maly, Pflüger's Arch., vol. ix, p. 585 : 1874.

170 LECTUEE XI

a single peptone or a mixture of different peptones. Maly
treated the clear and highly concentrated peptone solution
with strong alcohol, until a portion of the peptone separated
out in flocculent masses (fraction 1); the filtrate was again pre-
cipitated out with alcohol (fraction 2) ; and, finally, the remain-
ing alcoholic solution was evaporated to dryness (fraction 3).
If the peptone solution contained several different peptones, we
should expect to find that the various fractions possessed a
varying composition ; for we cannot assume that the different
peptones have the same power of dissolving in dilute alcohol.
Maly found that the figures were so nearly the same in the ulti-
mate analysis of his three fractions, that he came to the con-
clusion that only one peptone was formed. Maly's pupil,
Herth,^ came to the like conclusion, from experiments carried
out on the same principle with solutions of peptone obtained
from egg-albumin.

Maly's and Herth's figures have not convinced me of the
justice of this conclusion. It is particularly to be regretted
that, in the ultimate analyses, the amounts of sulphur in the
fractional precipitations were not determined. We should most
readily have expected to see a difference in the amount of sul-
phur. If we regard the proteids as compounds of the pep-
tones, we must assume that there are several peptones, some
rich and some poor in sulphur, or else some containing sul-
phur and others without any sulphur, for the reason that the
amount of sulphur in the different kinds of proteid varies so
remarkably. But if, on the other hand, we do not regard
the peptones as produced by the splitting of the proteid mole-
cule, we must assume as many different peptones as there are
proteids of varying composition. There are, at any rate, sev-
eral peptones. A. Krüger ^ has recently made analyses of pro-
teid and peptones, in which he has bestowed especial care
upon the estimation of sulphur ; but unfortunately, instead of
using pure material, he employed fibrin and egg-albumin. The
latter, like the proteid of blood-serum (vide Lecture XIV.), is
a mixture of at least two different kinds of proteid, a globulin
and an albumin.

The quantitative estimates of the amounts of carbon, hy-
drogen, and nitrogen in the purest of the peptone prepara-
tions hitherto made, have always given figures which are

^ Robert Herth (Maly's laboratory in Graz), Zeitschr. f. physiol. Chem., vol.
i. p. 277 : 1887. Compare also A. Henninger, " De la nature et du role physio-
logique des peptones": Paris; Compt. rend., vol. Ixxxvi. pp. 1413, 1464: 1878.

2 Albert Krüger, Pfliiger's Arch., vol. xliii. p. 244: 1888. This paper con-
tains a summary of the earlier literature on the amount of sulphur in the various
kinds of proteid and the different ways in which sulphur is combined.

DIGESTION IN THE INTESTINE 171

within th^ limits between which the composition of proteid
varies.^

Whether all proteid, in order to become absorbed, must be
previously peptonized, or whether a part is taken up unaltered ;
whether the peptones are again reconverted into proteid after
absorption, and where this conversion takes place; — are ques-
tions which will be treated more in detail in Lecture XIII.,
after we have become acquainted with the parts played by the
remaining digestive secretions, the intestinal juice and the bile.

^ The divergence in the results recently obtained by Kühne and Chittenden
awaits further investigation {Zeitschr, /. Biolog., vol. xxii. p. 423 : 1886). It was
attempted to obtain further insight into the nature of peptones by comparative
experiments on the optical characteristics of the proteids and peptones, on their
refractive power, and their behavior towards polarized light. But these inves-
tigations have not led to any unanimous or conclusive results (see J. Bechamp,
Compt. rend., vol. xciv. p. 883 : 1882 ; A. Poehl, " Ueber des Vorkommen u. die
Bildung des Peptons ausserhalb des Verdauungsapparates u. über die Rück-
bildung des Peptons in Eiweiss," Dorpater Dissert. : St. Petersburg, Röttger,
1882; and Ber. d. deutsch, ehem. Ges., p. 1152: 1883). The fact observed by
Danilewski, that the heat of combustion of the peptones is less than that of the
proteids {Centralbl.f. d. med. Wissensch., Nos. 26 and 27 : 1881), can also be in-
terpreted in several ways. This fact agrees with the decomposition hypothesis
just as well as with the theory that hydration is the essence of peptonization. It
has been, moreover, quite lately noted that the peptones could be reconverted
into proteids by the action of dehydrating agents. But all these statements bear
the character of preliminary communications. They are not therefore suitable
for critical discussion in a text-book. See Henninger, Compt. rend., vol. Ixxxvi.
p. 1464: 1878; Hofmeister, Zeitschr. f. physiol.Chem., vol. ii. p. 206: 1878; and
vol. iv. p. 267: 1880; Danilewski, Centralbl.f. d. med. Wissensch., No. 42: 1880;
Schmidt-Mülheim, Du Bois' Arch., p. 36: 1880; A. Poehl, loc. cit., and Ber. d.
deutsch, ehem. Ges., p. 1355 : 1881 ; p. 1163 : 1883. Compare also O. Loew, Pflüger's
Arch., vol. xxxi. p. 405 : 1883 ; and R. Neumeister, Zeitschr. f. Biolog., vol.
xxiii. p. 394 : 1887.

LECTURE XII

INTESTINAL JUICE AND BILE

Thiey,^ bj his bold vivisection, was the first to obtain and
examine the intestinal juice, the secretion of Lieberkühn's
glands, in a pure state. Thiry opened the abdomen of dogs,
after they had fasted for twenty-four hours, by an incision in
the linea alba. A coil of small intestine was drawn out, and
a piece from 10 to 15 cms. in length was resected without
injury to the mesentery. The edges of the two ends of the
intestine were sewn together in the usual way. One end of the
resected piece of intestine was closed with crossed sutures and
replaced ; the other end, left open, was sewn into the abdominal
wound. Although Thiry did not treat the wound antiseptically,
he succeeded in preventing peritonitis in a few cases, and in
getting the wound to heal quickly. In from two to five days
the animals could again receive food into their shortened intes-
tine, and remained in good health for months. Quincke ^ has
repeated these experiments several times ; one of the dogs ex-
perimented upon lived for nine months after the operation, and
died from an accident. An abundant secretion of intestinal
juice was brought about in this isolated piece of intestine by
mechanical and chemical stimulation, especially by acids. The
juice was readily obtained for examination by putting in
small pieces of sponge, which were removed after a time and
squeezed out.

To the obvious objection that a secretion thus obtained was
not normal intestinal juice, Thiry and Quincke replied with the
following arguments : 1 . The microscopic examination of the
intestinal wall showed no changes in its histological structure
as a whole, or in Lieberkühn's glands, even several months
after the operation. 2. The circulation in the mesentery and
the innervation did not appear to be disturbed; the reflex
mechanism was maintained. 3. Intestinal parasites continued
to live in the isolated piece of intestine : a Nematode and a Tenia

■* Thiry, Sitzungsber. d. Wiener A/cad., vol. 1. p. 77 : 1864.
* H. Quincke, Du Bois' Arch., p. 150 : 1868. Compare also Leube, Centralbl.
f. d. med. Wissensch., p. 289 : 1868.

172

INTESTINAL JUICE AND BILE 173

serrata, tbe latter of which from time to time cast off ripe
segments. This last argument is rendered convincing by the
fact that these creatures exist only under certain conditions, and
that most kinds of intestinal worms live only in certain portions
of the alimentary canal of definite animal species.

The secretion obtained from the isolated piece of intestine
proved to have no action on any of the three main groups of
organic food-stuffs ; fats and starch flour remained unaltered.
Of the proteids, according to Thiry, only the blood-fibrin was
dissolved, but no other kinds of proteid, such as bits of meat
or coagulated egg-albumin ; gelatin did not lose its power of
gelatinizing. Quincke could not even confirm the action of
the secretion upon fibrin ; he found the intestinal juice quite
inactive on all food. Lehmann ^ also came to the same con-
clusions, when he examined the secretion from an isolated piece
of goat's intestine. Many further experiments on artificial
digestion have been carried out with extracts from the intes-
tinal mucous membrane of various animals. In these experi-
ments there was either no action to be observed on any article
of diet, or a very slight one only on boiled starch flour, when
sugar was formed. But no importance should be attached to
the last results, as a ferment with a slow action upon boiled
starch may be extracted from every tissue.

Lastly, Demant ^ has more recently made experiments on
the action of the intestinal juice in human beings. Demant
had the opportunity of collecting pure intestinal juice from the
lower portion of intestine, in a case of artificial anus after
herniotomy, which occurred in Leube's hospital-practice in
Erlangen. A part of the intestine bulged out like a sausage
from the fistulous opening (of which there were two) belonging
to the lower portion of the intestine. Usually but little juice
oozed out of this opening ; the supply was however abundant
after meals, and could be collected in a glass beaker which was
held underneath without touching the intestinal mucous mem-
brane. In this manner, from 15 to 25 c.cms. of the secretion
were obtained in the course of one day. The secretion thus
occurred without any direct chemical or mechanical stimula-

^ Karl B. Lehmann, Pflüger's Arch., vol. xxxiii. p. 180 : 1884. Compare also
J. Wenz, Zeitschr.f.Biolog.,y(A.-s.-K.i\.T^.l: 1886; Fr. Pregl, Pflüger's ^rcA.,
vol. Ixi. p. 359 : 1895. L. Vella obtained different results on repeating Thiry's
experiments on dogs (Moleschott's Unt. zur Naturlehre, «fee, vol. xiii. p. 40 :
1881) ; he found that the juice acted on all the main groups of food-stuffs. This
divergence of opinion does not as yet admit of explanation.

2 Bernh. Demant, Virchow's Arch., vol. Ixxv. p. 419 : 1879. Compare the
observation of a similar case by H. Tubby and T. D. Manning, Guy's Hosp.
Reports, p. 271 : 1892.

174 LECTURE XII

tion of the raucous membrane, merely from the normal reflex
irritation, which proceeded from the upper portions of the
alimentary canal. It is therefore probable that Demant really
obtained the normal secretion, and not an inflammatory tran-
sudation of mucous membrane, brought about by abnormal
irritation.

The intestinal juice of man, experimented upon by Demant,
appeared to produce no change in any form of proteid, nor in
fibrin and fats. It had a very slight action on boiled starch,
which in numerous experiments never occurred till five hours
had elapsed, at from 36° to 38° C. No trace of sugar could
be detected before this time had passed.

If the intestinal juice has no action upon food, of what im-
portance is it? Will not its chemical composition enlighten us
here? Quincke found that it contained remarkably little of
any organic constituents ; in fact, only 0.5 per cent., which
was chiefly proteid. Thiry found somewhat more. Both in-
vestigators agree that the amount of inorganic salts was 0.9
per cent.; among these carbonate of soda is the chief. Both
Thiry and Quincke remarked that the intestinal juice efiervesces
on the addition of acids, and the same thing has been noticed
by Demant with the human secretion.

The importance of the intestinal juice lies undoubtedly in
the large amount of carbonate of soda it contains. Its function
is to neutralize the acids of the intestinal contents, and to
emulsify the fats with the surplus carbonate of soda (compare
above, p. 165). It has to supersaturate not only the hydro-
chloric acid of the gastric juice, but also the acids, sometimes
existing in far larger quantities, which arise from the butyric
and lactic acid fermentations. The rapidity of the passage of
the carbonate of soda through the intestinal wall must there-
fore be proportionate to the acidity of the intestinal contents.
For as soon as the carbonate of soda became over-saturated,
the absorption of fat would necessarily be at a standstill [as-
suming that emulsification is a necessary preliminary to ab-
sorption] . This is prevented by reflex mechanism. Thiry and
Quincke observed that, on stimulating the intestinal mucous
membrane with acids, the secretion of the alkaline intestinal
juice at once became more copious.

To this interpretation, that the emulsifying and absorption
of fats is brought about by the carbonate of soda in the in-
testinal juice, the objection has been raised that the absorption
of fats begins early in the upper part of the intestine, where
the reaction of the intestinal contents is always acid. Further,
it is well known that during digestion the chyle-vessels in the

INTESTINAL JUICE AND BILE 175

duodenum become opaque and white, through being filled with
droplets of fat, and also that the contents of the entire small
intestine as far as the cecum occasionally give an acid reaction.^
To this I would reply, that it is not the reaction of the internal
part of the food-mass which is of importance, but the reaction
of its surface which comes in contact with the absorbing intes-
tinal wall. That this latter always remains alkaline is due to
the above-mentioned reflex mechanism.

It appears to me that the carbonate of soda in the in-
testinal juice also serves another purpose. The food absorbs
hydrochloric acid in the stomach ; the molecules of hydro-
chloric acid are distributed among the minutest particles of
organic food. When the sodium carbonate neutralizes the
acid, the carbonic acid thus liberated effectually separates the
minute particles of the organic food from each other. The
bulk of the food is more thoroughly broken up, and the
digestive ferments gain more complete and easy access to the
individual particles, and so effect the rapid solution of the food
in the intestine.

In conclusion, I must not omit to mention that another
explanation has been given by Hoppe-Seyler of the action
of the intestinal juice, which is opposed to mine. Hoppe-
Seyler's^ view is that probably no special intestinal juice
exists as a secretion of Lieberkühn's glands, or of the in-
testinal mucous membrane ; at any rate, he sees at present no
proof of its existence. He thinks that, the quantitative com-
position of the supposed intestinal juice being identical with
that of the blood-plasma and of lymph, we cannot regard the
fluid obtained from Thiry's intestinal fistula as being anything
but a transudation brought about by abnormal stimulation.

In reply, I would merely ask how we are to explain the
fact that the intestinal contents, which give an acid reaction
in the upper portion of the small intestine, even after ad-
mixture with the pancreatic juice and with bile, are nearly
always markedly alkaline^ in the lower portion of the intes-
tine, and this in spite of the incessant lactic and butyric acid
fermentations.

Hoppe-Seyler teaches that the recesses of the intestines,
designated as Lieberkühn's glands, serve only to enlarge the
absorbent intestinal surface, and that the supposed glandular
epithelium is only a continuation of the absorbent epithelium

1 Th. Cash, Du Bois' Arch., p. 323 : 1880.

2 Hoppe-Seyler, " Physiologische Chemie," pp. 270, 275 : Berlin, 1881. Com-
pare Arthur Hanau, Zeitschr. f. Biolog., vol. xxii. p. 195 : 1886.

ä Gley and Lambling, Rev. biol. du Nord de la France, vol. i. : 1888.

176 LECTURE XII

of the villi. On the other hand, Heidenhain ^ asserts that the
epithelium of Lieberkiihn's glands differs very much morpho-
logicallv from the epithelium of the villi, and that, as the
intestinal contents never penetrate into Lieberkiihn's glands,
these could not serve for absorption.

The BILE, the secretion of the liver, is the only secretion
poured into the alimentary canal which remains for our con-
sideration. The secretion of bile is not the only function of
the liver. This is soon seen by comparing the size of the
liver and the small amount of bile produced with the size of
other glands and the quantity of their secretions. The human
liver weighs from 1500 to 2000 grms., and produces in twenty-
four hours about 400 to 800 grms. of bile.^ The parotid,
which weighs only from 24 to 30 grms., produces in the same
time from 800 to 1000 grms. of secretion. This simple fact
shows that the liver probably has other functions to perform.
We must refer our readers to another lecture (Lecture XXII.)
for an account of the numerous and complicated chemical proc-
esses that go on in this the largest of all the glands, and of
the origin of the bile from the constituents of the blood. At
present we have only to do with the secretion, when aifected,
and its significance in intestinal digestion.

The digestive secretions which have been under considera-
tion do not contain any specific constituents, if we exclude the
ferments which we are unable to isolate. So far as our knowl-
edge goes, they consist only of substances which are distrib-
uted all over the body. The chief solid constituents of the
bile, on the other hand, are found to consist of specific organic
compounds, which are either not met with at all elsewhere in

1 Heidenhain, Pfliiger's Arch., vol. xliii. Sup. p. 25 : 1888.

2 For the method of establishing a biliary fistula, and of determining the
amount of bile produced in twenty-four hours, see Schwann, Arch. f. Anat. u,
Physiol., p. 127: 1844; Blondlot, "Essai sur les fonctions du foie," &c. : Paris,
1846; Bidder and Schmidt, "Die Verdauungssäfte u. der Stofi"wechsel," p. 98;
Leipzig and Mitau, 1852. The amount of bile secreted in twenty-four hours in
cases of men with biliary fistulse, was estimated by J. Ranke, "Die Blutverthei-
lung und der Thätigkeitswechsel der Organe," pp. 39, 145: Leipzig, 1871; v.
Wittich, Pflüger's Arch., vol. vi. p. 181: 1872; Westphalen, Deutsch. Arch. f.
Hin. Sied., vol. xi. p. 588: 1873; Gerald F. Yeo and E. F. Herroun, Journ. of
Physiol., vol. v. p. 116 : 1884. Copeman and Winston, Journ. Physiol., vol. x.
p. 213: 1889. Mayo Robson, Proc. Roy. Soc, vol. xlvii. p. 499: 1890; Noel
Baton and J. M. Balfour, Rep. Lab. Roy. Coll. Phys., Edin., vol. iii. p. 191:
1891. The amount of bile in twenty-four hours estimated in the case of men
with biliary fistula is certainly too small, for the ductus choledochus was open,
and a part of the bile escaped into the intestine. With animals where the ductus
choledochus had been tied, a far larger amount of bile was obtained proportionate
to their weight. Bidder and Schmidt {loc. cit., pp. 114-209) found from 13 to 29
grms. of bile in tweuty-four hours to every kilogramme of weight, in the case of
dogs; with cats, an average of 14.5; sheep, 25.4; rabbits, 136.8.

INTESTINAL JUICE AND BILE 177

the animal ^ body or only in traces. We will therefore proceed
to examine these compounds more closely.

The sodium salts of two complex acids form the chief
constituents of the bile ; glycocholic acid and taurocholic acid.
The former of these acids splits up, on boiling with acids and
alkalies as well as when acted on by ferments with hydration,
into an acid free from nitrogen, cholalic acid, and into a sub-
stance containing nitrogen, glycocoll. The taurochloric acid
splits up, by the same means, into cholalic acid, and into a
body containing both nitrogen and sulphur, taurin.^

In spite of numerous investigations,^ little is known con-
cerning the constitution of cholalic acid. It appears that the
cholalic acids from the biliary acids of various animals have a
different composition, although possessing similar physical and
chemical qualities. The formula for the cholalic acid of human
bile was found by H. Bayer to be C^gH2g04, while that of the
cholalic acid in bullock's bile was found to be C„,II.„0,.

24 40 5

The constitution of glycocoll (glycin) is accurately known.
This substance can be synthetically produced from monochlor-
acetic acid and ammonia, and is therefore the same as amido-
acetic acid — CIl2(NIl2)COOH. It cannot be traced in a free
state in the animal body, but occurs in combination with
another acid than cholalic acid, as hippuric acid. We shall
soon meet with it again. It undoubtedly originates in the
animal body from proteid. It can be artificially prepared from
gelatin by boiling with dilute acids, and gelatin is a derivative
of proteid. Being produced from gelatin, amido-acetic acid
received the name glycocoll (gelatin sugar).

Taurin shows its origin from proteid by the amount of
sulphur it contains. Kolbe^ succeeded in producing it syn-
thetically in the following manner : chlorethyl-sulphonate of

1 The researches of Adolph Strecker in Liebig's Ännal. (vol. Ixv. p. 130 :
1848 ; vol. Ixvii. p. 1 : 1848 ; and vol. Ixx. p. 149 : 1849) form the groundwork
of all subsequent investigations on the bile-acids. Among later works, I must
particularly notice a series of experiments carried out by Heinrich Bayer in
Hoppe-Seyler's laboratory at Strassburg, " Ueber die Säuren der menschlichen
Galle " {Zeitschr. f. physiol. Chem., vol. iii. p. 293 : 1879). A summary of the
earlier work done in this field is also given here.

^ Of late years the following authors have worked more particularly on the
subject of the constitution of cholalic acid : Tappeiner, Zeitschr. f. Biolog., vol.
xii. p. 60: 1876; Sitzungsher. d. Wiener Akad., vol. Ixxxvii. part ii.: April,
1878: Ber. d. deutsch, ehem. Ges., vol. xii. p. 1627 : 1879. Compare also Lats-
chinoff, Ber. d. deutsch, chem. Ges., vol. xii. p. 1518: 1879; vol. xiii. pp. 1052,
1911 : 1880 ; vol. xv. p. 713 : 1882 ; and vol. xviii. p. 3039 : 1885 ; as well as
Hammarsten, Jüova Acta Heg. Soc. Scient. Upsala, ser. iii.: 1881; Kutscheroff,
Ber. d. deutsch, chem. Ges., vol. xii. p. 2325: 1879; Cleve, Compt. rend., vol.
xci. p. 1073: 1880; and Oefversigt af Kongl Vetenkaps. Akad. förh., No. 4,
1882.

' Kolbe, Ann. d. Chem. u. Pharm., vol. cixii. p. 33 : 1862.

12

178 LECTURE xn

silver, CjH^ClSOgAg, heated at 100° C. in sealed tubes with
a concentrated solution of ammonia, yields silver chlorid and
amido-ethyl sulphonic acid, C2H^(NH2)S03H. This is identical
with the taurin obtained from bile.

The comparative amounts of taurocholic and glycocholic
acids vary in the bile of different mammals. Glycocholic acid
predominates in bullock's bile, whereas the bile of Carnivora
appears to contain taurocholic acid only ; at any rate, this is
true of dog's bile.^ Both acids are found in human bile in
very varying proportions, although glycocholic acid always
predominates.^ Jacobsen even found the human bile in one
case quite free from sulphur, and in three other cases the
sulphur was only contained as a sulphate.^

To the specific constituents of bile belong also the bile
pigments, of which two occur in the bile of most vertebrates ;
one red-brown, bilirubin, and the other green, biliverdin. The
first is readily converted into the second by oxidation. Accord-
ing to the preponderance of one or the other, and according to
the amount of each, the bile is of a yellow, brown, or green
color. Both coloring matters have been obtained in a crystal-
line form. Bilirubin has the composition CjgHggN^Og ; bili-
verdin, CggH^gN^Og.* They are closely related to hematin
and hemoglobin, and we shall have later on to consider their
mode of origin from the latter in greater detail. Both color-
ing matters behave like acids ; they form soluble compounds
with metals of the potassium group, insoluble ones with those
of the calcium group. Certain gall-stones owe their origin to
the formation of these insoluble compounds in the bile-ducts,
under conditions which have not yet been sufficiently investi-
gated. The amount of coloring matter in normal bile is always
very small. Stadelmann ^ found, for instance, an average of
0.16 grm. of bilirubin in a dog's bile in twenty-four hours.

^^{Strecker, Ann. d. Chem. u. Pharm., vol. Ixx. p. 178: 1849; Hoppe-Seyler,
Journ. f. prakt. Chem., vol. Ixxxix. p. 283 : 1863.

2 O. Jacobsen, Ber. d. deutsch, chem. Ges., vol. vi. p. 1026 : 1873 ; Trifa-
nowsky, Pfl tiger's ^rcA., vol. ix., p. 492: 1874; Socoloff, ibid., vol. xii. p. 54:
1876 ; Hammarsten, Upsala Läkareförenings förhandlingar, vol. xiii. p. 574 :
1878; Hoppe-Seyler, " Physiologische Chemie," p. 301: Berlin, 1881. Gerald
F. Yeo and E. F. Herroun, Journ. of Physiol., vol. v. p. 116: 1884.

^ O. .Jacobsen, loc. cit., p. 1028.

* Städeler, Vierteljahr schrift der Züricher naturf. Ges., vol. viii. p. 1 : 1863 ;
Ann. d. Chem., vol. cxxxii. p. 323: 1864; Thudichura, Journ. f. prakt. Chem.,
vol. civ. p. 193 : 1868 ; Maly, Journ. f. prakt. Chem., vol. civ. p. 28 : 1868 ; or
Sitzungsber. d. Wiener A kad. d. Wissensch., yol.lvn. part ii. : 1868; vol. Ixx.
part iii.: July, 1874; vol. Ixxii. part iii.: October, 1875; Ann. d. Chem. u.
Pharm., vol. clxxxi. p. 106: 1876.

5 Ernst Stadelmann, Arch. f. exper. Path. u. Pharm., vol. xv. p. 349 :
1882.

INTESTINAL JUICE AND BILE 179

These pigments do not appear to be of any importance in in-
testinal processes.

Besides these specific constituents, the bile always contains
soaps, lecithin, and Cholesterin (see Lecture VI.). The quantity
of the latter is considerable ; it may amount to 2 J per cent. It
is absolutely insoluble in pure water, and is kept dissolved in
the bile by the presence of soaps and bile-salts. Under patho-
logical conditions, of which nothing definite is known, Choles-
terin separates out in the bile-ducts and forms concretions,
which are partly pure and partly mixed with bilirubin and car-
bonate of lime.

Lastly, mucin belongs to the constant biliary constituents.
This is not however a product of the liver-cells, but of the
epithelial cells which line the mucous membrane of the larger
bile-ducts, and especially of the gall-bladder. The latest and
most complete experiments on the chemical qualities of mucin
have been carried out by Landwehr.^ He arrives at the con-
clusion that mucin is a compound of proteid with a colloid
carbohydrate, which latter he designates " animal gum."

[Of late years the mucins and mucoids have been the
subjects of several careful investigations, the true starting-
point of which may be found in Schmiedeberg' s masterly
work^ on the composition of chondrin. He found that
chondrin could be regarded as a combination of gelatin with
a conjugated sulphuric acid, viz., chondretin-sulphuric acid.
Chondretin, itself not a reducing substance, could be converted
by boiling with dilute acids into chondrosin, which has a
strongly reducing action on cupric hydrate, and can be re-
garded as a combination of glycosamine (CgH^^O^NHj) and
glycuronic acid (COOH • C.HgO.). In chondrin therefore the
group which gives rise to the reducing substance on boiling
with acids, contains nitrogen. This is also the case with the
mucins so far as they have been investigated. Thus Müller ^
obtained pure glycosamine hydrochlorate from mucin of the
submaxillary gland. Leathes* investigated the mucoid of
ovarial cysts. On digestion and treatment in alkaline solution
with copper acetate, a gelatinous precipitate is formed which
contains the reducing groups of the mucin. The results of
analysis gave the formula for this compound Cj2H2iCuNOjg
-f- 2HC1. The reducing substance therefore has probably the

^H. A. Landwehr, Zeitschr. f.physiol. Chein., vol. viii. pp. 114, 122: 1883;
and vol. ix. p. 361 : 1885 ; also Centralbl. f. d. med. Wissensch., p. 369 : 1885.

' O. Schmiedeberg, Arch. f. exper. Path. u. Pharm., vol. xxviii. p. 355 : 1891.

? Müller, Sitzungsher. d. Gesell, s. BeförderuTig d. ges. Naturwissensch. z.
Marburg, No. 6, p. 117-126 : 1898.

* J. B. Leathes, Arch. f. exper. Path. u. Pharm., vol. xliii. p. 245 : 1899.

180

LECTURE XII

formula Ci2H23NOi^

Leathes gives it the name of para-mu-
cosin and regards it as possibly a dihexosamine.]

I subjoin the following analyses as instances of the highly
variable quantitative composition of human bile : —

Obtained fkom the Gall-Bladdek.

From a
Fistula.

Frerichs.*

Gorup-Besanez.»

Trifanowsky.»

Hoppe-

Seyler.*

Jacob-
sen.»

IN 1000 PARTS OF BILE.

2^
g => si

^x 5
» OS a

ja -a
bo . _r
.Sr© ja

H =« g

|P

^|g

OS Ko

0)

.5 6 .
1 c3 a)

■£ O c3
- C8 »

1 q5

a Ca a)

Is"

'^ 3

Collected from
gall-bladders
in post-
mortems.

.2

TS
O

•Ö
CS

<s

i

I. II.

Water

Solid substances

Mucin ^

Other substances insoluble >■

in alcohol J

Sodium taurocholate . . . \
Sodium glycocholate ... J
Sodium palmitate and stea-

rate

860.0
140.0

26.6
102.2

3.2

1.6
6.5

2.5

2.0

1.8

0.2
Trace

859.2
140.8

29.8
91.4

9.2^

2.6J

7.7

2.0
2.5

2.8

0.4
Trace

822.7
177.3

22.1
107.9

47.3
10.8

898.1
101.9

14.5
56.5

=1

30.9/
6.3

908.8
91.2
24.8

4.6

7.5
21.0

8.2

5.2

2.5

910.8
89.2
13.0

14.6

19.3
4.4

16.3

3.6
0.2
3.4

12.9 ■»

L4/

8.7
30.3

13.9

7.3/

5.3

3.5

Trace

977.4
22.6

2.3

10.1
1.4

Sodium oleate

Fat

0.10

Lecithin

Cholesterin

Inorganic salts

KCl

NaCl

0.05

0.56

8.5

0.28

5.5

Na^COa

NajPO^

0.95
1.3

CaCOg

Ca(PO,), ■>

Mg^p^o, ;

CaSO-

FePO,

0.37
Trace

Trace

These analyses show that the bile obtained from the gall-
bladder is much more concentrated than that obtained from
the fistula. It is therefore evident that an absorption of water
occurs in the gall-bladder. The analyses of dog's bile by

1 Frerichs, Hannover Ann., Jahrg. v. Heft i.: 1845.

2 Von Gorup-Besanez, Prager Vierteljahr sehr., vol. iii. p. 86: 1851.
^ Trifanowsky, Pfliiger's Arch., vol. ix. p. 492 : 1874.

* Hoppe-Seyler, " Physiologische Chemie," p. 301 : Berlin, 1881.

"O. Jacobsen, Ber. d. deutsch, ehem. Ges., vol. vi. p. 1026 : 1873. The bile
was taken, at intervals of a few days, from a biliary fistula open for several
weeks, the patient being a powerful man.

INTESTINAL JUICE AND BILE

181

Hoppe-Seyler/ in which he compared the bile found in the
bladder, and collected while the animal was fasting, with that
from a temporary fistula on the same animal, are in accordance
with this observation.

Bile from bladder.

Bile from fistula.

I.

II.

I.

n.

Mucin

0.454

0.245

0.053

0.170

Alkaline taurocholate

11.959
0.449

12.602
0.133

3.460
0.074

3.402

Cholesterin

0.049

Lecithin

2.692

0.930

0.118

0.121

Fats

2.841

0.083

0.335

0.239

Soaps ...

3.155

0.104

0.127

0.110

Other organic substances, not soluble in alcohol

0.973

0.274

0.442

0.543

Inorganic substances, not dissolved in alcohol

0.199

—

0.408

—

In the above : KoSOi •

0.004
0.050

z

0.022
0.046

NajSO^

— .

NaC12

0.015
0.005
0.080

—

0.185
0.056
0.039

NajCOg

Ca,2(P0).

FePOi

0.017

—

0.021

—

CaCOg

0.019
0.009

—

0.030
0.009

MgO

—

More recently Hammarsten^ has had the opportunity of
analyzing a number of specimens of human bile obtained from
the gall-bladder as well as from fistulse.

Solids

Water . . .

Mucin and pigment
Bile-salts

Taurocholate . . .
Glycocholate
Fatty acids . . .
Cholesterin . . .
Lecithin . .

Fat

Soluble salts . .
Insoluble salts . .

Bile from fistula.

1.63
98.37
0.36
0.26
0.06
0.20
0.04
0.05

0.02

0.85
0.04

2

3

4

5

2.06

2.52

2.84

2.45

97.94

97.48

97.16

97.55

0.28

0.53

0.91

0.88

0.85

0.93

0.81

0.56

0.11

0.30

0.05

—

0.74

0.63

0.76

—

—

0.12

0.02

—

0.08

0.06

0.10

0.06

0.03

0.02

0.05

0.08

0.02

0.80

0.81

0.81

0.89

0.02

0.03

0.04

0.03

3.53
96.47
0.43
1.82
0.21
1.61
0.14
0.16
0.06
0.10
0.68
0.05

2.54
97.46
0.52
0.90
0.22
0.69
0.10
0.15
0.07
0.06
0.73
0.02

From gall-bladder.

17.03
82.97
4.19
9.70
2.74
6.96
1.12
0.99
0.22
0.19
0.29
0.22

16.02
83.98
4.44
8.72
1.93
6.79
1.06
0.87
0.14
0.15
0.30
0.24

1893.

^ Hoppe-Seyler, loc. cit., p. 302.

2 The greater part of the NaCl was dissolved by alcohol, and not estimated.

^ Olf Hammarsten, J}fova Acta Beg. Societat. Scient. JJpsal., ser. iii., vol. 16 ;

182 LECTURE XII

Having ascertained the composition of the bile, we must
now consider its uses. There has been much dispute on this
point. Some have even denied that it is of any essential use
whatever, and have regarded it simply as an excretion like the
urine. The fact that the bile is poured into the commencement
of the intestine, into the duodendum, is opposed to this view.
If the bile were an excretion, we should expect the bile-duct to
open into the lower end of the rectum, just as the ureter opens
into the cloaca in the lower vertebrates. It is impossible not to
believe that bile, in its long passage through the intestines, must
have some serious duties to perform.

The constituents of the bile are, to a very large extent, re-
absorbed by the intestine — a fact which is strongly opposed to
its being an excretion. The bile acids, which are the most im-
portant constituents, are split up by the ferments contained in
the intestine into cholalic acid and taurin or glycocoll ; the lat-
ter, a very easily soluble substance, disappears entirely.^ Of
the cholalic acid only a very small part is excreted in the feces.
Concerning the ultimate fate of the taurin nothing is known
with certainty.^

If the bile were an excretion like urine, we should expect
to find the quantity of nitrogen and sulphur in the bile varying
proportionately with the amount of proteid decomposed in the
body. As a matter of fact, this is not the case. We know
from the researches of Kunkel ^ and Spiro,"* conducted on dogs
with biliary fistulse, that only a small part of the sulphur and
nitrogen resulting from proteid metabolism appears in the bile,
and that it is but very slightly increased by a larger supply of
food. When the amount of proteid allowed the dog was mul-
tiplied eightfold the nitrogen and sulphur of the bile were only
doubled.

All these facts speak in favor of the view that the bile
must be regarded as a secretion, like the other secretions which
are poured into the alimentary canal and exert a manifestly im-
portant influence in the process of digestion. But the follow-
ing fact shows that the bile occupies a peculiar position. The
secretion of the bile begins in the third month of embryonic

■^ On the further fate of the glycocoll, see Lecture XIX.

2 The most extended researches on taurin have been made by Salkowski, Ber.
d. deutsch, ehem. Ges., vol. v. Heft, xiii.: 1872; vol. vi. pp. 744, 1191, 1312: 1873;
Virchow's Arch., vol. Iviii. p. 460: 1873.

3 Kunkel, "Unt. über den Stoffwechsel in der Leber": Würzburg, 1875:
Ber. d. sack. Ges. d. Wissensch.: November, 1875 ; Pflüger's Arch., vol. xiv. p.
344: 1876.

* Spiro, Du Bois' Arch., Suppl., p. 50: 1880 (from Ludwig's laboratory in
Leipzig).

INTESTINAL JUICE AND BILE 183

life ; the activity of all the other glands which empty their
secretions into the alimentary canal does not commence till after
birth, when food is first taken. ^ Moreover the observation of
Lukjanow^ that the secretion of bile in guinea-pigs is only
slightly diminished during starvation is against the conception
of bile as a digestive secretion.

It has been attempted to decide the question as to the func-
tion of the bile in intestinal processes by watching the digestive
disturbances which occur when the bile is withdrawn.^ It
appears that dogs with a biliary fistula digest proteid and
carbohydrates as completely as healthy dogs. They can be
adequately fed on lean meat and bread. Fat is the only
food-stuff that they cannot entirely digest, and a considerable
part of it — more than half if much be eaten — reappears in
the feces, which for this reason are of a light gray or white
color. This is not owing to the want of the bile pigments,
as was originally thought. The black color of the normal
feces after meat diet is not caused by the bile pigments, but
by hematin and sulphid of iron. If the light gray feces of
an animal with a biliary fistula or of a jaundiced person be
extracted with ether, which dissolves the fat, the dark color is
again evident. In consequence of the imperfect absorption of
the fat, the other food-substances cannot be completely digested.
The fat encloses the proteids, which become decomposed by
the putrefactive organisms of the intestine. This explains the
putrefactive smell of the feces and the intestinal gases in
dogs with a biliary fistula. The breath of the animals be-
comes fetid. These symptoms are all absent when a diet with-
out fat is given.

Many of the dogs with a biliary fistula that have been
under observation became very thin, and a few died with every
symptom of starvation. This is readily comprehensible if we
consider how high the heat-equivalent of fats is, and how

^Zweifel, " Unt. über den Verdauungsapparat des Neugeborenen" : Berlin,
1874. An account of the comprehensive literature on the action of the digestive
glands in embryonic life is to be found in W. Preyer's " Specielle Physiol, des
Embryo," p. 306: Leipzig, 1885.

2 S. M. Lukjanow, Zeitschr, f. physiolog. Chem., vol. xvi. p. 87: 1891.

3 Schwann, Arch. /. Anat. u. Physiol., p. 127 : 1844 ; Blondlot, " Essai sur les
fonctions du foie et de ses annexes " : Paris, 1846 ; Bidder and Schmidt, loc. cit.;
Köllicker and Müller, Verh. d. phys. med. Ges. zu Würzburg, vol. v. p. 232 : 1854;
vol. vi. : 1855 ; Arnold, " Zur Physiol, der Galle," Denkschrift für Tiedemann :
Mannheim, 1854 ; and " Die physiol. Anstalt der Universität Heidelberg " : 1858 ;
C. Voit, Beitr. zur Biolog. Festgabe Th. Bischoff zum Doctorjubiläum, Stutt-
gart, p. 104; F. Röhmann, Pflüger's Arch., vol. xxix. p. 509: 1882. The
observations on icteric patients are in complete harmony with those on dogs with
biliary fistulse. In this connection see Fr. Müller, Sitzungsber. der physikal. med.
Ges. zu Würzburg, No. 7 : 1885.

184 LECTURE XII

difficult it is to replace this potent source of energy by other
articles of food. It is necessary for this purpose to consume
very large quantities of proteid and carbohydrates, and the
digestion of these substances is disturbed by the presence of the
unabsorbed fat. Therefore only those dogs kept their weight
which were fed on food as far as possible free from fat, and that
in very large quantities.

It is therefore an undoubted fact that bile aids iu the absorp-
tion of fat. This power is partly explamed by the emulsi-
fying action on fats already mentioned (p. 164), which the
bile possesses in common with the pancreatic and intestinal
juices. In agreement with this is the fact that the with-
drawal of the bile only diminishes the absorption of fat, and
does not completely stop it. Possibly it is not only the
emulsifying action of the bile which assists in the absorption
of fat. Wistinghausen ^ showed that, when oil is separated
from a watery fluid containing bile in solution by an animal
membrane soaked in bile, it filters through without any pres-
sure, whereas it can only be made to pass through a membrane
soaked m water by the employment of high pressure. But the
intestinal wall does not behave like a dead membrane. Than-
hoifer,- who first observed in the frog's intestine the active func-
tions of the epithelial cells iu the absorption of fats, also
mentions that the movement of the protoplasmic processes
becomes more active when the epithelial cells are moistened
with bile.

The process of fat absorption is however by no means ex-
plained by the facts we have discussed. The emulsion of the
fat by the alkaline constituents of the intestinal pancreatic
juices and of the bile will not serve alone to explain the
process. The pancreatic secretion and bile have still an-
other part to play in the process. We know for certain that
the absorption can only take place by the cooperation of both
juices. In the rabbit the pancreatic duct opens into the
duodenum 10 cms. lower down than the bile duct. After
the administration of fatty food the lacteals may be seen to be
transparent in the interval between these two openings, and
only assume the milky appearance below the orifice of the
pancreatic duct. Dastre experimentally changed the relative
position of the two ducts. He ligatured the common bile duct
and made a fresh opening for the bile by a commnnication

^ Wistinghausen, " Experimenta quaedam endosmotica de bills in absorptione
adipum neutralium partibus," Dissert.: Dorpat, 1851. A translation of this
dissertation was publisiied by J. Steiner in Du Bois' Arch., p. 137 : 1873.

2 Ludwig von Thanhoffer, Pfliiger's Arch., vol. viii. p. 40 1874.

INTESTINAL JUICE AND BILE 185

between the gall-bladder and the small intestine some distance
below the opening of the pancreatic duct. After this procedure
the milky appearance of the lacteals first became evident below
the point of entry of the bile. We must therefore conclude
that neither the bile by itself, nor the pancreatic juice by itself,
can effect any considerable absorption of fat.

[It seems most probable that the absorption of fat resembles
that of the other food-stuffs in that it takes place in a state of
solution. The pancreatic juice first causes a splitting of the fat
into fatty acid and glycerin. If the reaction is alkaline the
fatty acid may combine with the alkalies to form soaps. What-
ever be the reaction of the intestinal contents, however, the fat
is absorbed either as a solution of fatty acids in the bile-salts or
as a solution of soaps in the bile. The cooperation of both
juices is therefore necessary : the pancreatic juice to split the
fats, the bile to dissolve the products of this fermentative
action and carry them into solution into the epithelial cells of
the intestine, where the fatty acids and soaps are resynthesized
with glycerin to form neutral fats, while the bile-salts are
carried by the portal blood to the liver to be turned out again
into the beginning of the intestinal tract and serve as a vehicle
for a still further quantity of fat.]

No action of bile on proteid could be demonstrated in
experiments on artificial digestion. A slight diastatic effect
was indeed noticed, but, for the reasons above stated no weight
can be attached to this observation. Bile must however have
some other functions besides that of assisting in fat absorption,
since the quantity of bile secreted by herbivora, whose diet is
poor in fat, is much greater than that formed by Carnivora with
their rich fatty diet.

An antiseptic property has also been ascribed to bile on
account of the putrefactive phenomena, mentioned above, which
appeared in the intestine of animals with a biliary fistula.
But, as was then shown, these signs of putrefaction are capable
of another explanation ; they depend only indirectly upon the
absence of the bile. For as the bile cannot protect even itself
from putrefaction, it is evident that it can have but little anti-
septic power. Any one who has experimented with bile knows
that it emits a strong putrefactive odor after a few days, even
when kept at the temperature of a dwelling-room. The
doctrine of the antiseptic properties of bile has recently again
found supporters in Maly and Emich.^ They affirm that the
bile acids, and especially taurocholic acid, prevent the develop-
ment of putrefactive organisms, and that taurocholic acid in

1 Maly and Fr. Emich, Blonatshefte f. Chem., vol. iv. p. 89 : 1883.

186 LECTUKE XII

many cases is nearly as powerful as salicylic acid and phenol.
This view has been confirmed by Lindberger* as well as by
Gley and Lambling.^ But still it is only the free bile acids that
hinder putrefaction, and not the salts. This explains why bile
itself which is alkaline or neutral, rapidly decomposes outside
the body, whereas the bile acids can develop their antiseptic
properties only in the upper portion of the small intestine,
where an acid reaction prevails.

' V. Lindberger, Bulletin de la Soc. imp. des naturalistes de Moscou : 1884.
* Gley and Lambling, Rev. hiol. du Nord de la France, vol. i.: 1888.

LECTURE XIII

THE PATHS OF ABSORPTION, AND THE IMMEDIATE DESTINA-
TION OF THE ABSORBED FOOD-STUFFS

We have hitherto been considering the fate of the food-sub-
stances in the intestine and the preparation they undergo
previous to absorption. Our attention must now be given to
the paths which the food-stuflPs follow in undergoing absorp-
tion.

The investigations of Ludwig and of his pupils Röhrig/
Zawilski/ von Mering,^ and Schmidt-Mülheim/ have thrown an
unexpected light on this subject. Till modern times it was
commonly assumed that the main stream of nutriment passed
from the intestine through the thoracic duct. But Ludwig's
experiments have shown that it is only the fats which take this
path. The whole stream of watery solutions, carbohydrates,
proteids, salts, etc., proceeds from the intestine to the heart,
through the portal system and the liver. The watery solutions
penetrate the walls of the capillaries which form a network on
the internal surface of the intestine, and enter the blood direct.
The droplets of fat alone are brought to the commencement of
the lacteals by the active movements of the epithelial cells.

If, in a living dog, the spot where the thoracic duct opens
into the jugular vein ^ be laid bare, a cannula may be intro-
duced into the duct, and the amount of chyle that flows out in
a given time estimated. The astonishing fact was discovered
that the amount was no greater during digestion than in a
fasting animal.^ The sole difference was that the fluid was
transparent in the case of fasting animals, whereas after food

1 A. Röhrig, Ber. d. sacks. Ges. d. Wissensch. Math. phys. Classe, vol.xxvi.:
1874.

2 Zawilski, Arbeiten aus der physiol. Anstalt zu Leipzig, p. 147 : 1876.
ä von Mering, Du Bois' Arch., p. 379 : 1877.

*A. Schmidt-Mülheim, ibid., p. 549.

^ For the mode of operation and the precautions adopted during the sub-
sequent post-mortem, see A. Röhrig, loc. cit., pp. 12, 13 ; and Schmidt- Mülheim,
loc. cit., pp. 559-561.

« Zawilski, loc. cit., pp. 161, 162.

187

188 LECTURE XIII

it was white and opaque from the presence of min ate particles
of fat.

On the other hand, the amount of sugar in the chyle was
not found to be greater during the digestion of starch and
sugar than in the fasting animal — 0.1 to 0.2 per cent.^ The
amount of sugar in the chyle was always the same as in the
lymph from the cervical lymphatic trunks, and in the serum ^
of the arterial blood. The sugar of the chyle had therefore
passed through the walls of the intestinal capillaries into the
chyle-vessels along with the blood-plasma. From the intestine
no sugar had got through into the chyle.

Three hundred and fifty cubic centimeters of chyle, con-
taining only 0.45 grm. of sugar, flowed during the space of
four and a half hours from the thoracic duct of a dog, after
it had eaten 100 grms. of grape-sugar and 100 grms. of
starch.^

We must therefore conclude that the sugar reaches the
capillaries and the portal system direct from the intestine.
But uow we see that the amount of sugar in the blood is not
increased even after a meal rich in carbohydrates. An adult
man has about 5 liters of blood, and in each liter 0.5 to 1.5
grms. sugar, rarely more than 2 grms., so that the whole blood
contains at most 10 grms. This amount remains the same in a
hungry as in a well-fed animal. During the few hours elapsing
after a meal rich in carbohydrates, as much as 400 grms. of
sugar may pass into the blood. What becomes of this sugar ?
It cannot always be employed as a source of energy as quickly
as it is absorbed, especially when the body is at rest and does
not need to produce much heat. The sugar must therefore be
stored up somewhere and in some form or other, in order that
it may serve as a store of potential energy for later utiliza-
tion.

We naturally think first of glycogen, the colloid carbo-
hydrate stored up in the liver and muscles, which we shall have
to deal with more fully later on. We know that this store of
glycogen gradually disappears in hunger and during work
(compare Lectures XXII. and XXIII.), and rapidly increases
in amount after ingestion of carbohydrates.

But the large quantities of sugar which are frequently
absorbed from the intestine into the blood within a short space
of time cannot possibly be all stored up as glycogen. The

1 von Mering, loc. cit., pp. 382-384, 398.

2 The blood-corpuscles contain no sugar, or only a trace of it (see von Mering,
loc. cit., p. 382 ; and A. M. Bleile, Du Bois' Arch., p. 62 : 1879).

* von Mering, loc. cit., p. 398.

THE PATHS OF ABSORPTION 189

total amount of glycogen in the liver in man never exceeds 150
grms., and a similar quantity might be stored up in the whole
mass of muscles. This store however is by no means used up
at the time when fresh carbohydrates are taken into the body,
and disappears only after several weeks' starvation. If there-
fore 400 grms. of sugar are poured into the blood within a few
hours after a carbohydrate meal, it is evident that only a small
proportion of it can be laid down as glycogen ; and we must
assume that the greater part of it is converted into fat. In this
form very large quantities of food can be stored up in the con-
nective tissue of all the organs, and we shall see later (Lecture
XXIV.) that carbohydrates are, as a matter of fact, converted
into fat in our tissues.

The present state of our knowledge enables us therefore to
form the following conception concerning the fate of the sugar
that is taken into our body: — Sugar is an important food-stuff —
an important source of energy for the muscles and probably for
all contractile tissues. Hence provision has been made in our
bodies for a certain percentage of it to be constantly present
in the blood which circulates through all the tissues. If its
amount in the blood increases to more than 3 per mille, excre-
tion of sugar takes place through the kidneys (compare Lecture
XXVI.). This loss of precious food-stuff is prevented by the
fact that the liver and muscles at once store up as glycogen any
excess above the normal resulting from a rapid absorption. If
the consumption be increased by work and heat production so
as to diminish the normal percentage of sugar in the blood, the
muscles and liver at once give back a portion of the glycogen
to the blood in the form of sugar. If the store of glycogen
is insufficient, fat is converted into sugar and transferred to
the blood. In a subsequent lecture (Lecture XXII.) we shall
deal with the grounds for assuming that such a conversion
takes place. We know for a fact that, after long-continued
hunger, when the store of glycogen has quite disappeared, the
percentage of sugar in the blood remains constant. Sugar is
also in all probability formed from proteid (compare Lecture
XXIL).

The question now arises as to the reason why the amount of
FAT in the blood is not regulated in the same way ? The stream
of fat being poured freely into the innominate vein goes almost
directly to the heart. May not this be fraught with danger ?
The blood is in fact frequently flooded by the stream of fat.
If blood, which has been taken from a dog a few hours after a
meal containing an abundance of fat, be defibrinated, the serum
separated out after the blood-corpuscles have sunk, appears

190 LECTURE xni

as white as milk, occasionally with a regular cream-like layer
on the top. This abundance of fat in the blood is quite harm-
less, because the fat-droplets are so small that they circulate
without hindrance through the capillaries. The fat gradually
disappears from the blood, for the obvious reason that it travels
through the walls of the capillaries, and becomes stored up in
the cells of the connective tissue (compare Lecture XXIV.).
It is impossible for the fat to be decomposed within the vessels,
since, as we know, processes of oxidation never take place in
the blood (see Lecture XVIL).

The fat which reaches the blood under abnormal conditions
behaves very diiferently. In comminuted fractures of the
bones causing a destruction of the marrow which contains a
great deal of fat, or when the soft parts containing much fat
are damaged in any way, fat-droplets are often drawn into the
lymph-vessels and carried with the lymph into the blood. If
the amount of fat is considerable, the larger particles of fat
block the pulmonary capillaries over wide areas, edema of the
lungs is set up, and it occasionally happens that the patient dies
with all the signs of increasing dyspnea. The fat may in these
cases seek a way out through the kidneys, and the occurrence of
droplets of fat in the urine after fractures of bone is not at all
uncommon.

The question might now be raised as to why this fat,
which reaches the blood from the tissues, is not emulsified
into minute droplets, seeing that the blood contains sodium
carbonate and other basic alkaline salts. The answer is
to be found in the fact already mentioned (p. 164), that
sodium carbonate can only emulsify fat which has a little
free fatty acid mixed with it, and not neutral glycerids such
as fresh fats are. But no fat can be fresher than when it
comes straight from the living tissues into the current of
blood.

It has not yet been decided whether all fat passes from the
intestine into the lacteals, or whether a part enters the blood
directly through the walls of the capillaries of the intestinal
villi. Even if a portion does take the latter path, it appears
to be inconsiderable. Zawilsky found very little fat in the
blood of a dog, which had been fed on a highly fatty diet,
and whose chyle was drawn off. If fat passed into the cap-
illaries of the intestinal villi to any extent, we should expect
to find that an abundant diet of fat would be followed by a
perceptibly larger increase in the portal than in the arterial
blood. Comparative estimates, made in Heidenhain' s labora-
tory, showed that there was the same amount of fat in both

THE PATHS OF ABSORPTION

191

kinds of blood. ^ An average of five analyses of blood from the
same number of dogs gave —

Dry residue.

Amount of fat in
total blood.

Amount of fat in
dry residue.

Carotid . .
Portal vein

22.34 per cent.

22.84

0.86 per cent.
0.85

3.65 per cent.
3.35

The only question that remains for us to consider refers
to the path the Proteids take in order to become absorbed.
There are special difficulties to contend against in experiments
on this subject, because proteids already form the chief con-
stituents of blood and lymph. If we consider how large is
the amount of blood which passes through the intestinal capil-
laries, we cannot expect to be able to trace an increase of
proteid in the blood in consequence of intestinal absorption.
Ludwig and Schmidt-Mülheim therefore adopted another
method. They tied the thoracic duct, and found that this did
not in any way prevent the absorption of the proteid, and that
therefore the proteid takes, the other path, through the portal
vein. I will here quote one of these experiments.^

Weight of dog, 14.73 kgrms. The dog, which had pre-
viously fasted for four days, passed all his urine before the
operation. The jugular and subclavian veins and lymphatic
ducts on both sides were now tied. An hour after the opera-
tion, and again on the following afternoon, the dog ate on each
occasion 400 grms. of meat ; and the whole time was in ex-
cellent condition. Forty-eight hours after the operation, the
animal was killed by opening the carotid. On post-mortem
examination, the chyle was found completely shut off from the
blood-vessels. The alimentary canal contained 7.37 grms. N.
It thus appears that 583.24 grms. of meat were absorbed after
complete interruption of the chyle-current. The urine secreted
after the operation contained 21.95 N, an amount correspond-
ing to the food absorbed.

Four other experiments carried out in the same manner
gave the same result. We thus see that proteid, like all food-
substances dissolved in water, enters the blood directly through
the walls of the intestinal capillaries.

The question now arises, whether all proteid, in order to be
able to follow this path, must be peptonized beforehand, or
whether a portion of the proteid is absorbed as such.

* Heidenhain, Pflüger's Arch., vol. xli. Sup., p. 95 : 1888.
2 Schmidt-Mülheim, loc. cit., p. 565, Exp. 5.

192 LECTUEE XIII ^

There is no ä priori ground for supposing that proteid is not
absorbed unchanged. If fat-droplets, visible under the micro-
scope, and even entire leucocytes, can leave the blood-capillaries
and travel through the tissues, why may not a proteid molecule
find its way through the capillary wall? Voit and Bauer
have endeavored to prove this experimentally/ A coil of
small intestine of a live dog or cat was cleansed of all contents,
and a piece of a certain length was tied at both ends with
a double ligature ; a solution of proteid was then injected into
this ligatured piece, the coil replaced, and the abdominal
wound closed. The percentage of proteid contained in the
solution being known, the operators estimated the quantity
injected by the loss of weight of the syringe used. After
a few hours the animal was killed, and the amount of proteid
in the piece of intestine was estimated. It was invariably
found that a considerable portion had disappeared in from one
to four hours — from 16 to 33 per cent, of egg-albumin, from
28 to 95 per cent, of acid-albumin prepared from muscle.
Voit and Bauer refute the obvious objection that the coil of
small intestine was not thoroughly cleansed from the peptic
and pancreatic ferments, as they found that the remainder
of the proteid in the piece that had been tied was always com-
pletely coagulable by boiling. No peptone was present with
the proteid.

Voit and Bauer have also injected solutions of proteid into
the rectum of fasting dogs, and determined the absorption of
the unchanged proteid from the increased secretion of urea.
Eichhorst ^ draws the same conclusion from similar experiments.
These experiments are open to the objection that the pancreatic
ferment may extend into the rectum. The experiments of
Czerny and Latsch enberger,^ however, are free from this
objection, because they were made on a man with an artificial
anus at the sigmoid flexure. The rectum could be syringed
quite clean through the fistula. If a solution of proteid were
then injected, and the rectum again washed out after from
twenty-three to twenty-nine hours, it was found that from 60
to 70 per cent, of the proteid had disappeared. Nencki * and
his pupils came to the same conclusion as the result of a
similar experiment on man.

A few authors have gone so far as to maintain that only

1 C. Voit and J. Bauer, Zeitschr. f. Biolog., vol. v. p. 562 : 1869.
^Hermann Eichhorst, Pflüger's Arch., vol. iv. p. 570 : 1871.
^ V. Czerny and J. Latschenberger, Virchow's Arch., vol. lix. p. 161 : 1874.
^ MacFadyen, Nencki and Sieber, JrcA. /. exper. Path. u. Pharm., vol. xxviii.
p. 344 : 1891.

THE TATHS OF ABSORPTION 193

the unaltered proteid is of any use after absorption in replacing
the proteid 'used up in the tissue, and that the peptones, on the
contrary, undergo rapid further decomposition, and only serve
as sources of energy.

Certain facts seem to agree with this view. A fasting
animal is very economical with its store of proteid, and its
excretion of urea is very limited ; whereas, after a meal con-
sisting largely of proteids, an amount of nitrogen closely corre-
sponding to the proteid eaten reappears in the urine in the
course of the next twelve hours. It might ä priori be expected
that the nitrogenous equilibrium would be maintained if a fast-
ing dog were to eat as much proteid as corresponds to the
nitrogen excreted in hunger, together with plenty of non-
nitrogenous food. It might be thought that it would be in-
diiferent whether the necessary proteid were derived from the
food, or from the animaPs own tissues. But it is not so. If
a fasting dog be given only as much proteid as corresponds to
the proteid used up in fasting, it still goes on consuming the
nitrogenous constituents of its own tissues. Nitrogenous equi-
librium, i. e., the condition in which the animal excretes no
more nitrogen than he takes in, is not established until three
times as much proteid is given. ^

Ludwig and Tschiriew ^ injected into the vein of a dog
defibrinated blood from another dog. This caused only an in-
considerable increase of nitrogenous excretion. But if they
gave the dog the same quantity of blood by the mouth, the ex-
cretion of nitrogen rose proportionately to the amount given.
Förster^ attained the same result in similar experiments.
[Pflüger however has shown that the assimilation of serum is
as complete when it is administered intravenously as when it is
given by the mouth.]

Proteid therefore behaves very differently according to the
way in which it reaches the blood and the tissues. When
taken up from the intestine, it rapidly undergoes a destructive
metabolism.

This fact was quoted in support of the theory that peptones
are not assimilable. It was claimed that proteids absorbed
from the intestine, being mostly peptonized, must therefore go
on decomposing rapidly ; and, further, that only that portion of
the proteid which is absorbed as such can be used in building
up the tissues.

But the facts are capable of another interpretation, for we

^ Voit, Zeitschr.f. Biolog., vol. iii. pp. 29, 30 : 1867.

^ S. Tschiriew, Arbeiten au^ dem physiol. Institut su Leipzig, p. 441 : 1874.

^ J. Forster, Zeitschr. f. Biolog., vol. ii. p. 496 : 1875.

13

194 LECTURE XIII

now know that the peptones are, after absorption, regenerated
into proteid. The following experiments show this to be the
case.

Plosz ^ fed a dog ten weeks old for eighteen days on an
artificial milk, in which the casein and the proteids were re-
placed by peptones. The animal kept its health on this diet,
and its weight increased from 1335 to 1836 grms., or 37.5 per
cent. It is very improbable that the weight could increase so
much without a corresponding growth of the tissues containing
proteid, which must therefore have been formed from the pep-
tones of the food.

Plosz and Gyergyai ^ made a second experiment on a full-
grown dog. The animal was fed for six days on an artificial
mixture, containing peptone instead of proteid. During this time
the weight mcreased somewhat, and the excretion of nitrogen
was a little less than that taken in. This experiment, again,
can only be interpreted to mean that proteid had been formed
from the peptones.

The proteid stored in the animal tissues may come from two
sources : from that which has been absorbed unaltered, and
from that formed by the regeneration of the peptones. But
what quantitative proportion do they bear to each other?
How large is the portion of the proteid of the food which is
peptonized in the intestine? Schmidt-Mülheim^ tried to find
an answer to this in the following manner. He fed six dogs
on boiled meat, killed them one, two, four, six, nine, and
twelve hours after the meal, and examined the contents of
stomach and intestine. In each case he found considerably
more peptone than dissolved proteid, both in stomach and in-
testine. It thus appears that the greater part of the proteid
became absorbed after peptonization.

What is the fate of peptones after absorption ? They are
either not found at all or only in very small amount in the
blood of digesting animals. Schmidt-Mülheim gives the maxi-
mum as 0.028 per cent, of serum ; Hofmeister found that it
amounted to as much as 0.055 per cent, of the total blood.
Peptones are not found in the blood of fasting animals.* As
might be expected, they cannot be detected in chyle, not even

p. Plosz, Pfliiger's Arch., vol. ix. p. 323 : 1874. Compare Maly, ibid., vol.
ix. p. 609 : 1874.

2 P. Plosz and A. Gyergyai, ibid., vol. x. p. 545 : 1875.

3 Schmidt-Mülheim, Du Bois' Arch., p. 43 : 1879.

"^ Ibid., pp. 38-42 : 1880; Hofmeister, Zeitschr. f. physiol. CAem., vol. v. p.
149 : 1881 ; and vol. vi. p. 60, et seq. [The small amounts of peptone found by
these observers are due to errors of analysis. The blood of healthy animals,
whether fasting or fed, never contains the slightest traces of proteoses or peptones.]

THE PATHS OF ABSORPTION 195

when they are found in the blood.^ If peptone be injected
into the blood, it passes into the urine,^ and none can be traced
in the blood after from ten to sixteen minutes.^ Hofmeister
has shown also, that after subcutaneous injection the greater
part of the peptone — as much as 72 per cent. — reappears in
the urine.*

As normal urine never contains peptone, the peptone ab-
sorbed from the intestine must be prevented by some means or
other from passing into this secretion. The larger portion does
not apparently enter the general circulation as peptone, but is
previously converted into proteid. But where does this regen-
eration of peptone to proteid take place ? Is it in the liver ?
If the peptones are considered as decomposition-products from
proteid, then the formation of proteid from peptone would be
analogous to the formation of glycogen from sugar in the liver.
But the portal blood either contains no peptone, or not more
than arterial blood. ^

The only remaining supposition is that the conversion of
peptones into proteid takes place mostly within the intestinal
walls. The facts observed by Hofmeister are in harmony with
this view. He most carefully examined the viscera of dogs
while digesting, and found that the stomach and intestinal wall
are the only parts of the body in which a supply of peptone is
always found during digestion. In most cases small quantities
of peptones were also found in the blood, and in four out of
ten cases in the spleen. No peptone was ever detected in any
other organs or tissues.^ Hofmeister has also shown that the
peptones are always stored in the mucous membrane, and never
in the muscular walls of the alimentary canal.''

Lastly, Hofmeister has discovered the important fact that
peptone soon undergoes a change in the gastric and intestinal
wall.^ The stomach of an animal, immediately after it had
been killed, was divided into two symmetrical halves by in-
cisions in the large and small curvatures, or else a piece of in-

1 Schmidt-Müllieim, Du Bois' Arch., p. 41 : 1880 ; Hofmeister, Arch. f. exper.
Path. u. Pharm., vol. xix. p. 17 : 1885.

2 P. Plosz and A. Gyergyai, Pflüger 's ^rcA., vol. x. p. 552 : 1875; Fr. Hof-
meister, Zeitschr. f. physiol. Chem., vol. v. p. 131 : 1881.

3 Schmidt-Mülheim, Du Bois' Arch., pp. 46-48 : 1880 ; Fano, ibid., p. 281 : 1881.
[By the employment of trichloracetic acid as a precipitant for the proteids, it is
possible to detect the presence of peptone in blood for as much as two hours after
its injection into a vein.]

4Fr. Hofmeister, Zeitschr. f. physiol. Chem., vol. v. pp. 132-137 : 1881.

5 Schmidt-Mülheim, Du Bois' Arch., p. 43 : 1880.

6 Hofmeister, Zeitschr. f. physiol. Chem., vol. vi. p. 51 : 1882.

' Hofmeister, Arch. f. exper. Path.u. Pharm., vol. xix. p. 9 : 1885.
* Hofmeister, Zeitschr. /. physiol. Chem., vol. vi. pp. 69-73; and Arch.f.
exper. Path. u. Pharm., vol. xix. pp. 8-15 : 1885.

196 LECTURE XIII

testine was separated by two incisions lengthwise into two equal
portions. The mucous membrane was washed with a dilute
solution of common salt^ one half was thrown at once into boil-
ing water, whereas the other one was previously put for a little
time into a moist chamber at 40° C. Far more peptone was
always found in the first half than in the second. If the
second half were not placed in the boiling water for two or
three hours, no peptone was ever found in it. It is for teleo-
logical reasons very improbable that the peptone is further
split up in the mucous membrane. One can only suppose that
the peptone is reconverted into proteid in the mucous mem-
brane of the digestive canal. That it is a vital process is
rendered probable from a fact observed by Hofmeister. If one
half of the stomach were thrown at once into boiling water,
and the other kept in water at 60° C. for a few minutes before
being placed for two hours in a temperature of 40° C, the
amount of peptone proved to be the same in both halves. A
temperature of 60° C. has been found by experience to destroy
living animal cells, but not all unorganized ferments. The
conversion of peptone into proteid must therefore be brought
about by the vital functions of the surviving cells of the ex-
tirpated stomach.

The following observation, made by Salvioli ^ in Lud wig's
laboratory in Leipzig, perfectly agrees with these results of
Hofmeister's. A coil of small intestine, with the piece ot
mesentery attached, was cut out of a dog that had just been
killed. One gramme of peptone in 10 c.cms. solution was
placed in the piece of intestine and the ends closed. Then,
after tying the collateral vessels, a current of warm defibrinated
blood, diluted with a solution of common salt, was directed
into a branch of the mesenteric artery and allowed to flow out
again by the corresponding vein. Whilst the blood circulated,
the intestine showed marked peristalsis. After the current
had lasted four hours, the intestinal contents were examined
and were found to consist of about half a gramme of coagulable
proteid, with mere traces of peptone. Nor was there any
peptone in the blood that had made the circuit. But if peptone
were added to the blood beforehand, it was always found un-
altered at the end of the experiment. The peptone therefore
disappears in the intestinal wall on the way from the intestinal
contents into the blood.

I must now return to an observation on the behavior of
peptones, and discuss it in somewhat greater detail. We have
seen that the reconversion of peptones into proteid within the

1 Gaetano Salvioli, Du Bois' Arch., Sup., p. 112 : 1880.

THE PATHS OF ABSOEPTION 197

intestinal wall is nsually not very complete ; a part of the
peptone generally passes, unchanged by digestion, into the
blood. Now, what is the further fate and the significance of
this portion ? Why does it not pass into the urine, considering
that the peptone artificially introduced into the blood does so
at once? Hofmeister^ remarked this fact, for he calculated
that the amount of peptone which reached the blood after
subcutaneous injection, and passed into the urine, was much
less than the quantity that was found in the blood of animals
while digesting and which did not pass into the urine. Thus
the peptone that has entered the blood from the intestine be-
haves diiferently from that which reaches it in any other way.
Hofmeister explains this fact by saying that the peptone which
has reached the blood from the intestine is not contained in the
plasma but in the lymph-cells. The reasons which cause him
to adopt this view are as follows :

1. Considerable quantities of peptone are found in pus,
and, moreover, principally or even exclusively in the pus-cells,
which are identical with the lymph-cells and the colorless
blood-corpuscles or leucocytes.^

2. When the blood of an animal was examined during
digestion, the serum was free from peptone ; whereas the upper-
most layer of the blood-clot, which always exhibits most leuco-
cytes (compare Lecture XIV.), was found to contain 0.09 per
cent, of peptone.^

3. The percentage of peptone in the spleen, which is well
known to contain leucocytes in abundance, was always found to
be higher than that in the blood of the same animal.

4. The adenoid tissue, ^vhich contains a moderate number
of lymph-cells in famishing and hungry dogs, is literally over-
flowing with them in the case of well-fed dogs.''

5. The cells in the adenoid tissue of animals while digesting
show more nuclei undergoing karyokinesis than those of fasting
animals.^

Finally, Hofmeister's pupil, J. Pohl,^ has shown that the

^Hofmeister, Zeitschr. f. physiol. Chem., vol. v. p. 148: 1881.
^Ibid., vol. iv. p. 274, et seq. : 1880.

3 Ibid., vol. vi. p. 67 : 1882.

4 Ibid., vol. V. p. 150 : 1881.

5 Hofmeister, Arch. f. exper. Path. u. Pharm., vol. xix. p. 32 : 1885. Com-
pare also vol. XX. pp. 291-305 : 1885 ; and vol. xxii. p. 306 : 1887. [These obser-
vations of Hofmeister's possess now little more than historic interest, as the pep-
tone he discovered in the blood was certainly produced during his manipulations
for the purposes of analysis. The peptone found in the spleen has been shown
lately by Hedin to be due to the presence in the cells of this organ of a special
proteolytic ferment, which resembles trypsin in the products of its action, but
requires an acid medium.]

6 Julius Pohl, ibid., vol. xxv. p. 31 : 1888.

198 LECTUEE XIII

number of leucocytes in the blood increases during the digestion
of food rich in proteid, but not during the absorption of carbo-
hydrates, fats, salts, and water. Pohl has also shown that this
increase of leucocytes proceeds from the intestinal wall, for
there was always a much larger number in the intestinal veins
than in the corresponding arteries.

Thus it appears that the lymph-cells serve not only as the
means of transport for the peptones in the blood-current ; their
increase and growth seem to be intimately connected with the
absorption and assimilation of nitrogenous food. As the num-
ber of leucocytes in our body is always the same, it follows
that, as the proteid becomes absorbed and new cells are pro-
duced by division, a corresponding amount of old lymph-cells
must die off and decay. This perhaps partially explains the
above-mentioned fact, that the absorption of large quantities of
proteid is followed by rapid destruction of a corresponding
amount of proteid.

At the same time, we are not bound to assume that all the
peptone which disappears in the intestinal wall is reconverted
into proteid in the lymph-cells of the adenoid tissue, and that
this reconversion takes place only through the assimilation,
growth, and division of lymph-cells. Heidenhain ^ has called
attention to the fact that the nuclei undergoing karyokinesis in
the lymph-cells of adenoid tissue are not sufficiently numerous
to justify such a conclusion. He considers that the recon-
version of the peptones into proteid may occur to a large
extent in the epithelial cells, which then surrender it to the
blood-plasma of the capillaries forming a network around the
intestinal villi, immediately below the epithelial cells.

We must now consider what happens to the peptone which
has reached the blood from the intestine. As already men-
tioned, it very soon disappears from the blood, without passing
into the urine. Where does it undergo a change ? The
conversion does not take place in the blood itself. Hofmeister ^
took two samples of blood from the carotid of a dog during the
process of digestion. The first was immediately tested for
peptone ; the second was kept for two and a half hours at
37° C. before being tested. The amount of peptone was found
to be exactly the same in both cases. Hofmeister also laid
bare to the utmost extent the carotid and . crural arteries of a
living dog, applying ligatures above and below as well as to the
lateral branches. After half an hour the pieces of artery which
had been tied were taken out and their contents removed.

1 Heidenhain, Pflüger's Arch., Suppl., vol. xli. pp. 72-74 : 1888.

2 Hofmeister, Arch. f. exper. Path. u. Pharm., vol. xix. p. 23 : 1885.

THE PATHS OF ABSOEPTIOX 199

Peptone was found in them. It does not therefore disappear
in the blood, and must consequently pass into the tissues from
the capillaries/ [It can, in fact, be detected in the lymph
flowing from the thoracic duct withm half a minute of its
injection into the blood-stream.]

Armed with this knowledge concerning the behavior of
peptones in the body, we are now in a position to explain the
hitherto enigmatic appearance of peptone in the urine in cer-
tain forms of disease. We have seen that the peptones pass
into the urine as soon as they reach the blood by some other
means than from the intestine. This is obviously the case in
all those pathological processes in which peptonuria occurs.
Probably in all such cases there is a pathological disintegration
of necrotic tissue, as the result of which peptone is formed and
is absorbed into the blood ; ^ as for instance in those diseases
in which there is a considerable accumulation and decomposi-
tion of pus — in empyema, purulent peritonitis, pyelitis, in some
cases of phthisis with large cavities, and the like. The appear-
ance of peptone in the urine in the stage of resolution of
croupous pneumonia may be explained in a similar manner :
the peptone reaches the blood when the exudation in the lung
is absorbed. As a matter of fact, Hofmeister was able to
demonstrate the presence of a considerable quantity of peptone
in the infiltrated pneumatic lung.

1 Hofmeister, Arch. f. exper. Path. i,. Pharm., vol. xix. p. 30 : 1885.

2 E. Maixner, Prager Viertelj., vol. cxliii. p. 75 : 1879 ; Hofmeister, Zeitschr.
f.physiol. Chem., vol. iv. p. 265 : 1880; R. von Jaksch, Zeitschr. f. klin. Med.,
vol. vi. p. 413 : 1883 ; H. Pacanowski, ihid., vol. ix. p. 429 : 1885.

LECTURE XIV

THE BLOOD

Havixg followed the course of the food-stuifs as far as their
entrance into the bloody we will now proceed to consider the
blood itself.

The first thing that strikes us when we begin to examine
the blood, and that which oifers the greatest difficulties to
chemical analysis, is the phenomenon of coagulation. As soon
as the blood leaves the vessels of the living animal, a part
of the proteids passes from the apparently soluble into the
coagulated condition. The quantity of this colloid substance,
commonly called fibrin, is relatively very small. It does not
usually exceed from 0.1 to 0.4 per cent, of the weight of
the blood. Nevertheless the passage of this small amount
into the coagulated state converts the whole blood into a more
or less solid jelly-like mass. On standing, this mass contracts,
sometimes to half of its original volume, and squeezes out the
contained fluid, whilst the corpuscles are almost wholly retained.
Thus the coagulated blood separates into clot and serum.
Serum is therefore plasma minus fibrin ; the clot consists of the
closely packed blood-corpuscles, with a small residue of serum
and the coagulated proteid, or fibrin.

If, however, the blood be beaten with a glass rod whilst
coagulation is proceeding, the coagulating substance attaches
itself to the rod in the form of small fibrous masses,
which coalesce with one another, and contract round the
rod so that they can be removed with it. In this way
so-called defibrinated blood is obtained, which remains fluid,
and consists of serum with blood-corpuscles suspended in
it. When we remember how great a tendency to pass into
a coagulated modification is shown by all colloid bodies,
the phenomenon of coagulation ought not to surprise us.
Moreover, it is by no means a peculiarity of the blood. Lymph
and chyle are likewise coagulable. The appearance of rigor
mortis in dying muscle depends upon an essentially similar
process, and it is probable that the death of every living
vegetable and animal tissue is accompanied by a passage

200

THE BLOOD 201

of a part of the proteid constituents from the fluid to the
coagulated state. Coagulation of the blood is therefore not
a vital process — it indicates the commencing dissolution of the
dying blood ; hence it might be thought that the subject of
coagulation was beyond the scope of physiology.

The coagulation of the blood however subserves a very
important process ; it greatly aids in preventing bleeding when
a blood-vessel is injured, and so far it may be considered as
a physiological process, one of the means of self-preservation
possessed by the organism.

The nature and causes of coagulation possess an extreme
interest from a pathological point of view. For it is well
known that, under certain pathological conditions, coagulation
of the blood takes place in the vessels during life ; and this
process leads to disturbances of the most varied character, and
may be a cause of death.

Hence it is a question of great importance to know what
causes the blood to remain fluid under normal conditions in the
vessels during life ; what the exact nature of the whole process
is ; what the substance is which separates out ; and what the
causes of its separation are. In spite of many researches, we
are not yet in a position satisfactorily to answer this question.
The little that is positively known we will consider in detail.
First of all, we know that the contact of the blood with the
normal living vessel- wall prevents coagulation.^ If, in a living
animal, a blood-vessel be tied at two points, the enclosed stag-
nating blood does not coagulate for several hours, but it does so
very quickly if it be allowed to escape from the vessel.

Brücke showed that the blood in the heart of the tortoise
remained fluid after the heart had been removed from the body,
when the vessels had been tied. If minute glass tubes were
inserted into some of the vessels, so as to fit them exactly,
and to prevent the blood from coming into contact with the
wall of the vessel, it was found that the blood clotted in these
tubes, but remained fluid elsewhere, in the other vessels and
in the heart. Indeed, Brücke observed that any foreign body
introduced into the blood became covered with a layer of
fibrin.

When a vessel is ligatured, the blood after a time coagulates
from the point ligatured down to the first branch given oif from
the vessel. The coagulation always starts from the ligatured
spot, where the endothelium of the vessel is injured. It may
also be supposed that the whole endothelial lining, from the

^ E. Brücke, Virchow's ^rcÄ., vol. xii. pp. 81, 172 : 1857.

202 LECTURE XIV

injured spot to the first brauch, is altered and no longer normal,
since it does not obtain the usual amount of specific nutriment
in consequence of the stagnation of the blood.

In this way the occurrence of thrombosis, in consequence
of atheromatous degeneration of the lining membrane, or as the
result of the compression of the vessel by a new growth, &c.,
may be explained/

We know further that the coagulation of the blood is
constantly preceded by the death and breakmg up of the
white blood-corpuscles. It would appear that in some way
or other the products of the breaking down of leucocytes
enter into the formation of the clot.^ Mantegazza pointed
out that only those fluids are spontaneously coagulable which
contain leucocytes, such as blood, lymph, and pathological
transudations,^ and that the fluids lose their power of clotting
as soon as the leucocytes can be removed. Johannes Müller*
had shown that, if frog's blood be diluted with a solution of
sugar and filtered, the large red blood-corpuscles remain in
the filter, whereas the filtrate coagulates. Johannes Muller
therefore concluded that the coagulating matters arise from
the plasma. But Mantegazza showed that the small and
soft colorless blood-corpuscles get through the filter paper
in this experiment, and that if the colorless corpuscles are
retained by the use of very fine filter paper, the filtrate is not
coagulable.'^

When Mantegazza drew a silk thread through the vein of a
living animal, he found that in two minutes it was covered with
leucocytes, and some fibrin, which was commencing to form
round them. If the experiment lasted longer, the thread

^ On the origin of thrombi vide Virchow's researches in his " Gesammelten
Abhandlungen zur wissenschaftlichen Medicin," pp. 59-732 : Frankfurt a. M.,
1856; further F. W. Zahn, Virchow's ^Irc/i., vol. Ixii. p. 81 : 1875; and J. C.
Eberth and C. Schimmelbusch, Virchow's Arch., vol. ciii. p. 39 : 1886 ; and vol.
cv. pp. 331, 456 : 1886. A general survey of the literature of the subject is given
here.

2 The view that fibrin arose from the breaking up of the leucocytes was first
adopted by William Addison, London Medical Gazette, new ser., vol. i., for the
session 1840-1841, pp. 477, 689; and by Lionel Beale, Quar. Journ. of Micros.
Science, v6\. xiv. p. 47: 1864; subsequently by Paolo Mantegazza, " Ricerche
sperimentali sull ' origine della fibrina e sulla causa della coagulatione del
sangue": Milano, 1871. A complete account of this work, by Boll, appeared in
1871, in the Centralhl. f. d. med. Wissensch., p. 709 ; and in 1876 Mantegazza
published his work in German in Moleschott's Untersuch, z. Naturlehre des Men-
schen n. der Thiere, vol. xi. pp. 523-577. Compare E. Tiegel, "Notizen über
Schlangenblut," Pflüger's Arch., vol. xxiii. p. 278 : 1880.

3 Mantegazza, Moleschott's Untersuch, z. Naturlehre, vol. xi. pp. 552, 557.

4 .Johannes Müller, Handb. d. Physiol, des Menschen, 4th edit., vol. i. p. 104 :
Coblentz, 1844.

5 Mantegazza, loc. cit., p. 556.

THE BLOOD 203

became siirronnded with a strong white coaguhim, which Avas
always crowded with leucocytes. Other foreign bodies intro-
duced into the blood-current behaved hi the same manner, and
moreover the rougher their surface the more extensive was
the coagulum, and the more readily did the leucocytes attach
themselves to it. Xo coagulum formed round a smooth thin
platinum wire.^

Zahn ^ made similar experiments with the same result. If
he introduced small glass rods with smooth surfaces into the
heart of a living animal, no clot was produced. But if he
roughened the rod with a file before insertion, a coagulum
formed on the uneven surface. Zahn showed further that a
grouping together and breaking up of leucocytes always pre-
cedes formation of a thrombus.

Finally, Alexander Schmidt has carried out very extensive
experiments on the relation of colorless blood-corpuscles to
coagulation.^ He found that horse's blood was very suitable
for this purpose, being possessed of two peculiarities in which
it differs from the blood of other animals hitherto examined :
firstly, it clots more slowly ; and, secondly, the red blood-cor-
puscles sink far more rapidly. It is thus possible to remove
the plasma which remains after the red corpuscles have sunk
to the bottom, before coagulation sets in. By the use of cold,
clotting is still further delayed. If the blood be allowed to
run from a horse's vein straight into a vessel surrounded with
ice, the red corpuscles fall completely to the bottom, and the
specifically lighter colorless cells, which sink more slowly,
form a layer over the red corpuscles (bufpy-coat). The larger
portion of the plasma can now be removed and filtered. The
colorless cells remain in the filter, owing to the solid con-
sistency acquired in the cold, which prevents their accommo-
dation to the form of the filter-pores and their consequent

^ Mantegazza, Moleschott's Untersuch, z. Naturlehre, vol. xi. pp. 558-563.

2 F. W. Zalm, loc. cit., pp. 104-112.

^ Alexandei' Schmidt has published an account of the main facts of his com-
prehensive researches, with the title, " Die Lehre von den fermentativen Gerin-
nungserscheinungen iu den eiweissartigen thierischen Körperflüssigkeiten "
(Dorpat, C. Mattiesen, 1S76). Alexander Schmidt's more recent investigations
on the coagulation of the blood are contained iu the dissertations by his pupils
for their doctorate : — " L. Birk and J. Sachsendahl, 1880; X. Bojanus and Ferd.
Hoffmann, 1881 ; Ed. von Samsou-Himmelstjerna and X. Heyl, 1882 ; H. Feiertag,
F. Slevogt, Fr. Eauschenbach, and Ed. von Gotsehel, 1883 ; 0. Groth and W.
Grohmann, 1884; and Jacob von Samson-Hinimelstjerna, 1885. Compare O.
Hammarsten, Pfliiger's Arch., vol. xiv. p. 211 : 1877; and vol. xxx. p. 4.37: 1883;
L. Fredericq, Bullet, de. I' Acad. roy. de Belg., ser. ii. t. Ixiv. Xo. 7: Juillet,
1877 ; Ann. de la Soc. de Med. de Gand. : 1877 ; " ßecherches sur la constitution
du plasma sanguin," Gand, Paris, Leipzig, 1878; and L. C. Wooldridge, "The
Xature of Coagulation," 1888.

204 LECTURE XIV

passage ; and a pure clear plasma is obtained as filtrate, which
now clots very slowly and yields a very slight coagulum. If
leucocytes from the filter be added to this plasma, abundant
coagulation takes places. If all the blood, the coagulation of
which had been prevented by cooling, be allowed to clot at the
temperature of the room, the firmest coagulum occurs in the
buify-coat.

My Dorpat colleague has repeatedly been so kind as to
show me these experiments with the uncoagulated horse's
blood. The amount of leucocytes is most surprising. They are
undoubtedly far more numerous than in defibrinated blood.
But the extraordinary variety of the forms is still more
astonishing : from the smallest colorless corpuscles, with a
diameter hardly greater than that of the red corpuscles, such
as one is accustomed to see in defibrinated blood, to the large
granulated yellowish cells with nuclei, and a diameter of more
than double — (Schmidt's granule masses).^ After complete
coagulation, these granule masses disappear. Schmidt and his
pupils say that they have watched their breaking up into
minute granules,^ and the gradual change of the latter into
the fibrin-coagulum, under the microscope. These granule
masses, and the transitional forms between them and the
ordinary colorless blood-corpuscles, appear to be much less
numerous and to break up more rapidly in the blood of other
mammals, so that it is difficult to obtain a view of them under
the microscope.^

We are unable as yet to decide whether the debris of
leucocytes are themselves a part of the material which forms
the coagulum, or whether certain products of decomposition,
resembling ferments, give the impulse for the passage of
certain proteids of the plasma into the coagulated modifica-
tion.

1 A diagram of these granule masses and their products of decomposition is
given in the Dissertation of George Semmer, " Ueber de Faserstoff bildung im
Amphibien- und Vogelblute und die Entstehung der rothen Blutkörperchen der
Säugethiere " : Dorpat, Mattiesen, 1874.

2 Mantegazza also noticed the granules in the plasma from horse's blood {loc.
CiL, p. 563).

3 With the aid of the improved microscopes, small granules and ' ' Plättchen '^
have recently been discovered in the blood, which are considered to be form-
elements, and are supposed to participate in the coagulation of the blood.
Alexander Schmidt explains these structures as being the debris of his granule
masses. In this connection vide G. Hayem, Compt. rend., vol. Ixxxvi. p. 58 :
1878 ; J. Bizzozero, Virchow's Arch., vol. xc. p. 261: 1882 ; M. Löwit, Sitzungsber.
der Wiener Akad., vol. Ixxxix. p. 270; and vol. xc. p. 80 : 1884; and L. C-
Wooldridge, in the " Beiträge zur Physiologie, Carl Ludwig zu seinem siebzig-
sten Geburtstage gewidmet von seinen Schülern," p. 221 : Leipzig, Vogel,
1887.

THE BLOOD 205

The following observation must be cited as being particu-
larly important. It appears that a part of the substances
which excite coagulation remains in the blood after the
separation of the fibrin Alexander Schmidt showed that, if
defibrinated blood or serum be added to lymph or to serous
transudations, which coagulate very slowly of themselves, and
give very little fibrin, the fluid would soon be entirely con-
verted into a gelatinous mass. The fluids of the pleural and
the pericardial cavities of human beings and of horses are
usually quite free from lymph-cells, and therefore uncoagu-
lable. But they coagulate on the addition of blood-serum.
The fact that coagulation occurs in the vessels after the trans-
fusion of defibrinated blood is capable of the same explana-
tion. Armin Köhler^ showed that if blood were taken from
a rabbit, defibrinated, and then injected into the vessels of the
same animal, death ensued owing to clotting in the vessels.
For this reason, the therapeutic use of transfusion has fallen
into disuse.^ An important contribution to the explanation of
blood-clotting has been afforded by Arthus and Pages,^ who
have shown that coagulation is prevented if all the lime salts
be precipitated from the plasma by the addition of a small
quantity of sodium oxalate or fluorid."*

From these remarks on the coagulation of the blood it
may be seen what difficulties have to be encountered in the
chemical examination of the blood, and especially in any
attempt to obtain a separate quantitative analysis of plasma
and of blood-corpuscles.

The pure unaltered plasma, as procured from horse's blood,
according to Alexander Schmidt's method, has never been
analyzed. The serum has been analyzed, and the composition
of the plasma has been deducted from that of the serum. It
was considered that the composition of the plasma was ascer-
tained when the fibrin was added to the serum. But we now
know that the calculation is not so easy. We do not know
which constituents of the plasma take part in the coagulation,
nor which products of the decomposition of lymph-cells pass

1 Armin Köhler, " üeber Thrombose und Transfusion, Eiter und septische
Infection, u. deren Beziehungen zum Fibrinferment " : Dorpat, 1877.

2 E. von Bergmann has published, in the form of a lecture, a very interesting
account and criticism of the literature on the transfusion of blood, " Die Schick-
sale der Transfusion im letzten Decennium" : Berlin, Hirschwald, 1883. Com-
pare A. Landerer, Virchow's Arch., vol. cv. p. 351 : 1886.

^M. Arthus, "Recherches zur la coagulation du sang," These, Paris, 1890.
Arthus and Pages, Arch, de Physiol, norm, et path., vol. xxii. p. 739 : 1890.

^ [For discussion of the more recent work and views on the subject of the
coagulation of the blood, the reader is advised to consult the article on this sub-
ject in Shäfer's "Text-book on Physiology," vol. i.]

206 LECTURE XIV

into the serum. We do not know what should be removed
from or what added to the serum in order to determine the
composition of the plasma.

We are met by insuperable difficulties in the endeavor to
free the red blood-corpuscles from the serum, and to analyze
them in a pure state. The means adopted by chemists to
separate a precipitate from a solution cannot be used in this
case. The large blood-corpuscles of amphibia may be collected
on the filter, but not those of mammals. This is not due to
their minuteness ; for they are far larger under the microscope
than, for instance, the crystals of a precipitate of sulphate of
barium or oxalate of lime, which do not go through the filter.
The red blood-corpuscles pass through the filter, because,
owing to their soft and yielding consistency, they adapt them-
selves to the form of the filter-pores. The method of decanting
remains as a last resource, but this alone does not suffice, and
must be followed by washing ; but what liquid will serve for
this purpose? The usual medium, water, cannot be employed
in this case, for as soon as the red blood-corpuscles come into
contact with water, the red coloring matter, hemoglobin,
is dissolved. Now, as this forms the chief constituent of the
red corpuscles, nothing remains but so-called stromata, re-
duced, pale, round, very feebly refractive, specifically light
cUbrisJ

If, instead of water, a dilute salt solution of a certain
concentration be employed, i. e., from 1^ to 3 per cent, of
sodium chlorid, no change in the corpuscles apparent under
the microscope takes place. If the solution of salt is stronger,
they shrink ; if more dilute they swell, and lose some of their
hemoglobin in it.

By thus decanting and washing with dilute salt solution,
the blood-corpuscles of defibrinated blood can be completely
separated from all the constituents of serum. But do they
retain their original constitution? May not the salt or the
water pass into the blood-corpuscles ; and, on the other hand,
may not constituents of the blood-corpuscles have passed into
the salt solution by osmosis ? We can only be certain of one
thing, and that is, that no hemoglobin has escaped, as this
would be at once discovered by its brilliant color. It is
likewise extremely probable that the genuine colloid sub-
stances, the proteids, which diffuse with great difficulty, do
not quit the blood-corpuscles. We are therefore in a position
to form a quantitative estimate of the quantity of hemoglobin

1 For the properties and constitution of the stromata, vide L. C. Wooldridge,
Du Bois' Arch., p. 387 : 1881.

THE BLOOD 207

and of proteid in the corpuscles of a definite amount of
blood. If moreover the quantity of hemoglobin and of
proteid in the total blood, and the amount of proteid in the
serum, be estimated, we are in possession of all the figures
necessary to compute the proportion that the weight of the
serum bears to that of the blood-corpuscles in the total blood.

This is the method of quantitative analysis of the blood
proposed by Hoppe-Seyler.^ An example will serve to ex-
plain the method of computation.^

In 100 grms. of defibrinated pig's blood were found —

\b\ 1888 ~*"™^^'^= 18.90 Proteids + liemoglobin.

In the blood-corpuscles of 100 grms. of the same blood were
found —

(a) 15.04 1

{b) 15.13 ^mean: 15.07 proteids + hemoglobin.

(c) 15.05 j

In the serum of 100 grms. of blood —

18.90 — 15.07 = 3.83 grms. proteids.
In 100 grms. of serum —

(h) 6'79 ^ average: 6.77 proteids.

From this the amount of serum in 100 grms. of defibrinated
blood may be computed —

- -^ • 100^56.6 per cent, serum.

100 — 56.6 = 43.4 per cent, blood-corpuscles.

Aji analysis of the total blood and another of the serum
is now all that is necessary to enable us to compute the exact
proportion of each constituent in defibrinated blood.

In order to prove the reliability of this method, I deter-
mined the proportion of the serum to the corpuscles in the
same blood by another method. We are in fact able to
estimate this proportion, as soon as we are in a position to
ascertain accurately that any one of the constituents of the
serum does not occur in the corpuscles. This is the case

^Hoppe-Seyler, " Handb. der physiol. u. pathol. chemisch. Analyse," § 272,
5th edit., p. 441 : Berlin, Hirschwald, 1883. This method is rendered much more
simple by the use of the centrifuge {vide L. von Babo, Liebig's AnnaL, vol.
Ixxxii. p. 301 : 1852); without this, the repeated sinking of the blood-corpuscles
for the purpose of decanting the fluid would necessitate a process occupying sev-
eral weeks, and even at a low temperature decomposition and escape of hemo-
globin would be unavoidable.

2 G. Bunge, " Zur quantitativen Analyse des Blutes," Zeitschr. f. Biolog.,
vol. xii, p. 191 : 1876.

208 LECTURE XIV

with sodium in some kinds of blood. It was rendered prob-
able by the earlier experiments of C. Schmidt ^ and of Hoppe-
Seyler's pupil, Sacharjin/ and the following analyses made
by myself put the matter beyond all doubt.

If defibrinated pig's blood be acted on by the centrifugal
machine, the red corpuscles separate from the serum as a
thick paste, which is found to be very poor in sodium. It
contains seven times less sodium than the serum. Supposing
the deposit to contain only one-seventh of its total bulk of
serum, this would, suffice to cover its whole amomit of sodium.
Now, there was no difficulty iu determining by the microscope
a considerable amount of interstitial fluid among the cor-
puscles. If the blood-corpuscles contain any sodium at all,
it must be present in exceedingly mmute quantities, and we
should commit no serious error in determining the quantity of
serum in blood, by calculating it from the amount of sodium
in the blood and the serum.

The analysis and calculation gave the following results : —
In the total blood —

\b) 0 2409 I'^ean: 0. 2406 per cent. Na^O.
In serum —

[b] 0 4260 }°^e^°= 0.4272 per cent. NaA

0.2406^^,„. -, „

w-TK^ X 1Ö0 = 56.3 per cent, serum.

100 — 56.3 = 43.7 per cent, blood-corpuscles.

The numbers agree remarkably with those obtained for the
same pig's blood by Hoppe-Seyler's method.

In the case of the blood of the horse, I made an analysis
according to Hoppe-Seyler's method, and found 46.5 per cent,
serum, and 53.5 per cent, corpuscles ; by means of the sodium
calculation, the result was 46.9 per cent, of serum, and 53.1
per cent, of blood-corpuscles. This correspondence cannot
be accidental. We must conclude from it (1) that Hoppe-
Seyler's method gives correct results ; and (2) that in the
blood of the pig and the horse, the sodium occurs only in the
plasma.

Unfortunately the latter conclusion is not true for all
varieties of blood. In dog's and bullock's blood the corpuscles
contain sodium as well as the serum. The easy and exact
method for determinmg the relative proportions of corpuscles

^ C. Schmidt, "Charakteristik der epidemischen Cholera": Leipzig and
Mitau, 1850.

2 G. Sacharjin, " Zur Blutanalyse," Virchow's Arch., vol. xxi. p. 387 : 1861.

THE BLOOD

209

and serum .by means of the amount of sodium is in so far
of very great value, as it enables us to put to the proof other
methods which are applicable to all varieties of blood.

In the following tables the results of my analyses of blood
are given : —

One Thousand Grammes of Defibrinated Blood Contain —

Pig.

Horse.

Bullock.

436.8 Cor-

563.2

531.5 Cor-

468.5

818.7 COE-

681.3

puscles.

Serum.

puscles.

Serum.

PUSCLES.

Serum.

Water

276.1

517.9

323.6

420.1

191.2

622.2

Solids

160.7

45.3

207.9

48.4

127.5

59.1

Proteid and hemo-

globin . . .

151.6

38.1

—

—

123.6

49.9

Other organic sub-

stances . ,

5.2

2.8

—

—

2.4

3.8

Inorganic substances

3.9

4.3

—

—

1.5

5.4

K2O .

2.421

0.154

2.62

0.13

0.238

0.173

Na^O

0

2.406

0

2.08

0.667

2.964

CaO .

0
0.069

0.072
0.021

—

—

0.005

0.070

MgO.

0.031

Fe^Os

—

0.006

—

—

—

0.007

CI . .

0.657
0.903

2.034
0.106

1.02

1.76

0.521
0.224

2.532

PA-

0.181

Oae thousand grammes Cor-
puscles contain—

One thousand grammes
Serum contain —

Pig.

Horse.

Bullock.

Pig.

Horse.

Bullock.

Water

Solids

Proteid and hemo-
globin

Other organic sub-
stances .

Inorganic substances

K2O

NasO

CaO

MgO

Fe.,03

CI ...

PA

632.1
367.9

347.1

12.0
8.9
5.543
0
0
0.158

1.504
2.067

608.9
391.1

4.92
0

1.93

599.9
400.1

387.8

7.5

4.8

0.747

2.093

0

0.017

1.635
0.703

919.6

80.4

67.7

5.0

7.7

0.273

4.272

0.136

0.038

3.611

0.188

896.6
103.4

0.27
4.43

3.75

913.3

86.7

73.2

5.6

7.9

0.254

4.351

0.126

0.045

0.011

3.717

0.266

E. Abderhalden ^ has carried out two complete analyses

of blood according to this method.

^E. Abderhalden (Bunge's laboratory), ZeUschr. f. physiol. Chem., vol.
xxiii. p. 521 : 1897.

14

210

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THE BLOOD

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212

LECTCTEE XIV

In order to give an idea of the composition of human blood,
I subjoin the analysis of my revered teacher, Carl Schmidt,^
one that has not yet been surpassed, though it may be
remarked that the method employed gave too high an
estimate for the corpuscles in proportion to the volume of
blood.

BLOOD OF A MAN TWENTY-FIVE YEARS OF AGE.

One Thousand Grammes of Blood.

513.02 BLOOD-COKPUSCLES.

Water ; • • 349.69

Substances not vaporizing at
120° 163.33

Hematin ...

'Blood casein,' etc
Inorganic constituents

7.70 (including 0.512 iron)
151.89
3.74 (excluding iron)

Chlorin . ._ 0.8981

Sulphuric acid 0.031

Phosphoric acid 0.695

Potassium 1.586

Sodium 0.241

Phosphate of lime ._ . . . 0.048

Phosphate of magnesium . 0.031

Oxygen 0.206

'Chlorid of potassium .

. 1.887

Sulphate of potassium .

. 0.068

Phosphate of potassium

. 1.202

Phosphate of sodium .

. 0.325

Soda . . . .

. 0.175

Phosphate of lime . .

0.048

Phosphate of magnesium

. 0.031

Total

3.736

486.98 INTERSTITIAL FLUID (PLASMA).

Water ; • • 439.02

Substances not vaporizing at

120° 47.96

Fibrin 3.93

'Albumin,' etc _ 39.89

Inorganic constituents ... 4. 14

Chlorin . ._ 1.7221

Sulphuric acid 0.063

Phosphoric acid .. 0.071

Potassium 0.153

Sodium . . ._ 1.661

Phosphate of lime .... 0.145

Phosphate of magnesium . 0.106

Oxygen 0.221J

'Sulphate of potassium . 0. 137

Chlorid of potassium . . . 0.175

Chlorid of .sodium .... 2.701

Phosi)hate of sodium . . . 0.132

Soda 0.746

Phosphate of lime .... 0.145

Phosphate of magnesium . 0.106

Total 4.142

Specific Gravity = 1.0599.

1 C. Schmidt, "Charakteristik der epidemischen Cholera," pp. 29, .32;
Leipzig and Mitau, 1850.

THE BLOOD

213

BLOOD OF A MAN TWENTY-FIVE YEAES OF AGE— (ccmimucc?).

1000 GRAMMES OF BLOOD-CORPUSCLES.

Water : ■ • ^^^-^^

Substances not vaporizing at

120^

318.37

Hematin 15.02 (including 0.998 iron)

'Blood-casein,' etc 296.07

Inorganic constituents . . . 7.28 (excluding iron)

Chlorin ..... 1.750

Sulphuric acid ..... 0.061

Phosphoric acid 1.355

Potassium 3.091

Sodium 0.470

Phosphate of lime ._ . . . 0.094
Phosphate of magnesium . 0.060
Oxygen ... . . 0.401,

Total of inorganic constituents (exclusive of iron

Specific Gravity = 1. 0886.

Sulphate of potassium . .
Chlorid of potassium . .
Phosphate of potassium
Phosphate of sodium . .

Soda

Phosphate of lime . . .
Phosphate of magnesium

0.132
3.679
2.343
0.633
0.341
0.094
0.060

7.282

1000 GRAMMES OF INTERSTITIAL FLUID (PLASMA).

Water _ . . 901.51

Substances not vaporizing at
120° ... .... 98.49

Fibrin 8.06

'Albumin,' etc._ 81.92

Inorganic constituents ... 8.51

Chlorin 3.536

Sulphuric acid 0.129

Phosphoric acid 0. 145

Potassium . . .. 0.314

Sodium 3.410

Phosphate of lime _ . . 0.298

Phosphate of magnesium . 0.218

Oxygen 0.455

Total of inorganic constituents
Specific Gravity = 1.0312.

1000 GRAMMES OP SERUM.

Water : • • 908.84

Substances not vaporizing at

'Sulphate of potassium

0.281

Chlorid of potassium . .

0.359

Chlorid of sodium . . .

5.546

Phosphate of sodium . .

0.271

Soda . . ....

1.532

Phosphate of lime . . .

0.298

Phosphate of magnesium

0.218

120°

91.16

Albumin, etc 82.59

Inorganic constituents ... 8.57

Chlorin _ 3.5651

Sulphuric acid . . ... 0.130

Phosphoric acid 0.146

Potassium 0.317

Sodium 3.438

Phosphate of lime .... 0.300

Phosphate of magnesium • 0.220

Oxygen 0.458

Total of inorganic constituents
Specific Gravity = 1.0292.

r = i

Sulphate of potassium . .
Chlorid of potassium . .
Chlorid of sodium . . .
Phosphate of sodium

Soda , .

Phosphate of lime
Phosphate of magnesium

8.505

0.283
0.362
5.591
0.273
1.545
0.300
0.220

8.574

214

LECTUEE XIV

BLOOD OF A WOMAN THIKTY YEAES OF AGE.
One Thousand Grammes of Blood.

396.24 BLOOD-COKPUSCLES.

Water ... ._ . 272.56
Substances not vaporizing at
120° 123.68

Hematin .

' Blood-casein,' etc. .

Inorganic constituents

6.99 (including 0.489 iron)
113.14
3.55 (excluding iron)

1.412
0.648

0.086

0.370

Chlorin 0.6431

Sulphuric acid . . . 0.029

Phosphoric acid 0.362

Potassium .

Sodium . . ...

Phosphate of lime . . .

Phosphate of magnesium

Oxygen

> = i

'Sulphate of potassium .
Chlorid of potassium
Phosphate of potassium
Potash ......

Soda ... ...

Phosphate of lime . . .
Phosphate of magnesium

Total of inorganic constituents (excluding iron)

603.76 INTERSTITIAL FLUID (PLASMA).

Water ... . . 551.99

Substances not vaporizing at

120° 51.77

Fibrin 1.91

Albumin, etc 44.79

Inorganic constituents 5.07

Chlorin . ._ 2.2021

Sulphuric acid 0.060

Phosphoric acid 0. 144

Potassium ... .. 0.200

Sodium 1.916

Phosphate of lime . . .
Phosphate of magnesium

Oxygen 0.211,

0.332

y = <

Sulphate of potassium
Chlorid of potassium
Chlorid of sodium .
Phosphate of sodium
Soda . ■ ■ •

Phosphate of lime . . .
Phosphate of magnesium

0.062
1.353
0.835
0.340
0.874

0.086

3.550

0.131

0.270
3.417
0.267
0.648

0.332

Total of inorganic constituents 5.065

Specific Gravity = 1 . 0503.

1000 GRAMMES OF BLOOD-CELLS.

Water 687.88

Substances not vaporizing at

120° 312.12

Hematin 18.48 (including 1.229 iron)

'Blood-casein,' etc. . . .' . 284.68

Inorganic constituents ... 8.96 (excluding iron)

Chlorin 1.6231

Sulphuric acid 0.072

Phosphoric acid 0.913

Potassium . . .... 3.565

Sodium . _ 1.6.35

Phosphate of lime . . . \ q ^j^g
Phosphate of magnesium /
Oxygen 0.933J

Total of inorganic constituents (excluding"!
iron of hemoglobin) J

Specific Gravity = 1.0883.

'Sulphate of potassium .
Chlorid of potassium .
Phosphate of potassium

Potash

Soda .......

Phosphate of lime . . . \
Phosphate of magnesium J

0.157
3.414
2.108
0.857
2.205

0.218

8.959

THE BLOOD

215

BLOOD OF A WOMAN THIETY YEAKS OF A.GY^{continued).

1000 GRAMMES OF INTERSTITIAL FLUID.

Water 914.25

Substances not vaporizing at

120° .... ... 85.75

Fibrin 3.16

Albumin, etc. . . . 74.20

Inorganic constituents ... 8.39

Chlorin 3.6471

Sulpburic acid 0.100

Phosphoric acid .... 0.237

Potassium 0.332

Sodium 3.173

Phosphate of lime . . .
Phosphate of magnesium

Oxygen . ...... 0.351

0.550

Sulphate of potassium 0.217

Chlorid of potassium . . . 0.447

Chlorid of sodium .... 5.659

Phosphate of sodium . . . 0.443

Soda ........ 1.074

Phosphate of lime . . 1 n ^«^0
Phosphate of magnesium J

Total of inorganic constituents 8.390

Specific Gravity = 1.0269.

1000 GRAMMES OF SERUM.

Water _ . . 917.15

Substances not vaporizing at

120°

82.85

Albumin, etc 74.43

Inorganic constituents . . 8.42

Chlorin 3.6591

Sulphuric acid 0.100

Phosphoric acid .... 0.238

Potassium 0.333

Sodium 3.183

Phosphate of lime

Phosphate of magnesium

Oxygen 0.351

0.552

'Sulphate of potassium . . . 0.218

Chlorid of potassium 0.448

Chlorid of sodium .... 5.677

Phosphate of sodium . . . 0.444

Soda 1.077

Phosphate of lime \ ^ p.^„

Phosphate of magnesium J ^-om

Total of inorganic constituents 8.416

Specific Gravity ^1.0261.

Hemoglobin ^ therefore is the only organic substance which
is peculiar to the red corpuscles. It also forms the chief con-
stituent of the dried corpuscles. We have already considered
the composition of hemoglobin and the question of its origin,
and we shall shortly have to discuss the importance of hemo-
globin in respiration (Lecture XVII.). The products of de-

1 A description of all the physical and chemical properties of hemoglobin
would be beyond the scope of the present text-book. I therefore refer the reader
to the accounts of Hoppe-Seyler in his 3Ied. chem. Unters. : Berlin, 1866-1871 •
and to those of Hiifner and his pupils in the Zeitschr. f. physiol. Chem. ; and in
the latest volumes of the Journ. f. prakt. Chem. Compare also Nencki and
Sieber, Arch.f. exper. Path. u. Pharm., vol. xviii. p. 401 : 1884 ; and vol xx pp
325,332: 1886.

216 LECTURE XIV

composition will also be considered at a later period (Lectures
XXI. and XXII.).

The organic substances found in serum are proteid, fat,
soaps, Cholesterin, lecithin, sugar, urea, kreatin, and a yellow
coloring matter soluble in alcohol and ether, called lutein.
Among the proteids, which make up the chief part of the
organic substances, two groups are to be distinguished, the
albumins and the globulins. The former are soluble, the
latter insoluble, in water, but globulins are dissolved by dilute
solutions of sodium chlorid. If serum be subjected to dialysis,
the salts of the alkalies diffuse and the globulins are pre-
cipitated, whilst the albumins remain dissolved. The relative
proportion of the two varies much. The result of starvation
is to reduce the quantity of albumin and to increase the
quantity of globulin. It would thus appear that globulin
is the form which proteid assumes in its transference from
one organ to another. We know that in starvation the more
important organs, the centers of life, are nourished at the ex-
pense of the other organs, chiefly of the skeletal muscles.^ Thus
Voit ^ found that the brain and spinal cord of a cat, after thir-
teen days' starvation, had lost only 3.2 per cent, of its weight,
the heart only 2.6 j)er cent. ; the skeletal muscles, on the other
hand, 30.5 per cent. Miescher found, in his observations al-
ready quoted (p. 79), that the Rhine salmon, during its so-
journ in fresh water, eats nothing, and that the organs of re-
production, ovary and testes, increase at the expense of the
muscles. Miescher^ at the same time called attention to the
fact that during this period the globulins of the blood, which
are so similar to those of muscle, increase in quantity, and the
maximum of this increase was found to correspond to the period
of maximum growth of the ovary.

E. Tiegel* found in the blood serum of snakes, whose
alimentary canal was empty, only globulin, and no albumin ;
whereas in the blood of snakes whilst digesting, both varieties
of proteid were constantly present. Burckhardt,^ Miescher's

1 Chossat, Mem. presentes ä I' Acad, des Sciences de I' Institut de France : vol.
viii. : 1843 ; Bidder and Schmidt, " Die Verdauungssäfte u. der Stoffwechsel," p.
327 : 1852.

2 C. Voit, Zeitschr. f. Biolog., vol. ii. p. 355 : 1866.

^ F. Miescher-Riisch, " Statistische u. biologische Beiträge zur Keniitniss
vom Leben des Rheinlachses." Separatabdruck aus d. Schweiz. Literatursamm-
lung zur internationalen Fischereiausstellung in Berlin, 1880, p. 211.

* E. Tiegel, Pflüger's Arch., vol. xxiii. p. 278 : 1880.

5 Burckhardt, Arch. f. exper. Path., vol. xvi. p. 322: 1883. The apparently-
contradictory results of G. Salvioli are probably due to the fact that the period of
starvation was very short in his experiments. Moreover Salvioli used another
method for separating the two proteids (Du Bois' Arch., p. 268 : 1881).

THE BLOOD 217

pupil, has shown that the globulins in the blood of starving^
animals are increased at the expense of the albumins.

The conclusions of Danilewsky/ that the muscles of an
animal which have the least work to do are richest in globulin,
harmonize with these observations. It would appear that the
muscles are not only organs of locomotion, but also storehouses
for proteid.

' A. Danilewsky, Zeitschr. f. physiol. Chem., vol. vii. p. 124: 1882.

LECTURE XV

LYMPH.^

The substances which pass from the blood into the other
tissues, there to be used up by the cells as food, do not reach
these elements directly through the capillary wall ; but proceed
first into the lymph spaces, which are present in all the tissues.
In the same manner, the final products of the metabolism of
each cell do not pass straight into the blood, but must first be
taken up by the lymph which bathes all the tissue-elements.

The only exception to this rule is furnished by Bowman's
capsule in the kidney, which is closely applied to the walls of
the blood-vessels of the glomerulus without the intervention of
any appreciable lymph space. This arrangement seems to be
connected with particularly rapid and complete transference of
urinary constituents from the blood to the renal tubules. If
we consider how large an amount of urea is excreted by these
paths, or moreover that only a small proportion of the total
arterial blood-stream passes through the kidneys and remains
but a short time in these organs, we shall see how necessary
some such arrangement is.

Such a rapid passage of material from the blood does not
appear to be essential in the other organs. Most physiologists
have therefore conceived the idea that a large quantity of plasma
is always proceeding through the capillary walls into the lymph
spaces, thence penetrating the tissues, where every cell extracts
the substance which it needs for its sustenance.

■^ [Throughout this chapter the author takes no notice of any work on the
subject of lymph-formation since the publication of Heidenhain's paper in 1891.
For an account of the present state of the question the reader is referred to
Schäfer's "Text-book of Physiology," vol. i. p. 285, et seq. It may here be
merely mentioned that recent experiments of Starling, Cohnstein and others
have tended to show that mechanical factors play a much larger part in the pro-
duction and absorption of lymph than was imagined by Heidenhain. Ludwig
ascribed the formation of lymph to the cooperation of several factors : (1) Filtra-
tion, depending on the difference of pressure between the blood in the capillaries
and the extravascular fluid, and on the permeability of the capillary wall ; and
(2) on the osmotic interchanges determined by chemical changes, i. e., metabolic
activity of the tissue-cells. Recent investigations have served to confirm rather
than to refute Ludwig's ideas on the subject.]

218

LYMPH 219

This interpretation seemed to be justified by the circum-
stance that the qualitative composition of the lymph is identical
with that of the plasma. Quantitatively however there is a
difference ; for, while the inorganic salts contained in the
lymph are alike in amount and composition to those in the
plasma, the amount of proteid in the lymph is much smaller
than in the blood-plasma.

No definite conception has been formed concerning the
mode in which the constituents of the plasma traverse the
capillary wall. It is not possible that they can pass through by
diffusion, since the colloid proteid would be left behind in the
blood. The filtration hypothesis is equally untenable, since by
this means all the constituents of the plasma would proceed to
the lymph spaces in the same proportion as they occur in the
blood. A compromise was therefore struck between diffusion
and filtration, and it was sought to explain that the lymph is
rich in diffusible constituents — salts, and relatively poor in non-
diffusible substances — proteids. Only a very hazy notion could
be formed concerning the nature of this process, therefore a
suitable epithet was hailed in the word " transudation," the
lymph being called the " transudate of the plasma."

These theories had to be abandoned when the processes
came to be tested quantitatively by measuring the lymph-
stream.

In twenty-four hours about 600 c.cm. of lymph flows through
the thoracic duct of a dog 10 kg. in weight.^

If we assume that the flow of lymph is as slow in man as in
the dog, it would amount to about 4 liters, in proportion to the
body-weight. The small quantity of lymph flowing through
the right thoracic duct into the blood may be disregarded.

This stream of lymph is much too slow to justify the
assumption that all the cells derive their nourishment from it.
This statement may be proved by a simple calculation.

Normal plasma contains only from 1 to 2 grm. sugar to
the liter. In the course of the twenty-four hours therefore at
most 8 grms. of sugar would be conveyed to the tissues in the
4 liters of transuded plasma. This amount is certainly not a
sufficient one. As a matter of act in one day 500 to 1000 grms.
of sugar are taken up from the intestines into the blood (Lecture
XIIL). This amount is not destroyed in the blood itself (compare
Lecture XVII.). It must therefore reach the tissues through
the capillary walls. Hence it follows that a very concentrated
solution of sugar traverses the cell-walls in those tissues where

1 Vide Heidenhain, Pfliiger's Arch., vol. xlix. p. 216 : 1891. There the figures
for the amounts of lymph in dogs are given. Compare also Lecture XIII.

220 LECTURE XV

a rapid consumption of sugar as a source of energy takes place,
as for instance in the muscles, or where there is a storing up
of material free from nitrogen, such as glycogen or fat, as in.
the liver or in the connective tissues/

We may adduce another example.^ The milk of animals,
which develop rapidly is very rich in lime. Dog's milk has
from 4 to 5 grms. of lime to the liter.^ A bitch from 20 to 30
kg. bodyweight secretes in twenty-four hours as much as ^
liter of milk, which contains therefore from 2 to 2|^ grms. of"
lime. A liter of plasma contains only about 0.2 grm. of lime,*
or from 10 to 12 times less than the milk. If therefore the
epithelial cells of the mammary glands take the material they
need for the formation of the milk from the transuded plasma,,
at least 10 liters of plaSma would have to flow through the
mammary glands in the twenty-four hours. This is not possible :
only from 1 to 2 liters of lymph flow through the whole body —
how much less therefore must flow through the mammary glands ?
Hence it follows that a fluid very rich in lime must be exuded
from the blood capillaries in their course through the mammary
glands, or, in other words, that the endothelial cells of the
capillary wall must exercise a power of selection, as in fact does
every cell, every living being.

That the capillary wall is able to give out substances in a,
much more concentrated state of solution than that in which
they are contained in the plasma may be seen from the
capillaries of the kidney. The plasma contains at most 1 grm.
urea to the liter, the urine may contain as much as 40 grm. or
even more.^ Heidenhain ^ has shown that, after the injection
of solutions of sugar into the blood, the amount of sugar in
the lymph rises more than that in the blood plasma.

1 [This and the following example will serve as a criticism of the views of"
Bartholini but not of those of Ludwig. The passage of sugar or other diffusible
substance from blood to tissue-cell occurs by diffusion. The consumption of any
substance, whether it be oxygen or glucose, by a tissue-cell, leads to a diminished
tension of this substance in the neighborhood of the cell ; and a passage by
diffusion of the substance naturally occurs from blood through lymph-space to
cell. Such a process is absolutely independent of lymph-flow, and would occur if
there were no fresh lymph production at all. An argument therefore as to the
concentration of the transudation from the vessels which is based on the con-
sumption of a substance by any given tissue, has no bearing on the point in
question.]

2 These two examples were introduced by myself as arguments against the-
prevailing views on the flow of plasma at the International Physiological Congress,
held at Basel in September, 1889, during the discussion which arose after-
Heidenhain's address.

3 Bunge, Zeitschr. f. Biolog., vol. x. pp. 301 and 303 : 1874.

* In 1 liter of dog's serum I found 0.176 CaO. The figure must be some-
what raised for the plasma, since a little lime is carried down with the fibrin.
5 Vide Lecture XXI. for the composition of urine in man when on a meat diet».
•^ Log. cit., p. 63, et seq.

LYMPH 221

In every organ and in every tissue the capillary wall allows
a fluid of special constitution to pass through it, according to
its various requirements : in the muscles this fluid is richer in
ßugar, in the mammary glands, in lime, and so on. After these
special substances have been utilized, these fluids flow back
into the main lymph-trunks, so that the mixture takes on a
•composition very similar to that of the original plasma. The
lymph is therefore probably of very different constitution in
the lymph-spaces of the various tissues. The analysis of
lymph taken from the large lymphatics cannot give us any
information as to the composition of the tissue-fluids them-
selves.

For those who wish to maintain the old theory of diffusion
and to consider the capillary wall as a dead membrane passively
concerned in the operation, the cells may be regarded as taking
from the lymph the special substances which they need, con-
verting them into an insoluble or colloid combination, which
has thus lost all power of diffusion, e. g., sugar into glycogen or
fat, the soluble into insoluble compounds of lime. In this way
the special substance would become less concentrated in the
lymph than in the plasma, and a fresh supply would be con-
tinually passing according to the laws of diffusion through
the capillary walls from the blood into the lymph, without the
simultaneous passage of water. But there is really no reason
for refusing to the capillary walls of the endothelial cells the
' active ' functions which it is allowed are involved in the case
of all other cells. However this may be, the old idea of the
plasma stream ^ must be relinquished.

Impossible as it is for the food-stuffs to be conveyed to the
various cells by a stream of plasma common to all alike, so it is
equally impracticable for the end-products of metabolism to be
returned by the common lymph stream to the blood. We
must rather assume that these final products penetrate through
the neighboring lymph-spaces into the nearest capillaries.

The most important of these waste materials, carbonic acid,
•can be proved to make its exit in this manner. The tension of
■CO2 is less in the large lymph-trunks than in the blood (compare
Lecture XVIII.) . Moreover the lymph-flow is much too slow
to carry off the large amounts of carbonic acid quickly enough.
The passage of 800 to 1000 grms. of this gas through these
organs in the twenty-four hours could not be effected unless
the CO2 were conveyed directly into the circulation. And this
is probably the case with urea and the other end-products of
metabolism. We must assume that these latter reach the

^ [J. e., the irrigation theory of Bartliolini.]

222 LECTURE XV

blood directly through the capillary walls and not through the
medium of the lymph.

We have now to ask : What are the functions of the lymph ?
What are the objects of the lymph-spaces? Might not the
interchange of material proceed in all the other organs as it
does in the glomeruli of the kidney ?

In the first place, the lymph-spaces have a purely mechanical
use, inasmuch as they enable the blood-vessels to alter their
lumen and so regulate their pressure. Were the blood-vessels
surrounded with rigid tissue, this would be impossible. They
need to be set in a compressible medium, which can adjust
itself to the variations of the vascular lumina. Secondly,
supposing that every cell were in immediate contact with a
capillary vessel, as in the Malpighian glomerulus, the capillary
system would become so enlarged that the circulation of the
blood would become too much slowed down.

These considerations however refer to the uses of the
lymph-spaces only, and not to those of the larger lymphatics.
They do not explain why the fluid collects from the lymph-
spaces into larger and larger vessels, which finally empty
themselves into the blood-stream. Could not the food-stuffs
pass through the capillary wall of the blood-vessels straight
into the lymph-spaces, and, conversely, could not the final
products of metabolism find their way directly from the lymph-
spaces through the capillary wall into the blood ? What is the
need for a special stream of lymph ?

In answering this question we have an indication in the
fact that in the course of the lymphatics are interposed lym-
phatic glands, in which the lymph-cells are being continually
formed by division.

We do not yet know very much of a definite character
concerning the cells of the lymph, the leucocytes ; although
they undoubtedly are of great importance in the animal economy.
We know that they can make their way out through the
capillary wall and wander among the tissues. They may be
seen assembling in masses wherever injurious substances are
formed, where foreign bodies, poisonous matters, or micro-
organisms penetrate the tissues, as well as in cases of inflam-
mation and all kinds of pathological processes which accompany
the degeneration of tissue. It appears that their function is to
clear away the products of tissue-disintegration ^ and to render
noxious substances harmless. They may be seen enclosing

1 An account of the literature on the behavior of leucocytes under normal
and pathological conditions is given in the monograph of Herm. Rieder, " Beitr.
z. Kenntniss der Leucocytose." Leipzig, Vogel : 1892.

LYMPH 223

within their protoplasm solid particles, or invading micro-
organisms ; ^ 'and it is probable that they also take up and alter
substances in a fluid and dissolved condition. I have already
mentioned the part which has been ascribed to them in the ab-
sorption of proteid, in the regeneration of peptone into proteid
within the intestinal wall, and in the conveyance of the peptone
which reaches the blood in this form.

Now there is a constant disintegration of lymph-cells
going on. We know, for instance, from Stöhr's experiments ^
that leucocytes emigrate in masses through the epithelium
from the adenoid tissue of the tonsils and of the follicles of the
tongue, as well as from the follicles of the whole intestinal and
bronchial mucous membranes. Stöhr considers that an expul-
sion of " used-up material " is involved. These leucocytes
must be replaced by the formation of new ones in the lymph-
glands and by a supply of young cells passing with the lymph
into the blood.

Finally the lymph-glands may have the function of altering
the various kinds of lymph which flow into them from all
the tissues, so as to assimilate it to the plasma before it enters
the circulation. Without such previous assimilation a fluid,
which had been changed by the processes of metabolism in the
tissues, might either disintegrate the blood-corpuscles when it
passes into the blood-stream or do mischief in some other direc-
tion.

It is known that injurious substances of all kinds, as w^U as
microorganisms, are detained in the lymph-glands so that they
cannot enter the blood, there to be passed on to the tissues.
With this fact is also connected the swelling of the lymph-
glands as a result of infection.

In the following table I append some of the most
reliable analyses as examples of the composition of lymph.

' It is well known that El. MetchnikofF was the first author to introduce the
view that the leucocytes wage war against the intruding microorganisms and
other injurious and foreign substances — the so-called doctrine of phagocytosis.
Arb. a. d. Zoolog. Inst, zu Wien, vol. v. Hft. ii. : 1883 ; Biolog. Centralbl., vol. lii.:
1883-1884; Virchow's Arch., vol. xcvi. p. 177: 1884; vol. xcvii. p. 502: 1884;
vol. cvii. p. 209: 1887; vol. cix. p. 176 : 1887; vol. cxiii. p. 63 : 1888: Annales
de rinstiua Pasteur, p. 321: 1887; p. 604: 1888. [See also his work, "The
Pathology of Inflammation," Paris, 1892, translated by E. H. Starling.
London, Kegan Paul & Co., 1893.] This doctrine has been the subject of much
dispute. Compare Baumgarten, Berlin. Min. Wochenschr., -p. SIS : 1884; and
Centralbl. f. klin. 3Ied., 'No. 26 : 1888; and Weigert, i^oj-i'scA?-. d. Med., p. 732:
1887 ; and p. 83 : 1888. On the other hand a highly interesting observation,
which bears out Metchnikoff^s theoi-y, has been recently published by Vaillard &
Vincent : Annales de l' Institut Pasteur, Annee 5, p. 34 : 1891.

2 Ph. Stöhr, Biolog. Centralbl., \ol. ii. p. 368 : 1882 ; Sitzungsber. d. physik.
med. Ges. zu Würzburg, May 19, 1883 ; Virchow's Arch., vol. xcvii. p. 211 :
1884.

224 LECTURE XV

To these I have added a few analyses of the ' pathological
transudations/ ascitic fluid, pleural and pericardial effusions,
dropsical fluid, and hydrocele fluid, which are considered by
most authors as lymph increased above the normal by patho-
logical conditions and obstructed absorption. Even the fluid
contained in the ventricles of the brain, which it is well known
may be increased largely in disease (e. ^., hydrocephalus), is
regarded as lymph by many authors because the ventricles of
the brain communicate by means of the foramen of Magendie
with the lymph-spaces of the subarachnoid tissue. Some ob-
servers however deny that this communication exists. It must
also be remembered that the ventricles of the brain are covered
with epithelium, and that the fluid in them might be a specific
secretion of these cells. The cerebro-spinal fluid is not spon-
taneously coagulable.

Finally, I have included a few analyses of chyle in Table
I. I have already shown that the chyle of fasting animals
is nothing but lymph, and that fat droplets are mixed with
this lymph only during the digestion of fatty food (Lecture
XIIL).

I. C. Schmidt, "Charakteristik der epidemischen Cholera." Mitau u.
Leipzig, p. 29 : 1850. II. and III. Gubler & Quevenne, Gaz. Med. de Paris,
Nos. 24, 27, 30, and 34: 1854. The different specimens of lymph were obtained
■by pricking the varicose enlargements of the lymph-vessels in the skin of a
woman's thigh. As the woman, with the exception of this lymph obstruction,
was otherwise in a normal condition, we may jjerhaps regard this as ordinary
lymph. IV. Eees, Phil. Trans., p. 81 : 1892. V. Hoppe-Seyler, " Physiol.
Chem.," Berlin, Hirschwald, p. 597 : 1881. Effusion of chyle into the peritoneal
cavity in consequence of rupture of the chyle-vessel. The chyle was obtained by
tapping the abdomen. Hoppe-Seyler thought that it was undoubtedly normal
•chyle. VI. C. Schmidt, ^oc. cii., p. 140. VII. and VIII. Hoppe-Seyler, ^oc. ci<. ,
p. 505. IX. -XI. Herm. Nasse, " Ueb. Lymphe u. deren Bildung," Akad.
Gelegenheitschr., Marburg, 1872. XII. C. Schmidt, loc. cit,, p. 138. Taken
from the same dog from which the blood for Analysis VI. was drawn. XIII.-
XVII. C. Schmidt, Bulletin de St. Petersbourg, vol. iv. p. 355 : 1861.

I. -III. V. Hensen and C. Dähnhardt, Virchow's Arch., vol. xxxvii. p. 55 :
1866. Both legs of the patient were swollen from the extensive thickening of
the subcutaneous tissue and corium ; heart failure and ascites were also present.
IV.-VI. Hoppe-Seyler, Virchow's Arch., vol. ix. p. 250: 1856. VII. Gorup-
Besanez, " Lehrb. d. physiol. Chem.," 3d edit., p. 415. Braunschweig, Vieweg
and Sohn, 1874. VIII. Wachsmuth, Virchow's Arch., vol. vii. p. 334 : 1855.

IX. Hoppe-Seyler, " Physiolog. Chem.," Berlin, Hirschwald, p. 605: 1881.

X. Scherer, Verhandl. d. med. phys. Ges. zu Würzburg, vol. vii. p. 268 : 1857.

XI. Hammarsten, Upsala Läkareförenings For handling a,r, vol. xiv. p. 33 : 1878.
XII. -XV. C. Schmidt, " Charakteristik d. epidem. Cholera," Leipzig u. Mitau,
pp. 122 and 123 : 1850. XVI.-XVIII. Hoppe-Seyler, Virchow's Arch., vol. ix.
p. 250 : 1856.

I.-V. Hoppe-Seyler, Virchow's Arch., vol. xvi. p. 391 : 1859. VI. and VII.
Halliburton, Journ. of Physiol., vol. x. pp. 233 and 234 : 1890. VIII. and IX.
•C. Schmidt, " Charakteristik de epidem. Cholera," Leipzig and Mitau, pp. 135-
138: 1850. X. C. Schmidt, loc. cit., p. 136. "Fluid between the dura mater
and the vault of the skull, which was greatly expanded." XI. Hoppe-Seyler,
loc. cit.

LYMPH

225

W

XI

Bj0 8[iqo

CO lO

■B JO 3iiqo

o o

»—I 03
CD CO

CO O

IBO J 'B JO orjBqd

-tail iBOtAjao

TOOjj iidnijf'x

• 1130 J BJO DiiBqd
rooJj qdnijfi

•[BOjI b raojj
lanjos-pooig

uaiKHOS '0

•SI[BUlds

-ojqaiao jonbtq;

z6 CO

M

X

X

3iqB:>aS8A ^0

® 2 H

a

■^8ia ^B8W no

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l-H

"Sod aiuBS
eq^ niojj aijtqo

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■ranJ8s-pooig

^ 1<^ I I I I I I I

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■(SOQ)

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CD ^ O <»
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OO o CO CO lO I— I O

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cq 00 CO 'CH C<I

i>^ Ö T-H o4 !>;

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B taojj ai^fqo

a H
a o

CO lO CO CO ^

OS rH lO t^ t^

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GO O CO CO lO I— I o

qo;

1 f^ h-1 o cc <1 W !^ o izi ;zi M

fu

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lO'd

15

226

LECTURE XV

1
o

l-H

>

X

aqj JO BinapH

From one and the same
subject.

Hoppk-Seyler.

982.2
17.8

3.6
9.0

1-5
1— (

>

X

|E9no;iJ8tj

967.7
32.3

16.1

H-5

>
X

•DorjEpnsnBJx
IBinaiji

957.6
42.4

27.8

kJ 1 'mB-ia

^ JO s8iOTi;n9A
?<( rao^ ptnij

o

a

983.5
16.5

8.0

8.5

^ gqij JO sragpa

From one and the s
subject.

C. Schmidt.

988.7
11.3

3.6

7.7

1—!
1— I
1— 1

X!

•aoiiBpnsnBix
IBauoiiaea:

978.9
21.1

11.3

9.8

M •noii'BpnsuBJX

964.0
36.0

■ 28.5

7.6

' ' 1

1— i

X
X

Hydrocele.

•sasÄiBny cs-icotj^, oeoSo, ,
U JO UBajij cä^öcrI -^cicdr^i 1
■naxsavKKVH co co ^

Ol

•aaaanos
Xq sisXi'Bnv'

!>: W O'^ 1 051> 1 1 1 1
1C-* CO ' 1 1 1 1

G5

X

t— 1

hH

1— 1

1— I
>

Liquor Pericardii.

•aaiias
-aadOH

961.8
38.2

24.6

•HIQHSHOT^

962.5
37.5

22.8

•zasvsaa

-diiaoo

^q stsiiBOV

IC Tj^ Ö -^ C4 1 CO 1 1 i 1
IC •* C<1 I-l 1 1 1 1 1
G5

>
>
>

h-{

Peritoneal Trans-
udation in a case of
Cirrhosis of the Liver.
Hoppe-Sevleb.

•qjB9(I J9JJY

983.3
16.7

61.1

8.2

•SniddBX

pn'039g

982.5
17.5

7.7
8.1

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984.5
15.5

6.2

8.5

h- 1

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1-5

Human Lymph from a
Fistula ig the Thigh.

Hensen and

DÄUNHARDT.

985.2
14.8

986.1
13.9

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t> CO CO CO o ■* T-i ic ic 1-1
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00 -H _>^_

Ol

Water . . .
Dried subst.
Fibrin . . .
Proteid
Extractives .
Fat, lecithin,
Cholesterin
Ash ....
NaCl . . .

CaO ....

LYMPH

227

-^

^

8h

c

X

X

X

>

\\ I-*

iC iC t^

ciÖÖ

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rg 5 a a H =)

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Ci Ort i

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ci Ö Ö

t^ CO iC

o cc c<i !

lO lO O
l>r C4 rH

00 rH

Mill

I I

I I I

I I I I I I I I

as -2

in :S Ort C

_ ■'0 ■

I— I cv> a:

S C '

o v.o-^

228 LECTURE XV

From these tables it may be seen that the lymph drawn
from different parts of the body is highly variable in its
composition, and especially as regards its proportion of proteid.
This is also the case with the pathological transudations. The
amoimt of proteid varies between 0.3 and 4.9 per cent. The
quantity of fibrin is always less than in the blood ; it varies in
the lymph between 0.04 and .02 per cent., in the blood between
0.2 and 0.4 per cent.

The proportion of the two kinds of proteid, the globulins
and the albumins, varies in the lymph between as wide limits
as they do in the blood-plasma (compare Lecture XIV.).
Experiments made so far on this subject have given the
noteworthy results^ that if blood, lymph, and chyle, or blood
and a pathological transudation be taken from one and the
same individual, these two kinds of proteid are nearly always
present in the same proportion in the transudations and in the
lymph, however great the difference may be in the total amount
of proteid.

We cannot, within the scope of this book, treat of the
causes and mode of formation of the pathological transudations.
We know that nerve fibers run to every single endothelial cell
of the capillary wall, and that therefore disturbances in the
innervation of the capillary wall may be reflexly transmitted
from any organ to any other organ. We must likewise
remember that every mechanical disturbance of the circulation
and every change in the chemical composition of the blood
interfere with the normal nutrition of the capillary wall and
lower the power of resistance possessed by the endothelial cells,
so that they are not so capable of preventing the escape of
constituents of the blood-plasma. Finally, we must not forget
that abnormal constituents of all kinds act directly as irritants
on the endothelial cells of the capillary wall, so soon as they
enter the blood, and may thus alter their functions. The cause
of the formation of transudations, which have been patholog-
ically increased and altered, may therefore be of a very vary-
ing character in different organs. Their study must for the
present be left to the domain of special pathology, where the
results so far attained in physiological experiment may be
utilized. A critical account of the physiology of lymph may
be found in the work of Heidenhain already referred to.

^G. Salvioli, Du Bois' Arch., p. 268: 1881 ; F. A. Hoffmann, Arch. f. exp.
Path. u. Pharm., vol. xvi. p. 133 : 1882.

LECTURE XVI

THE SPLEEN

Before leaving the subject of lymph and the lymphatic
glands, we will take for our consideration another organ which
is supposed to have similar functions, viz., the spleen.

With the single exception of the amphioxus, the spleen is
invariably present in all vertebrates, and is in all cases of very
similar structure.

There is however an essential difference between the spleen
and the lymphatic glands, in that the leucocytes formed in the
spleen enter directly into the blood-stream. The blood of the
splenic vein contains more leucocytes than the arterial blood.
This was shown by Kölliker and Hirt,^ whose experiments
were afterwards confirmed by numerous observers.^ In his
investigations on the metabolism of Rhine salmon (vide p. 79),
Miescher^ carried out a number of very careful estimates on
this point, the average number of white corpuscles to every 100
red blood-corpuscles being

Cardiac Blood. Splenic Blood.

1.79 1.79 8.31 7.1 white corpuscles.

The earliest investigations on the functions of this organ dealt
v/ith the effects of its extirpation. Even Pliny * mentions as
well known the fact that dogs will survive the extirpation of
the spleen. Since that time occasional extirpations of the
spleen have been successfully performed on diiferent animals.®
But it is only since the aseptic treatment of wounds has

■^ Hirt, " De copia relat. corpusc. sanguin. alb.," Dissert. Leipzig : 1855.

2 P. Emelianow, Arch. d. Sciences biolog., St. Petersbourg, vol. ii. p. 145 :
1893. The earlier literature is here quoted.

3 Miescher, Du Bois' Arch., Anat. Abth., p. 212 : 1881.
* Plinius, "Histor. naturalis.," lib. xi. c. xxxvii.

^ An account of the earliest literature on extirpations of the spleen is given
by G. Adelmann, Deutsche Klinik, p. 183 : 1856.

229

230 LECTUEE XYI

been introduced that these operations have formed the bases
of systematic series of experiments. Among the latest re-
searches of this nature we may mention the following : Guido
Tizzoni ^ cut out the spleen in eighteen rabbits, young and
old. The longest time during which the animal was under
observation was 240 days. He could discover no ill effects
from the operation. In the young animals the growth
proceeded as usual, and in adults the sexual fimctions were
undisturbed and healthy offspring were produced. In the
same way, Konrlow^ found that gumea-pigs bear extirpa-
tion of the spleen well, and that they grow and propagate
like normal animals. A. Dastre^ cut out the spleen in young
dogs, cats, rats, and guinea-pigs, and compared their rate of
growth with that of normal animals from the same litter.
He could discover no difference. Unfortunately the obser-
vation lasted but a short time — only four months in the case
of the cats, and until they were full-grown in the case of the
guinea-pigs.

The question now arises as to whether, if the animals sur-
vive the removal of their spleen, changes may not occur in one
or other of their functions. Alterations in blood formation
were especially anticipated. Of the numerous experiments
made in this connection may be mentioned the most recent.
P. Emelianow ^ found that, after extirpation of the spleen in
dogs, the number of red blood-corpuscles diminished, while
that of the white was increased. O. Vulpius,^ experiment-
ing on rabbits and goats, also observed that, when the spleen
was excised, the red blood-corpuscles decreased by not more
than 20 per cent., but that this diminution was made up after
about a month had elapsed. The number of white blood-
corpuscles immediately after the operation rose to double
the normal, the increase however lasting at the most nine
weeks.

From this increase of white and diminution of red blood-
corpuscles it is natural to conclude that in the spleen the

^ G. Tizzoni, Archivio per It scienze mediche, vol. viii. No. 13, p. 255. Sum-
marized in Arch. ital. d. Biol., vol. vi. p. 103 : 1884.

^Kourlow, Vratsch, Nos. 23, 24, 1889; No. 19, 1892 (Russian).

* A. Dastre, Comptes rend. Soc. Biol., p. 584: 1893 ; and Arch. d. Physiol.,
July, 1893.

■*P. Emelianow, Arch. d. Sciences bioL, St. P^tersbourg, vol. ii. p. 157: 1893.
The earlier literature is here quoted.

^O. Vulpius, Beitr. z. klin. Chir., vol. xi. p. 684: 1894. This author gives
a summary of the earlier and very abundant literature on the infiuenee of ex-
cision of the spleen on the amount of red and white blood-corpuscles. There is
also an account on pages 687 and 688 of the numbers of blood-corpuscles in man
after extiri^ation of the spleen.

THE SPLEEX 231

red are formed from the white corpuscles. Moreover some
observers "have described in the splenic pulp nucleated red
blood-corpuscles similar to those in embryonic tissue. It
might be assumed that these nucleated red blood-corpuscles
formed the intermediate steps in the conversion of white into
the non-nucleated red corpuscles. ]Miescher's observation ^ that
the spleen is richer in hemoglobin than the blood deserves our
notice. This author, adopting Hüfner's method, found that the
salmon had twice as much hemoglobin in the spleen as in the
blood.

We have now to consider whether the transitory character
of the disturbances in the blood formation, which appear after
excision of the spleen, may not be accounted for by the fact
that other organs of the body may take up the splenic functions.
It is often stated that the lymphatic glands swell after removal
of the spleen. This is however by no means a constant phenom-
enon, and was absent, for example, in a number of experi-
ments of this description carried out by Vulpius ^ in rabbits and
goats. Swelling of the lymphatic glands has often been
observed in man as a result of excision of the spleen. In
this case however it is doubtful whether this change should
rather be ascribed to the disease which necessitated the
operation.

It seems to me more probable that the duties of the spleen
are fulfilled by another tissue, viz., the red marrow of bones.
In 1869 Xeumann ^ and Bizzozero * showed that the red marrow
of the flat bones, the bodies of the vertebrse, and the proximal
epiphyses of the bones of the limbs in mammals contained
nucleated cells tinged with hemoglobin, resemblmg in every
respect embryonic red blood-corpuscles. It is thought that these
cells are formed from leucocytes and, multiplying by cell-division,
are converted into non-nucleated red blood discs. The red bone-
marrow presents one striking similarity to the splenic tissue,
in that the veins appear to lose their proper wall, thus allow-
ing the blood to come into immediate contact with the tissue-
cells.^ It seems tlierefore a likely hypothesis that the red
bone-marrow should be able to take up the functions of the

iMiescher, Du Bois' Arch., Aiiat. Abth., p. 212 : 1881.

2 Vulpius, loc. cit., p. 694, contains full references to previous work on the
subject.

*E. Neumann, Arch. d. Heilkunde, Jahrgang x. p. 68: 1869; Yirchow's
Arch., vol. cxis. p. 385 : 1890.

^ Bizzozero, " Sul midollo delle ossa," Kapoli : 1869.

5 Hover, 3Ied. Centralbl., Nos. 16 and 17: 1869; G. E. Eindfleisch, Arch. f.
mikr. Anat., vol. vii. p. 1 : 1880.

232 LECTURE XVI

spleen when this organ was removed. Thus P. Emelianow^
foimd in the red marrow, after extirpation of the spleen in
dogs, an increase of leucocytes containing hemoglobin, as well
as of the transition-forms between these and the red blood-
corpuscles. The observations of Pouchet ^ show however that
the harmlessness of this operation does not depend on changes
in the red marrow, since the spleen may be removed in the
fish which have no bone-marrow without causing any alteration
in the composition of their blood.

A number of cases are on record in which the spleen has
been excised in man. In some instances this was rendered
necessary by the prolapse of the organ through a wound in the
abdominal wall. Many such cases have recovered even in the
pre-antiseptic days. Morgagni^ records the case of a woman
in whom a prolapsed spleen was removed, and who lived for
five years afterwards and bore children. In 1678 a Colburg
surgeon, Nicolaus Matthia, extirpated the spleen of a young
man which had prolapsed in consequence of a dagger wound
of the abdomen. The patient lived at least six years after the
operation, went about his ordinary occupations, and begat
children.*

Encouraged by these results, surgeons have tried the effect
of excising spleens in diseased conditions, such as hypertrophy,
sarcoma, hydatid cysts, floating spleen, etc. In the days
before asepsis and antisepsis were practiced, a violent dispute
arose as to whether such a bold operation was justifiable. We
may refer our readers to the treatises, which appeared in 1855
on the occasion of Küchler's operation.^ This surgeon had
ventured to remove a spleen in a man suffering from hyper-
trophy in consequence of malaria, and had lost his patient.
On this account he was violently attacked by many of his
colleagues and especially by Gustav Simon, ^ a surgeon in
Heidelberg ; and as vigorously defended by G. Adelmann,^ a

1 p. Emelianow, Arch. d. Sciences biolog., St. Petersbourg, vol. ii. p. 135 :
1893. The earlier literature is here quoted.

2 Pouchet, Gaz. med. d. Paris, p. 316 : 1878.

^Morgagni, "De sedibus et caus. morbor," lib. v. epist. 65, art. 10, p. 368:
Patavii, 1765.

* " Ephemerides Medic. Physic. Natur. Curiosor," Decuria ii. Ann. ii. (1684),
p. 378 : Norimb. 1685.

^H. Küchler, " Exstirpation eines Milztumors; wissenschaftliche Beleuch-
tung der Frage über Exstirpation der Milz bei dem Menschen," &c., Darmstadt :
1855.

" G. Simon, "Die Exstirpation der Milz am Menschen nach dem jetzigen
Standpunkte der Wissenschaft beurtheilt," Giessen : 1857.

' G. Adelmann, Bemerkungen zu Dr. Küchler's Schrift : " Exstirpation eines
Milztumors," Deutsche Klinik, Nos. 17 and 18, pp. 175 and 183 : 1856, contains a
critical account of all the earlier works on the extirpation of the spleen.

THE SPLEEN 233

surgeon of Dorpat. Since aseptic precautions have been
brought to' perfection, removal of the spleen has become much
more frequent and has been attended with more and more
favorable results. In those cases which do not succeed the
failure should probably hardly ever be ascribed to the loss of
the splenic function. Of course in such operations it is difficult
to say whether death, if it ensues, is due to the consequences of
the disease or to the absence of the organ. In the cases which
survive the operation unfortunately no record is usually kept of
the length of the subsequent life. In 1876 however, P6an^
showed a woman at the Parisian Academic de M^decine M^hose
spleen had been excised ten years previously, in consequence
of cystic degeneration, and who had remained throughout that
time in excellent health. Vulpius ^ records the case from
Czerny's clinique in Heidelberg of a woman in whom a hyper-
trophied floating spleen was extirpated. The patient recovered
slowly, apparently because, in addition to hypertrophy, she
suffered from severe nervous troubles and attacks of hys-
teria. Fifteen years after the operation however, she still
enjoyed moderately good health. The nervous symptoms had
abated, and the blooming color on her cheeks showed that there
was no disturbance in her blood formation. In the first
few years after the operation there had been some swelling
of the inguinal and cervical glands, but this had gradually dis-
appeared.

In certain cases of enlarged spleen, such as leukemia and
lardaceous disease, other organs — liver, lymphatic glands,
kidneys — are usually affected at the same time ; and therefore
no cure can result from removal of the spleen. Idiopathic
tumors of the spleen rarely occur, but here again the blood is
in an abnormal condition, as shown by the existence of anemia,
leucocytosis, etc. Better results might be anticipated from this
operation in cystic disease, e. g., hydatids, but here a partial
resection is usually sufficient. Extirpation is also indicated in
cases of floating spleen, where this organ, especially if it be
hypertrophied, sinks occasionally into the pelvis and produces
painful stretching of the duodenum and stomach, strangu-
lation of the blood-vessels, disturbances in digestion and nutri-
tion, &c.

In 1893 A. Dandolo ^ collected all the cases in which ex-
cision of the spleen had been performed.

1 Pean, Bulletin de VAcacl. de Med., No. 29 : 1876.

2 Vulpius, Beitr. z. klin. Chir.. toI. xi., pp. 638-641 : 1894.
^ Dandolo, Gazs. med. lombarda, Nos. 7-9 : 1893.

234

LECTURE XVI

Cases.

Cure.

Death.

Floating spleen

Suppuration

Simple cysts . . . . . .

Hydatid cysts

Amyloid spleen

Fibroma ...

Sai'coma

Lympho-sarcoma . . .

Venous engorgement.
Simple hypertrophy . . . .

Malarial hypertrophy . .
Leukemia and pseudo-leukemia

17

2

4

4

1

1

2

2

3

18

23

25

102

15
2
4
3

1

2

7
12

1
1
1
1

3
11
11

25

56

In 1894 O. Yulpius^ published a list of 117 extirpations,
50.4 per cent, of which resulted in cure, 49.6 in death.

Cases.

Cure.

Death.

Leukemia .

Simple and malarial

and floating spleen
Hydatid . ...
Simple cysts ....

hypertrop

hy

28

66
5
4
4
3
3
1
1
2

32

42
3
4
3
3

1

25

24
2

Sarcoma

Suppuration ....
Venous congestion .
Amyloid . . .

1

3
1

Syphilis . ...

Kupture ....

2

117

59 (50.4%)

58 (49.6%)

As regards the operations for enlargement of the spleen in
leukemia, again only one is reported by Vulpius to have
resulted in a permanent cure, and even in this case there was
some doubt as to the diagnosis. If we deduct the cases of
leukemia, heart and amyloid disease, in which the patients
certainly did not die from the effects of the excision, but
from the original incurable disease, there remain fifty-six cures
in eighty-five cases, i. e., 65.9 per cent., or two-thirds of all the
cases.

^ O. Vulpius, Beibr. z. klin. Chir., vol. xi. p. 655 ;
2 Only one was permanent.

1894.

THE SPLEEN 235

Since therefore we learn from innumerable experiments on
man and animals that the absence of the splenic functions does
not endanger the life and health of the individual, the sug-
gestion occurs that the functions of this organ may have some
connection with the sexual functions. So far as we are aware,
all the functions of our body serve directly or indirectly two
purposes only : the preservation of the individual and the
maintenance of the race. It would be interesting to know
whether the persons whose spleen has been removed show any
alteration in their sexual life. As regards animals, the follow-
ing observation of Miescher's^ is in favor of some such con-
nection between the splenic and sexual functions. Miescher
noticed that the size of the spleen varied greatly in the
ßhine salmon, and that this difference in its volume depended
upon the increase or diminution of the blood in it. The
swollen spleen of a salmon contained sometimes one-fourth,
sometimes even as much as one-half of the total blood. In
the female this repletion occurs pretty regularly at certain
definite seasons in the year : the spleen is at its smallest
two months before (September and October) and during
the period of spawning (November) ; and swells up after
this time. In the male no such regularity could be at-
tested ; although the spleen was again at its smallest in
November during the time of spawning. It appears that the
spleen regulates the amount of blood in the other organs, as
well as the processes of oxidation and other metabolic phenom-
ena, thereby indirectly acting upon the development of the
ovaries and testes. A similar connection between pairing
time and the size of the spleen and the amount of blood in
that organ was observed by A. Leonard Gaule in frogs."

The relation of the splenic to the sexual functions can-
not however be of very great importance, as may be inferred
from the fact mentioned above that both man and animals
retain their powers of propagation after removal of the
spleen (compare p. 232).

Since therefore the spleen is not essential in the normal
organism either to the maintenance of the individual or of the
species, we must finally inquire whether it may not have a
significance in abnormal conditions. It has been regarded
as a means of protection against injurious substances and in-
fective germs, which have entered the blood. This supposi-
tion appeared to be confirmed by the fact that in many
infectious diseases the spleen swells. This phenomenon seems

^ F. Miescher-Riisch, Du Bois' Arch., Anat. Abth., p. 193: 1881.
^ A. Leonard Gaule, Journ. Morphol., vol. viii. p. 403 : 1893.

236 LECTURE XVI

to be analogous to the swelling of the lymph-glands, which
evidently has the object of retaining and rendering innocuous
the poison which has been absorbed. It is possible that
spleenless animals would be more readily infected, and when
infected, more seriously ill than normal animals. Observations
on man are urgently needed as to how those persons whose
spleen has been removed, withstand the infectious diseases
which they may subsequently acquire. Such observations, so
far as I know, have never been carried out, but the patients
have, as a general rule, been completely lost sight of.

To the THYMUS has been ascribed functions similar to those
of the spleen, the bone-marrow, and the lymphatic glands.
In its histological aspect the thymus displays its close relation
to the lymphoid organs. Besides leucocytes it contains nucle-
ated red blood-corpuscles.^ We must therefore assume that
the red blood-cells are formed here as well as the leucocytes.
But in warm-blooded animals however this function is con-
fined to the embryonic period, until the true lymph-glands
are developed. Later on it undergoes retrograde changes,
and in the adult has almost completely disappeared. That
the thymus takes no further part in extra-uterine life is
apparent from the experiments of Von Braunschweig.^ This
observer remarked that after bleeding or removal of the spleen,
the thymus underwent no change either in quite young or in
full-grown animals ; no increase of cell division was observed ;
the number of karyomitoses did not rise above the normal.

In cold-blooded animals such as the frog, the thymus per-
sists throughout life. In these instances it is a double organ.
In the frog it is situated under the depressor mandibule muscle,
which becomes visible when the skin behind the tympanum
and the angle of the jaw is removed. According to Abelous
and Billai'd,' in the frog excision of the thymus on both sides
invariably causes death three to fourteen days afterwards, with
the accompaniment of paralytic symptoms, a tendency to ulcera-
tion, hydremic consistency of the blood and hemorrhages. Re-
moval of one thymus however does not prove fatal in a healthy
frog ; the only difference is that such an animal tires more
readily than a normal frog.

^ J. Schaffer, 3Iecl. Centralhlatt, pp. 401 and 417 : 1891 ; and Sitzungsber. der
Wiener Akad. d. Wissensch. Math-natur. Kl., vol. cii. p. 336 : 1894.

2 R. von Braunschweig, " Exper. Unters, üb. d. Verhalten der Thymus bei
der Regeneration der Blutkörperchen," Diss. Dorpat : 1891.

3 Abelous et Billard, Arch. d. Physiol., 5 (viii.), p. 898 : 1896.

LECTURE XVII

GASES OF THE BLOOD AND RESPIRATION BEHAVIOR OF

OXYGEN IN THE PROCESSES OF EXTERNAL
AND INTERNAL RESPIRATION

In our remarks on the composition of blood, no account
has been given of its gaseous constituents. Three gases can
be pumped out of blood : ^ oxygen, carbonic acid, and nitro-
gen.

The amount of nitrogen is inconsiderable ; it does not occur
here in larger quantities than it does in watery fluids which
come into contact with atmospheric air. Nitrogen is simply
absorbed by the blood,^ and it appears to take no part in vital
processes.^

The two other gases, on the other hand, are of great physio-
logical importance : oxygen is, as we have seen, an essential
food-stuif, the most potent source of energy ; carbonic acid is
one of the end-products of metabolism, the compound in which
the bulk of the carbon leaves the animal body.

' A diagram and descrii)tion of the apparatus used for pumping out the gases
— the gas-pump of Ludwig and of Pflüger — are given in every text-book of gen-
eral physiology. As I assume that all my readers possess such a work, I shall
not describe it here. The original description and diagram of the gas-pump, with
which most of the experiments on the blood-gases were carried out in Ludwig's
laboratory, will be found in Alexander Schmidt's paijer in Berichte über die
Verhandl. d. k. sächsischen Ges. d. Wissensch. sii Leipzig, Math, physik. Classe,
vol. xix. p. 30 : 1867 ; and the description of the apparatus constructed by
Geissler and Pflüger in Pflüger's " Untersuchungen aus dem physiologischen
Laboratorium zu Bonn," p. 183 : Berlin, 1865. For the methods of gas-analysis,
vide Bunsen, " Gasometrische Methoden," Braunschweig, 2d edit.: 1877; and
J. Geppert, " Die Gasanalyse und ihre physiologische AuAvendung nach verbes-
serten Methoden": Berlin, 1866.

2 A knowledge of the laws that govern the absorption of gases is essential for
the comprehension of the respiratory processes. The beginner who is not thor-
oughly conversant with Dalton's law, the meaning of coefficient of absorption,
partial pressure, &c., must study a text-book of physics before proceeding with
this and the following lectures.

^ The theory that a small part of the nitrogen issues as a free element from
the decomposition and oxidation of the nitrogenous food-stuffs in the animal body,
has been upheld by some until quite recently, but has never been confirmed by
accurate experiment. For this tedious contest, vide Pettenkofer and Voit,
Zeitschr. f. Biolog., vol. xvi. p. 508 : 1880 ; Seegen and Norwak, Pflüger's Arch.,
vol. XXV. p. 383 : 1881 ; Hans Leo, Pflüger's Arch., vol. xxvi. p. 218 : 1881 ; J.
Eeiset, Compt. rend., vol. xcvi. p. 549 : 1883. The earlier literature is quoted in
these works.

237

238 LECTTJEE XVII

The absorption of oxygen and the excretion of carbonic
acid take place among the lower animals over the whole surface
of the body ; among the higher animals, j^rincipally or ex-
clusively in differentiated organs, such as lungs, gills, and
tracheae. This process is termed external, as distinguished
from internal, respiration, which last term we apply to the
consumption of oxygen and the formation of carbonic acid in
the tissues. A few authors understand by this latter term, how-
ever, only the physical process of the interchange of gases
through the walls of the blood-capillaries (the diffusion of car-
bonic acid from the tissues into the blood, and of oxygen from
the blood into the tissues), and not the chemical processes of
oxidation, of the assimilation of oxygen and the formation of
carbonic acid in the tissue cells. Venous blood is rendered
arterial by the process of external respiration ; arterial blood
venous by that of internal respiration.

As the skin and the lungs are also tissues requiring oxygen
for the performance of their functions, the process of internal
respiration goes on at the same time along with that of external
respiration — the latter preponderating in the lung. For this
reason the pulmonary vein carries arterial blood to the heart.
The former process preponderates in the skin of most animals,
and the blood contained in the cutaneous veins is therefore
venous.

We will now consider more closely the behavior of the
oxygen and carbonic acid in the processes of external and in-
ternal respiration. Let us first take oxygen.

Arterial dog's blood, which has served for most of the
analyses on the gases of blood,^ contains in 100 vols, from 19
to 25 vols, of oxygen, computed at 0° C, and 760 mm. Hg.
The amount of oxygen in the arterial blood of herbivora (sheep,
rabbit) is found to be smaller, viz., from 10 to 15 volumes
per cent.^

This amount of oxygen is far too large to remain merely
absorbed in the blood. One hundred volumes of water absorb
4 vols, of oxygen at 0° C. from an atmosphere of pure oxygen ;
and from the ordinary atmosphere, in which the tension of the
oxygen is five times less, it would therefore absorb less than
1 vol. of oxygen, and at the temperature of the body even still
less. Watery solutions also absorb less than pure water ;
a large proportion of the 10 to 25 vols, of oxygen in arterial

^ Pflüger, Centralhl. f. d. med. Wissensch., p. 722 : 1867 ; and Pfliiger's Arch.,
vol. i. p. 288: 1868. The previous analyses are also given here.

2 Sczelkow, Du Bois' Arch., p. 516: 1864; Preyer, Wiener med. Jahrher.,
p. 145 : 1865 ; Fr. Walter, Arch. f. exper. Path. u. Pharm., vol, vii. p. 148 : 1877.

GASES OF THE BLOOD AND RESPIRATION 239

blood must therefore be chemically combined.^ We know,
in fact, that 'it is the hemoglobin which serves for this loose
combination.^ This is shown by the fact that a pure solution
of hemoglobin, containing the same amount of hemoglobin
as the blood, combines with as much oxygen and gives off
as much in vacuo as the blood does. The larger proportion
of oxygen in dog's blood than in the blood of herbivora
is explained by the fact that the former is endowed with
a larger amount of blood-corpuscles and of hemoglobin. The
amount of hemoglobin, and therefore of oxygen, is much less
considerable in the blood of cold-blooded than in that of warm-
blooded animals.

The compound of oxygen with hemoglobin, or ' oxyhemo-
globm,' is well known to be of a lighter color than reduced
hemoglobin, and shows different lines of absorption in the
spectrum. The bright red coloring of arterial, and the dark
red tint of venous, blood depend upon this fact.

If oxygen is chemically combined with hemoglobin, we
should expect them to be combined in molecular proportions.
It would be interesting to ascertain how many atoms of oxygen
go to one atom of iron. The analyses made up to the present
time are not exact enough for this purpose ; they show how-
ever that about 2 or 3 atoms of oxygen correspond to 1 atom
of iron.-^ The figures, so far, only demonstrate that there is at
least four times as much oxygen taken up in the transition of
hemoglobin into oxyhemoglobin, as there is in the transition
from suboxid to oxid of iron, or from ferrocyanid to ferricy-
anid of potassium. Possibly the sulphur of the hemoglobin
also plays a part in the loose oxygen compound, and a similar
part may be assigned to the sulphur atoms in all proteids.
It is noteworthy that, according to previous analyses, the
animals that require more oxygen (compare Lecture XIII.)
have likewise more sulphur in their hemoglobin. Four atoms
of sulphur in the hemoglobin of the horse, six in that of the
dog, and nine in that of the hen, go to two atoms of iron.* Is
this an accidental correspondence?

^Liebig iu his Ann. d. Chem. u. Pharm., vol. Ixxix. p. 112: 1851; Lothar
Meyer, "Die Gase des Blutes," Dissert.: Göttingen, 1857; also Henle and
Pfeufer's Zeitschr. f. rat. Med., N. F., vol. xviii. p. 256 : 1857.

2 Hoppe-Seyler, Arch. f. path. Anat., vol. xxix. p. 598: 1864; and Med.
chem. Unters., p. 191 : 1867.

^ Hiifner, Zeitschr. f. physiol. Chem., vol. i. pp. 317, 386 : 1877 ; vol. iii. p. 1 :
1880. John Marshall, Zeitschr. /. physiol. Chem., vol. vii. p. 81 : 1883. Hiifner,
Zeitschr. f. physiol. Chem., vol. viii. p. 358: 1884. The previous determinations
are quoted here. Compare also Hoppe-Seyler, ibid., vol. xiii. p. 477 : 1889. G.
Hiifner, Du Bois' Arch., p. 130 : 1894. ■

*A. Jaquet, " Beitr. zur Kenntniss des Blutfarbstoffes," Dissert.: Basel,
1889.

240 LECTURE XVII

The oxygen in loose combination with the hemoglobin may-
be displaced by an equal volume of carbonic oxid/ or of nitric
oxid/ a fact which likewise speaks for the chemical union of
the oxygen.

It may be objected that the oxyhemoglobin combination
could hardly be destroyed by a mere vacuum, if it were really
a chemical compound. But, as a matter of fact, it is not
the vacuum which splits up the oxyhemoglobin, but the heat.
A solution of oxyhemoglobin may be evaporated to dryness
at a very low temperature, i. e., below 0° C. in vacuo; the
oxyhemoglobin crystals are not affected. The higher the tem-
perature, the greater must be the pressure of oxygen in order
to counterbalance the dissociating force of heat. The affinity
of a substance increases in proportion to the number of atoms
which cooperate in the attraction, or in proportion to the
number of atoms in the unit of volume. This phenomenon
is called the influence of mass.^ Two antagonistic forces
are at work in the formation and decomposition of oxyhemo-
globin : heat endeavors to separate, chemical affinity seeks to
unite. Affinity increases with the influence of mass, with the
density, with the partial pressure of the oxygen. The vacuum
therefore acts only by reducing the mass-influence of the oxy-
gen to a minimum, and thus enabling the antagonistic heat to
attain supremacy.

1 may here remind my readers of an analogous phenomenon
well known in inorganic chemistry. When chalk is burnt, the
carbonic acid is separated from the lime by heat. But this
separation does not take place in an atmosphere of pure
carbonic acid ; on the contrary, quicklime unites with COg at a
high temperature, if the partial pressure of the carbonic acid
be sufficient. If the carbonate of lime is to be rapidly converted
into quicklime, a stream of another gas must be passed over it,
so as to reduce the partial pressure of the carbonic acid. The
same thing takes place in the relation of hemoglobin to oxygen.

^ Cl. Bernard, " Lejons sur les effets des substances toxiques," &c. : Paris,
1857 ; Hoppe-Seyler, Virchow's Arch., vol. xi. p. 288 : 1857 ; and vol. xxix. pp.
233,597: 1863; Lothar Meyer, "De Sanguine oxydocarbonico infecto," Dissert.
Vratislavise : 1858; Hoppe-Seyler, Med. chem. Unters., p. 201 : 1867; Zeitschr. f.
physiol. Chem., vol. 1, p. 131: 1877; John Marshall, Zeitschr. f. physiol. Chem.,
vol. vii. p. 81: 1883; R. Kiilz, ibid., p. 384; G. Hiifner, Journ. f.prakt. Chem.,
N. F., vol. xxx. p. 67 : 1884.

2 L. Hermann, Du Bois' Arch., p. 469 : 1865 ; Hoppe-Seyler, Med. chem.
Unters., p. 204: 18G7 ; W. Preyer, "Die Blutkrystalle," p. 144: Jena, 1871;
Podolinski, Pfliiger's Arch., vol. vi. p. 553 : 1872.

^ For the explanation of" the phenomenon of the influence of mass, afforded
by the mechanical theory of heat, see Lothar Meyer, "Die modernen Theorien
der Chemie," 5th edit., p. 479: Breslau, 1884, or "Lehrbuch der allgemeinen
Chemie," by W. Ostwald, vol. ii. part ii. : Leipzig, 1887.

GASES OF THE BLOOD AND RESPIRATION 241

In the alveoli of the lungs, where the partial pressure of the
oxygen is considerable, the hemoglobin is completely or very
nearly saturated with oxygen. In the capillaries of the tissues,
where the oxygen that has been simply absorbed diffuses itself
or enters into combination with reducing substances, so that
the partial pressure diminishes, a portion of the combined
oxygen is at once set free by the liberating force of heat, and
the partial pressure of the oxygen rises again till it balances
the effect of the heat. In this way, the red blood-corpuscle is
always surrounded by oxygen under a definite pressure.

This arrangement serves a double purpose. Firstly, there
is far more oxygen brought to each tissue by the blood-current
in a definite period than would be possible by simple absorption
of the oxygen without chemical combination. The processes
of oxidation might go on much more rapidly, and yet there
would not be a scarcity of oxygen. The amount of oxygen
in the plasma is very little less when the oxygen is lavishly
used up than when it is economically expended. The store
of oxygen in the capillaries is never exhausted under normal
conditions. In venous blood, at least 5 per cent, by vol-
ume of oxygen is always found, and generally far more.
Only in asphyxial blood does the oxygen almost entirely dis-
appear.^

Secondly, the chemical combination of oxygen offers the
great advantage that the intensity of the processes of oxidation
is, to a great extent, independent of the partial pressure of the
oxygen in the surrounding media. Direct experiment has
shown that the partial pressure of the oxygen in the surround-
ing atmosphere may increase threefold or diminish to one-half
without any disturbance being manifested in the breathing of a
mammal.^

When the partial pressure is reduced still further, the fre-
quency of respiration increases ; and when it sinks to 3.5 per
cent, of an atmosphere, the animals die.^

Fraenkel and Geppert* allowed dogs to breathe rarefied
atmospheric air, and analyzed the gases of their arterial blood.

^ N. Stroganow, Pfliiger's Arch., vol. xii. j). 22 : 1876. The previous experi-
ments on the blood of asphyxiated animals are quoted here.

^"VVilh. Müller, Ann. d. Chem. u. Fharm., yoI. cviii. p. 257: 1858. Paul
Bert, "La pression barometrique ": Paris, 1878. A. Fraenkel and J. Geppert,
" Ueber die Wirkungen der verdünnten Luft auf den Organismus": Berlin,
Hirschwald, 1883. Vide also L. de Saint Martin, Comiot. rend., vol. xcviii. p.
241 : 1884 ; and S. Lukjanow, Zeitschr. f. physiol. Chem., vol. viii. p. 313 : 1884.

^N. Stroganow, Pflüger's Arch.; vol. xii. p. 31 : 1876. Au account of former
work is given here.

* Fraenkel and Geppert, loc. cit., p. 47. The experiments similar to those of
Paul Bert are also critically discussed here.

16

242 LECTURE XVII

They found that when the pressure of air sank to 410 mm. Hg.
the normal amount of oxygen was retained in the arterial
blood. If the pressure of air sank to between 378 and 365
mm. Hg., or to half an atmosphere, the amount of oxygen in
the arterial blood was somewhat diminished. But it was not
until the atmospheric pressure sank below 300 mm. that a con-
siderable decrease of oxygen was observed.

The partial pressure of oxygen might a priori have been
thought to exercise a much slighter influence than we have
shown it to possess ; for, according to the experiments of
Worm Müller/ the blood outside the body becomes almost com-
pletely saturated with oxygen on being shaken with atmospheric
air of only 75 mm. Hg. But these experiments were carried
out at the temperature of the room. At the temperature of the
body, decomposition of the oxyhemoglobin begins at a higher
partial pressure, as Paul Bert ^ and Fraeukel and Geppert ^ have
shown. And besides it must be remembered that, in the lungs,
oxygen at a low tension cannot be diffused through the walls
of the alveoli rapidly enough to saturate each blood-corpuscle
during its short transit through the capillaries.

The experience obtained in mountain and balloon ascents is
in complete harmony with the results of the experiments on
animals.^ Real dyspnea does not begin till a height of 5000
meters is reached, which corresponds to a mercurial pressure of
400 mms. Human beings and animals live as well on the high
plateaus of the Andes at 4000 meters above the level of the sea
as on the sea-coast.

The poisonous influence of carbonic oxid depends perhaps
only on the displacement of the oxygen. J. Haldane^ found
that the poisonous effect was smaller, the greater the partial
pressure of the oxygen. If the oxygen pressure amounted to
two atmospheres, the carbonic oxid pressure could be raised to
as much as one atmosphere, without any inconvenience to the
animal. Animals devoid of hemoglobin (e. g., black-beetles),
are not influenced in the slightest degree by the presence of
carbonic oxid in the air.

We must now ask in what organs and tissues of our bodies
the oxygen gets used up.

Lavoisier, who first recognized the importance of oxygen in
vital processes, thought that combustion occurred exclusively

* Worm Müller, Bcr. d. sacks. Ges., vol. xxii. p. 351 : 1870.
2 Paul Bert, " La pression barometrique," p. 691.

' Fraenkel and Geppert, " Ueber die Wirkungen der verdünnten Luft auf
den Organismus," p. 57.

* Paul Bert, loc. eit., gives an interesting account of these experiences.
^ J. Haldane, Journ. of Physiol., vol. xviii. p. 201 : 1895.

GASES OF THE BLOOD AXD RESPIRATION 243

in the lung. It was not until Magnus ^ had analyzed the gases
of the blooJ that it was proved that oxygen passes on to the
capillaries, and there partially disappears. But the question as
to whether the processes of oxidation are completed only within
the closed blood-current, or whether free oxygen is diffused
through the walls of the capillaries into the tissues, has not yet
been decided.

The former theory, i. e., that the oxygen is consumed within
the blood-vessels, has found supporters even up to the present
time. The most obvious objection to it is that kinetic energy
is liberated in the tissues, and particularly in the muscles, and
that the most fertile source of energy lies in the affinity of
oxygen for the substances of nutrition. But, on the other hand,
we know that there is stored up in food a considerable amount
of chemical potential energy, which is converted into kinetic
energy by the mere decomposition of the food-stuffs, without
any oxidation taking place (compare Lectures X. and XXIII.).
The amount of this potential energy is not exactly known ; it
must be admitted that it may be sufficient to perform the work
of muscle, and that the products of decomposition thus formed
may diffuse into the capillaries, to be there oxidized, and then
to serve as sources of bodily heat.

This view appeared to receive confirmation from the follow-
ing experiment of Ludwig and Alexander Schmidt.^ It has
already been mentioned that the blood of animals which have
died from suffocation contains only traces of oxygen, and some-
times none at all. If oxygen be added to such blood outside
the body, a part of the oxygen thus artificially introduced
rapidly disappears, and the carbonic acid is increased. The
blood from asphyxiated animals contains substances that are
readily oxidized. The blood of other animals also combines with
some oxygen outside the body,^ but the oxygen absorbed is much
less in amount and disappears much more slowly than in the case
of the blood from asphyxiated animals.* Ludwig and Alexander
Schmidt explain these facts thus : Under normal conditions,
readily oxidized compounds are continually finding their way
from the tissues into the capillaries, where they are immedi-
ately decomposed by the free oxygen, so that they cannot be
traced in normal blood. In asphyxiated animals, on the other

^ G. Magnus, Ann. d. Physik, vol. xl. p. 583 : 1837 ; and vol. Ixiv. p. 177 :
1845.

^ Alex. Schmidt, Ber. über die Verhandl. der sacks. Gcs. der Wissensch. zu
Leipzig, Math. phys. Classe, vol. xix. p. 99 : 1867. Vide also N. Stroganow,
Pfliiger's Arch., vol. xii. p. 41 : 1876.

3 Pflüger, Centralbl.f. d. raed. Wissensch., pp. 321, 722: 1867.

4 Alex. Schmidt, loc. cit., p. 108.

244 LECTURE XVII

hand, tlney remain stored up in the blood in consequence of the
absence of oxygen. According to the laws which govern the
diffusion of gases, we should expect to find that the oxygen in
the blood would penetrate the liquids of all the tissues. It is
however conceivable that the oxygen may be hindered from
doing so by the reducing substances which, flowing unintermit-
tently from the tissues into the blood, meet the oxygen on its
way and prevent its advance beyond the capillary wall.

The opposite view, that oxidation takes place in the other
tissues as well,^ rests upon the following facts of comparative
physiology.^ It is well known that nearly all the lower animals
which have no blood, die at once without oxygen, and that this
source of energy is indispensable to every cell.^ The vegetable
cell has likewise essentially the same metabolism, and cannot
live without free oxygen. The higher animals, with a diiferen-
tiated system of blood-vessels, require oxygen in the first stages
of existence, even before the formation of blood-corpuscles, as
the respiration of a bird's egg shows.*

Nevertheless we cannot admit that these facts afford in-
dubitable proof of respiration in the tissues of the higher
animals when fully developed ; for the essence of the higher
organization consists in the fact that there is, synchronous with
the differentiation of the tissues and organs, a division of
labor. It is quite conceivable that decomposition and oxida-
tion may take place in the same cell among the lower animals
only, and that in the more highly organized ones the duty of
oxidation is exclusively relegated to the blood, the processes of
decomposition going on in the other tissues.

But it can be shown that oxidation also occurs in the
tissues of insects, which possess a vascular system although
not so highly developed as the vertebrata. This is proved by
the fact that the finest branches of a trachea run down as far
as the individual cells of the tissue.^ The observations made

^ The first decided advocate of this view was, so far as I know, Moritz
Traube, Virchow's Arch., vol. xxi.p. 386 : 1861.

2 Pflüger, in his Arch., vol. x. p. 270 : 1875.

^ It is still a matter of controversy whether certain organisms of the lowest
kind — yeast-cells, certain bacteria — can live entirely without free oxygen, " anae-
robic." It appears however that this question may now be answered in the
affirmative. VideJ. W. Gunning, Journ.f.prakt. Chem., vol. xvi. p. 314 : 1877 ;
vol. xvii. p. 266 : 1878; and vol. xx. p. 434: 1879; Nencki, Jour^i. f. x>rakt.
Chem., vol. xix. p. 337 : 1879 ; Br. Lachowicz und Nencki, Pfliiger's Arch., vol.
xxxiii. p. 1 : 1883 ; and Nencki, Pfliiger's Arch., vol. xxxiii. p. 10 : 1883. Com-
pare also G. Bunge, "lieber das Sauerstoffbedürfniss der Darmparasiten,"
Zeitschr. f. physiol. Chem., vol. viii. p. 48 : 1883.

* J. JBaumgärtner, " Der Athmungsprocess im Ei," Freiburg i. B. : 1861.

5 Kupflfer, "Beiträge zur Anatomie und Physiologie, als Festgabe C. Lud-
wig gewidmet von seinen Schülern," p. 67 : 1875 ; Fiukler, Pflüger's Arch., vol.
X. p. 273 : i875.

GASES OF THE BLOOD AND EESPIHATION 245

by Max Schultze ^ on the Lampyris splendidula are particularly
conclusive, . In the glow organs of this animal certain cells
adhere to the tracheal endings, " like the flowerets of an um-
belliferous plant." These cells, as well as the tracheal endings,
stain a deep black with osmic acid, owing to the separation of
the metallic osmium ; consequently there is present in these
cells a substance with a powerful attraction for oxygen. It
may therefore readily be supposed that this substance, by com-
bining with the oxygen introduced through the tracheae, brings
about the development of light. The illuminating power of the
paired glow organs continues after they have been isolated, and
even after a microscopic section has been made. Max Schultze
observed under the microscope that " with the rhythmic increase
and diminution of the light, which these animals generally ex-
hibit distinctly, the first appearance of the light is characterized
by minute coruscations in the glow organ, which correspond in
number and arrangement to the terminal cells of the tracheae."
When the oxygen is withdrawn, the illuminating power ceases.^
Max Schultze also remarks that the tracheal terminations in
other organs, as well as those in the glow organs, are rapidly
stained black if the animals be placed alive in osmic acid.

In view of these facts, it cannot be doubted that free
oxygen is used up in the tissues of insects. A critical observer
will nevertheless hesitate before applying these results to the
vertebrata. In the case of the latter, it is only in the placenta
of mammals and in the salivary glands that the oxygen has
been definitely proved to make its way out through the capillary
walls.

The blood of the umbilical vein is of a brighter red than
that of the umbilical arteries, and oxyhemoglobin can be
traced in the former by the spectroscope.^ It is well known
that the blood-vessels of the mother and of the embryo do not
communicate in the placenta ; they form two separate capillary
systems. The oxygen must therefore be first diffused through
the capillary walls of the mother's vascular system, and then
through those of the fetus, before reaching the blood of the
latter.

^ Max Schultze, Arch. f. mik. Anat., vol. i. p. 124: 1865.

2 An interesting account of the numerous observations on the illuminating
power of various animals, and its dependence on the presence of oxygen, is
given by Milne Ed\yards, " Lecons sur la physiologie et I'anatomie comparee,"
vol. viii. pp. 93-120: Paris, 1863; and by Pflüger, in his Arch. f. d. ges. Phys.,
vol. X. pp. 275-300 : 1875. For the experiments on the chemical side, vide
Radziszewski, Ber. d. deutsch, ehem. Ges., vol. xvi. p. 597 : 1883, where the pre-
vious writings on this siibject are quoted.

3 Zweifel, Arch. f. Gynäkologie, vol. ix. p. 291 : 1876 ; Zuntz, Pflüger's Arch.,
vol. xiv. p. 605 : 1877.

246 LECTURE XVII

That oxygen passes through the capillary wall in the
salivary glands is apparent, for the simple reason that the
saliva contains free oxygen. So large an amount of oxygen
passes out of the blood therefore, that the cells of the
glandular tissue cannot consume it, and the excess escapes
with the secretion. Pflüger ^ ascertained the presence of
absorbed oxygen in the submaxillary secretion with the aid
of the gas-pump ; he found that it amounted to from 0.4 to 0.6
per cent, of the volume of the saliva. This fact was confirmed
by Hoppe-Seyler, who used a very sensitive test for free oxygen,
a hemoglobin solution which, on coming into contact with
fluids containing oxygen, at once shows the absorption-bands
characteristic of oJcyhemoglobin.^ Hoppe-Seyler found that
the secretions of both the submaxillary and of the parotid
contained oxygen.

Hoppe-Seyler, on the other hand, could detect no trace of
oxygen in the bile and urine with the aid of his sensitive
reagent.^ Nor has any free oxygen been found definitely in
lymph. Free oxygen has therefore not been proved with
certainty to exist in most organs of vertebrata.

Pflüger and Oertmann ^ founded their proof on the follow-
ing experiment. They showed that a frog, in whose vascular
system a solution of common salt circulated instead of blood,
used up as much oxygen, and produced as much carbonic
acid in an atmosphere of pure oxygen, as a normal frog would
do. A fine cannula is tied into the central end of the abdominal
vein^ of a frog, and a 0.75 per cent, solution of salt injected,
until increasingly diluted blood and finally pure salt solution
flows from the peripheral opening of the vein.^ Frogs thus
treated generally lived one or two days. If such frogs were
introduced into an atmosphere of pure oxygen, they consumed
as much oxygen and developed as much carbonic acid in from

^ Pflüger, in his Arch., vol. i. p. 686 : 1868.

2 Hoppe-Seyler, Zeitschr. f. physiol. Chcm., vol. i. p. 135 : 1877. The appa-
ratus used by him to admit of the action of the hemoglobin solution on the
secretion, without coming in contact with the atmospheric air, is described
here.

3 The traces of oxygen which Pflüger {Arch., vol. ii. p. 156 : 1869) found in
the gases that were pumped out of the urine, milk, and bile, were probably only
due to the unavoidable contamination with atmospheric air.

* E. Oertmann, Pflüger's Arch., vol. xv. p. 381 : 1877.

^ The work of Alex. Ecker, " Die Anatomie des .Frosches," Vieweg and Sohn,
1864-1882 [translated into English by G. Haslam, Foreign Biological Memoirs ;
Clarendon Press, Oxford] , will serve to acquaint the reader with the anatomy of
the frog. It is plentifully supplied with illustrations, and contains a complete
account of the literature of the subject. [A new edition of this work, edited by
Gaupp, is now appearing.]

^ This method of obtaining frogs free from blood was first introduced by
Cohnheim (Virchow's Arch., vol. xlv. p. 333 : 1869).

GASES OF T:IE BLOOD AND RESPIRATION 247

ten to twenty hours as a normal animal. Oertmann concluded
from this experiment that oxidation proceeded only in the
tissues, because they alone used up as much oxygen as the
tissues and the blood together. But this is not a necessary
conclusion. The facts may equally well be interpreted in
support of the opposite view. It might be argued in this
case that, again, only processes of decomposition had taken
place in the tissues of the ' salt-frog ' ; that the products of
decomposition had been diffused throu:gh the capillary wall
into the solution of salt containing oxygen, and had been
oxidized within the closed vascular system. The partial pres-
sure of the oxygen, being five times greater than normal, had
made up for the want of hemoglobin.

In conclusion, we must however mention the following
very interesting fact, ascertained by Ludwig and his pupils.
Afonassiew ^ found that the reducing substances of the blood
from asphyxiated animals occur only in the blood-corpuscles,
and not in the serum ; and Tschiriew ^ found that the lymph
of such animals is also free from these substances.

It thus appears that the blood is only concerned in proc-
esses of oxidation in so far as living cells are suspended in
it ; that all oxidations in our body proceed exclusively in the
active elements of the tissues — in the cells and the products of
the metamorphosis, but not in the fluids surrounding them.

This theory is rendered so probable by all the facts and
analogies of the case that it is accepted by every physiologist.

We have now to consider how the rapid and complete
oxidation of the food-stuflPs in our tissues is to be explained.
The food eaten at the most abundant meal becomes, before six
hours have elapsed, nearly all converted by oxidation into the
end-products, carbonic acid, water, and urea ; whereas proteid,
fats, and carbohydrates are not affected by oxygen external to,
and at the temperature of, the body. Other conditions favor-
able to oxidation must therefore be present in the body.

The most obvious suggestion was that the alkalinity of the
blood, of lymph, and of protoplasm had something to do with
the matter. It is known that the oxidation of organic sub-
stances proceeds more rapidly in an alkaline than in a neutral
or acid solution. I may remind my readers of the behavior
of pyrogallol — and, indeed, of all polyatomic phenols — of the
leuco-compounds of numerous dye-stuffs, of grape-sugar, &c.
The latter, dissolved in soda, absorbs oxygen rapidly at the
temperature of the body. But it must be remembered that

1 N. Afonassiew, Ber. d. sacks. Ges. d. Wissensch., vol. xxiv. p. 253 : 1872.
^ S. Tschiriew, ibid,, vol. xxvi. p. 116 : 1874.

248 LECTUEE XVII

for this purpose free alkali is necessary, whereas our tissues
contain only carbonates or possibly bicarbonates of the alkalies,
since free carbonic acid penetrates all tissue elements.

Xencki and Sieber ^ have indeed shown that dilute solutions
of sodium carbonate and grape-sugar or proteid also absorb
oxygen. But the amount absorbed is small, and the absorp-
tion takes place very slowly. Schmiedeberg- showed that
benzylalcohol and salicylaldehyde are not appreciably oxidized
by the atmospheric air in the presence of water. If these
substances were brought into contact with blood or dilute
sodium carbonate solution instead of water, a small trace of
the benzylalcohol was oxidized to benzoic acid. The salicyl-
aldehyde was also under these circumstances imchanged. If
however these substances were passed with oxygenated defi-
brinated blood through the kidneys or lungs of dogs or pigs, a
considerable amount of both was oxidized to benzoic acid and
salicylic acid respectively. The same result was obtained when
watery extracts of these organs mixed with salicylaldehyde
were exposed in thin layers to the action of the atmospheric
oxvgeu. The quantity of salicylic acid formed however was
only small. Boiling destroyed the oxidizing action of the
extracts.^ It seems to me that we cannot at present draw any
conclusion as to the behavior of the food-stuffs in our body
from a consideration of the changes undergone by such easily
oxidizable substances.

In order to explain the rapid oxidation of fox)d-stuffs in
the body, recourse has been had to the assumption that a
portion of the inspired oxygen is converted in our tissues into
that powerful oxidizing modification termed ozone. Even
Schönbein,* the discoverer of ozone, mentioned this hypothesis.
What therefore is known concerning ozone ?

If induced currents be allowed to pass through oxygen,
condensation takes place, and the oxygen now contains ozone.
A small part only of the oxygen — at most 5 per cent. — is
converted into ozone. The volume of the ozone amounts to
only two-thirds of that of the oxygen from which it was
formed. Soret^ has ascertained this in the following manner.
Oil of turpentine absorbs only the ozone from oxygen con-

^ Nencki and Sieber, Journ. f. prakt. Chem., vol. xxvi. p. 1 : 1882.

2 Schmiedeberg, Arch. f. exper. Path. u. Pharm., vol. xiv. pp. 288 and 379 :
1881. Compare also Salkowski, Zeitschr. f. physiol. Chem., vol. vii. p. 155 : 1882 ;
and Centralhl. f. d. med. Wissensch., p. 849 : 1892.

3 A. Jaquet, Arch.f. exper. Path. u. Pharm., vol. xxix. p. 386 : 1892.

4 Schöllbein, Poggendorff's Annul., vol. Ixv. p. 171 : 1845.

5 Soret, Ann. Chem. Pharm., vol. cxxvii. p. 38 : 1863 ; vol. cxxx. p. 95 : 1863 ;
Suppl. V. p. 148: 1867; Compt. rend., vol. Ivii. p. 604: 1863.

GASES OF THE BLOOD AND RESPIRATION 249

taining ozone, the amount of which is ascertained from the
diminution of volume. If a sample of this oxygen con-
taining ozone be heated, the ozone is destroyed, and the
volume increases. This increase of volume is always half as
much as the diminution of volume by absorption. Therefore
on heatino- oue volume of ozone becomes one and a half vol-
umes of oxygen, two volumes of ozone become three volumes
of oxygen. It follows, both from this fact and from Avogadro's
hypothesis (that equal volumes of gas contain an equal number
of molecules), that ozone contains three atoms of oxygen in
each molecule. Three oxygen molecules of two atoms each
have produced two ozone molecules of three atoms. We may
imagine that the two atoms in the oxygen molecule become
separated from each other by the kinetic energy of the electric
current, and each of them attaches itself loosely to an intact
oxygen molecule. This third oxygen atom, thus loosely com-
bined, has a strong affinity for oxidizable substances.^ In fact,
in oxidation by ozone, never more than a third of the weight
of the ozone enters into combination, and no diminution of
volume of the oxygen containing ozone occurs.

This theory is also strictly in accordance with the fact that
even at a low temperature ozone oxidizes substances which
ordinary oxygen does not attack except at a high temperature.
In the case of ordinary oxygen, the atoms must first be sepa-
rated by the kinetic energy of heat. With ozone, this was
done beforehand by the kinetic energy of the electric current.

It is well known that ozone also arises as a by-product
during the slow oxidation of phosphorus. An idea can be
formed of this process by the following explanation : during
the slow oxidation only one of the two atoms of the oxygen
molecule enters into combination with the phosphorus ; and
the other attaches itself to an undecomposed molecule of
oxygen.

It may be seen from the above that the third oxygen atom
in the ozone molecule, which causes the powerful oxidations,
can have no other properties than that of nascent oxygen. In
fact it can be proved that wherever slow oxidation occurs,
a part of the oxygen acquires 'active qualities,' and acts in
the same way as the ozone formed during slow oxidation of
phosphorus. We cannot expect that ozone should be formed
when oxidizable substances are present, as these fix the nascent
oxygen atom before it can unite with a molecule of oxygen
to form one of ozone.

It is with such conditions that we have to deal in the
1 Clausius, PoggendorfPs Annul., vol. cxxi. p. 250: 1864.

250 LECTURE XVII

organism, and for these reasons ozone is never formed in the
body, though we meet with energetic processes of oxidation.
Ä priori there is no point in trying to trace ozoüe in the
animal body. Many liters of oxygen containing ozone might
be introduced into the blood, and yet we could not pump out
a single molecule of ozone.

The following experiments show that some of the oxygen
atoms attain ' active properties ' during slow oxidation by
ordinary oxygen.

If ammonia be present during the oxidation of pyrogallol
in alkaline solution by atmospheric oxygen, it becomes oxidized
into nitrous acid.^ Peroxid of hydrogen is formed during the
oxidation of benzaldehyde.^ If metallic sodium be oxidized by
air in the presence of petroleum-ether, the hydrocarbons, which
compose the latter, are converted into the corresponding alco-
hols and acids. ^

It is well known that benzol cannot be converted into
phenol by the action of the ordinary oxidizing agents, but that
it can by means of ozone.^ It can however be done by ordinary
oxygen, if ferrous or cuprous sulphate are present.^ We must
imagine that the suboxid fixes one of the two oxygen atoms,
while the one set free oxidizes the benzol.

Palladium-hydrogen has the same eifect as the suboxid
of iron or copper. Graham has shown that, if palladium foil
be employed as the negative electrode in the electrolysis of
water, no hydrogen is developed at this pole. The hydrogen
unites with the palladium. The metal takes up nine hundred
times its volume of the gas, while at the same time its own
volume increases. This combination gradually liberates a part
of the hydrogen ; it behaves like nascent hydrogen. When
therefore the palladium-hydrogen comes in contact with atmos-
pheric oxygen, the hydrogen becomes oxidized, a part of the
oxygen is rendered ' active,^ and if benzol is present, it is con-
verted into phenol, as it would be by ozone.*^

^ This experiment of Baumann's was communicated by Hoppe-Seyler, Ber. d.
deutsch, ehem. Ges., vol. xii. p. 1553 : 1879.

2 Radenowitsch, Ber. cl. deutsch, ehem. Ges., p. 1208: 1873.

3 Hoppe-Seyler, Ber. d. deutsch, ehem. Ges., vol. xii. pp. 1553, 1554: 1879.

* Nencki and P. Giacosa, Zeitschr. f. physiol. Chem., vol. iv. p. 339 : 1880.
Leeds {Ber. d. deutsch, ehem. Ges., vol. xiv. p. 975: 1881) could not confirm
this statement; in his experiments, the benzol was oxidized into carbonic acid,
oxalic acid, formic acid, and acetic acid. But the conditions under which the
experiments were carried out differed in the two cases.

5 Nencki and Sieber, Journ. f. prakt. Chem., vol. xxvi. pp. 24, 25 : 1882.

"Hoppe-Seyler, Zeitschr. f. physiol. Chem., vol. ii. p. 22: 1878; and vol. x.
p. 35: 1886; Ber. d. deutsch, chem. Ges., vol. xii. p. 1551: 1879; and vol. xvi.
pp. 117, 1917: 1883. Compare also Leeds, ibid., vol. xiv., p. 975: 1881; and
Moritz Traube, ibid., vol. xv. p. 659 ; vol. xvi. pp. 123, 1201 : 1883 ; and vol.

GASES OF THE BLOOD AND RESPIRATION 251

Nascent oxygen, as might ä p)-iori be assumed, acts as a
more energetic oxidizer even than ozone. Ozone, for instance,
cannot oxidize free nitrogen, any more than it can carbonic
oxid. The nascent oxygen, on the other hand, arising from
the action of palladium-hydrogen on ordinary oxygen, oxidizes
free nitrogen to nitrous acid, and carbonic oxid to carbonic
acid.^

If benzol is introduced into our body, it mostly reappears in
the urine as phenol.^ We may therefore assume that reducing
substances also occur in our tissues, and play a part similar to
that taken by them in the above-mentioned experiments with
palladium-hydrogen or the metallic suboxids. I have already
stated (pp. 244, 247) that such reducing substances are
found in the blood of asphyxiated animals ; and they are
moreover to be met with in all tissues. Ehrlich^ showed
that blue coloring matters, as alizarin blue, indopheuol blue,
lose their color in the tissues of living animals, and that the
tissues turn blue again on contact with the air. We may
assume that these readily oxidizable reducing substances arise
by fermentative action from the food-stuffs along with other
products of decomposition that are not readily oxidizable.
But as soon as the readily oxidizable substances become oxi-
dized by the inspired oxygen, a part of the oxygen attains
' active ' properties, and oxidizes those which are not readily
oxidizable.

That reducing substances do arise by fermentative action
in the cells, may be seen in butyric acid fermeutation. The
hydrogen liberated in this process becomes oxidized by ordi-
nary oxygen to form water. Hydrogen never proceeds from
fermentative processes, if there has been a sufficient access of
air.* This explains the absence of hydrogen in the atmosphere
in spite of the extensive processes of fermentation going on all
over the surface of the earth.

The formation of saltpeter shows us moreover in a very

xviii. pp. 1877-1900 : 1885 ; also Baumann and Preusse, Zeitschr. f. pliysiol.
Chem., vol. iv. p. 453: 1880; Nencki, Journ.f. prakt. Chem., vol. xxiii. p. 87:
1880; and Baumann, Zeitschr. f. physiol. Chem., vol. v. p. 244: 1881; and Ber.
d. deutsch, chem. Ges., vol. xvi. p. 2146: 1883. Moritz Traube has raised objec-
tions of considerable weight to the theory that oxygen is rendered active by
reducing substances. I have given this theory in my account, but must expressly
state that it may involve hypotheses and analogical inductions from' facts which
possibly are capable of a diflerent interpretation. The reader may form his own
judgment from the interesting and instructive works quoted above.

^ Baumann, Zeitschr. f. physiol. Chem., vol. v. p. 244 : 1881.

2 Schnitzen and Naunyn, Reichert and Du Bois' Arch., p. 349 : 1867.

^P. Ehrlich, "Das Sauerstoif bedürfniss des Organismus": Berlin, 1885.

* Hoppe-Seyler, Pflüger's Arch., vol. xii. p. 16: 1876; Zeitschr. f. physiol.
Chem., vol. viii. p. 214 : 1884.

252 LECTURE XVII

remarkable way, how processes of oxidation may go on in a
most energetic manner at the same time as processes of decom-
position produced by putrefactive organisms. Nitrogen, which
has but a slight affinity for oxygen, is raised to the highest
stage of oxidation by the oxygen-atoms which are liberated
during the oxidation of the reducing putrefactive products
and which oxidize the ammonia resulting from the decom-
position. Recent researches have proved that certain living
putrefactive organisms take an active part in the formation of
saltpeter.^

It is probable that all the cells in our bodies have the same
power as these unicellular beings, these organisms associated
with fermentation and decomposition. But we need not
assume that the reducing substances formed by them are
always the same. Hoppe-Seyler ^ is of opinion that hydrogen
is liberated in the tissues of the animal body just as it is in
certain unicellular putrefactive organisms. That the hydrogen
cannot be detected m the tissues is no argument against this
view. But, however this may be, the nascent hydrogen need
not be the only reducing substance by means of which active
oxygen arises in our tissues. These reducing substances may
be of very different kinds in the various cells ; they may even
be numerous and changeable in one and the same cell, accord-
ing to the functions it is required to perform at a given
moment.^

The ' spontaneous combustion ' of hay affords a striking
example of the activity which oxidation of the organic food-
stuffs may attain when decomposition of the latter has pre-
viously set in. If hay is stacked before it is thoroughly dry,
decomposition begins in the middle of the damp stack through
the action of organized or unorganized ferments. As all
decomposition by ferments is accompanied by hydration,
drying is the best means of preventing it. Heat is liberated
by the decomposition, and proportionately with the rise in
temperature in the middle of the stack an ever-increasing
accumulation of easily oxidizable decomposition-products is
formed. If the hay be now disturbed so that there is free

^ Muntz et Schlösing, Compt. rend., vol. Ixxxiv. p. 301 : 1877 ; vol. Ixxxv. p.
1018 : 1877 ; vol. Ixxxix. p. 891 : 1879 ; Warrington, Chem. News, vol. xxxvi. p.
263: 1877; vol. xxxix. p. 224: 1879; S. Winogradsky, Compt. rend., vol. ex.
p. 1013 : 1890.

2 Hoppe-Seyler, Pfliiger's Arch., vol. xii. p. 16: 1876. Compare Nencki,
Journ. f. prakt. Chem., vol. xxiii. p. 87 : 1880 ; and Baumann, Zeitschr.f. physiol.
Chem., vol. v. p. 244 : 1881.

^ Compare Br. Radziszewski, " Zur Theorie der Phosphorescenzerscheinung,"
£er. d. deutsch. Chem. Ges., vol. xvi. p. 597 : 1883.

GASES OF THE BLOOD AND EESPIRATION 253

access of atmospheric oxygen to the internal parts of the stack,
the whole blazes up and is consumed/

The rapid oxidation of food-stuffs which takes place in our
tissues offers no mystery if the analogies that we have dwelt
upon are taken into consideration. We must however not
forget that the participation of active oxygen iu the process is
at present only an hypothesis, and that the facts are capable of
another explanation.

The following facts observed by me ^ are not explicable
on Hoppe-Seyler's hypothesis. Certain intestinal parasites,
especially ascarides, can live and perform vigorous move-
ments for several days without oxygen (compare Lecture
XXIII.). The kinetic energy of these movements can only
come from processes of disintegration, and we should therefore
expect, according to Hoppe-Seyler, that hydrogen would be
produced together with easily oxidizable substances. This is
not the case. The animals give off a quantity of gas, which
can be proved to consist of pure carbonic acid, since it is
entirely absorbed by potash. No hydrogen was therefore
formed. When I brought oxygen in contact with the fluid in
which the worms had lived without oxygen for several days, and
had during this time carried out active movements, no oxygen
was absorbed. We must conclude therefore that no easily
oxidizable j^roducts had arisen as a result of the disintegrative
processes.

Another hypothesis, first started by Moritz Traube,^
seems to me therefore worthy of attention. I refer to the
idea that ' oxygen-carriers ' are the active factors in the
chemical processes of our body. By this term are meant
substances which combine loosely with oxygen and readily give
it up to others which do not directly unite with oxygen. A
well-known example of such an oxygen transport is seen in the
part played by nitric oxid in the preparation of sulphuric acid.
Sulphurous acid cannot unite with oxygen directly. But if
nitric oxid be present, sulphuric acid results ; for the former
body forms a loose compound with oxygen, and gives up the
oxygen to the sulphurous acid. A small quantity of nitric
oxid is capable of converting an unlimited quantity of sul-
phurous into sulphuric acid.

A similar action to that of nitric oxid in the oxidation of

1 This process so long known to farmers has recently been the subject of
numerous chemical investigations. A summary of these experiments will be
found in the Chem. Centralbl., p. 316, year 17: 1886. Compare also Th. Schlös-
ing, Compt. rend., vol. cvi. p. 1293 : 1888, and vol. cviii. p. 527 : 1889.

- G. Bunge, Zeitschr. f. physiol. Chem., vol. xiv. p. 318 : 1890.

3 M. Traube, "Theorie der Fermentwirkungen": Berlin, 1858.

254 LECTURE XVII

sulphurous acid is manifested by sulphindigotate of potassium
in the oxidation of grape-sugar. If a sohition of grape-sugar
be heated in the presence of air with some carbonate of soda,
only a very insignificant and unimportant absorption of oxygen
takes place. But if sulphindigotate of potassium be present, it
gives up its loosely combined atom of oxygen to the grape-
sugar and becomes decolorized. On shaking up the solution
with air it again becomes blue ; the sulphindigotate of potassium
has again taken up oxygen from the air. On letting the solution
stand for a brief period it again becomes decolorized. The blue
color remains permanent only at the surface, where the solution
continues in constant contact with the air. In this manner a
small quantity of sulphindigotate of potassium is able to effect
the oxidation of large quantities of grape-sugar, provided a free
admission of atmospheric air be allowed.

The same result can also be produced by cupric oxid. A
blue ammoniacal solution of cupric oxid is decolorized when
heated with grape-sugar. The cupric oxid is reduced to
cuprous oxid ; it has given up one atom of oxygen to the
grape-sugar. On shaking it up with air it again becomes blue,
and so on. The cuprous oxid here plays the same part as
oxygen-carrier that the nitric oxid does in the formation of
sulphuric acid.

The oxidation of oxalic acid in the presence of a salt of iron
affords another example. Under the influence of light, oxalic
acid is oxidized, carbonic acid is formed, while the ferric oxid
is reduced ; the admission of air causes the ferrous oxid thus
formed again to absorb oxygen ; and thus a small amount of
ferric salt has the power of gradually causing the oxidation of
a large quantity of oxalic acid.^ A similar part may possibly
be played by the iron in our tissues, since this substance is
present in loose combination wherever proteid and nuclein are
to be found.

A familiar example of this carriage of oxygen is to be
seen in the oxidation by means of atmospheric oxygen of
methyl and ethyl alcohol vapors to formic and acetic acids, in
the presence of finely divided platinum, e. g., spongy platinum.
Here also we might consider the metal as an oxygen carrier,
though chemists are generally content to speak more vaguely of
a ' contact effect.' Many attempts have been made to show
that in this process the platinum could be replaced by organic
substances, by ' ferments.' It is still undecided however
whether organized ferments may not have been responsible for
all these fermentative processes, as e. g., the mycoderma aceti in

1 Pfeffer, Unlcrs. aus dem botan. Institut zu l'übingcn, vol. i. p. 679 : 1885.

GASES OF THE BLOOD AND RESPIRATION 255

the rapid process of vinegar-making. We cannot however
exclude the ' possibility that unorganized ferments may also
effect the oxidation. We have already seen how the same
result may be produced by a metal, an organic substance or a
living cell. In the same way ferments might be the oxygen
carriers in our tissues. They must however be much more
energetic in their action than the mycoderma aceti, since
alcohol is oxidized in our body to its end-products, carbonic
acid and water, and does not stop at the stage of acetic acid.
We should have to assume the presence in our tissues of fer-
ments which, in the shortest possible time, converted fats, car-
bohydrates, and proteids into their end-products, carbonic acid,
water, urea, and sulphuric acid.

The theory of the presence of active oxygen in the tissues
has also been shown to be at variance with the fact that certain
very readily oxidizable substances remain wholly or partially
unaltered in their passage through the tissues of our body, such
as pyrogallol,^ pyrocatechin,^ and phosphorus.^ Carbonic oxid *
which is converted into carbonic acid by nascent oxygen, and
oxalic acid which is so readily oxidizable,^ are quite unaltered
in the organism.

But these facts too may be explained in another way.
Every molecule, while on its travels, does not necessarily reach
that point where it would meet with nascent oxygen. It even
appears a plausible assumption that substances which do not
belong to normal nutrition, or such as are poisonous, do not
reach those cells in which the most intense oxidation occurs, to
constitute a source of energy for the performance of normal
functions. These cells, like all others, make their choice ; they
work with definite material, and reject that which is likely to
be injurious.

Another explanation of the fact that pyrogallol and pyro-
catechin do not become oxidized, is that they do not circulate
in a free state through the body, but, like all hydroxyl deriva-
tives of the aromatic hydrocarbons, i. e., all phenols, com-

^ CI. Bernard, " Lecons sur les proprietes physiologiques, &c., des liquides de
I'organisme," vol. ii. p. 144 : 1859; Baiimann and Herter, Zeitschr. f. physioL
Chem., vol. i. p. 249 : 1877.

2 Baumann and Herter, ihicl., p. 249.

3 Hans Meyer, Arch. f. exper. Path. u. Pharm., vol. xiv. p. 329 : 1881. The
previous literature on this subject will be found quoted here.

* Gaetano Gaglio, ibid., vol. xxii. p. 236 : 1887. In Gaglio's experiments the
carbonic oxid was inspired. St. Zaleski (ibid., vol. xx. p. 34 : 1885) found that,
after intraperitoneal injection of carbonic oxid blood, no carbonic oxid was
given out by the lungs. It thus appears that carbonic oxid, introduced in this
way, becomes oxidized.

5 Gaglio, loc. cit., p. 246.

256 LECTURE XVII

bine with the sulphuric acid which arises from tlie decomposi-
tion of the proteids in the tissues. The phenols play the same
part here that the alcohols do in the formation of the sulphuric
ethers. A union accompanied by dehydration takes place ; the
sulphuric acid is converted from a dibasic into a monobasic
acid, and reappears in the urine as an alkaline salt.

These conjugated sulphuric acids were discovered by Bau-
mann. He showed that the urine of herbivora always contains
an abundance of phenolsulphate of potassium.^ Together with
this another conjugated sulphuric acid occurs, in which the
phenol is replaced by a methylated phenol called cresol,^ and
also sulphuric acid conjugated with pyrocatechin ^ and with
indoxyl.^ These combinations were also found to be invariably
present in human urine, and only absent in the urine of Car-
nivora if nothing but meat were eaten. If however phenol be
administered to dogs, it appears in the urine as the corresponding
conjugated sulphate (compare Lectures XXI. and XXII.).

It seems that sulphuric acid which, being the extreme stage
of oxidation of sulphur, is not capable of further oxidation, also
protects the organic conjugate against oxidation, even if the
latter belongs to the group of fats. Salkowski ^ found that
ethylsulphuric acid, when given to a dog, passed unaltered into
the urine.

The question whether the nucleus of benzol is ever broken
up by the decomposing and oxidizing agents occurring in our
tissues, has not yet been settled. All aromatic compounds,
whose behavior in the animal body has been examined in
detail, reappear in the urine as aromatic compounds, although
mostly in an altered form. Thus it is certain that benzoic and
salicylic acids, when introduced into the body, can be entirely
recovered from the urine, either unaltered or combined with
glycin to form hippuric acid or salicyluric acid respectively.®
(Compare Lecture XIX.) But the experiments with other aro-
matic compounds have not been executed quantitatively. The
possibility remains that at least a small part is decomposed.
Outside the organism, benzol can be oxidized by the action of
ozone at an ordinary temperature, and thus converted into
carbonic acid, oxalic acid, formic acid, acetic acid, and an

1 Baumann, Pflüger's Arch., vol. xii. p. 69 : 1876 ; and vol. xiii. p. 285 : 1876.

2 C. Preusse, Zeitscltr. f. physiol. Cheni., vol. ii. p. 355: 1878; and Brieger,
iUd., vol. iv. p. 204 : 1880.

^ Baumann, Pflüger's Arch., vol. xii. p. 63 : 1876.

■* Baunaannand L. Brieger, Zeitschr. f. physiol. Chem., vol. iii. p. 254: 1879.
5 E. Salkowski, Pflüger's Arch., vol. xii. p. 63 : 1876.

^ W. V. Schröder, Zeitschr. f. physiol. Chem., vol. iii. p. 327: 1879; U. Mosso,
Arch.f. exper. Path. u. Pharm., vol. xxvi. p. 267 : 18S9.

GASES OF THE BLOOD AND RESPIRATION 257

amorphous black residue.^ Should a really active oxygen be
demonstrated as existing in our tissues, we might infer that a
complete decomposition of the benzol would also occur in
them.

Phenol is oxidized and split up by permanganate of
potassium in an alkaline solution, with the production of
oxalic acid. This fact led Salkowski ^ to examine the blood
of rabbits poisoned by phenol for oxalic acid. Oxalic acid was
detected in two out of three cases, but not in the blood of two
healthy rabbits.

Experiments carried out by Tauber^ and Auerbach* in
Salkowski's laboratory and by SchafFer ^ in Nencki's laboratory,
showed equally that if phenol be given to dogs, only a part,
varying from 30 to 70 per cent, according to the amount intro-
duced, ever reappears in the urine and feces. But it should
not be immediately assumed that the phenol which has dis-
appeared, has undergone combustion. It is quite possible that
the benzol was not destroyed, but that the phenol had passed
into another aromatic compound. Schaifer in fact found, in
two experiments in which he estimated the amount of conju-
gated sulphuric acids, that these latter were increased after the
addition of phenol, and in the exact ratio of the amount of
phenol administered. No increase of oxalic acid in the urine
could be detected in these experiments, nor in those of Tauber
and Auerbach. Nor was the latter able to find any oxalic acid
in the blood.

After Schotten ^ and Baumann ^ had introduced certain
aromatic amido-acids, with three carbon atoms in the side-
chain (tyrosin, phenylamidopropionic and amidocinnamic acids),
into the organism of men, dogs, and rabbits, they could find no
increase of any known aromatic compound in the urine. Hence
they concluded that these aromatic compounds had been com-
pletely oxidized.^

Finally N. Juvalta^ has shown by careful quantitative
experiments that phthalic acid is in great part destroyed in the

' Leeds, Ber. d. deutsch, ehem. Ges., vol. xiv. p. 975 : 1881.

2 Salkowski, Pfliiger's Arch., vol. v. p. 357 : 1872.

3 Tauber, Zeitschr. f. physiol. Chem., vol. ii. p. 366 : 1878.
■* Auerbach, Virchow's Arch., vol. Ixxvii. p. 226 : 1879.

5 Schaflfer, Journ. f. prakt. Chem., N. F., vol. xviii. p. 282 : 1878.

* Schotten, Zeitschr. f. physiol. Chem., vol. vii. p. 23 : 1882 ; and vol. viii. p.
60: 1883.

'Baumann, ihid., vol. x. p. 130 : 1886. Compare also K. Baas, ibid.,\o\.
xi. p. 485 : 1887.

^ Vide also Nencki and P. Giacosa, ibid., vol. iv. p. 328 : 1880.

^N. Juvalta (Bunge's laboratory), Zeitschr. f. physiol. Chem., vol. xiii. p.
26 : 1888.

17

258 LECTURE XVII

organism of dogs. Of 22.4 grms. which had been introduced
into the stomach, only 7 grms. reappeared in the urine and
feces. No other aromatic compounds were to be found.

What is actually known concerning the changes which
aromatic compounds undergo through oxidation in the animal
body is as follows :

The hydrocarbons are hydroxylized, the benzol being con-
verted into oxybenzol and dioxybenzoP — hydrochinon and pyro-
catechin. Oxidation does not advance a step further ; for, after
the administration of a few milligrammes of dioxybenzol (pyro-
catechin), it reappears unaltered in the urine.^

If the aromatic combination introduced into the animal
body has a side-chain belonging to the fat-group, it is in most
cases attacked by oxygen.^ Thus toluol (CgH,— CHg), ethyl-
benzol (CgHg— CjHj), propylbenzol (C^H.— CgH^), benzylalcohol
(CgHg— CH.,OH), are all converted by oxidation into benzoic
acid (CgH.COOH). On the contrary, phenylacetic acid (CgH^ —
CH2— COÖH) is not attacked by oxygen. The inoxidizable
carboxyl group appears in this case to protect the adjoining
carbon atom in the same way as we have seen happen in the
inoxidizable sulphuric acid. Group CHg in phenylacetic acid
is protected on one side by the indestructible benzol ring, on
the other by carboxyl. But if more than one atom of carbon
is inserted between the benzol ring and carboxyl, this protec-
tion does not suffice. Phenylpropionic acid (CgH^ — CHg —
CH2-COOH) and cinnamic acid (CgH,-CH=CH-COOH)
are converted into benzoic acid (CgHgCOOH) by oxidation. If
more than one side-chain be present of the benzol nucleus,
only one of them is converted by oxidation into carboxyl.
Thus the following changes are produced by oxidation : —

f PIT "1 r OTT 1

Xylol, CgHi i QfT^ > is converted into CgH^ < qqAjx \ toluylic acid.

fCHS rCH3 ]

Mesitylene, CgHo^CHa V " " CgHä -^ CH., V mesity lerne acid.

[CHs j iCOOHJ

Cymol, CgH, | g»^' | " " CeH, { g^'jj } cuminic acid.

In the animal body many aromatic compounds enter into
combination with members of the fat-group which are easily
oxidizable, and protect these from oxidation. The best-known

* Baumann und C. Preusse, Zeitschr. f. physiol. Chem., vol. iii. p. 156 :
1879.

2 De Jonge, ibid., vol. iii. p. 184 : 1879.

* Schnitzen und Naunyn, Reichert and Du Bois' Ar-ch., p. 349 : 1867 ; Nencki
and P. Giacosa, Zeitschr. f. physiol. Chem., vol. iv. p. 325 : 1880.

GASES OF THE BLOOD AND RESPIRATION 259

instance of this kind is the formation of hippuric acid from
glycocol and .benzoic acid —

I +1=1 +HA

COOH COOH COOH

When no aromatic compounds are present in the animal body,
glycocol undergoes complete oxidation, and is converted into
carbonic acid, water, and urea (see Lecture XIX.) ; but, by
uniting with the indestructible benzoic acid, it is protected
against the influence of oxygen, and appears in the urine as
hippuric acid (see Lecture XIX.).

Schmiedeberg and his pupils ^ have observed an interesting
synthetic process of this kind in which a product of the oxida-
tion of sugar unites with an aromatic compound, and is thus
protected against further decomposition and oxidation. If
camphor (Cj^HjgO) be administered to a dog, this substance
is hydroxylized in the same way as we have seen happen with
regard to benzol ; and campherol [Cj(,Hjg(OH)0] is formed.
But this product does not pass as such into the urine, but com-
bined with glycuronic acid, with which it has united with
dehydration. The formula of glycuronic acid is CgHj^O^ and,
judging from all its properties and reactions, it must be regarded
as a derivative of grape-sugar, and as a result of incipient
oxidation.^ If we break up the compound of campherol and
glycuronic acid by boiling with dilute acids, the liberated
glycuronic acid is rapidly decomposed ; it becomes brown, and
carbonic acid is developed. It is difficult to obtain a satisfactory
quantity undecomposed for analysis. The ease with which this
acid is decomposed and oxidized explains why we do not meet
with it in the normal metabolism of animals. Here we find
that the sugar, as soon as its oxidation has commenced, is
rapidly decomposed into carbonic acid and water. It appears
that fats offer definite points of attack for oxygen ; and if these
points are protected by non-oxidizable substances, the oxygen
is unable to operate upon them. As soon as these points are
undefended, they are rapidly decomposed and oxidized.

Schmiedeberg ^ has met with glycuronic acid a second time
under different circumstances. He fed a dog on food contain-
ing no proteid, such as bacon and starch paste, and then

^ C. Wiedemann, Arch. f. exper. Path. u. Pharm,, vol. vi. p. 230 : 1877 ;
Schmiedeberg and Hans Meyer, Zeitschr. f. physiol. Chem., vol. iii. p. 422 : 1879.

2 On the chemical properties of glycuronic acid, vide H. Thierfelder, ibid.,
vol. li. p. 388 : 1887.

' Schmiedeberg, Arch. f. exper. Path, u. Pharm., vol. xiv. pp. 306, 307 : 1881.

260 LECTURE XVII

administered benzol. In order to form phenolsulphuric acid,
the organism in this case had at its disposal only a minute
quantity of sulphuric acid, resulting from the decomposition
of proteids in the tissues — no sulphur having been introduced
with the food. It follows that all the phenol formed from the
benzol did not appear in the urine conjugated with sulphuric
acid. It was proved that a part appeared as conjugated glycu-
ronic acid.

Other inquirers have also repeatedly met with glycuronic

acid. Jaffe ^ found that orthonitroluol | CgH^ < pxr^ )
is converted, in the dog, into orthonitrobenzyl alcohol
lCgH^< PTT^OTtI This alcohol appears in the urine con-
jugated with an acid, which seems to be identical with
Schmiedeberg's glycuronic acid. Mering and Musculus ^ found,
in the urine of men and dogs to whom hydrate of chloral or of
butylchloral had been administered, the corresponding alcohols,
trichlorethylalcohol and trichlorbutylalcohol conjugated with
glycuronic acid. It is to be noted that in this process the con-
jugate of glycuronic acid is formed by reduction, while in the
processes observed by Schmiedeberg and Jaffö, it was due to
oxidation. Again, in the experiments of Mering and Musculus,
it was not an aromatic compound which protected the gly-
curonic acid from oxidation, but one belonging to the fatty
series, which had been rendered more or less incombustible by
chlorin.

* Jaffe, Zeitschr.f.physiol. Chem., vol. ii. p. 47 : 1878.

* Von Mering and Musculus, Ber. d. deutsch, chem. Ges., vol. viii. p. 662 :
1875 ; von Mering, Zeitschr. f. physiol. Chem., vol. vi. p. 480 : 1882. Vide also
Külz, Pflüger's Arch., vol. xxviii. p. 506 : 1882 ; and Kossel, Zeitschr. f. physiol.
Chem., vol. iv. p. 296: 1880; and M. Lesnik, Arch. f. exper. Path. u. Pharm.,
vol. xxi. p. 168: 1887.

LECTURE XVIII

THE GASES OF THE BLOOD AND RESPIRATION (continued)

BEHAVIOR OF CARBONIC ACID IN THE PROCESSES
OF INTERNAL AND EXTERNAL RESPIRA-
TION CUTANEOUS RESPIRATION

INTESTINAL GASES

In our previous remarks on the gases of the blood and on
respiration we have become acquainted with the behavior of
oxygen and the processes of oxidation in the tissues. It now
only remains for us to consider the ultimate gaseous product
of the processes of oxidation and decomposition, carbonic acid,
together with its behavior in the processes of internal and
external respiration.

In the venous blood of the dog, the carbonic acid amounts
to from 39 to 48 vols, per cent, (reckoned at 0° C. and 760
mm. Hg.) ; in the arterial, to an average of about 8 vols, per
cent, less.^

Carbonic acid, like oxygen, is not simply absorbed in the
blood, as there is far too large an amount. Water absorbs
double its own bulk from an atmosphere of pure carbonic acid,
at 0° C. ; at the temperature of a room, it absorbs its own
volume, and at the temperature of the body, half its volume or
50 vols, per cent, of this gas. Very nearly as much as this is
contained in venous blood. If therefore the carbonic acid were
simply absorbed, its partial pressure would amount to a whole
atmosphere. This cannot be the case, for the partial pressures
of all the gases of the blood together can never amount to
much over an atmosphere.

The partial pressure of the carbonic acid in the blood is
accurately known from the researches of Pflüger and his pupils
Wolflfberg,^ Strassburg,^ and Nussbaum.^ They introduced
blood from the vessels of a living dog into the upper end of a

■* A. Sehöflfer, Wien. akad. Sitzungsher., vol. xli. p. 589: 1860; Sczelkow,
ibid., vol. xlv. p. 171 : 1862.

2 Wolffberg, Pfliiger's Arch., vol. iv. p. 465 : 1871 ; and vol. vi. p. 23 : 1872.
^ Strassburg, ibid., vol. vi. p. 65 : 1872.
•* Nussbaum, ibid., vol. vii. p. 296 : 1873.

261

262 LECTURE XVIII

vertical glass tube which contained nitrogen with a small
percentage of carbonic acid. The blood ran down against the
sides of the tube without coagulating, and was at once removed
when it reached the lower end by a particular arrangement
which prevented any air getting to it.^ If the tension of the
carbonic acid in the blood is greater than in the gas inside the
tube, then the amount of carbonic acid in the gas must increase ;
if the tension in the blood is less, then the amount of carbonic
acid in the gas must diminish. It was proved by numerous
experiments that the pressure of COg amounts to 54 per cent,
of an atmosphere in the blood of the large veins of a dog and
in that from the right heart, and to 2.8 per cent, in arterial
blood.^'

Now, as water at the temperature of the body takes up
only about 50 vols, per cent, of COg from an atmosphere of
pure carbonic acid, it follows that venous blood, which is under
a carbonic acid pressure of only 5 per cent, or gV ^^ ^^
atmosphere, cannot contain more than about |^ = 2| vols, per
cent, of CO2 simply absorbed. The remaining 36 to 46 vols,
per cent, must be in a state of chemical combination, and a
glance at the composition of the ash of blood shows us
that the substances, which fix carbonic acid, must be soda
and potash. The ash of the plasma has never been analyzed.
I found that serum, the ash of which cannot be of very differ-
ent constitution from that of the plasma, has the following
composition : — ^

One Thousand Geammes of Serxjm from Dog's Blood Contains —

K2O 0.202

Na^O 4.341

CaO 0.176

MgO 0.041

FeA 0.010

PA 0.489

CI 3.961

We need take no notice of the minute proportion of potassium,
which probably arises mostly from the breaking up of the
leucocytes, and of which there is only a trace in the plasma of
the living blood. Nor is it necessary to take into consideration
the small amount of lime and magnesia ; they are for the most
part combined with the albumins and nucleo-albumins, and
perhaps are not at all concerned in fixing carbonic acid.
Anyhow, the bulk of the carbonic acid in the plasma is com-

^ Diagrams and description of the apparatus are given by Strassburg, Pflüger 's
Arch., vol. vi. p. 69 : 1872.

2 Strassburg, loc. cit.

3 The analysis has been published only in part {Zeitschr.f. Biolog., vol. xii.
p. 204: 1876).

GASES OF THE BLOOD AND RESPIRATION 263

bined with sodium : 3.463 of the 4.341 grms. of sodium are
sufficient to saturate the only strong mineral acid of the
plasma, the hydrochloric acid. The remainder, 0.878 grm. of
sodium, is able to fix 0.623 grm. COg =316 c.cms. carbonic acid
gas (computed at 0° C. and 760 mm. Hg. pressure), besides an
equal additional amount when the bicarbonate of soda is
formed. 632 c.cms. of carbonic acid (i. e., 63 vols, per cent.)
may therefore be chemically combined in a liter of blood-
plasma. It must however be remembered that the carbonic
acid never really reaches quite 63 volumes per cent., as the
0.878 grm. sodium must be divided amongst the other weak
acids — such as phosphoric acid, proteid, and perhaps many
others, each of which is of little importance singly, but which
altogether exert some influence. As a fact, from 43 to 57 vols.
per cent, of carbonic acid have been found in arterial blood-
serum of the dog. The amount of CO2 must be still larger in
the serum of venous blood, where the disposable sodium is perhaps
almost completely saturated with carbonic acid. How large a
share of the sodium falls to the lot of the carbonic acid depends
on ' mass influence,' i. e., on the partial pressure of the carbonic
acid.^ In the tissues where COg is liberated by oxidation and
decomposition, and its partial pressure rises, sodium bicarbonate
must be formed at the cost of the sodium albuminate and of
the dibasic sodium phosphate (Na2HPOJ, which latter gives
up one-half of its sodium and is converted into the acid salt
(NaH^POJ. In the alveoli of the lungs, where the partial
pressure of the carbonic acid is diminished in consequence of
the constant mechanical ventilation, the blood gives off a
portion of its carbonic acid by diifusion ; the mass-influence of
the CO2 in the blood becomes lessened, and that of the other
acids relatively increased ; again sodium albuminate and dibasic
sodium phosphate (ISTa^HPO^) are formed at the cost of the
sodium bicarbonate. As soon as the amount of free carbonic
acid decreases, however little, the amount of the loosely com-
bined CO2 also diminishes, and even to a considerable extent.
By this arrangement the amount of carbonic acid of the blood
can vary within wide limits without the total pressure of the
gas being materially altered. A change of pressure up to 2.6
per cent, of an atmosphere produces an alteration of 8 vols, per
cent, in the carbonic acid of the blood. This allows of large
quantities of CO2 being transported in a short time from the
tissues into the lungs.

1 N. Zuntz, Centralbl. f. d. med. Wissensch., p. 527 : 1867; F. C. Bonders,
Pfliiger's Arch., vol. v. p. 20 : 1872. Vide also J. Gaule, Du Bois' Arch., p. 469 :
1878.

264 LECTURE XVIII

Hoppe-Seyler and his pupil Sertoli ^ have shown that proteid
does indeed compete with the carbonic acid for the possession
of the sodium. Proteid drives out carbonic acid in a vacuum
from a solution of simple sodium carbonate ; the amount driven
out is however very small, as might ä priori be anticipated,
owing to the great molecular weight of the proteid.^

The occurrence of phosphates of the alkalies in the plasma
has frequently been doubted.^ The phosphoric acid in the ash
has been ascribed to the lecithin and nuclein, but the amount
is too large for this purpose, at any rate in dog's blood ; in
bullock's and pig's blood it is certainly much smaller.^ But,
at any rate, it is only a small portion of the alkalies which is
combined with phosphoric acid in the plasma. In the cor-
puscles, on the contrary, there is no doubt that phosphates play
an important part in fixing carbonic acid.

The way in which the phosphoric acid is driven from the
possession of the sodium by the carbonic acid, and vice versa,
may be demonstrated by a simple experiment. If to a solution
of NagHPO a few drops of litmus solution be added, the solu-
tion becomes blue. If COg be now introduced the solution
becomes red ; the carbonic acid is not the cause of this change
in color, as a control experiment shows, but the formation of
NaH2PO^. NaHCOg is formed simultaneously. If the vessel
be left open, the carbonic acid gradually disappears, the mass
influence of the phosphoric acid becomes relatively greater, it
again takes possession of the second sodium equivalent, of
which it had been robbed by the COg, and the blue color reap-
pears. This process can be hastened by boiling.

Carbonic acid is found not only in the blood-plasma but
also in the corpuscles, though not in such large quantities.
This follows from the simple fact that the total blood contains
less CO2 than the serum. But the difference is not sufficient to
enable us to ascribe all the carbonic acid to the serum.^

The carbonic acid cannot be completely removed from the
serum by the air-pump, a proof that the amount of the non-
volatile weak acids is less than the equivalent of the 0.9 per
1000 sodium just estimated. But more than half can be
removed,*' a proof that the process is not merely a transition

1 Sertoli, Hoppe-Seyler's Med. chem. Unters., Heft iii. p. 350 : Berlin, 1868.

2 Hoppe-Seyler, "Physiologische Chemie," p. 503 : Berlin, 1879.
^ Sertoli, loc. cit.

4 Vide Bunge, Zeitschr. f. Biolog., vol. xii. pp. 206, 207 : 1876 ; and Sertoli,
loc. cit.

* Alexander Schmidt, Berichte über die Verhandlungen, der königl. sächs.
Ges. d. Wissensch. zu Leipzig, Math. phys. Classe, vol. xix. p. 30 : 1867.

ß Pflüger, " üeber die Kohlensäure des Blutes," p. 11 : Bonn, 1864.

GASES OF THE BLOOD AND RESPIRATION 265

from sodium bicarbonate into carbonate, but also a partial dis-
placement of the firmly combined carbonic acid by the other
weak acids, proteid, phosphoric acid, &c.

The carbonic acid may, on the contrary, be completely
pumped out of the blood.^ And moreover Pflüger ^ has
shown that if sodium carbonate be added to the blood, the
CO2 may be driven out even from this in a vacuum. In order
to explaia these facts, we must assume either that acids from
the corpuscles diffuse into the plasma, or that sodium carbonate
diffuses from the plasma into the corpuscles.

With regard to the acids of the blood-corpuscles, the most
important place is held by the phosphoric acid, in which the
corpuscles at any rate are far richer than the plasma. Only a
very small portion of this large amount of phosphoric acid can
be contained in the corpuscles as an organic compound. In the
second place, probably the oxyhemoglobin is of influence for,
as Preyer ^ has shown, it drives out COg from sodium carbonate
in a vacuum.

It has been much disputed whether the giving off of car-
bonic acid from the capillaries of the lungs into the air of the
alveoli simply follows the laws of diffusion, or whether we
must assume that special excretory forces are at work in the
lung-tissue. The results of the following experiment of
Pflüger and his pupils, Wolff berg* and Nussbaum,^ are in
favor of the former view. If the giving off of carbonic acid
in the alveoli of the lungs simply follows the laws of the
diffusion of gases, we should expect ä priori that, if a lobe of
the lung were blocked by closing the corresponding bronchus,
the carbonic acid pressure would rise in the air-cavities of the
lung thus closed in, until it balanced the carbonic pressure in
the venous blood flowing in, and that then the blood flowing
out, i. e., the arterial blood of the pulmonary veins in this same
lobe, would also have the same COg tension. The experiments
of Wolffberg and Nussbaum have in fact shown that, under
these conditions, the pressure of CO^ in the alveoli is the same
as in the venous blood.

One pulmonary lobe was successfully closed in the follow-
ing manner. An elastic catheter ^ was introduced into a branch
of one bronchus of a dog that had been tracheotomized.

^ Setschenow, Sitzungsber. d. Wien. Äkad., vol. xxxvi. p. 293 : 1859.
2 Pflüger, loc. cit., pp. 5, et seq.
^W. Preyer, " Die Blutkrystalle " : Jena, 1871.

4 Wolffberg, Pfliiger's Arch., vol. iv. p. 465 : 1871 ; and vol. vi. p. 23 : 1872.
' Nussbaum, ibid., vol. vii. p. 296 : 1873.

^ A description and illustration of the ' lung-catheter ' are given by Wolff-
berg, ibid., vol. iv. p. 467, &c. : 1871.

266 LECTURE XVIII

The catheter had a double wall ; the outer, which was made of
india-rubber, was thinner towards the end inserted in the
bronchus, so that, when inflated, this end expanded, whilst
the thicker portion of the wall remained the same. This
flask -like expansion of the tube ensured a completely air-tight
closure of the bronchus. Ventilation went on unimpeded in
the other lobes of the same lung and in the other lung, so that
there could be no retention of COg in the blood. The pressure
of carbonic acid was thus also normal in the blood-vessels of
the lobe that had been stopped up. When the closure had
lasted long enough, a sample of the gas could be drawn out
through the inner tube of the catheter, and used for analysis.
The means of numerous estimates of the enclosed pulmonary air
gave an average pressure of COg of 3.84 per cent, of an atmos-
phere, and of 3.81 per cent, for the blood from the right
heart. The fact that the latter figure is lower than in the
above-mentioned experiments of Strassburg, who found a mean
of 5.4 per cent., is explained by the fact that the animals were
not tracheotomized in Strassburg's cases, and that, in conse-
quence of tracheotomy, the ventilation of the lung is far more
complete, and the retention of carbonic acid in the blood is
much less.

Under normal conditions, if the interchange of gas simply
follows the laws of difiJusion, the pressure of CO2 could never
be higher in the alveoli of the lungs than in the arterial blood,
the two being equally balanced. If the balance is complete,
the pressure must be the same ; if incomplete, the pressure in
the alveoli must be lower, but can never be higher. If it were,
we should have to assume that forces were at work in the lung-
tissue to expel it. How do the facts agree with this deduction ?
Strassburg found that the pressure of carbonic acid in the
arterial blood of the dog was from 2.2 to 3.8 per cent., or on an
average 2.8 per cent, of an atmosphere.^

The normal CO2 pressure in the alveoli cannot be ascer-
tained, but we can determine its minimal value by estimating
the CO2 pressure in the total air expired, which is a mixture of
alveolar air and atmospheric air. If this minimal value should
prove higher than the carbonic acid pressure in the arterial
blood, the assumption that the interchange of gases proceeds
only by diffusion would be refuted ; we should be forced to
consider that there were other special expelling forces at
work.

The amount of carbonic acid in the expired air of the
dog has, so far as I am aware, only been estimated once.

^ Strassburg, Pfliiger's Arch., vol. vi. p. 77: 1872.

GASES OF THE BLOOD AND RESPIRATION 267

Wolff berg ^ found from 2.4 to 3.4, a mean of 2.8 per cent.
Wolffberg's dog was tracheotomized. The COg tension in the
expired air would be higher in a dog breathing normally, and
still higher in the alveolar air than in the expired air. These
experiments urgently require repetition. These facts, so far, are
only partially reconcilable with the theory that the interchange
of gases in the lungs proceeds merely according to the laws of
diffusion.

The amount of COg in the air expired by human beings is
much larger: Vierordt^ found 4.6 per cent. COg in the air
normally expired, and 5.2 per cent, in that expired after a very
deep inhalation. The pressure of carbonic acid in the arterial
blood of human beings is not known.

In the short time during which the blood flows through the
capillaries of the lungs, the equalization of the difference in
tension is accomplished with a completeness which is sur-
prising. This phenomenon is explained if the extent of the
surface be considered over which the interchange takes place.
According to an approximate valuation of the anatomist
Huschke, the total inner surface of the human lungs amounts
to 2000 square feet, and the whole of this vast surface is
thickly interwoven with a network of capillaries.

The experiments made to estimate the pressure of carbonic
acid in the tissues are attended with great difficulties. Ä
priori, it must be assumed that the greatest pressure will be
where the development of carbonic acid is most considerable :
therefore probably in the cells, in the muscular fibers, in all the
active elements — in fact, wherever most kinetic energy is
liberated. Now the pressure of COg cannot be directly
estimated in the cells themselves; an endeavor has there-
fore been made to estimate the partial pressure of this gas in
the fluids which come most in contact with the cells, i. e., the
lymph. It was imagined ä priori that the lymph, which flows
so slowly round the cells, would be saturated far more com-
pletely with carbonic acid than the blood, which passes through
the capillaries so rapidly. But as a matter of fact this is not
so. Strassburg ^ found the tension of carbonic acid invariably
less in the lymph than in venous blood. It thus appears that
the stream of COg from the cells into the lymph does not
simply follow the laws of diffusion. Why does the bulk of it
diffuse directly into the blood ? The purpose is evident ; the

1 Wolfiberg, Pflüger's Arch., vol. vi. p. 478 : 1871.

2 Vierordt, " Physiol, des Athmens," p. 134 : Heidelberg, 1845.

2 Strassburg, loc. cit., pp. 85-91. Vide also Gaule, Du Bois' Arch., pp. 474-
476 : 1878.

268 LECTURE XVIII

carbonic acid reaches the lungs most rapidly in this manner.
The cause, however, is not yet known.

Strassburg has also estimated the tension of carbonic acid
in dog's urine, and found it to be about 9 per cent, of an atmos-
phere, and in the bile 7 per cent. Finally, he endeavored
to estimate it in the tissues of the intestinal wall, by injecting
atmospheric air into a ligatured coil of intestine of a living
dog, and analyzing a sample of the air after from half an hour
to three hours ; he found from 7 to 9| per cent. CO2. From
these facts it follows that the tension of carbonic acid is
greater in the tissues than in the blood, which we should
expect to be the case.

But what would happen if an animal were brought into an
atmosphere where the pressure of carbonic acid was already
as great as in the venous blood ? The interchange of gases in
the alveoli would be stopped, but only for an instant ; for the
development of carbonic acid proceeds unremittingly in the
tissues. The amount of COg rises above the normal both in
the tissues and in the blood, and then it will again be given off
by the walls of the alveoli, in consequence of the difference in
tension which arises.

But a retention of carbonic acid in the blood and in the
tissues will occur much sooner, long before the amount of COg
in the inspired air is the same as that of the normal alveolar
air. The smaller the difference of the tension of carbonic acid
in venous blood and in the alveolar air, the more slowly will
CO2 be given off from the blood to the alveolar air, and the
greater must be the retention of carbonic acid in the blood and
in the tissues.

The abnormally high tension of this gas in the tissues is
the cause of disturbances, especially in certain parts of the
central nervous system. The increasing partial pressure of the
carbonic acid acts above all on the respiratory center, causing
deeper respiration. If the retention of carbonic acid be so
great that the deeper respiration cannot overcome it, it acts also
on other parts of the central nervous system, and the animals
finally die with symptoms of narcosis.

If animals be placed in an air-tight compartment, and be
made to breathe an artificial mixture of air rich in oxygen, they
die of carbonic acid poisoning long before the partial pressure
of the oxygen has sunk to normal.^

^ Müller, Sitzungsber. d. Akad. d. Wissensch. zu Wien., Math. Nat. Classe,
vol. xxxiii. p. 1.36, et seq. : 1859; P. Bert, "La pression barometrique," p. 983 :
Paris, 1878 ; Friedländer and Herter, Zeitschr. /. physiol. Chem., vol. ii. p. 99 :

1878.

GASES OF THE BLOOD AND RESPIRATION 269

If the volumes of the inspired and expired air in normal res-
piration be compared, the latter is always found to be larger.
The explanation is to be sought in the fact that the air has be-
come warmer in the lung and, owing to the temperature of the
body, has been almost saturated with aqueous vapor. The quan-
tity of water which leaves the body in this way during the course
of a day amounts to from 400 to 800 grms. It varies with the
dryness of the inspired air.

But if, on the other hand, the volumes of the inspired and
expired air be compared after desiccation, and reduced to the
same temperature and pressure, the volume of expired air is
usually somewhat smaller. This is readily explained if we
consider that, in the combustion of food-stuffs, it is only the car-
bohydrates which produce a volume of carbonic acid equal to
that of the oxygen used up, the proteids and fats yielding a
smaller one.

The carbohydrates are known to contain exactly so much
oxygen as is requisite for the saturation of the hydrogen. If
therefore the entire molecule becomes oxidized to carbonic acid
and water, exactly two oxygen atoms must be taken up to every
carbon atom. Two atoms (that is, one molecule of oxygen)
form with one atom of carbon one molecule of carbonic acid.
Now, it is well known that an equal number of molecules oc-
cupies an equal volume. Consequently, the volumes of COj
formed during the combustion of the carbohydrates must be
equal to the volume of oxygen used up.

The fats, on the other hand, contain fewer oxygen atoms
than are necessary for the saturation of the hydrogen atoms : in
stearic acids (CjgHggOg), only four of the thirty-six hydrogen
atoms can be saturated by the oxygen present ; sixteen more
atoms of the inspired oxygen must be used up in order to com-
plete the combustion of the hydrogen, and these do not reappear
in the expired air. Glycerin (CgHgOg) also contains two atoms
more hydrogen than are saturated by the oxygen present. Thus,
for the complete combustion of the fats, far more oxygen must
be taken up than is requisite for the combustion of their carbon ;
and for this reason all the inspired oxygen does not reappear in
the expired carbonic acid.

This is also the case with the proteids. One hundred grms.
of proteid contain 7 grms. of hydrogen. In order to reduce
these to water by combustion, 7 x 8 = 56 grms. of oxygen are
necessary. But 100 grms. of proteid matter contain at most
24 grms. of oxygen. Extra oxygen must therefore be inspired
for the purpose of oxidizing the hydrogen, besides the amount
necessary for the oxidation of the carbon. Only the estimate

270 LECTURE XVIII

is rendered more complicated with proteid, because hydrogen
and oxygen atoms are also eliminated in the nitrogenous waste
products, and because oxygen is also used up in oxidizing the
sulphur.

The proportion of the expired volimie of carbonic acid
to the inspired volume of oxygen is termed the respiratory
quotient.

The carbohydrates preponderate in the diet of herbivora.
The respiratory quotient in these cases is nearly equal to 1.
With Carnivora, on the other hand, where the food is poor in
carbohydrates and rich in proteids and fats, the respiratory
quotient must be considerably less than 1. It is usually found
to be about |.

The respiratory quotient estimated from the constituents of
food only agrees with that actually found ^ if the estimation of
the respiratory gases be carried out for some time, if possible
for twenty-four hours. In short spaces of time, the propor-
tion may be very materially altered, because the taking in of
oxygen and the giving out of carbonic acid do not occur simul-
taneously. A considerable part of the carbon may be split
off from the carbohydrates as carbonic acid without any oxy-
gen being taken in, as we see in alcoholic and butyric acid
fermentation ; the by-products then formed, which are poor in
oxygen, are oxidized later, after the COg previously given off
has been expired. In this way it may happen that the expired
volume of COg may for a time be larger than the inspired
oxygen volume, and the respiratory quotient may be greater
than 1.

In herbivora, it sometimes happens that the whole volume
of COg expired in twenty-four hours is larger than the volume
of inspired oxygen. The following statement will explain this.

^ A description and illustration of the apparatus used for the quantitative
estimate of the interchange of gases during longer periods, and especially of Reg-
nault's, Reiset's, and Pettenlcofer's respiratory apparatus, are to be found in every
text-book of physiology. Any one desirous of reading the original description
by the authors, is referred to the celebrated work of Regnault and Reiset in the
Ann. de Ohim. et de Phys.^ vol. xxvi.: 1849 ; also under the separate title, " Re-
cherches chimiques sur la respiration des animaux des diverses classes " : Bach-
ellier, 1849 ; translated in Liebig's Ann. d. Chem. u. Pharm., vol. Ixxiii. pp.92,
129, 257 : 1850. The description of Pettenkofer's respiratory apparatus is to be
found in Liebig's ^nw. de Chem. u. Pharm., vol. ii. p. 1, Suppl.: 1862. This ap-
paratus was specially constructed for experiments on human beings. Voit modi-
fied it somewhat for smaller animals. The exact illustration and description are
given in Zeitschr.f. Biolog., vol. xi. p. 541 : 1875. A modification of Regnault's
and Reiset's apparatus for examining the respiration of aquatic animals was de-
scribed by Jolyet and Regnard in Arch, de physiol. normale et patholog., ser. ii.
vol. iv. p. 44 : 1877. More recently Hoppe-Seyler has constructed a respiratory
apparatus on Regnault's principle for experiments on man. Zeitschr. f. physiol.
Chem., vol. xix. p. 574 : 1894.

GASES OF THE BLOOD AND RESPIRATION 271

"Vegetable food contains organic acids, which are richer in
oxygen than the carbohydrates, and for this reason they use up,
during their conversion into carbonic acid and water, a smaller
volume of oxygen than that corresponding to the volume of
carbonic acid formed. Tartaric acid with 2^ vols, of oxygen
gives 4 vols, of CO^ : CJip, -f 50 = 4CÖ^ + 3Hp. But
carbonic acid may be developed from another source without
oxygen being taken up. The carbohydrates may undergo
marsh-gas fermentation in the intestine : CgH^jOg = SCOg +
3CH,. The carbonic acid is absorbed from the intestine and
breathed out from the lungs, but the marsh-gas remains unoxi-
dized (pp. 279, 280).

It is important to know all these conditions upon which the
respiratory quotient depends. In the experiments on meta-
bolism, the size of this quotient affords many indications
from which the chemical processes in the tissues may be
judged.

In speaking of respiration, we have hitherto meant only the
respiration through the lungs. The question now remains for
us to consider whether there is, in human beings, such a thing
as CUTANEOUS RESPIRATION. It Undoubtedly exists among the
lower animals, as well as among certain of the lower vertebrata.
Among the amphibia, the interchange of gases goes on more
extensively by means of the skin than by the lungs. This was
known even to Spallanzani.^ He proved that many kinds of
amphibia lived longer after extirpation of the lungs than after
their skins were varnished over. There is however this objec-
tion to the above experiment, i. e., that the varnishing of the
skin would be prejudicial in other ways. Spallanzani's experi-
ments have therefore been repeated with many alterations.'
Fubini estimated the whole of the COg given out by normal
frogs and, on comparing it with that given out by frogs with
their lungs extirpated, found that the latter amount was only
a little less. To this experiment the objection may also be
raised that after extirpation of the lungs the output of COg by
the skin was no longer normal, but increased by vicarious
activity. Ferd. Klug therefore constructed a special apparatus,
in which the head and body were each in separate compart-
ments. The separation was effected by means of a sheet of
india-rubber, through which the head was passed. The result

^ Spallanzani, "Memoires sur la respiration, traduits par Senebier," p. 73 :
Geneve, 1803.

2 Vide Fubini, Moleschott's Unt. z. Naturlehre, vol. xii. p. 100 : 1878 ; and
Ferd. Klug, DuBois' Arch., p. 183 : 1884, containing also a critical notice of the
earlier literature.

272 LECTTJEE XVIII

of this experiment was found to be that only a very small part
of the CO2 was given out through the lungs.

The most exact estimates on the output of COg through the
skin of human beings were made by H. Aubert.^ The person
experimented on sat naked in an air-tight box, the top of which
was made of india-rubber. The head came out of a round hole
in this covering, which fitted tightly round the neck, so that no
air could get in. A stream of air was now admitted into the
enclosed space. The air had been previously freed from all
carbonic acid, and on coming out was passed through flasks
containing baryta water. The experiment lasted for two hours.
From the carbonic acid absorbed during this time by the
solution of baryta, the quantity eliminated in twenty-four hours
was estimated. Seven experiments showed that in twenty-four
hours a man gives out by the skin a maximum of 6.3 grms., a
minimum of 2.3, or an average of 3.9 grms. of carbonic acid.

This amount of COg is exceedingly small in comparison with
that proceeding from the lungs, which in human beings amounts
to from 800 to 1200 grms. in twenty-four hours. It is even
doubtful whether the small quantity of COj found was really
given off by the skin in the form of gas. It is possible that it
arose from the decomposition of the secretions of the skin and
of the cast-off epidermis. Still more dubious are the state-
ments that small quantities of oxygen are taken up through
the human skin.

Until quite recently, it was believed that not only is
carbonic acid given out through the skin, but also certain
gaseous organic compounds of a more complex nature. This
has been the explanation offered for the injurious effects of a
great many people being shut up together in a small room. It
was thought that these organic vapors have a very low tension ;
that the air soon reaches saturation as far as they are concerned,
and cannot receive any more of them from the organism, unless
it be rapidly changed and renewed. If these vapors, in how-
ever small a quantity, remain behind and collect in the body,
they act on certain parts of the nervous system, and through
these on the whole metabolism, just as they do on our olfactory
nerves after they have passed into the air, when they may even
cause vomiting.^

This idea of the injurious effects arising from the suppressed
action of the skin is as old as the history of medicine, and even
up to the present time the perspirabile retentum plays an im-
portant part in the etiology of certain diseases. This idea in-

^ H. Aubert, Pfliiger's Arch., vol. vi. p. 539 : 1872.

2 Pettenkofer, Liebig's Ann. d. Chem. u. Pharm., vol. ii. Suppl. p. 5 : 1862.

GASES OF THE BLOOD AND EESPIEATION 273

duced Pettenkofer, in his researches on respiration, to abandon
the method of Regnault and Reiset, and to construct a new
respiratory apparatus, in which a constant current of fresh air
passed through the compartment that held the person or ani-
mal. Pettenkofer had found that when the proportion of COg
had risen to 0.1 per cent, in a room filled with people, the air
began to smell, and that when it rose to 1 per cent, the air
became almost unendurable. But if he developed carbonic
acid in a room, by acting on bicarbonate of sodium with sul-
phuric acid until the COg in the air amounted to 1 per cent.,
he found that he could remain in this room quite comfortably
for a considerable time. It is therefore not the carbonic acid
itself that is the harmful product in so-called bad air; but,
according to Pettenkofer, the CO2 is a measure of the injurious
products of perspiration which are as yet unknown to us.

All endeavors to discover what these harmful products of
perspiration are have hitherto failed. The latest experiments
were made by Hermans^ in the Institute of Hygiene in
Amsterdam. A man was shut in an air-tight case of sheet-
iron. The first signs of dyspnea appeared when the COg in
the air rose above 3 per cent. If the carbonic acid was re-
moved by absorption, no inconvenience was experienced, even
when the amount of oxygen in the box sank to 10 per cent.
In order to discover the supposed organic products of perspira-
tion, air was first passed through the case, and then through an
absorption apparatus. When passed through titrated sulphuric
acid, the titre was always found to be unaltered. If the air
was passed over red-hot oxid of copper, the amount of CO2
and of water did not increase. In the same way the titre of a
boiling acid or alkaline permanganate solution was found to be
unchanged, even after many liters of the air taken from the
case towards the end of the experiment had been slowly passed
through it. Neither did the condensed water, obtained from
the issuing air after being cooled by ice, nor the condensed
water from the sides of the case, alter the titre of boiling per-
manganate solution. There was likewise no disagreeable smell.
The greatest care had been taken to see that the clothing and
person of the man experimented upon were perfectly clean.
Hermans therefore comes to the conclusion that when healthy
people give out malodorous substances in the atmosphere, these
come, not from normal perspiration, but from the processes of
decomposition caused by the dirty state of the body or clothes.

The medical men who believe in the harmfulness of the
perspirabile retentum, ground their belief on the following facts :

1 Hermans, Arch. f. Hygiene, vol. i. p. 5 : 1883.
18

274 LECTURE XVIII

(1) The injurious effect on animals whose skin has been ren-
dered impervious to perspiration by varnishing ; and (2) the
fatal effect of extensive burns of the skin. But these facts
must be differently interpreted.

The death of varnished animals may be explained by an in-
creased loss of heat.^ In the first place, the animals in all such
experiments were shaved before being varnished, thus being
deprived of their natural protection ; in the second place, the
varnishing appears to damage the vasomotor nerves ; the
cutaneous vessels become dilated, the surface of the body
becomes warmer than it normally is, and the loss of heat is
greater. In consequence of this, the temperature of the body
sinks,- and the animals die of cold. If an animal be only
partially varnished, it is found that the varnished parts are
warmer than the rest of the skin. A varnished animal gives
out more heat in the calorimeter than a normal one does. If
the cooling be prevented by wrapping the varnished animal in
wool, or by placing it in a warm place, it remains alive and
does not become ill. Besides, only those animals fall ill on
being varnished that have a delicate skin, and a surface that is
large in proportion to their small weight, as for instance rabbits.
Larger animals with a tough skin, such as dogs, remain per-
fectly well with their whole body varnished over.

Senator,^ in Berlin, even ventured to varnish human beings.
He had two patients suffering from rheumatism, which is often
thought to be caused by the arrest of the action of the skin.
Any interference with this action should therefore be attended
with dire consequences. The extremities of these patients
were encased in sticking-plaster, and almost the whole trunk
was thickly painted with collodion, mixed with a little castor
oil to make it less brittle. Only the skin of the head, neck,
buttock, and genitals remained free. One patient twice re-
mained in this condition for twenty-four hours, the other for
fully eight days ! The third experiment was made on a female
patient with chronic pemphigus. The whole body, and even
the face, was thickly covered with common tar, and the head,
which had been shaven, with oleum rusci.^ This air-tight

' Laschkewitsch, Arch. f. Anat. u. Physiol., p. 61 : 1868 ; K. Winternitz,
Arch. J. exper. Path. u. Pharm., vol. xxxiii. p. 286: 1894.

^»Senator, Virchow's Arch., vol. Ixx. p. 182 : 1877.

' [Oleum rusci sive pix betulimum sive oleum betulse empyreumaticum, is a
tarry product obtained from all parts of the birch tree, and in great favor as a
popular remedy for all kinds of diseases in Poland and Russia. It is also em-
ployed in the fabrication of certain liqueurs, and especially in the preparation of
Russian leather, to which it imparts its characteristic odor (see Dr. Hager's
"Handbuch der pharmaceutischen Praxis": Berlin, 1880; and the United
States Dispensary : 1883).]

GASES OF THE BLOOD AND RESPIEATION 275

covering was not removed for ten days, but no injurious conse-
quences occurred in any of the three cases.

Finally, as regards the fatal effect of extensive burns on the
skin, there may be other explanations than that of the perspira-
bile retentum; in fact, in recent times many others have been
attempted. We know that even a moderate rise of temperature
will alter and destroy the blood-corpuscles.^ This led to the
supposition that the blood-cells which pass through the capil-
laries of the skin during a burn become destroyed by the higher
temperature, and that their decomposition-products indirectly
cause the symptoms which ensue. And in fact a constituent of
the corpuscles, the hemoglobin, was found in the plasma of the
blood after a burn, and the hemoglobin, or a derivative, was
found in the urine.^ According to Hoppe-Seyler's ^ and Tap-
peiner's * investigations, however, the amount of hemoglobin in
the blood-plasma after burns is very slight, and was even en-
tirely absent in one case which ended fatally. Neither it nor
its derivatives invariably occur in the urine. On the other
hand, the following fact observed by Tappeiner is very inter-
esting : he found the blood of patients with extensive skin-burns
to be much richer in corpuscles and poorer in plasma than nor-
mal blood. This thickening of the blood is accounted for by
the transudation of lymph at the burnt places, and is perhaps
the primary cause of all the symptoms and of death.

We thus see that there is no real ground for assuming that
any gaseous products are excreted by the human skin. Our
knowledge of the chemistry of cutaneous activity is altogether
very limited. Nothing certain is known concerning the chemical
composition of perspiration,' and there is at present no reason
for considering this secretion to have any other use than that
of the purely physical action in regulating the temperature of
the body. The evaporation of water on the surface of the body
is the most effectual means of cooling it. It must not be for-
gotten what an enormous amount of heat becomes latent when

1 Max Schultze, Arch. f. mik. Anat., vol. i. p. 26 : 1865.

^ Wertheim, Wiener med. Presse, No. 13 : 1868 ; Ponfick, Berl. klin. Wo-
chenschr., No. 46: 1877; Centralbl.f. d. med. Wissensch., Nos. 11, 16: 1880; von
Lesser, Virchow's Arch., vol. Ixxix. p. 248 : 1880.

* Hoppe-Seyler, Zeitschr. f. phyaiol. Chem., vol. v. pp. 1, 344: 1881.

■* Tappeiner, Centralbl. f. d. med. Wissensch., vol. xix. pp. 385, 401: 1881.

^ Vide 0. Funke, Moleschott's Unter, z. Naturlehre d. ßlenschen u. der
Thiere, vol. iv. p. 36 : 1858 ; and W. Leube, " Ueber den Antagonismus zwischen
Harn- und Schweissecretion und dessen therapeutische Bedeutung," Deutsch.
Arch. f. klin. Med., vol. vii. p. 1 : 1870. An account of the previous literature
is also given. Compare also A. Kast, "Ueb. aromatische Fäulnissprodukte im
menschlichen Schweisse," Zeitschr. f. physiol. Chem., vol. xi. p. 501 : 1887. P.
Argutinsky, Pflüger's Arch., vol. xlvi. p. 594: 1890; E. Cramer, Arch. f. Hy-
giene, vol. X. p. 231 : 1890.

276 LECTUEE XVIII

water passes from the liquid to the gaseous state. The secre-
tion of perspiration is entirely absent in many animals, as in
the dog, and is replaced by a more copious evaporation from the
surface of the lungs.

Before concluding the chapter on respiration and the behavior
of gases in the body, we must consider the gases which occur in
the alimentary canal, their origin, and their behavior under
physiological and pathological conditions.

The GASES in the alimentary canal arise from four
sources : (1) Atmospheric air is continually being swallowed
with the saliva, with food and drink ; part of it escapes again by
the esophagus, but the rest passes into the intestine ; (2) gases
arise by fermentative processes in the contents of the stomach
and intestine ; (3) gases diffuse from the tissues of the intes-
tinal wall into the intestine ; and (4) CO2 is liberated when the
sodium carbonate of the intestinal juice is neutralized.

The following gases have, up to the present, been detected
in the alimentary canal of human beings and of mammals : ^
O, N, CO,, H, CH„ H,S.

Oxygen reaches the alimentary canal only by the air that is
swallowed, and disappears almost entirely in the stomach, partly
by uniting with the reducing substances which proceed from the
fermentative processes already set up in the stomach, and espe-
cially with the nascent hydrogen arising from butyric acid fer-
mentation, and partly by diffusion into the tissues of the gastric
wall. Traces of oxygen could still be found in the gases
obtained from the upper portion of the intestine, but none in
that from the lower parts. Planer injected atmospheric air into
a ligatured small intestine of a living dog, and even after one
and a half hours, half of the oxygen had disappeared from the
air and had been replaced by carbonic acid. In the case of a
few fish, the diffusion of the atmospheric oxygen swallowed by
them through the walls of the alimentary canal, plays an impor-
tant part in the process of respiration.^

Nitrogen also reaches the alimentary canal with the air
swallowed, but does not diffuse into the tissues of the intestinal
wall, because the partial pressure of the nitrogen is very nearly
the same in this latter as in atmospheric air. It must, on the

^Planer, Sitzungsber. d. k. Akad. d. W. zu Wien., vol. xlii. p. 307: 1860; E.
Ruge, ibid., vol. xliv. p. 739 : 1862 ; C. B. Hofmann, Wiener med. Wochenschr.,
1872 ; Tappeiner, Zeitschr. f. physiol. Chem., vol. vi. p. 432 : 1882 ; Zeitschr. f.
Biolog., vol. xix. p. 228 : 1883; and vol. xx. p. 52: 1884; Arbeit, a. d. pathol.
Inst. z. München., edit, by Bollinger, pp. 215, 226 : Stuttgart, 1886.

2Erman, Ann. d. Physik, vol. xxx. p. 113 : 1808 ; Leydig, Arch. f. Anat. u.
Physiol., p. 3 : 1853 ; Baumert, " Chemische Untersuchung über die Respiration
des Schlammpeitzgers " : Breslau, 1855.

GASES OF THE BLOOD AND RESPIRATION 277

contrary, be assumed that nitrogen diffuses out of the tissues of
the intestinal wall into the intestine. This occurs in the lower
portion of the intestine, in proportion as other gases are de-
veloped by fermentation and the partial pressure of the nitrogen
sinks. The intestinal gases as a matter of fact always contain
an abundance of nitrogen.

Hydrogen is formed in large quantities by fermentative
processes, and especially, together with COg, in butyric acid
fermentation. This latter form of fermentation can always
be detected in the contents of the large and small intestine.^
As already mentioned, marsh-gas arises, with carbonic acid,
by the decomposition of cellulose. But these are not the only
two processes of fermentation by which CO2, H, and CH^
are formed in the intestine. Ruge found marsh-gas in the
gases of the colon of living people, even after a diet exclusively
composed of meat ; and Tappeiner found abundance of marsh-
gas and hydrogen in the gases of pigs' colons, after they had been
fed for three weeks entirely on meat. These gases proceed
not only from the decomposition of carbohydrates, but also of
proteids. KunkeP found that the gases produced by artificial
pancreatic digestion, without excluding the fermentative organ-
isms, contained as much as 60 per cent. H, and 1.6 per cent,
marsh-gas ; and Tappeiner ^ showed that sterilized solutions of
common salt with peptone and fibrin, when mixed with a little
of the intestinal contents, developed a mixture of gases which
contained as much as 40 per cent. H, and as much as 19 per
cent. CH^. It is noteworthy that in one of these experiments
Tappeiner produced from a solution of peptone a mixture of
gases which contained 99.65 per cent. CO2, as well as 0.14 H
and 0.21 CH^. In the intestine fermentations appear to go
on in which carbonic acid alone, without any other gas, is
developed from proteid.

Besides this, carbonic acid is developed in large quantity
through the neutralization of the acid chyme by the sodium
carbonate of the intestinal juice. If we may assume for
human beings the same proportion of hydrochloric acid in the
gastric juice which was found by Carl Schmidt in the dog, it
would appear that 6 liters of CO2 are daily liberated in our
intestine by neutralization of the hydrochloric acid. We have
to add the still larger quantity set free by the neutraliza-
tion of lactic and butyric acids, which are constantly formed

^ Compare Eubuer, Zeitsclir. f. Biolog., vol. xix. p. 84, et seq. ; 1883.
2 Kunkel, Verhandl. d. physik.-med. Gesellsch. in Wurzburg, N. F., vol. viii.
p. 134 : 1874.

^ Tappeiner, Ärb. a. d. patholog. Inst, in München, vol. i. p. 218 : 1886.

278

LECTURE XVIII

in the intestine from the carbohydrates of food. Still, we are
not inconvenienced by these large volumes of COg, for the co-
efficient of absorption of carbonic acid is very high, and the
partial pressure of COg in the intestinal walls is scarcely ever
higher than 10 per cent, of an atmosphere. Therefore, as
soon as the bowel contains more than 10 per cent, of COg,
diffusion into the blood must commence. The proportion of
carbonic acid in intestinal gases is commonly from 20 to 50
per cent., and more. It follows that there is constantly an
active current of carbonic acid from the intestine into the
blood. In the experiments on dogs with duodenal fistulae,
Mering has shown that the absorption of COg begins even in
the stomach. The COg developed in the bowel is exhaled by
the lung.

On the other hand, hydrogen may give rise to much dis-
comfort, owing to its very low coefficient of absorption. It
follows that patients suffering from chronic dyspepsia and
disposed to flatulence, must be extremely careful to avoid such
articles of diet as tend to a butyric fermentation. According
to the observations of Huge and Tappeiner, milk appears to be
especially injurious in this respect. The experience of many
patients coincides with this view. In the same way starchy
foods, which are hard to digest, are to be avoided, because they
convey large quantities of carbohydrates into the lower portion
of the small intestine, the alkalinity of which encourages
butyric fermentation. It would be wise to administer carbo-
hydrates in the form of stewed fruits, because we thus convey
with them acids into the bowels and because the acids prevent
butyric fermentation. There are many patients with whom
cereals, the leguminosse, and potatoes disagree, but who are
able to take stewed fruits with rice, which is easily digested
and which is manifestly almost entirely absorbed in the upper
part of the bowel.

The following table gives the coefficients of absorption of
the intestinal gases. They have been determined by Bunsen
at a temperature of 15° C. It is to be regretted that they
have not also been determined for the body-temperature.

Nitrogen 0.01478

Hydrogen 0.01930

Oxygen 0.02989

CH^ 0.03909

CO, 1.0020

H,S 3.2326

The amount of sulphuretted hydrogen contained in the intes-
tinal gases is very small, and cannot be quantitatively deter-
mined. It is however conceivable that the amount developed
in the bowel is sometimes larger than might be supposed

GASES OF THE BLOOD AND RESPIEATION 279

from the small amount contained in the intestinal gases. We
must not forget how high the coefficient of absorption of sul-
phuretted hydrogen is, being one hundred times higher than
that of oxygen which is so easily diffusible. Sulphuretted hy-
drogen, in proportion as it is set free, must at once diffuse into
the blood. Planer injected into the rectum of dogs sulphu-
retted hydrogen diluted with hydrogen, and observed toxic
symptoms within one or two minutes. When, in certain proc-
esses of disease, abnormal decomposition takes place in the
contents of the bowel, it is possible that a large quantity of
sulphuretted hydrogen may be developed. In the artificial di-
gestion of fibrin by pancreatic juice, without excluding bacteria,
Kunkel found that the gases contained as much as 1.9 per cent,
of HgS. It is possible that in the headache, vertigo, and nau-
sea frequently accompanying gastric and intestinal catarrh and
persistent constipation, poisoning by sulphuretted hydrogen
plays a part. Senator^ communicates the following case, which
he regards as undoubtedly one of poisoning by sulphuretted
hydrogen. He succeeded in finding sulphuretted hydrogen in
the urine of a patient suffering from acute intestinal catarrh, as
it distinctly gave a brown color to a visiting-card which con-
tained lead. The eructations of the patient caused a distinct
odor of sulphuretted hydrogen. He also had repeated attacks
of vertigo, accompanied by epigastric oppression and a dark
complexion. It is stated that persons engaged in the emptying
of cesspools, and exposed to sulphuretted hydrogen gas, have
experienced similar symptoms.

We have at present little certain knowledge as to what be-
comes of the absorbed hydrogen and marsh-gas. They either
become oxidized or reappear in the exhaled air. An experi-
ment made in Zuntz's ^ laboratoiy in Berlin, with a tracheoto-
mized rabbit showed that the air exhaled by these animals in-
variably contains hydrogen, and generally marsh-gas as well —
to a greater extent even than the gases voided during the same
period per anum. It has not yet been determined whether
all hydrogen and all marsh-gas which are absorbed from the
intestine reappear in the expired air, or whether a part is oxi-
dized in the body. The decision of this question would be of
great interest for the theory of internal respiration. (Com-
pare p. 238.)

The quantitative composition of intestinal gases necessarily

1 Senator, Berlin. Min, WochcTisch., Jahrg. v. p. 254 : 1868.

2B. Tacke, " üeber die Bedeutung der brennbaren Gase im thierischen
Organismus," Inaug. Dissert. : Berlin, 1884. Also Ber. d. deutsch, ehem. Ges.,
vol. xvii. p. 1827 : 1884.

280

LECTURE XVIII

varies greatly according to the diet aud the condition of the en-
tire digestive apparatus, and especially according to the extent
to which fermentation can be resisted. Thus for instance Ruge
found in the intestinal gases of the same person : —

After milk diet.

After four days'

dietof leguminosse

only.

After three
days' diet of
meat only.

Oxygen

36.71
54.23

9.06

18.96
4.03
55.94
21.05
Trace

64.41

Hydrogen

0.69

CH,

COj

26.45
8.45

HjS

Tappeiner ^ found that the gases removed half an hour after
death from the corpse of a man who had been executed, exhib-
ited the following composition :

stomach.

Ileum.

Colon.

Bectum,

Oxygen

Nitrogen

Hydrogen

CH,

COj

9.19 \

74.26/

0.08

0.16

16.31

67.71
3.89

28.4

17.46
0.46
0.06

91.92

62.76

0.9
36.4

* Tappeiner, Arb. a. d. patholog. Inst. d. München, vol. i. p. 226 : 1886.

LECTURE XIX

THE NITROGENOUS END-PRODUCTS OF METABOLISM
HIPPURIC ACID, UREA, CREATIN

The examiriation of the processes of respiration has shown
us that the bulk of the carbon is eliminated from our body by
the lungs as carbonic acid. The remainder of the carbon takes
a different course. It quits our body in combination with the
bulk of the nitrogen, in the form of a series of compounds very
rich in nitrogen, through the kidneys. Among these nitrog-
enous end-products the chief in man are urea, uric acid,
hippuric acid, creatin, and Creatinin. A considerable portion
of nitrogen appears in urine as an inorganic compound — as a
salt of ammonia.

We will now pursue the origin of these end-products in the
animal body as far as the present state of our knowledge
permits. We will begin with hippuric acid, because the
origin of this compound has been more carefully studied and is
better known than that of any of the other nitrogenous
end-products. The constitution of hippuric acid is accurately
known. The following mode of preparation makes it very
clear : —

CgHj — CO — N< +CH2CI — COOH =
Benzamide. Monochloracetic acid.

CjHj — CO — N< +C1

^CHj- COOH

Hippuric acid.

If we boil hippuric acid with strong mineral acids or with
alkalies, or subject it to the action of ferments, it splits up
with hydration into benzoic acid and amido-acetic acid
(glycocol).

281

282 LECTURE XIX

CfiHj — CO — N< + HP =

\CHj — COOH

Hippuric acid.

/^
CgH. — COOH + H — N<

NdHj — COOH
Benzoic acid. Glycocol.

Hippuric acid is again formed with dehydration, from these two
products of its decomposition, if they are allowed to act upon
one another at a high temperature and under increased pressure.
To effect this they are inserted dry into a glass tube, the ends
of which are fused, and the tube is kept at a temperature of
160° C. for twelve hours.^

Hippuric acid is also formed in the animal body by the
combination of benzoic acid and glycocol. If benzoic acid is
introduced into the stomach of an animal or a human being, it
reappears as hippuric acid in the urine. Doubtless the gly-
cocol used in its formation arises from the decomposition of
the Proteids of the tissues. Free glycocol has certainly not
as yet been proved to exist in animals. As little are we able
to obtain it by the artificial decomposition of proteid, but we
know that the immediate derivatives of proteid, the collagenous
substances, when decomposed either by ferments, by acids or
by alkalies, readily yield glycocol. In combination with an
acid glycocol also appears, as we have seen, in bile as glyco-
cholic acid.

Hippuric acid is also constantly found in the urine of
the herbivora, without the artificial administration of benzoic
acid. The numerous aromatic compounds which are contained
in the tissues of plants, and which in the animal body are con-
verted by oxidation into benzoic acid, evidently yield the ma-
terial for its formation. However, small quantities of hip-
puric acid may be found in the urine of dogs fed only upon
meat, and also during inanition.^ In this case the benzoic acid
is formed from the aromatic radicals which are contained in the
proteid molecule.^

The amount of hippuric acid contained in the urine of man
in twenty-four hours is generally less than 1 grm.; but after

^ Dessaignes, Journ. Pharm,,, vol. xxxii. p. 44 : 1857.

^E. Salkowski, Ber. d. deutsch, ehem. Ges., vol. xi. p. 500 : 1878.

^E. and H. Salkowski, ibid., vol. xii. pp. 107, 648, 653: 1879; Zeitschr. f.
physiol. Cliem., vol. vii. p. 161: 1882; E. ^ViWioviski, Zeitschr. f. physiol. Chem.,
vol. ix. p. 229 : 1885. Compare also Tappeiner, Zeitschr. f. Biolog., vol. xxii. p.
236 : 1886 ; and E. Baas, Zeitschr. f. physiol. Chem., vol. xi. p. 485 : 1887.

NITROGENOUS END-PEODUCTS OF METABOLISM 283

the consumption of certain berries and fruits it amounts to sev-
eral grammes.

The fact that benzoic acid introduced into the stomach
reappears as hippuric acid in the urine was discovered as early
as 1824 by Wöhler.^ This discovery was afterwards confirmed
by numerous experiments, and excited some attention, for it
was the first synthetic process which was proved to occur in the
animal body. Since then a long series of other syntheses have
been discovered in the animal body. I need only remind my
readers of the formation of the conjugated sulphuric acids and
glycuronic acids, and of the formation of glycogen from sugar.
It is probable that the formation of proteid from peptone be-
longs to this category. We shall soon become acquainted with
other synthetic processes.

There are two reasons why these synthetic processes in the
animal body have excited the interest of physiologists and
chemists during the last twenty years : in the first place, these
facts were in contradiction to the dominant doctrine of Liebig
with regard to the universal contrast between the metabolic
processes in plants and in animals ; in the second place, the
syntheses in animals are an unsolved problem to chemists,
although it is the rapid progress in our knowledge of the
syntheses of organic compounds which constitutes the greatest
triumph of modern chemistry. We are already able artificially,
to build up, atom for atom, out of their elements, a series of
organic compounds, some of a very complex character. We
no longer doubt that all the rest, even the most complex, will
be thus produced ; it is merely a question of time. Still, this
in no way represents the synthetic processes in the living cell,
for all our artificial syntheses can only be achieved by the
application of forces and agents which can never play a part in
vital processes, such as extreme pressure, high temperature,
strong galvanic currents, concentrated mineral acids, free
chlorin — factors which are immediately fatal to a living cell.

Thus we have seen that the artificial synthesis of benzoic
acid and glycocol to hippuric acid could only be induced by
heating both substances in a dry condition, in a closed tube, to
a temperature of 160° C. This implies extreme pressure,
extreme temperature, and absence of water. The very reverse
is the case in the animal body, where we find water in every
tissue, and the ordinary atmospheric pressure and temperature
in every cell. Even cold-blooded animals form hippuric acid.
It follows that the animal body has command of ways and

^Berzelius, "Lehrbuch der Chemie," translated by Wöhler, vol. iv. p. 376;
Vote. Dresden, 1831.

284 LECTURE XIX

means of a totally diiferent character, by which the same
object is achieved. An inquiry into these would be of extreme
interest to the chemist and to the physiologist ; the former
would thus obtain new methods for rising to still more com-
plicated combinations, and the physiologist would be enabled to
explain many of the most obscure processes in metabolism.

For this reason, Schmiedeberg and I conjointly ^ resolved to
study the conditions under which the synthesis of hippuric acid
takes place in the animal body.

In order to be able to trace benzoic and hippuric acids
through the tissues of the animal body, we required above all,
a precise method for their detection and estimation. This we
succeeded in obtaining after many experiments. We now
possess a method^ which enables us to separate these acids
from all other constituents of the animal body, and to weigh
them in a pure crystalline form without any appreciable loss.

We had next to determine in what organs and in what
tissues the synthesis takes place. We naturally thought first
of the liver. It is known that here another acid, conjugated
with glycocol (glycocholic acid), is formed ; besides, synthetic
processes have often been assigned to the liver. If this view
were correct, the removal of the liver must cause the benzoic
acid introduced into the blood to circulate unaltered in it, and
to pass out by the kidneys unchanged.

This experiment could not be carried out in mammals
because, after ligature of the hepatic vessels, the bulk of the
blood accumulates in the portal system, and the circulation
in the other organs is almost entirely arrested. Dogs
die from thirty to fifty minutes after this operation. It
may be said that they begin to die as soon as the portal vein
is tied.

We therefore instituted our experiments on frogs. They
bear the extirpation of the liver very well, surviving the oper-
ation for three or four days. They run about during this time
with almost undiminished vigor. If we introduced benzoic
acid into the dorsal lymphatic sac, the frogs invariably formed
hippuric acid, which was more copious when, in addition to
benzoic acid, glycocol was injected. Unless benzoic acid was
injected, no trace of hippuric acid was ever to be found in the
tissues or in the secretions of the frog. It follows of necessity
that the liver is not the locality, at all events not the exclusive
locality, for the formation of hippuric acid.

' Buuge and Schmiedeberg, Arch. f. exper. Path. u. Pharm., vol. vi. p. 233 :
1876.

2 The method is described, loc. cit., pp. 234-239.

NITEOGENOUS END-PEODUCTS OF METABOLISM 285

We then thought that the synthesis might possibly occur
in the kidney. In order to decide this, it was necessary to
have recourse to warm-blooded animals. Dogs survive the
ligature of the vessels of both kidneys for several hours, and
the circulation in their other organs is not materially affected.
We injected glycocol and benzoic acid into the blood of dogs
thus operated upon, bled them to death after three or four
hours, and examined the blood of the liver and muscles for
hippuric acid without ever finding a trace of it ; we found only
benzoic acid. It therefore appears that all the other organs
together cannot, without the kidneys, combine glycocol and
benzoic acid, and that the kidney is the locality in which the
synthesis is performed.

A sceptical critic will not be satisfied with this conclusion.
There is still room for objection. The ligature of the kidneys
may be regarded as so violent an operation as to produce direct
and indirect disturbances of all kinds in all parts of the
organism. We must therefore admit the possibility that dis-
turbances may be produced in tissues with which we are as yet
unacquainted, and in which the synthesis is effected.

The hope remained that if we could show that the kidney,
separated from other organs, was able to produce the synthesis
by itself, we should be in a position to prove that the formation
of hippuric acid took place in that organ. This hope was
realized. We bled a dog to death, removed the kidneys, added
glycocol and benzoic acid to the defibrinated blood, and con-
veyed it, under an approximately normal pressure, through the
artery, and allowed it to flow out of the veins of one of the
kidneys. The blood that passed out of the vein was returned
to the reservoir, from which it reentered the artery ; and this
process was continued for several hours. Hippuric acid was
invariably found in the blood after its passage through the
kidney, and in the fluid which during its passage escaped by
the ureter. But in the other kidney, and in a portion of the
blood which had not traversed the kidney, no trace of hippuric
acid could at any time be discovered. It follows that hippuric
acid was formed in the excised kidney.^

If we added benzoic acid without glycocol to the blood
that was passed through the kidney, the quantity of hippuric
acid formed was small ; but it was considerable when glycocol
was mixed with it. As a matter of fact, the two ingredients
had entered into combination, with separation of water. It
was indifferent whether we raised the temperature of the

1 Wilh. Koehs has confirmed these results by a series of careful experiments
in Pfliiger's laboratory (Pfliiger's Arch., vol. xx. p. 64 : 1879).

286 LECTÜEE XIX

kidney and the blood to the temperature of the body, or
cooled it to that of the room. In either cases the synthesis
was effected. It was remarkable how long the excised kidney
retained the faculty of forming hippuric acid. In one of our
experiments we allowed the kidney to remain for forty-eight
hours in an ice-chest. We passed the blood of another dog
through it, which had been obtained twenty-four hours pre-
viously ; nevertheless some hippuric acid was formed.

We now inquired whether the living tissue of the kidney is
essential for the synthesis. Does the result depend upon the
formed elements and upon a definite histological arrangement,
or is this function of the kidney only due to its containing
certain chemical substances? In the latter case, it might be
possible to isolate these substances, and then to effect the syn-
thesis artificially.

Accordingly we destroyed the renal tissue. We chopped
up the kidney and pounded it into a homogeneous pulp. To
this we added blood, glycocol, and benzoic acid, and allowed
the mixture to stand, shaking it at frequent intervals. We
varied the experiment, applied different temperatures, provided
a copious supply of oxygen, but we never succeeded in finding
a trace of hippuric acid.

This experiment was repeated in Pfliiger's laboratory by
Kochs.^ When the kidney had only been chopped up, Kochs
discovered minute traces of hippuric acid, but if it had been
not only chopped up, but also rubbed up " in a mortar with
large pieces of glass " to an almost homogeneous mass, not a
trace of hippuric acid was to be found ; nor was it met with
when the kidney, before being chopped up, had been frozen at
- 20° C, and thawed at 40°.

These experiments appear to prove that the synthesis is due
to the living cells of the kidney, and not to one of its chemical
components.

We now inquired whether the blood-corpuscles are essential
for the production of the synthesis. We therefore conducted
serum which had been deprived of all cells by the centrifugal
machine, together with glycocol and benzoic acid, through the
excised kidney. In this case no hippuric acid was formed. It
follows that the blood-corpuscles also take an active part in the
synthesis.

We now proceeded to inquire into the part played by the
blood-cells in this process, and to determine whether they act
only as oxygen-carriers.

In order to decide this question, Schmiedeberg and Arthur

1 Wilhelm Kochs, Pfliiger's Arch., vol. xx. p. 70, et seq.: 1879.

NITROGENOUS END-PRODUCTS OF METABOLISM 287

Hoffman^ conducted blood mixed with glycocol and benzoic
acid, and in which the oxygen had been replaced by carbonic
oxid, through the kidneys. The result was that no hippuric
acid was formed. The blood-cells therefore also act as oxygen-
carriers in the synthetic process, but whether they have only
this function remains uncertain. It may be objected that the
carbonic oxid, besides driving out the oxygen, has a toxic
effect on the renal cells. The following experiment of
Schmiedeberg and Hoffman goes to prove that certain poisons
do deprive the cells of the power of effecting syntheses. They
conducted blood, to which, besides glycocol and benzoic acid,
quinine had been added, through the kidneys. Only a very
small quantity of hippuric acid was subsequently found. It is
known, from the investigations of C. Binz,^ that quinine arrests
the ameboid movements of the cells. The same influence that
kills the cell likewise deprives it of the capability of bringing
about syntheses.

With regard to the locality where hippuric acid is formed
in the animal body, I would add that its exclusive formation in
the kidney is only proven in the case of the dog. Schmiede-
berg and I have already shown that frogs form hippuric acid
even after extirpation of the kidney. Salomon^ discovered
subsequently that certain mammals do not form hippuric acid
exclusively in the kidney. Salomon, after giving benzoic acid
to rabbits which had been deprived of their kidneys, found
abundant hippuric acid in their blood, muscles, and liver.

If benzoic acid be introduced into birds, it appears in the
urine, not as hippuric acid, but combined with a base, which
Jaff6* described as Ornithin, having the formula CgH^2^2Ö2'
It is probably diamido-valerianic acid. Two other diamido-
acids were discovered later by Drechsel among the products of
disintegration of proteids, viz., diamido-acetic acid and diamido-
caproic acid or lysin. These latter have hitherto been obtained
only outside the organism by the artificial hydrolysis of pro-
teids, whereas diamido-valerianic acid has only been detected
as the result of the natural decomposition of proteids in the
body. The compound of benzoic acid and Ornithin has been
called ornithuric acid by Jaff§.

But, as already mentioned, a very inconsiderable portion of
the nitrogen in human beings is eliminated as hippuric acid.
The bulk of it, in man and mammals, appears in the urine as

^ Arthur Hoffman, Arch. f. exper. Path. u. Pharm,, vol. vii. p. 239 : 1877.
2 C. Binz, Arch. f. mikr. Anat., vol. iii. p. 383 : 1867.
* Salomon, Zeitschr. f. physiol. Chem., vol. iii. p. 365.

'^ JaSe, Per. d. deutsch, chem. Ges., vol. x. p. 1925: 1877; vol. xi. p. 406:
1878. Hans Meyer, ibid., vol. x. p. 1930 : 1877.

288 LECTURE XIX

UEEA. The amount of urea excreted is therefore regarded as
an index of the consumption of proteid in the body. The
greater portion of nitrogen is introduced in the form of
proteid. Nearly half the weight of urea consists of nitrogen.
The 100 grms. of proteid daily used up by one person contain
about 16 grms. of nitrogen, to which 34 grms. of urea corre-
spond. This is about the quantity found in a man's urine
during twenty-four hours.

The constitution of urea is known. Its formation from
carboxyl chlorid (COClj) and ammonia, as well as from ethyl
carbonate and ammonia, undoubtedly shows that urea should be
regarded as the amid of carbonic acid, Carbamid [CO(HN2)2] .
On heating with acids or alkalies or by the action of ferments,
urea takes up two molecules of water and is converted into car-
bonate of ammonia. Urea is a neutral compound, capable of
crystallization and very readily soluble in water.

How does urea arise from proteid, and what are the inter-
mediate stages ? A recapitulation of our previous remarks on
the changes of proteid in the body may not be out of place
here. It was shown that proteid was converted by the digestive
ferments into peptones ; that the peptones are probably prod-
ucts of decomposition ; and that, by continued action of the
digestive ferments or of other ferments of decomposition, a
part of the nitrogen is split off in the form of amido-acids, as
amido-caproic acid or leucin [C5H,q(NH2)COOH] , as tyrosin,

an aromatic amido-acid lCgH^-( p it /-vrtr \rir)r)Ti ) > ^^^ ^s

amido-succinic acid or aspartic acid ^ [C2H3(NH2)(COOH2)]
and its homologue, glutamic acid, C3H.(NH2)(COOH)2. The
proteids also give the same products of decomposition on boil-
ing with acids or with alkalies." We have moreover seen that
a portion of the proteids is converted in the animal body into
collagenous substances which, under the same conditions as
the ])roteids, produce amido-acids, and especially leucin and
glycocol.^

1 Radziejewski and E. Salkowski, Ber. d. deutsch, ehem. Ges., vol. vii. p.
1050: 1874; W. von Knieriem, Zeitschr.f. Biolog., vol. xi. p. 198 : 1875.

^Hlasiwetz and Habermann, Ann. d. Chem. u. Pharm., vol. clxix. p. 150:
1873 : E. Schulze, J. Barbieri und E. Bossard, Zeitschr. f. physiol. Chem., vol.
ix. p. 63: 1884; E. Schulze und E. Bossard, ibid., vol. x. p. 134: 1885; M. P.
Schiitzenberger, Bull, de la SociHe chim., vol. xxiii. pp. 161, 193, 216, 242, 385,
433; vol. xxiv. pp. 2, 145: 1875; vol. xiv. p. 147: 1876; Schützenberger et A.
Bourgeois, C'ompt. rend., vol. Ixxxii. p. 262 : 1876. Compare also R. Maly,
Sitzungsber. d. k. Akad. d. W. in Wien., Math. nat. CI., vol. xci. part ii., Feb.,
1885; vol. xcvii. part ii., March, 1888; and vol. xcix. part ii., Jan., 1889.

^Nencki, " Ueber die Zersetzung der Gelatine und des Eiweisses bei der
Fäulniss mit Pankreas " : Berlin, 1876. .Jules Jennaret, i/bitrn.. /. jpra/jf. Chem.,
N. F., vol. XV. p. 353: 1877 (from Nencki's laboratory).

UREA 289

More recently a number of basic substances have been dis-
covered among the products of disintegration of proteids. As
we have already mentioned, Drechsel found diamido-acetic
acid/ diamido-caproic acid or lysin/ and a body to which he
gave the name of lysatin and which has been since found to
consist of a mixture of lysin with another base, arginin.^ This
substance, together with histidin,^ was first discovered by
Hedin.

Arginin (CgHj^N^Oj) and histidin (CgHgNgO^) had already
been discovered by Kossel, together with lysin, among the
decomposition products of certain bases which occur in the
spermatozoa of certain fish. Miescher^ had previously found
a base of the composition CjgHggNgOg in the spermatozoa of
Rhine salmon and had given it the name of protamin. Kossel ®
found similar bases in the spermatozoa of other Salmonidse as
well as of the sturgeon and herring. It is remarkable that the
Protamins give the most constant proteid reaction, viz., the
biuret reaction.

These facts suggest that all these nitrogenous substances
might be regarded as the precursors of urea. So far only
the amido-acids have been the subject of direct experiment.
Schnitzen and Nencki^ administered leucin and glycocol to
dogs, and found that these compounds did not reappear in the
urine, but that there was a corresponding increase of urea.
Salkowski,^ on repeating these experiments, fully confirmed these
results. Knieriem ^ showed, by a similar method of research,
that aspartic acid is also converted into urea.

But even these facts tend but little to the elucidation of the
origin of urea. It is only the smallest part of urea which can
be formed from amido-acids. This is seen by a glance at the
empirical formula of proteids. We have shown (pp. 49-51) that

' E. Drechsel, Ber. d. k. sack. Ges. d. Wissensch., p. 115 : 1892.

*E. Drechsel and R. Krüger, £er. d. deutsch, ehem. Ges., vol. ixv. p. 2454:
1892.

ä Hedin, Zeitschr. f. physiol. Chem., vol. xx. p. 186 : 1895 ; vol. xxi. p. 155 :
1896. Compare also E. Schulze and E. Steiger, ibid., vol. xi. p. 43 : 1887.

* Hedin, Zeitschr. f. physiol. Chem., vol. xxii. p. 191: 1896. Compare M.
Bauer, ibid., vol. xxii., p. 284: 1896.

s Miescher, Verhandl. d. naturf. Ges. in Basel, p. 138 : 1874. J. Piccard,
Ber. d. deutsch, chem. Ges., vol. vii. p. 1714: 1874. Posthumous paper of
Miescher, edited by O. Schmiedeberg, Arch. f. exper. Bath. u. Pharm., vol.
xxxvii. p. 100 : 1896.

8 Kossel, Sitzungsber. d. Ges. z. Befdrd. d. ges. Naturwissensch. z. Marburg,
No. 5, p. 56 : July, 1897.

' Schultzen and Nencki, Zeitschr. f. Biolog., vol. viii. p. 124 : 1872.

"E. Salkowski, Zeitschr. f. physiol. Chem., vol. iv. p. 100: 1879.

** W. von Knieriem, Zeitschr. f. Biolog., vol. x. p. 279 : 1874.

19

290 LECTÜEE XIX

the following formulse may be deduced from the most reliable
analyses of the purest preparations of proteids.

Egg-albumin, CawHjjjNsjOegSj.

Proteid in hemoglobin from horse. CjgoHioggNjioOjiiSj.

Proteid in hemoglobin from dog. CYjeHnnNig^OanSj.

Globulin from pumpkin seeds. C292H4giN9o083S2.

"We see that there is not nearly sufficient carbon in the proteid
to permit of all the nitrogen issuing as an amido-acid. In the
various kinds of proteid, from three to four atoms of carbon go
to one atom of nitrogen ; in aspartic acid, four atoms of carbon
to one of nitrogen ; in leucin, six ; and in tyrosin, as many as
nine. Glycocol indeed contains only two atoms of carbon to
one of nitrogen. But it is questionable whether it is this amido-
acid which is formed in especially large quantity from the proteid
in the animal body. As stated, it cannot be obtained from the
proteid outside the organism, but only if the proteid has been
previously changed by the vital process in the animal into a
collagenous substance ; and it is only the smallest portion of the
proteid of the food which undergoes this conversion. It must
also be taken into consideration that the proteid in the animal
body also yields products of decomposition free from nitrogen
and very rich in carbon. What follows will make it apparent
that fat and glycogen can be formed in the animal body from
proteid. We are thus obliged to conclude that the largest por-
tion of the nitrogen is split off from the proteid molecule as a
compound containing very little carbon.

It is possible that a part of the urea in the animal body is
separated directly from the proteid as a neutral compound.
But it is also possible that ammonia and carbonic acid split
off from the proteid, subsequently combining, with elimination
of water, to form urea. This would be a process completely
analogous to that involved in the formation of hippuric acid.
As monobasic benzoic acid unites with a molecule of a sub-
stituted ammonia (glycocol), losing one molecule of water, to
form hippuric acid, so dibasic carbonic acid unites with two
molecules of ammonia, losing two molecules of water, to form
urea —

^= o + 2NH3 = 2H2O +0=0

OH \NH,

•^

The conversion of the amido-acids into urea may be thus repre-
sented : they are first split up and oxidized into carbonic acid

UREA 291

and ammonia, and in this state yield the material for the
formation of urea. In any case, we have to deal with
another synthetic process, for the leucin and glycocol contain
but one atom of nitrogen in the molecule, whereas urea has
two.

The supposition that carbonate of ammonia was the ante-
cedent of urea was based upon the following observations of
Buchheim and his pupil Lohrer.^ The latter took 3 grms. of
ammonia in the form of citrate, expecting that it would behave
in the body like citrate of potash or soda, which are known to
pass into the urine as carbonates of potash or soda, and to
render the urine alkaline. But this did not happen. The
urine remained acid. The carbonate of ammonia formed must
therefore have been converted into a neutral compound. It
was readily assumed that urea had been formed.

In order to decide the question whether ammonia is con-
verted in the animal body into urea, careful experiments on
the metabolic changes were made by Knieriem^ on dogs and
on human beings, and by Salkowski^ on dogs and on rabbits.
The experiments made on rabbits gave results which were
quite definite : after the administration of chlorid of ammonia,
the excretion of ammonia was scarcely increased at all, whereas
that of urea was increased. The experiments on human beings
and on dogs were not so definite. Part of the ammonia
appeared unaltered in the urine, and it remained doubtful
whether the extra excretion of urea was to be ascribed to the
ammonia administered, or to an indirect increase of proteid-
decomposition produced by the ammonia. This difference in
its action in rabbits as compared with human beings and dogs
may be explained as follows. The hydrochloric acid of the
chlorid of ammonia introduced, by its strong affinity for
ammonia, prevents the union of the latter with the carbonic
acid to form urea. Now, in the organism of herbivora this
hindrance is overcome, because the vegetable food yields an
alkaline ash; carbonate of potash is also formed in the
organism by combustion; this, together with the chlorid of
ammonia, is converted into chlorid of potash and carbonate of
ammonia, which latter is changed into urea. The mixed diet
of human beings and of dogs in Knieriem's and Salkowski's
experiments would necessarily give a feebly acid ash; the
conversion of the ammonia into urea was therefore not so

^ Julius Lohrer, " Ueber den Uebergang der Ammoniaksalze in den Harn,"
Inaug. Dissert. Dorpat, 1862, pp. 36, 37.

2 von Knieriem, Zeitschr. f. Biolog., vol. x. p. 263 : 1874.
^ E. Salkowski, Zeitschr. f. physiol. Chem., vol. i. p. 1 : 1877.

292 LECTURE XIX

complete. Feder/ who experimented with chlorid of ammonia
upon fasting dogs, recovered all the ammonia from the urine.
For the fasting dog is nourished by some of the proteid of its
tissues, and a great deal of sulphuric acid is set free. This
prevents the ammonia from uniting with the carbonic acid.
Fr. Walter^ and Coranda^ showed the excretion of ammonia
to be considerably augmented in dogs and in man after the
administration of hydrochloric acid. The latter impedes the
normal formation of urea. The administration of carbonate
of soda diminishes the normal excretion of ammonia.* For
this reason the experiments on the formation of urea were
repeated in Schmiedeberg's laboratory/ but the ammonia was
not administered in combination with strong mineral acids, but
simply as carbonate. The dog swallowed the carbonate of
ammonia wrapped in meat readily enough ; in this manner 3
grms. NHg were administered to the animal on two successive
afternoons. The excretion of ammonia in the urine was not
found to be augmented, but there was an increase of urea, and
the urine remained acid. Thus there can be no doubt that
carbonate of ammonia is converted into urea.

Hoppe-Seyler ^ and Salkowski^ have arrived at other
views concerning the origin of urea. They regard cyanic
acid as the immediate precursor of urea, and DrechseP
considers that urea arises from carbamate of ammonia. This
last opinion is not at variance with the idea that urea
originates in carbonate of ammonia. For carbamate of

ammonia < C=0 V stands midway between carbonate

I \0(NH,)j

^ Feder, Zeitschr. f. Biolog., vol. xiii. p. 256 : 1877.

2 Fr. Walter, Arch. f. exper. Path. u. Pharm., vol. vii. p. 148 : 1877.

3 Coranda, ihid., vol. lii. p. 76 : 1880.

"^Munk, Zeitschr. /. physiol. Chem., vol. ii. p. 29: 1878; E. Hallervorden,
Arch. f. exper. Path. u. Pharm., vol. x. p. 124: 1879.

^Hallervorden, loa. cit., whose results have been confirmed by Feder and
Voit, Zeitschr. f. Biolog., vol. xvi. p. 177 : 1880.

* Hoppe-Seyler, Ber. d. deutsch, chem. Ges., vol. vii. p. 34: 1874; and
"Physiologische Chemie," pp. 809, 810: Berlin, 1881.

■^ E. Salkowski, Centralbl. f. d. med. Wissensch., p. 913: 1875; Zeitschr. f.
physiol. Chem., vol. i. pp. 26-42 : 1877. Compare also Schmiedeberg's objections
in the Arch. f. exper. Path. u. Pharm., vol. viii. p. 4, et seq.: 1878; and
Schroder's, ibid., vol. xv. pp. 399, 400 : 1882.

* E. Drechsel, Ber. d. sächs. Ges. d. Wissensch., p. 171 : 1875 ; Journ.f.prakt.
Chem., N. F., vol. xii. p. 417 : 1875 ; vol. xvi. pp. 169, 180 : 1877; vol. xxii. p.
476 : 1880. Compare also the objections raised by Franz Hofmeister, Pfliiger's
Arch., vol. xii. p. 337 : 1876. Considerable difficulties, which have not yet been
successfully overcome, are met with in the attempt to detect and determine
quantitatively the carbamic acid in the urine and tissues. Compare Hahn and
Nencki, Arch. d. 8c. bioL, vol. i. p. 447 : St. Petersburg, 1892.

ußEA 293

of ammonia < C=0 V and urea ^ C=0 V. By

i \0(NHjj l \nhJ

eliminating one molecule of water, carbonate of ammonia yields
carbamate of ammonia ; by elimination of a second molecule,
urea. As it would lead me too far to enter into these theories
at greater detail, I refer the reader to the interesting original
works that deal with the matter.

The most complete and reliable researches as to the locality
in which urea is generated have been made by W. von
Schröder.^ He extirpated both kidneys in a dog, and took a
specimen of the blood from the carotid immediately after the
operation. The dog was bled to death twenty-seven hours
afterwards. The quantity of urea in each sample of blood
was determined.^ In the first case it amounted to 0.5 per
thousand ; in the second, to 2 per thousand. The urea in the
blood is therefore increased fourfold by the extirpation of the
kidneys, and it follows that the kidneys cannot be the only
place where urea is formed.^

But the possibility still remained that urea was formed in
the kidney as well. Schröder therefore conducted blood, to
which carbonate of ammonia had been added, through the
excised kidneys. The amount of urea in the blood remained
the same, both before and after it had been passed through the
kidneys. As the formation of urea from carbonate of ammonia
is a process entirely analogous to that of the formation of
hippuric acid from glycocol and benzoic acid, and as the
excised kidney still brings about the latter synthesis, this
experiment renders it extremely probable that carbonate of
ammonia does not, in normal conditions, undergo conversion
into urea in the kidneys.

Urea is therefore not formed in the kidneys but merely
excreted by them. But where is it formed ? As the muscles
constitute 40 per cent, of the whole weight of the body, it was
natural to think of them first. The compound, which forms

1 W. von Schröder, Arch. f. exper. Path. u. Pharm., vol. xv. p. 364: 1882;
and vol. xix. p. 373 : 1885.

2 The admirable care with which the methods of determining the urea were
controlled and carried out renders Schroder's researches so valuable, and raises
them far above those of his predecessors. In the decisive experiments the urea
was weighed in pure crystals, which were subsequently analyzed to test their
purity. The method is described loc. cit., pp. 367-377.

^ The results of previous work are in harmony with this, especially those of
Prevost and Dumas in the Ann. de Chim. et de Phys., vol. xxiii. p. 90 : 1823. An
account of the earlier literature is given by Voit, Zeitschr.f. Biolog., vol. iv. p.
116, et seq. : 1868; and by Schröder, loc. cit., pp. 364, 365.

294 LECTUEE XIX

the bulk of the nitrogenous end-products, might arise in the
muscles. Schröder therefore conducted blood impregnated with
carbonate of ammonia through the hind quarters of a dog
which had been bled to death. The blood was introduced into
the abdominal aorta below the renal arteries, and flowed out
of the inferior vena cava. In one of the experiments 1100
c.cms. of blood were passed repeatedly through the limbs, so
that the total flow during 4f hours amounted to 40 liters.
"During the first four hours the limbs moved spontaneously,
obviously from the stimulation to the spinal cord ; its irrita-
bility continued to the end of the experiment. If one electrode
was inserted into the spinal cord and the other applied to the
leg, tetanus ensued. A part of the spinal cord evidently pre-
served its vitality, for stimulation of one leg produced contrac-
tion of the other." But the amount of urea in the blood was
exactly the same before and after the passage of the blood.
The conclusion therefore is that no urea is formed from carbon-
ate of ammonia in the muscles and tissues of the body ; unless
indeed the objection were raised that the extremities could not
be regarded as being under normal conditions in spite of the
remarkable way they appeared to retain their vital properties.

The liver was the next organ to be thought of. It was to
be expected that large quantities of urea could be formed only
in a large organ. There are various reasons for believing
that extensive metabolic processes go on in the liver, the
largest of the glands. Schröder therefore conducted blood
containing carbonate or formate of ammonia through the liver.
The organ was removed from a small dog, whose blood was
mixed with that of a large dog. The blood was introduced into
the portal vein, and flowed out of the vena cava above the
diaphragm. The hepatic artery was closed. After the blood
had been allowed to pass for from four to five hours, the
urea was found to amount to between double and treble the
previous quantity. If blood without any carbonate of am-
monia was conducted through the liver, the amount of urea
increased but little, and then only in those experiments in
which the liver and the blood were taken from dogs during
digestion. If the blood and liver were removed from fasting
dogs, and carbonate of ammonia was not mixed with the blood,
no urea was formed ; but this occurred directly carbonate of
ammonia was added.

These results of Schroder's have been confirmed by Salo-
mon,^ who made his experiments on herbivora (sheep) as well
as on dogs.

* W. Salomon, Virchow's Arch., vol. xcvii. p. 149 : 1884.

UREA 295

Hence it follows that the synthesis of carbonate of ammonia
into urea takes place in the liver.

Even this knowledge however does not advance our acquaint-
ance with the precursors of urea. The antecedents of the small
amount of urea, obtained by passing through the liver blood
which had been taken from dogs during digestion, are still
unknown. In all the other experiments the precursor (carbon-
ate of ammonia) was artificially introduced. What justification
is there for the conclusion that carbonate of ammonia is also
normally the precursor of urea ?

Schröder based his views on this subject upon pathological
facts. If normally urea really arises in the liver from car-
bonate of ammonia, we should expect that in diseases of the
liver the formation of urea would be arrested, and that a
portion of the precursors would pass unchanged into the urine.
We should especially anticipate this in cirrhosis of the liver,
when the specific hepatic cells are pressed upon by the en-
croaching connective tissue, become atrophied, and in great part
disappear.

The above assumption has been confirmed by observation.
Investigators have found that in interstitial hepatitis the elimi-
nation of ammonia is increased both absolutely and relatively
in proportion to the excretion of urea.^ Healthy people excrete
from 0.4 to 0.9 grm. of ammonia in twenty-four hours, and in
cases of cirrhosis it rises to 2.5 grms.

It is thus rendered probable that part of the urea does arise
normally from carbonate of ammonia, but the actual quantity
is not yet known. It may be that only the small amount of
ammonia produced by bacterial putrefaction in the intestines is
absorbed by the blood of the portal vein to undergo this con-
version in the liver into the innocuous urea. (Compare Lecture
XXII.) Ammonia is a poison, and one of the functions of the
liver is the prevention of ammonia intoxication. We must
therefore acknowledge the possibility that the bulk of the urea
takes its origin from another source.

The question as to the part played by the liver in the
formation of urea might be definitely decided if we could
succeed in keeping mammals alive for a considerable time after
complete extirpation of the liver, or at any rate after cutting
this organ out of the circulation. I have already mentioned
(p. 284) the chief difficulty which prevents the carrying out
of this operation, viz., the complete stasis which occurs in the

■^ Hallervorden, Arch. f. exper. Path. u. Pharm., vol. xii. p. 237 : 1880 ;
Stadelmann, Deutsch. Arch. f. klin. Ned., vol. xxxiii. p. 526 : 1883.

296 LECTUEE XIX.

veins of the abdominal viscera as a result of ligature of the
portal vein. This difficulty has been overcome by establishing
an artificial communication between the portal vein and the
left renal vein or with the inferior vena cava.^ The latter
operation has been more especially carried out by V. Massen
and J. Pawlow on dogs with such skill that several of the
animals survived the operation for mouths. A complete
exclusion of the liver from the circulation was not however
effected, since the hepatic veins remained open, and since, even
after ligature of the hepatic artery, blood could reach the liver
by collateral anastomoses. In animals which had undergone
this operation the ammonia of the urine was found to be
increased to as much as 0.85 grm. in the twenty-four hours.
The great bulk of the nitrogen, however, was still secreted as
urea. In normal dogs the proportion of ammonia to urea was
found to vary between J^ and yL • in the operated dogs between
1 and J^.2

Massen and Pawlow also attempted to extirpate the liver
after establishing the venous fistula and tying the hepatic
artery. As much as seven-eighths of the liver could be de-
stroyed in this way, but the dogs never survived this operation
more than six hours, and generally only two or three hours.

In our previous remarks on the precursors of urea no notice
has been taken of a proteid product of decomposition which is
very rich in nitrogen, i. e., creatin. And yet creatin is im-
portant, as no other nitrogenous end-product of metabolism
occurs in so large a quantity in the body. Only very small
quantities of urea (of which from 30 to 40 grms. pass daily into
the urine) are at all times found in the body. The total blood
contains at most 2 grms., and it could not be detected in muscle.
On the other hand, creatin, of which only from 0.5 to 2.5 grms.
per diem pass as such or as Creatinin into the urine, is found
in the muscles alone to the extent of about 90 grms. This fact
renders it probable that creatin is converted into urea and thus
passes into the urine. This view has been held by many
physiologists, but the following observation seemed opposed to
it. It was found that creatin, introduced into an animal,
reappears in the urine either unaltered or, consequent upon the

^ N. V. Eck, Travaux de la Soc. des Naturalistes de St. Petersbourg, vol. x.:
1879. Bulletins de la Section Zoologique. Stolnikow, Pflüger's Arch., vol. xxviii.
p. 266 : 1882 ; Stern, Arch.f. Path. u. Pharm.,vo\. xix. p. 45 : 1885 ; W. v. Schröder,
ibid., vol. xix. p. 373 : 1885 ; Hahn, Massen, Nencki et Pawlow, Arch. d. Sc. bioL,
vol. i. p. 401 : St. Petersburg, 1892.

^Hahn and Nencki, Arch. d. Sc. biol., vol. i. pp. 461-465: St. Petersburg,
1892.

CKEATIN 297

loss of one molecule of water, as Creatinin.^ Hence it was
inferred that creatin could not be one of the antecedents of
urea. But this inference is incorrect ; because the creatin
introduced into the stomach or direct into the blood remains
unaltered, it does not follow that the creatin formed in the
muscles behaves in the same way. It is quite impossible for us
artificially to introduce substances to the part where they would
be decomposed in health. The muscular fibers withdraw from
the blood nutritive substances only, and throw off the end
products in an opposite direction. It is therefore even ä priori
unlikely that creatin, when artificially introduced, would enter
the muscle and be decomposed. It must be noted that it is
not only possible, but probable, that the large amount of
creatin formed in muscle becomes further split up and,
when converted into urea, given off to the blood. It is true
that urea cannot be detected in muscle. Liebig, in his
celebrated work on meat, says, " I think that I should be able
to detect urea in meat-juice if only one-millionth part were
present." ^ But it does not therefore follow that urea is not
formed there. It is quite possible that it is formed in the
muscle, but that it is immediately carried off into the blood-
current.

I have already given the reasons for my view that the
compounds into which the bulk of the nitrogen in the proteid
molecule splits up are very poor in carbon. Creatin answers to
this description ; it contains only four atoms of carbon to three
of nitrogen.

The composition of creatin has been thoroughly known
since Volhard and Strecker succeeded in producing it syn-
thetically. Volhard^ heated an alkaline solution of sarcosin
(methylglycocol) and cyanamid to 100° C. for a few hours in
a closed vessel. On cooling, creatin crystallized out. Strecker
went still more simply to work. If he allowed a saturated
watery solution of sarcosin, with the requisite amount of
cyanamid and a few drops of ammonia, to stand in the cold, a
large quantity of creatin was obtained.*

The constitution of creatin may be more readily understood
from a comparison of the composition of guanidin, which is

^G. Meissner, Zeitschr. f. rat. 3Ied., vol. xxiv. p. 100: 1865; vol. xxvi. p.
225 : 1866 ; vol. xxxi. p. 283 : 1868 ; C. Voit, Zeitschr. f. Biolog., vol. iv. p. Ill :
1868.

2 Liebig, Ann. d. Chem. u. Pharm., vol. Ixii. p. 368: 1847.

^ Volhard, Sitztmgsber. d. Munch. Akad., vol. ii. p. 472 : 1868 ; or Zeitschr. f.
Chem., p. 318 : 1869.

* Strecker, Jahresber. über Fortschr. d. Chem., note to p. 686 : 1868. Vide
also Horbaczewski, Wien. med. Jahrb., p. 459 : 1885.

298

LECTURE XIX

quite analogous to creatin both in synthesis and in decomposi-
tion. Creatin is a substituted guanidin.

= C = NH

Guanidin.

\ /CH,

^CHa — COOH

Creatin.

C = N

+

l(— H

Cyanamid.

+

/CH3
N — H

\CH,-

-COOH

Cyanamid.

Sarcosin.

The analysis corresponds to the synthesis. On boiling with
baryta water, the guanidin again splits into ammonia and cyan-
amid. But the cyanamid takes up one molecule of water
and passes into urea. In the same way creatin breaks up into
urea and sarcosin, a substituted ammonia. The close affinity
of creatin to urea, and the possibility of its conversion into the
latter, is thus amply proved.

Creatin is a neutral compound. By elimination of one
molecule of water it passes into a strong base — creatin.
This conversion is readily effected in an acid solution ; creatin
is as readily reformed by an alkaline solution. In conformity
with this, the small amount of creatin daily excreted through
the kidneys occurs chiefly as Creatinin in acid urine, and as
creatin in alkaline urine.^

DrechseP has prepared a base homologous with creatin
(C^H^NgO) by the hydrolytic decomposition of various proteids,
such as casein, conglutin, and gelatin. This body, which he
called lysatin, has since been shown to be a mixture of lysin and
arginin ; and it is the latter body which belongs to the creatin
group and like creatin yields urea on decomposition with
baryta water.

As creatin breaks up into urea and methyl-amido-acetic acid,
so arginin, on hydrolysis, yields urea and diamido- valerianic
acid (Ornithin). Drechsel reckons that ^ of the total urea pro-
duced in our bodies by the decomposition of proteid may arise
in this way by simple hydrolytic dissociation. We see therefore
that some at any rate of the urea can be formed independently
of the processes of oxidation and subsequent synthesis.

1 Voit, Zeitschr. f. Biolog., vol. iv. p. 115 : 1868.

2 Drechsel, Ber. d. deut. chem. Ges., vol. xxiii. p. 3096 : 1890.

LECTUEE XX

THE NITROGENOUS END-PRODUCTS OF METABOLISM [continued)
URIC ACID AND THE XANTHIN GROUP

Uric acid is the only nitrogenous end-product leaving the
body in any quantity that remains for our discussion.

The amount of uric acid excreted in twenty-four hours
varies greatly in the case of human beings. It depends upon
the nature of the food. With a purely vegetable diet it
amounts from 0.2 to 0.7 grm., and with a full meat diet it rises
to 2 grms. and more. These differences cannot be explained
merely by the varying amount of proteid in the food, for the
proportion of uric acid to urea and to the total amount of
nitrogen varies greatly. For instance, I found that the pro-
portion of urea to uric acid in twenty-four hours in the urine of
a healthy young man, when eating nothing but bread, = f -^f
= 82 ; and when living on meat, = -y-| = 48. Uric acid is
sometimes entirely absent from the urine of carnivorous ani-
mals, such as cats and dogs, and only a trace is generally
found in the urine of herbivora. The bulk of the nitrogen
however appears in this form in the urine of birds and reptiles.

Uric acid has the composition C^II^N^Og. One of the four
hydrogen atoms is easily replaced by metals. If the uric acid
be dissolved in a solution of sodium carbonate, the compound
CgllgNaN^Og is obtained. This compound is termed an acid
urate. On dissolving in free alkalies, a second hydrogen atom
is replaced by the alkaline metal. This compound is called a
neutral urate. It is not known whether it occurs in the ani-
mal body.

Uric acid and all its ' acid salts ' are with difficulty soluble
in water. It is important, from a physiological and pathological
point of view, to be accurately acquainted with its various
degrees of solubility. It is well known that in disease, uric
acid and urates may be precipitated from the fluids of the body,
and become deposited in the joints and other organs and tissues,
or from the urine in the tubules and pelvis of the kidney and
in the bladder. The painful symptoms of what are known as

299

300 LECTURE XX

the uric acid diathesis and of gout are due to this. It is there-
fore highly interesting to know under what conditions uric acid
is soluble, and under what circumstances it is precipitated.

A gramme of free uric acid requires for its solution, at the
temperature of the room, about 14 liters of water ; at boiling
heat, nearly 2 liters ; and at the temperature of the body, from
7 to 8 liters.^ The acid sodium urate dissolves in 1100 parts
of cold and 124 of boiling water. The ammonia salt and the
salts of the alkaline earths are much less soluble.

Sometimes as much as 2 grms. of uric acid are entirely
dissolved in the normal urine, the volume of which in twenty-
four hours ordinarily amounts to from 1500 to 2000 corns. It
cannot be dissolved as a free acid, for, as we have just seen, 2
grms. of free uric acid require 15 liters of water at the tem-
perature of the body, or ten times more than actually suffices
for its solution. We must therefore assume that the uric acid
is dissolved as an alkaline salt. But this is apparently opposed
to the following fact : if clear acid urine be allowed to cool to
the temperature of the room, the greater part of the uric acid
usually separates out as a free acid in large and beautiful
crystals, which are colored brown by the coloring matter
brought down with it. The weight of the crystals obtained
from the normal urine of twenty-four hours may amount to as
much as 1 grm. How is this to be explained ? If 2 liters of
uric acid solution, saturated at the temperature of the body, be
allowed to cool, only about 1 decigrm. of uric acid is precipi-
tated. How then can it reach ten times that amount ?

The explanation is as follows : If, at the temperature of
the body, a saturated solution of acid urate of soda, with a
neutral reaction, be mixed with a solution of acid phosphate of
soda (NaH2P0^), with an acid reaction, the mixture will be
acid. But if it be left to cool at the temperature of the room,
the reaction becomes alkaline, and free uric acid crystallizes out.
The mass-influence of the uric acid is diminished by cooling,
because fewer of its molecules are dissolved in the unit of space.
The mass-influence of the phosphoric acid becomes relatively
stronger. This acid therefore takes possession of the sodium
of the uric acid, and passes into the alkaline salt NagHPO^. If
the solution be heated afresh, the uric acid crystals redissolve,
and the solution now gives an acid reaction. The uric acid in
acid urine, which is always rich in phosphates of the alkalies,

* As no account, so far as I know, has ever been given of the solubility of
uric acid at the temperature of the body, I have made two determinations, vary-
ing between 35° and 40° C: 1 grm. of uric acid required 7680 c.cma. of water in
the first experiment, in the second 7320 c.cms., for solution.

UEIC ACID 301

behaves in exactly the same way. It can be proved that, on
cooling the 3,cid urine, the acidity decreases in proportion as
the uric acid crystallizes out. When raised to the temperature
of the body, the crystals redissolve.^

The phosphates of the alkalies thus play the same part in
the solution of the uric acid that they do in the absorption of
the carbonic acid in the blood and in the tissues (pp. 263-265).

It is doubtful whether the solution and elimination of the
uric acid is to be thus explained in all cases. The acidity of
the urine is occasionally found to be increased after the pre-
cipitation of uric acid.^ It is possible that acids split off from
neutral compounds by fermentation, or that dibasic arise from
monobasic acids by decomposition. This process may at times
be completed even within the urinary passages, the consequence
being that uric acid is precipitated. We are as yet far from
having obtained a satisfactory explanation of the manner in
which the solution of uric acid is effected.

If the urine be only feebly acid or alkaline, as it is fre-
quently with a vegetable or mixed diet, no free uric acid will
be deposited on cooling ; but if the urine be concentrated, acid
urate of soda will be precipitated. This appears in exceedingly
fine round granules which, like the free uric acid, are brown
or red-brown, owing to the coloring matter brought down
with them ; this is found at the bottom of the vessel, and con-
stitutes what is known as the lateritious deposit.

The uric acid sediment was formerly employed as a guide
in diagnosing disease, but was very misleading. For instance,
it was incorrectly assumed that an increase of sediment meant
an increase of uric acid secretion. We have seen that the
precipitation of uric acid depends not only on its absolute
amount, but also on the concentration and acidity of the
urine.^ It appears however to depend on other conditions as
well. It is often found that urines which deposit crystalline
uric acid are neither richer in uric acid nor more concentrated ;
nor do they contain more free acid than others which remain
clear or deposit urates.^

It is conceivable that uric acid circulates in the fluids of
the body as a readily soluble compound with an organic
substance, which appears in the urine, and is then split up

^Vide Voitand Hofmann, " Ueber das Zustandekommen der Harnsäuresedi-
mente," Sitzungsber. d. bayr. Akad., vol. xi. p. 279 : 1867. I have confirmed
Voit and Hofmann's account by numerous experiments.

2 Bartels, Deutsch. Arch. f. Min. Med., vol. i. p. 24: 1866.

^ Compare Botho Scheube, Arch. f. Heilkunde, vol. xvi. p. 185 : 1876.

■* Bartels, loc. cit., p. 28.

302 LECTUEE XX

by a fermentative process. If this happens in the organs or
within the urinary passages, gouty concretions and vesical
calculi are formed. At any rate, no increased formation of
uric acid has hitherto been found in gout and in the uric acid
diathesis. There is even less uric acid eliminated during an
attack of gout.'

Besides, there is the important fact that a large amount of
hydrochloric acid is necessary^ in order to separate the uric
acid from the urine for quantitative analysis, and that even
then it separates very slowly and incompletely, and sometimes
not at all, in spite of its being present in abundance.^ This
fact likewise argues that, at any rate, not all the uric acid is
simply dissolved in the urine as a salt.

The chemical constitution of uric acid has been the subject
of investigation by a large number of eminent chemists,* and
its synthesis has been successfully accomplished.

Among the numerous modes of decomposition of uric acid,
which have been accurately studied, the following is of peculiar
physiological interest, because the products obtained play an
important part in the animal economy.

Strecker ^ showed that uric acid, when heated with concen-
trated hydrochloric acid in a closed tube to 170° C, splits up,
with hydration, into glycocol, carbonic acid, and ammonia :

CsH.NA 4- SHijO = CH2(NH2)COOH + SCOj + 3NH3.

Strecker thought that uric acid would, while taking up only

' Garrod, "The Nature and Treatment of Gout": London, 1859. An
account of the literature on gout is given by Ebstein in his monograph, "Die
Natur und Behandlung der Gicht " : Wiesbaden, 1882.

2 This phenomenon is probably to be explained by the formation of a soluble
compound of the uric acid with urea. The uric acid can therefore only be pre-
cipitated when an amount of hydrochloric acid has been added equivalent to
that of the urea. Compare G. Bunge, Sitzungsb. d. Naturforsch. Gesell, z.
Dorpat, vol. vii.. Appendix, p. 21: 1873; G. Rudel, Arch. f. exper. Path. u.
Pharm., vol. xxx. p. 1 : 1892.

^Salkowski, Pfliiger's Arch., to\. v. p. 210 : 1872; Maly, ibid., vol. vi. p.
201: 1872.

^Wöhler, Poggendorflfs Annal., vol. xv. p. 119: 1829; Liebig, ibid., vol.
IV. p. .569 : 1829 ; and Ann. d. Chem. u. Pharm., vol. v. p. 288 : 1833 ; Wöhler
and Liebig, Ann. d. Chem. u. Pharm., vol. xxvi. p. 241 : 1838 ; Adolf Baeyer,
ibid., vol. cxxvii. pp. 1, 199 : 1863 ; Strecker, ibid., vol. cxlvi. p. 142 : 1868 ; and
vol. civ. p. 177: 1870; Kolbe, Ber. d. deutsch, chem. Ges., vol. iii. p. 183: 1870.
Among the latest works on the constitution of uric acid may be mentioned L.
Medicus, Ann. d. Chem. u. Pharm., vol. clxxv. p. 230 : 1875 ; Hill, Ber. d.
deutsch, chem. Ges., vol. ix. p. 370: 1876; and vol. xi. p. 1329: 1878; Horbac-
zewski, Sitzungsber. d. Wien. Akad., vol. Ixxxvi. p. 963 : 1882 ; or Monats-
hefte f. Chem., vol. iii. p. 796 : 1882 ; and vol. vi. p. 356 : 1885 ; and Emil
Fischer, Ber. d. deutsch, chem. Ges., vols, i., xvii. pp. 328, 1776: 1884.

^ Strecker, Liebig's Annal., vol. cxlvi. p. 142 : 1868.

URIC ACID 303

two molecules of water, break up first into glycocol and three
molecules of cyanic acid :

CsH^N.Oa -f 2HjO = CH2(NHj,)C00H + 3C0NH.

It is well known that cyanic acid, on coming in contact with
water, is at once converted into carbonic acid and ammonia.
I may remind my readers that the watery solution of cyanate
of potash effervesces with acids like a carbonate.

Strecker therefore regarded uric acid as a compound
analogous to hippuric acid. As hippuric acid is a glycocol
conjugated with benzoic acid, so uric acid is a glycocol conju-
gated with cyanic acid.

The synthesis of uric acid, which Horbaczewski ^ successfully
accomplished in E. Ludwig' s laboratory in Vienna, exactly cor-
responds to the decomposition observed by Strecker. Horbac-
zewski obtained uric acid by melting glycocol and urea together
at from 200° to 230° C. It is well known that, on heating
urea, ammonia volatilizes and cyanic acid is formed : —

C< = O — NH3 = CONH.

Thus if urea be melted with glycocol, nascent cyanic acid is
allowed to act on the glycocol ; one decomposition product of
the uric acid in a nascent state acts upon the other. This might
ä priori be expected to develop uric acid.

The following physiological fact observed by Wöhler ap-
pears to harmonize with these results of decomposition and
synthesis. Wöhler ^ found uric acid, but no hippuric acid, in
the urine of sucking calves, so long as they consumed nothing
but milk. But as soon as they passed on to vegetable food, the
uric acid disappeared, and hippuric acid was substituted.

It thus appears that the benzoic acid arising from vegetable
diet seizes upon the glycocol and prevents the synthesis of uric
acid.

If this interpretation be correct, we should expect, by the
addition of aromatic compounds, to be able to prevent the
formation of uric acid in human beings as well. This might
even be of a therapeutic advantage in the treatment of gout.
It is useless merely to give benzoate of sodium, as I have
proved by many experiments. But here again it should not

1 Horbaczewski, Sitzungsber. d. Wien. Akad., vol. Ixxxvi. p. 963 : 1882 ; or
Monatshefte f. Chem., vol. iii. p. 796: 1882 ; and vol. vi. p. 356: 1885.

2 Wöhler, Nachr. d. k. Ges. d. Wissensch. zu Göttingen, vol. v. pp. 61-64 : 1849.

304 LECTURE XX

be forgotten that it is not in our power to make the benzoic
acid reach the proper point at the proper moment when the
glycocol, before its union with the cyanic acid, could react with
it. As already mentioned, the benzoic acid in vegetable food is
not generally contained as such, but is formed in the body
by the decomposition and oxidation of more complex com-
binations. It is quite possible that these latter are taken up
by the cells in which glycocol occurs, while the benzoic
acid already formed is rejected. At any rate, it must be
remembered that to prevent the formation of uric acid in
gout would only affect the symptoms. It is impossible to
treat the essential cause of the disease, because it is quite
unknown to us.

With a view to obtaining further insight into the constitu-
tion of uric acid, the products of its simultaneous decomposi-
tion and oxidation have been investigated — products obtained
by the action of oxidizing agents. These products are like-
wise of great interest, because among them compounds occur
which are also met with in the metabolism of the animal
body.

A solution of permanganate of potash causes uric acid to
break up, even in the cold, into allantoin and carbonic acid : ^
C,H,NP3 -F O + HP = C,H,NP3 + CO,.

Allantoin was discovered by Vauquelin^ in the allantoic
fluid of the cow, was subsequently found by Wöhler ^ in calves'
urine as well, and was further investigated both by him and
by Liebig.* Later this compound was also detected in the
allantoic fluid and in the urine of new-born children, and oc-
casionally in dogs' urine.^

The further action of oxidizing agents upon allantoin ^ pro-
duces urea and oxalic acid, and the latter ultimately, under the
same influence, yields carbonic acid.

If nitric acid be employed for the purpose of splitting up
and oxidizing uric acid, urea and carbonic acid are again
obtained as end-products. Compounds occur as intermediary
products which, although they do not appear in the animal

^ Claus, Ber. d. deutsch, ehem. Ges. d. Wissensch. zu Göttingen, vol. v. pp.
61-64: 1849.

^Buniva et Vauquelin, Ann. de Chim., vol. xxxiii. p. 269, ann. viii«. : 1799.
Vide also Lassaigne, Ann. de Chim. et de Phys., vol. xvii. p. 301 : 1821.

^ Wöhler, Nachr. d. k. Ges. d. Wissensch. zu Göttingen, p. 61 : 1849.

^ Wöhler and Liebig, Ann. d. Chem. u. Pharm., vol. xxvi. p. 244 : 1838.

^ E. Salkowski, Ber. d. deutsch, chem. Ges., vol. ix. p. 719 : 1876 ; and vol.
xi. p. 500: 1878.

Ö For the synthesis and composition of allantoin, vide Grimaux, Compt. rend.
vol. Ixxxiii. p. 62 : 1876.

UEIC ACID 305

body, are of interest in so far as they help to throw some light
upon the consstitution of uric acid. Alloxan and urea are the
first compounds formed by the nitric acid in the presence of
cold :

O— NH NH,

C5H4N A + O + H2O = CO Co + c = o

Uric acid. io-NH NH,

Alloxan. Urea.

Alloxan, when heated with nitric acid, passes into parabanic
and carbonic acids :

CO— NH CO— NH

CO CO + O = CO2 + CO

CO— NH CO— NH

Alloxan. Parabanic acid, or Oxalylurea

The parabanic acid, with hydration, passes into oxaluric
acid :

CO— NH CONHCONHj

>C0 = 0 + H20= I '

CO-iH COOH

Parabanic acid. Oxaluric acid.

The latter, by taking up a second molecule of water, breaks
up into oxalic acid and urea :

CONHCONH2 COOH /NH2

+ H,0= +<C0

COOH ^ ' COOH X^Ha

Oxaluric acid. Oxalic acid. Urea.

Oxaluric acid occurs in the human urine ^ in minute
quantities.

The following formula, which was composed by Medicus ^
and confirmed by Emil Fischer^ from extensive observations,

■I Ed. Schunck, Proceed. Roy. Soc, vol. xvi. p. 140: 1868; C. Neubauer,
Zeitschr. f. anal. Chem., vol. vii. p. 225 : 1868.

2 Medicus, Ann. d. Chem. u. Pharm., vol. clxxv. p. 230 : 1875.

^ Fischer, Ber. d. deutsch, chem. Ges., vol. xvii. pp. 328, 1776 : 1884.

20

306 LECTURE XX

agrees with all the decompositions of uric acid we have
described :

HN— C NH

Another synthesis of uric acid/ also discovered by Horbac-
zewski, agrees well with this structural formula. He found it
could be synthesized by fusing together trichlorlactic acid and
urea.

As we have seen that uric acid is transmuted into urea and
carbonic acid by oxidizing agents outside the organism, we
should expect to find the same process going on within the
organism, and that uric acid is one of the antecedents of urea.
If uric acid be introduced into the organism of a dog, it cer-
tainly becomes almost entirely changed into urea,^ But it by
no means follows that part of the urea normally formed arises
from uric acid. This idea is frequently met with, and especially
in pathological literature. It was thought that, in disturbances
of external and internal respiration (such as affections of the
lungs, anemia, etc.), an increase takes place in the elimination
of uric acid as a product of incomplete combustion. This
supposition has not, however, been confirmed. Senator ' could
detect no increase in the excretion of uric acid in dogs, cats,
and rabbits when respiratory disturbances were artificially in-
duced ; nor could Naunyn and Riess * do so after venesections.
Moreover the numerous accounts given of the increased elimina-
tion of uric acid in human beings in consequence of respiratory
disturbances, do not rest on exact observation. In the first
place, investigators fell into the error, already alluded to, of
inferring an increase of uric acid from an increase of sediment ;
and in the second place, they did not sufficiently take into con-
sideration how much the formation of uric acid depends upon
diet. It should be especially noted that a fasting, and particu-
larly a febrile person — in whom it is well known that the pro-

1 J. Horbaczewski, Monatshefte für Chemie, vol. viii. pp. 201, 584: 1887.

^Zabelin, Liebig's Annal. d. Chem. u. Pharm., SuppL, vol. ii. p. 326: 1862
and 1863. The views of earlier authors on the conversion of uric acid into urea
will be found here. [It has been shown recently by Minkowski that a consider-
able amount of the uric acid is converted in the organism of the dog into allan-
toin, in which form it is excreted in the urine. Minkowski, Arch. f. exper. Path.
u. Pharm., vol. xli. p. 375 : 1898.]

^Senator, Virchow's Arch., vol. xlii. p. 35: 1868.

* B. Naunyn and L. Riess, Du Bois' Arch., p. 381 : 1869.

URIC ACID 307

teid-decomposition is increased — behaves exactly like a person
who lives on meat. The results of all calculations bearing upon
the elimination of uric acid in respiratory disturbances, and
concerning the relation of uric acid to urea in these affections,
vary within the same limits as they do in the case of healthy
people.

Increased excretion of uric acid has hitherto been proved
only in the case of one disease, leukemia. Bartels^ recounts
that he found 4.2 grms. of uric acid in the urine of a leukemic
patient during twenty-four hours, of which 1.8 grm. had crys-
tallized out. O. Schultzen^ even found, in the urine of a case
of leukemia during twenty-four hours, a sediment consisting of
4.5 grms. of free uric acid and 1.45 grm. of urate of ammonia.
Such large amounts have never been observed in healthy
people. In the cases of leukemia where the amount of uric
acid does not exceed that of healthy people, the proportion of
uric acid to urea is increased, frequently in the proportion of
only 12 grms. of the latter to 1 grm. of uric acid.^ Fleischer
and Penzoldt"' have made a careful investigation on this subject.
They dieted a leukemic patient and a person in good health in
precisely the same way ; they both excreted the same amount of
urea, but the leukemic patient eliminated daily an average of
1.29 grm. of uric acid, while that eliminated by the healthy
person amounted to 0.66 grm., or half as much. Careful exper-
iments carried out by Stadthagen^ in Kossel's laboratory led to
similar results.

This occurrence cannot, for the reasons already given, be
referred to a diminution of oxygen in consequence of the de-
crease in red blood-corpuscles. It was therefore thought that
the cause was to be sought in the enlargement of the spleen
and in the increase of leucocytes. Uric acid is constantly
found in the spleen, which has given rise to the idea that it
is chiefly formed here. Enlargement of the spleen, however,
occurs in other diseases, in intermittent fever and in typhoid,
without any increase of uric acid that could be detected.^ Nor
could Stadthagen confirm the view that uric acid occurred in
the spleen ; he could not detect even a trace of it in the liver

1 Bartel's Deutsch. Arch. f. Min. Med., vol. i. p. 23 : 1866.

2 Steinberg, " über Leukämie," Inaug. Dissert.: Berlin, 1868.

*H. Ranke, "Beobachtungen und Versuche über die Ausscheidung der
Harnsäure," p. 27: München, 1858; and Salkowski, Virchow's Arch., vol. 1. p.
1'74 : 1870 ; and vol. lii. p. 58 : 1871.

■* Fleischer and Penzoldt, Deutsch. Arch. f. Min. Med., vol. xxvi. p. 368 :
1880.

5 Stadthagen, Virchow's Arch., vol. cix. p. 396 : 1887.

« Bartels, Deutsch. Arch. f. Min. Med., vol. i. p. 28 : 1866.

308 LECTURE XX

and spleen of either a leukemic patient or a healthy person.
It is possible that uric acid may be a product of the metabolism
of leucocytes, independent organisms which travel through
our tissues, after the manner of ' symbionta.' Uric acid has
been observed to be the end-product of tissue-change in all
kinds of the lower animals. In this connection it is note-
worthy that quinine, which diminishes the ameboid move-
ments of leucocytes, also lessens the elimination of uric
acid.^

Horbaczewski ^ confirms Stadthagen's statement that the
spleen contains no uric acid. In the fresh splenic pulp of
calves directly after death he could detect no, or only the
slightest trace of, uric acid. If, however, the fresh splenic pulp
were allowed to stand with blood at the temperature of the
body, considerable quantities of uric acid were formed,^ e. g., .14
grm. from 100 grms. of splenic pulp in seven and a half hours.
This formation of uric acid also occurred if, instead of splenic
pulp, an extract obtained by boiling the spleen with normal
salt solution were used, and allowed to stand some hours with
blood at the body temperature. In this process oxygen is
necessary, since only small quantities of uric acid are formed,
if hydrogen be led through the mixture of splenic pulp and
blood. If the splenic pulp be allowed to putrefy with water
at 50° C, xanthin and hypoxanthin can be prepared from the
watery extract. These bases however, like the uric acid, could
not be found by Horbaczewski pre-formed in the splenic pulp.
Moreover they are not the precursors of uric acid since, as is
well known, they are not converted by oxidation into uric acid.
We must assume that the xanthin bases and the uric acid are
formed according to the varying conditions under which the
experiment is carried out, from some common precursor. This
precursor is a substance derived from some nuclein compound
of the nuclei of the leucocytes, and probably occurs in all other
tissues which contain nuclein.

The theory that uric acid is the result of imperfect respira-
tion is negatived by the simple fact that in birds, which of all
animals have the most active respiration, the bulk of the
nitrogen leaves the body as uric acid. The nitrogen may be
introduced into the organism of the bird in whatever form you

^ Ranke, loc. cit. This account has been amply confirmed, especially by
Prior's thorough investigation, Pfliiger's Arch., vol. xxxiv. p. 237 : 1884. The
■whole literature will be found here.

^ J. Horbaczewski, Sitzungsb. d. Akad. d. Wissensch. in Wien., Math.-nat.
Kl., vol. xcviii. pt. iii., July, 1889, and vol. c. pt. iii., April, 1891.

^ These results have been confirmed by P. Giacosa, Wien. med. Blätter, No.
32: 1890,

UEIC ACID 309

like — as an amido-acid : leucin, glycocol, or aspartic acid ; ^ as
urea ; ^ as carbonate or formate of ammonia ; ^ as hypoxanthin ^
— it invariably appears in the urine as uric acid.

We cannot even guess in what way these nitrogenous com-
pounds take part in the synthesis of uric acid. For instance,
carbonate of ammonia alone cannot furnish material for the
formation of uric acid ; a further compound, rich in carbon,
and containing little or no nitrogen, is required. Either glyco-
col or lactic acid would satisfy these requirements, but nothing
definite is known on this point.

It now only remains for us to consider where the uric acid
is formed. This is important from a physiological as well as
from a pathological point of view. The most complete inves-
tigations upon this subject of recent times have been made by
Schröder ^ and Minkowski.^

Schröder succeeded, in Ludwig's laboratory, in overcoming
the immense difficulties encountered in the extirpation of the
kidneys of birds. Hens lived from five to ten hours after their
kidneys had been either extirpated or detached from the
circulation by ligaturing the aorta and vena cava above the
kidney. In this time uric acid had accumulated in the organs.
A considerable amount of uric acid was obtained from the
heart and the lungs together with the blood in them, but none
from the normal organs, by the method adopted by Schröder.
Hence it follows that the uric acid is not produced, or at any
rate not exclusively formed, in the kidneys of fowls. Experi-
ments in which snakes' kidneys were extirpated gave the same
results, only that here the amount of uric acid that accumulated
was larger, because snakes survive the operation for a much
longer time. They lived from five to nine days afterwards,
and after death a large quantity of uric acid was found in all
their organs, but most abundantly in the spleen. A consider-
able amount of uric acid was obtained from the blood. Hence
also in snakes uric acid is not primarily formed in the kidneys.

The locality of the formation of uric acid in mammals has
not been experimentally investigated. At the same time, the
existence of small amounts of uric acid in the liver, lungs, and

' Von Knieriem, Zeitschr. f. Biolog., vol. xiii. p. 36 : 1877.

2 Meyer and Jaife, Ber. d. deutsch, ehem. Ges., vol. x. p. 1930 : 1877. Vide
also Cech, ibid., vol. x. p. 1461 : 1877.

* Von Schröder, Zeitschr. f. physiol. Chem., vol. ii. p. 228: 1878.

*"W. von Mach, Arch. f. exper. Path. u. Pharm., vol. xxiv. p. 389 : 1888.

5 Von Schröder, Du Bois' Arch., Sup., p. 113: 1880; and "Beiträge zu
Physiol., Carl Ludwig zu seinem 70 Geburtstage gewidmet von seinen Schülern,"
p. 89 : Leipzig, 1887.

« Minkowski, Arch. f. exper. Path. u. Pharm., vol. xxi. p. 41 : 1886.

310 LECTURE XX

other organs has been ascertained.^ The occurrence in gout oi
large quantities of uric acid in the joints, tendons, and liga-
ments, under the skin, and in other organs, without any
previous disturbance in the functions of the kidney, seems to
show that uric acid is not primarily formed in the kidneys in
the case of mammals any more than it is in the case of birds
and reptiles.

Minkowski ^ endeavored to ascertain whether this process
went on in the liver. He carried out his experiments on birds.
The difficulties met with in mammals, in endeavoring to cut the
liver out of the circulation, do not occur in birds, and there is
no need in the latter to guard against the intense congestion
in the portal system by establishing artificial communication.
Fortunately, such a communication has a natural existence in
birds. Birds have a vascular system in the kidney similar to
the portal circulation in the liver. There is a vena advehens in
the kidney which brings to that organ the blood of the caudal
vein, the iliac veins, and the veins leading from the pelvic
organs. This vena advehens communicates with the portal
veins by means of Jacobson's vein. After tying the portal vein
therefore, the blood from the intestine can pass through the
kidneys to the inferior vena cava, and no stagnation occurs.^
Minkowski therefore tried, by experiments on birds, to find
out what influence the removal of the liver has upon the
composition of urine. He made his experiments on geese,
because these large birds yield a sufficient amount of urine for
the purpose of analysis, and because they secrete urine in
abundance after removal of the liver. He operated upon as
many as sixty geese, and in most cases, not only tied the
hepatic vessels, but also completely extirpated the liver, except
a very small remnant which he was obliged to leave in the
immediate neighborhood of the vena cava, as in birds this
latter passes through the liver. This remnant was destroyed by
crushing. The animals thus operated upon mostly lived for
more than six hours, and a few of them for twenty hours. The
large intestine was tied above the cloaca in order to obtain the
urine in a pure condition.

The result obtained was that the total nitrogen eliminated
after the extirpation of the liver was not greatly diminished ;
it amounted to about from one-half to two-thirds of the

^ An account of the literature is given by Schröder, Du Bois' Arch., Sup.,
p. 143. For the opposite view of Stadthagen, see the earlier reference.

^ Minkowski, loc. cit., and Arch. f. exper. Path. u. Pharm., vol. xxxi. p.
214: 1893.

* Stern, Arch.f. exper. Path. u. Pharm., vol. xix. p. 45: 1885.

UEIC ACID 311

quantity normally excreted by geese in the same time. On
the other hand, the proportion of uric acid to the total nitrogen
in the urine was very diiferent. In healthy geese the nitrogen
eliminated as uric acid amounts to from 60 to 70 per cent, of
the total nitrogen ; in geese after removal of the liver, only to
from 3 to 6 per cent.

The relative amount of another nitrogenous constituent of
the urine, ammonia, is altered in the reverse direction after
extirpation of the liver. The ammonia in the urine of normal
geese amounts to from 9 to 1 8 per cent, of the total nitrogen ;
that in the urine of geese after extirpation of the liver, from
50 to 60 per cent.

From this Minkowski concludes that ammonia is a normal
antecedent of uric acid, and that the synthetic conversion of
ammonia into uric acid in the organism of birds can only take
place if the liver is free to perform its functions. Minkowski
does not say that the liver is the locality of uric acid forma-
tion. It is possible that the functions of the liver are only
indirectly called into play in the formation of uric acid in other
organs.

The following very important fact observed by Minkowski
may be interpreted in this sense. A very large quantity of
lactic acid was found in the urine of geese after removal of the
liver. Minkowski could not detect any lactic acid in the
normal urine of geese, whereas after the operation there was so
large a quantity as to be equivalent to the amount of ammonia
excreted, and sufficient to make the urine strongly acid.

The extirpation of the liver is, therefore, in some way as yet
inexplicable, followed by the appearance of large quantities of
lactic acid, and the formation of uric acid being inhibited in
any organ is perhaps only indirectly the consequence of the
occurrence of the acid. We have already seen that acids check
the formation of urea and increase the elimination of ammonia
in the organism of mammals. Why may not acids have the
same inhibitory effect upon the formation of uric acid in the
organism of birds? In fact, by administering sodium car-
bonate, Minkowski succeeded in reducing the elimination of
ammonia in a normal goose from 11 to 3 per cent, of the total
nitrogen.

I will only add that in diseases of the liver, and especially
in acute atrophy of the liver, and in cases of phosphorus
poisoning, large quantities of lactic acid have been observed
in the urine.^ May not the increased elimination of ammonia
in cirrhosis of the liver (p. 295) be likewise referred to this

^ Schultzen and Riess, Ann. des Charite-Krankenhauses, vol. xv. : 1869.

312 LECTUEE XX

fact ? So far as my knowledge extends, no determinations have
ever been made of the acidity of, and the lactic acid present in,
the urine of persons suflFering from cirrhosis of the liver.

1 will also take this opportunity of mentioning that the oc-
currence of an organic acid (oxybutyric acid) and simultaneously
an increased elimination of ammonia has also been observed in
cases of diabetes mellitus.^

It may even be doubted whether ammonia is the normal
antecedent of urea and of uric acid. It is possible that the
nitrogen, which under normal circumstances splits off from the
proteid molecule as a neutral compound, separates as ammonia
under the influence of the abnormal acids.

The facts observed by Minkowski may therefore be inter-
preted in many different ways. Minkowski himself inclines
to the idea that the bulk of the uric acid in the liver is
normally formed by synthesis from ammonia and a non-
nitrogenous substance, and imagines this latter to be lactic
acid.^ Minkowski grounds this view on the probability of
ammonia and lactic acid both having a common source in
proteid. As already stated, he always found the lactic acid in
quantities equivalent to the ammonia. It increased in quantity
with the amount of proteid in the food, and was independent
of the addition of carbohydrates ; it increased also under the
same condition under which an increase of uric acid normally
takes place.

Of the numerous facts ascertained by Minkowski, I would
emphasize the following :

Besides the uric acid and the ammonia, which form the
bulk of the nitrogenous compounds in the normal urine of

' Hallervorden, Arch. f. exper. Path. u. Pharm., vol. xii. p. 268: 1880;
Stadelmann, ibid., vol. xvii. p. 419 : 1883 ; Minkowski, ibid., vol. xviii. pp. 35,
147: 1884; Kiilz, Zeitschr. f. Biolog., vol. xx. p. 165: 1884; H. Wolpe, Arch.f.
exper. Path. u. Pharm., vol. xxi. p. 138 : 1886.

2 The lactic acid found by Minkowski in the urine of geese whose livers
had been removed was the optically active sarcolactic acid. There are known to
be three isomeric lactic acids: ethylene lactic acid [CH2(OH)CH2COOH] or
hydr'acrylic acid, which has not been detected in the animal body, and the two
ethylidene lactic acids [CH3CH(0H)C00H]. Of the two last, the lactic acid of
fermentation, which is formed by the fermentation of sugar of milk in milk, and
by the fermentation of the carbohydrates in the intestine, is optically inactive ;
the other, the sarcolactic acid, is optically active, as it rotates the plane of
polarization to the right. The latter is obtained from muscles (compare Lecture
XXIII.), and is met with frequently in pathological products : in urine, in
phosphorus-poisoning and atrophy of the liver, in osteomalacia, in the sweat in
puerperal fever, and in various pathological exudations. We owe the most
minute inquiries into isomeric lactic acids to J. Wislicenus {Ann. d. Chem. u.
Pharm., vol. clxvi. p. 3: 1873; and vol. clxvii. pp. 302, 346: 1873), and to E.
Erlenmeyer {ibid., vol. clviii. p. 262: 1871; and vol. cxci. p. 261; 1878). A
summary of the literature on isomeric lactic acids is given in these works.

XANTHIN AND HYPOXANTHIN 313

birds, there is always a small amount of urea. The nitrogen
eliminated in this form amounts to from about 2 to 4 per
cent, of the total nitrogen. The proportion of urea to the
total nitrogen remained unaltered after extirpation of the
liver. The urea in the urine of birds is therefore not formed
in the liver. But of course this does not justify any con-
clusion with regard to the locality of the formation of urea
in mammals.

If urea be artificially introduced into the organism of
normal birds, the nitrogen of the urea, according to the experi-
ments of Meyer and Jaff§ already quoted, reappears as uric
acid in the urine. Minkowski injected solutions of urea either
subcutaneously or into the stomach of his geese, after removal
of the liver ; the urea reappeared in the urine unaltered. This
fact also seems to warrant the conclusion that uric acid is
formed by synthesis in the liver, but it is capable of being
otherwise interpreted. I may express the hope that the arti-
ficial transmission of blood through the excised liver of birds
may soon give a satisfactory reply to this question.

The facts obtained both by Meissner * and by Schröder ^
agree in showing that the amount of normal uric acid is always
larger in the liver than in the blood of birds ; and they are
moreover in harmony with the theory that uric acid, or at any
rate a portion of it, is formed in the liver of birds.

These experiments on birds do not permit of any conclusion
being drawn as to the seat of formation of uric acid in mam-
mals, and there are no grounds for assuming that the chief part
of the uric acid in mammals is also formed in the liver. The
fact that the excretion of uric acid is unaltered in cirrhosis of
the liver is against such a view.

In all the tissues of our body, and especially in the nuclei
of the cells, there are small quantities of two bases rich in
nitrogen, the empirical formulge of w^hich would lead to the
conclusion that they are closely related genetically to uric acid.
I mean xanthin and hypoxanthin, or sarcin.^ They differ
from uric acid only in their smaller amount of oxygen :

Uric acid CäH^N^Os

Xanthin C5H4NA

Hypoxanthin C5H4N4O

' Meissner, Zeitschr. f. rat. Med., vol, xxxi. p. 144: 1868.

*W. von Schröder, " Beiträge zur Physiol., Carl Ludwig zu seinem 70
Geburtstage gewidmet von seinen Schülern," p. 98, Leipzig : 1887.

^ J. Piccard, Ber. d. deutsch, ehem. Ges., vol. vii. pp. 1714-1719: 1874;
Kossei, Zeitschr. f. physiol. Chem., vol. vi. p. 422: 1882; vol. vii. p. 7: 1882.

314 LECTUEE XX

As yet however no one has succeeded in transmuting the three
compounds into one another/ The facts that xanthin on oxi-
dation yields alloxan and, when acted on by fuming hydro-
chloric acid, glycocol, seem to point to its having a constitu-
tion somewhat analogous to that of uric acid.^

But there is, in close affinity to xanthin, a third compound,
GUANiN^ (CgHjNgO), which frequently occurs in the tissues
together with xanthin and hypoxanthin, and, like these, is a
decomposition-product of the nuclein of the cell-nuclei. This
is converted into xanthin by the action of nitrous acid.

More recently Kossel^ has discovered a fourth base rich
in nitrogen as a constituent of the nuclei ; this he terms
ADENIN. It has the composition C^H^Ng and is therefore a ,
polymer of hydrocyanic acid, and is related to hypoxanthin in
the same way as guanin is to xanthin. It is converted into
hypoxanthin by nitrous acid.

Only a very small quantity of xanthin is invariably present
in human urine ; ^ in rare cases it may form vesical calculi.

Xanthin, hypoxanthin, guanin, and adenin, which are
usually designated by the generic name of xanthin bases, un-
doubtedly belong to the antecedents of urea or of uric acid.^
They occur in too large a quantity in the tissues, and in too
small a one in the urine, for it to be possible that they are
eliminated unchanged. Guanin is, like creatin, a substituted
guanidin. All the reasons which were adduced in favor of
the conversion of creatin into urea are equally applicable to
guanin.

The xanthin bases are however not merely end-products :
they are also initial products of metabolism, since they form
important constituents of the heads of spermatozoa. The
chemical constitution of these bases acquires therefore consider-
able physiological interest. Even if we are unable at present

^ Emil Fischer {Ber. d. deutsch, ehem. Ges., vol. xvii. pp. 328, 329 : 1884)
was uiiable to confirm Strecker's account that uric acid could be reduced to
xanthin and hypoxanthin by nascent hydrogen, and that hypoxanthin could be
oxidized into xanthin by nitric acid. Vide also Kossel, Zeitschr. f. physiol.
Chem., vol. vi. p. 428: 1882.

2 For the composition of xanthin, see Emil Fischer, Ann. d. Chem. u.
PAarm., vol. ccxv. p. 253 : 1882; Ber. d. deutsch, chem. Ges., vol. xv. p. 453:
1882 ; and Arm. Gautier, Compt. rend., vol. xcviii. p. 1523 : 1884 (Synthesis of
xanthin).

•■' J. Piccard, loc. cit.; Kossel, Zeitschr. f. physiol. Chem., vol. vii. p. 16 :
1882; vol. viii. p. 404: 1884.

^ Kossel, ibid., vol. x. p. 250: 1886.

* Neubauer, Zeitschr. f. analyt. Chem., vol. vii. p. 225 : 1868.

* Vide Stadthagen, Virchow's Arch., vol. cix. p. 390: 1887. An account of
the literature on the xanthin bodies, and the part they play in the formation of
uric acid, is given here.

THE XANTHIN BASES 315

to say anything concerning their function, we must expect that
the knowledge of their properties will in the near future open
up a whole series of important questions. According to the
most recent researches of Emil Fischer, the constitution of the
xanthin bases may be represented as follows :

HN — CO HN — CO

CO C — IfH HN = C C — NH

I \ PTT \ PIT

1 II yy^^ I //^°'

HN— C— N^ HN — C— N^

Xanthin. Guanin.

HN — CO N = C — NH,

HC C — HH HC C — NH

II 11 >C!H II I \CH

N — C— N'^ N— C^N'«^

Hypoxanthin. Adenin.

LECTURE XXI

THE FUNCTIONS OF THE KIDNEYS, AND THE COMPOSITION
OF THE UEINE

In the last lecture we became acquainted with the end-
products in which the bulk of the nitrogen leaves the body-
through the kidneys. The elimination of the nitrogenous end-
products of metabolism is not, however, the sole function of the
kidneys. To the kidneys is assigned the duty of maintaining
the composition of the blood invariable, of rejecting from the
blood everything that does not belong to it normally, whether
an abnormal constituent or a normal one that has increased
beyond its normal amount.

This function is usually ascribed to the epithelial cells of
the renal tubules, although it appears to me that it might with
equal justice be referred to the cells of the capillary wall. There
is no reason for assuming that the capillary wall plays a passive
part in the process of secretion. We know that it consists of
cells joined together like mosaic work, and that each of these
cells is a living unit, an organism by itself, to which we are
d priori justified in ascribing as complex functions as to the
epithelial cells of the tubules.

The cells of the capillary wall and those of the epithelium
perform the work of rejecting the substances which do not
normally form part of the composition of the blood, and this
they do without regard to the laws of diffusion and endos-
mosis or to the conditions of solubility. They eliminate
everything useless or superfluous — crystalloid and colloid
substances, both soluble and insoluble, both alkaline and
acid.

Sugar and urea are both easily soluble in water and readily
diffusible ; they are both always circulating with the blood
through the renal capillaries. Sugar, which is an important
food-stuff, is retained ; urea, which is an end-product, is excreted.
The purpose is manifest, though we are unable to explain the
reason. It does not at present admit of a mechanical ex-
planation. If the sugar exceed the normal quantity, it is
secreted.

316

THE FUNCTIONS OF THE KIDNEYS 317

Proteins form the main constituents of blood-plasma ; but
they are never allowed to pass by a healthy epithelium. The
normal proteids of the plasma appear in the urine only when
the renal epithelium has undergone pathological alteration, or
has been impaired by impeded circulation of the blood and by
an arrest of the supply of oxygen.^ But the normal proteids
of the plasma cannot pass the normal and well-nourished
epithelium ; and this not by reason of their colloid nature, for
as soon as a proteid that does not belong to the normal con-
stituents of the plasma, such as egg-albumin or a solution of
casein, is allowed to enter the blood, it reappears in the urine.^
This applies not only to colloid substances, but also to such as
are absolutely insoluble and immiscible with water, which are
removed by the activity of the cells into the commencement of
the renal tubules, if they do not belong to the normal con-
stituents of the blood. Among these we may mention foreign
fatty matters (cod-liver oil), superfluous Cholesterin, resins, and
the like.

If the blood becomes too alkaline, as it may by conversion
of vegetable salts of alkalies into carbonates, the renal cells
separate the excess of these carbonates from the blood. If the
alkalescence of the blood be diminished — perhaps by the
liberation of sulphuric acid and phosphoric acid, caused by the
decomposition of proteids of nucleins and lecithins — the renal
cells take up the neutral salts of the blood, separate them into
acid and alkaline, convey the acid salts into the urine, and the
alkaline back into the blood, until the normal alkalinity is
restored.

The epithelial cells are of very varying form and size in
different parts of the urinary tubules. This renders it probable
that different portions have different functions to perform;
that only certain constituents of the urine are eliminated by

1 Heidenhain in Hermann's " Handbuch der Physiol.," vol. v. pt. i. pp. 337,
371 : Leipzig, 1883.

2 J. Forster, Zeitschr. f. Biolog., vol. xi. p. 526 : 1875. In this paper the
earlier views of Bernard, Lehmann, Stokvis, and Creile are mentioned. See
further R. Neumeister, " Zur Frage nach dem Schicksal der Eiweissnährung im
Org2im&m.\xs," Sitzungsher. d. phys. med. Ges. z. Würzburg: 1889. Albuminuria
occurs as a symptom of so many and various diseases, and can be caused in so
many diiferent ways that a discussion of the subject is best left to the pathologist.
At present chemistry can contribute little to the explanation of albuminuria or of
its relation to the other symptoms of the diseases in which it occurs. A con-
nected account of our present knowledge of the subject has been given by H.
Senator, "Die Albuminurie in physiologischer u. klinischer Beziehung u. ihre
Behandlung," 2d ed., Berlin : 1890. For the methods of detection of proteid in
urine, I v/ould refer the reader to the well-known "Handbuch d. physiologisch-
u. pathologisch-chemischen Analyse " by Hoppe-Seyler.

318 LECTURE XXI

one part, and different ones by another. It is known as a fact
that the coloring matter, carmine, when it gets into the blood,
is excreted by the Malpighian bodies,^ whereas indigo ^ and
bile pigments^ are excreted by the convoluted tubules and
Henle's loops. In birds, uric acid is found only in the
epithelium of the convoluted tubules, never in other parts.*
The purpose of this arrangement is evident : were the uric acid
to be excreted by the Malpighian bodies, it might remain
there and form concretions ; whereas the crystals eliminated by
the convoluted tubules are being constantly washed down by
the fluid secreted by the glomeruli.

The structure of the glomeruli is very puzzling, and is seen
in no other gland. The widening of the arteries into the
capillary system, and their reunion to form an efferent vessel,
which is narrower than the afferent one, appear to be arranged
for the purpose of slowing the blood and of increasing the
pressure. But we are at present incapable of even suggesting
a theory as to what significance this precaution has in the
formation of urine, and as to what constituents are formed or
eliminated in the glomeruli. It has not been found that blood-
pressure has any influence in any part of the body upon the
quantity and quality of the transudation formed.^

It has hitherto not been proved that the nervous system
exercises any direct influence upon the epithelial cells of the
kidney, as it has been ascertained to exercise in the case of the
salivary glands, and as is also probable in the case of the
remaining glands of the digestive apparatus. The renal nerves
appear only to act upon the vessels. This difference might
d pr^or^ have been expected. The digestive glands form their
secretion from the normal constituents of the blood. The
impulse to greater activity of the epithelial cells cannot
therefore proceed from the blood, but from the alimentary
canal, where the need of more secretion makes itself felt ; this
necessitates the intervention of nerves. The kidneys behave
differently ; for the impulse to increased activity of the renal
cells must proceed from the abnormally increased constituents

■■ Chrzonaczewski, Virchow's Arch., vol. xixi. p. 189: 1864; Wittich, Arch.
/. mikrosk. Anat., vol. xi. p. 77 : 1875.

' Heidenhain, ibid., vol. x. p. .30 : 1874 ; Pfliiger's Arch., vol. ix. p. 1 : 1875.

3 Möbius, Arch. f. Heilk., vol. xviii. p. 84 : 1877.

•*"Wittich, Virchow's Arch., vol. x. p. 325: 1856; Zalesky, "Unt über den
urämischen Process und die Function der Niere," p. 48: Tübingen, 1865;
Meissner, Zeitschr. f. rat. Med. (3), vol. xxxi. p. 183 : 1867.

* Vide Paschutin, " Arbeiten aus der physiologischen Anstalt zu Leipzig,"
p. 197 : 1872 ; and Emminghaus, ibid., p. 50 : 1873. [See however remarks in
note on p. 218.]

THE COMPOSITION OF UEINE 319

of the blood, to remove which is the duty of the kidneys.
This does not necessitate any nervous apparatus.^

We should ä priori expect that the kidneys would be all
the more active, the more substances there were in the blood
to be excreted, and the greater the amount of blood flowing
through the kidneys in a unit of time. All the facts observed
agree with this view. Whatever enlarges the lumen of the
renal vessels and increases the rapidity of the blood-current,
such as section of the splanchnic nerve and stimulation of the
spinal cord, also increases the quantity of urine secreted.
Whatever causes contraction of the vessels and diminishes the
rapidity of the current, as stimulation of the splanchnic,
mechanical narrowing of the renal artery, or section of the
cervical spinal cord, also diminishes the urine. There is at
present no ground for assuming that the blood-pressure in the
renal vessels has a direct influence upon the secretion of urine.

From these observations on the functions of the kidneys,
it follows that the composition of ueine must necessarily be
a very varying one. Besides the nitrogenous end-products,
the amount of which chiefly depends upon the proteid intro-
duced and undergoes great fluctuations, the urine always contains
the inorganic salts which remain over from the decomposition
of the organic food-stuifs, as well as sulphuric and phosphoric
acids, which proceed from the oxidation and splitting-up of
the proteids, nucleins, and lecithins ; and finally we find in it
certain products of metabolism — notably aromatic compounds
and oxalic acid — which are oxidized with difficulty and which
contain no nitrogen. Besides the substances which occur in
large quantities and have been subjected to careful investiga-
tion, there are numerous other substances in the urine which
are scarcely known, as they occur in such small quantities.
There is also a large class of substances which only appear
occasionally under certain normal and pathological conditions
that are little known ; and lastly, we meet with substances of
all kinds which have been accidentally introduced either with
food or as medicines, and which have not been destroyed in
the body.

In order to give an idea of the composition of normal urine,
two analyses are appended, which I carried out on the urine
of a young man in good health, both when on animal and on
vegetable diet.^ An estimate was made of almost all the con-

* Vide W. voa Schröder, " Ueber die Wirkung des Caffeins als Diureticum,"
Arch. f. exper. Path. u. Pharm., vol. xxii. p. 39 : 1886.

2 The literature of physiology, so far as I know, affords no analysis of urine
in which all the more important constituents were determined in the same

320

LECrUEE XXI

stitnents of the urine which normally occur in any quantity.
After two days' exclusive diet of beef, the urine was collected
on the second day. The beef eaten was roasted with a little
salt, the only beverage being spring water. In the second
case the urine was also collected on the second day, after an
exclusive diet of wheat-bread, butter, a little salt, and spring
water.

Composition of Twenty -Four Hours' Urine After a Diet of-

Meat.
Total amount ..... 1672 c.cms.

Urea . .
Uric acid
Creatinin
K2O . .
Na^O. .
CaO . .
MgO, .
CI . .
SO3' . .

67.2 grms.
1.398
2.163
3.308
3.991
0.328
0.294
3.817
4.674
3.437

Bread.
1920 corns.
20. 6 grms.
0.253 ■
0.961
1.314
3.923
0.339
0.139
4.996
1.265
1.658

Both urines had a strong acid reaction. If we calculate the
equivalent of the strong acids and bases, we find that in both
the sulphuric acid and the chlorin suffice by themselves to
neutralize all inorganic bases :

3.308 Kfi
3.991 Na^O
0.328 CaO
0.294 MgO

= 2.177 NajO
= 3.991 Na^O
= 0.364 lyXO
= 0.455 Na^O

3.817 CI
4.674 SO3

4.996 CI
1.265 SO3

= 3.337 NajO
= 3.622 Na^O

6.959 Na^O

1.314 KoO
3.923 Na^O
0.339 CaO
0.139 MgO

6.987 Na^O
= 0.865 Na^O
= 3.923 Na^O
= 0.376 Na^O
= 0.216 NajO

= 4.368 NajO
= 0.980 Na^O

5.348 NaaO

6.380 Na,0

But, in addition to the sulphuric and hydrochloric acids,
the urines contain also considerable amounts of phosphoric
and uric, besides some hippuric and oxalic, acids. It would
therefore follow that they contain free mineral acids, had not
the organism the means about to be detailed of preventing

specimen. I therefore venture to communicate these analyses, which were under-
taken on the occasion of certain experiments relating to metabolism, and which
have not yet been published.

^ The entire amount of, including the conjugated, sulphuric acid, was
determined. The urine was boiled with hydrochloric acid and chlorid of
barium.

URIC ACID 321

the occurrence of free strong acids in the urine. In the first
place, thet-e is the formation of ammonia. In the above
analyses the ammonia has, unfortunately, not been determined.
Normal urine generally contains from 0.4 to 0.9 grm. In
order to convert the 1.66 grm. of phosphoric acid into the acid
ammonia salt, exactly 0.4 grm. of NHg suffice ; 0.8 grm. of
ammonia are equivalent to 3.44 grms. of phosphoric acid. A
second mode of diminishing the acidity of the urine consists in
a portion of the dibasic sulphuric acid being converted into a
monobasic acid by union with aromatic compounds.

Normal urine becomes alkaline only after a vegetable diet
containing potash salts of combustible acids. These are
largely present in acid fruits and berries which contain the
acid potash salts of tartaric, citric, malic, and other organic
acids. After combustion of the acids, the potash appears in
urine as a carbonate. The urine exhibits a strong alkaline
reaction, and effervesces on the addition of acids. Potatoes
cause a strongly alkaline urine, because they contain little
proteid and therefore little sulphuric acid ; on the other hand,
they contain much malate of potash, which is converted into a
carbonate. The most important articles of vegetable diet, the
cereals and the leguminosse, yield urine which is as acid as
that due to a diet of meat, because they are rich in proteid and
phosphates.

These observations afford some hints as to the diet of
persons who are predisposed to the formation of uric acid,
gravel, and concretions in the bladder. I have already shown
that we are not fully acquainted with all the conditions of the
precipitation of uric acid ; but we do know that the acidity of
the urine has to be considered as well as the amount of uric
acid. Patients should be forbidden food rich in proteid, and
poor in bases which are able to neutralize the uric and sul-
phuric acids formed from the proteid. Cheese appears to me
in this respect the most injurious article of food. In making
cheese, the basic alkaline salts pass into the whey, and the
casein, on undergoing combustion in the organism, yields
large quantities of uric, sulphuric, and phosphoric acids, which
are not sufficiently neutralized by bases. In certain parts of
Saxony, as in Altenburg, where the people eat a great deal
of cheese, uric acid calculi are said to be very common.^
Calculus is rare in Switzerland, although cheese is also an
important article of diet there, probably for the reason that a

^ Lehmann, Sitzung sber. der Ges. f. Natur und Heilkunde zu Dresden, p. 56 :
1868; W. Ebstein (" Die Natur und Behandlung der Harnsteine," pp. 145-156;;
Wiesbaden, 1884) gives a full account of the geographical distribution of calculi.

21

322 LECTURE XXI

considerable quantity of fruit is eaten at the same time. The
ingestion of salt meat and salt fish also causes a very acid urine
containing much uric acid, because, in the process of salting, the
basic salts (basic phosphates and carbonates of the alkalies) pass
into the lye, and are replaced by neutral chlorid of sodium.
Russian physicians have informed me that in certain districts of
their country, the people living mainly on salt fish frequently
exhibit uric acid calculi. If it be desired to prevent the forma-
tion of uuic acid sediments, or to dissolve concretions that are
already formed, by the administration of alkalies, it is more
sensible to advise the use of fruits and potatoes than to order
alkaline mineral waters, the continued use of which may produce
disturbances which we are unable to estimate. Because the
combination of uric acid and lithia is more soluble in water
than its combination with soda or potash, it has been thought
necessary to treat the uric acid diathesis with a few decigrammes
of carbonate of lithia, or even with mineral waters containing
one centigramme of lithia to the liter. This naive idea simply
implies ignorance of Berthollet's law. We know that, in solu-
tions of bases and acids, every acid is distributed to all the
bases in proportion to their quantity. It follows that only the
very smallest portion of uric acid will combine with the lithia,
the largest proportion combining with the preponderating quan-
tity of soda, which we introduce as chlorid of sodium. The
largest proportion of lithia will reappear in the urine, united
with the chlorin of the chlorid, with sulphuric and phosphoric
acids. There will be no increase in the solubility of the uric
acid.

It is well known that under pathological conditions urine
may become alkaline, by the conversion of urea into carbonate
of ammonia. This change always takes place when urine has
been exposed to the air for some time, and is effected by
certain forms of bacteria.^ If these organisms reach the
bladder, the conversion may begin there ; the urine becomes
alkaline, and the alkaline earths, which were held in solution in
the acid urine, are precipitated as phosphate of lime and triple

1 P. Cazeneuve et Ch. Livon, Compt. rend., vol. Ixxxv. p. 571 : 1877 ; R. von
Jaksch, Zeitschr. f. physiol. Chem., vol. v. p. 395: 1881; W. Leube, Ritzungsber.
d. phys. med. Soc. zu Erlangen, Nov. 10, 1884, p. 4 ; and Virchow's Arch., vol. c.
p. 540 : 1885. The ferment may be extracted from the bacteria, but during life
they do not yield it to the surrounding fluid {Maaculas, Compt. rend., vol. Ixxviii.
p. 132: 1874; and Pfliiger's ylrcA., vol. xii. p. 214 : 1876; A. Sheridan Lea, i/owrn.
of Physiol., vol. vi. p. 136: 1885). It appears therefore that in the conversion
of urea into carbonate of ammonia, chemical potential energy is converted into
kinetic energy, and this kinetic energy is used in the vital processes by the fer-
mentative organisms.

PIGMENTS 323

phosphate of magnesia. In this way urinary calculi may be
formed.

We have now become acquainted with all the ingredients of
any importance constituting normal urine. Of the innumerable
substances which, besides these, are found in small quantities, I
will describe a few, so far as we have any definite knowledge of
their origin and significance.

First, the coloring matters. Physicians have long ob-
served the remarkable diiferences in the color of urine under
various normal and pathological conditions, and have tried to
avail themselves of these diiferences for diagnostic purposes.
The numerous endeavors to isolate the coloring matters and
to study their properties led to no results, because the quan-
tity was always too small. We have therefore been obliged
to content ourselves with applying Greek and Latin names
to these numerous pigments, with which I. will not trouble the
reader, excepting with regard to the only one of which we
know the composition and mode of origin. I refer to urobilin,
which was discovered by Jaife.^ He found this reddish brown
coloring matter constantly in normal urine, and in increased
quantities in febrile urine. Its absorption-spectrum and the
green fluorescence which its ammoniacal solution assumes,
especially after the addition of chlorid of zinc, are charac-
teristic. The composition of this pigment, which can only
be obtained in very small quantities from urine, would not
have been known had not Maly^ succeeded in producing it
artificially by the action of nascent hydrogen upon bilirubin,
the chief coloring matter of bile.^ This fully explains the
invariable presence of urobilin in the contents of the intestine,
as we have seen that nascent hydrogen constantly acts there
upon the bile-pigment. Human feces are colored brown chiefly
by urobilin, and rarely contain any unaltered bile-pigment.
It is quite possible that the urobilin occurring in urine is
also derived from the intestine, though we are not forced to
this assumption, as urobilin might also be formed in other or-
gans. As a matter of fact, Jaffe found urobilin in human bile.
Hoppe-Seyler * has since shown that urobilin may also be

^ M. Jaflfe, Virchow's Arch., vol. xlvii. p. 405 : 1869 ; and Centralbl. f. d. med.
Wissensch., p. 241 : 1868 ; p. 177 : 1869 : and p. 465 : 1871.

2R. Maly, Centralbl. f. d. med. Wissensch., No. 54: 1871 ; Annal. d. Chem.,
vol. clxiii. p. 77 : 1872.

^ [It has been shown by Garrod and Hopkins {Journ. Physiol., vol. Ixxii. p.
451 : 1897) that in spite of the close similarity in physical characters, the urobilin
of urine and feces has a diflerent constitution to that of the hydrobilirubin of
Maly. Whereas the latter contains about 9 per cent, nitrogen, urobilin only
contains about 4 per cent.]

■* Hoppe-Seyler, JBer. d. deutsch, chem. Ges., vol. vii. p. 1065: 1874.

324 LECTURE XXI

formed by the action of nascent hydrogen upon hematm. We
thus arrive at a simple genetic connection between the three
coloring matters : ^

Hematin CgjHajN^O^Fe

Bilirubin CsjHjgN^Og

Urobilin [or, rather, hydrobilirubin] CajH^oN^O^J

Indigo^ is generally regarded as belonging to the urinary
coloring matters, although it does not occur as such in urine,
but as a colorless compound, as an alkaline indoxyl-sulphate.^
If concentrated hydrochloric acid, with an oxidizing agent like
chlorid of lime or bromin water, be added to urine, the con-
jugated sulphuric acid is split up, and the indoxyl is oxidized
into indigo :

2C8H6NKSO, + Oj = CieHioN^Oj + 2HKS0i
Indoxyl-sulphate of potash. Indigo blue.

The amount of indigo thus formed is generally very small,
but is seldom entirely absent from human urine. On shaking
the coloring matter with chloroform, a beautiful blue solution
is obtained.

We are not in doubt as to the origin of indigo in the animal
body, since we know that indol, which is the basis of the entire
indigo-group, is obtained by bacterial putrefaction of proteid,
and is uniformly found in the intestinal contents.* The reab-
sorbed indol is oxidized in the tissues into indoxyl. This process
is completely analogous to the conversion of benzol by oxidation
into phenol.

CgH^N + O = CgHgCOH)^
Indol. Indoxyl.

Indoxyl combines, like most of the aromatic hydroxylized
compounds (phenol, cresol, pyrocatechin, etc.), with sulphuric
acid, undergoing dehydration (p. 256). Jaffe^ showed that,
after the subcutaneous injection of indol, the conjugated indoxyl
compound reappears copiously in the urine.

' This genetic connection is more fully discussed in the next lecture, as well
as the appearance of blood and bile-pigments in the urine under pathological
conditions.

2 On the synthesis and chemical constitution of indigo, vide A. Baeyer, Ber.
d. deutsch, ehem. Ges., vol. xiii. p. 2254: 1880; and vol. xiv. p. 1741 : 1881.

^E. Baumann and L. Brieger, Zeitschr. f. physiol. Chem., vol. iii. p. 254:
1879. The older literature on the indigo-forming substance of the urine is
appended.

*S. Radziejewsky, Du Bois' Arch., p. 37: 1870 ; W. Kühne, Ber. d. deutsch,
chem. Ges., vol. viii. p. 206: 1875; Nencki, ibid., vol. viii. p. 336: 1875; Sal-
kowski, Zeitschr. f. physiol. Chem., vol. viii. p. 417 ; and vol. Ixxii. p. 8 : 1884.

^ M. Jafie, Virchow's Arch., vol. Ixx. p. 72 : 1877.

ETHEREAL SULPHATES 325

In cases of intestinal obstruction a larger quantity of the
indoxyl compound has been found in the urine. It is quite
possible that this occurrence of large quantities of indigo might
be utilized for diagnosis, by enabling us to determine in which
section of the intestine the obstruction had taken place. Jaffe
has shown, for instance, that the increase in the secretion of
indoxyl occurred in dogs after ligature of the small, but not
after ligature of the large, intestine. This is explicable from
the fact that proteid, which yields the material for the formation
of indol, is absorbed before reaching the large intestine. When
the small intestine is ligatured, the proteid stagnates and under-
goes putrefaction. Corresponding with this, JafFe has observed
an increased excretion of the indoxyl compound in man occur-
ring only in obstruction of the small, and not in fecal ob-
struction of the large, intestine. This is explained by the
fact that the proteids, which furnish the indol by their putre-
faction, are all absorbed before they reach the large intestine.
Similarly Baumann has observed an increased excretion of the
indoxyl compound in men in cases of obstruction of the small
intestine, but never in cases of fecal obstruction of the large
intestine.

All the other aromatic compounds which occur in the urine
as ETHEREAL SULPHATES arise, like the indol, from putrefaction
of proteid in the intestine. Baumann ^ has shown that if a
dog's intestine is cleared out and disinfected by the administra-
tion of calomel, the ethereal sulphates entirely disappear from
the urine. If, on the other hand, the putrefactive processes
in the intestine are increased by neutralizing the antiseptic
hydrochloric acid of the gastric juice by the administration
of calcium carbonate, we get an increased amount of the
ethereal sulphate in the urine.^ We thus see that an estima-
tion of these acids in the urine may be of great value as
a means of diagnosis, since we gain an insight into the intensity
of the putrefactive changes in the alimentary canal. Thus, for
example, if it be wished to disinfect the intestine previous to
resecting it, we can determine when this is effected, by noting
the time when the ethereal sulphates disappear from the
urine.^

The question now arises : where and in what organs does

1 E. Baumann, " Die aromatischen Verbindungen im Harne und die Darm-
fäulniss," Zeitschr. f. physiol. Chem., vol. x. pp. 123-133 : 1886. We particularly
recommend this short and lucid statement of Baumann's to the student.

2 A. Kast, " Ueb. d. quantitative Bemessung der antiseptischen Leistung des
Magensaftes," " Festschr. z. Eröffnung d. neuen allg. Krankenhauses zu Ham-
burg-Eppendorf " : 1889.

^ A. Kast und H. Baas, 3Iünchener med. Wochenschrift, No. 4: 1888.

326 LECTURE XXT

the conjugation of the aromatic compounds, formed in the in-
testine, with sulphuric acid take place? This much is certain,
that it does not primarily take place in the kidney, for after
the administration of phenol, phenolsulphuric acid is found in
the blood/

Phenol is a violent poison, but the phenolsulphate does not
exert toxic effects. Baumann therefore recommends sulphate of
soda as an antidote to phenol-poisoning. He found that when
phenol was applied to a dog's skin, the animal bore the poison
better and yielded more phenolsulphuric acid, when at the same
time sulphate of soda was administered. This would not be in-
telligible if the combination primarily occurred in the kidney.

Baumann found a much larger amount of ethereal sulphates
in the liver than in the blood. This renders it probable that
the synthesis occurs in the liver ; that the poisonous aromatic
compounds reaching it from the intestine are here subject to a
transformation into innocuous combinations before entering the
general circulation (vide Lecture XVIII.).

As yet we have only become acquainted with two sorts of
compounds of sulphur as constituents of the urine : the salts of
the ordinary dibasic and of the monobasic conjugated sulphuric
acids. The quantity of sulphuric acid occurring in the latter
form in human urine averages one-tenth of the amount of
ordinary sulphuric acid.^ But there is a much larger number
of sulphur compounds in the urine. If urine acidulated with
acetic acid is precipitated with chlorid of barium, the ordinary
sulphates are precipitated. If we now boil the filtrate, rendered
strongly acid by the addition of hydrochloric acid, the ethereal
sulphates are broken up, and this portion of sulphuric acid may
also be precipitated as a salt of barium. If this filtrate is now
evaporated to dryness and fused with saltpeter, we again obtain
a considerable amount of sulphuric acid. This third group of
sulphur compounds contains from 10 to 20 per cent, of all the
sulphur excreted in human urine. In dogs and rabbits, the
quantity of these organic compounds of sulphur is much larger.'
Let us now consider what is really known about these organic
sulphur compounds, and their relation on the one hand to pro-
teid, and on the other to sulphuric acid.

^ Baumann, Pflüger's Arch., vol. xiii. p. 285: 1876.

2E. V. d. Velden, Virchow's Arch., vol. Ixx. p. 343: 1877.

^ See Voit and Bischofif, " Die Gesetze der Ernährung des Fleischfressers," p.
279: Leipzig, 1860; Voit, Zeitschr. f. Biolog., vol. i. p. 127: 1865; vol. x. note
to p. 216: 1874; Salkowski, Virchow's Arch., vol. Iviii. p. 460: 1873; Kunkel,
Pflüger's Arch., vol. xiv. p. 344 : 1877 ; R. Lepine, Guerin et Flavard, Revue de
Medecine, vol. i. pp. 27, 911 : 1882; St. Bondzynski and R. Gottlieb, Centralbl. f.
d. med. Wissenach., No. 33: 1897.

CYSTIN 327

It is net much we know, but we will endeavor to collect
and review the fragments of our knowledge.

We are compelled to assume at least two atoms of sulphur
in a molecule of proteid, one oxidized and the other unoxidized.^
If we heat proteid with potash, one sulphur atom goes to
form sulphid of potash, the other forms sulphate of potash.
The former may be easily recognized on boiling with an
alkaline solution of lead oxid when it is precipitated as lead
sulphid. The proteids such as casein, the proteid moiety of
hemoglobin or legumin, which are poorer in sulphur, do not
give this reaction. Among the organic decomposition-prod-
ucts of proteid in the animal body, we meet with the oxidized
atom of sulphur in taurin, with the unoxidized in cystin.
If we boil cystin with an alkaline solution of oxid of lead, a
black sulphid of lead is thrown down. Of course taurin,
which we have already shown to be amido-ethylsulphonic acid
(p. 178), cannot give this reaction.

Cystin has the formula C3HgNS02.^ It does not occur in
the normal organism.^ We are not yet acquainted with the
abnormal conditions under which a large amount of the sulphur
is secreted in the urine as cystin. It appears however that
even in normal metabolism, in the course of the formation of
sulphuric acid products, a body is formed which is closely allied
to cystin, and is distinguished from it only by an additional
atom of hydrogen, viz., cystein. A substituted cystein, for
instance, appears in the urine of dogs after the administration
of brombenzol. Baumann,* to whom we are indebted for the
most searching inquiries into the origin of cystin, regards cys-
tein as a lactic acid, in which H is replaced by NH«, and the
OH by SH—

CH3

i\
I ^SH

COOH

^ The latest and most careful researches on the condition of the sulphur in
proteids have been carried out by A. Krüger (Pflüger's Arch., vol. xliii. p. 244:
1888). Unfortunately, Krüger did not make use of pure material for his
researches.

2 E. Külz, Zeitschr. f. Biolog., vol. xx. p. 1 : 1884.

2 Stadthagen, Zeitschr. f. physiol. Chem., vol. ix. p. 129 : 1884.

* E. Baumann and C. Preusse, Ber. d. dexUsch. chem. Ges., vol. xii. p. 806:
1879 ; Zeitschr. f. physiol. Chem., vol. v. p. 309 : 1881 ; M. Jaffe, Ber. d. deutsch,
chem. Ges., vol. xii. p. 1092 ; 1879 ; Baumann, ibid., vol. xv. p. 1731 : 1882 ;
Zeitschr. f. physiol. Chem., vol. viii. p. 299 : 1884. Vide also E. Goldmann, ibid.,
vol. ix. p. 260 : 1884.

328 LECTURE XXI

The substituted cystein which appears in the urine after ad-
ministration of brombenzol when boiled with dilute acids, is
broken up, with hydration, into acetic acid and bromphenyl-
cystein —

CH3

h

^S(CeH,Br)
COOH

Baumann obtained cystein from cystin by the action of nascent
hydrogen. The oxygen of atmospheric air reconverts the
cystein into cystin.

?

H2N — C — SH + O + HS

OOH

The empirical formula of cystiu must therefore be doubled :
0^11^21^2820^. The origin of cystin in the animal body is prob-
ably due to a synthetic process, and possibly two molecules of
proteid always yield the material for the formation of one
molecule of cystin.

The formation of bromphenylcystein would accordingly be
a process quite analogous to that of cystin. Here again a
divalent oxygen atom takes a hydrogen atom from cystin and
from brombenzol, and effects the linking of the liberated
affinities —

CH3 CH3

H,N — C — SPI + O + HCe H,Br = HjO + H^N - C — S(C6H,Br)
COOH COOH

Cystin does not dissolve readily in water, it therefore
always occurs in urine as a sediment, and very occasionally
causes the formation of vesical calculi. There are some people
who secrete a large quantity (about one-quarter) of the

TÄUBIN 329

sulphur as- cystin, without exhibiting any derangement in their
health. This rare anomaly of metabolism sometimes occurs,
probably as the result of heredity, in several members of the
same family/

Under normal conditions cystin, or its antecedent cystem,
breaks up still further and is oxidized, and the greater portion
of its sulphur appears in the urine as sulphuric acid. This is
confirmed by an experiment made in Baumann's laboratory by
Goldmann.^ He gave a little dog 2 grms. of cystein, and
found that the greater portion, about two-thirds, appeared as
sulphuric acid in the urine. The remainder had served to in-
crease the organic sulphur compounds in the urine. This view,
that the larger portion of the sulphur of cystein is converted by
oxidation into sulphuric acid, is confirmed by the fact that in the
cystinuria of man, the urine has generally an alkaline or very
feebly acid reaction.

"VVe know little positively with regard to the fate of tauein
[CH2(NH2) - CH2SO3H] . ■ I have already stated that the
amount of sulphur which occurs as taurin in bile constitutes
only a minute portion of the sulphur of the decomposed pro-
teid, and is only slightly increased if more proteid is taken
(compare p. 182). It is questionable therefore whether a taurin
molecule results from each molecule of proteid. In bile, taurin
is conjugated with cholalic acid. In the intestine, the ferments
of digestion and putrefaction doubtless cause this compound
to break up with hydration. We do not know whether the
liberated taurin is absorbed as such, or after previous change.
We have not been able as yet to prove its presence in the
feces or in the urine. No satisfactory results have been ob-
tained with regard to the further destination of taurin from
experiments^ consisting in its artificial introduction into the
body. If large quantities of taurin are administered to man or
dogs, the process of absorption does not take place slowly
enough to allow of its complete change into the normal end-
products ; one portion of the taurin appears as such in the urine,
another as a substituted urea —

' F. W. Beneke, "Grundlinien der Patliologie des Stofiweelisels, " p. 255
Berlin, 1874. Compare also A. Niemann, Detitsch. Arch. f. Min. 3Ied., vol
xviii. p. 232: 1876; W. F. Löbisch, Liebig's Annal., vol. clxxxii. p. 231 : 1876
W. Ebstein, " Die Natur und Behandlung der Gicht," p. 130 : Wiesbaden, 1882
and "Die Natur und Behandlung der Harnsteine," p. 172: Wiesbaden, 1884
Stadthagen, Virchow's Arch., vol. c. p. 416 : 1885.

2 E. Goldmann, Zeitschr. f. physiol. Ckem., vol. ix. p. 269 : 1885.

3 E. Salkowski, Ber. d. deutsch, ehem. Ges., vol. vi. pp. 744, 1191, 1312 : 1873 ;
and Virchow's Arch., vol. Iviii. p. 460 : 1873.

330 LECTURE XXI

=0

H

CHn — CHo — SOqH

The presence of this substituted urea has not so far been
positively demonstrated in normal urine. In the rabbit, it is
not found even after the artificial introduction of taurin. Al-
most all the sulphur of the taurin reappears as sulphuric and
THiosuLPHUEic acid in the urine of these animals. The con-
version into thiosulphuric acid however occurs only when the
taurin is introduced into the stomach ; if it is injected sub-
cutaneously, the greater part reappears unaltered in the urine.
The thiosulphuric acid is evidently formed by the processes of
reduction taking place in the intestine. In the normal urine
of rabbits, thiosulphuric acid has not been found, though it
occurs frequently in that of cats and dogs.^ In human urine,
it has only been once found in typhoid.^

SuLPHOCYANic AciD,^ (CNSH), also belongs to the sulphur
compounds occurring in the urine. Gscheidlen found these
acids constantly in human urine, and in that of horses, cattle,
dogs, cats, and rabbits. On an average, one liter of human
urine contained 0.02 grm. Munk found the average of three
determinations to be 0.08 grm. Sulphocyanates were also found
in dogs' blood. Gscheidlen proved that they are derived from
the salivary glands. The saliva of mammals invariably con-
tains small quantities of sulphocyanates. Gscheidlen and
Heidenhain divided all the ducts of the salivary glands in
dogs, and thus prevented the saliva from entering the mouth.
The alkaline sulphocyanate was now found to have disappeared
from the blood and the urine ; although it was still present in
the saliva flowing from the wounds. It follows that in the
normal condition sulphocyanic acid is formed in the salivary
glands, passes with the saliva into the intestinal canal, whence
it is absorbed into the blood and appears in the urine. We

■^ O. Schmiedeberg, Arch. d. Heilk., vol. viii. p. 422: 1867; Meissner,
Zeitschr.f. rat. Med., vol. xxxi. p. 322: 1868.

2 Ad. Strümpell, Arch. d. Heilk., vol. xvii. p. 390: 1876.

^Leared, Proc. Roy. Soc, vol. xvi. p. 18: 1870; Gscheidlen, Tageblatt d.
47 Vers. d. Naturf. u. Aerzte in Breslau, p. 98 : 1874 ; and Pfliiger's Arch., vol.
xiv. p. 401 : 1877 : Kiilz, Sitztingsber. d. Ges. z. Bef'order. d. ges. Naturw. in
Marburg, p. 76: 1875; J. Munk, Virchow's Arch., vol. Ixix. p. 354: 1877.

OXALIC ACID 331

are ignorant as to the significance of these small quantities of
sulphocyanic acid in the functions of the saliva, or in any other
processes of the organism.

Of the organic constituents of the urine, only those which
are free from sulphur and nitrogen remain for our consideration.
Lactic acid, sugar and oxalic acid belong to this class.
Lactic acid however has never been detected with certainty in
normal urine. It has only been found in phosphorus-poison-
ing, atrophy of the liver,^ osteomalacia,^ and trichinosis.^ On
teleological grounds, we must doubt whether lactic acid passes
into normal urine, as this would be a waste of potential energy.
The same argument applies in a still more forcible manner to
sugar. All analyses of normal urine have the more positively
shown the absence of sugar, the more carefully the investiga-
tion was carried out. Even those writers who assert the pres-
ence of sugar in normal urine, admit that they have only suc-
ceeded in finding it in very minute quantities.*

Oxalic acid is a constant ingredient in normal human
urine after a mixed diet, but it never occurs except in very
small quantity, at most 0.02 grm. in twenty-four hours' urine.*
This oxalic acid, in all probability, arises from the oxalic acid
which is contained in the vegetable articles of food. There is
at present no sufficient reason for assuming any other source
for the oxalic acid of normal urine. I was unable to detect
any oxalic acid in the urine of a young man in good health
after two days' exclusive diet of meat, nor in the urine of
another healthy young man after he had eaten nothing but fat
meat and sugar.^ It therefore appears that oxalic acid does
not normally arise from any of the three main classes of

' Schultzen and Riess, Annalen des Charite-Krankenhauses, vol. xv.: 1869.

2 Moers and Muck, Deutsch. Arch. f. klin. Med., vol. v. p. 485 : 1869. The
method of testing used in this experiment was, however, unsatisfactory. Com-
pare the critique of Nencki and Sieber, Journ. f. prakt. Chem., vol. xxvi. p. 41 :
1882 ; and E. Heuss, Arch. f. exper. Path. u. Pharm., vol. xxvi. p. 147: 1889.

* Th. Simon und F. Wibel, Ber. d. deutsch, ehem. Ges., vol. iv. p. 139 :
1871.

•* In this connection see E. Kiilz, Pfliiger's Arch., vol. xiii. p. 269 : 1876 ; M.
Aheles, Centralbl. f. d. med. Wissensch., Nos. 3, 12,22: 1879; J. Seegen, ibid.,
Nos. 8, 16 ; Regulus Moscatelli, Moleschott's Unters, zur Naturlehre des Menschen
u. d. Th., vol. xiii. p. 103: 1881; L. v. Udranszky, Zeitschr. f.physiol. Chem.,
vol. xii. p. 377 : 1888 ; and Bericht, d. naturforsch. GeseUsch. z. Freiburg i. B.,
vol. iv. part v.: 1889. Compare the works quoted on pp. 259, 260, on glycuronic
acid.

* P. Fiirbringer, Deutsch. Arch. f. klin. Med., vol. xviii. p. 143 : 1876 ; an
account of the literature on the excretion of oxalic acid is given here. Fiir-
bringer adopted Neubauer's method. O. Schultzen (Du Bois' Arch., p. 719 :
1868) found higher values by employing another method. A critique of both
methods is given by Wesley Mills, whose researches on the subject were carried
out under Salkowski, Virchow's Arch., vol. xcix. p. 305 : 1885.

" I made use of Neubauer's method in testing for it.

332 LECTUEE XXI

food. But the oxalic acid contained in vegetable articles
of diet must pass into the urine. Experiments carried out
by Gaglio^ in Schmiedeberg's laboratory at Strassburg show
that oxalic acid is not destroyed in the animal body. No
oxalic acid was excreted either by a dog that was starving or
by one that was fed on meat.^ But if only from | to 1 mgrm.
of oxalic acid or of oxalate of soda was injected subcutaneously,
the presence of oxalic acid was demonstrated in the urine
within the next twenty-four or forty-eight hours. If a neutral
solution of oxalate of soda was injected into the crop of a cock,
nearly all the oxalic acid was found in the discharge of the
cloaca.

Somewhat different conclusions were arrived at by P.
Marfori/ who took 1 to 1.5 grms. oxalic acid and determined
the amount of this substance excreted in the feces and urine.
Only a small portion of the oxalic acid reappeared in the
feces. So that the greater part was absorbed. Of the amount
absorbed, only 4 to 14 per cent, could be recovered from the
urine.

It seems however that, under abnormal conditions,'' oxalic
acid may appear as the result of metabolism, owing to an
imperfect oxidation of articles of diet. Medical literature con-
tains numerous cases illustrating increased excretion of oxalic
acid in jaundice, diabetes, scrofula, hypochondriasis, and other
disorders. We even find oxaluria spoken of as an independent
disease. But we seek in vain for trustworthy quantitative
determinations, with due consideration of the constituents of
the food. The conditions underlying the occurrence of oxalic
acid in the urine have great practical interest, because oxalic
acid may lead to the formation of calculi. The lime salt of
this acid is well known to be insoluble in water ; hence this
salt is frequently to be found in urinary sediments in the well-
known octahedral form. If the oxalate is precipitated in the

iGaetano Gaglio, Arch.f. exper. Path. u. Pharm., vol. xxii. p. 246 : 1887.

2 In contradiction to this account of Gaglio's, we find it stated by W. Mill
(Virchow's Arch., vol. xcix. p. 305 : 1885) that he detected minute quantities of
oxalic acid in the urine of dogs fed exclusively on meat or on meat and bacon.

^PioMarfori, "Sulle trasformazioni di alcuni acidi della serie ossalica nel
organismo dell'uomo," Milano, 1890.

* In this respect we should note the statements of Gaglio, who uniformly
found oxalic acid in the urine of frogs, when he arrested their muscular move-
ments by destruction of the spinal cord, by paralyzing poisons, or by mere fix-
ation {Giornale della R. Accad. di Med. di Torino, ji. 178 : 1883); and also
those of Hammerbacher, who found the excretion of oxalic acid increased in dogs
after the administration of bicarbonate of soda (Pfliiger's Arch., vol. xxxiii. p.
89,: 1883). This effect of bicarbonate of soda was not confirmed by Fiirbringer
{loc. cit.) in man.

OXALIC ACID 333

bladder, it may lead to the formation of vesical calculi. The
solution of oxalate of lime in the urine depends mainly on its
acidity. A solution of acid phosphate of soda dissolves oxalate
of lime.^ We can thus explain how it is that oxalate calculi
sometimes form under similar conditions as phosphatic calculi,
and that occasionally vesical calculi consist of both ingredients,
mixed up together or in concentric layers. I wish again to lay
stress on the fact that increase in the sediment of oxalate of
lime does not justify the inference that there is an increased
secretion of oxalic acid. This erroneous conclusion has led to
many mistakes.

^ C. Neubauer, Arch, des Vereins für gemeinschaftliche Arbeiten zur Förde-
rung der wissenschaftlichen Heilkunde, vol. iv. pp. 16, 17 : 1858 ; and Modder-
mann, Nederl. Tijdschr.: 1864, summarized in Schmidt's Jahrbücher der gesamm-
ten Med., vol. cxxv. p. 145 : 1865.

LECTURE XXII

METABOLISM IN THE LIVER FORMATION OF

GLYCOGEN

We now approach one of the most involved and difficult
subjects in the whole range of physiological chemistry : the
metabolism in the liver.

Like the kidney, the liver has to fulfil the function of
maintaining the uniform composition of the blood. While
the kidney removes all superfluous and foreign ingredients,
the liver revises everything before it enters the blood. For
this reason, it is interposed in the current that passes from the
intestine to the heart. We have seen how it guards against
the blood being overwhelmed with sugar, while, on the other
hand, it prevents a deficiency of this important article of
nutrition in the blood (p. 189). We have also seen that it
is constantly converting ammonia, which is a virulent poison,
into harmless compounds, such as urea and uric acid (pp. 294,
310). Similarly, the liver converts the equally poisonous
aromatic products of putrefaction, which originate from the
proteids in the intestine, into harmless compounds, by conjuga-
tion with alkaline sulphates (pp. 256, 326). We also know
that many poisons, such as metals, alkaloids,^ etc., are arrested
in the liver.

It also appears that the system of innervation of the liver
is identical with that of the kidney. We have not hitherto
been able to prove a direct influence of nerves upon the hepatic
cell. The functions of the liver, like those of the kidney, are
regulated directly by the composition of the blood. This fact
also indicates that the chief duty of the liver consists in regu-
lating the composition of the blood (compare p. 189).

In addition to this function, the liver, as we have seen
above, performs that of secreting bile. We have already
mentioned the grounds for our belief that bile is not merely
an accidental product which is excreted during the essential

^ G. H. Roger, Arch. d. physiol. norm, et path., V. vol. iv. p. 24 : 1892 ; E.
Kotliar, Arch. d. Sc. Mol., vol. ii. p. 586: 1893.

334

METABOLISM OF THE LIVER 335

changes taking place in the liver, and removed by the in-
testine, but that is a secretion which performs important
duties in the processes occurring in the bowel (vide supi-a, pp.
182-186).

All these facts tend to show that the liver, the largest of
all glands, is the seat of numerous and complex chemical
changes. It has been hoped, by comparing the composition of
the inflowing and outflowing blood, to obtain an insight into
these processes, or at least to suggest certain fruitful inquiries.
Numerous comparative analyses have been made of the blood in
the portal and hepatic veins.^ But when we consider how
large a quantity of blood passes through the liver, and how
trifling the amount of bile and lymph formed is in comparison,
we can scarcely expect to be able to demonstrate marked dif-
ferences in the composition of the inflowing and outflowing
blood. It is probable that the differences in the analyses of
the blood of the portal and hepatic veins are due to experi-
mental errors, for they have been smaller in proportion to the
care bestowed on the analyses, and, in the most reliable deter-
minations, are Avithin the limits of unavoidable errors.

Another method of obtaining an insight into the processes
occurring in the liver would consist in extirpating that organ,
or at least in isolating it from the circulation of the blood, and
noticing what changes take place in the animal metabolism
as a result of the operation. In this way we might hope, in
the first instance, to decide whether the constituents of bile, the
bile acids and pigments, are formed in the liver or are conveyed
to it by the blood. If the latter were the case, the liver would
be only an excretory organ, and its extirpation would cause an
accumulation of the biliary constituents in the blood and in the
organs.

We have already seen, when discussing the question as to
the locality of the formation of hippuric acid, that frogs survive
the extirpation of the liver for several days, but the experi-
ments which have been carried out with reference to the
present question, have been inconclusive, because the inquirers
were unable to overcome the difficulties which present them-
selves in the endeavor to demonstrate the constituents of bile
in the organs of the frog.^

^ C. Flügge gives a critical account of these works, Zeitschr.f. Biolog., vol.
xiii. p. 133 : 1877; compare also W. Drosdoff, Zeitschr. f.physiol. Chem., vol. i.
p. 233 : 1877.

- These experiments are criticised by Hans Stern, Arch. f. exper. Path. u.
Pharm., vol. xix. pp. 42-44: 1885. None of the investigators has proved, by
control experiments, that he can demonstrate small quantities of biliary constitu-
ents in frog's tissue.

336 LECTURE XXII

I have already repeatedly mentioned that, on account of
the accumulation of blood in the portal system after extirpa-
tion or isolation of the liver in mammals, this operation has
not as yet been successful in them (p. 295). In discussing
the formation of uric acid, we have seen that this difficulty
does not present itself in birds, owing to their possessing
a normal communication between the portal and renal
veins (p. 310). Naunyn, Stern, and Minkowski have utilized
this circumstance, in order to determine the question as
to the seat of the formation of the biliary constituents in
birds.

Stern ^ ligatured the bile-ducts and all the vessels passing
to the liver in pigeons, including not only the portal vein
and the hepatic artery, but also the small veins. After
from ten to twenty-four hours, the animals were bled to
death. No secretion of urine had taken place after the
operation, as renal activity always ceases in pigeons after
ligaturing the liver.^ If the biliary constituents were formed
outside the liver, they would now accumulate in the blood
and in the tissues, as they would have no exit. Stern paid
special attention to the bile pigment, which is easy of
detection ; but it was nowhere to be found, not even in the
serum on the application of Gmelin's very delicate test, nor
in any tissues or organs ; there was no icteric discolora-
tion anywhere. On the other hand, if in pigeons the bile-
ducts only were ligatured, bile pigment was found after an
hour and a half in the urine, and with perfect certainty in'
the serum after five hours. It follows, from these valuable
inquiries, that the coloring matter of bile is formed in the
liver.

The same applies to the bile acids. This has already been
proved by an inquiry carried out by FleischP in Ludwig's
laboratory. Bile acids cannot be shown to exist in normal
blood.* If the bile-duct be ligatured, the biliary constituents
pass into the lymphatics of the liver, and thence direct through

1 Hans Stern, Arch. f. exper. Path. u. Pharm., vol. lix. p. 39 : 1885.

~ Fowls, ducks, and geese continue to secrete urine after the liver has been
ligatured and extirpated (Minkowski and Naunyn, Arch. f. exper. Path. u.
Pharm., vol. xxi. p. 3: 1886).

ä E. Fleischl, Per. d. k. sächs. Ges. d. Wissensch., Math.-physikal.-Klasse,
Sitzung vom 8 Mai, p. 42 : 1874. Vide also Kuflferath, Du Bois' Arch., p. 92 r
1880, and V. Ilarley, ibid., p. 292 : 1893.

* We must however assume that traces of bile acids do occur in normal blood,
as they are absorbed from the intestine. Dragendorff (Zeitschr. f. anal. Chem.y
vol. XI. p. 4G7 : 1872) and Joh. Hone (Dissert.: Dorpat, 1873) found traces in
normal human urine. Hoppe-Seyler and L. v. Udranszki dispute this statement
(Zeilschr. f. physiol. Chem., vol. xii. p. 375;

BILE PIGMENTS 337

the thoracic duct into the blood. If, after ligaturing the bile-
duct, a cannula be introduced into the thoracic duct so as to
collect the chyle, bile acids may be shown to be contained in it.
If the bile-duct and the thoracic duct be ligatured at the same
time, the latter becomes distended with lymph, but no trace of
bile acids can be found in the blood.

The observations of Minkowski and Naunyn^ perfectly
harmonize with the results obtained by Fleischl, as after shut-
ting out the liver from the circulation, they were never able to
detect bile acids in the blood.

We may therefore conclude that the specific constituents
of the bile acids and pigments are formed in the liver.

We now come to the question as to the origin of the
specific biliary constituents. With regard to the bile acids,
their nitrogenous moieties, glycocol and taurin, are doubtless
derived, as I have already shown (pp. 177, 288), from proteid.
Cholalic acid, which is non-nitrogenous, does not necessarily
originate in the same material. It is conceivable that it may
be derived from another source, and subsequently combine
with the nitrogenous compounds by a process of synthesis,
with loss of water ; this would be entirely analogous to the
mode of formation of hippuric acid. We should note the
small amount of hydrogen contained in cholalic acid (p. 177).
If it be formed from fats or carbohydrates, the carbon
atoms of the molecule must become linked by two bonds of
affinity instead of one, as in the case of these two classes.
This would only be a further proof that syntheses occurring in
the animal are as complicated as those occurring in the vege-
table cell.

The coloring matter of bile, bilirubin (vide p. 323), almost
certainly arises from the coloring matter of the blood, hematin.
The following facts support this view.

Bile pigments are found only in animals whose blood con-
tains hemoglobin, i. e., the vertebrata. The invertebrata have
not hitherto been shown to possess them. It might be objected
that this depends upon some other peculiarity of the vertebrata,
as blood-cells containing hemoglobin are not the sole feature
which distinguishes the vertebrata from the invertebrata.
With regard to this, it is interesting to observe that the
amphioxus, which has no red blood-corpuscles, but Avhich from
its whole structure, belongs to the vertebrata, forms no bile
pigment. Hoppe-Seyler ^ has searched for it without success.

1 Minkowski and Naunyn, Arch. f. exper. Path. u. Pharm, vol. xxi. p. 7 :
1886.

2 Hoppe-Seyler, Pflüger's Arch., vol. xiv. 399 : 1877.
22

338 LECTURE XXII

It is well known that the liver of the amphioxus is a mere
cecal appendage of the intestine, the gland being only indi-
cated as in the embryos of the higher vertebrata.

It is almost certain that there is a genetic relation between
bile pigments and hematin, if we compare their constitution
(compare pp. 178, 323) —

Hematin C32H3jN404Fe.

Bilirubin C32H3gN40j.

Biliverdin C32H36N4O8.

Hematoporphyrin, a pigment isomeric with bilirubin, can
be artificially prepared from hematin by treatment with hydro-
bromic acid.^

The following fact may also be brought forward as an
argument : in extravasations of blood the coloring matter of
the blood disappears, and in place of it we find a crystallized
pigment, which Virchow^ was the first to examine carefully,
and named hematoidin. The same writer pointed out its
resemblance to bile pigment. Subsequently Robin,^ JaflFe,* and
Salkowski^ proved the identity of hematoidin and bilirubin.
Langhans ^ took the blood from the vein of a living pigeon and
injected it under the skin of the same animal ; after two or
three days the coloring matter of the blood had disappeared
from the subcutaneous clot, and was replaced by bilirubin
and biliverdin. Quincke '^ performed the same experiment on
dogs. In this case the conversion occupied more time ; the
bilirubin did not appear in the subcutaneous injection before
the ninth day. Cordua^ injected blood into the abdominal
cavity of dogs, and found bilirubin after so short a time as
thirty-six hours. Finally, Recklinghausen ^ has seen bile pig-
ment formed in the blood of frogs outside the body after from
three to ten days.

Our clinical experience entirely accords with these experi-
ments upon animals, for we see that after hemorrhages under

' M. Nencki and N. Sieber, Sitz. d. K. Akad. d. Wissensch. i. Wien, Math.-
nat. -Klasse, vol. xcvii. pt. 2: 1888.

2 Virchow in his Arch., vol. i. pp. 379, 407 : 1847.

^ Robin, Covipt. rend., vol. xli. p. 506: 1855. Robin obtained 3 grms. of
hematoidin crystals from an hepatic cyst, and analyzed them.

''Jaffe, Virchow's Arch., vol. xxiii. p. 192: 1862.

^ E. Salkowski, Hoppe-Seyler's Med. chem. Unters., Heft iii. p. 436 : 1868.

^ Th. Langhans, Virchow's Arch., vol. xlix. p. 66 : 1870.

' H. Quincke, Virchow's Arch., vol. xcv. p. 125 : 1884.

5 Herrn. Cordua, " Ueber den Resorptiousmechanismus von Blutergüssen":
Berlin, Hirschwald, 1877.

s Recklinghausen, "Handbh. der allgem. Patholog. d. Kreislaufes und der
Ernährung," p. 434: Stuttgart, Enke, 1883.

BILE PIGMENTS 339

the most varied conditions (in cerebral hemorrhage, in pul-
monary infarcts, in hematocele, in extravasations depending
upon mechanical injury, in abdominal hemorrhages consequent
upon extrauterine pregnancy, in rupture of the sac, &c.),
urobilin [vide p. 323) the product of the conversion of bili-
rubin occurs in large quantities in the urine.^

Bilirubin is sometimes found in the urine, if from any
cause hemoglobin passes out of the blood-corpuscles into the
plasma. This may be brought about by the injection of water
in large quantity, of chloroform, ether, or glycerin into the
blood, or merely by the injection of a solution of hemoglobin.^
It may however be questioned whether the relation is as simple
as it appears, and whether the bile pigment occurring in the
urine is formed from the hemoglobin that has passed into the
plasma within the circulation. The connection is probably one
of an indirect character.^ The presence of hemoglobin in the
plasma sometimes causes only hemoglobinuria, sometimes both
hemoglobinuria and bilirubinuria, or, again, bilirubinuria alone ;
sometimes neither of these occurs. We have not yet satis-
factorily settled the conditions under which the unaltered
coloring matter of blood or its product is found in the
urine.

We have seen that bile pigment is normally formed in the
liver, but the observations made upon extravasations of blood
show that in abnormal conditions it may also arise elsewhere.
Hence it has been asked whether the bile pigment occurring
in jaundice is invariably formed in the liver. The most fre-
quent cause of jaundice, which is characterized by the appear-
ance of bile pigment in the tissues and in the urine, is well
known to be a narrowing or a complete occlusion of the bile-
ducts. This generally occurs at the orifice of the common bile-
duct, in consequence of catarrh of the duodenum, or from the
presence of biliary calculi, tumors, and the like. In this way
the bile is blocked up, and reaches the lymphatics of the liver,
passes into the blood through the thoracic duct, and thus into
all the tissues and the urine. We term this form obstructive,
mechanical, or hepatogenous jaundice. In contrast to this an

' E. von Bergmann, " Die Hirnverletzungen mit allgemeinen und mit Herd-
symptomen," in E.. Volkmann's Sammlung klinischer Vorträge, No. 190 : Leipzig,
Breitkopf and Härtel, 1881 ; B. Dick, Arch. f. Gynäkologie, vol. xxiii. p. 1 :
1884. Comp, also G. Hoppe-Seyler, Virchow's Arch., vol. cxxiv. p. 30 : 1891 ;
and vol. cxxviii. p. 43 : 1892.

2 Kühne, Virchow's Arch., vol. xiv. p. 338: 1858. M. Hermann, "De
effectu sanguinis diluti in secretionem urinae," Dissert, inaug.: Berolini, 1859.
Nothnagel, Berl. klin. Wochensch., p. 31 : 1866. Tarchanoff, Pflüger's Arch.,
vol. ix. p. 53 : 1874.

Vide E. Stadelmann, Arch. f. exper. Path. u. Pharm., vol. xv. p. 337 : 1882.

340 LECTURE XXII

an - hepatogenous, hematogenous, or chemical jaundice ^ has
been assumed, which was attributed to a conversion of the
coloring matter of blood into bile pigment outside the liver.
A case was assigned to the latter class when no definite lesions
could be discovered in the liver, and when, the flow of bile
into the intestine being apparently unchecked, the feces
did not exhibit the "clay color" characteristic of jaundice
(compare p. 1 83) ; moreover, certain forms of poisoning, as
from arseniuretted hydrogen, chloroform, ether, fungi, and cer-
tain severe infective diseases, like typhus, malaria, pyemia,
gave countenance to this view. In many of these cases a
passage of hemoglobin from the blood-corpuscles into the
plasma could be directly shown under the microscope. Stromata
were also occasionally found in the blood, and hemoglobin was
seen to pass into the urine. It was therefore considered that
in these cases a portion of the hemoglobin, which had passed
into the plasma, had been converted into bilirubin outside the
liver.

One might have expected to be able to distinguish the two
forms of jaundice by the passage of the bile acids into the
urine together with the bile pigments in obstructive but not in
hematogenous jaundice. But it is manifest that the bile acids
are speedily destroyed after their passage into the blood ;
even in undoubted obstructive jaundice, their presence in the
urine can sometimes not be traced. On the other hand, they
are sometimes discovered in small quantities in normal urine
(compare p. 336, note 4). Large quantities of bile acids in the
urine certainly allow us to conclude that we have to do
with obstructive jaundice ; but their absence does not justify
the inference that we have to deal with the hematogenous
form.

More recent research has proved that there is not at
present any sound basis for the conclusion that the bile
pigment occurring in jaundice has any other source than the
liver.

Minkowski and Naunyn^ removed the liver of a goose,
and immediately exposed it, as well as a healthy goose, to the
influence of arseniuretted hydrogen. After half an hour, the
control goose evacuated urine containing considerable quantities
of biliverdin, which continued to be secreted for two days.

1 H. Quincke, Virchow's Arch., vol. xcv. p. 125 : 1884. Minkowski and
Naunyn, Arch. f. exp. Path. u. Pharm., vol. xxi. p. 1 : 1886. A critical account
of the comprehensive literature on the various forms of jaundice is given by these
authors.

2 Minkowski and Naunyn, loc. cit., p. 18. Compare also Valentini, Arch. f.
exper. Path. u. Pharm., vol. xxiv. p. 412 : 1888.

JAUNDICE 341

On the other hand, the urme of the goose without the liver
at first showed only a minute quantity of biliverdin ; but
after half an hour's exposure to the poison hemoglobin ap-
peared in the urine, and the urine subsequently discharged
was perfectly free from bile pigment. The blood also con-
tained neither bilirubin nor biliverdin. It is therefore ex-
tremely probable that the bile pigment appearing in the urine
after poisoning with arseniuretted hydrogen has its source in
the liver.

According to my view, every form of jaundice is induced
by obstruction. We must not forget that it is not necessary
that the larger bile-ducts should be completely obstructed in
order to cause the passage of bile into the blood. The slightest
disturbance, the least arrest of the flow from the primary bile-
ducts, suffices to induce it.

So long as there is an unimpeded flow into the intestine,
the bile pigment follows this route, and does not pass into
the urine. Tarchanoff" injected a solution of bile pigment
directly into the blood of a dog with a biliary fistula, and
found an increased secretion of pigment in the bile which
proceeded from the fistula; but there was none in the urine.^
We may therefore assume that whenever bile pigment occurs
in the urine, it is a sign of biliary obstruction. The bile pig-
ment which is formed in extravasations of blood reappears in
the urine, as already said, not in its original form, but re-
duced to urobilin. We need not be surprised at such a reduc-
tion taking place in the tissues, as we know from the researches
of Ehrlich that very energetic processes of reduction occur in
many organs and tissues.^ Ehrlich injected into living ani-
mals blue dye-stuffs, as alizarin blue, indophenol blue, which
are decolorized by the withdrawal of oxygen. These dyes
circulated in the blood-plasma without being altered. But
in certain tissues, especially in the connective and adipose
tissues, they were decolorized. When an incision was made
into the tissues, they at first appeared colorless ; the blue
color did not appear until the oxygen of the air had ope-
rated for some time. Possibly the reducing power of the
tissues explains the increased excretion of urobilin which
accompanies the fading of jaundice. The bilirubin which had
penetrated the tissues during the biliary obstruction now

^Tarchanoflf, Pfliiger's Arch., vol. ix. p. 332: 1874. Adolf Vossius has con-
firmed these results by fresh experiments {Arch. f. exper. Path. u. Pharm., vol.
xi. p. 446: 1879). Vide also A. Kunkel, Virchow's Arch., vol. Ixxix. p 463-
1880.

2 P. Ehrlich, " Das Sauerstoflfbediirfniss des Organismus" : Berlin, Hirsch-
wald, 1885.

342 LECTUEE XXII

returns to the blood as urobilin, and passes out through the
kidneys into the urine/

The obstruction of the bile which occurs in the jaundice
resulting from poisoning by arseniuretted hydrogen is probably
caused in the following manner. There is an increased secre-
tion of bile, for the intestine in the poisoned animals is loaded
with bile. It is therefore perfectly plausible to assume that
the copious inspissated bile cannot discharge itself quickly
enough, and that this alone suffices to induce obstruction;^ for
the pressure in the bile-ducts is very slight, and can be over-
come by a trifling resistance.^ Stadelmann ^ has convincingly
shown that the jaundice resulting from poisoning by arseni-
uretted hydrogen or toluylendiamin is due to obstruction.
When dogs with biliary fistulse were poisoned with these sub-
stances, there was a great increase of bile in the secretion,
which was moreover very thick and tenacious. They never
found catarrh of the duodenum, nor occlusion of the common
bile-duct, in their numerous autopsies. It was evident that
jaudice resulting from the action of toluylendiamin was due to
obstruction, from the simple fact that large quantities of bile
acids were found in the urine. In the jaundice due to poison-
ing by arseniuretted hydrogen, large amounts of bile acids
were also sometimes met with in the urine.

We may now dismiss the subject of jaundice and the forma-
tion of bile pigments in the liver. We possess no positive
knowledge as to the fate of the iron which, in the process that
we have been discussing, must be detached from the hematin.
In the liver we find very numerous compounds of iron, in which
the iron is more or less firmly fixed ; from very simple inor-
ganic forms, such as oxid and phosphate of iron, and organic
compounds in which it is more stable, to those in which the
iron is as firmly bound as in hematin.^ We know nothing as
to the genetic connection of these compounds, which have
scarcely been submitted to any inquiry.

As already mentioned, the formation of glycogen is one
of the functions of the liver. The reasons why we are compelled

^ Vide Kunkel, loc. cit., p. 463. Compare also Quincke, loc. cit., p. 138.

2 Minkowski aud Naunyn, loc. cit., p. 12.

^ Heidenhain, in Hermann's "Handb. d. Physiol.," vol. v. part i. p. 268 :
Leipzig, Vogel, 1883.

■* E. Stadelmann, Arch. f. exp. Path. u. Pharm., vol. xiv. pp. 231, 422 :
1881 ; vol. XV. p. 337 : 1882 ; vol. xvi. pp. 118, 221 : 1883. Compare also Afanas-
siew, Zeitschr. f. Jdin. 3Ied., vol. vi. p. 281 : 1883.

^ Vide St. Sz. Zaleski, Zeitschr. f. physiol. Chem., vol. x. p. 453 : 1886, where
a fall account of the literature on the relations of iron in the liver is given.
Compare also the interesting illustrations of the microscopical preparations in
the work of Minkowski and Naunyn, loc. cit.

GLYCOGEN 343

to assume that the sugar which passes frcm the intestine into
the portal blood is deposited in the liver as glycogen, have
already been given (p. 188). Glycogen plays, in the metab-
olism of animals, a part similar to that which belongs to
starch in the metabolism of plants : it is the form in which
the excess of carbohydrates is stored up in the organism for
future use.

Glycogen ^ is distinguished from starch by its property of
swelling up and being apparently dissolved in cold water. The
solution is however never clear, but opalescent and not diffusible.
Glycogen therefore in this respect resembles the colloid gummy
carbohydrates, dextrin, arabin, bassorin, and the like ; but it is
more complicated than dextrin, as this is obtained by the de-
composition of glycogen. It yields products similar to those
derived from starch when broken up, and is probably of as com-
plex a nature.

There is no room for the storage of the whole excess of
carbohydrates in the liver. The liver of mammals rarely yields
as much as 10 per cent, of glycogen, and generally much less.
The human liver therefore, which weighs 1500 grms., con-
tains at most 150 grms. of glycogen. After a meal in which
carbohydrates have been copiously consumed, much larger
quantities often pass into the portal vein within a few hours,
and we must bear in mind that at the commencement of a
meal the liver contains some glycogen. It only becomes
perfectly free from glycogen after several weeks' starvation.
A large portion of the sugar, derived from the intestine, must
therefore pass through the liver. But as the amount of sugar
in the blood does not rise after a diet rich in that substance,
the sugar must be deposited in other organs than the liver.
We do, in fact, know that the muscles contain glycogen.^ The
percentage amount of this carbohydrate in the muscles is much

Cl. Bernard {Gas. med. de Paris, No. 13 : 1857; Compt. rend., vol. iliv.
p. 578: 1857) and V. Hensen (Virchow's Arch., vol. xi. p. 395: 1857) each dis-
covered glycogen independently of the other, and isolated it from the liver.
Brücke [Sitsungsber. d. Wien. Akad., vol. Ixiii. part 2, p. 214 : 1871) has shown
a method for the quantitative estimate of glycogen. Vide also O. Nasse, Pflüger's
Arch., vol. xxiv. pp. 1-114: 1881: R. Böhm and Fr. A. Hofmann, Arch. f.
exper. Path. u. Pharm., vol. vii. p. 489: 1877; vol. viii. pp. 271, 375: 1878;
vol. X. p. 12 : 1879 ; Pflüger's Arch., vol. xxiii. pp. 44, 205 : 1880. Compare also
Külz, Pflüger's Arch., vol. xxiv. pp. 1-114 : 1881, for a complete account of the
literature on the subject.

^ The occurrence of glycogen in the muscles was discovered by Bernard
{Compt. rend., vol. xlviii. p. 683 : 1859) and by O. Nasse (Pflüger's ^rcA., vol. ii.
p. 97: 1869; and vol. xiv. p. 482: 1877). A summary of the first accounts of
glycogen in muscle is given by E. Külz, loc. cit., p. 42. Glycogen in small
quantities is also present in other organs. Compare M. Abeles, Centralbl. f. d.
med. Wiss., p. 449 : 1885.

344 LECTURE XXII

smaller than that in the liver, and seems to vary in different
animals ; the muscles at the most contain 1 per cent., generally
less than ^ per cent. Böhm ^ found the absolute quantity
contained in the muscles of the cat nearly as large as that in
the liver. The muscles of a horse, after nine days' starvation,
still contained from 1 to 2.4 per cent, glycogen.^ As we shall
see directly, glycogen is the material of muscular work. It
disappears entirely from the muscles and liver after fatigue
and want of food ; ^ and sooner from the liver than the
muscles.* It may be taken as a fact that when there is an
insufficient supply of food the organs which are at rest give
up their store of glycogen to those that are working.

It is probable that glycogen is conveyed from one part of
the system to another in the form of grape-sugar. When
broken up by ferments, glycogen is converted, m the first
instance, into a carbohydrate resembling dextrin, and into a
variety of sugar resembling maltose.^ But in the living
body, the passage of the glycogen from the tissues into
the blood causes a further advance in this change, and the
glycogen is as completely converted into molecules of grape-
sugar as it would be by boiling with dilute sulphuric acid.
The majority of inquirers have been unable to show the
presence of glycogen or of any colloid carbohydrates in the
blood.^

Glycogen is not only a source of power for the muscles ; it
is likewise a source of heat. If we lower the temperature of
a rabbit by cold baths and cold air, all but minute traces of
the glycogen is found to have disappeared from the liver after
a few hours,'' Starvation deprives warm-blooded animals more
rapidly of their glycogen than cold-blooded animals, and among

1 R. Böhm, Pfliiger's Arch., vol. xxiii. p. 51 : 1880.

2 G. Aldehoflf (Kiilz's lahoraXotj) , Zeitschr. f. Biolog., vol. xxv. p. 162 : 1888.
^ B. Luchsinger, " Experimentelle und kritische Beiträge zur Physiologie

und Pathologie des Glycogens," Vierteljahrschr. der Züricher naturforschenden
Gesellschaft : 1875. See also Pfliiger's Arch., vol. xviii. p. 472 : 1878. G.
Aldehoff, Zeitschr. f. Biolog., vol. xxv. p. 137 : 1889.

* Aldehoff", loc. dt.

^ O. Nasse, Pfliiger's Arch., vol. xiv. p. 478 : 1877 : Musculus and von
Mering, Zeitschr. f. physiol. Chem., vol. ii. p. 413 : 1878 ; E. Külz, loc. cit.,
pp. 52-57 and 81-84.

® O. Nasse, " De materiis amylaceis, num in sanguine animalium inveniantur,
disquisitio," Dissert.: Halle, 1866: Hoppe-Seyler. "Physiol. Chem.," p. 406 :
Berlin, 1881. Salomon comes to different conclusions {Deutsche med. Wochenschr.,
No. 35 : 1877). Frerichs (" Ueb. d. Diabetes," p. 6 : Berlin, 1884) also comes to
the conclusion that there is constantly a small amount of glycogen in the blood,
for the most part contained in the white blood-corpuscles. This however is not
a peculiarity of leucocytes, but is probably common to all cells.

■^ E. Külz, Pfliiger's Arch., vol. xxiv. p. 46 : 1881. Vide also Böhm and
Hoflfmann, Arch. f. exper. Path. u. Pharm., vol. viii. p. 295 : 1878.

GLYCOGEN 345

the former small animals with a relatively large surface lose
it sooner than the bigger ones.^ Starving rabbits lose their
glycogen in from four to eight days ; dogs not before two or
three weeks ; frogs, in summer, after from three to six weeks.
Frogs which have had no food during the whole winter do not
show an entire absence of glycogen until the spring. Hiber-
nating mammals are equally slow in consuming their store of
glycogen.^

If we introduce carbohydrates into the stomach, or directly
into the blood of rabbits, whose liver, after six days of
starvation, has been rendered quite free from glycogen, a
large amount of glycogen is found in the liver after a few
hours.^

It is probable that the glycogen stored in the liver and the
muscles is not derived exclusively from the carbohydrates of
the food. It appears that the albuminous and gelatinous sub-
stances of the food also take part in the formation of glycogen.
Animals that have been exclusively fed for a considerable
period on lean meat, exhibit large stores of glycogen in their
liver and muscles. Naunyn * fed fowls for a long time (in one
experiment for six weeks) exclusively on muscle, which had
been stewed down and squeezed out, and therefore was almost
entirely free from carbohydrates ; and he then found large
quantities of glycogen (as much as 3.5 per cent.) in the
liver. Von Mering^ fed a dog, which had been previously
starved for twenty-one days, for four days exclusively on
washed bullock's fibrin. The animal was killed six hours after
it had been last fed, and the liver, which weighed 540 grms.
contained 16.3 grm. of glycogen. A control animal of nearly
the same size showed, after twenty-one days of starvation,
0.48 grm. of glycogen in the liver. It would necessitate very
forced modes of explanation to assume from these and many
other similar experiments that the glycogen did not arise from
the proteid.

We may also quote, in support of the view that carbo-

''■ B. Luchsinger, loc. cit.

2 Schiff, " Unt. ueber die Zuckerbildung in der Leber," p. 30: Würzburg,
1859; Valentine, Moleschott's Unters, zur Naturlehre, &c., vol. iii. p. 223: 1857;
C. Aeby, Arch. f. exper. Path. u. Pharm., vol. iii. p. 184: 1875 ; Voit, Zeitschr.
f. Biolog., vol. xiv. p. 118 : 1878.

^ E. Kiilz, Pflüger's Arch., vol. xxiv. pp. 1-19 : 1881. The numerous experi-
ments of a similar nature made by earlier authors are given here.

* B. Naunyn, Arch. f. exper. Path. u. Pharm., vol. iii. p. 94 : 1875.

s Von Mering, Pflüger's Arch., vol. xiv. p. 282 : 1877. The experiments
made on this subject by earlier authors are appended. Vide also Benj. Finn,
Verhandl. d. physik. med. Ges. zu Würzburg, N.F., vol. xi. Heft i., ii. : 1876;
and S. Wolfiberg, Zeitschr. f. Biolog., vol. xii. p. 310 (Exp. 4): 1876.

346 LECTUEE XXII

hydrates are formed from proteid, the fact that in the severe
form of diabetes mellitus, under a protracted and exclusive
flesh-diet, the secretion of sugar does not cease, and that the
quantity of sugar increases in proportion to the amount of
proteid consumed.^

Von Mering's experiments on phloridzin diabetes are well
worth mentioning.^ Phloridzin is a glucosid found in the
root cortex of apple and cherry trees. If we administer a
certain amount of this to a dog (1 grm. per kilo, body-weight)
we find, after a few hours, sugar in the urine. This glycosuria
ceases in two or three days, and we then find the liver and
muscles totally free from glycogen. If we now give another
dose of phloridzin, we again find a large amount of sugar ex-
creted. Von Mering concludes that this must be derived from
proteid. We must however acknowledge the possibility that
this sugar may arise from fats. I have already (Lecture XIII.)
noted certain fats which point to a conversion of fat into
sugar, and would cite especially the constant percentage of
sugar in the blood of starving animals which have long used
up their store of glycogen, and sparing their proteid as much
as possible, are living mainly at the expense of their fat. A
conversion of fat into sugar has long been familiar to the
vegetable physiologist. Certain seeds contain no starch, the
place of this substance being taken by fat. If such seeds are
allowed to germinate in the dark in order to prevent the
formation of new organic substances, the fat is seen to dis-
appear from the cotyledons and is replaced by starch, gum,
sugar and cellulose.^ If starchy seeds germinate in a glass
tube over mercury no alteration occurs in the volume of the
air in the tube. If oily seeds are placed under the same
conditions, the mercury rises in the tube, since oxygen is
used up in the transformation of fats into carbohydrates.* J.
Seegen is of opinion that a similar conversion of fat into
carbohydrate occurs in the liver of the mammal, and bases his
argument on the following experiment. Pieces of liver from a
freshly killed animal are weighed, cut up finely, and allowed to
stand with defibrinated blood at the body temperature. To one

1 Von Mering, " Tageblatt der 49 Naturforscherversammlung in Hamburg,"
summarized in the Deutsche Zeilschr.f. prakt. Med., No. 40: 1876; and No.
18: 1877; Kiilz, Arch, f. exper. Path. u. Pharm., vol. vi. p. 140: 1876.

2 Von Meriug, Verhandl. d. Congr. f. inn. Medicin., Fünfter Congress, Wies-
baden, p. 185 : 1886 ; and Sechster Congress, Wiesbaden, p. 349 : 1887.

^ Sachs, Potan. Zeit.: 1859; Peters, "Landw. Versuchsstationen," vol. iii.:
1861.

* An experiment by Wiesner, described by Seegen in " Die Zuckerbildung im
Thierkörper," &c., p. 155: Berlin, 1890.

GLYCOGEN 347

portion of this mixture a fine emulsion of fat is added. Air is
then allowed to bubble through the mixtures for five to six
hours. At the end of this time the amount of sugar is
determined in the mixtures, and is found to be always higher
in the liver to which fat has been added. Seegen concludes
that fat is converted in the liver into sugar. In harmony with
this assumption is the fact that the blood of the hepatic veins
is almost free from oxygen, whereas the blood flowing from
other organs always contains considerable quantities of this gas.

We must conclude therefore that as soon as the amount of
sugar in the blood sinks below normal, the liver pours into the
blood sugar which may be derived not only from glycogen and
proteid, but also from fats. Whether the other organs can also
convert their fat into sugar, or whether the fat must be first
transported to the liver in order to effect this conversion cannot
as yet be determined.

Many attempts have been made to decide by experiment
whether glycogen arises from the fatty materials of food.
Almost all authors ^ agree that the glycogen of the liver does
not increase in amount after fatty food.

* A summary of these authors is given by Von Mering, Pflüger 's Arch., vol.
xiv. p. 282 : 1877.

LECTURE XXIII

THE SOURCE OF MUSCULAR ENERGY

In our last observations on the formation of glycogen and
the behavior of carbohydrates in the body, I repeatedly stated
that glycogen must be regarded as the material of muscular
work. We will now proceed to consider the facts which
have led to this view, and to give a connected account of
all that is at present known concerning the source of muscular
energy.

The most obvious theory that the source of muscular work
is the metabolism of those substances which form the main
constituents of muscle, viz., proteids, was obstinately main-
tained by Liebig ^ to the end of his life. This teaching was
however shown to be erroneous by the following experi-
ment : —

Fick and Wislicenus, from the Lake of Brienz,^ ascended
the Faulhorn, the summit of which is 1956 meters above the
level of the lake. The urine excreted during the six hours'
ascent and for the succeeding six hours was collected, and the
nitrogen contained in it was estimated. During this time, and
for twelve hours previous to the commencement of the experi-
ment, only non-nitrogenous food, starch, fat, and sugar, had been
taken. The consumption of proteid was calculated from the
nitrogen found in the urine. In Fick it amounted to 38, and
in Wislicenus to 37 grms. From the amount of heat produced
by the combustion of the carbon and hydrogen in the proteid, a
maximal value ^ was deduced for the heat-equivalent of the

^ It is very instructive to read the original works in which the reasons
adduced in favor of and against Liebig's doctrine are given. To this end we
recommend Liebig's treatise, " Ueber die Gährung und die Quelle der Muskel-
kraft und über Ernährung ; " Liebig's Ann. d. Chem. u. Pharm., vol. cliii. pp. 1
and 157 ; and Voit's reply, " Ueber die Entwickelung der Lehre von der
Quelle der Muskelkraft und einiger Theile der Ernährung seit 25 Jahren,"
Zeitschr.f. Biolog. , vol. vi. p. 305 : 1870. The older literature on this question
is here critically treated.

2 A. Fick and J. Wislicenus, Vierteljahr sehr, der Züricher naturforschenden
Ges., vol. X. p. 317: 1865.

3 That this value must be much too high is evident from what we have men-
tioned before (p. 61 et seq.).

348

THE SOURCE OF MUSCULAR ENERGY 349

proteid, and it was found that 37 grms. of proteid yielded 250
units of heat, which corresponds to 106,000 kilogram meters of
work. Wislicenus weighed 76 kgrms. It follows that, in
merely raising his body to the summit of the mountain, he had
done work amounting to 76 x 1956 = 148,656 kilogrammeters.
But the work done during the ascent was really much greater ;
Fick and Wislicenus calculated that the work done by the
heart and by respiration in the same time amounted to 30,000
kilogrammeters. We have also to consider that even on level
ground every step entails work, which is converted into heat
and is lost, and that the other parts of the body, the head and
arms, are moved during the ascent, etc. It follows that much
more work had been done than would be covered by the
potential energy contained in the proteid consumed. The non-
nitrogenous constituents of the food and of the body must
therefore have been utilized as sources of energy.

The view that proteid is the exclusive working material of
muscle is more precisely controverted by a series of very care-
ful experiments on metabolism. These show that the excretion
of nitrogen during twenty-four hours of extreme labor is as
great as, or but little more than, the quantity excreted during
rest ; but that, on the other hand, the excretion of carbonic
acid and the absorption of oxygen is much increased on the
days of work, and that therefore during muscular work non-
nitrogenous food is chiefly consumed.

Voit ^ was the first to carry out a careful experiment of this
kind. He caused dogs to run in a large tread-mill. On the
days before and after the day of work, the animals were
quiescent with the same food. Some of the experiments were
made on fasting animals. The output of nitrogen for twenty-
four hours was accurately determined, and it resulted, from two
experiments with fasting animals, that the excretion of nitrogen
was not increased on the working days. In two other experi-
ments with a fasting animal, and in two with a diet of lean
meat, the increase was very slight.

More recently, O. Kellner^ has instituted similar experi-
ments on horses at the experimental farm of Hohenheim. On
the working days, he found a greater increase in the excretion
of nitrogen than was shown in the experiments of Voit. It
was only when very large quantities of carbohydrates were
given to the horses that this increase failed.

1 C. Voit, "Unt über den Einfluss des Kochsalzes, des Kaffees und der
Muskelbewegungen auf den Stoffwechsel," p. 153, et seq.: München, 1860; and
Zeitschr. f. Biolog., vol. ii. p. 339 : 1866.

- O. Kellner, Landwirthshaftliche Jahrbücher, vol. viii. p. 701 : 1879 ; and
vol. ix. p. 651 : 1880.

350 LECTURE XXIII

Pettenkofer and Voit ^ have also made experiments on man
to determine the influence of work upon the excretion of nitro-
gen. The elimination of carbonic acid, and indirectly the
amount of oxygen consumed, was determined at the same time
by the respiratory apparatus. They foimd that on the working
days the excretion of nitrogen was identical with that on the
days of rest, the food being the same. The amount of sul-
phuric and phosphoric acids secreted was not increased on the
working days, but the excretion of carbonic acid and the
absorption of oxygen rose very considerably.

Lavoisier^ had already shown that the absorption of
oxygen and the excretion of carbonic acid were increased
by muscular work. Vierordt,^ Scharling,* Ed. Smith,^ C.
Speck,^ and others, using more perfect methods, have confirmed
this discovery. The increase in the absorption of oxygen and
in the excretion of carbonic acid has been determined not only
by the investigation of the interchange of gases in the respira-
tory apparatus, but also by a comparative determination of the
oxygen and the carbonic acid in venous blood, taken from the
quiescent and the tetanized muscle. This was done by Ludwig
and Sczelkow,^ and finally in a masterly inquiry carried out in
Ludwig's laboratory by Max von Frey,* with the advantage of
all the improved technical aids.

From the experiments that have been quoted, it is apparent
that muscle chiefly works with non-nitrogenous food, and carbo-
hydrates readily suggest themselves, as they are invariably
stored up in muscle in the form of glycogen. CI. Bernard, the
discoverer of glycogen, was also the first to observe that this
store of glycogen disappears during work.^ He also found that

1 Pettenkofer and Voit, Zeitschr. f. Biolog., vol. ii. pp. 488-500 : 1866. Com-
pare also Felix Schenk, Arch. f. exper. Path. u. Pharm., vol. ii. p. 21 : 1874 ; and
Oppenheim, Pflüger's ^rcA., vol. xxiii. p. 484: 1880.

* Seguin and Lavoisier, " Premier memoire sur la respiration des animaux,"
Mem. de I' Acad, des Sciences, p. 185 : 1789 ; CEuvres de Lavoisier, Paris, Im-
primerie imperiale, vol. ii. pp. 688, 696 : 1862 ; and Lavoisier's letter to Black,
dated November 19, 1790, printed in the "Ptcportof the Forty-first Meeting of
the British Assoc, for the Adv. of Science," held at Edinburgh, in August, 1871,
p. 191 : London, 1872.

^ Vierordt, " Physiologie des Athmens " : Karlsruhe, 1845.

■* Scharling, Ann. d. Chem. u. Pharm., vol. xlv. p. 214 : 1843 : Journ. f. prakt.
Chem., vol. xlviii. p. 435 : 1849.

sEd. Smith, Phil. Trans., vol. cxlix. (2) pp. 681, 715: 1859; Medico-
chirurg. Trans., vol. xlii. p. 91 : 1859.

* C. Speck, Schriften der Ges. zur Beförderung d. get. Naturioissensch. zu
Marbiirg, vol. x.: 1871 ; Arch. f. exper. Path. u. Pharm., vol. ii. p. 405 : 1874.

' Ludwig and Sczelkow, Wiener Sitzungsher., -vol. -sly. t?. 171 : 1862; Zeitschr.
f. rat. 3fed., vol. xvii. p. 106 : 1862.

» Max von Frey, Du Bois' Arch., pp. 519, 533 : 1885.
9 CI. Bernard, Compt. rend., vol. xlviii. p. 683 : 1859.

THE SOURCE OF MUSCULAR ENERGY 351

when a muscle is artificially brought to a state of quiescence
by division of its nerve, its glycogen increases. These state-
ments of Bernard have been subsequently confirmed by many
experiments.^ If one of the hind legs of a frog be tetanized,
it is always found to contain less glycogen than the other,
which has been at rest.

Külz^ allowed dogs that had been previously well fed to
starve for one day, and on this day to drag a heavy cart for
from five to seven hours. The dog was then immediately killed,
and the amount of glycogen in his liver determined. Of five
dogs employed in this experiment, the liver in four showed that
all but mere traces of glycogen had disappeared. The liver of
the fifth, which was distinguished from the others by being old,
very fat and sluggish, weighed 240 grms., and contained 0.8
grm. of glycogen. I have previously remarked that during
starvation without work glycogen does not disappear from the
liver of a dog until the third week (pp. 344-345).

Hence there can be no doubt that carbohydrates serve as a
source of muscular energy.

However, it would be too much to assume that carbo-
hydrates are the sole source of muscular energy. We have
just become acquainted with experiments from which it appears
very probable that glycogen is formed from proteid (p. 345).
Hence we infer that proteid may also serve as a source of
muscular energy. It is a fact that Carnivora may be fed for
a long time exclusively on lean meat, without impairing mus-
cular vigor. I cannot conceive any explanation of the metab-
olism of the animals thus fed, without assuming that proteid
may serve as a source of muscular power.

Nor is it improbable that fat may serve for the same
purpose. It would not be difficult to determine this question
by experiments upon fasting dogs. Külz has already shown
that a fasting dog consumes its store of glycogen on the very
first day of hard work. A determination of the excretion of
nitrogen and carbon on subsequent days, when the work was
continued, would afford a certain reply to the question whether
chiefly proteid or chiefly fat supplies the animal with working
power. When Voit made his experiments on fasting dogs, the
animal generally worked only one day ; in one of his experi-
ments ^ however, the work was continued for three successive
days, and they had been preceded by three fasting days with-

1 An account of these is given by E. Kiilz, Pfliiger's Arch., vol. xxiv. p. 42 :
1881 ; and Ed. Marche, Zeitschr. f. Biolog., vol. xxv. p. 163 : 1889.

2 E. Kiilz, loc. cit., p. 45.

3 Voit, " Ueb. d. Einfl. d. Kochsalzes," &c., pp. 157, 158.

352 LECTURE XXIII

out work. Kiilz's dogs worked and fasted for one day only,
previous to which they had been supplied with ample food for
some days, and still after the first day of work their glycogen
had disappeared. It follows therefore that Voit's dog must
have been quite free from glycogen on the second and third
days of hunger and work. Nevertheless there was only a
trifling increase in the excretion of urea. I think therefore
it must be concluded from this experiment that the store of
fat in this dog had been drawn upon to carry on its muscular
work.

I hold that muscle draws its energy from all the three
main classes of food-stuffs. We might assume ä priori, on
teleological grounds, that in the performance of its most
important functions, the organism is to a certain extent
independent of the quality of its food. As long as non-
nitrogenous food is supplied in adequate quantity or is stored
up in the tissues, muscular work is chiefly maintained from
this store. When it is gone the proteids are attacked. The
results obtained from the above-mentioned experiments of
Kellner entirely agree with this statement ; he found that, in
the horse, the excretion of nitrogen is increased by muscular
work only when the animal does not receive a sufficient supply
of carbohydrates.

It has often been surmised that muscular energy is not
derived from the processes of oxidation, but from those of de-
composition. Certain facts seemed to favor this view. Thus
Hermann ^ found that an excised muscle contains no removable
oxygen, and that nevertheless it executes numerous contractions
and gives off carbonic acid when placed in a medium de-
prived of all oxygen. We know that the chemical potential
energy introduced by food may in part be converted, by mere
breaking up without oxidation, into kinetic energy ; that the
heat of combustion of decomposition products is lower than
that of the original food-stuffs, and that therefore heat must
be liberated during decomposition. We have given direct
proof that this development of heat accompanies many proc-
esses of decomposition. (Compare pp. 64, 153.)

The above-mentioned fact, that in muscular work the
consumption of oxygen is increased, is not opposed to the
assumption that only a part of the chemical potential energy
is transmitted into kinetic energy during decomposition.
The two processes, decomposition and oxidation, might occur
at different periods ; the former serves for muscular work, the

1 L. Hermann, " Unt. üb. d. Stoffwechsel der Muskeln, ausgehend vom
Gaswechsel derselben" : Berlin, 1867.

THE SOURCE OF MUSCULAR ENERGY 353

latter provides heat. Both processes might also be separated
as to their locality, the decomposition occurring in the proto-
plasm of muscular fiber, while possibly the oxidation of the
decomposition products occurs in other tissue-elements.

From this point of view the absorption of oxygen would
mainly serve for the production of heat. There is a remarkable
difference in animals in their requirement of oxygen, and
it appears that the want is regulated by the amount of heat
generated. A mammal requires at least from ten to twenty
times as much oxygen, in proportion to its weight, as a cold-
blooded animal. A bird uses up more than a mammal, A
small animal, giving off more heat from a relatively larger
surface, requires more than closely allied animals of a large
size. Young animals require more than full-grown animals of
the same species. These differences are well shown in the
following table :

Amount of Oxygen Consumed in Twenty-Foue Hours, in Pkoportion
TO 1 Grm. of Weight, in c.cm. at 0° C. and 760 mm. Hg.i

Sparrow

Duck

Dog

Man

Frog ...

Earthworm

Tench .

Eel

Lizard, hibernating . . .

If it is correct to regard muscular energy as mainly pro-
duced by the decomposition of food, and heat chiefly by
oxidation, we should expect that animals which develop no
heat would require the smallest amount of oxygen. This is
the case with the entozoa of warm-blooded animals, which
reside in a uniformly high temperature. We know that the
intestinal parasites live in a medium which is almost entirely
free from oxygen, for the most recent and most careful
analyses of intestinal gases have demonstrated no oxygen in
them. We know that active processes of reduction occur in
the intestinal contents ; that they constantly give rise to
nascent hydrogen ; that sulphates are reduced to sulphids,
and oxid to suboxid of iron. The amount of oxygen taken
up by the intestinal parasites must therefore be excessively

^ The figures given for the consumption of oxygen in man are derived from
the work of Pettenkofer and Voit [Zeitschr. f. Biolog., vol. ii. pp. 486, 489 : 1866) ;
those for fish from that of Jolyet and Regnard {Arch, de Physiol, norm, et path.,
Serie ii. vol. iv. pp. 605, 608 : 1877). The remaining figures are from the work
of Regnault and Reiset {Ann. de Chim. et de Phys., vol. xxvi.: 1849).

23

161.0

23.0 -

- 32.0

15.0 -

- 23.0

7.0 -

- 11.0

1.0 -

- 2.0

1.7

1.3

0.97-

- 1.2

0.41

354 LECTUEE XXIII

small. It is possible that they attach themselves to the walls
of the intestine and take up oxygen which is diiFused from
the tissues of the bowel, before it is taken possession of by
the reducing substances of the intestinal contents. But it
is also possible that mere traces of oxygen are sufficient for
their wants, or even that they require no oxygen, as is asserted
of certain bacteria and fungi (compare above, pp. 158, 244, note
3). This question can only be decided experimentally. I have
made many experiments with the round worm (^Ascai-is mystax)
of the cat, and have satisfied myself that these animals can
live in media entirely free from oxygen for from four to five
days, and be extremely active during the whole time.^ Who-
ever has seen these movements must be convinced that oxidation
is not the source of muscular energy in these animals.

The objection might be raised that they have a store of
oxygen in their bodies, which is but loosely fixed. We must
admit this possibility. Ascarides are sometimes found in the
stomach. It is possible that they rise into the upper part of
the digestive tract in order to supply themselves with oxygen.
But this proceeding has no analogy with what is observed in
higher animals ; as soon as the supply of oxygen is cut off,
the store contained in the oxyhemoglobin is consumed in a few
minutes and the animals perish. Pflüger ^ and Aubert ^ have
certainly shown that frogs may remain alive for several days
in an atmosphere containing no oxygen, but only at a very low
temperature, which causes a reduction of the entire metabolism
of these animals to the lowest point.* If they are left at the
temperature of the room, they become motionless after a few
hours ; while ascarides move about most actively at a tempera-
ture of 38° C. for several days in media devoid of all oxygen.
I am far from applying to higher animals the conviction
derived from the observation of these animals, that muscular
energy is mainly due to processes of decomposition. Intestinal
parasites, which are constantly surrounded by food-supplies,
can afford to be wasteful of their potential energies, and only
utilize that portion of them which is converted into kinetic
energy by mere decomposition. Such a proceeduig would be

^ G. Bunge, Zeitschr. f. physiol. Chem., vol. viii. p. 48 : 1883.

2 Pflüger, in his Arch., vol. x. p. 313 : 1875.

3 Aubert, ibid., vol. xxiv. p. 293 : 1881.

* As we might cl priori expect, we find that in cold-blooded (Poikilothermie)
animals, a rise of the temperature of their environment causes increased metab-
olism and consumption of oxygen, whereas the reverse is the case in warm-
blooded or homoiothermic animals. A critical account of the numerous experi-
ments by which this statement has been established will be found in a paper by
Voit, Zeitschr. f. Biolog., vol. iv. p. 57: 1878. Compare also Max Eubner, Du
Bois' Arch., pp. 38, 248 : 1885.

THE SOURCE OF MUSCULAR ENERGY. 355

purposeless in the higher animals. I have already mentioned
the reasons in favor of the view that in the higher animals
oxygen penetrates through the capillary walls into the tissues
(p. 244). With regard especially to muscular tissue, we
have to add an important fact to the reasons adduced : the
occurrence of hemoglobin in muscle.' Both probability and
analogy justify the view that the hemoglobin performs the
same functions in muscle as in blood, i. e., that of oxygen-
carrier.

The amount of kinetic energy, which may develop by mere
decomposition without oxidation from the chemical potential
energies of food, is much too small adequately to explain mus-
cular work. Let us first consider the carbohydrates, which
certainly are the chief source of muscular energy.

Unfortunately we are not sufficiently familiar with the
nature of the process of decomposition of the carbohydrates
in muscle. It has often been opined that they break up in
the first instance into sarcolactic acid.^ Normal blood in-
variably contains some lactic acid ; the amount increases in
tetanized animals, and when blood is artificially passed through
a living and working muscle.^ But it appears that the amount
of lactic acid formed in muscle is too trifling to allow this proc-
ess of decomposition to serve as a source of muscular energy.
At any rate, we do not know how much of the carbohydrate
in muscle undergoes this decomposition. We do not even
know whether the lactic acid occurring in muscle is formed
from the carbohydrates.'* It is possible that during work
there is not more lactic acid formed in the muscle than during
rest, but that more is transmitted to the blood. Astaschewsky
found less lactic acid in the tetanized than in the quiescent
muscle.^ The heat-equivalent of lactic acid has never been

^ W. Kühne, Virchow's^r-cA., vol. xxxiii. p. 79 : 1865; and Ray Lankester,
Pflüger's Arch., vol. iv. p. 315: 1871. These statements with regard to the
occurrence of hemoglobin in muscle have been repeatedly doubted, but, as it
appears to me, without adequate grounds. Vide St. Zaleski, Centralbl. f. d. med.
Wissensch., Nos. 5, 6 : 1887. The earlier authors are here mentioned.

"■ Compare above, p. 312, note 2.

^ Vide P. Spiro, Zeitschr. f. physiol. Chem., vol. i. p. Ill : 1877 ; Max von
Frey, Du Bois' Arch., p. 557 : 1885 ; Gaglio, ibid., p. 400 : 1886 ; Wissokowitsch,
ibid., Suppl., p. 91 : 1877 ; and M. Berlinerblau, Arch. f. exper. Path. u. Pharm.,
vol. xxiii. p. 333 : 1887.

* In favor of the view that lactic acid arises from the carbohydrate, Ber-
linerblau ( loc. cit. ) points out that when blood to which glucose or glycogen has
been added, is artificially passed through the muscles, more lactic acid is formed
than without them. Considerable quantities of lactic acid are formed in the
dying muscle, but whence it arises is entirely unknown. Roehm has shown that
it is not formed from glycogen (Pflüger's Arch., vol. xxiii. p. 44 : 1880).

^ Astaschewsky, Zeitschr. f. physiol. Chem., vol. iv. p. 397 : 1880.

356 LECTURE XXIII

determined, so that we are unable to state how much kinetic
energy is liberated during lactic fermentation.

Let us endeavor to represent to ourselves the amount
of kinetic energy which may proceed from the decomposition
of carbohydrates, by picturing to ourselves two processes in
which the amount of kinetic energy liberated has been exactly
determined : alcoholic fermentation and butyric acid fermenta-
tion. The amount of heat liberated during the latter process
is larger than in the former, and we may assert that no greater
amount of heat can be liberated in any of the various processes
which sugar undergoes in decomposition. For of the three
products resulting from butyric fermentation (butyric acid,
carbonic acid, and hydrogen), only butyric acid can be further
broken up, and but little heat can be liberated in this process.
The breaking up of butyric acid into propane and carbonic
acid is entirely analogous to the splitting up of acetic acid
into methane and carbonic acid — a process in which we are
equally unable to show a development of heat. Taking the
numbers quoted at p. 62 as a foundation, I have calculated the
combustion-heat of sugar and of its products of decomposition
as follows :

Calories, Kgrms.
or metric muscular
heat-units. work.

1000 grms. of grape-sngar on complete combustion
to CO2 and HA yield . 3939 = 1,674,000

1000 grms. of grape-sugar, when split up into

alcohol and CO2, yield . 372= 158,100

1000 grms. of grape-sugar, when split up into

butyric acid, CO^, and H, yield ...... 414 = 176,000

The amount of work done by Wislicenus in as-
cending the Faulhorn in six hours amounted to 148,656

The amount of work done by heart and respira-
tion during the same ascent amounted to , . . 30,000

Accordingly we see that, had the work done during the
ascent of the Faulhorn been carried out by the decomposition
of carbohydrates, more than 1000 grms. of carbohydrates would
have been required in six hours ! This is out of the question.
On the other hand, 100 grms. of sugar, if completely broken
up and oxidized, would have sufficed to execute the work.
This amount of carbohydrate is always stored up in our muscles,
besides an equal quantity in the liver.

I think that my calculation proves that to perform their
work our muscles not only utilize the kinetic energy liberated
by the decomposition of the food, but that oxygen also pene-
trates the protoplasm of muscular fiber, and its affinity to the
products of decomposition serves as a source of energy.

THE SOURCE OF MUSCULAR ENERGY 357

Here we may again refer to the question of the value of
alcohol as a food. Even if we grant that alcohol is turned
to account in the body as a source of energy, yet this store
of energy is far smaller than that contained in the carbohydrate
from which the alcohol was prepared. In the fermentation
of a kilogram of sugar, as we have just seen, an amount of
energy is wasted which would serve to carry a heavy man
to the top of the Faulhorn. We must remember too that
certain cells of our body can probably only avail themselves of
the energy set free in the breaking down of food-stuflPs, since no
free oxygen ever reaches them (compare p. 341). We thus
see how foolish it is for men to give the nourishing carbo-
hydrates of the grape-juice and grain to be devoured by the
yeast-fungus, while they themselves feast on the excreta of the
fungus. Fruit berries, and milk too, are deprived of all their
value in this way.

LECTURE XXIV

FORMATION OF FAT IN THE ANIMAL BODY

The question regarding the origin of fat in the tissues of
the animal body, a most important part of metabolism, remains
for our consideration. Our views on this subject have under-
gone constant fluctuations and controversies during the last
few decades ; but we have arrived at the conviction, after
many and careful experiments, that the fat in the tissues
may be formed from all the three chief classes of organic
food-stuffs, viz., from the fats, the proteids, and the carbo-
hydrates.

From the comprehensive literature on the formation of fat,^
I shall select those works which constitute the firmest basis of
our present knowledge of this subject.

It was long doubted whether the fat of the tissues was
derived from the fat of the food ; chiefly on the grounds that
fat, being absolutely insoluble in water, could not as such
penetrate the intestinal wall, and that it would previously
have to be converted in the bowel into a soluble soap and
soluble glycerin. The view that glycerin and fatty acids
might again unite in the tissues on the other side of the
intestinal wall was opposed by the belief that no syntheses
could occur in the animal body. We have seen that both
these objections have now been overcome ; we know that
all kinds of synthetic processes occur in the animal body,
and that neutral fat does pass through the intestinal wall.
Now, if fat globules permeate the tissues of the intestine,
why may they not pass through the walls of the capillaries
and through all the organs of our body ? Ä priori therefore,
there is nothing opposed to the view that the fat of our tissues
is derived from the fat of our food. Franz Hofmann^ was the
first to give experimental proof that this is the case.

1 Voit supplies an interesting survey of the older literature on this subject.
" Ueber die Fettbildung im Thierkörper," Zeitschr. f. Biolog., vol. v. p. 79 : 1869.
Compare also "Ueber die Entwiekelung der Lehre von der Quelle der Muskel-
kraft und einiger Theile der Ernährung seit 25 Jahren," ibid., vol. vi. p. 371 :
1870.

* Franz Hofmann, Zeitschr. f. Biolog., vol. viii. p. 153: 1872.

358

FOEMATION OF FAT IN THE ANIMAL BODY 359

Hofmann deprived a dog of all fat by starving him for
thirty days. We are able to determine the exact period when
all the fat that is stored in the tissues is consumed. We
have already seen that a starving animal at first lives mainly
upon its store of glycogen, and subsequently upon its fat.
It uses the greatest economy with regard to its proteid.
That very little of the latter is decomposed is shown by the
minute excretion of nitrogen, which at first falls, and then
remains almost permanently the same. It is only after a
longer period, which may vary from the fourth to the fifth
we'ek according to the original amount of fat, that a sudden
rapid increase takes place in the excretion of nitrogen. This
is the period at which the store of fat is used up, and when the
animal commences to depend exclusively upon its store of
proteid. The animal will now speedily perish. If the animal is
killed at the time when the sudden increase of the nitrogenous
excretion occurs, all the organs and tissues are found to be
deprived of fat. If it is killed earlier a certain amount of fat
is still found.^

Armed with this knowledge, Hofmann was able to determine
when his starving dog was free from all fat. He now fed him
on a diet containing a great deal of fat and but little proteid,
viz., bacon and a small quantity of meat. The amount of
proteid and fat in the food had been accurately estimated.
After five days the animal was killed, and the amount of fat
and proteid remaining in the intestine, as well as the fat in
the whole body, was measured. It was found that during the
five days the dog had absorbed 1854 grms. of fat and 254 grms.
of proteid, and had deposited 1353 grms. of fat in his body.
This large amount of fat could not have arisen from the proteid.
It follows therefore that the fat of the food had been deposited
in the tissues.

Pettenkofer and Voit ^ obtained the same result by a dif-
ferent method. They fed dogs with fat and a little meat,
and by the use of the respiratory apparatus they measured
the total income and output. Their experiments showed that
all the nitrogen consumed was reexcreted, but not all the
carbon. A very large proportion of the carbon was retained.
It was to be inferred that a non-nitrogenous compound had
been stored in the tissues, and this could be nothing but fat,
because there is no other non-nitrogenous compound which

^ When the fasting animal, at the commencement of the experiment, is un-
usually fat, it may happen that it dies from failure of its proteids even before the
supply of fat is consumed.

2 Pettenkofer and Voit, Zeitschr. f. Biolog., vol. ix. p. 1 : 1873.

360 LECTUEE xxrv

is met with in the tissues in such large quantities. The fat
deposited in the tissues could not be due to the decomposed
proteid, as its amount was proportionately too large. It was
possible to calculate with precision how much proteid had
been decomposed by the quantity of nitrogen excreted. The
maximum amount of fat formed from the decomposed proteid
could be calculated on the assumption that the nitrogen had
been separated from the proteid molecule as urea. The amount
of fat resulting from this calculation was much less than that
actually found in the body ; it was therefore evident that this
must be derived from the fat of the food.

We must now inquire whether it is only that portion of
the fat of food which is absorbed unaltered as a neutral
glycerid that can be stored up in the tissues, or whether that
part which is split up in the intestine (compare pp. 164—166)
can also be regenerated and assimilated.

Munk ^ has recently performed the most careful investi-
gations to determine this question. He showed, in the first
instance, that free fatty acids are absorbed from the intestine
in large quantities as neutral fats. If free fatty acids are
shaken up with a dilute solution of alkaline salts, a small
portion of the fatty acids is saponified, the remainder is emul-
sified ; the same takes place in the intestine. Dogs, after the
consumption of a large quantity of free fatty acids, exhibited
only a very small portion in their feces, but their chyle-ducts
were full of a white emulsion.

The same inquirer also proved that free fatty acids exercise
the same economizing effect upon proteids as neutral fats.
A carnivorous animal, in order to maintain its body weight,
requires nearly one-twentieth of this weight daily of lean
meat.^ A dog weighing 25 kgrms. consequently requires
1200 grms. of meat. If we give him less, he excretes more
nitrogen than he consumes, and he feeds upon the proteids
of his tissues. But if we add fat to the meat of his food,
the dog, although consuming less meat, maintains his nitro-
genous equilibrium.^ Munk established the nitrogenous
equilibrium in a dog weighing 25 kgrms. with 800 grms. of
meat and 70 grms. of fat, and then showed that this equi-
librium remained the same if, instead of the 70 grms. of fat,

1 Immanuel Munk, Du Bois' Arch. f. Physiol., p. 371 : 1879; and p. 273:
1883 ; Yirchow's Arch., vol. Ixxx. p. 10 : 1880 ; and vol. xcv. p. 407 : 1884. The
earlier literature is here quoted.

* Bidder and Schmidt, " Die Verdauungssäfte und der Stoffwechsel," p. 333 :
Mitau and Leipzig, 1852; Pettenkofer and Voit, Ann. d. Chem. u. Pharm.,
SuppL.ii. p. 361: 1862.

* Munk, Virchow's Arch., vol. Ixxx. p. 17 : 1880.

FORMATION OF FAT IN THE ANIMAL, BODY 361

lie gave the dog, with the same amount of meat, the free
fatty acids obtained from the 70 grms. of fat. In a second
experiment, the nitrogenous equilibrium was produced in a
dog weighing 31 kgrms. with 600 grms. of meat and 100
grms. of fat, and this was maintained when subsequently the
free fatty acids of 100 grms. of fat were given him with the
same amount of meat for three weeks.

The important fact has further been determined by Munk^
that, after feeding with free fatty acids, only a very small
quantity of fatty acids and soaps, but much neutral fat, was
contained in the chyle. He fed dogs with meat and fatty
acids, and introduced a cannula into the thoracic duct ; a few
hours later, he determined the amount of chyle flowing out,
and the quantity of neutral fat, fatty acids, and saponified
matter contained in it. He found that, in the same time,
from ten to twenty times more neutral fat passes through the
thoracic duct than during the digestion of pure proteids, while
the amount of soaps remains unaltered. The proportion of the
free fatty acids generally reached only to between one-twentieth
and one-tenth, in one case less than one-thirtieth, of the neutral
fats. It follows that a synthesis of fatty acids with glycerin
takes place during the passage from the intestinal surface to
the thoracic duct.^ We have no precise information as to the
locality where this synthesis is effected. It may be in the
epithelial cells, in the adenoid tissue of the intestine, or in
the lymphatic glands of the mesentery. A preliminary com-
munication made by Ewald ^ shows that this synthesis also
occurs in the intestinal mucous membrane after it has been
excised.

We do not know the source from which the glycerin arises
that is necessary for this synthetic process. At all events,
Munk's experiment proves that the glycerin in the fat of our
body need not always be derived from the fat of our food ; it
may possibly result from the breaking up of the proteids and
carbohydrates.

We must confess that the fate of the glycerin in our body
is entirely unknown to us, and at present we are unable to
say what becomes of the glycerin which is separated in the

^ Munk, Virchow's Arch., vol. Ixxx. p. 28, et seq.: 1880.

^O. Minkowski (Arch. f. exper. Path. u. Pharm., vol. xxi. p. 373: 1886)
arrived at the same result. He had the opportunity of experimenting on a
patient suffering from extreme ascites, the result of a rupture of a chyle-vessel.
A large quantity of chyle was obtained by puncture. After administering to this
patient free erucic acid, the neutral glycerid of this acid was detected in the
chyle.

3 C. A. Ewald, Du Bois' Arch., p. 302: 1883.

362 LECTURE XXIV

intestine from the fat. If a large quantity of glycerin is
introduced into the stomach of a man or a dog, diarrhea occurs,
and of the glycerin that is absorbed a portion passes unaltered
into the urine/ Smaller quantities do not produce such con-
sequences ; in the dog, the proportion ought not to exceed
1.5 grm. to 1 kgrm. of weight.

Finally, Munk has given definite proof that the fat
synthetically formed is also stx)red up in the tissues of the
body.' A dog weighing 16 kgrms. was rendered almost
devoid of fat by starvation for nineteen days, during which
time he lost 32 per cent, of his original weight. In the
course of the next fourteen days the dog consumed 3200
grms. of meat, and 2850 grms. of fatty acids prepared from
mutton fat. With this diet, its weight rose again by 17 per
cent. The animal was now killed, and showed an enormously
developed panniculus adiposus; there was a copious deposit
of fat in the intestines, and a well-marked fatty liver. The
deposit of fat removed by scalpel and scissors yielded nearly
1100 grms. of fat that was solid at the temperature of the
room, and only melted at a temperature of 40° C. while normal
dog's fat is semi-fluid at 20°. It follows that the fatty acids
which had been introduced were deposited after combining
with glycerin that had formed in the body. If the deposit
of fat be attributed to an economizing influence, exercised
by the fatty acids introduced, and all the fat deposit be
regarded as entirely originating from the proteid, it is not
intelligible why mutton fat was deposited instead of normal
dog's fat.

In a second experiment,^ Munk fed a dog, which had been
deprived of fat by starvation, with colza oil. In this case
four-fifths of the fat deposited in the organs were liquid at
the temperature of the room ; when warmed to 23°, the whole
of it melted ; and at 14° a granular crystalline sediment formed.
This fat contained 82.4 per cent, of oleic acid, and 12.5 per
cent, of fixed acids ; whereas normal dog's fat yields on an
average only 65.8 per cent, of oleic and 28.8 per cent, of solid
acids. In addition to this, erucic acid (CjgH^^Og); which is an
ingredient of colza oil but absent from animal fat, was proved
to be present.

Previous to Munk, two similar experiments had been

' B. Luchsinger, "Experimentelle und kritische Beiträge zur Physiologie
und Pathologie des Glycogens." Inaug. Dissert., p. 38, et seq.: Zurich, 1875 ;
Munk, Virchow's Arch., vol. Ixxx. p. 39, et seq. : 1880; Arnschink, Zeitschr. f.
Biolog., vol. xxiii. p. 413 : 1887.

2 J. Munk, Du Bois' Arch., p. 273 : 1883.

* J. Munk, Virchow's Arch., vol. xcv. p. 407 : 1884.

FORMATION OF FAT IN THE ANIMAL BODY 363

carried out by Lebedeff' with the same result in two dogs,
one of which had been fed with linseed oil, the other with
mutton fat. The fat in the tissues of the former did not
congeal at 0°, the fat of the latter had a melting-point at
above 50°.

All these experiments prove conclusively that the fat of
food is absorbed and deposited unchanged.

We will now consider the second point as to whether fat
is formed from Proteid in the animal body. As fat takes
the place of proteid in the cells and fibers in cases of fatty
degeneration, we should suppose that fat necessarily proceeds
from this source. But this fact cannot be interpreted as
absolute proof of the origin of fat from proteid. We must
not forget that in the living body there is a constant nutritive
interchange going on directly or indirectly between all the
tissue-elements. It is possible that in cases of fatty degene-
ration the proteids or their decomposition-products may pass
away from the degenerating tissues, and be replaced by fat or
its components from other tissues.

An exact quantitative examination of the total metabolism
during a process of fatty degeneration, such as occurs in
phosphorus-poisoning in which all parts of the body are
rapidly involved, would show whether fat arose from proteid
or not. The most careful investigation of this process was
carried out in Voit's laboratory at Munich by J. Bauer.^ He
estimated the output of nitrogen and carbonic acid and the
income of oxygen in fasting dogs. He then poisoned them
with phosphorus, which was either given them by mouth in
small doses spread over several days, or subcutaneously in-
jected dissolved in oil. The consequence was that double the
amount of nitrogen was eliminated,^ and that the -amount of
carbonic acid excreted and of oxygen absorbed, dropped to
one-half. The nitrogen from a large amount of proteid there-
fore was split off with a small quantity of carbon by the action
of the phosphorus ; a remnant free from nitrogen remained
unconsumed in the body. If the animals died a few days after
the administration of phosphorus, a post-mortem examination

' A. Lebedeff (Salkowski's laboratory in Berlin), 3Ied. Centralbl., No. 8 :
1882.

2 Jos. Bauer, Zeitschr. f. Biolog., vol. vii. p. 63 : 1871 ; and vol. xiv. p. 527 :
1878.

' The increase in the excretion of nitrogen after phosphorus-poisoning was
shown before Bauer by O. Storch, "Den acute Phosphorforgiftning," &c.,
Dissert. : Kjobenhavn, 1865. Paul Cazeneuve has confirmed Storch's and
Bauer's results in the Revue mensuelle de Medec. et de Chirurg., vol. iv. pp. 265,
444: 1880.

364 LECTURE XXIV

showed all the organs to be in a state of fatty degeneration.
In one case, the dried muscles contained 42.4 per cent., the
dried liver 30 per cent, of fat, whereas only 16.7 per cent, was
found in normal dried dog's muscle and only 10.4 per cent, in
normal dried liver. Fat was therefore formed from proteid in
phosphorus-poisoning. It cannot be objected that the fat had
passed in from the fatty connective tissue in the muscles and
in the liver, because the dog had been starved for twelve
days before the commencement of the poisoning, and died on
the twentieth day of starvation. But experience has shown
that in dogs all fat visible to the naked eye disappears from
the subcutaneous cellular tissue and the mesentery after twelve
days of starvation.

Arsenic and antimony, which are chemically so closely
related to phosphorus, seem to operate in a similar manner.
They need not however be administered as free elements, as
they also, when in the oxidized condition, cause increased
elimination of nitrogen and fatty degeneration of the organs.^
We are at present unable even to suggest an explanation of
this action.

The experiments with phosphorus-poisoning only prove the
origin of fat from proteid under these definite abnormal con-
ditions. The question is whether this conversion likewise takes
place under normal circumstances.

The following simple experiment made by Franz Hofmann^
on fly-maggots, undoubtedly proves that fat does arise from
proteid under normal conditions. It is an easy matter to
collect, free from impurity, the eggs of the Museida vomitoria,
which are laid in heaps on a corpse in the summer-time.
Part of the eggs so obtained was employed by Hofmann to
estimate the amount of fat ; the other part was allowed to
develop on blood. The fat in the blood was also determined.
After the maggots were full-grown, the fat in them was like-
wise ascertained. It was found that there was ten times as
much fat in the full-grown maggots as in the eggs and blood
together. For instance, in one experiment, 0.02 grm. of eggs
containing 0.001 grm. of fat developed in 52 grms. of blood,
which had 0.017 grm. of fat, the full-grown maggots contain-
ing 0.201 grm. of fat. This can only have been formed from
the proteid of the blood ; it cannot be referred to the sugar of

^Gähtgens, Centralbl. f. d. med. Wissensch., -p. 529: 1875; Kossel, Arch.f.
exper. Path. u. Pharm., vol. v. p. 128 : 1876 ; Gähtgens, ibid., vol. v. p. 833 :
1876; and Centralbl. /. d. med. Wissench., p. 321: 1876; and Salkowsky,
Virchow's Arch., vol. xxxiv. p. 73: 1865.

2 Franz Hofmann, Zeitschr.f. Biolog., vol. viii. p. 159 : 1872.

FORMATION OF FAT IN THE ANIMAL BODY 365

the blood, for 50 grms. of blood seldom contains more than
0.07 grm. of sugar, and even this far too small a quantity must
have decomposed very rapidly; besides, the maggots had not
consumed nearly all the blood.

From the following experiments on dogs, Pettenkofer and
Voit^ came to the conclusion that fat may be formed from
proteid in mammals with a normal dietary. They fed them
on large quantities of lean meat, and with the help of the respi-
ratory apparatus they determined the total income and output.
It was found that all the nitrogen, but not all the carbon, of
the meat reappeared in the excretions. In one experiment,^
for instance, in which a dog of 34 kgrms. weight ate 2800
grms. of meat, the whole of the nitrogen was eliminated,
against only 271 grms. of the carbon, of which 313 grms.
had been taken ; 42 grms. were therefore missing. These
remained behind in the body as a non-nitrogenous compound,
and moreover, as Pettenkofer and Voit concluded, in the form
of fat. It may be objected that this compound may have
been glycogen just as well as fat. The amount of glycogen
stored in the body of the Carnivora is by no means inconsider-
able, and varies widely. Böhm and Hofmann^ found it
amounted from 1.5 to 8.5 grms. per kilogramme of a cat's
weight. The 42 grms. of carbon correspond to about 100
grms. of carbohydrates. If therefore we assume that the
former are stored in this form, there must be an increase of
glycogen amounting to 3 grms. per kilogramme of the body-
weight, which does not appear impossible. But we ought
not to forget that this increase of glycogen must take place
in one day ; the animal had had the same food on the previous
day, therefore so great a change in the amount of glycogen
was not very probable. But the experiments must be con-
tinued over a longer time before this point can be definitely
settled. It might however be decided in another way, i. e.,
if it were possible to make an exact comparison of the income
and output of oxygen. The difference in the amount of
oxygen in fat and glycogen is very considerable. It must
therefore be possible to determine the form in which carbon
is stored up from the quantity of the oxygen remaining in
the body. But at present we have no method of directly
estimating the amount of oxygen in food, and even the in-

^ Pettenkofer and Voit, Liebig's Annal., Suppl. ii. p. 361 : 1862; Zeitschr.
/. Biolog., vol. vi. p. 377 : 1870 ; and vol. vii. p. 433 : 1871.

2 Ibid., vol. vii. p. 487 : 1871.

' Böhm and Hofmann, Arch. f. exper. Path. u. Pharm., vol. viii. p. 290:
1878.

366 LECTURE XXIV

spired oxygen is calculated, according to Pettenkofer's method,
from the diiFerence.

One more objection may be raised to the experiment made
by Pettenkofer and Voit, i. e., that the meat was not quite free
from fat and carbohydrates. The formation of fat from
proteid in the organism of the mammal under normal con-
ditions has therefore not yet been decisively proved.^ But it
is however highly probable, because it is certainly the case
with the lower animals under normal circumstances, and
with mammals under pathological conditions. Moreover, it
may be adduced in favor of the normal formation of fat
from proteid that, as we have already seen (p. 345), gly-
cogen owes its origin to proteid, and fat to glycogen, and in
fact to any carbohydrates, as will be shown directly. No
chemical explanation of the formation of fat from proteid can
at present be oifered. However, the process must not be re-
garded as of so simple a nature that the fat is immediately split
off from the gigantic proteid-molecule as a preformed radical.
Profound decompositions, metamorphoses, and consequent syn-
theses are going on, of which we cannot at present form even
a conception.

We now come to the third and last point, as to whether
the CARBOHYDRATES are converted into fat in the animal body.
From the numerous experiments made on this subject, we
will select the following, as being perfectly reliable in their
results.

N. Tschervinsky ^ made his experiments with young pigs.
In one he used two of ten weeks old from the same litter,
No. 1 weighing 7300 grms., and No. 2 7290 grms. It would
therefore be supposed that each had about the same proportion
of fat and proteid as the other. No. 1 was killed, and all the
fat in the body was estimated, as well as the nitrogen, from
which the maximum of proteid was determined. No. 2 was
then fed on barley for four months. The barley was analyzed,
and an account was kept of the barley consumed. The
amount of undigested fat and proteid was also estimated by
analysis of the excretions ; and in this way, the quantity of

1 The remaining experiments quoted in favor of the view that fat is formed
from proteid are likewise inconclusive. Compare Subbotin, Virchow's Arch.,
vol. xxxvi. p. 561 : 1866 ; and Kemmerich, Centralbl. f. d. med. Wissensch., p. 465 :
1866 ; and p. 127 : 1867. Compare also Pfliiger's criticism of Voit's experiments,
Pflüger's Arch., vol. li. pp. 229 and 317 : 1891.

2 N. Tschervinsky, ZancZw. Versuchsstationen, vo\. xxix. p. 317 : 1883. Ex-
periments of a similar character by other authors led to the same results (F.
Soxhlet, Zeitschr. d. landwirthschaftlichen Vereins in Bayern, August-Heft, 1881 ;
B. Schulze, Landw. Jahrb., 1, 57 : 1882 ; St. Chaniewski, Zeitschr. f. Biolog.,
vol. XX. p. 179: 1884).

FOEMATION OF FAT IN THE ANIMAL, BODY 367

these two substances absorbed by the animal in the four
mouths was ascertained. The animal, whose weight had in-
creased to 24 kgrms., was now killed, and the proportion of
proteid and fat in the whole body determined.

No. 2 contained . . . . 2.52 kgrms. proteid, and 9.25 kgrms. fat.
No. 1 " .... 0.96 " " " 069 " "

Thus there were added . 156 " " " 8.56 " "

Taken up with the food . 7.49 " " "0^ "

Difference ... —5.93 +7.9

Thus 7.9 kgrms. of fat had been added in the body — an
amount which could not have originated from the fat of the
food ; of this only the smallest portion could have arisen
from the 5.93 of the proteid that was derived from the food,
and was not deposited in the form of proteid. At least

5 kgrms. of fat must therefore owe its origin to the carbo-
hydrates of the diet. This is so large a proportion as to
refute all doubts, and particularly the objection that the
identity in the amount of fat and proteid in both animals,
upon which the whole experiment rests, as an arbitrary
assumption.

A different method was adopted by Meissl and Strohmer.^
They fed a one-year-old Yorkshire pig (a good fattening
breed), weighing 140 kgrms., for seven days upon rice, which
is poor in fat and proteids and rich in carbohydrates. Two
kgrms. were administered to the animal every day. The
rice had been analyzed ; the urine and feces were collected
and also analyzed. On the third and sixth days of the
experiment the animal was placed in Pettenkofer's respira-
tory apparatus, in order to determine the excretion of carbonic
acid. The result was that 289 grms. of the carbon daily in-
gested, and 6 grms. of the nitrogen, were retained in the body :
38 grms. of proteid with 20 grms. of carbon correspond to the

6 grms. of nitrogen. It follows that 269 grms. of carbon must
have been daily retained in the body as fat. It is impossible
that so large a quantity of carbon could every day have been
stored up as glycogen. How then was this quantity of fat
formed? Of the daily food, 5.3 grms. of fat and 104 grms.
of proteid had been digested ; of the latter, 38 grms. had been
deposited. The remaining 66 grms. of proteid and the 5.3
grms. of fat cannot have yielded the 269 grms. of carbon

^E. Meissl and F. Strohmer, Sitzungsher. d, k. Akad. d. Wissensch. iyiWien.,
vol. Ixxxviii., Abth. III., Juli-Heft, 1883.

368 LECTURE XXIV

necessary for the deposit of fat, which must therefore be derived
from the carbohydrates.

It has often been asserted that the formation of fat from
carbohydrates takes place only in herbivora and omnivora,
and not in Carnivora. I therefore briefly mention the following
experiment, which Rubner/ with the help of a respiratory
apparatus, made on a dog. The animal, after fasting two
days, was fed on cane-sugar and starch. A large quantity of
carbon was retained — much too large, in fact, to be accounted
for by the deposit of glycogen ; it follows that fat had been
formed from carbohydrates.

The formation of fät from carbohydrates offers a complete
enigma to the chemist, and, more than anything else, proves
that the synthetic processes occurring in the animal cell are
as complicated as those in the vegetable cell.

Many attempts have been made to utilize our knowledge
with regard to the formation of fat, in order to determine the
causes of corpulency in man, and the means of counteracting
and preventing it. The error has been committed of attribut-
ing the cause of obesity to too ample a diet, or even to an
unsuitable combination of food, such as a diet with an excessive
proportion of carbohydrates or of fat.

It is both right and natural for a man to eat whatever he
likes and as much as he likes, and, if he otherwise leads a
healthy life, this system does not conduce to corpulency.
Why should we accuse a normal function of being the cause
of a pathological process? Obesity is in all cases due to
insufficient employment of the muscles. A person taking
bodily exercise does not become fat, whatever form of diet he
adopts. I quite admit that the tendency to corpulency may
vary considerably in different people ; but this only shows that
the organs which constitute half the weight of the body may
not be suffered to become atrophied with impunity in every
case. There is no such thing as a disposition to stoutness
which may not be overcome by muscular work. Show me a
single fat field-laborer ! It cannot be said that all these
people are badly fed ; many of them are as well nourished as
it is possible to be, and their diet is certainly never poor in
carbohydrates, nor often in fatty matter.

It is well known that the deposit of fat is encouraged by
the use of alcohol, for which we are at present unable to give
a satisfactory explanation. It readily suggests itself that alco-
hol, as a very combustible substance, exercises an economizing
effect upon organic articles of diet, which are all capable of

1 Max Rubner, Zeitschr. f. Biolog., vol. xxii. p. 272 : 188^!.

FORMATION OF FAT IN THE ANIMAL BODY 369

being converted into fat. But it is possible that alcohol pro-
motes the formation of fat, in the same way as we have seen
with other poisons, such as phosphorus, arsenic, and antimony
{vide supra, pp. 120-121 and 363-364). In a great measure,
the influence of alcohol on fat-formation may be attributed
to the paralyzing influence it exerts upon the human brain,
causing indolence and indisposition to bodily exertion. The
therapeutics of corpulency are therefore very simple : the
patient must be prohibited the use of all alcoholic beverages,
and he must be required to take exercise. In many cases, to
forbid alcohol is all that is required. If the heart however
already shows signs of weakness and fatty degeneration, it is
necessary to be cautious in ordering muscular exercise, and
not to advise sudden and violent exertion. Corpulency should
not be met by a so-called short cure, such as mountaineering
during a few weeks in the year. The cure should last as long
as life, and should merely consist in putting the muscles to
their natural use. That however is the very thing the wealthy
patient will not do, any more than he will renounce his alcohol.
Physicians therefore have devised the most extraordinary
methods for reducing fat, by which possibly some thousands
have been cured to death. The absurdity of all these cures
consists in trying to substitute one abnormality for another.
The physician endeavors to compensate for insufficient muscular
work by insufficient nourishment, or by a badly composed
diet, or even by causing an imperfect digestion of the food
(through administering saline purgatives) ; in other cases, he
permits the continued use of alcohol while withdrawing the
carbohydrates and fats.

If the first irregularity be entirely and permanently over-
come, it is unnecessary to interfere in any other way with the
natural course of the vital functions.

24

LECTURE XXV

lEON

The amount of iron contained in the adult human body is
not accurately known. We can only estimate it approximately
from the quantities which I have found in the total organism
of small mammals.

A mouse gontains 100 mg. Fe 1

A guinea-pig " 52 " " V per kilo, body-weight.

A rabbit " 46 " " j

It thus appears that animals are relatively poorer in iron as
the body-weight increases, and that we must therefore reckon
not more than 46 mg. Fe per kilo, in man. The amount of
iron in a body weighing 70 kilos, would therefore be 3.2 gr.,
and this is a maximum value. A minimal estimate may be
computed from the amount of iron in the blood. According
to Bischoif, our body contains 7.1—7.7 per cent, blood, and in
the blood, according to C. Schmidt, the iron amounts to
0.049—0.051 per cent. Hence the iron in the blood of a man
weighing 70 kilos, may be reckoned at something between
2.4—2.7 gr. and therefore the total amount in the body must be
between 3.2 and 2.4. This iron is chiefly contained in the hem-
oglobin of our blood. We have therefore to inquire : From
what is the hemoglobin formed? It does not exist in the
food of most vertebrates, except in the case of those Carnivora
and omnivora which live upon other vertebrates. Among the
invertebrates there are only a very few which contain a small
quantity of hemoglobin in certain tissues. The majority of
the vertebrates must therefore form their hemoglobin from
other compounds of iron, the nature of which we will now
consider.

Until recently little investigation has been made on this
subject. As oxid of iron was found in the ash of all articles
of diet, it was assumed that hemoglobin, which is well known
to be a compound proteid, was formed by synthesis from oxid
of iron and proteid.

It is difficult to understand how such a theory could have

370

ißON 371

been universally adopted at a time when Liebig's doctrine of
the universal antithesis in the metabolism of plants and animals
prevailed. As is well known, Liebig had taught that synthetic
changes could only be carried out in plants, the animal body
being able to eifect only disintegrative changes. It is true
that this theory was shortly afterwards overthrown by Köhler's
discovery of the synthesis of hippuric acid in the animal body.
But hippuric acid is relatively a very simple compound ; it
contains only 9 atoms of carbon in the molecule, whereas
hemoglobin has at least 700. It is therefore inconceivable
how anyone could ever imagine that such a complex com-
pound could be produced in our body ; that moreover the
inorganic iron should combine with its 32 atoms of carbon
to form so stable a compound as hematin, which is united
with proteid in the hemoglobin molecule. The iron cannot be
separated from the hematin even with the strongest reagents.
It cannot be detected in the hematin by means of ammonium
sulphid ; it is not split oif on boiling with alkalies or most
acids.

The universal acceptance of this doctrine concerning the
synthesis of hemoglobin from oxid of iron and proteid would
be quite incomprehensible were it not for the success which
physicians think they have achieved in the treatment of chlorosis
by the administration of inorganic preparations of iron. In
chlorosis the amount of hemoglobin in the body is diminished ;
after iron salts have been taken it is increased. Hemoglobin is
an iron compound. What could be more natural than the con-
clusion that the iron administered was used to form the hemo-
globin? Nevertheless this conclusion seems to have been
erroneous.

Later investigation has shown that the iron given by physi-
cians in chlorosis, with the object of making hemoglobin from
it, is probably not absorbed at all.

So far as I am aware, the first experiments which threw a
doubt upon the absorbability of preparations of iron were pub-
lished by Yincenz KletzinskyMn 1854. His communication
however is short and lacking in precision ; the figures appear
so little trustworthy that no notice was taken of the work.
It was quite unknown to me at the time that I undertook my
experiments on iron. Kletzinsky found that, in seven ex-
periments on himself, metallic iron, oxid of iron, sulphid of
iron, iodid of iron, acetate, lactate, and malate of iron could
be recovered without loss from the feces. The same result

^ V. Kletzinsky, Zeitschr. d. k. k. Gesellsch. d. Aerzte s. Wien., Jahrgang 10,
vol. ii. pp. 281-289 : 1854.

372 LECTURE XXV

was obtained from careful experiments carried out by E. W.
Hamburger ^ with ferrous sulphate on the dog, and by Marfori ^
in Schmiedeberg's laboratory with lactate of iron on the same
animal.

The inorganic preparation of iron administered by the
mouth does not enter into the urine, which in a normal state
contains an inappreciable quantity of this substance. In ex-
periments on animals in which inorganic compounds of iron
were given internally, the amount of iron in the urine rose
slightly only if the doses were so large or were continued so
long as to render it probable that the intestinal epithelium was
inflamed.^

We might conclude from these researches that inorganic
preparations of iron are not absorbed from the normal intestine.
But there is still an objection which must be refuted, viz., the
possibility that the iron taken may be absorbed, but may be
again excreted in the intestine. This objection has the more
weight owing to the fact that the iron absorbed from the food
and set free in the normal process of metabolism takes this
path. This may be seen in fasting animals. The iron which
appears in the feces of fasting animals cannot come from un-
absorbed iron, but must have been excreted into the intestine.
Bidder and Schmidt* found 6 to 10 times more iron in the feces
than in the urine of fasting cats. The same result was obtained
in recent experiments on the metabolism of fasting men ; 7 to 8
mg. iron were found daily in the feces.^

As regards the path by which the iron reaches the intestine,
we can only say with certainty that it is not by way of the bile,
since the latter contains almost unweighable amounts of this
substance. It is therefore probable that the main bulk of the
iron is eliminated through the intestinal wall. The justice of
this assumption is most clearly shown by an experiment of
Fritz Voit.^ In the dog he isolated a length of small intestine

^ E. W. Hamburger, Zeitschr. f. physiol. Chem., vol. ii. p. 191 : 1878.

2 Pio Marfori, Arch. f. exper. Path. u. Pharm., vol. xxix. p. 212 : 1892.

^ In many of the most recent experiments on the administration of inorganic
forms of iron, this substance has been found in larger quantities in the intestinal
wall, in the liver, in the chyle, &c. But in all these cases the small animals were
given too large amounts of iron in proportion to their body-weight. Vide H. W.
F. C. Woltering, Zeitschr. f. physiol. Chem., vol. xxi. p. 186: 1895; J. Gaule,
Deutsch, med. Wochenschr., Nos. 19 and 24: 1896; W. S. Hall, Arch. f. Anat.
u. Physiol., p. 49: 1896; Hochhaus u. Quincke, Arch. f. exper. Path. u.
Pharm., vol. xxxvii. p. 159 : 1896.

* Bidder u. Schmidt, "Die Verdauungssäfte u. d. Stoffwechsel," Mitau u.
Leipzig, p. 411 : 1852.

* C. Lehmann, Fr. Mueller, J. Munk, H. Senator u. N. Zuntz, Virchow's
Arch., vol. cxxxi. Suppl., pp. 18 and &7 : 1893.

« Fritz Voit, Zeitschr. f. Biolog., vol. xxix, p. 325 : 1893.

lEON 373

with the same procedure as in Thiry's experiment (see p. 172),
the only difference being that after the isolated piece of intes-
tine had been cleansed, both ends were sewn up ; the piece of
intestine was then replaced, and the abdominal wound closed.
The animals were fed upon meat for three weeks, at the end of
which time they were killed, and the iron was estimated both
in the contents of the isolated length of intestine and in the
feces which had been formed in the remaining part of the intes-
tines during the period of the experiment. Per unit area of
mucous membrane, as much iron was found in the isolated coil
as in the feces obtained from the remaining intestine.

If reduced iron were added to the meat diet, the proportion
of iron in the contents of the isolated piece was not increased.
From these experiments Voit concludes that the iron contained
in normal diet is absorbed by the intestinal wall, and again
excreted through the intestinal wall ; and that, on the other
hand, the inorganic preparations of iron administered artificially
are not absorbed to any appreciable extent.

The objection to this last deduction is that the inorganic
iron when absorbed may be eliminated only in certain sections
of the intestinal tube, and that this particular isolated portion
did not have that power. This question may therefore be re-
garded as still undecided.

But if we accept the conclusion that the inorganic forms of
iron are not absorbed, it follows that our food must contain other
combinations of organic iron,^ which are assimilable and serve
as the precursors of hemoglobin. I have sought to discover the
nature of these compounds, using the yolk of egg as the basis
for my experiments.^ Yolk of egg does not contain any
hemoglobin ; but it must contain a precursor of this substance,
since hemoglobin is found in the egg during incubation without
the introduction of any material from without. I succeeded in
isolating this precursor in a quantity sufficient for an exact re-
search. If the yolk of hens' eggs be extracted with alcohol
and ether, no iron passes out with the extract, but remains in
the residue, which forms one-third of the dried substance of the
yolk and consists of proteids and nucleins. The large amount of
iron in this residue does not occur in the form of a salt, as may
be proved by the fact that it cannot be extracted with alcohol
containing hydrochloric acid ; whereas all salts of iron, whether
in combination with inorganic or organic acids — and amongst

* Kletzinsky, loc. cit., ascribes this theory in the first place to Hannon, whose
writings are not accessible to me. But the existence of organic compounds of iron
in our food has in nowise been proved by either of these authors.

2 G. Bunge, Zeitschr. f. physiol. Chem., vol. ix. p. 49 : 1884.

374 LECTURE XXV

these we must reckon proteids — at once yield their iron to the
acid alcohol. The remainder of the yolk of egg which is in-
soluble in ether, dissolves readily in very dilute (1 per M.)
hydrochloric acid. If to this solution tannic or salicylic acid
be added, a white precipitate is thrown down ; but if even the
slightest trace of ferric chlorid be shaken up with this solution,
and it be now treated with tannic or salicylic acid, it turns
either of a blue or red color respectively.

Iron occurs in yolk of egg as a nucleo-albumin. In artificial
gastric digestion of yolk of egg, the proteids are converted into
peptones, and the iron remains in the indigestible insoluble
residue, the nuclein.^ As in the case of the original compound,
the iron in this nuclein cannot be extracted by hydrochloric
acid alcohol. The iron is slowly split off by a watery solution
of hydrochloric acid, and more quickly according to the con-
centration of the acid.

The nuclein-iron compound is soluble in ammonia. If to the
ammoniacal solution some potassium ferrocyanid and excess
of hydrochloric acid be added, a precipitate is produced, which
is at first white, and gradually becomes blue, the change occur-
ring more rapidly as the concentration of the hydrochloric
acid is increased. If, instead of the ferrocyanid, potassium
ferricyanid and hydrochloric acid be added to the ammoniacal
solution, the precipitate remains white. The iron is therefore
split off from the organic compound as ferric, and not as
ferrous, oxid.

If to the ammoniacal solution of the iron-nuclein compound
a drop of ammonium sulphid be added, no change of color
is at first observed : after a little time, however, the solution
takes a slightly greenish tinge, which increases in intensity
until finally the next day it becomes black and opaque. The
change in color proceeds with greater rapidity according to
the amount of ammonium sulphid added. Ammoniacal solu-
tions of artificial albuminates of iron change color almost in-
stantaneously when treated with ammonium sulphid.

' A nuclein was first prepared by Miescher from the yolk of egg. His method
of preparation was however different from mine, and I imagine that the iron had
been mostly split off from the compound by the action of the hydrochloric acid
in the gastric juice. Otherwise the large amount of iron could not have escaped
Mieseher's notice. In my preparation the pepsin ferment acted only a very short
time on the solution of the nucleo-albuminates in very dilute hydrochloric acid. In
Mieseher's preparation the yolk of egg, after extraction with ether and alcohol,
was allowed to digest for 18 to 24 hours in gastric juice, containing 3 to 4 per mille
HCl (10 ccm. of fuming HCl to 1 liter of water), at a temperature of 40° C. In
my method of preparation the hydrochloric acid amounted only to a little over
1 per mille, and the solution was kept at body temperature only until the iron-
nuclein compound began to separate out of the solution as a cloudy precipitate.
( Vide Miescher, in Hoppe-Seyler's Med. chem. Unters., pp. 454 and 504: 1871.)

IRON

375

Iron therefore is more closely combined in the nuclein of
yolk of egg than in the iron albuminates, but far more loosely
than in hematin, in which it cannot be detected by means of
the ordinary reagents.

The elementary analysis of the iron-nuclein compound gave
the following composition :

C 42.11

H 6.08

N 14.73

S 0.55

P

Fe

O

5.19

0.29

31.05

This compound is undoubtedly the precursor of hemoglobin,
since there are no other iron compounds present in any quan-
tity in yolk of egg. I have therefore suggested that this
substance should be termed hematogen (blood-forming).* If
we imagine the phosphorus to have been split off from the
hematogen as phosphoric acid, we get a molecule containing
the same amount of iron as hemoglobin. The hemoglobin of
hen's blood possesses 0.34 per cent. Fe.^

Following the same method by which I prepared hemato-
gen from hens' eggs, an exactly similar compound was obtained
from carps' eggs in Kossel's^ laboratory. The elementary
analysis of this compound gave the following figures :

Preparation I.

Preparation II

c

48.0

47.8

H

7.2

7.2

N

14.7

12.7

S

0.30

—

P

Fe

2.4

2.9
0.25

That hematogen may be absorbed and assimilated is shown
by the experiments carried out by C. A. Socin * in my labora-
tory. Mice fed on an artificial diet, which contained no
compound of iron except hematogen, lived for a hundred days,
and gained in weight.

In our most important articles of vegetable diet the iron
is also united loosely with organic substances as in hematogen.

1 The name hemoglobinogen would be more suitable but too lengthy. The
name hematogen has been objected to on the score that it already occurs in
medical nomenclature as an adjective: "hematogenic icterus." But as recent
research has shown that there is no such thing as hematogenic icterus, we
shall soon be able to do without the term altogether.

2 A. Jaquet (Bunge's laboratory), Zeitschr. f.physiol. Chem., vol. xiv. p. 289 :
1889.

^ G. Walter, Zeitschr, f. physiol. Chem., vol. xv. p. 489 : 1891.
* C. A. Socin (Bunge's laboratory), ^eitecAr. /. physiol. Chem., vol. xv. p. 93 :
1891.

376

LECTURE XXV

But the attempt to isolate these compounds is attended with
much greater difficulty, since several different kinds are here
met with.

I found it particularly hard to prepare iron-compounds
from milk, because not only does the iron occur in union
with various substances, but it is also present in very small
quantities. A glance at the following table ^ will show that
there is less iron in milk than in almost any other article of
food :

OiJ^E Hundred Grms. Dried Substance Contain the Following
Amounts of Iron in Milligrammes.

Blood serum . . .
White of hen's egg

Eice

Pearl barley . . .
Wheat flour (sifted)
Cow's milk . . .

0

Trace

1.0-2.0

1.4-1.5

1.6

2.3

Human milk 2.3-3.1

Dog's milk 3.2

Figs 3.7

Raspberries 3.9

4.3
4.5
4.5
4.9
4.9
5.5
5.7
6.4
6.2-6.6

Hazel nuts (kernel only). .

Barley

Cabbage (inside yellow leaves)

Eye

Almonds (peeled) ....

Wheat

Bilberries

Potatoes

Cherries (black, without stones) 7.2

Beans (white) 8.3

Carrots 8.6

Wheat-bran 8.8

Strawberries 8.6-9.3

Linseed ........ 9.5

Almonds (brown skins) . . 9.5
Cherries (red, without stones) 10
Hazel nuts (brown skins) . 13
Apples ...... 13

Dandelion leaves . . 14

Cabbage (outer green leaves) 17

Beef 17

Asparagus 20

Yolk of egg 10-24

Spinach 33-39

Pig's blood 226

Hematogen ....... 290

Hemoglobin 340

This fact caused me surprise, as ä priori I had anticipated
the contrary, viz., that milk, being the exclusive food of the
growing organism which is always increasing its blood-supply,
would contain more iron than the food of full-grown animals
which merely have to maintain their previous store of iron.
The small amount of iron in the milk is the more remarkable
since all other inorganic food-stuifs are contained in milk in just
the proportion in which they are needed for the growth of the
sucking animal.

1 The original sources, from which all the analyses in this table are taken, are
given by G. Bunge, Zeitschr. f. physiol. Chem., vol. xvi. p. 174: 1891 ; and by
E. Häusermann (Bunge's laboratory), Zeitschr. f. physiol. Chem., vol.xxiii. p.
586: 1897.

IRON 377

On,e Hundred Parts by Weight of Ash Contain :

In New-born Puppy. Dog's Milk.

K2O 11.42 14.98

NajO 10.64 8.80

CaO 29.52 27.24

MgO 1.82 1.54

FeA 0.72 0.12

P2O5 39.42 34.22

CI 8.35 16.90

With the exception of the iron, the relative proportion of
the remaining constituents in the ash is almost identical. The
object of this uniformity is evidently to ensure the greatest
possible economy. The maternal organism gives nothing
which cannot be utilized by the oifspring. An • excess of any
constituent would be wasted. This marvellous adaptation of
means to an end appears however to be rendered futile by the
small amount of iron in the ash of milk : it is six times less
than that in the ash of the sucking animal. According to this,
the maternal organism would seem to part with six times too
much of the remaining constituents to its offspring. Appa-
rently only one-sixth can be employed to build up the organs,
and the remaining five-sixths are thrown away !

The explanation of this contradiction is that the young
animal contains at birth a large store of iron for the growth of
its tissues. In a series of estimations of iron in the total
organism of young dogs, cats, and rabbits, I have shown that
the amount of iron is the highest at birth, and that it gradually
diminishes afterwards.^ At least five times more iron is found
in the liver of new-born than in that of full-grown animals.
In the same way the other tissues must possess their store of
iron which can be drawn upon to meet the rapid development
of the blood.

The advantage of this arrangement seems to be as follows :
The assimilation of organic compounds of iron is obviously
attended with great difficulty, hence the maternal organism
uses up its acquired store with the greatest economy. The
amount which must be conveyed to the infant organism can
reach it in two ways : through the placenta and through the
mammary glands. The former way is preferred as the more
secure. If the main proportion of the organic compounds of
iron was conveyed by the mammary gland, it might become a
prey to bacteria in the alimentary canal and before absorption
had begun. But if it reaches the fetus through the placenta, its
safety is assured.

^ G. Bunge, Zeitschr. f. physiol. Chem., vol. xvi. p. 177 : 1891, and vol. xvii.
p. 63 : 1892.

378

LECTURE XXV

In the following table ^ I give the figures for the amount
of iron in young rabbits and guinea-pigs.

RABBITS.

(Age of the animals.)

Mg. Fe
to 100 grins,
body-weight.

Embryos arranged according J nV
to increasing body-weight. 1 o'a

1 hour after birth
1 day

4 days

5 "

6 "

7 "
11 "
13 "
17 "
22 "
24 "
27 "
41 "

45 "

46 "
74 "

18.2
13.9
9.9
7.8
8.5
6.0
4.3
4.5
4.3
4.3
3.2
3.4
4.5
4.2
4.1
4.6

GUINEA-PIGS.

(Age of the animals.)

Embryos ,

6 hours after birth

U days "

3 u a II

K li <( ((

9 " " "

15 " " "

22 " " "

25 " " "

53 " " "

Mg. Fe
to 100 grms.
body-weight.

r4.6

4.4
5.6
5.3
5.0
6.0
5.4
5.7
5.7
4.4
4.4
4.4
4.5
5.2

I have ascertained from repeated and continued investiga-
tion of the gastric contents that young rabbits are nourished
during the first fortnight exclusively on the mother's milk.
About the middle of the third week they begin to take vege-
table food as well as the milk, and in the fourth week the
stomach contains principally vegetable matter. As the above
figures show, the fourth week is the time when the store of
iron has become used up and the amount of iron in proportion
to the body-weight has reached its minimum. With the
commencement of a vegetable dietary rich in iron, the amount
of this substance in the body again begins to rise.

The case of guinea-pigs is very different. These animals
begin by eating vegetable food from the first day and select by
preference the leaves which are very rich in iron, and during
the subsequent days milk plays but a subordinate part com-
pared to this form of food. And correspondingly we find that
(as may be seen from the above figures) guinea-pigs have at
birth a very small store of iron in their organs. Thus in these
two nearly related animal species, Nature herself has made an
experimentum crucis, which confirms my conception concerning
the significance of the store of iron provided for new-born
animals.

Very little iron is assimilated from the milk during the

^ G. Bunge, idem.

IRON 379

suckling period. In the young rabbit the absolute amount of
iron remains nearly constant, whereas the body increases in
weight sixfold by the end of the fourth week. The relative
proportion of iron therefore falls to one-sixth, as reference to
the above table will show. The animals at this time appear
to be already anemic. But they now begin to take food con-
taining abundance of iron, when the amount of this substance
at first rises. Subsequently the absolute quantity of assimilated
iron grows in proportion to the body-weight, and the relative
amount remains nearly constant. If the attempt were made
to feed the young animals exclusively with milk after the
period of suckling had elapsed, they would certainly become
anemic.

This condition of anemia has been utilized by me to decide
the question as to the assimilability of inorganic iron. At the
end of lactation, the young animals were fed entirely on milk,
or on milk and rice. Rice, as we may seß from the table, is
even poorer in iron than milk. One half of the animals em-
ployed in this experiment received in addition to this food, a
small quantity of ferric chlorid daily. After this diet had
been given from one to three months, and the animals had
doubled their weight, they were killed and the amount of
hemoglobin in the total body was estimated, as well as, in the
case of small animals, the amount of iron.

In this manner E. Häusermann carried out experiments in
my laboratory on 24 rats, 17 rabbits, 14 dogs, and 3 cats. The
rats all became highly anemic ; for at the end of the experi-
ment the percentage of hemoglobin was diminished to about
half that of animals from the same litter which had received
their normal food — meat, flies, yolk of egg, fruit, vegetables.
The rats, which had taken ferric chlorid in addition to the milk
and rice, contained no more hemoglobin than those which had
received milk and rice only. Moreover the amount of iron
was in each case the same. In one experiment alone, in which
the addition of ferric chlorid was continued for three months,
was the iron found to be double as much in the animals which
received it as in those which had only milk and rice. But here
again the proportion of hemoglobin remained the same in both
instances. We thus see that some iron is absorbed if small
doses of iron are persisted in for a long time, as well as if
large amounts be suddenly administered. But this inorganic
iron, when absorbed, is not utilized in the formation of hemo-
globin to any appreciable extent, but remains unused in the
tissues. Whether inorganic iron was absorbed in the ex-
periments, which lasted only from one to two months, cannot

380 LECTURE XXV

be decided : it is possible that same of it was absorbed and was
again eliminated in the same degree. Certainly no storing up
nor increase of iron could be detected in the whole organism.

The experiments on rabbits gave less decisive results : the
average proportion of hemoglobin in the animals that received
iron was somewhat higher than that in the animals which were
fed on milk and rice only. But if the great individual differ-
ences between various animals be taken into consideration, I
do not think we must ascribe too much importance to this
slight divergence. At any rate the amount of hemoglobin in
the control animal, which received its normal diet — fresh green
cabbage, bran, etc. — was nearly twice as high as in the animal
which received the iron.

The experiments on dogs were not attended with decisive
results. Dogs are not suitable animals for these experiments
owing to their individual differences. Moreover the growth of
these animals after the period of lactation is at a much slower
rate, and their appetite so enormous that they might be readily
able to assimilate sufficient hemoglobin even from a material so
poor in iron as milk, while their appetite remained normal.
Häusermann found the largest proportion of hemoglobin in a
dog which had been fed exclusively with milk. The animals
which received ferric chlorid in addition to a milk diet certainly
contained no more hemoglobin than animals from the same
litter which were fed on meat and bones. Cloetta^ carried out
some experiments on the same principle as ours, and came to the
conclusion that iron was assimilated in its inorganic form. We
are not at present in a position to corroborate this statement.

Häusermann further conducted a research on the question
as to whether the hemoglobin of the food was assimilable. It
appeared that young rats, which were given dried, powdered
hemoglobin in addition to milk and rice, formed twice as much
hemglobin as the animals from the same litter, which received
milk and rice alone. The hemoglobin of the food therefore
appears to be absorbed and assimilated. This experiment with
hemoglobin was however performed on only two animals, and I
intend therefore to repeat it.

In order to obviate misapprehension,^ I may be allowed

^ M. Cloetta, Arch. f. exper. Path. it. Pharm., vol. xxviii. p. 161 : 1897.

' My previous publications on the iron question have been continually mis-
represented by the medical press. In particular the statements which were
made by me at the Clinical Congress at Munich in the spring of 1895 have been
reported in quite a contrary sense. At the Congress I gave an account of the
present state of the question from an objective standpoint, reserving my
judgment, speaking sceptically and affirming nothing. Comp. Verhandl. des
Congresses f. inn,. Med., Cong, xiii., Wiesbaden, Bergmann, pp. 133 and 191 :

IRON 381

to shortly recapitulate the results of the investigations on the
absorption and assimilation of inorganic iron :

1. So far it has not been proven that any part of the
inorganic preparations of iron given in the small quantity
(0.1—0.2 grm. Fe per diem) Avhich is necessary in order to
avoid digestive disturbances, is absorbed either in man or in
the smaller animals, to which correspondingly less iron can be
administered. We must however concede the possibility that
small amounts may be absorbed.

2. If large quantities of iron be given, or if the administra-
tion of small doses be continued over a long period, part of the
iron passes the intestinal wall. But it cannot be ascertained
whether this iron is assimilated, although such a possibility
cannot be denied.

3. Even if the assimilation of inorganic preparations of
iron be granted, it is indisputable that the iron which exists in
normal food in the form of organic compounds is far more
readily and more completely absorbed.

Should further research show that inorganic iron is utilized
in the production of hemoglobin, the fact would be of the
greatest theoretical interest. It would furnish fresh proof that
syntheses occur as complex in the animal as in the vegetable
cell. Hitherto scientific men, steeped in Liebig's doctrine, have
ascribed too little power to the animal cell. But even if the
assimilation of inorganic iron was a proved fact, it would have
no importance in medical practice since, as our experiments show,
the iron required for the formation of hemoglobin is much
more readily and plentifully assimilated from the organic iron-
compounds of our normal dietary. Hence there is in no case
any reason to prescribe preparations of iron for the production
of hemoglobin in people who can take their natural food with
a good appetite.

It is quite another question as to whether anemic patients
should be given preparations of iron, not indeed as material for
conversion into hemoglobin, but in order to influence the
formation of blood in some indirect way. That these prepara-
tions may have such an effect cannot be denied, although there
is so far no adequate proof on the matter. It is not sufficient
evidence to say that the experience has been made ; we must
know how it has been done. Where are the statistics ? Where
are the control experiments ? ^

1895. I request that for the future I may be attacked only for what I have said,
and not for what I have never said.

^ Compare my critique of the therapeutics of iron in the Verhandl. des Con-
gresses f. inn. Med., Congr. xiii., Wiesbaden, Bergmann, pp. 143-147 and 191 :
1895.

382 LECTURE XXV

If thus all previous experimentation teaches us decisively
that iron is most surely and abundantly assimilated from our
natural food, it follows that it is highly desirable for us to
know the proportion of iron contained in the various articles of
our diet. This knowledge will be of the greatest value both as
a weapon and as a prophylactic against poorness of blood. Let
us therefore again glance at the table on p. 376. It is a very
surprising fact that, next to milk, the cereals, which are the
most important articles of vegetable food, contain the least
iron, that is to say, in the form in which they are generally
consumed, when deprived of their husks, the so-called bran.
Rice, as it comes into the market, is already deprived of its
husk ; it does not correspond to barley or wheat corn but to
pearl barley or wheat flour. In sifting the flour, the husks,
the so-called bran, are separated from the flour. From the
table we see that the cereals, when freed from their husks,
contain only half as much iron as milk. The iron of the cereals
exists in the husks. Whole wheat-meal therefore contains five
times as much iron as the ordinary wheat-flour.

This shows how irrationally anemic people are fed. We
may take as an instance the poor bloodless seamstresses, who
eat white bread and drink tea ! With the aid of all our
chemical knowledge we could not give to animals which we
wished to make anemic any food with less iron it !

It would be very interesting to ascertain experimentally
whether the iron compounds in the bran are assimilable. If
this were so, whole meal bread would be preferable to white
bread. I am now engaged on experiments with the object of
deciding this question.

At the Munich Medical Congress Professor Heubner ^
stated that " 15 kilograms of meat,^ so far as I am aware, cost
about thirty shillings, and that 300 Blaud's pills cost three
shillings. I fear that a large number of people will continue
to take the pills." I would, however, point out that there are
many cheap articles of food which contain sufficient iron, such
as potatoes, carrots, cabbage. But it is still an open question
whether in the equally cheap leguminosse, as in the cereals, the
iron is not principally confined to the husks, and whether the
iron in the husks is assimilable.

The danger of taking food which is too poor in iron is also
present in children, who are nourished principally with milk
for a long time after lactation has ceased. The normal duration

^Heubner, loc. crt., p. 174.

2 1 had estimated {loc. cit., p. 144) that 15 kilos, meat contained 0.6 grm.
Fe, or sufficient to produce one-third of the total hemoglobin in a man.

IRON 383

of suckling in human beings is unknown to us. The instincts
of neither mother nor child give us any clue. Even the habits
of aboriginal races furnish us with no data. Instinct is dying
out, never to return ; but it is the noble duty of science to
replace unerrmg instinct by conscious knowledge. If we could
determine the time at which the store of iron possessed by the
infant at birth becomes used up in the organs, the problem
would be solved. This solution would be practicable if estima-
tions were made on the bodies of healthy children which had
suddenly met with an accidental death. In the light of our
present knowledge however, it seems probable that children
are often rendered anemic by the milk diet being too prolonged
or too exclusively employed ; and I am pleased to hear that this
observation of mine is confirmed by children's physicians of
experience. For instance, Professor Heubner stated at the
Munich Congress : ^ " For many years a number of children's
physicians have recommended that a purely milk diet should
not be continued too long towards the end of the suckling
period. For about ten years I have myself adopted and have
also taught the principle of giving other food as a supplement
to milk after the infant has reached the age of 9 or 10 months,
and this not only in cases of anemia, but also in other cachectic
conditions of rickety children, although I am not able to adduce
any reason for this treatment. I may add that I was very
pleased to read the first work published by Professor Bunge on
this subject, and have followed his experiments with the greatest
interest. Since then I have found it highly beneficial to give
even vegetables to young children. In my practice I have
met with the greatest astonishment on the part of parents who
consulted me, when I told them to give the child (which
perhaps had eight teeth) a small spoonful of spinach or
cabbage or something of the kind every day. This advice was
however the result of a long and favorable experience.
The advantage of this treatment must have recently become
known in Berlin. A short time ago I was somewhat reproach-
fully asked by the father of an infant eight months old, which
had not cut any teeth, why I did not order the child spinach
and apple sauce. I am quite sure that this gentleman had no
idea of Professor Bunge's investigations."

Dr. Freund wrote to me on April 19, directly after my com-
munication at the Munich Congress : " I have long since
observed and frequently state that an exclusive or even pre-
ponderating milk diet for children when they are weaned is not
only insufficient, but also harmful, in that the children become
^ Heubner, loc. cit., p. 174.

384 LECTURE XXV

pale and weak, and suffer from poorness of blood. The
children of the lower classes, especially in the country, with
their rosy cheeks, might well be objects of envy to many
mothers among the upper ten thousand, and I would point out
that these children partake of the same food as their parents
towards the end of their first year of life."

Professor Monti ^ of Vienna says in the article he has just
published on weaning and nutrition : "If children be nursed up
to the twelfth and fifteenth month, they do not grow as they
should, even when the milk is sufficient in quantity. They be-
come anemic, their muscles become flabby, and their develop-
ment is delayed, so that, instead of attempting to walk at the
end of the first year, they do not begin to do so until they are
about eighteen or nineteen months old." "There are certainly
a few races where it is customary to feed children at the breast
after they have attained their first year. We have compara-
tively often had the opportunity of seeing some of these chil-
dren, which are usually of Slavonic parentage, and in all cases
the state of nutrition was a bad one. Other food than the
mother's milk is imperatively indicated." "The custom of
over-prolonged nursing exists in France, in a few parts of
Italy, and, according to hearsay, in Japan. All authorities are
agreed however that the continuation of the suckling beyond
the proper time always induces disturbances in the child's nu-
trition, and that many cases of rickets must be ascribed to this
practice."

The other day I came across a very interesting and doubt-
less unusual case, where an exclusive milk diet had been con-
tinued into adult life. A youth of eighteen, from the technical
schools at Aarau, has lived on nothing but milk from the time
of his birth. He states that he has occasionally tried a piece of
bread or a pear, but that it had not agreed with him. He has
an invincible dislike to all animal and vegetable food. His face
is pale, as well as the mucous membrane of the tongue and of
the conjunctivae. He suffers from cold feet and hands, is easily
tired in walking, and has palpitation of the heart when he goes
upstairs. E. Häusermann found that, although his blood con-
tained five million blood-corpuscles in the cmm., it had only 8.6
per cent, hemoglobin, whereas a normal person has 12—16 per
cent. These are therefore conditions similar to those occurring
in cases of chlorosis, viz., about the usual number of blood-cor-
puscles, with a diminished amount of hemoglobin.^

1 Alois Monti, " Ueb. d. Entwöhnung, Ernährung," &c., Wien. u. Leipzig,
Urban u. Schwarzenberg, p. 104 : 1897.

2 Häusermann gives a detailed description of this case, loc. cit., p. 585.

IRON 385

In order to obviate misimderstaüding, I would, in conclu-
sion, lay stress upon the fact that I do not maintain that all
forms of anemia, and especially chlorosis, may be cured by a
diet rich in iron. The etiology and the nature of chlorosis are
entirely obscure, and any treatment with iron, even if it be only
the iron in the food, is at the best but dealing with the symp-
toms. But in anemia, the first thing to do is to cease taking
food which would make even a healthy person bloodless, and
afterwards to think of medicines.

As regards treatment with drugs, I do not deny the use of
medical experience on the old system. Any unprejudiced per-
son of good memory may store up abundant statistical material,
together with the needful control experiments, without writing
down his observations and communicating them to his colleagues.
As a matter of fact many thousands of experiences in other
practical departments, which are likewise concerned with com-
plex manifestations of life, such as farming, horticulture, cattle-
breeding, hunting, fishing, are collected in this manner, and
subsequently confirmed by science. But both in science and
in practice it is good to demand strict proofs, proofs which may
not only convince individuals, but may be binding on all ex-
perts as well as on future generations.

I therefore venture to make the following proposition with
regard to the investigation into the action of iron. In the first
place, cases of anemia as like each other as possible should be
sought out. Half of these should be selected by lot and be
treated with some definite preparation of iron, while the other
half should receive no iron, but in its stead some indifferent
medicine, with the assurance that this latter was an unfailing
remedy. The time should then be determined at which the
amount of hemoglobin and the number of blood-corpuscles had
risen by a certain percentage. Disturbing factors, such as the
varying idiosyncrasies of the different cases, can only be eliminated
by taking a sufficiently large number of cases for the experiment.
In private practice we shall always have to deal with the diffi-
culty of being able to ensure that the medicine prescribed is
really taken. I myself have known of many cases where the
doctor triumphantly ascribed the credit of the chlorotic patient's
red cheeks to the influence of the Blaud pills, whereas, as a,
matter of fact, not a single pill had been taken.

25

LECTURE XXVI

DIABETES MELLITUS

In our remarks on metabolism in the liver, and on the
source of muscular energy, we became acquainted with the des-
tiny of carbohydrates in the body, and with the way in which
they are utilized under normal conditions. We are now there-
fore in a position to consider the ijitricate investigations con-
cerning the destiny of carbohydrates under pathological condi-
tions, and especially the researches into the causes and nature of
diabetes mellitus. This is a subject with touches on all branches
of physiological chemistry, and about which a complete library
of books ^ has been written, the references to which would alone
form a good-sized volume.

These remarks will be confined to the chronic form of
diabetes. Transient glycosuria^ occurs as a consequence, and
sometimes as an unimportant symptom in a great variety of
maladies, such as zymotic diseases, digestive disturbances,
neuralgia, cerebral concussion and hemorrhage, cerebro-spinal
meningitis, epilepsy, psychical excitement, poisoning by various
substances,^ &c. No satisfactory explanation to account for the
appearance of glycosuria in all these cases has yet been given,
and it would lead us too far to discuss all the maladies of which
glycosuria forms a symptom.

But even if we confined ourselves to that chronic disorder
which is strictly termed diabetes, a complete account of the
disease and its numerous and varying symptoms would be

1 An account of the most important works on diabetes mellitus is given by
CI. Bernard, " Le5ons sur le diabete": Paris, 1877; Ed. Kiilz, "Beiträge zur
Pathologie und Therapie des Diabetes mellitus " : Marburg, 1874 and 1875 ;
Frerichs, " Ueber d. Diabetes " : Berlin, 1884. Frerichs has watched no less than
four hundred cases of diabetes, and has recorded the results of his wide experi-
ence in a clear, comprehensive, and critical work, especially remarkable for its
objectivity. We strongly recommend this book to the student. Compare also
F. W. Pavy, " On the Nature and Treatment of Diabetes," 2d edit., London ;
and J. Seegen, " Der Diabetes mellitus," Aufl. ii. : Berlin, 1875 ; and Arnoldo
Cantani, " Der Diabetes mellitus." Deutsch von S. Hahn : Berlin, 1880.

^ Frerichs {loc. cit,, pp. 25-61) gives a comprehensive account of all forms of
transient glycosuria.

^ Of these substances, phloridzin must be particularly mentioned ; its
glycosuric action on animals containing no glycogen has been already noticed
(p. 346).

386

DIABETES MELLITUS 387

oeyond the scope of the present lecture. It is merely our
intention to collect the chief results of the experimental investi-
gations carried out for the purpose of determining the causes
and nature of this disease.

Up to the present, pathological anatomy has led to no con-
clusion. Post-mortem examination of the bodies of diabetics
proves that there is not a single organ which does not occasion-
ally show anatomical changes ; on the other hand, there is not
a single organ that does not frequently appear normal. It is
likewise impossible, in all cases, to decide whether these anato-
mical changes are the cause or the consequence of the chemical
changes,^

We will therefore restrict ourselves to the consideration
of those data which bear upon physiological chemistry. The
most obvious symptom, the occurrence of sugar in the urine,
has always formed the basis of these observations.

As already stated, normal urine contains no sugar, or at
most a trace. In diabetes, often a very considerable amount
is found, varying from a few grammes to one kilogramme
in twenty-four hours' urine. This sugar is invariably dextro-
rotatory grape-sugar.^ With many patients who have the
disease in a mild form, the sugar disappears from the urine
if carbohydrates are excluded from the diet ; with others who
are more seriously affected, the excretion of sugar continues,
even though an exclusive meat diet be adopted. In what way
can we account for the appearance of this large amount of
sugar in the urine ?

Only two suppositions are open to us. Either the kidneys
have lost their power of preventing the sugar, normally present
in the blood, from passing into the urine ; or else the kidneys
have retained their usual function, but the amount of sugar in
the blood has abnormally increased.

The latter supposition must- be regarded as the correct
one ; for the former would imply that there is less than the
normal amount of sugar in the blood of diabetic patients,
whereas the quantity found is, as a matter of fact, always
above the normal.^ The blood of man and of the dog normally

^Frerichs (loc. cit., pp. 144-183) gives a comprehensive and instructive
tabulated account of the results of fifty-five autopsies.

2 J. Seegen states that he has found levorotatory sugar in the urine of a
person suffering from 'diabetes intermittens' {Centralbl. f. d.med. Wissensch.),
No. 43 : 1884. Compare E. Kiilz, Zeitschr. f. Biolog., vol. xxvii, p. 228: 1890,
where a critical summary will be found of all the statements relating to the
occurrence of levorotatory sugar in urine.

^ A diminution of the sugar in the blood is found in phloridzin diabetes. This
is therefore a different condition to the ' natural ' diabetes, and cannot be directly
applied to the explanation of the latter condition. In phloridzin diabetes it is

388 LECTURE XXVI

contains from 0.05 to 0.15 per cent, of sugar; the blood of
diabetic patients from 0.22 to 0.44 per cent.^ If the propor-
tion of sugar in a dog's blood be artificially increased to more
than 0.3 per cent, by the injection of a solution of this sub-
stance, sugar passes through the normal kidneys into the urine.
No afPection of the kidneys has ever been discovered in the first
stages of diabetes.

It is therefore certain that an abnormal increase of sugar
in the blood is the cause of the appearance of sugar in the
urine.

We now come to the question as to the cause of the
increase of sugar in the blood, and again we have to choose
between two explanations. There must be either a larger
quantity of sugar formed, or a smaller amount of sugar de-
composed.

The first explanation cannot be accepted, for from what
could the large proportion of sugar be formed? Not from
the other carbohydrates, as this would be a normal process ;
not from the fats, as diabetic patients can digest and assimi-
late them in large quantities.^ As to the proteids, assuming
that a diabetic patient consumed 300 grms.^ in a day (which
it would be difficult to do), even this amount of proteid would
not form more than about 200 grms. of sugar ; for a large
proportion of the carbon must be given off with the nitrogen.
But even if 200 grms. of sugar reached the blood in the course
of each day, it would not cause diabetes, so long as the de-
composition of sugar remained normal. A. man, on a diet of
potatoes, will form from 600 to 1000 grms. of sugar per diem
from the starch in his food, without any sugar passing into the
urine.

We must therefore accept the other explanation, that the
increase of sugar in the blood of diabetic patients is due to a
diminished sugar destruction.

The power of decomposing sugar is never entirely arrested ;

probably the kidneys which are primarily at fault. Compare Minkowski, Berlin,
klin. Wochenschr., No. 5:1892; and "Untersuch, üb. d. Diabetes mellitus,"
p. 64 : Leipzig, 1893.

' Carl Bock und Frdr. Albin Hofmann, " Experimentelle Studien über
Diabetes," p. 61 : Berlin, 1874 ; Frerichs, loc. cit., p. 269.

2 Pettenkofer and Voit, Zeitschr. f. Biolog., vol. iii. pp. 406, 408, 416, 428,
436 : 1876. L. Block {Deutsch. Arch. f. klin. Med., vol. xxv. p. 470 : 1880) found
that only 9 grms. out of from 120 to 150 grms. of fat reappeared in the feces of
diabetic patients.

' With a diabetic patient, the urea excreted in twenty-four hours seldom
amounts to more than 100 grms., which corresponds to 300 grms. of proteid.
Pettenkofer and Voit {loc. cit., p. 424) found from 46 to 86 grms. of urea in a
severe case of diabetes, the patient being allowed to eat whatever he liked.

DIABETES MELLITUS 389

it is only more or less impaired. Külz ^ has shown that, even
in severe cases of diabetes, there is a smaller amount of sugar
in the urine than would correspond to the carbohydrates of the
food.

We will now proceed to inquire how the power of splitting
up sugar is impaired — a question which again appears to be
capable of but two answers. We are only acquainted with two
processes by which the food-stuffs are destroyed in our tissues :
decomposition and oxidation. One of these two processes must
be diminished.

No decline in the process of oxidation in diabetes has so far
been proved from observations and experiments. The ultimate
products of proteid combustion are normal, and the fat appears
to be completely oxidized to carbonic acid and water. Salts of
vegetable acids and lactates reappear in the urine as carbonates.^
Benzol is oxidized to phenol.^ Certain carbohydrates even (such
as levulose, inulin and inosit), and mannite, which is so closely
related to the carbohydrates, are decomposed.* How is it that
grape-sugar alone remains unoxidized ?

That oxidation is not impeded is further proved by the cir-
cumstance that no increase of sugar in the blood, or passage of
sugar into the urine,^ has ever been observed either in diseases
connected with disturbances of external and internal respira-
tion, or in artificial respiratory disturbances.®

We must therefore conclude that the grape-sugar cannot be
oxidized because its decomposition is impeded ; decomposition
must precede oxidation ; if the former be impaired, the latter
cannot take place, although neither external nor internal res-
piration is disturbed.

O. Schnitzen^ endeavored to support this view by com-

' Kiilz, " Beitr. z. Path. u. Therap. d. Diabetes mellitus," pp. 110-119 : Mar-
burg, 1874.

^ O. Schultzen, Berliner klin. Wochenschr., No. 35 : 1872 ; Nencki and Sieber,
Zeitschr. f. prakt. Chem., vol. xxvi. p. 34: 1882.

'" Nencki and Sieber, loc. cit., p. 36.

*E. Kiilz, "Beitr. z. Path. u. Therap. d. Diabetes mellitus," pp. 127-175:
Marburg, 1874. The experiment with mannite does not seem to be convincing,
because borborygmi, flatulence, and diarrhea occurred after taking it. It is pos-
sible that the mannite introduced was mostly decomposed by fermentative organ-
isms in the alimentary canal. A small amount was found unaltered in the urine.
With respect to inosit, vide also E. Kiilz, Sitzungsber. d. Ges. z. Beförderung d.
ges. Naturw. zu Marburg, No. 4: 1876.

5 Von Mering, Arch. f. Physiol., p. 381 : 1877.

^ Senator, Virchow's Arch., vol. xlii. p. 1 : 1868.

■^ O. Schultzen, loc. cit. The view that sugar could only be oxidized sub-
sequently to decomposition was first suggested by Scheremetjewski in a research
published from C. Ludwig's laboratory {Arb. au-s d.physiol. Anstalt zu Leipzig,
p. 145: Jahrg. 1868; Leipzig, 1869). Compare also Nencki and Sieber, loc. cit.,
p. 39.

390 LECTUEE XXVI

paring observations on diabetics with those on persons suffering
from phosphorus-poisoning. As we have already seen (p. 363),
oxidation is diminished in cases of phosphorus-poisoning.
Instead of sugar, lactic acid occurs in the urine ; and this
Schnitzen regarded as a normal product of the decomposition
of grape-sugar. He therefore said that, after phosphorus-
poisoning, the power of oxidation was lost, but not that of
decomposition, while the reverse was the case in diabetes.
Hence, after phosphorus-poisoning, the normal product of de-
composition appears in the urine, while in diabetics, in spite of
undisturbed oxidation, the unaltered grape-sugar appears in the
urine.

The following experiment of Pettenkofer and Voit^ may
be interpreted in the same way. By means of their respiratory
apparatus, they showed that a diabetic took in less oxygen and
excreted less carbonic acid than a healthy person.

It was not that less sugar was broken up because the in-
come of oxygen was reduced, but that less oxygen was used up
because the formation of oxidizable products of decomposition
was diminished.

This theory is very inviting, but objections may be raised
to it. The fact, already mentioned in our remarks concern-
ing internal respiration (p. 259), that certain substances,
after introduction into the body, appear in the urine con-
jugated with glycuronic acid, is opposed to the view that
decomposition must precede oxidation. Glycuronic acid is
undoubtedly a product of oxidation, but not of decomposition ;
all six atoms of carbon are still united, and yet oxidation has
begun. Conjugation alone prevents its completion ; and as
soon as the compound is split up, nothing can stop its further
progress.

Nencki and Sieber say, " We do not doubt that, if the
diabetic could break up sugar to form lactic acid, he would
afterwards be able completely to oxidize the sugar." ^ But
lactic acid is evidently not the normal product of decompo-
sition of sugar in the body. The sarcolactic acid, which is
invariably present in the organs, probably arises from proteid
(p. 312). As nothing is yet known concerning the course
and sequence of the decomposition and oxidation of sugar in
the organism under normal conditions, we are scarcely in a
position to inquire into the abnormal chemical processes occur-
ring in diabetes.

' Pettenkofer and Voit, Zeitschr. f. Biolog., vol. iii. pp. 428, 429, 431, and
432 : 1867.

^ Nencki and Sieber, Journ. f. prakt. Chem., vol. xxvi. p. 37 : 1882.

DIABETES MELLITUS 391

Attention must be particularly called to the occurrence in
the diabetic urine of substances which are evidently products of
incomplete oxidation : oxybutyric acid, aceto-acetic acid, and
aceton. ^ They probably arise from the proteids, for their
amount is independent of any addition of carbohydrates to the
diet, but increases with increased proteid metabolism.^ They
do not occur in all cases of diabetes, but generally in the more
severe forms of the disease, in which the destructive metabolism
of proteid is augmented.

The oxybutyric acid in diabetic urine is the levorotatory
/3-oxybutyric acid (CH3-CH(OH)-CH2-COOH). TheacetJ-
acetic acid (CH3— CO— CH2— COOH), which can be artificially
produced by oxidation from /?-oxybutyric acid, breaks up readily
into aceton and carbonic acid : CH3 — CO — CHg — COOH =
CH, — CO — CH3 + COg. The aceto-acetic acid and the aceton
in diabetic urine have probably originated in the same way in
the organism.

In the last stage of diabetes, when coma sets in, the amount
of oxybutyric acid increases, while that of aceton diminishes. ^
This fact also appears to argue in favor of an increasing decline
in the power of oxidation.

It must however be noted that the occurrence of oxybutyric
acid, aceto-acetic acid, and aceton is not confined to diabetes,
but has been observed in many other maladies.^ These anom-
alous products of metabolism may possibly be a direct conse-
quence, not of diabetes itself, but of certain complications which
frequently accompany the disease.

On the other hand, it must be remembered that wasting of
the tissues and general cachexia, in short, increased destruction
of the nitrogenous constituents of the body, invariably take
place in all the diseases in which acetonuria has been observed,
such as febrile infectious diseases, carcinoma, mental affections

^ Stadelmann, Arch. /. exper. Path. u. Pharm., toI. xvii. p. 419: 1883 ; and
Zeitschr. f. Biolog., vol. xxi. p. 140: 1885; Minkowski, Arch. f. exper. Path. u.
Pharm., vol. xviii. pp. 35, 147: 1884; E. Kiilz, Zeitschr. f. Biolog., vol. xx. p.
165 : 1884 ; and vol. xxiii. p. 329 : 1886 ; and Arch. f. exper. Path. ii. Pharm., vol.
xviii. p. 291 : 1884 ; End. von Jaksch, " Ueber Acetonurie u. Diaceturie " : Berlin,
1885 ; H. Wolpe, Arch. f. exper. Path. u. Pharm. ,yoI. xxi. p. 138 : 1886 ; Frerichs,
loc. cit., pp. 114-118.

^G. Rosenfeld, Deutsch, med. Wochenschr., No. 40: 1855; Wolpe, loc. cit.,
pp. 150-155. The older literature is here quoted. Also M. J. Rossbaeh, Corre-
spondensblatt des allgem. ärztlichen Vereins für Thüringen, No. 3 : 1887 ; Chem.
Centralbl. p. 1437 : 1887.

^ Wolpe, " Unters, ü. d. Oxybuttersäure des diabetischen Harnes," Dissert.:
Königsberg, 1886 ; Arch. f. exper. Path. u. Pharm., vol. xxi. p. 157 : 1886.

^R. von Jaksch, "Ueber Acetonurie u. .Diaceturie," pp. 54-91: Berlin,
1885 ; Külz, Zeitschr. f. Biolog., vol. xxiii. p. 329 : 1886; A. Baginsky, Du Bois'
Arch., p. 349 : 1887.

392 LECTURE XXVI

accompanied by inanition, &c. The occurrence of aceto-acetic
acid has likewise been noticed in the urine of healthy persons
after prolonged fasting.^ Increased decomposition of proteid
now appears to be an accompaniment of diabetes also : at least,
it was proved, by careful experiment in three severe cases, that
the patient excreted more nitrogen than a healthy person on
exactly the same diet. The first investigation of the kind was
carried out by Gaehtgens ^ in his clinique at Dorpat, the second
by Pettenkofer and Voit, ^ and the third by Frerichs.*

These experiments might be taken to mean that the increased
decomposition of proteids in diabetes was a consequence of the
inadequate breaking up of the sugar ; that, because the chemical
potential energy of the sugar was not completely utilized, the
proteid must assist in furnishing the kinetic energy necessary
for the performance of the functions of the body. This would
be analogous to the behavior of normal muscle, which, as we
have seen, has recourse to its store of proteid as soon as the
supply of non-nitrogenous food runs short. But this is only a
teleological, not a physico-chemical explanation, and gives no
account of the causal connection. We must concede the pos-
sibility that the increased decomposition of proteid may be the
first sign of disturbance in the metabolism of the organs, and
may usher in the wasting of the tissues and all the other
troubles. It may be also that the occurrence of oxybutyric
acid, aceto-acetic acid, and aceton in diabetes is not due to the
reduced supply of oxygen, any more than it is in the case
of the other diseases mentioned. The tissues may receive their
normal supply of oxygen, but the products of decomposition
may have risen above the normal amount ; and that part of
them which reaches the blood in a state of incomplete oxi-
dation, cannot be further oxidized there because, as we have
already seen (p. 247), no processes of oxidation take place in
the blood.

The power possessed by a diabetic of utilizing levorotatory
sugar is a remarkable fact, which was observed by Kiilz.^

^ See the interesting notice in the report of the investigations carried out on
the 'professional faster,' Cetti, in Berlin {Berliner Wochenschrift, vol. xxiv. p.
434:1887).

^Carl Gaehtgens, " Ueber den Stoffwechsel eines Diabetikers, verglichen
mit dem eines Gesunden," Dissert.: Dorpat, 1886.

3 Pettenkofer and Voit, Zeitschr. f. Biolog., vol. iii. pp. 400, 408, 412-414,
425. An account of the older literature will be found here, pp. 425-426.

* Frerichs, loc. cit., p. 276, et seq.

5 Külz, loc. cit., pp. 130-167. Also Worm-Müller, Pfliiger's Arch., vol.
xxxiv. p. 576: 1884; S. de Jong, " Overomzetting van milksuiker by diabetes
mellitus," Dissert.: Amsterdam, 1886 ; and Franz Hofmeister, Arch. f. exper. Path,
u. Pharm., vol. xxv. p. 240: 1889.

DIABETES MELLITUS 393

He showed that after eating 100 grms. of levorotatoiy fruit-
sugar, no sugar appeared in the urine of a patient who was
but slightly affected with the disease, and that the amount
of sugar, which consisted only of dextrorotatory grape-sugar,
was not increased in the urine of a patient who had a severe
form of diabetes.

Inulin behaves in the same manner as levulose. It is
found in the roots of elecampane, chicory, and dandelion, and
in the tubers of dahlias, where it plays the same part as the
starch in the potato tubers. Inulin stands in the same rela-
tion to levulose as starch does to dextrose : on boiling with
dilute acid, it is split up with hydration to form levulose, just
as starch is changed into dextrose. Inulin evidently under-
goes this decomposition in the organism as well ; like levulose,
it is consumed in the body of a diabetic.

It is M'ell known that, on boiling with acids as well as
by the action of ferments, cane-sugar is split up into equal
quantities of levulose and dextrose. In conformity with this,
Kiilz observed that, after the administration of cane-sugar in
the aggravated form of diabetes, the increase in the excretion
of dextrose was equal to half the amount of the cane-sugar
eaten. These experiments of Kiilz on the fate of levorotatory
sugar in diabetics have since been repeated many times.^
The results are however contradictory, and it appears that
different patients vary in their power of utilizing this sugar.
In general, the statement that levorotatory sugar is entirely
or in greater part assimilated has been confirmed. In many
cases, however, a small quantity of dextrorotatory sugar
appeared in the urine as a result of the ingestion of levo-
rotatory ; and the question has still to be decided whether in
such cases the levorotatory sugar has been directly converted
into dextrorotatory, or whether it has merely exercised in
the body a sparing influence on the latter.

This limitation of the power in diabetics to utilize levo-
rotatory sugar only is no isolated phenomenon in animate
nature. Certain fungi and bacteria act in the same way as the
cells.^ Of the optically inactive lactic acid, which contains equal

^ J.B.B.&Tcr&tt, Zeitschr. f. physiol. Chem., vol. xix. p. 137: 1884; P.
Palma, Zeitschr. /. Heilk., vol. xv.: 1894; W. Hale White, Zeitschr. f. Hin.
3fed., vol. xxvi. p. 332: 1894; Karl Grube, ibid., vol. xxvi. p. 340: 1894;
C. A. Socin, " Wie verhalten sich Diabetiker Lävulose-Milchzuckerzufuhr
gegenüber?" Dissert.: Strassburg, 1894. The earlier literature is here given.

2 Pasteur, Compt. rend., vol. xlvi. p. 615 : 1858 ; vol. li. p. 298 : 1860 ;
vol. Ivi. p. 416 : 1863; J. A. Le Bel, ibid., vol. Ixxxvii. p. 213: 1878 ; vol.
Ixxxix. p. 312 : 1879 ; vol. xcii. p. 843 : 1881 ; J. Lewkowitsch, Ber. d. deutsch.
Chem. Ges., vol. xv. p. 1505 : 1882 ; vol. xvi. pp. 1569, 2720, 2722 : 1883. Also

394 LECTURE XXVI

quantities of dextrorotatory and levorotatory lactic acid, the
Fenicillium glaucum consumes the latter only, leaving the
former untouched ; in the same way, this fungus leaves the
dextrorotatory only in a mixture of both kinds of mandelic
acid. Saccharomyces ellipsoideus, on the contrary, consumes
the dextrorotatory mandelic acid only, leaving the levorota-
tory ; and this is also the case with a certain variety of bac-
terium. PenieiUium glaucum behaves in the opposite way
towards tartaric and glyceric acids compared with its action on
lactic and mandelic acids ; it leaves the levorotatory tartaric
and glyceric acids untouched.

From the above remarks, it appears that so far we have
only definitely ascertained that the power of utilizing dextro-
rotatory sugar is diminished in diabetes.

Now, as the bulk of the sugar is normally decomposed in
the muscles, it seems probable that diabetes may fundamentally
be due to a disturbance of the chemical processes in muscle.

Insufficient use of the muscles, a sedentary mode of life,
are frequently given as causes of diabetes. This harmonizes
with the fact that the disease comparatively often (30 per
cent, of all cases) occurs in stout people. Obesity is invari-
ably a result of insufficient muscular exertion (see end of
Lecture XXIV.). Moveover, a few cases of diabetes have
been successfully treated by systematic muscular exercise.^

But the chemical processes in muscle are subject to the
influence of the nervous system, and numerous observations
tend to show that the symptoms in diabetes are caused by
disturbances which originate in the central nervous system.
The disease sometimes occurs immediately after and may be
traced to, injury to the head, or it accompanies organic affec-
tions of the brain (hemorrhages, tumors, sclerosis), or other
nervous diseases, psychoses, &c. Occasionally violent mental
excitement or neuralgia has caused an outbreak of the
malady. In post-mortem examinations of diabetics, the brain
more frequently shows pathological changes than any other
organ.

Seegen,^ who has treated over a thousand cases of diabetes,
declares that 90 out of every 100 of such cases suffer from some
form of nervous disorder, and adds that, in the numerous cases
of hereditary diabetes in one and the same family, some may
suffer from some form of psychical disorder, in most cases

Em. Bourquelot, Compt. rend., vol. c. pp. 1404,1466; vol. ci. pp. 68, 958: 1885 ;
Maumene, ibid., vol. c. p. 1505 ; vol. ci. p. 695 : 1885 ; H. Leplay, vol. ci.
p. 479 : 1885.

1 Külz, loc. cit., vol. i. pp. 179-216; and vol. ii. pp. 177-180.

2 J. Seegen, " Die Zuckerbildung im Thierkörper, &c.," p. 263 : Berlin, 1890.

DIABETES MELLITUS 395

melancholia, leading off into suicide, while other members are
diabetic.

Much confusion has arisen owing to the endeavor to ex-
plain the nature of chronic or ' natural ' diabetes (as it has
been called), from the observations carried out on ' artificial '
diabetes. CI. Bernard has shown that a puncture in the floor
of the fourth ventricle, midway between the origins of the
auditory and pneumogastric nerves, is followed by the passage
of sugar into the urine. This artificial diabetes is obviously
quite a different process to the natural disease. It lasts only
for a few hours ; and if, at the expiration of this time, when
the urine has again become free from sugar, the animal be
killed, no glycogen will be found in the liver. If all glycogen
be removed from a dog by starvation, puncture of the ' diabetic
center' remains without effect.^

If a solution of grape-sugar be injected into the mesenteric
vein of a healthy dog, which has been deprived of glycogen by
starvation, very little sugar appears in the urine. But if the
liver be freed from glycogen by puncture of the floor of the
fourth ventricle, and the injection into the mesenteric vein
be then given, a very large amount of sugar is found in the
urine.^

Artificial diabetes therefore is due to the inability of the
liver, in consequence of disturbed innervation, to retain the
glycogen. The blood becomes flooded with sugar, which passes
into the urine.

If natural diabetes were due to the same cause, and if the
liver had lost its power of regulating the amount of sugar in
the blood, of storing carbohydrates during absorption, and of
supplying sugar to the blood according to the needs of the
economy, we should expect to find that the amount of sugar
in the blood of diabetics would sometimes be above and some-
times below normal. This is not the case ; it has always been
found to be increased.

The objection may be raised that the diabetic patient
takes food in such quantities and so often, that absorption
is never interrupted, and that the blood is constantly loaded
with sugar.

We must therefore try to decide the question in a direct

^ Leopold Seelig, " Vergleichende Untersuchungen über den Zuckerverbrauch
im diabetischen und nicht diabetischen Thiere," Dissert.: Königsberg, 1873.
The works of Pavy and Dock are quoted here. Luchsinger has published a con-
firmation of these results : " Exper. u. krit. Beiträge zur Physiol, u. Pathol, des
Glycogens," Dissert., p. 72: Zürich, 1875.

^Naunyn, Arch. f. exper. Path. u. Pharm., vol. iii. p. 98: 1875. A critical
account is here given of the earlier works on this point.

396 LECTURE XXVI

manner, and ascertain whether a diabetic liver contains gly-
cogen. This method has actually been adopted.

Külz^ examined the liver of a patient who suffered from
the aggravated form of diabetes, and had been for a long time
before his death restricted to a diet of meat. The patient
had taken his last meal thirty-four hours before death, and
had been moribund for twenty-eight hours. The post-mortem
took place twelve hours after death. About the tenth part
of the liver served for the determination of glycogen, and
yielded roughly 0.7 grm. of glycogen. Külz estimated the
amount of glycogen in the whole liver at from 10 to 15 grms.
Besides this, it contained a large quantity of sugar, part of
which also originated from the glycogen.^ The amount of gly-
cogen during life must therefore have been very considerable.

Von Mering^ had the opportunity of examining the livers
of four diabetics in Frerichs' wards. " Two of them, who died
of phthisis, and who had no sugar in the urine eighteen and
twenty hours before decease (although there had previously
been a considerable amount), exhibited neither glycogen nor
sugar in their livers, although in one case the post-mortem
examination took place immediately after death. In the two
other cases where the diabetics died suddenly, and the urine
removed from the bladder after death was full of sugar, both
glycogen and sugar were found in abundance."

M. Abeles* examined the organs in the bodies of five
diabetics, in E. Ludwig's laboratory in Vienna. No glycogen
was found in any of the organs examined in two cases, one of
which had died of phthisis, and the other of prolonged furun-
culosis and metastatic purulent pericarditis. The remaining
patients had died from diabetic coma. The organs were not
examined for several hours after death. The liver was ex-
amined in two cases, and a little glycogen was found : 0.16
grm. and 0.59 grm. There was none of the muscles.

The liver of living diabetics has also been examined for
glycogen in Frerichs' wards.^ These experiments are so im-
portant that I will quote the passages, unfortunately very short,
in which they are described.

' Külz, Pflüger's Arch., vol. xiii. p. 267 : 1876. See also the older statemeata
of Kühne, Virchow's Arch., vol. xxxii. p. 543: 1865; and M. Jaffe, ibid., vol.
xxxvi. p. 20 : 1866.

^ To obtain an exact estimate of the glycogen, the liver must be immersed in
boiling water directly after death, in order to stop the fermentative action by
which the glycogen would otherwise be broken up.

■^ Von Mering, Pflüger's Arch., vol. xiv. p. 284: 1877.

* M. Abeles, Centralbl. f. d. med. Wissensch., p. 449: 1885.

^ Frerichs, loc. cit., p. 272. Also plates of the histological sections of the
livers.

DIABETES MELLITUS 397

" Professor Ehrlich eiFected it by means of a fine trocar,
which had been carefully disinfected, and which was inserted
in the parenchyma of the liver. When the instrument was
removed, sometimes a little blood only, but generally a few
hepatic cells, either isolated or united m groups, were found in
the tube ; there was occasionally a somewhat larger piece of the
liver, which was hardened in alcohol, and cut, after being im-
bedded in celloidon. In this way, we were able to examine the
hepatic tissue during life in three cases. They had all, both
healthy and diabetic, eaten heartily, especially of amylaceous
food. The puncture was made from four and a half to five and
a half hours after the meal.

" A considerable quantity of glycogen was found in the
first case, that of a healthy man, addicted however to
alcohol. The cells in the peripheral regions of the acini
had undergone fatty degeneration, but contained glycogen
as well.

" The second case was that of the diabetic Dn. The hepatic
cells were almost free from glycogen, though a few showed a
slightly brownish hue, denoting the presence of traces of this
substance.

" In the third case, that of a diabetic woman, a tolerably
large amount of glycogen was found in the hepatic cells. The
distribution of glycogen was very unequal, parts containing but
little alternating with others richly provided with it. Large
granules of glycogen, which frequently filled almost the whole
of the cells, were often found at the margin of the lobule.
They did not however consist of pure glycogen, but mainly of
a supporting subtance, as their yellowish color denoted. They
could not be regarded as artificial products caused by the alcohol,
as they occurred likewise in dried preparations. The nuclei
were generally free from glycogen, although in one place gly-
cogen appeared to be deposited round the nucleolus. This is
very analogous to the deposits of starch round the nucleoli in
plants.

" Examination of the dried preparations, which were ob-
tained from repeated punctures, showed the same result,
i. e., absence of glycogen in case 2, and a moderate amount
in case 3."

I think these facts also indicate that we cannot apply the
term diabetes to one single malady ; lesions similar to those
which produce artificial diabetes, may also produce certain
forms of the malady (and especially glycosuria from injury
to the medulla oblongata), but by no means all.

The fact that no sugar passes into the urine in cases of

398 LECTÜEE XXVI

extensive hepatic disease, in cirrhosis of the liver, and in phos-
phorus-poisoning, is very remarkable. Frerichs could not
detect any sugar in the urine, even after large quantities of
grape-sugar had been taken, in cases of cirrhosis of the liver,
where a subsequent autopsy showed complete degeneration of
that organ.^ After administration of from 100 to 200 grms. of
grape-sugar to patients suffering from phosphorus-poisoning in
Frerichs' wards a small amount of it was traced in the urine
in two cases, while in seventeen others the result was negative.
No trace of sugar or glycogen was ever found in the liver in
any case of phosphorus-poisoning, where fatty degeneration of
that organ had set iu.^

Diabetes is evidently not due only to a disturbance of the
glycogenic function of the liver. As far as I know, the muscle
of diabetics has only been examined for glycogen in two cases,
and, as already stated, with a negative result.^

Although the artificial diabetes discovered by Bernard does
not serve to explain the natural form of this disorder, another
kind of artificial diabetes, which has been the subject of much
research during the last few years, seems to bring us nearer to
a solution of the problem — I mean the diabetes that follows the
extirpation of the pancreas.

It was long ago pointed out that pathological alterations in
the pancreas are frequently to be found in autopsies on diabetics.
Frerichs* especially drew attention to this point, and showed
that, in fifty-five fatal cases of diabetes, well-marked macro-
scopic changes in the pancreas were to be found in eleven of
them. The experimental proof of the connection of the pan-
creas with diabetes could however only be given later, after
surgical technique and especially the aseptic method had
reached the state of perfection necessary for so serious an
operation.

J. von Mering and O. Minkowski^ have operated on more
than fifty dogs, and have found that, in all cases without excep-
tion where the complete extirpation of the pancreas had been
successfully carried out and the animals had survived more than
twenty-four hours, well-marked and severe diabetes was pro-
duced with all its characteristic symptoms, such as great thirst,
large appetite, polyuria, and rapid decline of strength.

^ Frerichs, loc. cit., p. 43. ^ Ibid., p. 45.

' Abeles, loc. cit.

* Frerichs, loc. cit., pp. 144-183. See also the case-histories, pp. 238-248.

^ J. von Mering and O. Minkowski, Arch. f. exper. Path. u. Pharm., vol.
xxvi. p. 371: 1890. Minkowski, Berl. klin. Wochenschr., No. .5: 1892; and
" Untersuch, üb. d. Diabetes mellitus nach Exs. d. Pankreas," Leipzig, 1893. In
this latter work the rest of the literature ou the subject is fairly fully given.

DIABETES MELLITUS 399

The excretion of sugar began in some cases four to six
hours after the operation, in most cases somewhat later, often
not until the next day. Within twenty-four to forty-eight
hours, the glycosuria reached its highest point, the sugar
amounting to between 5 and 11 per cent, of the urine, even
before the animals had taken any food whatsoever. Even after
seven days' starvation or exclusive meat diet, the sugar did not
disappear from the urine. For instance in one dog weighing
8 kilos, on a plentiful diet of meat and bread, the daily excre-
tion of sugar over a considerable time amounted to between 70
and 80 grms. In some cases large quantities of aceton, aceto-
acetic acid, and oxybutyric acid also made their appearance in
the urine. The sugar was also largely increased in the blood.
In one case, on the sixth day after the operation, it amounted
to 0.3 per cent. ; in another case, on the twenty-seventh day,
to 0.46 per cent.

The glycogen, all but minute traces, disappeared early from
the organs. Dextrorotatory grape-sugar, administered with the
food, reappeared without loss in the urine. Levorotatory
sugar was in great part utilized, though a certain proportion
was converted into dextrorotatory, and excreted by the kid-
neys.^ On feeding with levorotatory sugar, glycogen was de-
posited in the liver and muscles.

These statements of Mering and Minkowski have been con-
firmed by many other authors, especially by Lupine ^ and
H^don.^

If we now attempt to explain the connection between the
extirpation of the pancreas and diabetes, the idea naturally
presents itself that under normal circumstances the sugar-form-
ing food-stuffs are altered in some way in the intestine by the
pancreatic juice, and that this alteration is a necessary prelimi-
nary to their destruction in the tissues. Thus absence of pan-
creatic secretion would leave the sugar undestroyed.

It is quite true that certain disorders of digestion occur after
ablation of the pancreas. The examination of the feces of dogs
after this operation shows that a large amount of fat, proteid, and
starch escapes absorption. This will not however serve to explain
the symptoms of diabetes, since simple ligature of the pancreatic
duct is not followed by any diabetes. Moreover in many cases
the larger portion of the gland has been excised, and only a

^Minkowski, "Untersuch.," &c., p. 68. Compare Fr. Voit, Zeitschr. f.
Biol., vol. xxviii. p. 353, and vol. xxix. p. 147 : 1892.

- Lepine, Wien. lied. Presse, Nos. 27-32 : 1892. Here also most of Lepine's
previous papers are quoted.

^Hedon, Arch. d. Physiol.: April, 1892. Compt. rend., vol. cxii, p. 1027:
1891 ; and vol. cxv. p. 292 : 1892.

400 LECTURE XXVI

small bit has been left free from all connection with the duode-
num^ and yet no glycosuria has been produced. If fact diabetes
as a rule occurs only after complete extirpation of the gland.
If only a minute portion of the gland be left, there results either
no diabetes at all or only the milder form of this disorder, in
which sugar disappears from the urine on a purely proteid diet
or during starvation, to reappear after eating bread. If the ex-
tirpation is complete, the glycosuria persists, as I have already
mentioned, in spite of long-continued inanition. We must con-
clude therefore that the responsible factor is not a disturbance
in the intestinal functions, and that the gland, besides the for-
mation of its secretion, must possess other functions, which are
a necessary condition of normal sugar destruction in the body.
Before however we inquire into the nature of this fimction,
we must deal with an obvious objection that has been raised to
these experiments, viz., that the glycosuria is caused by the
unavoidable damage to neighboring organs, especially the solar
plexus, in the course of the operation. That this is not the case
is shown by the fact that any portions of the gland may be
removed piece by piece without the occurrence of glycosuria.
Only when the remaining fragment of the gland is extirpated
do symptoms of diabetes make their appearance. Destruction
of the solar plexus Avithout removal of the pancreas produces,
not diabetes but only acetonuria and transient glycosuria.^ Espe-
cially decisive is the following experiment. The lowest portion
of the descending limb of the pancreas in the dog is not con-
nected with the duodenum, but lies free in the mesentery. This
piece of the gland can be separated so as to be freely movable,
and attached only by a long pedicle containing its artery and
vein. It can therefore be taken out of the abdominal cavity
and be grafted under the skin near the opening in the abdo-
minal wall, without in any way interfering with its blood-
supply. When the animal has recovered from this operation,
the abdominal wound is again opened, and the whole remaining
portion of the gland extirpated, so that the animal has left only
the small portion of gland under the skin of the abdomen. After
this operation no diabetes occurs, and large quantities of carbo-
hydrates may be given to the animal, without giving rise to
glycosuria. The small subcutaneous bit of pancreas prevents
the development of diabetes, which at once follows in all its
intensity if this piece be removed. "■ It is thus possible in this
way to produce diabetes in its severest form leading to the
death of the animal by a small operation, which lasts only a few
minutes and is accomplished without opening the peritoneal
^ Lustig, Arch, per le scienze meddche, vol. xiii. Fas. 2 : 1889.

DIABETES MELLITUS 401

cavity, and in which there can be no suspicion of any kind of
injury to adjoining important structures." This experiment
has been several times successfully performed by Minkowski,
and in every case with the same result.

There can be thus no doubt that the pancreas influences
directly or indirectly the destruction of sugar, and that this in-
fluence is absolutely independent of processes which go on in
the small intestine. We must therefore assume either that the
sugar of the blood undergoes some changes in passing through
the gland, which prepare the way for its further destruction, or
that the gland gives oif some substance to the blood and tissues,
which enables directly or indirectly the destruction to take place
in other organs of the body.

The former assumption is rendered improbable by the fact
that only a small fraction of the whole blood passes through
the gland, especially in the experiments where the presence
of a tenth part of the whole gland has prevented the appear-
ance of diabetes. Moreover, in experiments carried out in
Strieker's laboratory' on the amounts of sugar in the blood
flowing to and away from the gland, no difference could be
found.

The second assumption seems therefore the only possible
one, viz., that the gland gives off some substance which influ-
ences the process of sugar destruction. This influence might of
course be very indirect. We might imagine for instance that
the substance in question plays a part in the functions of cer-
tain portions of the central nervous system, and that the meta-
bolism of the muscles, where the chief part of the sugar is
destroyed, is influenced by these nerve-centers. Analogies for
such an indirect process are not wanting, and I might remind
my readers of the extensive disturbances in the functions of the
central nervous system, which result from the extirpation of
the thyroid gland, and which are prevented so long as a piece
of the gland is left or is transplanted into the abdominal wall.^
We should thus return to our previous hypothesis, viz., that
disturbances in the functions of the central nervous system are
the cause of diabetes.

I would however once more emphasize the fact that the
various forms of diabetes may have different modes of causa-
tion, and we need not assume that a morbid affection of the
pancreas is in all cases a necessary preliminary. Even if
pathological changes could be detected in the pancreas in all

^Pal., Wien. Min. Wochenschr., No. 4: 1891.

-A. von Eiselsberg, Wien. klin. Wochenschr., -p. 81: 1892. Here the pre-
vious literature is also quoted.
26

402 LECTUEE XXVI

cases of diabetes, they might just as well be the consequence as
the cause of the nervous aifections.

A careful microscopical investigation of the pancreas in all
fatal cases of diabetes is much to be desired. Hitherto pathol-
ogists have for the most part been satisfied with a mere inspec-
tion of the organ.

The varying course and issue of the disease seem also to
show that there are many different forms of diabetes.^ We
can find all stages between transient and symptomatic gly-
cosuria on the one hand, and the chronic variety of diabetes
on the other. We occasionally see that the milder forms of
chronic diabetes are as completely cured as symptomatic
glycosuria. In chronic diabetes, a temporary disappearance
of glycosuria may, as we have already mentioned, be fre-
quently induced by a withdrawal of carbohydrates from the
food. If the patient takes active exercise, a considerable
quantity of carbohydrates may be borne without a passage of
sugar into the urine. In other cases again, the excretion of
sugar continues, although the food may consist exclusively of
proteid and fat. Slight forms of diabetes frequently become
aggravated, and, apart from this, they are not exempt from
fatal complications. The severe form also runs a varying
course. It is sometimes acute, and death occurs after a few
weeks, or it may be after a year or two; in others, it may
not take place for from ten to twenty years. Ordinarily
glycosuria is associated with polyuria, the daily amount of
urine rising to as much as 12 liters, while the patients are
tortured by continual thirst. On the other hand, sugar may
appear in the urine without polyuria and increased thirst.
Frerichs^ has observed more than thirty cases in which the
amount of urine did not exceed 1700 to 2000 cms., while the
quantity of sugar rose from 4 to 6, and even 8 per cent. In
rare cases, diabetes mellitus may pass into diabetes insipidus,*
polyuria without glycosuria. In diabetes, death is caused by

' Frdr. Albin Hoffmann has made an interesting attempt to classify and
define the various forms of diabetes ( Verhandl. d. Congr. für inn. Med., p. 159 :
Fünfter Congress, Wiesbaden, 1886). Compare also Kiilz, loe. cit., vol. i. p. 217 ;
and vol. ii. p. 144.

2 Frerichs, loc. cit., p. 192.

^ This shows that polyuria in diabetes mellitus is not a necessary conse-
quence, at any rate not in all cases, of the glycosuria, but may be the result of
a special nervous disturbance. Concerning diabetes insipidus, see Kiilz, " Beitr.
zur Pathol, u. Therap. des Diabetes mellitus u. insipidus," vol. ii. : Marburg,
1875. The previous literature on diabetes insipidus is summarized, pp. 28-31,
and particularly that dealing with the occurrence of inosit in the urine in this
disease. Vide Kiilz, Sitzwngshcr. d. Ges. z. Beford. d. ges. Naturw. zu Marburg,
No. 4: 1876. For the chemical properties of inosit, see Maquesne, Compt. rend.,
vol. civ. pp. 225, 297 and 1719 : 1887.

DIABETES MELLITUS 403

various complications, such as simple marasmus, pulmonary
phthisis, furunculosis or carbuncles, nephritis, &c., and is fre-
quently ushered in by diabetic coma.

I will dwell upon these symptoms a little more fully,
because recent researches afford a perfectly satisfactory chem-
ical explanation of them. The abnormal constituents of the
urine, to which I have already drawn attention, oxybutyric
acid, aceto- acetic acid, and aceton, which may frequently be
traced in small quantities during the earlier stages of the dis-
ease, become considerably increased in coma. We shall im-
mediately see that the cerebral symptoms occur at the same
time that these substances are produced.

A comatose condition certainly may occur towards the
close of the disease, without these abnormal products of metab-
olism being formed, but in these cases the coma depends upon
complications, such as acute cardiac insufficiency, cerebral hem-
orrhage, nephritis, and the like. But in most cases, the above-
named substances are demonstrable in the urine in diabetic
coma ; and the majority of authors have attributed this variety
of coma to their narcotic influence,^ especially to that of aceton,
which acts in this respect like alcohol, ether, and other mem-
bers of this group. But more careful experiments showed
that the narcotic action of aceton was not powerful enough to
account for diabetic coma,^ especially if it be considered that
aceton arises from proteid, and that the amount of the latter
decomposed is not sufficient to yield the quantity of aceton
required to produce coma.

The action of aceton resembles that of ethyl alcohol, but
is not quite as powerful. Aceton can be given to dogs in
the proportion of 1 grm. for every kilogrm. of body weight
without any effect. Doses of 4 grms. for every kgrm. cause
symptoms of intoxication with marked motor disturbances,
similar to those produced by ethyl alcohol. Eight grms. for
every kgrm. is the fatal dose of aceton, and from 6 to 8 grms.
that of ethyl alcohol.^ In order therefore to poison a person
weighing 70 kgrms., from 500 to 600 grms. must be taken.
This amount could not possibly be formed from decomposing
pro Leid.

1 A complete summary of all the literature on this subject is given by von
Buhl, Zeitschr. f. Biolog., vol. xvi. p. 413: 1880; and by Rudolf von Jaksch,
" Ueber Acetonurie u. Diaceturie " : Berlin, Hirschwald, 1885. Also Frerichs,
loc. CiL, pp. 114-120.

* Vide Peter Albertoni, Arch. f. exper. Path. w. Pharm., vol. xviii. p. 218 :
1884 (from Schmiedeberg's laboratory). This includes a complete report of the
numerous earlier experiments.

3 Albertoni, loc. cit., pp. 223, 224, 226.

404 LECTURE XXVI

That diabetic coma does not result from the narcotic
action of aceton is further proved by the fact already stated,
that the amount of aceton in the urine sometimes diminishes
during the stage of coma, while there is an increase in its pre-
cursor, oxybutyric acid, which has no paralyzing influence on
the brain/

Stadelmann^ and Minkowski^ have however offered a
satisfactory explanation of this condition. They refer it to
a saturation of the alkalies in the blood by the products of
incomplete combustion, which are of an acid nature like
oxybutyric acid. The symptoms of diabetic coma are in fact
similar to those observed by Fr. Walter* in animals, which
he poisoned with mineral acids. When dilute hydrochloric
acid was injected into the stomach of a rabbit, dyspnea
occurred, the animal lost the power of motion, and died with
all the signs of collapse. But if carbonate of soda were sub-
cutaneously injected after the symptoms of poisoning had
set in, the animals recovered. Walter estimated the car-
bonic acid in the blood of animals which had been poisoned
with acids, and found only from 2 to 3 per cent, by volume.
This, as I have shown in our remarks on the gases of the
blood (p. 262), is the amount of carbonic acid which is
simply dissolved in the blood. Consequently the blood of the
poisoned animals contained no alkalies that could fix the
carbonic acid, as they had been saturated with the hydro-
chloric acid.^ It follows that the blood had been deprived
of the carrier of the carbonic acid, which consequently ac-
cumulated in the brain, and produced the usual symptoms.
Walter has also demonstrated, as I have mentioned, that the
administration of acids increases the amount of ammonia in
the urine. Very similar phenomena are observed in diabetic
coma. The eifect of hydrochloric acid in the experiments on
animals is identical with that of oxybutyric acid in diabetic
coma. Here also dyspnea is a symptom ; the diabetic also
shows an increase of ammonia in the urine, and this increase

* Wolpe, " Unters, über die Oxybuttersäure des diabetischen Harnes," Dis-
sert. : Königsberg, 1886 ; Arch. f. exper. Path. u. Pharm., vol. xxi. p. 138 : 1886 ;
and O. Minkowski, Mittheilungen aus der medicin. Klinik zu Königsberg, vol.
xvii. p. 443: 1883.

2 E. Stadelmann, Arch. f. exper. Path. u. Pharm., vol. xvii. p. 443 : 1883.

ä O. Minkowski, loc. cit.

Tr. Walter, Arch. f. exper. Path. u. Pharm., vol. vii. p. 148: 1877 (from
Schmiedeberg's laboratory).

s Walter ( loc. cit. ) speaks of withdrawal of alkali, which has not been proved
by his experiments. The alkalies that are saturated by the acid may remain in
the blood as neutral salts, until the kidneys have excreted the acid, leaving the
bases in the blood.

DIABETES MELLITUS 405

reaches tlie highest point in the stage of coma.^ Minkowski
has also determined the amount of carbonic acid in the
blood of a comatose diabetic patient, and has only found a
volume percentage of 3.3. The blood had been taken a short
time before the death of a patient from his radial artery.^
Blood taken from the dead body had a distinctly acid reac-
tion, and contained large quantities of oxybutyric and sarco-
lactic acids.

Finally, I may be permitted to make a few remarks on the
treatment of diabetics from the chemical point of view.

So long as the causes of the diiferent forms of diabetes are
unknown to us, there can be no question of a rational mode of
cure. We can do nothing more than relieve the most painful
symptoms.

It has been quite right to try and reduce the amount of
undecomposed sugar in the body, not only because it is useless,
but because its circulation induces disturbances in all the
tissues, and because certain organs, especially the kidneys, are
overworked, and a tormenting thirst is induced. On this
ground, muscular work is strongly to be recommended. Kiilz,^
as we have already remarked, has shown that in many cases
muscular exertion materially diminishes the excretion of sugar.
Bouchardat asserts that he has obtained permanent improve-
ment in many cases by this method. It does not answer in all
cases, a circumstance which also tends to prove the existence of
different forms of diabetes.

If we desire to reduce the amount of carbohydates, we
must be prepared with a substitute. A diet consisting exclu-
sively of proteid is objectionable, because it gives rise to
acetonuria, and increases the danger of coma. So long as the
theory prevailed that diabetes consisted essentially in an in-
ability to decompose the sugar, it was sought to introduce the
products of decomposition with the food. But we are not
acquainted with the intermediate products of the decomposition
of sugar, and even if they were known to us, we could not
replace the sugar by introducing them, because at the moment
of decomposition kinetic energy is liberated, which is utilized
in the performance of muscular and other functions. Never-

^ Minkowski, loc. cit., p. 179.

2 I must refer to the extremely interesting original work for the details of
this experiment. It also contains important critical observations on recent liter-
ature of diabetes.

3 Kiilz, loc. cit., vol. i. pp. 179-216 (where the older statements of Trousseau
and Bouchardat are quoted), and vol. ii. pp. 177-180. Also Dr. Carl Zimmer,
" Die Muskeln eine Quelle, Muskelarbeit ein Heilmittel bei Diabetes ": Karlsbad,
1880; and von Mering, Verhandl. d. Congresses f. innere 3Iedicin, p. 171 : Wies-
baden, 1886.

406 LECTUEE XXVI

theless, some physicians have thought that the daily administra-
tion of from 5 to 10 grms. of lactic acid would serve as a sub-
stitute for the 300 to 800 grms. of carbohydrates required by
an adult ! Larger quantities of lactic acid cannot be given,
because they would disturb the digestion.

Acting on an erroneous supposition of O. Schultzen/ who
imagined glycerin to be one of the normal products of the de-
composition of sugar, they have tried to replace sugar by
glycerin. The latter has the advantage over lactic acid of
its sweet taste, but only a very small quantity can be pre-
scribed. After larger doses diarrhea occurs, and a part of
the absorbed glycerin passes unaltered into the urine (vide
supra, p. 362).^ Glycerin should therefore be given in its
natural form as fat.^ Fats can be digested very well by
diabetics (vide supra, p. 388), and are the best substitutes for
the carbohydrates.*

Many attempts have been made lately to administer levo-
rotatory sugar to diabetics. C. A. Socin,* however, as the re-
sult of a careful experiment, gives an emphatic warning against
this treatment. He finds that in the mild form of diabetes thä
levorotatory sugar is at first destroyed, but the body rapidly
loses this power. The same result is observed after the admin-
istration of small quantities of dextrorotatory sugar, for which,
even in the mild form of the disease, patients soon lose their
tolerance.

It is well known that essential improvement in the condition
of diabetics, especially with regard to the elimination of sugar,
is effected by the use of alkaline, and particularly of Carlsbad,
water in the water-cures. It was thought that the increased
alkalescence of the blood favored combustion {vide supra, p.
247). This explanation appears still more probable if we con-
sider the abnormal acids which occur in the blood of diabetics.
But it has been proved by direct experiments that the mere
administration of carbonates of alkalies without the mode of

*0. Schultzen, Berliner Hin. Wochenschr., No. 35 : 1872.

* To satisfy the sense of taste, saccharin has recently been introduced as a
substitute for sugar. With regard to the experiences of its use, see E. Kohl-
echiitter und M. Elsässer, Arch. f. klin. Med., vol. xli. p. 178 : 1887 ; and the
article " Saccharin," by T. Stevenson and L. C. Wooldridge, in the Lancet,
November 17, 1888.

3 Considerable variety and change of diet may be effected in the way of fats
with fat fish, of which a number are easy of digestion, yolk of egg, fresh cream
(one-half of its small production of milk-sugar being utilized by diabetics),
almonds, nuts, cocoa, and olives.

"* Pettenkofer and Voit, Zeitschr. f. Biolog., vol. ill. p. 441 ; 1867.

^ C. A. Socin, " Wie verhalten sich Diabetiker," <fec., Dissert., Strassburg :
1894.

DIABETES MELLITUS 407'

life adopted at watering-places, does not diminish the excretioil
of sugar.^

So far the attempts to subdue diabetic coma by the injection
of carbonate of soda into the blood have remained without any-
favorable results.^ We cannot expect to obtain any real im-
provement from the addition of alkalies, because this mode of
treatment deals only with the symptoms, and not with the cause
of the disease.

^ Frerichs, loc. cit., p. 263. Nencki and Sieber, Journ. f.prakt. Chem., vol.
xxvi. p. 33: 1882. Also Külz, loc. cit., vol. i. 31 ; ii. 154. A summary of all the
earlier literature will be found here.

2 O. Minkowski, Mittheilungen aus der medicinischen Klinik zu Königsberg,
i. Pr., pp. 183-186 : 1888.

LECTURE XXVII

INFECTION

The time-worn controversy as to the origin of infectious
diseases, whether they are brought about by living organisms
— the " contagium vivum/' or simply by poisons, i. e., definite
chemical substances, has been finally settled by the unceasing
labors of the last two or three decades in favor of the former
alternative. We know that the various infectious diseases are
due to the entry of different and definite bacteria into the tissues
of our body.

Now however arises the further question : Are the symp-
toms of these diseases the result of the mechanical disturbances
caused by the spread of the bacteria through the tissues, or have
we to do with the poisonous products of metabolism ? And the
conviction is growing more and more clear that the latter theory
is the right one.^

We may cite the following proofs in support of this con-
tention :

1 . In certain infectious diseases the pathogenic organisms do
not penetrate into the internal organs, but remain in the super-
ficial mucous membranes, as in the case of diphtheria, or in the
surface of the wound, as in tetanus. And yet in all these mal-
adies, a general intoxication ensues.

2. Certain pathogenic bacteria may be cultivated outside the
body in artificial nutrient fluids. Such a fluid can then be com-
pletely freed from bacteria by filtration, and the filtrate, when
injected into the body of a healthy animal, will produce symp-
toms of poisoning similar to those which would result if the
bacteria themselves were inoculated. ( Vide infra.)

The adherents of the theory of " living contagion " had now
the same duty to perform which had previously fallen to the lot
of its opponents, i. e., of isolating the poisons, of preparing
them as chemical entities, investigating their characteristics and
studying their behavior towards the constituents of the tissues.
The morphologist had done his part ; the chemist must now
intervene.

■• An account of the earlier literature on this subject is given by P. L. Panum,
Virchow's Arch., vol. Ix. p. 301 : 1874.

408

INFECTION 409

The poison was first thought to belong to the nitrogenous
organic bases, the alkaloids. This supposition was favored by
the facts that the most intense organic poisons belong to the
group of alkaloids, and that moreover nitrogenous bases may
result from the metabolism of the bacteria. Poisonous bases
readily arise from the decomposition of proteids, of the nu-
cleins, or by a conversion of the nitrogenous bases preformed
in the animal tissues, such as creatin, cholin, and the xanthin
bodies.

The first attempt to isolate the poisonous bases produced by
bacterial putrefaction was made by Bergmann and Schmiede-
berg,^ who prepared in a crystalline form the sulphate of an
organic base from putrid yeast. When injected into a dog, 0.01
gr. of these crystals produced vomiting and bloody diarrhea.

Of the numerous and more recent experiments conducted
with the object of isolating poisonous alkaloids from the bac-
terial products ^ I will only select those where a clearly defined
chemical individual has been obtained, which has been proved
to be acutely poisonous.

L. Brieger^ prepared from putrid meat and fish two bases,
which are closely allied to cholin and had probably been formed
from the cholin which occurs in the form of lecithin in all
animal tissues. One of these two bases was neurin ; the other
was isomeric with muscarin. ( Vide Lect. VI. p. 76.) The neu-
rin proved to be identical with that synthetically prepared by
Hofmann * and von Baeyer,^ which is distinguished from cholin
by the possession of one less molecule of water. It must there-
fore be regarded as trimethyl-vinyl-ammonium hydroxid :

1 E. Bergmann and O. Schmiedeberg, Centralbl. f. d. med. Wissensch., p. 497 :
1868. Bergmann, Deutsch. Zeitschr. f. Chirurgie, vol. i. p. 373 : 1872.

2 The comprehensive literature on this subject is quoted by F. Gräbner,
" Beitr. z. Kenntniss der Ptomaine," Diss., Dorpat : 1882. M. Nencki, Journ. f.
prakt. Chem., N. F., vol. xxvi. p. 47 : 1882. L. Brieger, " Ueber Ptomaine,"
Berlin, Hirschwald, 1885. " Weitere Unt. üb. Ptomaine," 1885. " Unt. üb.
Ptomaine." Dritter Theil, 1886, and Virchow's Arch., vol. civ. p. 483 : 1889.
Compare also F. Selmi, " SuUe ptomaine ed alcaloidi cadaverici e loro importanza
in tossicologia," Bologna : 1878, and Gau tier, " Cours de Chimie," " Chimie
biologique," Paris, pp. 261-270 : 1892.

^L. Brieger, "Ueber Ptomaine," Berlin, Hirschwald, pp. 34^36 and p. 48 :
1885.

*A. W. Hofmann, Compt. rend., vol. xlvii. p. 558 : 1858.

^ Baeyer, Ann. d. Chem. u. Pharm., vol. cxl. p. 311 : 1866.

410 LECTUEE XXVII

Both bases produced toxic effects similar to those of the
muscarin prepared from fly-fungus. Besides the above-
mentioned, Brieger' obtained from putrid meat, cheese and
gelatin (in small quantity also from fresh eggs and fresh
human brain), a base with the empirical composition C^Hj^Nj,,
the constitution of which could not be thoroughly ascertained.
On boiling with potash it gave off dimethylamin and trimethyl-
amiu. Brieger gave it the name of neuridin. This base again
produced in frogs and rabbits symptoms of poisoning similar to
those caused by muscarin, and 2 mg. of the hydrochlorate of
this base, when injected into the dorsal lymph -sac of a frog
proved fatal. In rabbits the lethal dose was 0.04 g. per
kilo, bodyweight.

Another base, methyl-guanidin, was isolated by Brieger ^ in
small amounts from horse flesh which had been undergoing
putrefaction for four months :

The poisonous character of this compound had already been
remarked by Baumann and Gergens ^ : 1 mg. injected into the
dorsal lymph-sac of a frog gave rise to definite toxic manifesta-
tions, consisting in fibrillar twitchings of the dorsal muscles ;
larger doses brought on convulsive movements of the extrem-
ities, which frequently became tetanic in character ; 0.05 g.
caused death, which occurred after the muscular symptoms had
lasted for some time, occasionally for as much as three days.
Brieger made a subcutaneous injection of 0.2 g. of methyl-
guanidin prepared from putrid meat into a guinea-pig, which
at once became paralyzed in the limbs and died twenty minutes
afterwards with general clonic convulsions. We may assume
that the methylguanidin was probably formed from the creatin
of the meat. (See page 298.)

I shall not give any account of the numerous other bases,
which have been isolated from bacterial products, since some
of these (such as mydalein, typhotoxin, mydatoxin, gadinin^
&c.) have not been obtained in a pure state, or if they have,
in such small amounts that their chemical properties and

1 Brieger, loc. cit., pp. 20-30, 51, 64, 57, 61.

2 Brieger, " Uat. üb. Ptomaine," Dritter Theil, Berlin, 1886, p. 34, et seq.
Compare Hofifa, Sitzungsber. d. phys. med. Ges. zu Würzburg, pp. 101 and 102 :
1889.

^ Baumann and Gergens, Pfilüger's Arch., vol. lii. p. 205 : 1876.

INrECTION 411

physiological effects could not be properly tested. On the
other hand others, such as methylamin, dimethylamin, trime-
thylamin, tetramethylendiamin (putrescin), pentamethylendia-
min (cadaverin), &g., have been found to be quite innocuous.
The investigation of the last-mentioned products forms a
valuable contribution to the material for a future physiology of
bacterial metabolism.^ But so far it has added nothing to
our knowledge of the etiology and symptoms of infectious
diseases.

In the case of the poisonous bases, there is not always
sufficient evidence that the poison is due to the bases them-
selves and not merely to the impurities in them. Researches
up to the present seem to show that the more carefully the
bases are purified, the less action do they have on the animal
body. It is greatly to be desired that in ftiture all investiga-
tion on the metabolic products of microorganisms should be
confined to " pure cultures," both with the object of obtaining
an insight into bacterial changes as well as for the purpose of
increasing our knowledge of the etiology of infectious diseases.
In this way it could always be definitely ascertained by which
species of bacteria the material under examination was formed.
Another point of great importance is that the chemical compo-
sition of the nutrient medium before the introduction of the
bacteria should be accurately determined. A beginning to in-
vestigations of so exact but laborious a nature has already been
made by Brieger/ Roux and Yersin/ Löffler,* Kitasato and
Weyl/ Tizzoni and Cattani,^ Nencki and his pupils, besides
others.

If we now proceed to inquire whether the symptoms of
infectious diseases may really be explained from the known
toxic effects of the bases which have been isolated from the
bacterial products, we must acknowledge at once that it is
impossible to expect any absolute agreement. We may in-

^ To this group belongs also the compound isomeric with collidin, which
Nencki prepared from putrid gelatin, and which was the first of the organic bases
isolated from bacterial products. Nencki, " Ueb. die Zersetzung der Gelatine und
des Eiweisses b. d. Fäulniss mit Pankreas," Festschrift, Bern. p. 17: 1876. See
also S. Adeodato Garcia, Zeitschr. f. physiolog. Chem., vol. xvii., pp. 543-595 :
1893.

2 Brieger, " Weitere Unt. üb. Ptomaine," Berlin, 1885, p. 67, et seq., and
" Unt üb. Ptomaine," Dritter Theil, p. 84, et seq.: 1886.

* E. Roux et A. Yersin, Annales de V Institut Pasteur, Annee ii., p. 642 :
1888.

■^F. 'Lö^QY, Deutsch, med. Wochenschr., Jahrgang 16, p. 109: 1890.
5 S. Kitasato u. Th. Weyl, Zeitschr. f. Hygiene, vol. viii. p. 404 : 1890, and
Kitasato, idem, vol. x. p. 267 : 1891.

* Tizzoni u. Cattani, Arch. f. exper. Path. u. Pharm., vol. xxvii. p. 432:
1890.

412 LECTURE XXVII

deed anticipate the direction in which the main differences
will lie.

In the first place, the artificial production of the disease by
the injection of a substance already prepared from the patho-
genic microorganisms, does away with the first characteristic
of all zymotic disease — that of incubation. If the infection is
caused by the entrance of a small number of bacteria, a certain
time must naturally elapse before these can increase and enter
the circulation and the chief organs, to the disturbance of whose
functions the salient symptoms of the disease are due. Whereas
with the injection of a poison — especially of such a poison as
the bases of a soluble salt — the disturbances must commence
at once, and the whole series of symptoms must run a more
rapid course. Further, we must not forget that the injected
poison does not necessarily reach all the organs, tissues, and
cells which the bacteria do, and that on the other hand, the
bacteria may not enter all the parts where the poison may
penetrate by diffusion. Finally, we must take into considera-
tion that there is probably more than one poisonous product
from each species of pathogenic microbes, and that the various
symptoms of any given zymotic disease may be caused by dif-
ferent poisons, or by a combination of two or more poisons.
The artificial injection of a chemical individual might not pro-
duce these identical symptoms.

But even when we have made every allowance for possible
differences, it remains improbable that the alkaloids of putre-
faction which have up to the present time been examined, are
responsible for the symptoms of the various infectious diseases,
for the reason that they are not nearly poisonous enough. We
must remember that the body possesses in a marked degree the
faculty of getting rid of injurious substances of all kinds as they
are formed. In seeking an explanation for the symptoms of
zymotic disease we may therefore restrict ourselves to the poisons
of great virulence.

The toxic action of the alkaloids of putrefaction, of the
so-called ptomains and toxins, has been much exaggerated,
because small animals, and especially mice, were used for the
experiments. Now we must not forget that the bodyweight
of a mouse is only about 10-17 g. If for example we take
tetanin — a base which was first isolated by Brieger from the
metabolic products of the tetanus bacilli, and considered to be
the specific tetanus poison — we find that 3 eg. of the hydro-
chlorate is necessary to kill a mouse when subcutan eously
injected, i. e., 2-3 g. per kilo, bodyweight. In the case of a
guinea-pig (about | kilo.) 0.5 g. (therefore 1 g. per kilo.) had

INFECTION 413

" but little eß'ect " siibcutaneously ; the animal did not succumb/
Whereas, according to Tizzoni and Cattani/ y^th drop of the
tetanus cuture filtrate, i. e., of the nutrient fluid from which
the tetanus bacilli had been entirely removed by filtration, was
sufficient to cause the death of medium-sized rabbits from
tetanus. Vaillard and Vincent ^ state that 1 ccm. of the filtered
culture of the tetanus bacilli in broth contained only 0.025 g.
organic matter, and that this amount — of which the poison
formed but a fraction — was enough to kill a thousand guinea-
pigs, or a hundred thousand mice !

Similar observations have also been made with other pure
cultivations of pathogenic bacteria. The fluids in which the
bacteria have lived contain poisons of far greater virulence than
the alkaloids which have been isolated from them.

Ceaseless endeavors have during the last few years been
made to investigate these powerful poisons. Here again the
same difficulties were met with as in the attempt to isolate
ferments (vide Lecture XI. p. 159). The toxic substances
cannot be separated from certain proteids. The first author,
who came to the conclusion that the poison produced by the
bacteria " clung to the proteids " was Panum.* He says : " It
almost seems as if, led away by the desire to find a crystallized
body, the investigator had overlooked the fact that impurities
with crystallized foreign substances are as much impurities as
the presence of substances which prevent the crystallization of
a body.^

Roux and Yersin^ filtered broth cultivations of diphtheria
bacilli through clay cells : the filtrate was still effective, 2 cm.
killing a rabbit when injected subcutaneously. But it proved
inoperative after being heated for ten minutes to 100° C: 35
ccm. could be injected directly into the vein of a rabbit with-
out any injurious consequences. These authors therefore imag-
ine that the active constituent might be of a nature similar
to that of the hydrolytic ferments. In common with the fer-
ments, it likewise possessed the property of being carried

1 S. Kitasato u. Th. Weyl, Zeitschr. /. Hygiene, vol. viii. p. 407 : 1890.

''■ Tizzoni u. Cattani, Arch. f. exper. Path. u. Pharm., vol. xxvii. p. 437 : 1890.
Compare also S. Kitasato, Zeitschr. f. Hygiene, vol. x. p. 267 : 1891.

2 Vaillard et Vincent, Annates de P Institut Pasteur, Ann. V. p. 15 : 1891.

■*Panum, "Bibliothek for Laeger," vol. viii. pp. 253-285: 1856. Summa-
rized in Schmidt's Jahrb., pp. 213-217: 1859; and Virchow's Arch., vol. Ix. p.
334: 1874.

5 Virchoiv's Arch., vol. Ix. p. 332 : 1874.

6 E. Roux et A. Yersin, Ann. de V Institut Pastetcr, Annee II. p. 642: 1888;
and Annee III. p. 273 : 1889. Compare S. Dzierzgowski et L. de Rekowski,
Arch. d. Sciences Biolog., publ. par I'Institut imperial de Med. exp. a St. Peters-
bourg, vol. i. p. 167 : 1892.

414 LECTURE XXVII

down by neutral precipitates such as phosphate of lime. Sub-
cutaneous injection of 0.02 g. of such a moist precipitatCj con-
taining less than 0.0002 g. of organic substance, killed a
guinea-pig in the space of four days. The poison, although
capable of being dialyzed, has no eifect when taken into the
stomach.

Löffler ^ was able to obtain the active toxic principle from
meat-broth in which a pure culture of diphtheria bacilli had
been made, by the same method usually employed for isolating
ferments : i. e., extraction with glycerin and precipitation with
alcohol. The poison thus obtained, when injected subcutane-
ously into guinea-pigs, occasioned the same local symptoms as
did the inoculation with the bacilli themselves.

L. Brieger and C. Fränkel ^ made similar experiments with
cultures of diphtheria, typhus, tetanus, and cholera bacteria,
with staphylococcus aureus, with watery extracts from the
organs of animals which had died of anthrax. They invari-
ably found that the toxic properties were associated with
certain proteid precipitates, which were thrown down on the
addition of alcohol or of a concentrated solution of ammonium
sulphate. If heated above 60° C. the substances were ren-
dered innocuous, although they withstood evaporation to dryness
at 50°.

Wassermann and Proskauer ^ repeated these experiments of
Brieger and Fränkel, and prepared proteid precipitates from the
filtrates from pure cultivations of diphtheria bacilli. About 10
mg. of such a precipitate injected under the skin killed a rabbit
in about 3 to 4 days.

Tizzoni and Cattani * precipitated a proteid with sulphate of
ammonia from the filtrate of pure cultivations of tetanus
bacilli. 4 mg. of this proteid precipitate injected subcuta-
neously killed a rabbit weighing 2 kg. with " all the signs of
tetanus."

From filtered cultures of the same bacillus, Vaillard and
Vincent* also obtained a proteid, which was either thrown
down from watery solutions by alcohol, or was carried down by
neutral precipitates such as phosphate of lime. This proteid,
however was less poisonous than the filtrate of the pure

' Löffler, Deutsch, med. Wochenschr., Jahrg. 16, p. 109: 1890.

^ L. Brieger and C. Fränkel, Berlin. Hin. Wochenschr., Jahrg. 27, pp. 241
and 268 : 1890.

3 A. Wassermann and B. Proskauer, DeiUsch. med. Wochenschr., Jahrg. 17,
p. 585: 1891.

^ Tizzoni and Cattani, Arch. f. exper. Path. u. Pharm., vol. xxvii. p. 447 : 1890.

5 L. Vaillard and H. Vincent, Ann. d. l'Institut Pasteur, Annee V. pp. 15,
19-20: 1891.

INFECTION 415

cultures from which it was prepared. Of the latter an amount
containing only 0.000025 g. of organic substance sufficed to kill
a guinea-pig, whereas it took 0.00015 g., or six times more of
the proteid precipitate, to produce the same effect.^ In the
various procedures adopted for isolating the toxin therefore it
has become partially destroyed. Kitasato was likewise unsuc-
cessful in obtaining a precipitate which was more poisonous
than the filtered cultures from which he started. Here again
we have an analogy with the hydrolytic ferments. Fresh gas-
tric and pancreatic juices or freshly prepared extracts from the
gastric mucous membrane or pancreas are always more active
than the ferments isolated from them. The poisonous products
of bacteria are therefore, like the hydrolytic ferments, ex-
tremely labile compounds. The same observation was made
by Wassermann and Proskauer.^

Among the products excreted by the tubercle bacillus there
is likewise a substance which is precipitated by alcohol or by a
concentrated solution of ammonium sulphate and dissolves again
in water. On addition of acetic acid and sodium chlorid to the
watery solution, a precipitate is thrown down which disappears
on heating. The substance is diffusible ; it is soluble in gly-
cerin, and may be precipitated from this solution by alcohol.
The toxic eifect is connected with this substance which, to judge
from its reactions, belongs to the precursors of proteid, the so-
called albumoses. The subcutaneous injection of a small
amount (about 1 mg.) into a healthy person caused a rise of
temperature to 39.1° C. ; in a woman suffering from lupus, an
amount five times less produced a rise to 40.4° C.^

From a pure cultivation of streptococcus pyogenes, N.
Sieber* obtained an albumose precipitate, of which 0.013 g.
injected under the skin of a rabbit caused the temperature to
run up to 39.2-40.6°.

From all these facts it is evident that the most virulent
products of bacterial metabolism are either proteids or sub-
stances which have solubilities similar to those of the proteids,
and hence are precipitated with them. Most authors who have
worked on this subject adopt the former view, and therefore
call these poisonous substances toxalbumins.

1 S. Kitasato, Zeitschr. f. Hygiene, vol. x. p. 296 : 1891.

2 Loc. cit.

^E. Koch, Deutsch, med. Wochenschr., No. 3, and No. 43: 1891. Martin
Hahn (Nencki's Laboratory), Berl. klin. Wochemchr., No. 30: 1891. The
earlier work on tubercle toxin is here quoted. Compare M. C. Helman, Arch,
d. sciences biol., publ. par I'Institut imp. de Med. exp. ä St. Petersbourg, vol. i.
p. 139: 1892. O. Bujwid, idem, p. 213, and W. Kühne, Zeitschr. f. Biol., vol.
xxix. p. 24 : 1892, and vol. xxx. p. 221 : 1893.

*N. Sieber, Arch. d. sciences biol., vol. i. p. 285: 1892.

416 LECTUEE XXVII

The toxalbumins are not exclusively confined to bacterial
products, but have been also found to exist in the animal and
vegetable kingdoms. Thus all recent workers^ on the poisonous
secretion of snakes have come to the conclusion that the active
toxic principles belong to the group of proteids. The poison
contained in the blood-serum of the muranids is shown by
Mosso ^ to be of the same nature as snake-poison. This author
considers that this substance is probably a proteid, an opinion
likewise held by Kobert concerning the poison of spiders.^ The
large spider, Lathrodectes tredecimguttatus, which occurs in the
south of Russia, contains poison in all parts of its body, even in
its legs and undeveloped eggs. If this poison be introduced
directly into the blood, its effect is more potent than strychnin
or hydrocyanic acid, although it has no action in the stomach,
and is destroyed on boiling.

The toxalbumins again are distributed over the vegetable
kingdom. To this class apparently belong the intensely poi-
sonous constituents of the jequirity seed* {Abrus precatorius),
and that of Ricinus communis^ as well as the poison of a
fungus, the Amanita phalloides,^ all of which resemble the
toxalbumins in their chemical and physical behavior. If
injected intravenously, 0.5 mg. per kilo, bodyweight is suf-
ficent to cause death in the case of the poisonous principle of
the Amanita phalloides, and 0.01-0.02 in the case of that of the
jequirity seed.'^

As the toxalbumins and the hydrolytic ferments, the so-
called enzymes, present the same conditions of solubility,
besides possessing many other chemical qualities in common,

1 R. Norris Wolfenden, Journ. of Physiol., vol. vii. pp. 327 and 357 : 1886.
S. "Weir Mitchell and Edward Reichert, "Researches upon the Venoms of
Poisonous Serpents." Smithsonian Contributions to Knowledge, 647, p. 186:
Washington, 1886. Brieger and Fränkel, Bcrl. klin. Wochenschr., Jahrg. 27,
p. 271 : 1890.

2 A. Mosso, Acad, dei Lincei, vol. iv. p. 665 : 1885 ; and Arch. f. exper. Path.
u. Pharm., vol. xxv. p. Ill : 1889. U. Mosso, Eendiconti delta r. Acad, dei
Lincei, p. 804: 1889.

^ Kobert, Sitzungsher. d. Naturforscher- Gesellsch. zu Dorpat, vol. viii. pp.
362 and 440: 1889.

■* Sidney Martin and R. Norris Wolfenden, Proc. Roy. Soc, London, vol.
xlvi. pp. 94 and 100: 1889. Sophie Glinka, " Beitr. z. Kenntniss d. giftigen
Princips d. Jequiritysamen," Diss., Bern. : 1891. The earlier literature is here
quoted. Nencki, Schweizer Wochenschr. f. Pharmacie, No. 29 : 1891. Reprint,
p. 5, Heinr. Hellin, "Der giftige Eisweisskörper Abrin.," Diss., Dorpat: 1891.
P. Ehrlich, Deutsch, med. Wochenschr., No. 44: 1891.

5 H. Stillmark, " Ueber Ricin," Diss., Dorpat: 1888. P. Ehrlich, Deutsch,
raed. Wochenschr., No. 32 : 1891.

8 Kobert, Sitzungsher. d. Nat. Ges. zu Dorpat, vol. ix. p. 541 et seq. : 1891.
This author gives a summary of our present knowledge concerning the various
poisons in the different fungi.

' Kobert, idem, vol. ix. pp. 116 and 553 : 1891.

INFECTION 417

it was fair to assume that they also shared the same poisonous
properties. Roussy ^ found that intravenous injection of in-
vertin in dogs gave rise to fever, less than ^ rag. to 1 kilo, body-
weight being sufficient to cause a rise of temperature to 42° C.
H. Hildebrandt ^ showed that the subcutaneous injection of
larger quantities (0.1 g.) of pepsin, invertin, diastase, was fatal
to medium-sized rabbits, the animals succumbing in 2 to 4
days. After doses of between 0.05 and 0.1 g. the animals did
not die until after the lapse of one or more weeks. With
emulsin and my rosin a dose of 0.05 g. was always fatal in 2
to 4 days. In dogs relatively larger amounts of pepsin and
invertin (0.1 to 0.2 g. per kilo.) were required to cause death.
In all the experiments there was a rise of temperature amount-
ing on the average to 2° C.

We might now ask : If the hydrolytic ferments have a
toxic action, might not the toxalbumins have an hydrolytic
action, and perhaps by this very means develop their poisonous
properties in the tissues? This does not however appear to
be the case. Direct experiment has shown that the diphtheria
and tetanus toxins do not act hydrolytically.^

It has frequently been stated that certain products of
artificial proteid digestion, certain peptones and their pre-
cursors, the so-called albumoses, have a poisonous action.*
This action is only produced on direct introduction of these
substances into the blood, probably for the reason that in the
passage through the intestinal wall the peptones are recon-
verted into proteids. But even in the former case the toxic
effects — narcosis and lowering of the blood-pressure — are only
brought about by very large doses — 0.3 g. per kilo, body-
weight. The poison is therefore not of a violent nature. It
is possible that both with these digestive products of the
proteids as well as with the enzymes, the toxic effect is to be
ascribed to an admixture of toxalbumins arising from bac-
terial metabolism. It is highly desirable that the experiments
should be repeated with absolutely sterilized material under
strict antiseptic precautions.

In the foregoing remarks we have enumerated the various

^ Roussy, Gaz. des Hop., No. 19 and No. 31 : 1891. Compare the appreciation
of this work presented to the Acad, by Schiitzenberger, Gautier, and Hayem :
Bull. d. I'Acad. de 3Ied., Serie 3, vol. xxii. p. 468 : 1889.

2 H. Hildebrandt, Virchotv's Arch., vol. cxxi. p. 1 : 1890.

* L. Vaillard and H. Vincent, Annates d. V Institut Pasteur, Ann. 5, p. 20 :
1891.

4 Schmidt-Mülheim, Du Bois' Arch., pp. 50-54 : 1880. Fano, idem, p. 277 :
1881. W. Kühne and Pollitzer, Verhandl. d. nat.-med. Vereins zu Heidelberg^
N. F., vol. iii. p. 292 : 1886. R. Neumeister, Zeitschr. f. Biol., N. F., vol. vi. p.
284 : 1888.

27

418 LECTURE XXVII

properties which the toxalbumins and the enzymes have in
common. There are however differences not only between
the toxalbumins and the enzymes but among the toxalbumins
themselves. A few of the latter are, like the globulins,
insoluble in water, as for instance the poisonous proteid
precipitates obtained from cultures of typhus bacilli and
staphylococcus pyogenes aureus. Most of the toxalbumins
however are, like £he ferments, soluble in water, but not
dialyzable. An exception to this is formed by the poison of
the rattlesnake,^ as well as of the tubercle bacillus, both of
which are dialyzable. Tetanus and diphtheria poisons dialyze
slowly.

A temperature of over 50° C. causes many of the solu-
tions of toxalbumin to lose their virulence ; but there are
some which will stand heating to 60° and higher, or
even for a short time to 100° C, as for instance the
poison of the Indian cobra and the toxalbumin of the tuber-
cle bacillus. We may assume perhaps that the toxalbumins
which are rendered innocuous by boiling belong to the pro-
teids properly so-called, whereas those which are not aifected
by this temperature may be referred to the peptons.^ If this
assumption be correct, we should expect to find that the tox-
albumins which are not affected by boiling are dialyzable.
This is the case with tubercle. When in a dry condition the
toxalbumins, like the ferments, can be raised to a high tem-
perature (e. g., certain snake poisons to 115° C.) without losing
their virulence.

Absolute alcohol has no effect on some of the toxalbumins,
e. g., the snake-poison, but others again it gradually renders
ineffective. Thus, according to Kitasato, the tetanus poison
loses its power if it be exposed to the action of 70 per cent,
ethyl alcohol for one hour or to that of 60 per cent, for twenty-
four hours.

Alkalies and acids weaken or destroy the operation of
many toxalbumins. The poisonous effect of snake-venom is
diminished by alkalies. Tetanus poison is destroyed by free
alkalies : a 0.3 per cent, solution of sodium hydrate, or a 3.7
per cent, solution of sodium carbonate will accomplish this in an
hour ; a 1 per cent, solution of ammonia must be allowed twenty-
four hours. Again, a solution of 0.365 per cent, hydrochloric
acid will take twenty-four hours, and one of 0.55 per cent, one
hour to destroy the tetanus poison. The toxin of muranids is

^ W. Heidenschild, " Unt üb. d. Wirkung d. Giftes d. Brillen- u. Klapper-
schlange," Diss., Dorpat : 1886.

2 S. Weir Mitchell and E. T. Reichert, loc. cit.

INFECTION 419

deprived of its activity by the action of acetic or hydrochloric
acid, or by that of gastric juice. If however the poisonous
serum be injected through the abdominal wall into the small
intestine, death ensues. I mentioned above that the poison of
spiders as well as the tubercle and tetanus toxins were innocuous
when introduced into the stomach.

Before leaving the consideration of the toxalbumins, I
must mention one observation which may perhaps have a very
wide bearing. Of late years many communications have been
made concerning the existence in normal blood of proteids
which behave towards certain bacteria like toxalbumins. An
attempt has been made to explain the phenomena of immunity
in this way, but the data are not yet sufficiently precise to per-
mit of a connected account.^

1 For a summary of the literature on this subject see R. Stern, Zeitschr. f.
Hin. lied., vol. xviii. p. 46: 1891. Compare also the Address given at the 11th
Congress for Clinical Medicine at Leipzig by H. Büchner, and printed in the
JBerl. klin. Wochenschr., No. 19 : 1892 : and H. Büchner, Arch.f, Hygiene, vol.
xvii. pp. 112, 138: 1893; G. Tizzoni u. J. Cattani, Berl. klin. Wochenschr.,
Nos. 49-52: 1893; and Nos. 3: 1894; M. Hahn, "Ueb. d. Beziehungen d.
Leukocyten z. bactericiden Wirkung d. Blutes," Pro venia legendi, München :
1895.

LECTURE XXVIII

FEVER

Almost all forms of infection lead to the complex of symp-
toms which we term fever. Of these symptoms the rise of
temperature is, as we know, the most readily measured and has
therefore been the subject of the most thorough investigation.
Teleologically this rise of temperature may be explained on the
assumption that by its means the pathogenic microorganisms
are killed, or at least arrested in their development, and their
pathogenic properties weakened.

Thus Heydenreich ^ observed that the spirilla of recurrent
fever lost their mobility much more readily at 40° C. than at
70° C. According to R. Koch ^ the most favorable tempera-
ture for the tubercle bacillus lies between 37° and 38° C. When
kept at 42° C. for three weeks, its further development is
impeded. For the gonococcus-Neisser the optimum tempera-
ture is between 33° and 37 C.^ A temperature of 39° C. kills
it in twenty-four hours, and one of 42° in twelve hours.* De
Simone^ found that the multiplication of the streptococcus
erysipelatosus stopped entirely at 39° to 40° C, and that the
organism died at 39.5° to 41 ° C Bard and Aubert ^ found that
of the medley of bacteria in the feces, all of them disappeared,
with the exception of the bacillus coli communis, under the
prolonged action of fever temperature. According to Fränkel "^
the virulence of the septicemic cocci of the sputum is entirely
abolished by growing it for two days at 42° C, or for four to
five days at 41° C. Pasteur^ discovered that anthrax bacilli,

* Heydenreich, Centralbl. f. d. med. Wissensch., No. 28: 1876.

*R. Koch, "Zur Aetiologie der Tuberculose," illfrWÄ. a. d. kais. Gesund-
keitsamte, vol. ii.: 1894.

* Bumm, " Der Micro-organismus d. gonorrhoischen Schleimhauterkrankung
Gonococcus-Neisser," Wiesbaden: 1887.

* Finger, Verh. d. deutsch. Dermatolog. Ges., IV. Congress, p. 181 : 1894.
6 Fr. de Simone, II Morgagni, Nos. 8-12 : 1885.

«L. Bard and P. Aubert, Gaz. hebdom. d. Mid. et de Chirurg., No. 35, p.
418 : 1891.

'A. Fränkel, Zeitschr.f. Hin. Med., vol. x. Hft. 5 and 6 : 1886.

* Pasteur in collaboration with Chamberlain and Roux, Comptes rend., vol.
xcii. pp. 422, 662, 666, and 1379: 1881. Compare R. Koch, "Zur Aetiol. d.

420

FEVER 421

after being exposed for some time to a temperature of 42° to
43° C, lost their pathogenic character, and that animals when
inoculated with the bacilli in this condition became immune
to the actual disease. G. and F. Klemperer^ heated broth-cul-
tures of pneumococci for two to three days to 41° to 42° C,
and found that when they were injected into rabbits the latter
were rendered immune to the infection of pneumococci.

These results not only explain the significance of fever
but also indicate how immunity may occur after infectious
diseases. In this connection we must remember that in fever
the average temperatures only are taken, and it is quite possible
that in certain tissues, and perhaps more esjsecially in those
parts where the bacteria most abound, the temperature runs
up to a much higher level. The rise of temperature in fever
would therefore be one of the processes of self-protection and
self-regulation, of which we have so many examples in the
body.^ This view concerning the significance of fever tempera-
tures is not contradicted by the fact that some of the pathogenic
organisms are able to withstand considerable rise of temperature.
For instance the temperature of 42 ° C. does not kill the typhoid
bacillus, and only slightly impedes its rate of propagation.
The typhoid bacilli must be exposed to a temperature of about
44.5° C. for a considerable time before any appreciable number
are killed.^

With regard to the mechanism by which the rise of tem-
perature is brought about, it was first considered that it was prob-
ably due to an increased metabolism. Alfred Vogel, * adopting
Liebig's titration method in 1854, found that the nitrogenous
excretion was augmented in cases of febrile diseases. This

Milzbrandes," Mitth. a. d. kais. Gesundheitsamt., vol. i. : 1881 ; and Arloing,
" Les virus," Paris : 1896.

^ G. and F. Klemperer, Berl. klin Wochenschr., Nos. 34 and 35 : 1891.

^ If this interpretation of the significance of fever be correct, the treatment
of febrile disorders by means of cold baths and antipyretic remedies would appear
to be a bad one. For information on these debated questions the following
articles may be recommended : Unverricht, Deutsch, med. Wochenschr., Jahrg,
13, pp. 452 and 478 : 1887 ; and Jahrg. 14, pp. 749 and 778 : 188 ; Liebermei-
ster, idem, vol. xiv. pp. 1 and 26 : 1888 ; Naunyn, Arch. f. exper. Path. u. Pharm..
vol. xviii. p. 49 : 1884; Arnaldo Cantani, "Ueb.Antipyrese," Vortrag, Verhandl.
d. X. internat. med. Congresses, Berlin, Hirschwald, p. 152 : 1891. A critical
account of the literature on the action of the antipyretic remedies is given by
Gottlieb, Arch. f. exper. Path. u. Pharm., vol. xxvi. p. 419: 1890; vol. xxviii.
p. 167 : 1891. Compare also A. Loewy and P. F. Richter, Deutsch, med. Woch-
enschr., No. 15, p. 240 : 1895 ; and Virchow's Arch., vol. cxlv. p. 49 : 1896.

'Max Müller, "Ueb. d. Einfl. v. Fiebertemp. a. d. Wachsthumgeschwind-
igkeit u. d. Virulenz d. Typhus bacillus," Diss., Breslau: 1895; reprinted from
the Zeitschr. f. Hygiene u. Infectionskrankheiten, vol. xx.

^A. Vogel, Zeitschr. f. ration. Med., N.F., vol. iv. p. 362: 1854; and "Klin-
ische Unt. Ü. d. Typhus," Erlangen : 1860.

422 LECTURE XXVIII

statement was subsequently confirmed by many observers.^ At
the same time elimination of the sulphuric acid is correspond-
ingly increased, as might have been expected.^

Liebermeister ^ and Ley den* found that the output of COj
was also increased in fever. These observations on man were
confirmed by experiments on animals carried out by different
observers/ and it was moreover ascertained that an increased
amount of oxygen was taken in as well as a larger amount of
carbonic acid eliminated.^

It is however doubtful whether this heightened metabolism
is the cause of the rise in temperature. In the first place, we
know that in a normal person a very considerable increase in
metabolism may occur (e. g., in strenuous muscular work) with-
out any rise of temperature, since the body possesses various
means of compensating for the increased heat production by
increasing the heat loss. In the second place, the metabolism
is not quickened in all fevers. Numerous experiments on man
and on animals have shown that in some cases of fever the
intake of oxygen and the output of carbonic acid remains the
same or is even less than normal.''

The rise of temperature must therefore have some other
cause than merely the increase of metabolism. There is only
one other theory left, i. e., that there is less heat given off.
This idea was warmly supported by L. Traube,^ who taught that

^ An account of the comprehensive literature is given by Senator, " Unt. üb.
d. fieberhaften Process," Berlin, 1873, p. 94 et seq.; and by Naunyn, Arch. f.
exper. Path. u. Pharm., vol. xxviii. p. 49 : 1884. Compare also L. Riess, Virchow's
Arch., vol. xiii. p. 127 : 1886 ; Hirschfeld, Berl. klin. Wochenschr., No. 2 : 1891 ;
G. Klemperer, Deutsch, med. Wochenschr., No. 15 : 1891.

- Fiirbringer, Virchow's Arch., vol. Ixxiii. p. 39 : 1878.

^ Liebermeister, Deutsch. Arch. f. Hin. Med., vol. vii. p. 75 : 1870 ; and vol.
viii. p. 153: 1871; "Handbuch d. Patholog. u. Therapie d. Fiebers," Leipzig:
Vogel, 1875.

*Leyden, Deutsch. Arch. f. klin. Med., vol. v. p. 237: 1869; and vol. vii.
p. 536: 1870. Centralbl. f. d. Med. Wissensch., No. 13: 1870.

s Silujanoff, Virchow's Arch., vol. liii. p. 327 : 1871 ; A. Fränkel, Verhandl.
d. physiolog. Gesellsch. z. Berlin, 4th Feb. 1894; E. Leyden and A. Fränkel,
Centralbl. f. d. med. Wissensch., p. 706: 1878; Virchow's Arch., vol. Ixxvi. p.
136: 1879.

® Colasanti, Pflilger's Arch., vol. xiv. p. 125 : 1876 ; D. Finkler, idem, vol.
ixix. p. 89 : 1887 ; A. Lilienfeld, idem, vol. xxxii. pp. 293-356 : 1883.

' Senator, Virchow's Arch., vol. xlv. p. 351 : 1869. " Unt. üb. d. fieberhaften
Process u. seine Behandl.," Berlin, Hirschwald, 1873. Du Bois' Arch., p. 1 :
1872; 'W^rth^im, Deutsch. Arch. f. klin. Med., vol. xv. p. 173: 1875. Wiener
med. Wochenschr., Nos. 3-7, 1876 ; Nos. 32, 34 and 35, 1878. Fr. Kraus, Zeitschr.
f. klin. Med., vol. xviii. p. 160 : 1891. A. Loewy, Virchow's Arch., vol. cxxvi.
p. 218 : 1891.

* L. Traube, Allgem. med. C'entralzeitung, July 1, July 8 and Dec. 22, 1863,
and March 23, 1864. " Ges. Beiträge z. Patholog. u. Physiolog.," Berlin, Hirsch-
wald, vol. ii. pp. 637 and 679 : 1871. A list of the numerous authors who prior
to Traube have put forward the theory of diminished heat loss in fever, although

TEVER 423

in fever a constriction of the peripheral blood-vessels occurred
with diminished flow of blood to the skin, so that there was
diminished heat loss, accompanied by congestion in the interior
of the body. By means of Mosso's Plethysmograph, Maragliano
showed that in various febrile diseases the cutaneous vessels
contracted, and moreover that they commenced doing so be-
fore the rise of temperature was perceptible. As contraction
continued, the temperature began to rise, both reaching the
maximum at the same time. An expansion of the blood-vessels
preceded the fall in temperature, which came down to normal
while the blood-vessels were still maximally dilated.^

The diminished loss of heat, especially in the first stages of
fever, has, with the help of the calorimeter, been proved by
many observers from direct experiments on man and animals.^

Many unsuccessful attempts have been made to decide ex-
perimentally what part the nervous system takes in the increased
metabolism and the diminished loss of heat. Numerous ex-
periments on animals have shown that by mechanical injury or
electrical stimulation of certain parts of the brain — e. g., the
median portion of the corpus striatum, &c., a lasting rise of
temperature may be induced, accompanied by increased metab-
olism. But this is a different process from that involved in
fever, since there is neither contraction of the blood-vessels nor
diminished loss of heat.^

Of the two factors which bring about a rise of temperature
in fever, i. e., the increased production of heat by more rapid
metabolism and the diminished loss of heat, the latter is
certainly the more important, since, as I have already men-
tioned, a febrile condition may occur in the absence of the first
factor. Some authors indeed have gone so far as to regard
the first factor, increased metabolism, as the consequence and

perhaps not in so clear and decisive a manner, will be found in Maragliano,
Zeitschr. f. klin. Med., vol. xiv. p. 309 : 1888, where a careful notice of the
literature on the subject is also given.

' Maragliano, loc. cit., pp. 316-319.

* Senator, " Unt üb. d. fieberhaften Process u. seine Behandlung." Berlin,
Hirschwald, 1873. Carl Rosenthal, Du Bois' Arch., p. 1 : 1888. J. Rosenthal,
Berlin, klin. Wochenschr., p. 785: 1891, and "Internat. Beiträge z. wissen-
schaftl. Med.," Festschrit., R. Virchow gewidmet. Berlin, Hirschwald, vol. i.
p. 413 : 1891.

^ Further discussion of these experiments would be beyond the scope of this
text-book. For further references I will mention : J. Ott, Journ. of Nervous
and Mental Diseases, 1884, and Therapeutic Gazette, Sept. 15, 1887 ; The Medical
News, Dec. 10, 1887; Aronsohn and Sachs, Pflüger' s Arch., vol. xxxvii. p. 232 :
1885; H. Girard, Arch, de Physiol., Serie III. vol. viii. p. 281 : 1886 : and Serie
IV., vol. i. pp. 312, 463 : 1888 ; Hale White, Journ. Physiol., vol. ii. Nos. 1 and 2
1890 ; Ugolino Mosso, Arch. f. exper. Path. u. Pharmakol., vol. xxvi. p. 316 :
1890.

424 LECTURE XXVIII

not as the cause of the rise in temperature, since direct
experiments on animals and on man have sho"\vn ithat, if the
temperature be artificially raised and the loss of heat be at the
same time prevented by warm baths, the excretion of urea is
increased.^

It is however very doubtful whether this increase in urea
observed with an artificial rise of temperature is a sufficient
explanation of the large quantity of additional urea eliminated
in fever. The increase of urea brought about by artificial
means was always much less than that in fever, and, in fact,
in some experiments it did not occur at all." Moreover the
theory that increased metabolism is due to the rise of tem-
perature is belied by the fact that the increased nitrogenous
excretion in fever does not run parallel with the heightened
temperature, but usually reaches its maximum after the crisis.^
In many cases the rise of temperature is only slight during the
febrile stage, and yet there is a large increase in the urea
excretion after the fever has abated. In one case of recurrent
fever 47.8 g. of urea were excreted on the second day after the
crisis,* in a case of typhus exanthematicus 160 g. of urea on the
third and fourth days after the temperature had fallen.^ Occa-
sionally in diseases dae to infection the proteid disintegation may
even precede the rise of temperature.*' Schimauski ^ showed that,
if pus was injected into fowls, there was frequently no alteration
in temperature, although a large additional amount of nitrogen
was excreted. LilienfekP found that after pyogenic injec-
tions an increase in the intake of oxygen and output of carbonic
acid occurred, even when the rise of temperature was prevented
by cold baths.

From these experiments we see that the increase in metab-
olism is not a consequence of the rise of temperature. On
the other hand, it is not improbable that the increased metab-
olism— especially in the later stages of the febrile process — may

■! Bartels, Griefswalder med. Beitr., vol. iii. p. 36 : 1865 ; Naunyn, Berl. klin.
Wochenschr., p. 42 : 1869 ; Du Bois' Arch., p. 159 : ,1870 ; Schleich, Arch,
f. exper. Path. u. Pharm., vol. iv. p. 82 : 1875 ; P. Pächter, Virchow's
Arch., vol. cxxiii. p. 118 : 1891 ; R. Topp, Therapeut. Ifonatshefte, pp. 1, 55 :
1894.

2 C. F. A. Koch, Zeitschr. f. Biol., vol. xix. p. 447 : 1883 ; N. P. Simanow-
sky, Zeitschr. f. Biol., vol. xxi. p. 1 : 1885.

3 Anderson, Edinh. Med. Journ., p. 708 : Feb. 1866. Compare Wood and
Marshall, Journ. of Nerv, and Meat. Diseases, No. 1 : 1891.

•* A. Pribram and J. ßcbitschek, Prag Vierteljahr sschr., vol. civ. p. 318 :
1869.

^ Naunyn, Arch. f. exper. Path. u. Pharm., vol. xviii. p. 83 : 1884.
^ Sydney Pi,inger, Lancet, Aug. 6, 1859.

' Schimauski, Zeitschr. f. physiol. Chem., vol. iii. p. 396 : 1879.
« A. Lilienfeld, Pfläger's Arch., vol. xxxii. p. 293 : 1883.

FEVER 425

be partly referred to the death of the aifected tissues, which must
be got rid of when they have undergone disintegration. This
death of individual tissue-elements may be traced by direct
anatomical observation.^

The red blood-corpuscles are among the elements which are
destroyed in this way, as evidenced by the production of a larger
amount of urobilin.^ (Compare pp. 323, 339.) The leuco-
cytes, on the other hand, are usually augmented in most of the
zymotic diseases, as in the case of many other disturbances,
which are connected with increased disintegration of the tissues.
It appears that the object of the multiplication of the leucocytes
is to render the waste-products harmless. Direct experiments
have shown that the number of leucocytes rises on the introduc-
tion of foreign substances of the most varied nature into the
body.^

There is probably a connection between the increased dis-
integration of proteid and the occurrence of organic acids —
volatile fatty acids* and lactic acid^ — as well as the diminution
of the alkalescence of and the carbonic acid in the blood, and
the passage of aceton, aceto-acetic acid, oxybutyric acid,^ and
volatile fatty acids '^ into the urine. (Compare pp. 391, 392.)
The amount of carbonic acid in the arterial blood may sink to
10.7 vol. per cent.® The increased elimination of ammonia in
fever (which may rise to as much as 2.7 g. per diem^) may be
connected with the increased formation of these organic acids.
(Compare pp. 292, 404.) The appearance of acids in the blood,
the diminution of the alkalescence and of the carbonic acid have
been likewise observed as results of the action of inorganic

^ These experiments are described by Liebermeister, " Handb. d. Patholog. u-
Therap. d. Fiebers.," chap. iv. p. 437, Leipzig, Vogel : 1875.

2 G. Hoppe-Seyler, Virchow's Arch., voL cxxiv. p. 30: 1891; and vol.
cxxviii. p. 43 : 1892. In the former volume all the previous work on the occur-
rence of urobilin in disease is collected.

3 An account of the complete and comprehensive literature on the behavior of
the leucocytes is given in the monograph of H. Rieder, " Beitr. z. Kenntniss d.
Leukocytose," Leipzig, Vogel : 1892. Compare also Lecture XV. p. 222.

* von Jaksch, " Klinische Diagnostik," 2d edition, p. 59 : 1889.

^ Minkowski, Arch. /. exper. Path. u. Pharm., vol. xix. p. 209 : 1885.

^ Deichmüller, Centralbl. f. klin. 3Ied., No. 1: 1882. Seifert, Verhandl. d-
Würzburger phys.-med. Ges., vol. xvii. p. 93: 1883. Liitten, Zeitschr. f. klin.
Med., vol. vii. Suppl. p. 82: 1884. Penzoldt, Deutsch. Arch. f. klin. Med., vol.
xxxiv. p. 127: 1884. v. Jaksch, " Ueb. Acetonurie u. Diacetonurie," Berlin:
1885. Kiilz, Zeitschr. f. Biolog., vol. xxiii. p. 336 : 1887.

■^ von Jaksch, Zeitschr. f. physiol. Chem., vol. x. p. 536 : 1886.

* Jul. Geppert, Zeitschr. f. klin. 3Ied., vol. ii. p. 355 : 1881. Compare also
Minkowski, loc. cit.

3 Hallervorden, Arch. f. exper. Path. u. Pharm., vol. xii. p. 249 : 1880. This
author also quotes the earlier work of Duchek and Koppe. Compare also
Bohland, i^üö'er's Arch.,Yo\. xliii. p. 30: 1888; and G. Gumlich, ZeiYscAr. /.
physiol. Chem., vol. xvii. p. 30 : 1892.

426 LECTURE XXVIII

poisons, such as arsenic, phosphorus, &c. ; ^ and it appears
therefore as if the toxins, which are the metabolic products of
the pathogenic bacteria and which occasion the febrile zymotic
diseases, involve a similar disturbance in the chemistry of the
blood.

Albuminuria,^ although not an invariable, is yet a frequent
accompaniment of high fever. Its connection with the other
changes in the chemistry of fever is not yet explained. It
would be an obvious assumption that the kidneys, in endeavor-
ing to rid the organism of the infective substances or even of
the pathogenic microorganisms themselves, become irritated by
these poisons which thus produce albuminuria. It has in fact
been stated that poisonous substances are to be found in the
urine of febrile patients.^ Brieger and Wassermann,* in exam-
ining the urine of a case of erysipelas, succeeded in isolating
a toxalbumin which had a poisonous effect on guinea-pigs.
The disease in which the pathogenic bacilli themselves have, so
far, been found in the kidneys are pyemia, anthrax, glanders,
diphtheria, scarlet fever, erysipelas, pneumonia, typhoid, and
recurrent fever.^ In typhoid, the specific bacteria were found
by Konjajeff ^ occasionally in the urine, as well as in the kid-
neys. In eleven out of forty-eight cases of the same malady,
Neumann^ detected bacilli in the urine. Karlinski^ asserts
that the typhoid bacilli can be detected far more readily in the
urine than in the feces. Whereas in the latter they could not
be discovered until the ninth day of the disease, they were fre-
quently found in the urine as early as the third day. Bacilli
were found in twenty-one out of forty-four cases.

There is another change which often occurs in the metabol-
ism in febrile diseases, i. e.,the diminution, often very remarkable,
in the excretion of chlorin. This substance sometimes almost

^Hans Meyer and Fr. Williams, Arch. f. exper. Path. u. Pharm., vol. xiii.
p. 70: 1881. Hans Meyer, idem, vol. xiv. p. 313: 1882; and vol. xvii. p. 304:
1883.

2 The literature is given by Senator, " Die Albuminurie," 2d edition, Berlin,
Hirschwald: 1890. Compare also Hiibener, "Ueb. Albuminurie b. Infections
krankheiten," Diss., Berlin: 1892.

3 The following works may be selected from the voluminous literature :
Bouchard, "Legons sur les auto-intoxications," Paris: 1887. F. Selmi, Accad.
d. scienze di Bologna, 1879 ; and Ann. di chim. e. di farm., vol. viii. p. 3 : 1888.
Compare also the discordant results of E. Bonardi, Riv. clinica, p. 389 : 1890.

* Brieger and Wassermann, Chariti-Annalen, Jahrg. 17, p. 834 : 1892.
»Eibbert, Deutsch, med. Wochenschr., No. 39, p. 805: 1889. This author

quotes the literature on this subject.

^Konjajeff, Jescheniedielnaja klinitscheskaja Gazeta, Nos. 33-38: 1888.
Summarized in Centralhl. f. Bacteriolog. u. Parasitenkunde, vol. vi. p. 672 : 1889.

'H. Neumann, Berlin, klin. Wochenschr., No. 6: 1890.

* J. Karlinski, Prag. med. Wochenschr., Nos. 35 and 36 : 1890.

FEVER 427

entirely disappears from the urine in cases of croupous pneu-
monia. ^ This symptom is however merely temporary, and
does not last more than three days at the most.^ No one has
yet succeeded in explaining this phenomenon or of determining
its connection with the other symptoms of fever.

* J. F. Heller, Helleres Arch. f. physiol. u. patholog. Chem. u. Mikroskop.
vol. iv. p. 523 : 1847; Kedtenbacher, Zeitschr. d. Ges. d. Atrzte in Wien., p. 373 :
1850; S. Moos, Zeitschr. f. rat. Med., N. F., vol. vii. p. 291: 1855; E. Unruh,
Virchow's Arch., toI. xlviii. p. 227 : 1869 ; Röhmann, Zeitschr. f. klin. Med., vol.
i. p. 513: 1880; E. Klees ("Over chloorvermindering in de urine," &c., Diss.,
Amsterdam : 1885) attempts to show that the diminished excretion of chlorin in
acute diseases is connected with a disturbance in the renal function (albu-
minuria).

* C. G. Lehmann, Lehr. d. physiol. Chem., vol. ii. p. 392, Leipzig : 1850.

LECTURE XXIX

THE DUCTLESS GLANDS : THE SUPRARENAL CAPSULES, THE
THYROID GLAND, THE PITUITARY BODY

There are three organs in our body which have the epithe-
lial structure of glands, but are without ducts : the suprarenal
capsules, the thyroid gland, and the pituitary body. If we
would attribute to these organs functions similar to those of
the glands, we must assume that they obtain from the blood
certain substances which undergo alteration in their epithelial
cells, the products of conversion being again returned to the
blood. These changes must be of the greatest importance in
the vital process, since extirpation of the suprarenal capsules
as well as of the thyroid gland is followed by the death of the
animal upon which the experiment is made.

In consequence of the well-known discovery, published
in 1855 by Addison,^ concerning the relation of bronzing
of the skin to disease of the suprarenal capsules, Brown-
S^quard^ investigated the results of the extirpation of these
organs in animals. He showed that such animals as rabbits,
guinea-pigs, cats, dogs and mice never survived the excision of
both suprarenals for more than two days at the most. After
the removal of only one suprarenal they lived for a longer time,
and Brown-S^quard considered that they might possibly be
kept permanently alive. This author endeavored by numer-
ous experiments to prove that death after excision of both
suprarenal capsules was not brought about by the operative
interference — the animals survived extirpation of the kidneys
longer than they did that of the organs under discussion — nor
by the injury done to the numberless nerve-fibers which run
from the suprarenals to the plexus semilunaris, but to the
abolition of the suprarenal functions. He showed that if the
blood of an animal, which was dying in consequence of the
removal of its suprarenal capsules, were injected into a vein

^Thos. Addison, "On the constitutional and local effects of disease of the
suprarenal capsules" : London, 1855.

^E. Brown-Sequard, Comjyies rendus, vol. xliii. pp. 422 and 542: 1856; and
vol. xiv. p. 1036 : 1857.

428

THE DUCTLESS GLANDS 429

of another animal in whom only one of these organs had been
cut out, the death of the second animal was hastened. Again,
if the blood of a normal animal were injected into a vein of an
animal, which was dying from the effects of excision of both
suprarenals, the life of the latter was prolonged.

Brown-Seqnard is therefore the founder of the modern
doctrine concerning the functions of the ductless glands, i. e.,
that these glands convert injurious into harmless substances
and produce the substances which are necessary for the normal
functioning of other organs. This work of the ductless glands
is termed "internal secretion." We may however here remark
that, besides the preparation of the secretions which are dis-
charged by the ducts, the glands properly so called may also
be forming an important internal secretion, as already proven
in the cases of the pancreas (p. 400) and liver (p. 334).

These operations of Brown-S§quard have been more recently
repeated with aseptic precautions, and the results confirmed.^
The animals experimented upon never survived extirpation of
both suprarenals for more than a few days. A different result
was however obtained by J. Pal,^ who succeeded in keeping a
dog alive for 4J months after excision of both suprarenals.
Pal controlled his experiments by an autopsy, thus removing
the obvious objection that the excision might have been incom-
plete. We must also take note of the statement that rats are
not affected by excision of the suprarenals.' In one of the
latest researches on the subject by Szymonowicz* however this
author declares his conviction that dogs never survive the ex-
tirpation of both capsules for more than fifteen hours at the
most, and that the statements of previous experimenters to the
contrary were either due to incomplete excision or to the fact
that accessory suprarenals were left behind.

Investigation of the functions of the suprarenal capsules is
rendered peculiarly difficult owing to the fact that this organ is
rich in sympathetic ganglion cells, from which numerous fibers
pass to other parts of the sympathetic nervous system. For
this reason operations on the suprarenals cause indirect disturb-
ances of the most varied nature.^

1 F. and S. Marino-Zucco, Atti della H. Accad. dei Lincei, S. V., toI. i. p.
122: 1894; Riforma med., vol. i. p. 709: 1894; E. Abelous and P. Langlois,
Comptes rend. Soc. biol., vol. xliv. pp. 165, 388, 410, 490, 864 : 1892. L. Szy-
monowicz, Pfliiger's Arch., vol. Ixiv. p. 97 : 1896.

2 J. Pal, Wien. klin. Wochenschr., p. 899: 1894.

3E. Boinet, Comp. rend. Soc. biol., vol. xlvii. pp. 273, 325, 498: 1895.

•*L. Szymonowicz, Pfliiger's Arch., vol. Ixiv. p. 97 : 1896.

5 G. Tizzoni, Arch. ital. de Biolog., vol. vii. p. 372 : 1888. G. Jacoby, Arch,
f. exper. Path. u. Pharm., vol. xxis. p. 171 : 1891. N. de Dominicis, Arch, de
Physiol., vol. xxvi. p. 810 : 1895. J. Pal, loc. cit.

430 LEcrruRE xxix

A voluminous literature has of recent years appeared on the
specific constituents of the capsules, on the poisons which are
stored up in them/ on the substances, which the suprarenals
pass on to the blood and which are supposed to have an influ-
ence on the innervation of the blood-vessels, heart, and respira-
tory organs,^ on the chromogens in the capsules, which are con-
sidered to be related to the dark pigment that is deposited in
the skin in Addison's disease,' etc. But for the present it is
not possible to give a short connected account of the indefinite
and contradictory statements.

An interesting observation has been made on animals, from
whom only one capsule had been removed, viz., that black
patches appeared on the skin,* corresponding to the dark pig-
mentation in patients suifering from Addison's disease.

The discovery that the thyroid gland was, like the
suprarenals, indispensable to the animal economy, was again
made in the domains of pathology. The earlier experiments
and speculations of the physiologists concerning the significance
of the thyroid gland had not borne any fruit.

In 1873 Sir William GulP showed at the Clinical Society
in Londou five cases of a disease to which he was the first to call
attention, and which he termed " a cretinoid state supervening
in adult life in women." In 1878 William M. Ord^ described
five other cases of the same malady. An invariable symptom
is present in the thickening and swelling of the skin, which
occurs usually in the face but sometimes extends also to the
extremities and other portions of the body, as well as to the
mucous membranes of the internal organs This thickening
cannot be regarded as edema ; if the swollen skin, be cut, no
serum flows out. It is due to an active new formation of a
connective tissue rich in mucin. On account of the invariable
occurrence of this symptom Ord called the disease " myxedema."
Other trophic disturbances were likewise present : dryness of
the skin in consequence of insufficient secretion of sweat and
sebum, baldness, atrophy of the nails and teeth, etc. By

1 P. Foa e P. Pellacani, Arch. p. I. scienze med., vol. vii. p. 113 : 1883. S.
Fränkel, Wien. med. Blätter, Nos. 14, 15 and 16: 1896.

2 G. Oliver and E. A. Schäfer, Proc. Physiol. Soc, March 10, 1894, and March
16, 1895, L. Szynionowicz, loc. dt.

3 Vulpian, Comptes rend., vol. xliii. p. 663 : 1856. M'Munn, Journ. Physiol.,
vol. V. p. 24: 1885. Krukenberg, Virchow's Arch., vol. ci. p. 542: 1885. S.
Fränkel, Wien. med. Blätter, Nos. 14, 15, 16 : 1896. Wien. klin. Woehenschr.,
p. 212 : 1896. G. Caussade, Comptes rend. Soc. Mol., p. 67 : 1896. O. v. Fürth,
Zeitschr. f. physiol. Chem., vol. xxiv. p. 1 : 1897.

•*F. and S. Marino-Zucco, loc. cit.
5 Wm. Gull, Trans. Clin. Soc, Lond. : 1874.

«William M. Ord, "On Myxedema," Medico-chirurg . Trans., 2d ser., vol.
xliii. p. 57 : 1878.

THE DUCTLESS GLANDS 431

degrees physical and mental feebleness supervenes, which in
many respects resembles cretinism.

Ord had already observed a shrinking of the thyroid gland
and the destruction of its follicle through the swelling connective
tissue/ but he looked upon it merely as a consequence of the
general myxomatous new-formation in the connective tissue.
He did not yet recognize that the degeneration of the thyroid
gland was the primary factor in the disease. Ord called
attention to the analogy between myxedema and cretinism,
and emphasized the fact that the latter condition is frequently
associated with the colloid degeneration of the thyroid gland
known as goiter.^ But he did not regard the change in the
gland as being the cause of cretinism. The connection between
the degeneration of the thyroid gland and the symptoms of
myxedema and cretinism was first recognized by the Swiss
surgeons Reverdin and Kocher.

On 13th September 1882 J. L. Reverdin^ described before
the Medical Society of Geneva the effects of fourteen complete
extirpations of goiters, and in April 1883 the two Genevese
surgeons J. L. Reverdin and A. Reverdin published in detail the
results of removing goiters in twenty-two cases.* Of these four-
teen were complete, i. e., excision of the whole diseased and of the
remaining sound tissue of the thyroid gland. As a consequence
of complete removal, they observed symptoms which bore a
striking resemblance to those of myxedema and of cretinism,
i. e., swelling of the skin of the face and extremities, diminished
perspiration, slowness and heaviness in the movements as well
as in the psychical functions,^ besides anemia, a readiness to
fatigue, a sensation of cold, and occasionally tetany.

The extirpation of the thyroid gland thus led to a series of
symptoms which resembled myxedema, in which disease the
thyroid gland undergoes degeneration.^ We may therefore
conclude that it is the absence of the function of the thyroid
gland which causes the symptoms in both cases, viz. — the ex-
tirpation and degeneration of the gland.

At the same time as Reverdin,^ Kocher was likewise

1 Ord, loc. cit., pp. 60, 67, 72, 73. B. Hadden, Brain, p. 193 : 1883, and Hun
and Prudden, The American Journ. of the Med. Sciences, vol. xcvi.: 1888.

^ Ord, loc. cit. p. 73. He here quotes the earlier authors who discuss the
question as to the connection between cretinism and goiter.

* J. L. Reverdin, Revue med. d. I. Suisse romande, 2 '^"«Ann., p. 539^: 1882.
'^ Revue med. d. I. Suisse romande, 3'«™« Ann., pp. 169, 233, and 309 : 1883.

* Reverdin, loc. cit., pp. 352 and 355.

* Idem, loc. cit., p. 356.

' In his first communication {Revue med. d. I. Suisse romande, p. 540 : 1882)
Reverdin mentions a previous communication of Kocher's on the consequences
of total excision of goiter.

432 LECTURE XXIX

engaged at Berne in performing the same operation of
complete extirpation; and in April 1883 he communicated the
results of his abundant experience at the Congress of the
German Surgical Society.^ These symptoms which occurred
after total excision were in all respects identical with those
described by Reverdin. If however a minute portion of the
gland were left, so that a small fresh growth of thyroid took
place/ these symptoms did not occur. To the latter, Kocher
gives the name of cachexia strumipriva/ and he describes them
as follows * :

Soon after their dismissal from the hospital, or in a few
cases, not until four or five months afterwards, the patients
begin to complain of lassitude, weakness, and weight in the
limbs. This is soon followed by a sensation of cold. In the
winter time the hands and feet become cold, swollen, of a
purple color, and chilblains ensue. The mental condition is im-
paired ; thought and speech become slower. All movements get
slower and more languid. At the same time swellings appear
on the face, hands, and feet ; in a few cases these are at first
temporary, and subsequently they become permanent. The
thickness of the face and the heaviness of the movements give
the appearance of idiocy. The whole skin seems swollen and
can only be raised from the body in large folds. Its surface is
dry, with scurf on the ears and cheeks, and the hair falls out.
In advanced cases, anemia is present to a marked degree. The
number of red blood-corpuscles was usually under 4 millions per
cb. mm., in four cases it sank to lower than 2.8 millions, and in
one case even to 2.2 millions. The white blood-corpuscles were
relatively somewhat increased. The anemia developed gradually,
and grew progressively worse as time elapsed after the operation.
If at the time of the operation the patients were children who
were growing fast, the stature was at once arrested in a striking
manner. In many cases attacks of vertigo were observed, but
convulsions were only noted in one instance, that of a girl.
The excellent development of the muscles formed a curious
contrast to the patients' complaints of feebleness and lassi-
tude.

The numerous excisions of goiters which have been carried
out in Billroth's hospital practice in Vienna have led to
divergent results, in so far as the cases were much more
frequently complicated with tetany than they were at Berne.

1 Kocher, Arch. f. klin. Chirurgie, vol. xxix. p. 254 : 1883.

"^ Idem, loc. cit., p. 278.

3 Idem, loc. cit., p. 28.5.

•* Idem, loc. cit., p. 279, et seq.

THE DUCTLESS GLAISTDS 433

A. V. Eiselsberg/ who has collected the statistics of fifty-three
complete excisions performed in Billroth's clinique, states that
attacks of tetany occurred in twelve cases, eight of which died
in consequence. It is noteworthy that all the twelve patients
were females.

Kocher considers that the arrest of physical and mental
development in cretinism is also due to disease of the thyroid
gland. ^ It is true that all cretins do not have goiters ; accord-
ing to the statistics of a French Commission the proportion is
somewhat more than 75 per cent. But it must not be over-
looked that in most cases cretinous children are descended from
goitrous parents, and that cretinism is inherited through several
generations.^

From these pathological facts, a number of physiological
questions arise. We see that the failure of the thyroid function
is the signal for the onset of the gravest physical and mental
disturbances. What is the connection between these functions ?
Are the substances which act harmfully upon the organism
altered and rendered innocuous as they pass through the gland ?
Or are substances formed in this organ which are essential to
the performance of physical and mental functions ? Or may
both these phenomena occur ? The fact already mentioned
that a small remnant of the thyroid gland is able to take the
place of the whole appears to show that the active principle
of the organ need only be present in a minute quantity in order
to affect the total metabolism, that in fact it is a question of
so-called ferment-action. Physiological experiment on animals
seems to confirm this view.

In 1884 Schiff* published an account of his experiments
on the extirpation of the thyroid gland in dogs, adding that he
had already written about them in 1859 but that no notice
had been taken of them by the surgical profession. Schiff
found that after complete extirpation of the thyroid gland all
the animals died from four to twenty-seven days afterwards.
These experiments have been confirmed by many observers.
The symptoms shown by the animals subsequent to the oper-
ation were however of very variable character, not only in

■^ A. von Eiselsberg, " Ueber Tetanie im Anschluss an Kropfoperationen,"
Wien, A. Holder : 1890. This author also gives a complete account of the
literature on the consequences of excision of goiters.

2 Kochner, loc. cit., p. 298 et seq.

^ The copious literature on the connection between goiters and cretinism is
quoted by A. Hirsch, " Handb. d. historisch-geographischen Patholog.," 2d
edition, Part II. pp. 137-140 : 1883.

*M. Schiff, Eev. med. d. I. Suisse rom., Ann. iv. p. 65, 15 F6v. : 1884. Transl.
in Arch. f. exper. Path. u. Pharm., vol. xviii. p, 25 : 1884.

28

434 LECTURE XXIX

different species, but also in different individuals of the same
species. A few of the animals succumbed rapidly in a few
days, frequently with the accompaniment of tetany ; others
lived for some months or even longer, and sank gradually from
general cachexia. The causes of this divergent behavior have
not so far been explained in any way, and the accounts are
very discordant.^

Horsley ^ found that older animals survived excision of the
thyroid for a longer time than young animals, and recalls the
observation of the anatomist Huschke that this organ is rela-
tively larger in youth, and diminishes with age. The thyroid
would thus appear to take a prominent part in the development
of the tissues. Moussu,^ Hofmeister,'' and others obtained the
same results as Horsley.

In dogs and cats thyroidectomy is usually fatal. The
first symptoms are those of general weakness, twitchings
of the muscles, and disturbance of the regulation of the
temperature. The muscular twitchings first appear as fibrillar,
and subsequently as clonic and tonic convulsions, and in the
worst form are of an epileptic character, followed by Cheyne-
Stokes respiration and deep coma. That this muscular excita-
tion is of central nervous origin was first shown by Schiff,^
who pointed out that the muscular tremors and the convulsions
were abolished by cutting through the peripheral nerves. If
in dogs the spinal cord be divided at the level of the eighth
dorsal vertebra, the characteristic convulsions which occur on
excision of the thyroid gland are confined to the fore limbs.^
In a few cases feeble isolated twitches were also observed in
the hinder extremities. The impulse for the spasmodic move-
ments of the extremities evidently travels from the brain to
the spinal cord by way of the pyramidal tracts. That the
disturbances consequent upon thyroidectomy are mainly of
central origin agrees well with the observations on man : e. g.,
the slowness of thought and speech ending ultimately in loss
of mental power. In the case of dogs, death generally occurs

1 On this question see V. Horsley, " Internat. Beitr. z. wissensch. Med.,"
Festschr., R. Virchow gewidmet., vol. i. p. 382 et seq.: 1891. Over 200 publi-
cations are here critically discussed. See further A. von Eiselsberg, " Ueber
Tetanie im Anscliluss an Kropfoperationen," Wien, A. Holder, p. 16 : 1890.

^Victor Horsley, Proc. Roy. Soc, vol. xl. p. 7 : 1886.

3 G. Moussu, 3fem. Soc. Biol., p. 271 : 1892.

* Hofmeister, Beitr. z. klin. Chirurg., vol. xi. : 1894.

^M. Schiff, Rev. med. d. I. Suisse rom., Ann. iv. p. 71 : 1884. Compare O.
Lanz, Mitth. a. Kliniken u. med. Instituten d. Schweiz., vol. iii. p. 512: 1895;
and P^r. de Quervain, Virchow's Arch., vol. cxxxiii. p. 481 : 1893.

*0. Lanz, Mitth. a. Kliniken u. med, Instituten d. Schweiz., vol. iii. p. 516 :
1895.

THE DUCTLESS GLANDS 435

within the first fortnight during an attack of tetany.^ Occa-
sionally however, a dog will survive the operation.^

In the case of rabbits the accounts are so much at variance
that for the present no reliable deductions can be drawn.'
E. Gley'* found that excision of the thyroid in rabbits was
not followed by death unless the small accessory thyroids ^ were
removed at the same time, and that in these cases the animals
generally succumbed with signs of tetany. F. Hofmeister ^
found that after the extirpation of the thyroid in young
rabbits cachexia was the invariable result, tetany occurring
if the accessory glands were likewise removed. Other eifects
observed by him were retardation of the growth of bone and
the ossification of the epiphyses. Blumenreich and Jacoby^
contest Gley's assertion. They found that it made no differ-
ence whether the accessory glands were removed with the
thyroid body or not. The behavior of the rabbits on whom
thyroidectomy has been performed varied greatly in every
particular. Many became cachectic, but tetany seldom occurred.
Some died soon after the operation, others did not succumb
until months later of some intercurrent disorder. In the
animals suffering from cachexia, atrophy of the lymphoid
tissues, and especially of the thymus, was observed, besides
disturbances of the biliary secretion and marked distention
and enlargement of the gastric intestinal canal. Lanz ^ states
that all the rabbits in which he excised the gland died either
of acute or of chronic tetany.

In the case of sheep, goats, and donkeys, cachexia did not
supervene until long after the operation.^ In young goats and
lambs V. Eiselsberg^" noticed that the growth of the bone-
substance was arrested both in length and breadth, and that

■T. M. Autokratow, Petersburg. Wochenschr., p. 105 : 1888: G. Fano e. L.
Janda, ArcMvio medico, vol. xiii. p. 365 : 1889 ; O. Lanz, loc. cit. p. 512 : 1895.

2 Ed. Wormser, Pfluger's Arch., vol. Ixvii. pp. 533-536: 1897. Compare
Drobnik, Arch. f. exper. Path. ii. Pharm., vol. xxv. p. 136 : 1888 ; and R.
Schwarz, Lo Sperimentale, Fasc. 1 : 1892.

' Vide F. Hertens, Zur Kenntniss d. Schilddrüse," Diss., Göttingen :
1890 ; J. R. Ewald u. John Rockwell, Biol. Centralbl., p. 568 : 1890.

4E. Gley, Arch, de Physiol., Jan. and Apr. 1892, p. 467 : 1893 ; p. 101 :
1894 ; p. 136 : 1897 ; and Pfluger's Arch., vol. Ixvi. p. 308 : 1897. The literature
of the subject will be found quoted here.

^ For the construction of the accessory thyroid glands see H. Cristiani, Arch,
de Physiol., p. 279 : 1893.

^ F. Hofmeister, Beitr. z. klin. Chir., vol. xi.: 1894.

' L. Blumenreich and M. Jacoby, Berl. klin. Wochenschr., p. 327 : 1896 ; and
Pfluger's Arch., vol. Ixiv. p. 1 : 1896.

8 O. Lanz, 3Iitth. a. Kliniken d. Schweiz., vol. iii. p. 541 : 1895.

* V. Horsley, Internat. Beitr. z. wissenschaftl. 3Ied., vol. i. pp. 390 and 391 ;
1891.

'** A. V. Eiselsberg, Langenb. Arch.f. klin. Chir., vol. ilix. p. 207 : 1895.

436 LECTURE XXIX

development of the horns and hair was affected ; these
symptoms were accompanied by a fall in temperature and
general apathy, recalling cretinism in man. Tetany however
did not occur either in these cases nor in the case of the
herbivora upon which Lanz ^ had performed thyroidectomy.
Philipeaux ^ states that removal of the thyroid gland had
no effect upon white rats, but it may be doubted whether
these investigations were pursued far enough. Cristiani^
showed that rats, as well as domestic and field mice, have
accessory thyroids, excision of which, together with the main
gland, produces death from tetany.

The consequences incident on the extirpation of the thyroid
glands in monkeys are described by Victor Horsley as
follows * :

Fibrillar muscular twitchings of the extremities may result
immediately ; but as a rule the animal remains quite healthy
for the first five days. These twitchings develop in twenty-
four hours into tetanic attacks, which usually last for about
twenty days and then gradually cease. At the same time the
symptoms of myxedema and cretinism slowly develop ; the
animal becomes more and more apathetic, taking no notice
of anything, in marked contrast to its former vivacity. The
skin on the face and abdomen becomes swollen. According
to the analysis made by Halliburton this swelling is due to
infiltration with mucin. The salivary glands are markedly
hypertrophied, and the parotid, which normally yields a liquid
secretion, now produces a thick saliva containing an abundance
of mucin. The blood shows extensive changes ; the red blood-
corpuscles diminish, the white ones are at first increased and
subsequently likewise diminish ; the blood now contains mucin
and the serum albumin is lessened. The body-temperature,
which had risen somewhat after the operation, becomes vari-
able, and gradually falls after about twenty-five days far below
normal. The animal dies in a state of coma.

In a second communication ^ Horsley states that he was
able considerably to prolong the life of his monkeys if he obvi-
ated the consequences of this fall in their temperature. He
kept the animals in a place maintained at a temperature of
32° C, and as soon as nervous symptoms, trembling of the
muscles, &., supervened, he put them in a hot-air bath of

^ O. Lanz, loc. cit., pp. 513 and 543.

2 Philipeaux, Compt. rend. Soc. d. Biol., p. 606 : 1884.

3 H. Cristiani, Arch, de Physiol., p. 39 : 1893.

4 V. Horsley, Proc. Roy. Soc., vol. xxxviii. p. 6 : 1885.

5 V. Horsley, loc. cit., vol. xl. pp. 7 and 8 : 1896.

THE DUCTLESS GLANDS 437

40.5° C. Under these conditions all the monkeys, with the
exception of the very young animals, lived four to five times
longer than the previous animals had done, that is to say, their
duration of life, instead of only four to seven weeks, was now
extended to as many months. The animals thus treated passed
through three stages — a neurotic, myxedematous, and atrophic.
The symptoms of the first stage were artificially combated and
scarcely showed themselves. The myxedematous swellings
were likewise diminished, and the parotid did not become en-
larged. The final stage was marked by loss of flesh, functional
paresis and paralysis, mental dulness, lowering of the blood-
pressure and of the body-temperature, ending in death from
coma.

On this subject we may describe two further observations
made by other investigators, v. Eiselsberg ^ experimented on
a young monkey (^Inuus ecaudatus). A week after the extirpa-
tion an attack of tetany supervened, which recurred several
times, and ended in complete apathy. Nine weeks after the
operation the animal was found dead in the cage. Dissection
showed that " the subcutaneous cellular tissue was remarkably
pale, and in patches somewhat jelly-like."

Lanz ^ records the case of a monkey which after removal of
its thyroid went into acute tetany, ending quickly in death.

Very few experiments in this connection have been made
on birds. Ewald and Rockwell ^ found that pigeons survived
the operation if it were performed with proper precautions.
After the lapse of three months they did not notice any eifects.
Perhaps the effects were overlooked, and the birds may not
have been sufficiently long under observation. Or must we
assume that the thyroid in pigeons is in a rudimentary condi-
tion, and that other organs have taken over its functions ?

The universal occurrence of the thyroid gland among all
the vertebrata shows that it is of vital importance to the
organism. It is found in all classes of fish, even in the lowest,
^■he petromyzon ; moreover, in the amphioxus and in the tuni-
cata — the invertebrata which are most nearly allied to the
vertebrata — it occurs as an extension of the front portion of
intestine in a form analogous to its embryonic position in the
higher animals.

Cristiani * cut out the thyroid gland in lizards and snakes,

^ A. von Eiselsberg, Langenb. Arch.f. klin. Chir., vol. xlix. pp. 223-226: 1895.

^O. Lanz, Mitth. a. Klinik, d. Schweiz., vol. iii. p. 513 : 1895.

* J. R. Ewald and J. Rockwell, Arch. f. d. ges. Physiol., vol. xlvii. p. 160 :
1890. Compare O. Lanz, infra, p. 486.

^ Cristiani, Arch, de Physiol., vol. vii. p. 356 : 1895 ; and Pev. med. de la
Suisse rom.. p. 37 : 1895.

438 LECTURE XXIX

which invariably died after a longer or shorter time. Lanz^
performed the same operation on skate at the experimental
station at Naples. Although he could detect no characteristic
symptoms of ill-health, yet they did not live so long as the
normal Selachians, which were kept in the aquarium under the
same conditions.

The observation that thyroidectomy is usually attended with
less ill-eifects in herbivora than in Carnivora ^ led to the assump-
tion that a meat diet was especially bad for animals which had
been deprived of these glands. It was thought that dogs and
cats bore the loss better on a milk diet. ^ On this account a
chiefly vegetable diet has been recommended for persons suffer-
ing from cachexia strumipriva. Ughetti* could not however
confirm the statements as to the favorable influence of milk
and vegetables on the symptoms resulting from removal of the
thyroid.

All observers are unanimous on one point, viz., that the
untoward results, including death, of extirpation of the thyroid,
are absent if even a small portion of the gland be left behind
in its normal position. It can be proved also that removal of
the thyroid is without effect if a little bit of the gland be
transplanted to some other part of the body. Experiments
of this nature had already been carried out by M. Schiff, ^ who
transplanted the thyroid of one dog into the abdominal cavity
of another, and, after two or three weeks extirpated the thyroid
gland of the second dog. The operation was successful in two
cases, in both of which the animals remained alive and well.
Schiff's transplantation experiment has been frequently con-
firmed, especially by A. von Eiselsberg. ^ This observer extir-
pated the thyroid in fifty cats, and found that in every case
the operation was followed by tetany and death. In another
cat he now excised only half the gland, which he transplanted
into the abdominal wall between the peritoneum and the fascia.
A month later he removed the other half of the gland. The
animal lived for another two months, and appeared normal in
every respect. At the end of this time, i. e., three months after
the transplantation, Eiselsberg cut out the transplanted bit of

^O. Lanz, Mitth. a. Kliniken u. med. Instituten d. Schweiz., vol. iii. p. 486 :
1895.

^G. Moussu, Mem. de la Soc. de Biol., p. 271 : 1892; 0. Lanz, loc. cit., p.
513 : 1895.

3 Leo Breisaeher, Du JBois' Arch., p. 509 : 1890. Of. Moussu, I. c; Fr, de
Quervain, Virchow's Arch., vol. cxxxiii. p. 504: 1893; and O. Lanz, I. c, p.
530.

* Ughetti, Riforma medica, December 1892.

* M. Schiff, Hev. med. de la Suisse rom., Ann, 4, p. 425 : 1884.

* A. Freiherr v. Eiselsberg, Wien. Min. Wochenschr., Jahrg. v. p. 81 : 1892.

THE DUCTLESS GLANDS 43^

gland, which he found well supplied with blood by two fairly
large vessels, and under the microscope presented a normal
appearance. The abdominal wound was carefully closed, but
on the evening of the next day typical tetany developed, and
the animal died on the third day after the operation. Eisels-
berg carried out this experiment four times with success.

These experiments are in so far instructive as they show
that the fatal results of removal of the thyroid are not
dependent on interference with nerves or the general circula-
tion, as was formerly maintained.^ Moreover the fatal results
could be prevented or at any rate postponed by giving the
operated animals thyroid glands of the same or other species
to eat, although a continuance of this treatment was not
without ill-effects on the general metabolism. These were
especially marked by an increase in the nitrogenous excretion
— an increase which is also observed even in normal animals.^
A series of careful experiments by Fr. Voit^ on the normal
dog showed that thyroid administration caused not only in-
creased proteid destruction but also increased excretion of car-
bon dioxid, so that the body- weight may fall to half its previous
amount.^

It is worth noting that, according to Lanz,^ the subcutane-
ous injection of the juice of the thyroid gland in normal animals
brings about atrophy of the thyroid.

All attempts to isolate the active principle of the thyroid
gland have so far led to no satisfactory result. Great interest
was excited by Baumann's discovery of iodin ^ in the thyroid
and by his suggestion that the active principle of the gland
was an iodin compound. Previous observations had already
suggested the investigation of the thyroid for iodin. Kocher^
who had been treating goiter by means of thyroid extract,
had been struck with the resemblance of its effects to those

^ A full and critical account of the literature on this subject is given by V.
Horsley, in the " Internat. Beiträgen z. wissensehaftl. Med., Festschr. E. Vir-
chow gewidmit," vol. i. p. 372 et seq.: 1891.

2 E. Roos, Zeitschr. /. physiol. Chem., vol. xxi. p. 19 : 1895. B. SchöndorflF,
Pflüger's Arch., vol. Ixiii. p. 423, and vol. Ixvii. p. 395 : 1897. Here the com-
prehensive literature on the influence of the thyroid gland on metabolism will be
found.

3 Fr. Voit, Zeitschr. f. Biol., vol. xxxv. p. 116 : 1897. Here a critical
account of the earlier literature is given.

■* K. Georgiewsky, Central b I. f. d. med. Wissensch., No. 27: 1895.

^ O. Lanz, Correspondenzbl. f. scMueizer Aerzte, Jahrg. xxv. p. 293 : 1895.

^E. Baumann, Zeitschr. f. physiol- Chem., vol. xxi. p. 319 : 1895 ; vol. xxii.
p. 1 : 1887. 3Iünchen. med. Wochenschr., No. 14 and 20 : 1896. Baumann and
E. Roos, Zeitschr. f. physiol. Chem., vol. xxi. p. 481 : 1896. E. Roos, ibid., vol.
xxii. p. 16 : 1897 ; and " Ueb. Schilddrüsentherapie u. Jodothyrin," Freiburg and.
Leipzig, Mohr : 1897.

440 LECTUEE XXIX

observed iu the ordinary treatment with iodin. Moreover it
had been suggested that the occurrence of goiter in certain
mountain valleys might be ascribed to the absence of iodin in
these places, though subsequent more exact experiments had
shown this idea to be devoid of foundation, iodin being con-
tained in the drinking-water as well as in the plants of certain
valleys where goiter was endemic/

From the thyroid gland Baumann extracted a substance
containing iodin in organic combination. This he regarded
as the active principle and called iodothyrin. This view is
open to many objections. Iodin is not found in the thyroid
gland of all animals. Thus the gland of a dog fed on meat
contains either no iodin or only traces,^ and in pigs, oxen, and
horses, iodin is found very seldom, and then only in minute
quantities.^ Finally Baumann himself states that iodin is not
a constant constituent of the thyroid gland in man.* We cannot
therefore regard the minute amount or the entire absence of
iodin in goiters as the cause of this disease.^ It is possible
that the iodin, which exists in small quantities in almost
all vegetable food, is withdrawn from the circulation and
retained as a harmful substance. In man the administration
of iodin or the treatment of wounds with iodoform leads
to an increased amount of iodin in the thyroid. Baumann
founds his identification of iodothyrin with the active principle
on the fact that administration of iodothyrin in goiter causes
disappearance of the tumor. But, as Coindet ^ pointed out
as early as 1820, this condition has also been successfully
treated with inorganic preparations of iodin. In this case
however much larger doses are necessary. But it is possible
that the organic form may be more readily absorbed and reach
the part where its influence is effective. In fact Kocher suc-
ceeded in reducing goiters by the administration of an artifi-
cially prepared iodin compound of casein.'^ Even before
Baumann's discovery, it was known that another artificial com-
pound of iodine — tetraiodopyrrol, had some effect on goiters. ^

^ An account of the comprehensive literature on this subject is given by A.
Hirsch, " Handb. d. historisch-geographischen Pathologie," Stuttgart, Enke,
Abth. ii. pp. 135 and 136 : 1883.

2 Baumann, Zeitsehr.f. physiol. Chem., vol. xxii. p. 14: 1896.

ä Töpfer, Wien. klin. Wochenschr., p. 141 : 1896.

* Baumann, loc. dt., pp. 3-12.

^ Baumann, München med. Wochenschr., No. 14 : 1896.
^ J. Fr. Coindet, Bibliotkhque universelle de Genhve, vol. xiv. p. 190 :
1820.

■^ Ed. Wormser, Pflüger's Arch., vol. Ixvii. p. 529 : 1897.

* O. Schorndorff, " Beitr. z. therapeutischen Verwerthbarkeit des Jodes,"
Diss., Würzburg: 1889.

THE DUCTLESS GLANDS 441

It is also claimed that good results have been obtained with
injections of iodoform.^ Certain sea animals and plants which
contain iodin have been used as medicaments, and especially
in cases of goiter, for hundreds of years before the discovery
of iodin. Harnack ^ has recently given an interesting account
of these iodin drugs. As I have already mentioned, Kocher ^
observed even in the earliest attempts to relieve the struma with
thyroid preparations, how much the mode of action resembled
that of the long-used iodin. As a final proof that iodothyrin
was the active principle of the thyroid. Baumann stated that
the tetanic convulsions occurring in dogs as a consequence of
thyroidectomy were prevented by the administration of iodo-
thyrin (2-3 grs. per diem).* This statement could not how-
ever be confirmed by Gottlieb and Wörmser. Gottlieb ^
showed in three experiments that the tetany and death resulting
from the extirpation of the thyroid could not be prevented by
the administration of iodothyrin. Kocher's pupil, E. Wörmser,^
comes to a similar conclusion. He finds that iodothyrin was
ineffective either in preventing an attack or in stopping an
attack which had already begun ; whereas all attacks of tetany
can be kept off and the life of the animal preserved for a long
time by administration of the whole thyroid gland.

All other efforts to isolate the effective principle of the
thyroid gland have been equally unsuccessful.'^ None of the
substances which have been isolated from the gland have been
of any use for counteracting the effects of thyroidectomy. The
only preparations which were of any value were those which
contained the proteids of the gland, though these were less
effectual than the whole gland, dried at 65° C, which in its
turn was inferior to the fresh raw gland.

At present there is no evidence against the view that the
active principle of the gland belongs to the class of labile proteids,
a class including all those substances which have the most

^ R. V. Mosetig-Moorhof, Wien. Press., No. 1 : 1890.

2E. Harnack, München, med. Wochenschr., No. 9 : 1896.

ä Kocher, Correspondenzbl. f. schweizer Äerzte, vol. iiv. p. 6 : 1895.

* Baumann and E. Goldmann, München, med. Wochenschr., No. 47 :' 1896.
F. Hofmeister, Deutsch, med. Wochenschr., p. 354 : 1896. H. Hildebrandt, Berl.
klin. Wochenschr., p. 826 : 1896. A. Irsai, 3fünchen. med. Wochenschr., p. 1249 :
1896.

^ Gottlieb, Deutsch, med. Wochenschr., -p. 235: 1896. Compare A. Notkin,
Wien. klin. Wochenschr., No. 43 : 1896.

^Edm. Wörmser, Pflüger' t Arch., vol. Ixvii. p. 505 : 1897.

' In this connection read : Drechsel, Physiol. Centralhl., vol. ix. p. 705 : 1895 ;
S. Fränkel, Wien. med. Blätter, No. 48 : 1895 ; Nos. 13-15 : 1896 ; J. Notkin,
Wien. med. Wochenschr., 'So. 45, p. 824: 1895; Virchoiv's Arch., vol. ciliv.;
Suppl., p. 224: 1896; ß. Hutchinson, Centralbl. f. d. med. Wi^sensch., -p. 209 :
1896.

442 • LECTURE XXIX

potent influence on the body functions, viz., the most useful
ferments and the most virulent poisons. (Compare Lectures
XI. and XXVII.)

We may conclude that the assumption that poisonous
products of metabolism are destroyed in the thyroid gland
must be discarded as extremely improbable. We could not,
on such an hypothesis, explain the fact that a very minute
fragment of the gland left behind at the operation or trans-
planted to some other part of the body, is sufficient to prevent
all the usual effects of thyroidectomy. Nor does it seem
probable that the blood flow through the small vessels of the
gland can be sufficiently abundant for such a process of puri-
fication to take place to any considerable extent. It is much
more probable that the gland is continually giving off to the
blood minute quantities of a ferment-like substance, which
influences the metabolism in other organs of the body. We
thus come to the same conclusion as we arrived at in dealing
with the internal secretion of the pancreas. (Compare p. 398.)

Attempts have naturally been made to utilize in therapeutics
the various results of chemical and vivisectional experiments
described above. The first object of these attempts was to
counteract the cachexia strumipriva which supervenes as the
result of total extirpation of the gland for goiter. But they
were naturally extended to the treatment of myxedema and
cretinism. The method first used was that of transplantation
of the gland, but it was found that the transplanted gland
underwent absorption after a short time, so that only transient
improvement was effected.^ The result was equally unsatis-
factory in a case where the human gland itself was used. A
female cretin, thirty-three years of age, developed severe myx-
edema with epileptic attacks and apathy, as the result of
total extirpation of the thyroid for goiter. Bircher ^ therefore
transplanted into the abdomen of this patient a bit of the
thyroid gland, which he had just removed from another patient
in an operation for goiter. Within a few days the patient was
markedly better, and at the end of four weeks her former
intellectual activity and power of work were fully restored.
After this came a relapse, and the condition grew steadily
worse for four weeks. A second transplantation was therefore
carried out in similar manner to the first. Three months
after the second transplantation the woman was perfectly well

^ Lannelongue, Wien. med. Blätter, No. 13 : 1890 ; P. Merklen and Ch.
Walther, Mercredi mtd.. No. 46 : 1890.

H. Bircher, "Das Myxödem u. d. cretinische Degeneration"; Volkmann's
" Sammlung klinischer Vorträge," No. 357, pp. 12-16 ; and Nachtrag, p. 32 : 1890.

THE DUCTLESS GLANDS 443

and worked the whole day ; but six months later the epileptic
attacks recurred. In the same way Kocher ^ succeeded in pro-
ducing only a temporary improvement in his attempts to treat
cachexia strumipriva by transplantation of the gland of men or
animals.

It seems therefore that transplantation succeeds only when
the transplanted piece of gland becomes vascularized — a proc-
ess which so far has occurred only in the transplantation in
healthy animals when their own gland has been used.

This method had therefore to be given up and trial was
made of the introduction of the active principle of the gland
by subcutaneous injection or administration by the mouth.
The latter mode has proved to be the simpler and more effective.
The results have been wonderfully good. The myxedematous
swelling diminishes and the general bodily and mental condi-
tion improves in a marked manner.^ Relapse however occurs
at once if the treatment be discontinued. Renewed administra-
tion of thyroid counteracts these effects for a time, but appar-
ently not permanently, since, as we have already seen in experi-
ments on animals, disturbances of metabolism occur, such as
increased output of nitrogen, showing a correspondingly in-
creased proteid disintegration in the tissues.^ The same result,
but to a less extent, follows the administration of thyroid in
healthy men,* and leads in time to diminished body-weight,^
and finally to glycosuria*' and albuminuria.^

These experiences have impressed on surgeons the necessity
of avoiding where possible complete extirpation of a goitrous
thyroid, and the operation is now only performed in certain
cases of malignant tumors, such as cancer or sarcoma. Thus
the clinical records gleaned by Kocher, Reverdin, and
Billroth from cases in which total extirpation of the thyroid in

■•Kocher, Correspoiulenzbl. f. schweizer Äerzte, Jahrg. 23, p. 529: 1893; and
Jahrg. 25, p. 9 : 1895.

2 Mackenzie, Brü. Med. Journ., Oct. 29 : 1892. Vermehren, Deutsch, med.
Wochenschr. , March 16, 1893. Yassale, Eiv. sperimentale, yol. xix. Fase. IL,
III. : 1893. Leichenstein, Deutsch, med. Wochenschr., Nos. 49-51 : 1893.
Costanzo, Rivista Veneta di scienze mediche, vol. xx. Fase. IL : 1894. Palleske,
Deutsch, med. Wochenschr., No. 7 : 1895. O. Lanz, Correspondenzbl. d. schweizer
Aerzte, Jahrg. 25, p. 296 : 1895.

^Mendel, Deutsch, med. Wochenschr., 'No. 2: 1893. Napier, Lancet, Sept.
30, 1893. Vermehren, Deutsch, med. Wochenschr., No. 43: 1893. Ord, Brit.
Med. Journ., vol. ii. p. 212 : 1893.

* Vermehren, loc. cit., A. Dennig, München, med. Wochenschr., Nos. 17 and
20. Bleibtreu and Wendelstadt, Deutsch, med. Wochenschr., No. 22 : 1895.

5 Reinhold, Münch. med. Wochenschr., July 31, 1894. Bruns, Deutsch, med.
Wochenschr., Oct. 11, 1894.

ß C. A. Ewald, Berl, Hin. Wochenschr., Nos. 2 and 3 : 1895. A. Dennig,
loc. cit. Bleibtreu and Wendelstadt, loc. cit.

' A. Dennig, loc. cit.

444 LECTURE XXIX

man for goiter has been performed, will be of inestimable value
for future physiological research, since they can never be
repeated.

As already mentioned (p. 441) attempts have been made to
treat goiter itself by administration of thyroid gland. Rein-
hold^ obtained an almost complete disappearance of the tumor
in five cases out of six that he treated in this manner, and
Bruns^ had equal success in nine out of twelve cases. Myxe-
dema and cretinism have also been successfully treated by the
administration of thyroid gland,^ as also by transplantation,
though in the latter case the good effects have been only
temporary.*

The cachexia and bodily and mental weakness, which
sometimes supervene after partial thyroidectomy, have also
been treated with great success by the administration of raw
thyroids.^

Finally a large number of the most diverse disorders have
been subjected to treatment with thyroid. Among these we
may mention obesity, psoriasis, eczema, lupus, syphilis, leprosy,
exophthalmic goiter, acromegaly, mental diseases, diabetes,
tuberculosis, uric acid diathesis, rickets, &c., &c. It is
however impossible at present to say how far this mode of
treatment has been of good or of harm in these various
maladies.^

Before leaving the subject of the thyroid gland, I may
mention the observations which point to some connection
between the activity of this organ and the sexual functions.
Impaired development and retarded descent of the testes has
been observed after excision of the thyroid in young animals. '^

1 Reinhold, loc. cit.

^ P. Bruns, JBeitr. z. klin. Chirurgie, 12, 1894. Compare also Kocher, Corre-
gpondenzbl. f. schweizer Aerzte, vol. xxv. p. 3 : 1895. O. Lanz, idem, Nos. 2 and
10 : 1895. A. Irsai, B. Vas, and Gesa Gara, Beut. med. Woch., No. 28 : 1896.
G. R.einbach, Mitt. a. d. Grenzgeb. d. Med. u. Chir., vol. i.: 1896. H. Stabel,
Berl. klin. Woch., No. 5 : 1896. O. Angerer, Munch, med. Wochenschr., No. 4 :
1896. P. Bruns, Bruns' Beiträge, vol. ivi. : 1896.

^ Beadle, Lancet, Feb. 17, 1894. E. Mendel, Deut. med. Woch., No. 7 : 1895.
C. A. Ewald, Berl. klin. Woch., Nos. 2, 3, and 30 : 1895. O. Lanz, Correspond-
enzbl. f. schweizer Aerzte, Nos. 2 and 10 : 1895. R. Abrahams, Med. Record,
April, 1895. Vermehren, "Studien üb. Myxödem," Diss. Copenhagen: 1895.
Middleton, Glasgow Journ., Feb. 1896. W. H. George, Brit. Med. Journ., Sept.
12, 1896. Rushton Parker, ibid., June 27, 1896. H. H. Vinke, Med. News, No.
12 : 1896.

* v. Gernet, Zeitschr. f. Chirurgie, vol. xxxix. : 1894.

5 Angerer, München, med. Wochenschr., No. 28: 1894. Sonnenburg, Lan-
genb. Arch., vol. xlviii.: 1894.

^ The literature on this subject will be found in a paper by E. Roos, " Ueb.
Schilddriisentherapie u. Jodothyrin," Freiburg and Leipzig, Mohr : 1897.

"> A. V. Eiselsberg, Arch. f. klin. Chir., vol. xlix. pp. 216 and 225 : 1895.

THE DUCTLESS GLANDS 445

Langhans found the testes atrophied in cretins.' A connection
of the thyroid gland with the sexual functions has been known
of for a long time.^ Swelling of the gland is often observed at
the menstrual period as well as during pregnancy, parturition,
and lactation, though this does not occur in the majority of
cases. Thus J. Fischer^ could only detect swelling of the
thyroid gland in two cases out of fifty during menstruation,
and in only one-third of the cases in pregnancy. The more
frequent occurrence of myxedema in women is worthy of
note. According to the results collected by a committee of the
Chemical Society,^ out of every hundred cases of myxedema,
eighty-six are women and only fourteen men. In the ovaries
of cretins, Langhaus' found the follicles but slightly devel-
oped ; only a few follicles were in a process of growth, while
the majority remained in their primitive condition. In the
transplantation experiment of Bircher^s,^ which I mentioned
above, the awakening of the psychical functions was attended
with a restoration of the sexual functions. Menstruation which
had ceased for a year, occurred again regularly after the trans-
plantation.

A connection of the gland with sexual life seems to be in-
dicated by the fact to which Schölein^ draws attention, viz.,
that the frequency of goiter shows two maxima, one at the time
of puberty and the other during senile involution.

An interesting observation has been made on birds by
Lanz,* who took two young hens of the same brood and in one
of them excised the thyroid gland. The operated animal
developed more slowly and was smaller than the other. Its
comb was also ill-formed. There was also a great difference
in the laying powers of the two hens ; the one which had lost
its thyroid laid only one egg four months after the extirpation.
This had a shell as thin as paper and weighed only 5 grms.,
whereas an ordinary hen's egg weighs 50 to 60 grms. In
another experiment Lanz took nine hens, all eighteen months
old, and to one of them gave 10 to 30 grms. of thyroid gland
every day to eat. While the other eight hens laid altogether

^ Th. Langhans, V-irchow's Arch., vol. cxlix. p. 155: 1897. The views of
earlier authors on the subject of the sexual organs in cretins are quoted here.

An account of our knowledge on this noatter is given by H. W. Freund,
Deut. Zeitschr. f. Chir., vol. xviii. p. 213 : 1883.

3 J. Fischer, Wien. med. Woch., Nos. 6, 7, 8 and 9 : 1896.

* Clin. Soc. Trans., supplement to vol. xxi. London : 1888.

5 Langhans, loc. cit.

6 Bircher, loc. cit., p. 3407.

'J. L. Schönlein, "Pathologie u. Therapie," part i. p. 81, St. Gallen:
1846.

* O. Lanz, Mitth. a. d. Kliniken d. Schweiz, iii. p. 540: 1895.

446 LECTURE XXIX

forty-two eggs in twenty-three days, the ninth that was fed
with thyroid laid in the same time sixteen eggs, i. e., three
times as many as the others. The weight of these eggs gradu-
ally increased ; the last egg laid before the thyroid feeding was
begun weighed 50 grms., while afterwards the weight gradually
rose to 60 grms.

I may now say a few words about the anterior glandular
portion of the pituitary body. The position of this gland
renders it extremely inaccessible to operative interference, so
that attempts at its removal are usually attended with fatal
results from the operation itself and teach us nothing con-
cerning the significance of the organ. The pituitary body has
sometimes been found hypertrophied in dogs and rabbits after
extirpation of the thyroid,^ and hypertrophy has also been
found in man in sporadic cretinism, accompanying atrophy of
the thyroid,^ as well as in one case of goiter.^ These facts, as
well as the occurrence of iodin in the human pituitary body,*
have led to the assumption of some analogy between the fiinc-
tions of this body and those of the thyroid.

Rogo witsch regards the pituitary body as equivalent to the
thyroid, and emphasizes the fact that rabbits, which withstand
the effects of thyroidectomy longer than do dogs or cats, pos-
sess also relatively larger pituitary bodies. In the rabbit the
thyroid is only three times as heavy as the pituitary, whereas
in dogs and cats it is fifteen to twenty times as heavy .^

Finally the view has been put forward that disease of the
pituitary leads to disorders of nutrition as extensive as those
following diseases of the thyroid. Just as the latter leads to
myxedema and cretinism, so the abolition of the functions of the
pituitary body is supposed to lead to acromegaly, i. e., a morbid
increase in the growth of the bones. In fact in some cases and
indeed in all since attention has been directed to the point,
hypertrophy or disease of the pituitary body has been found
post mortem in cases of acromegaly.^

IN. Rogowitsch, Arch. d. physioL, 4 Ser., vol. ii. p. 419: 1888; F. Hof-
meister, Beitr. z. klin. Chir., vol. xi. p. 2: 1894; L. Blumreich and M. Jacoby,
Pflilger's Arch., vol. Ixiv. p. 1 : 1896, could not confirm this statement as regards
rabbits, nor J. R. Ewald and J. Rockvirell as regards pigeons, Pflüger's Arch.,
vol. xlvii. p. 170 : 1890.

2 Bourneville and Bricon, Arch. d. Neurologie, 1886.

' K. Wolf, Ziegler's Beitr., vol. xiii. : 1893.

^Schnitzler and Ewald, Wien. klin. >Foc/i., No. 29 : 1896.

^ N. Rogowitsch, Beitr. z. pathol. Anat. u. allgem. Pathol, v. Ziegler, vol. iv.:
1889. Compare H. Stieda, " Ueb. d. Verhalten d. Hypophysis des Kaninchens
nach Entfernung der Schilddrüse," Diss., Königsberg, 1889, and Ziegler's Beitr.,
vol. vii. p. 537 : 1890.

* P. Marie and G. Marinesco, Arch, de mtd. experim., July 1, 1891. F. A.
Packard, American Journ., June, 1892; K. Wolf, Ziegler's Beitr., vol. xiii.:

THE DUCTLESS GLANDS 447

IJnless the methods of vivisection and asepsis make some
unexpected advance, we must in the near future await an
increase of our knowledge on this point rather from the side of
pathological anatomy and clinical observation.

1893. E. Caton and F. T. Paul, Brit. Med. Journ., Dec. 30, 1893. J. Arnold,
Virchow's Arch., vol. cxxxv.: 1894. M. Dallemagne, Arch, de med. exp.,
vol. vii.: 1895. Comini, Arch, per le scienze med., vol. xv. No. 21, p. 435 : 1896.
E. Eoxburgh and A. J. Collis, Brit. Med. Journ., p. 63, July 11, 1896.
A. Tamburini, Riv. sperim. di Freniatria e di Med. legale, vol. ix.: 1896. Ad.
Strümpell, "Lehrb. d. speciellen Path. u. Therapie," 10th ed., vol. iii. p. 165:
1896.

INDEX

Absorption of food, 3-4, 187-190, 360-

363
Acetic acid —

Avidity, 136

Decomposition, 157

Heat equivalent, 62
Aceto-acetic acid in diabetes, 391
Aceton, 391 ; in diabetic coma, 403
Acid —

Intoxication, 404

Mineral, secreted by lower animals,
133
Acids —

After extirpation of liver, 311

Elfect of, on ammonia excretion, 292 ;
on toxalbumins, 418

In stomach, 143

Of bile, 177, 182, 185

Of intestinal contents, 174

Of urine, 321

Vegetable, 321

Weaker and stronger, 135-136
Acromegaly, 446
Adenin, 77, 314
Adenoid, tissue, action on peptones,

197-198
Aerotonometer, 262
Albumin, 43-54

Alkali-, 45

Egg-, 45, 52

Serum-, 45
Albuminuria in fever, 426-427
Alcohol, 117-119

Action of, in moderation, 117-121 ; in
excess, 121-122

As food, 357

Energy derived from combustion of,
117

Fermentation product, 143

Influence on fat formation, 369

Value as a medicine, 122
Aleuron-crystals, 46
Alimentary canal, gases of, 276, 280
Alkalies —

Action on toxalbumins, 418

In diabetes, 406
Alkaline phosphates of plasma, 264
Alkaloids —

Isolation from bacterial products,
409-411

Containing cholin, 76
Allantoin, 304
Alloxan, 305
Alumina —

Colloidal form, 44

In soil, 25
Aluminium, circulation of, 25
Amanita phalloides, 416
Amido-acetic acid, 56, n. 2.

Amido-acids, 54

Aromatic, 257

Constitution, 288

Formation, 167-168

Influence on urea, 289
Ammonia —

After extirpation of liver, 311

Efiect of acids on excretion of, 292

Elimination of, in fever, 425

Hydrogen from, 14

Nitrogen from, 17

Precursor of urea, 290
Ammonia, nitrite of, 18
Ammonium carbamate, precursor of

urea, 293
Ammonium cyanite, precursor of urea,

292
Amebse, 3-4
Anemia, 379
Animal heat —

And vital functions, 64

Source of, 31-34
Animal life and vegetable, interdepen-
dence, 14, 16
Animals —

Containing chlorophyll, 39

Contrasts between plants and, 38-40
Anthrax bacillus —

Action of gastric juice and HCl on, 142

Influence of temperature on activity,
421
Antipyretic remedies in fever, 421, n. 2
Appetite, stimulation of, 11
Arcellfe, possible psychical processes in, 7
Argenin, 289
Aromatic hydrocarbons, 258

Sulphates, 256 ; in urine, 324
Arsenic, influence on nitrogen excre-
tion, 121
Arsenical poisoning, 426
Artificial feeding of infants, 108-112
Ascitic fluid, 226
Ash—

Of dog's blood, 83 ; dog's blood
serum, 83 ; dog's milk, S3, 377 ;
milk of ditferent mammals, 105 ;
puppy, 377 ; sucking animals, 83

Of meat extract, lime in, 126
Aspartic acid in the body, 289

T5 A PTT^'TIT A

Action of HCl on, 131-132, 142-143 ;

heat on, 161 ; leucocytes on, 222-

223
Action on cellulose, 163; on formate

of lime, 156-157
Optimum temperature, 420-421
Relation to infectious diseases, 408,

411-413

29

449

450

INDEX

Bacteria — continued

Eole of, in the maintenance of
organic life, 17-19
Bacterial poisons, 409-415
Benzoic acid, 282
Benzol, oxidation of, 256
Benzolic acid, formation of, 248
Beta altissima, 102
Bile, 176-186

Acids, 177-178 ; their origin, 336

Action on fat, 183-184

Antiseptic property, 185-186

Composition, 180-181

Constituents, 176-180

Functions, 182-186

Pigments, 178-179 ; their origin, 336,
337
Bilirubin, 178 ; origin of, 337
Biliverdin, 178
Blood-
Changes in, in fever, 425-426

Circulation of, 5

Coagulation of, 200-205

Corpuscles (red), 200, 206-215; de-
struction of, 340 ; in fevers, 425

Effect of extirpation of spleen on,
230 ; CO2 on, 265

Defibrinated, 200, 205, 207-211

Fat in, 189-190

Fibrin, 200, 212-215

Gases of, 238 ; in diabetic coma, 404

Leucocytes, 202, 204, 222, 425

Peptones in, 194-195

Pigment, fate of, 337

Plasma, 205-206, 212-215, 218, 225

Serum, 200, 206-211, 213-215, 216, 225,
262

Sodium in, 208

Sugar in, 188-189, 388

Tension of CO2 in, 262
Blood-vessels in fever, 423
Bone-substance, effect of extirpation of

thyroid on, 435-436
Bones, fluorin in, 24
Bouillon, food value of, 124-128
Brain, injury and temperature, 423
Bread, digestion of, 69, 72-74
Bromin, circulation of, 24
Brown bread, 69, 72-73
Burial versus cremation, 18-19
Burns, effect of, 275
Butyric fermentation, 142-143, 158-
159, 251, 277

Cachexia strumipriva, 432, 435, 442-443
Caffein —

Action, 123-124

Effects, 319

Occurrence, 123
Calcium, circulation of, 20
Cane-sugar, decomposition, 155-156
Carbohydrates —

A source of energy, 349

Absorption of, 71

As food, 42, 43, 60-74

Decomposition of, 255

Diminished assimilation of, 389

Effect on glycogen, 345

Fat formation from, 366

Pancreatic digestion of, 162-163
Carbon, circulation of, 13-14

Carbonate of soda in

Intestinal juice, 174-175

Pancreatic juice, 165
Carbonic acid —

Balance of oxygen and, 14-17

Circulating medium of carbon, 13-14

Effects of its retention, 268

Excretion of, 221, 439

In respiration, 261-271

Intoxication, 404

Of muscle, 350

Output in fever, 422

Production in intestines, 278

SolubUity of, 261

Struggle with silicic acid, 15-16

Tension in tissues, 267
Carbonic oxide, effects of, 242; hemo-
globin, 240
Carmine, excretion by kidneys, 318
Cartilage, gelatin of, 55; sodium in,

102-103
Caseinogen, 109
Cell life, continuity of, 64-65
Cells, functions of, 3-6, 137, 147
CeUulose, digestion of, 71-74, 163, 277 _
Central nervous system, effect of thyroi-
dectomy on, 434
Cephalopods, 26
Cereals, food value of, 70-71
Cerebrospinal fluid, 225, 226, 227
Cetacea, absence of salivary glands in,

130
Chemical elements, 13-26
Chemical potential energy, 29 ; conver-
sion into different forms of energy,
35-36
Children (see also Infants), food com-
pared with that of adults, 70, 82,
84-85
Chlorids, 83
Chlorin, circulation of, 20; in febrile

urine, 426-427
Chlorophyll —

In plants and animals, 38—40

Belation to iron, 22
Chocolate, value as food, 124
Cholalic acid, 177, 337
Cholesterin, 80-81, 179
Cholin, 75-76, 409
Chondrin, 42 ; composition, 179
Chyle, 187-188, 225
Circulation of blood, 5
Cirrhosis of liver, 295
Citric acid, as food-stuff, 42
Coagulation of blood, 200-205
Coal, carbon as, 14
Cocoa bean, 124
Coffee, 122-124
Cola nut, 123
Collidin, 411
Colloids, 44-45
Colostrum, 107
Colpodella pugnax, selection of food

by, 4

Combustion, effect on organic life, 18
Comma bacillus, action of HCl on, 142
Consciousness, relation to space, 2
Conservation of energy, in inorganic
nature, 27-30 ; law of, 29 ; relation
to animal life, 31-34; to psychical
processes, 34, 36-38

INDEX

451

Constipation, some causes, 72

Copper, circulation of, 26
Oxid of, colloidal form, 45
Compound of egg albumin, 51

Creatin, 125, 128, 296 ; synthesis of, 297

Creatinin, 125, 128, 297

Cremation versus burial, 18-19

Crustacea, copper in blood of, 26

Crystalline proteid, 46

Crystalloids, 46

Cystein, 327

Cystin, 327

Dextrin, 162

Diabetes, 386-407
Glycogen formation in, 346
Insipidus, 402
Pancreatic, 398
Phloridzin, 346

Diabetic coma, 391, 403
Puncture, 395

Diamond, carbon as, 14

Diatomacese, silica of, 23

Diet-
After thyroidectomy, 438
Percentage of food-stuffs in articles

of, 64-74
Regulation, 145

Diffusion and vital processes, 3-4

Digestion —
Artificial pancreatic, 163
Influence of alcohol on, 121
Pancreatic — see Pancreatic Juice
Poisonous products of, 417

Diphtheritic toxin, 413-414, 418

Diuretics, effects of, 319

Dolium galea, 133-134

Duodenal fistula, 278

Dyspnea, on mountains, 242

EcK's fistula, 296
Egg-albumin, 45

Copper compound of, 51

Crystallization of, 52

Proportion of sodium and potassium
in, 98

Silver compounds, 51-52
Eggs—

Fluorin in, 24

Silicic acid in, 24
Elastin, 58-59
Electric currents in nerve and muscle,

5
Electrical discharges in the atmosphere

formation of nitrites by, 18
Endothelial cells —

Nerve supply, 228

Of capillary wall, selective activity,
219-221
Energy, conservation of, 27
Enzymes, 416-418
Epithelial cells —

Of bile-ducts, 179

Of glands, 4, 83-84, 137, 138, 428

Of intestine, in food absorption, 3
Ethereal sulphates, 325
Evolution, theory of, salt in animals

explained by, 101-103

Fat—

Formation, 358-369

Fat — continued

In milk in different climates, 107-
108

Selection of, by epithelial cells, 3-5

Synthesis of, 361
Fats-
Absorption of, 71, 174, 184-185, 189-
191

Action of bile on, 183-184

As food-stuffs, 43, 60-74 ; as sources of
energy, 351

Conversion to sugar, 346

Emulsification of, 164-165, 174 •

Pancreatic digestion of, 163-165
Fatty acids in food, 360
Feathers, silicic acid in ash of, 24
Fermentation —
Feces, 79, 80

Alcoholic, 143, 158-159

Butyric, 142-143, 158-159, 251,277

Hydration always accompanies, 158-
159

In stomach, 143-144

Intestinal, 271

Lactic, 142-143, 158-159
Ferments, 152, 155-161

Ammoniacal, 322

Diastatic, 160

Heat, influence on activity of, 160-161

Isolation, 159

Organized and unorganized, 158-159,
161

Pancreatic, 161-171

Pepsin, 160

Rennet, 109-110

Yeast cells, 155
Ferrous oxid, oxygen fixed by, 16
Fever, 420-427
Fistula, composition of bile from, 180-

181
Flourin, circulation of, 24
Food-
Absorption of— see Absorption

Composition, 65-67
Daily ingestion (adults), 113-114

Digestibility of different kinds, 68-74

Of infants, 104-114

Potential energy of, 31

Selection of, by cells, 3-4
Food-stuffs —

Classes of, 42^3

Definition of term, 41

Digestibility of different, 68-74

Heat equivalent of, 61

Inorganic, 82-103

Iron in, 376

Organic, 42-81

Producing muscular energy, 63-64
Formate of lime, decomposition, 156-

157
Formic acid, 157

GALL-bladder, composition of bile from,

180
Gases —

Of alimentary canal, 276

Of blood, 229-280
Gastric juice, 130-150

Antiseptic action, 131-134, 142

Artificial, 160-161

Different reactions of, 138-139

452

INDEX

Gastric juice — continued

Pathological, 144

Reflex secretion of, 115-116
Gastric mucous membrane —

Alkaline reaction of, 134

Softening of, 145
Gastric ulcer, cause of, 147-148
Gelatin and gelatin-yielding substances,

42, 54r-59, 68, 125, 130-131, 177, 288
Glands —

Activity of, 83-84

Ductless, 428-447

Epithelial cells of, 4
Globulin, 46-54
Globulins —

In blood serum, 216

In muscle, 217
Glomeruli, 318
Glutin, 42

Glycerin, in diabetes, 406 ; in fat for-
mation, 361
Glycocholic acid, 177, 178
Glycocol, 177

Glycogen, formation of, 342-347; in
diabetes, 396; effect of diabetic
puncture, 395
Glycosuria, 386-407
Glycuronie acid, 259, 390
Goiter, 431-i33, 444 _
Gout, excretion of uric acid in, 302
Grape-sugar —

Decomposition, 154-155

Oxidation, 247
Graphite, carbon as, 14
Guanidin, 298
Guanin, 77, 314

Haik, silicic acid in ash of, 24
Heart-burn, 144
Hematin, fate of, 338
Hematogen, 375
Hematoporphyrin, 338
Hemoglobin, 21-22

Amount in blood, 206-207, 210-215

Combination with oxygen, 141

Crystals, 49-51
Hemoglobinuria, 339
Heat —

As source of motion, 29-31

Animal, source of, 31-34

Diminished loss of, in fever, 422-423

Effect on ferments, 153-161

Formation in decomposition of carbo-
hydrates, 346

Produced by work, 28-29, 31, 35
Heat-equivalents of food-stuffs, 61-62
Heat-regulation, effect of alcohol on,

117-118
Hippuric acid, 256, 259, 281-287
Human milk —

Analysis of, 104

Composition of, 104-109
Hydrobilirubin, 323
Hydrocele fluid, 226
Hydrochloric acid —

A remedy in dyspepsia, 144

Action, antiseptic, 131-132; possible
digestive, 130-131

Avidity of, 136

Formation from blood, 134-137, 139

Liberation of, 135-139

Hydrogen —

Circulation of, 14

Formation of, 251

In alimentary canal, 277

Peroxid of, 154
Hydrolytic ferments, 416-418
Hypoxanthin, 77, 313 ; in birds, 309

Immunity, 421
Indian cobra, toxin of, 418
Indigo, in urine, 324
Indol, 256 ; fate of, 324
Infants, food of, 104-114
Infection, 408-419

Inorganic salts, role of, in adult organ-
ism, 86-90
Inosit, 402 _
Insects, sodium in, 102
Internal sense, 1-2, 6, 9
Intestinal juice, functions of, 173-176

Obstruction, aromatic sulphates in,
325

Parasites, respiration of, 353

Wall, tension of COj in, 268
Intestine —

Epithelial cells of, 3-4

Excretion of iron by, 373

Fermentation in, 271

Gases of, 276, 278

Peristalsis of, influence of food, 71-73
Inulin, utilization by diabetics, 393
Invertebrates, sodium in, 102
Invertin, 156
lodin —

Circulation of, 23-24

In thyroid gland, 439-440
Iodoform, 440, 441
lodothyrin, 440, 441
Iron, 370-385

Absorption of inorganic, 371

Amount in body, 370

Circulation of, 21-22

Excretion of, 373

In young animals, 378

Of liver, 342

Oxidation of, 254
Iron, oxid of, colloid form, 44-45

Jaundice, pathology of, 339
Jequirity seed, 416

Keratin, 58
Kidneys —

Extirpation of, 293, 309

Functions of, 316-333

Hippuric acid formed in, 285

Overworked by excessive salt diet,
100

Pathogenic bacilli in, 426
Kinetic energy —

Conversion into other forms of energy,
27-29; 35-36

Liberation by chemical processes, 153

Of sunlight, 29-31
Koprosterin, 80-81

Lactic acid-
Excretion after extirpation of liver,

311
Formation, 355
From sugar, 390

INDEX

453

Lactic acid — continued

In diabetes, 406

Of urine, 331
Lerulose, utilization of, 392
Lathrodectes tredecimguttatus, 416
Lecithin, 75-77, 179
Leguminosse, 17-18, 70
Leukemia, uric acid in, 307
Leucin, 167
Leucocytes —

Blood coagulation and, 202-204

Digestion and, 197-198

Function of, 222-223

Increase of, in fevers, 425
Lieberkühn's glands, 172, 175
Lime —

In milk of different mammals, 106

Necessity for, in children's food, 84r-
85
Lime, formate of, decomposition, 156-

157
Limestone, 16
Liver —

Extirpation of, 296 ; in birds, 310

Glycogen formation in, 342

Iron in, 342

Metabolism in, 334-347

Urea formation in, 294
Lung catheter, 265
Lungs, tension of gases in, 266
Lymph, 21&-228

Cells, and digestion, 197-198

CO2 in, 267

Composition of, 225-228

Formation of, 219

Functions of, 222-223

Glands, function of, 223

Rate of flow, 219

Relation to cell nourishment, 219-221

Spaces, uses of, 222
Lysatin, 298
Lysin, 289

Magnesia compound of globulin, 46-

49
Magnesium, circulation of, 20
Maize, silicic acid in ash of, 23
Malic acid, 42
Malpighian bodies, 318
Maltose, 162

Mammals, composition of milk of dif-
ferent, 104-109
Manganese, circulation of, 25
Marsh-gas, 277
Mass influence, 136, 240, 263
Meat, nutrient value, 68
Meat diet, and need for salt, 90-100

Extracts, food value of, 124-128
Mechanism, as an explanation of vital

processes, 1-12
Metabolism —

During work, 349 ; during mental
work, 36-38

In fever, 421-424

Influence of alcohol on, 120 ; of thyroid
gland on, 439, 442

In liver, 334-337

Nitrogenous end-products of, 281

Products of bacterial, 408-419
Methylamin, 411
Methylguanidin, 410

Milk-
As food, 65-70, 104-114

Ash of, 82-83, 105, 376

Cholesterin in, 80

Composition, 65-67, 82, 104-114

Inorganic salts in, 81-86, 97, 98, 105

Iron in, 376

Lecithin in, 77

Nucleins in, 79 and n. 2
Milk diet, bad effects of, 72, 383
Millon's reaction, 56, n. 2
Molluscs, secretion of, 133-134
Monotropa, 39
Motion, different forms of, 27; origin

of, 29-30
Mucin, 179
Mucoid, 179-180
Muscarin, 76
Muscles —

Action of creatin and Creatinin on,
128

Functions of, how far explicable, 5

Destruction of sugar in, 394

Gases of, 350

Glycogen in, 343

Metabolism of, 294 _

Skeletal, in starvation, 216

Storage of proteid in, 217

Urea m, 297
Muscular energy, source of, 63, 64, 348-

357
Myxedema, 430

Nekve functions, how far explicable, 5
Nervous system, effect of thyroidectomy

on, 439
Neuridin, 410
Neurin, 409
Nitroglycerin, 153
Nitrogen —

Circulation of, 17-18

Elimination, 63, 120-121; in work,
349 ; in fever, 424-425

In feces, 69

In intestines, 276

In respiration, 237
Nitrogen, iodid of, 154

Trichlorid, 153, 154
Nitrogenous end-products, 281

Equilibrium, maintenance of, 193

Food, heat-equivalent of, in the body
and calorimeter, 63
Nucleic acid, 78-79
Nucleins, 77-80, 374

Obesity, 368
Organic acids —

As food-stuffs, 41-42

Avidity_ of, 136

Formation of, in the blood in fevers,
425
Organic compounds of iron, 373
Ornithin, 287, 298
Ornithuric acid, 287
Osmosis and vital processes, 3-4
Ossein, 42

Ovaries, iodin in, 25
Ovurp, development from, 4
Oxalic acid —

Fate of, in the body, 332

In urine, 331

454

INDEX

Oxaluric acid, 305
Oxidation —

In blood, 243

In diabetes, 389

In tissues, 244

Mechanism of, 247
Oxidizing property of tissues, 248
Oxybutyric acid, 312, 391
Oxygen-
Absorption of, 238_

Balance of carbonic acid and, 14-17

Carriers, 253

Circulation of, 14-17

In respiration, 237-260

In saliva, 246

Inspired, as a food-stuff, 42

Intake in fevers, 422

Eequirements of different animals,
353
Oxyhemoglobin, 240; dissociation of,

242
Ozone, 248
Pancreas, 152, 166 ; extirpation of,

398
Pancreatic diabetes, 398

Juice, 151-152, 161-171 ; action on
carbohydrates, 162-163; fats, 163-
166, 184-185; proteids, 166-171
Para nut, crystalloids, 46
Parabanic acid, 305
Parasites, metabolism of, 253
Pepsin, 160-161
Peptones —

Different forms of, 169-170

Fate of, 197-199

Formation of, 166-169

In urine, 199

Nature of, 171, n.

Regeneration of, 194-197
Pericardial fluid, 226
Peritoneal transudation, 226
Perspirahile retentum, 272
Perspiration, 275
Phenol, fate of, 257
Phloridzin diabetes, 346, 387
Phosphates of blood plasma, 263, 264
Phosphoric acid —

In milk of different mammals, 106

In plant life, 20
Phosphorus —

Circulation of, 20

Compounds, 75-80

Influence of nitrogen excretionon, 121

Oxidation of, 255

Poisoning, 426 ; assimilation of sugar
in, 398
Pigments rejected by epithelial cells,
3-4

Bile, 178 ; origin of, 336

Urinary, 323
Pinnipedia, salivary glands in, 130
Pituitary body, 446-447 ; iodin in, 25
Plants —

Contrast between animals and, 38-40 ;
interdependence, 14, 16

Iron in, 22

Silicic acid in, 23

Sodium in, 102
Pleural fluid, 226

Poisons — see Arsenic, Bacteria, Phos-
phorus

Polyuria in diabetes, 402
Potassium, circulation of, 20
Potassium chlorate, dissociation of, 154
Potassium salts —

Action of, 126-127

Distribution over the surface of the
globe, 101

In food, 83-103, 105

Injection of, into blood, 127
Potatoes —

Food value of, 68-70

Potassium salts in, 92, 97
Potential energy —

Chemical, 29

Conversion into kinetic energy, 27-29,
35-36

Of plants, 30
Proteid —

Absorption, 68-71, 191-199

Amount in different food-stuffs, 65-68

Classification and properties, 43-45

Conversion into peptones, 168-169;
reconversion of peptone, 197-199

Crystallization of, 46-54

Decomposition of, 288

Digestion of, 68-70

Disintegration of, in fever, 424-425

Effect on glycogen, 345

Fat formation from, 363

Gastric digestion of, 130-131

Importance as food-stuffs, 43 ; in vital
processes, 64

In blood serum, 207, 216

In Ij^mph, 228

In milk of mammals, 105-106

Molecular weight of, 47

Of bacterial poisons, 413-415

Pancreatic digestion of, 166-171

Source of energy, 351
Ptomains, action of, 412-413
Pulmonary catheter, 265
Putrefaction, alkaloids of bacterial, 409-

413
Pylorus —

Alkaline secretion of, 138

Resection of, 139
Pyrogallol, oxidation of, 250

Quinine, action on cells, 287

Effect on formation of uric acid, 308
Quotient, respiratory, 270

Rattlesnake, poison of, 418

Red marrow, changes after extirpation

of spleen, 231-232
Reducing powers of tissues, 341
Reflex secretion of gastric juice, 115-116
Rennet, action on milk, 109-110
Respiration, 229-280 ; at low pressures,
241
Cutaneous, 271
Respiratory exchange, 270 ; in diabet-
ics, 390
Respiratory foods, 63

Quotient, 270
Rhizopods, method of taking up food, 3
Rice —
Potassium salts in, 96-97
Suitability of, in renal disease, 100-
101
Rickets, 85

INDEX

455

Rock crystal, 46
Ruby, 46

Saliva, 129-130, 246

Salmon, synthesis of lecithins and nu-

cleins in, 79-80
Salt frog, 246

Saltpeter, formation of, 252
Secretions, cell functions in process of, 4
Serum of blood, 200, 206-211, 213-215,
216, 225

Salts of, 262
Serum-albumin, 45
Silicic acid, struggle with carbonic acid,

15-16 ; colloid form, 44
Silicon, occurrence, 23-24
Silver compounds of egg albumin, 51-

52
Skin, exchanges through, 274
Snake poison, 416
Soaps, formation in digestion, 164^165 ;

in bile, 179 ; in blood serum, 216
Sodium —

Circulation of, 20

Distribution over the surface of the
globe, 101

In blood, 208

In food, 83-103
Sodium Chlorid, 90-103
Sodium compound of globulin, 47
Specular iron ore, 46
Spermatozoon —

Hereditary transmission through, 8

Nucleic acid from, 79
Spiders, poisons of, 416
Spleen —

Extirpation, 229-234

Functions, 231, 235-236

Influence on uric acid, 307, 308

lodin in, 25

Peptones in, 197
Staphylococcus toxin, 418
Starch, digestion of, 156, 162-163
Starvation, effects of, 392
Sterilization of milk, 110
Stomach —

Functions of, 140-142, 148-150

Extirpation of, 140-141

Self-digestion of, 145-148
Streptococcus toxin, 415
Sugar —

Absorption of, 188-189

Assimilation in phosphorus poison-
ing, 398

Destruction in muscles, 394

Formation from fats, 346

In blood, origin of, 188-189

In normal urine, 331

Levorotatory, in diabetes, 387
Sulphates, aromatic, 256, 325
Sulphocyanic acid, 330
Sulphur —

As oxidizing agent, 21

Circulation of, 20

In proteid, 47-53

Of hemoglobin, 239
Sulphuretted hydrogen, 144, 278
Sulphuric acid —

Action after removal of basic salts
from food, 87-89

Avidity of, 136

Sulphuric acid — continued

Decomposition product from proteid,
87

Elimination in fever, 422

In saliva of molluscs, 134
Sunlight a source of energy, 29-31, 35
Suprarenal capsules, 428-430
Symbionta, 39 n. 4
Synthetic processes in the body, 283

Tartaric acid, as a food-stuff, 42
Taurin 177-178, 327 ; fate of, 329
Taurocholic acid, 177, 178
Tea, 122-124
Teeth, fluorin in, 24
Temperature —

After throidectomy, 436-437

Alcohol, effect on, 118

In fever, 420-424

Its influence on vital processes, 64
Tension of CO2 in blood, 262 ; in lungs,

266
Tetanus toxin, 412-413, 414-415, 418
Tetany, 435, 436
Theobromin, 124
Thiosulphuric acid, 330
Thrombosis, 202
Thymus, 25, 236
Thyroid gland —

Administration of, 439, 443, 444

Connection with pituitary body, 446-
447; with sexual functions, 444-
446

Extirjjation, 431-438

Functions, 442

lodin in, 25

Isolation of active principle, 439-441

Subcutaneous injection of the juice,
439

Transplantation, 438, 442-443
Tissue, non-digestion of living, 145-147

Change and food, 64-65

Development, relation of thyroid to,
434
Tissues, reducing power of, 251
Toxalbumins, 416-419
Toxins, 412-413

Transudations, analyses of, 225-226
Trimethyl - vinyl-ammonium-hydroxid,

409
Tubercle bacillus, 142, 420 ; products

of, 415, 418
Typhoid bacillus, 421
Typhus toxin, 418
Tyrosin, 56 n. 2, 57, 167

Urea—

Constitution of, 288

Excretion increased by rise of tem-
perature, 424

Formation from ammonia, 293
Uric acid, 299

Formula of, 306

Of birds, 309

Oxidation of, 304

Solubility in urine, 322

Synthesis of, 303
Urinary sediments, 301
Urine —

Abnormal acids in, 391

Ammonia of, 295

456

INDEX

Urine — continued

Analysis of, 320

Composition of, 316-333

Cystin of, 327

Hippuric acid in, 282

Indigo in, 324

In fever, 426

Iron in, 22

Peptones in, 199

Pigments in, 323

Sugar in, 387

Uric acid of, 300
Urobilin, 323; formation of, 339; pro-
duction in fevers, 425

Vampyrella Spirogyrce, selection of food
by, 3

Vegetable diet and need for salt, 91-100

Vegetables, nutrient value of, 68-74

Vegetarianism, 70-71

Vertebrates, sodium in, 102

Vital phenomena —
Mechanical explanation of, 1-12
Psychological explanation of, 6, 9-10

Vitalism, 1-2, 10-11
Vorticellse, 40

Water—
Absorption from the stomach, 148
Influence of mass, 136
Necessity of, in the organism, 86
Proportion by weight of oxygen in
total amount of, 14

Woody fiber, in digestion, 71-74

Work-
Definition of, 27
Influence on fat formation, 368
Source of, 348

Xanthin, 77, 308
Bases, 313

Yeast, nucleic acid from, 78 ; nuclein

from, 78
Yeast cells, 155
Yolkofegg, 85, 98

INDEX OF AUTHORS

Abderhalden, E., analyses of blood,

209
Abeles, M. —
Glycogen, 343, 396
Sugar in urine, 331
Abelmann, M., fat absorption after ex-
tirpation of pancreas, 166
Abelous, E., extirpation of suprarenals,

429 ; of thymus, 236
Abrahams, E.., administration of thy-
roid, 444
Addision, T,, disease of suprarenals,

428
Addison, W., fibrin, 202
Adlerskron, B. v., chlorin in cereals,

84 n.
Aeby, glycogen, 345
Afonassiew, N., reducing substances in

corpuscles, 247
Albertoni, acetone, 403
Aldehoflf, G.—
Functions of stomach, 148
Glycogen of muscles, 344
Altmann, nucleic acid, 78
Anderson, metabolism in fever, 424
Andre, A., heat-equivalents of food-
stuffs, 61-62
Andreasch, absorption of caffein, 123
Augerer, O., administration of thyroid,

444
Anrep, B. v., absorption in dog's stom-
ach, 148
Anstie, excretion of alcohol, 117
Argutinsky, P., sweat, 275
Arnold, J. —

Functions of bile, 183
Pituitary body, 447
Amschinck, glycerin, 362
Aronsohn, influence of nervous system

on fevers, 423
Aronstein, solutions of albumin free

from salts, 45 and n. 4
Arthus, M. —
Blood coagulation, 205
Ferments, 109, n. 4 ; 161
Aschaffenburg, G., alcohol, 118
Astachewsky, formation of lactic acid,

355
Aubert —
Cutaneous respiration, 272
Frog without oxygen, 354
Temperature and bacteria, 420
Auerbach, phenol, 257
Autokratow, P. M., extirpation of thy-
roid, 435
Avaldt, synthesis of fats, 361

Baas, acidity of gastric juice, 325
Baer, A., alcohol, 119

Baeyer, v. —

Cholin, 75

Indigo, 324

Neurin, 409

Uric acid, 302
Baginsky, A. —

Acetonuria, 391

Eickets, 85, n. 1

Sterilization of milk, 110
Balfour, J. M., bile fistula, 176
Barbieri, decomposition of proteids, 288
Bard, temperature and bacteria, 420
Barral, salt food for animals, 99
Bartels —

Leukemia, 307

Urea excretion and temperature, 424

Uric acid, 301
Barth, M —

Invertin, 156

Isolation of ferments, 160
Bartholini, lymph, 220 n. 1
Bary, W. de, bacteria in the stomach,

143
Bauer, J. —

Absorption of proteid, 192

Alcohol, 121

Phosphorus poisoning, 363
Baum, P., influence of food on the

composition of milk, 112
Baumann —

Aromatic amido-acids, 257

Cystin, 327

Indigo, 324

Intestinal obstruction, 325

lodin, 25; in thyroid gland, 439,
440, 441

Methyl-guanidin, 410

Nitrous acid, formation of, 250

Oxidation, 251
Baumert, intestines offish, 276
Baumgarten, leucocytes, 223
ßaumgärtner, oxidation in egg, 244
Bayer, H., bile acids, 177
Beadles, administration of thyroid, 444
Beale, L., fibrin, 202
Beaumont, W., gastric digestion, 151
Bechamp, J., peptone, 171
Beneke, crystinuria, 329
Berdez, alcohol, 121
Bergmann, E. v. —

Bacterial poisons, 409

Bile pigments, 339

Transfusion of blood, 205
Bernard, C. —

Carbonic oxid, 240

Diabetes, 386 ; diabetic puncture, 395

Digestion of living tissue, 146

Glycogen, 343; of muscle, 381

Pancreatic juice, 164

457

458

INDEX OF AUTHORS

Bernard — continued

Pvrogallol, 255
Bert, P.—

Effect of low pressure, 241

Poisonous effects of CO2, 268
Berthelot —

Electrical discharges, 18

Heat-equivalents of food-stuffs, 61-62
Berlinerblau, lactic acid, 355
Berzelius, hippuric acid, 283
Bezold, A. v., salt, 98
Bidder —

Absorption of iron, 372

Bile functions, 183 ; biliary fistula,
176

Gastric juice, 130, 132

Pancreatic juice, 165

Saliva, amount in 24 hours, 129 ;
secretion of dog's, 149

Starvation, 216
Biedert, Ph., artificial feeding, 108, 112
Bienstock, B., feces, 143
Bikfalvi, alcohol, 121
Billard, excision of thymus in frog, 236
Billroth, excision of goiter, 432
Binz, C—

Alcohol, 117, 118

Quinine, 287
Bircher, transplantation of thyroid, 442
Birk, L., blood coagulation, 203
Bischoff, E —

Meat extract, 126

Sulphur of urine, 326
Bizzozero, J., blood coagulation, 204
Bleibtreu, administration of thyroid,

443
Bleue, A. M.—

Colloid carbohydrates in portal blood,
163

Sugar in blood-corpuscles, 188, 01. 2
Blondlot, bile functions, 183 ; biliary

fistula, 176
Blumenreich, L. —

Extirpation of thyroids, 435

Pituitary body, 446
Boas, J., H2S in the stomach, 144
Bock, diabetes, 388

Bodländer, G., excretion of alcohol, 117
Boeck, alcohol, 121

Boedeker, analysis of secretion of mol-
luscs, 133-134
Boehm —

Cholin, 76

Glycogen, 365 ; of muscles, 344
Boettcher, A., hemoglobin crystals, 49,

TO. 2 _

Bohland, elimination of ammonia in

fever, 425
Böhm, R., glycogen, 343
Boinet, E., extirpation of suprarenals,

_ 429
Bojanus, N., blood coagulation, 203
Bökay, S.—
Lecithins, 77
Nuclein, 79, n. 3
Bonardi, E., febrile urine, 426
Bondzynski—
Albumin crystals from white of egg,

52-53
Koprosterin, 80
Sulphur of urine, 326

Bossar, decomposition of proteids, 288
Bouchard, febrile urine, 426
Bourgeois, decomposition of proteids,

288
Bourneville, pituitary body, 446
Boussingault, iron and chlorophyll in

plants, 22
Bramwell, B., crystallization of pro-
teids in urine, 53
Brandt, K., chlorophyll granules, 39
Braunschweig, v., thymus, 236
Brefeld, anaerobic fermentation, 158
Breisacher, L., thyroidectomy, 438
Bricon, pituitary body, 446
Brieger, L. —

Bacteria, 143 ; bacterial poisons, 409-
411, 414

Feces, 143

Febrile urine, 426

Indigo, 324

Tetanin, 412
Brown, H. T., digestion of starch, 163
Brown-Sequard, extirpation of supra-
renals, 428-429
Brücke —

Blood, 201

Conversion of proteid to peptone, 167

Digestion of starch, 162

Emulsifying action of alkalies, 165

Glycogen, 343

Isolation of ferments, 159

Reaction of gastric mucous mem-
brane, 134
Brunner, T., changes in composition of

milk, 107
Bruns, administration of thyroid, 443,

444 _
Buchheim, fate of ammonia salts, 291
Büchner, E., fermentation, 155
Büchner, H., natural immunity, 419
Büchner, W., alcohol, 121
Bujwid, 0., tubercle toxin, 415
Bunge, G. —

Analyses of blood, quantitative, 207 ;
comparative, of ash, 82-83, 105

Composition of milk, 107

Dog's milk, 220

Effect of potassium salts on gastric
mucous membrane, 101

Hippuric acid, 284

Inorganic salts, 88

Intestinal parasites, 353

Life without oxygen, 244

Meat extract, 126

Nuclein, 78

Organic iron, 373

Uric acid, 302
Bumm, temperature and bacteria, 420
Bunsen, gas analysis, 229
Bun tzen, vegetable diet, 71
Burckhardt, blood in starvation, 216-

217
Busch, emptying of the stomach, 151

Cahn, a., acids in the stomach, 144
Cannon, gastric digestion, 129
Cantani, diabetes, 386
Carvallo, J., extirpation of stomach,

140
Cash, Th., absorption of fats, 175
I Catou, R., pituitary body, 447

INDEX OF AUTHORS

459

Cattani,' bacterial poisons, 411, 413, 414,

419
Caussade, G., suprarenal capsules, 430
Cazeneuve, P. —

Ammoniaeal decomposition, 322

Phosphorus poisoning, 363

Sterilization of milk, 110
Cech, urea in birds, 309
Chittenden, R. S.—

Composition of elastin, 58

Digestion of proteids, 167, 171
Chossat, starvation, 216
Chrzonsczewski, indigo injection, 318
Cienkowski, L., [food selection by

amebse, 3-4
Cleve, cholalic acid, 177
Cloetta, M., assimilation of iron, 380
Coen, E., secretion of milk, 113
Cohnheim —

Isolation of ferments, 159

Salt-frog, 246
Cohnstein, lymph, 218
Coindet, iodin administration in goiter,

440
Colasanti, metabolism in fever, 422
Collis, A. J., pituitary body, 447
Connini, pituitary body, 447
Copeman, biliary fistula, 176
Coranda, excretion of ammonia, 292
Cordua, H., bUirubin,_388
Corvisart, pancreatic juice, 166
Costanzo, administration of thyroid,

443
Coutaret, L., digestion of starch, 162
Cramer, sweat, 275
Cristiani, H. —

Accessory thyroids, 435, n. 5 ; 436

Extirpation of thyroid, 437
Czerny, V. —

Absorption of proteids, 192

Extirpation of dog's stomach, 140

Dallemagne, M., pituitary body, 447
Danilewsky —

Attempt to isolate three pancreatic
ferments, 161

Comparison of heat-equivalents of
gelatin and proteid, 56, 171

Globulin in muscles, 217

Heat-equivalents of food-stuiFs, 60-62

Isolation of ferments, 159

Proteid in muscles, 217
Dastre, A. —

Extirpation of spleen, 230

Fat absorption, 184-185
Debray, decomposition of formic acid,

157
Deichmüller, febrile urine, 425
Demant, intestinal juice, 173-174
Demesmay, salt food for animals, 99
Demme, action of alcohol, 122
Dennig, administration of thyroid, 443
Desaive, salt food for animals, 99
Despretz, source of animal heat, 33
Dessaignes, synthesis of hippuric acid,

282
Deville, decomposition of formic acid,

157
Diakonow, lecithin, 75, 76
Ditmar, C. v., salt and meat diet,

93-94

Dominicis, X. de, extirpation of supra-

renals, 429
Donath, E., invertin, 156
Donders, carbonic acid, 263
Dragendorft^—

Absorption of caffein, 123-124

Bile acids, 336
Drechsel, E. —

Active principle of thyroid, 441

Diamido-acids, 289

Iodin, 25

Lysatin, 298

Organic silicon compound in birds'
feathers, 24

Ornithin, 287

Proteids, 45, 47

Urea, origin from carbonate of am-
monia, 292
Dreser, H., alcohol, 117
Drosdofif, analyses of portal and hepatic

blood, 335
Dulong, source of animal heat, 33
Dupre, excretion of alcohol, 117

Ebbstein—

Cystin in urine, 329

Gout, 302

Urinary calculi, 321
Eberth, J. C, origin of thrombi, 202
Eck, fistula of, 296
Edkins, pancreatic ferment, 161
Edmunds, A., rennet ferment, 109
Ehrlich—

Reducing substances, 251

Reduction in tissues, 341
Ehrenmeyer, lactic acids, 312
Eichhorst, absorption of proteids, 192
Eiselsberg, A. v. —

Excision of goiter, 433

Thyroid gland, 401, 444; extirpation
of, 435, 437 ; transplantation of, 438-
439
Elsässer, softening of the stomach, 145
Emelianow, P., extirpation of spleen,

229, 230, 232
Emich, antiseptic properties of bile,

185
Emminghaus, lymph-formation, 318
Engelmann —

Arcellse, 6-7

Chlorophyll, 39-40
Entz, G., chlorophyll-granules, 39
Erman, intestinal gases, 276
Etzinger, J., digestion of cartilage and

bone, 58 ; of elastin, 59
Ewald, C. A., administration of thy-
roid, 443, 444
Ewald, J. R.—

Extirpation of thyroid, 435, 437

Pituitary body, 446

Falk, tubercle bacillus, 142

Favre, heat-equivalents of food-stuffs,

61-62
Fechner, on sensations, 37
Feder, fate of ammonia in the body,

291
Feer, E., infant feeding, 108, 111, 112
Fehr, C, extirpation of salivary glands,

130
Feiertag, H., blood coagulation, 203

460

INDEX OF AUTHORS

Fick—

Artificial gastric juice, 160

Ascent of Faulhorn, 348
Filehne, action of theobromin, 124
Filippi, F. de, extirpation of stomach,

140
Finger, temperature and bacteria, 420
Finkler, D., metabolism in fever, 422
Finn, B., glycogen, 345
Fischer, E., 314

Caffein, 123

Uric acid, 302 ; reduction of, 314
Fischer, J., thyroid gland, 445
Flavard, sulphur of urine, 326
Flaum, M., artificial gastric juice, 160
Fleischer —

Bile acids, 336

Leukemia, 307
Flügge, analysis of portal blood, 335
Foa, P., suprarenal capsules, 430
Fokker, A. P., alcohol, 120
Forster —

Albuminuria, 317

Nitrogenous excretion, 193

Role of inorganic salts in the adult
organism, 87
Frank, action of HCl on certain bac-
teria, 142
Fraenkel, A. —

Anaerobic fermentation, 158

Influence of rarefied air, 241

Temperature and bacteria, 420

Metabolism in fever, 422
Fraenkel, C, bacterial poisons, 414
Fraenkel, S. —

Active principle of thyroid gland, 441

Suprarenal capsules, 430
Frankland —

Analysis of porpoise milk, 104, 105

Heat-equivalents of food-stufls, 60-62
Fredericq —

Blood coagulation, 203

Copper in blood, 26

Digestion in higher and lower ani-
mals, 152

Salivary glands of the octopus, 134
Frerichs —

Composition of bile, 180

Diabetes, 386

Freudenreich, E. v., bacteria in milk,
110
Freund, milk diet, 383
Freund, H. W., thyroid gland, 445
Frey, M. v. —

Emulsifying action of alkalies, 165

Gases of muscles, 350

Lactic acid in muscle, 355
Friedel, C, silicon compounds, 23
Friedländer, efiects of CO2, 268
Frommel, secretion of milk, 113
Fubini, respiration in frogs, 271
Funke, C, perspiration, 275
Fiirbringer —

Metabolism in fever, 422

Oxalic acid, 331
Fürer, C, alcohol, 118
Fürst, L., sterilization of milk, 110
Fürth, O. v., suprarenal capsules, 430

Gad, J., emulsifying action of alkalies,
165

Gaehtgens, C, diabetes, 392
Gaglio, G.—

Lactic acid, 355

Oxalic acid, fate of, 332
Gara, G., thyroid administration, 444
Garnier, P., action of alcohol, 122
Garrod —

Gout, 302

Urobilin, 323
Gaule, A. L., splenic functions, 235
Gaule, J. —

Absorption of iron, 372

Carbonic acid, 263
Gautier —

Bacterial poisons, 409

Xanthin, 314
Gavarret, source of animal heat, 34
Geddes, P., chlorophyll granules, 39
George, W. H., administration of thy-
roid, 444
Georgiewsky, K., influence of thyroid

on metabolism, 439
Geppert, J. —

Alcohol, 121

CO2 in febrile blood, 425

Gas analysis, 237

Influence of rarefied air, 241
Gergens, methyl-guanidin, 410
Gernet, administration of thyroid, 444
Giacosa —

Aromatic hydrocarbons, 258

Oxidation, 250

Spleen, 308
Gilson, E., lecithin, 75
Girard, H., influence of the nervous

system on fevers, 423
Gley-

Antiseptic properties of bile, 86

Extirpation of thyroid, 435

Reaction of intestinal contents, 152 175
Goldmann, E. —

Cystin, 327, 329

lodothyrin in goiter, 441
Gorup-Besanez —

Analysis of liquor pericardii, 226

Composition of bile, 180
Götschel, E. v., blood coagulation, 203
Gottlieb, iodothyrin after thyroid-
ectomy, 441
Gräbner, F., bacterial poisons, 409
Graham —

Colloids, 44

Decomposition of bisulphate of
potash, 138
Grimaux —

Alantoin, 304

Colloids, 44, 45
Grohmann, W., blood coagulation, 203
Groth, O., blood coagulation, 203
Grube, K., levulose in diabetes, 293
Gruber, G. —

Digestion of starch, 162, 163
Grübler, G., proteid crystals, 48
Grünewaldt, O. v., gastric digestion,

151
Gscheidlen, sulphocyanids, 330
Gubler, analysis of lymph, 225
Guerin, sulphur in urine, 326
Gull, Sir Wm., thyroid gland, 430
Gumlich, G., elimination of ammonia
in fever, 425

INDEX OF AUTHORS

461

Gunning, anaerobic life, 244

Giirber, albumin crystals from blood

serum, 53
Gyergyai, A., peptones, 194, 195

Habermann, decomposition of Pro-
teids, 288
Hadden, B., thyroid gland, 431
Hahn, M.—

Natural immunity, 419

Tubercle toxin, 415 _
Haldane, carbonic oxid, 242
Hale-White—

Influence of the nervous system in
fever, 423

Levulose in diabetes, 393
Hall, absorption of iron, 372
Hallervorden, ammonia, 292; in urine,

312 ; its elimination in fevers, 425
Halliburton, W. D —

Analysis of cerebrospinal fluid, 227

Mucin in abdomen after thyroidec-
tomy, 436
Hambui'ger, H. —

Absorption of iron salts, 372

Action of gastric juice on pathogenic
bacteria, 142
Hammarsten, O. —

Analysis of bile, 181 ; of hydrocele
fluid, 226 ; of milk, 109

Bile acids, 177, 178

Blood coagulation, 203

Ferments, 159

Nuclein of milk, 79

Rennet ferment, 109

Salivary digestion, 129
Hammerbacher, excretion of oxalic

acid, 332 n. 4
Hanau, A., intestinal juice, 175
Happel, functions of the stomach, 148
Harley, V.—

Absorption of fat after extirpation of
pancreas, 166

Reaction of intestinal contents, 152
Harnack, E. —

Copper compound of egg albumin, 51

lodin drugs, 24, 441

Lecithins, 76
Hart, A. S., composition of elastin, 58
Haubner, digestion of cellulose, 71
Häusermann, anemia, 379
Haycraft, levulose, 393
Hayem, G.j blood coagulation, 204
Hedin, argmin, 289
Hedon, E —

Absorption of fat after extirpation of
pancreas, 166

Pancreatic diabetes, 398
Heidenhain —

Absorption of fat, 190

Lieberkiihn's glands, 176

Lymph, 218, 219

Pancreatic ferment, 161

Reconversion of peptones, 198

Secretions of gastric glands, 139

Secretion of HCl by glands of cardiac
end of stomach, 132

Sulphur cyanates, 330

Urinary secretion, 317
Heidenschild, W. , poison of rattlesnake,
418

Heller, J. F., chlorin in febrile urine,

427
Helman, M. C, tubercle toxin, 415
Henneberg, decomposition of cellulose

in the alimentary canal, 163
Henninger, A., peptones, 170, 171
Hen sen —

Analysis of pathological lymph, 226

Glycogen, 343
Herter, efiects of CO2, 268
Hermann, L. —

Cutaneous respiration, 273

Gaseous exchanges of muscle, 252

Hemoglobinuria, 339

Nitric oxid hemoglobin, 240

Synthesis of proteid, 57
Heron, J., digestion of starch, 163
Herroun, E. F., biliary fistula, 176
Herth, R., peptones, 167, 170
Hertwig, 0., 39

Heubach, H., excretion of alcohol, 117
Heubner, O. —

Iron, 382

Rennet ferment, 110
Heuss, lactic acid, 331
Heyl, N., blood coagulation, 203
Hildebrandt, H —

Action of enzymes, 417

lodothyrin in goiter, 441
Hill, uric acid, 302
Hlasiwetz, decomposition of proteids,

288
Hobart, J., uric acid synthesis, 383
Hochhaus, absorption of iron, 372
Hoffman, A., hippuric acid, 287
Hoffmann, Ferd., blood coagulation,

203
Hofmann, A. W., neurin, 401
Hofmann, C. B., intestinal gases, 276
Hofmann, F. A. —

Diabetes, 388, 402

Proteid in lymph, 228
Hofmann, Fr. —

Absorption of proteid, 69

Cellulose, 73

Creatin in muscle, 128

Fat formation, 358, 364

Glycogen, 343, 365

Urinary sediments, 301
Hofmeister, Fr. —

Action of pancreatic ferment on gela-
tins, 166

Change in composition of milk, 107

Crystallization of egg albumin, 52

Diabetes, 392

Extirpation of thyroid, 434, 435

lodothyrin in goiter, 441

Peptones, 171, 194-99

Peptonuria, 199
Pituitary body, 446
Hone, J., bile acids in urine, 336
Hopkins, F. G.—

Crystallization of proteids, 53

Urobilin, 323
Hoppe-Seyler —

Action of heat on ferments, 160; of
bacteria on formate of lime, 156-
157

Anaerobic fermentation, 158

Analyses of transudations and cere-
brospinal fluid, 225-227

462

INDEX OF AUTHORS

Hojjpe-Seyler — continued

Bile-acids, 178 ; in urine, 336 ; analy-
sis of, 180-181 ; composition of, 180

Blood extravasations, 339

Carbonic oxid, 240

Digestion in higher and lower ani-
mals, 152; of cellulose, 163

Gases in the stomach, 143

Hemoglobin, 215, 239 ; after burns,
275

Hydration and fermentation, 159

Intestinal juice, 175

Lecithin, 75, 77

Nitric oxid hemoglobin, 240

Oxygen in saliva, 246

Proteid as acid, 264

Eennet ferment, 109

Urobilin, 324 ; in fevers, 425
Horbaczewski —

Creatin, 297

Digestion of elastin, 59

Uric acid in spleen, 308
Horsley, V., extirpation of thyroid,

434, 435, 436
Hoyer, red bone marrow, 231
Huber, A., ferments, 161
Hueppe, F., lactic and butyric acids,

143
Hüfner, G —

Carbonic oxid, 240

Ferments, action of heat on dried,
161 ; isolation of, 160

Hemoglobin, 215, 239

Isolation of pancreatic ferment, 162
Huldgren, E., absorption of proteid, 69
Hun, thyroid gland, 431
Hundeshagen, lecithin, 75
Hunter, J., self-digestion, 146
Hiippe, effect of temperature on dried

ferments, 161
Huschke —

Lung surface, 267

Thyroid gland, 434

Hutchinson, ß., active principle of
thyroid gland, 441

Iesai, a. —
lodothyrin in goiter, 441
Thyroid administration, 444

Jacobsen, bile, 178, 180

Jacoby, C, extirpation of suprarenals,

429
Jacoby, M. —

Extirpation of thyroid, 435

Pituitary body, 446
Jaquet, A. —

Alcohol, 117-118

Hemoglobin, 239, 375

Sulphur in proteid, 50
Jaffe —

Cystin, 327

Glycuronic acid, 260

Hematoidin, 338

Indol, 324

Ornithin, 287

Urea in birds, 309

Urobilin, 323
Jaksch, V. —

Acetonuria, 391

Ammoniacal fermentation, 322

Jaksch — continued

Metabolism in fever, 425

Peptonuria, 199
Jennaret, decomposition of proteid, 288
Jolyet, respiration of aquatic animals,

268
Jong, de —

Diabetes, 392

Pyrocatechin, 258
Juvalata, phthalic acid, 257

Kadkin, p. R., secretion of milk, 113
Kaiser, removal of dog's stomach, 140
Karlinski, typhoid bacillus in urine and

feces, 426
Kast —
Antiseptic action of gastric juice, 325
Sweat, 275
Keller, H., alcohol, 130; need for salt

caused by, 100
Kellner, metabolism during work, 349
Kennepohl, G., change in the composi-
tion of milk, 107
Kemmerich —
Fat formation, 366
Meat extract, 126-127
Kitasato, bacterial poisons, 411, 415, 418
Kjeldahl, J., diastatic ferments, 160
Klees, R., chlorin in febrile urine, 427
Klemensiewicz, secretions of gastric

glands, 139
Klemperer, G. and F., action of heat on

bacteria, 421
Klikowicz, alcohol, 121
Klug, F., respiration of frogs, 271
Knieriem, v. —
Amido-acid in birds, 309
Aspartic acid, 288, 289
Digestion of woody fibers, 71-72
Food value of keratin, 58
Kobert —
Creatin, 128
Poison of spiders, 416
Koch, A., ethereal oils in tea, 124
Koch, C. F. A., increase of urea with

temperature, 424
Koch, R —
Action of heat on bacteria, 161, 420
Comma bacillus, 142
Tubercle toxin, 415
Kocher, thyroid gland, 431, 432-433,439-

441, 443, 444
Kochs, W., formation of hippuric acid,

285
Köhler, A., blood coagulation, 205
Kolbe—
Taurin, 177
Uric acid, 302
Kölliker —
Blood of splenic vein, 229
Functions of bile, 183
König, J., analysis of food-stuffs, 65; of

milkj 104
Konjajeff, typhoid bacteria in kidneys

and urine, 426
Kossel —
Adenin, 314
Glycuronic acid, 260
Nucleins, 77, 78
Protamins, 289
Kotliar, effect of liver on poisons, 334

INDEX OF AUTHORS

463

Kourlow, extirpation of spleen, 230
Krsepelin, E. — ,

Alcohol, 117

Ethereal oils in tea, 124
Krasilnikow, ferments, 159
Kraus, Fr., metabolism in fever, 422
Kretschy, F. —

Alcohol, 121

Gastric digestion, 151
Krüger, A., sulphur of proteids, 170,

327
Krukenberg —

Digestion in higher and lower ani-
mals, 152

Suprarenal capsules, 430
Kufferath, bile acids, 336
Kuhn, Fr.—

Dilatation of the stomach, 143-144

Gases in the stomach, 143-144
Kühne —

Amido-acids, 167-168

Attempt to isolate three pancreatic
ferments, 161

Conversion of proteid to pepton, 167

Digestion products, 417

Hemolysis, 339

Indol, 324

Isolation of of ferments, 160

Pancreatic juice, 166

Peptone, 171

Tubercle toxin, 415
Külz—

Ammonia in diabetes, 312

Cystin, 327

Diabetes, 386, 391 ; diabetes insipi-
dus, 402, n. 3

Glycogen, 343

Glycogen, in diabetes, 396 ; influence
of work on, 351

Glycuronic acid, 260

Levulose, 387

Sugar in urine, 331
Kunkel, A. —

Bile, 182

Decomposition of cane sugar, 155

Gases of pancreatic digestion, 277

Jaundice, 341
KuplFer, oxidation in insects, 244
Kutscheroflf, cholalic acid, 177

Lachowicz, anaerobism, 244
Ladenburg, silicon compounds, 23
Lambling —
Antiseptic properties of bile, 186
Reaction of intestinal contents, 152,
175
Landerer, A., transfusion of blood, 205
Landergren, E., absorption of proteid,

69
Landwehr, mucin, 179
Langbein, H., heat-equivalents of food-
stuffs, 61-62
Langhaus —
Changes in hemoglobin, 338
Thyroid gland, 445
Langley, pancreatic ferment, 161
Langlois, P., extirpation of suprarenal

capsules, 429
Lankester, R.,hemoglobin ofmuscles,355
Launelongue, transplantation of thy-
roid, 442

Lanz, 0., thyroid, administration of,
443, 444; extirpation of, 434-438,
445-446; subcutaneous injection of
juice of, 439
Lapicque, L., need for salt, 97
Laplace, 32
Laschkewitsch, 274

Latschenberger, J., absorption of pro-
teid, 192
Latschinoff, cholalic acid, 177
Laurent, action of alcohol, 122
Lavoisier —

Influence of muscular work, 350

Source of animal heat, 32
Lea, Sheridan, pigments of urine, 323
Leathes, J. B., mucoid, 179-180
Lebedefl", fat formation, 363
Lebensbaum, M., 51
Leeds, oxidation of benzol, 250
Legrain, action of alcohol, 122
Lehmann, urinary calculus, 321
Lehmann, C. G., chlorin in febrile

urine, 427
Lehmann, F., decomposition of cellu-
lose, 163
Lehmann, J., milk, analysis of, 104;

lime in, 109
Lehmann, K. B. —

Food value of gelatin, 57-58

Intestinal juice, 173
Leichtenstein, administration oi thy-
roid, 443
Leo, Hans, nitrogen, 237
Lepine, E. —

Pancreatic diabetes, 399

Sulphur in urine, 326
Lesnik, glycuronic acid, 260
Lesser, v., burns, 275
Leube, perspiration, 275
Ley den, E., metabolism in fever, 422
Leydig, intestinal gases, 276
Liebermeister, output of CO2 in fever,

422
Liebig —

Allantoin, 304

Oxygen of blood, 239

Source of muscular energy, 63, 348

Sulphur cyanates, 330

Urea of muscles, 297

Uric acid, 302
Liebreich, lecithin, 76
Lilienfeld, A., metabolism in fever,

422, 424
Lindberger, antiseptic properties of

bile, 186 _
Litten, acids in febrile urine, 425
Locke, F. S., rennet ferment, 109
Loew, O. —

Isolation of ferments, 160

Nature of peptones, 171

Silver compounds of egg albumin,
51-52
Loewy, A., metabolism in fever, 422
Löfiier, bacterial poisons, 411, 414
Lohrer, fate of ammonia in the body, 291
Lossnitzer, attempt to isolate three pan-
creatic fei'ments, 161
Löwit, M., blood coagulation, 204
Lubavin, nuclein of milk, 79
Luca, de, saliva of Dolium Galea, 134,
137

464

INDEX OF AUTHOES

Luchsinger —

Diabetic puncture, 395

Glycerin, 362

Glycogen, 344
Ludwig —

Absorption of food-stufifs, 187 ; of pro-
teid, 191

Gases of muscle, 350

Lymph, 218

Nitrogenous excretion, 193

Reducing substances, 347

Stomach in digestion, 140-141
Lukjanow —

Bile, 183

Effects of rarefied air, 241
Lunin, N. —

Inorganic salts, 88

Milk diet, 72

Macfadyen—

Absorption of proteid, 192

Intestinal contents, amido-acids in,
188 ; bacteria in, 143
Mach, v., hypoxanthin, 309
Mackenzie, administration of thyroid,

443
MacMunn, suprarenal capsules, 430
Magnus, analysis of blood gases, 243
Maixner, E., peptonuria, 199
Mallevre, A., decomposition of cellulose

in the alimentary canal, 163
Maly—

Absorption of caffein, 123 ; of heat in
fermentation, 156

Antiseptic properties of bile, 185

Bilirubin, 178

Decomposition of proteids, 288

Diastatic ferments, 160

Displacement of strong acids by weak,
136-137

Isolation of ferments, 160

Peptones, 169-170

Saliva of Dolium Galea, 134

Uric acid, 302

Urobilin, 323
Manning, T. D., intestinal juice, 173
Mantegazza, P. —

Fibrin, 202

Granules in horse's plasma, 204
Maquesne, inosit, 402, n. 3
Maragliano, diminished heat loss in

fever, 425
Marcet —

Decomposition of fats in the stomach,
164

Emulsifying action of alkalies, 165
Marfori —

Absorption of iron, 372

Oxalic acid, 332
Marie, P., pituitary body, 446
Marinesco, G., pituitary body, 446
Marino-Zucco, F. and S., extirpation of

suprarenals, 429
Märker, digestion of starch, 162
Marshall, J. —

Carbonic oxid, 240

Hemoglobin, 239
Marshall, metabolism in fever, 424
Maschke, O., crystalloids, 46
Massen, Eck's fistula, 296

Matthia, N., extirpation of spleen, 232
Maydell, Baron, 94-95
Mayer, A., artificial manures, 19
Mayer, W., softening of the stomach,

145 n.
Medicus, uric acid, 302
Meissl, fat formation, 367
Meissner —

Creatin and Creatinin, 125, 297

Proteid digestion, 167

Thiosulphuric acid, 330

Uric acid, in birds' liver, 313[; in
birds' kidney, 318
Mendel, administration of thyroid, 444;
effect of its extirpation on metab-
olism, 443
Mering, J. v. —

Colloid carbohydrates in blood of
portal vein, 163

Digestion of starch, 162

Duodenal fistula, 278

Extirpation of pancreas, 398

Glycogen, formation, 345 ; in diabetes,
396 ; hydrolysis of, 345

Glycuronic acid, 260

Paths of absorption, 187, 188

Phloridzin diabetes, 346

Rickets, 85

Stomach, acids of, 144 ; functions of,
148-150
Merklen, P., transplantation of thyroid,

442
Mertens, F., extirpation of thyroid, 435
Metchnikoff, El., leucocytes, 223
Meyer, A., chlorophyll granules, 39
Meyer, G. —

Absorption of proteids, 69

Breads, 73
Meyer, Hans —

Inorganic poisons in the blood, 426

Ornithin, 287

Phosphorus oxidation, 255

Urea in birds, 309
Meyer, L. —

Blood gases, 239

Carbonic oxid, 240

Influence of mass, 240
Michel, 53
Middleton, administration of thyroid,

444
Mieseher —

Blood of splenic vein in fish, 229

Globulins of the blood in starvation,,
216

Nucleins, 77-80, 374

Protamin, 289

Spleen, 231, 235
Mill, oxalic acid, 332
Milne-Edwards, phosphorescence and

oxygen, 245
Minkowski, O. —

Diabetic coma, 404

Extirpation of birds' kidneys, 309 ; of
pancreas, 398

Fat absorption, 361

Jaundice, 340

Metabolism in fever, 425

Phloridzin diabetes, 387

Stomach contents, 144

Uric acid in dog, 386

INDEX OF AUTHORS

465

Miquel —

Bacteriainmilk, 110

HCl as antiseptic, 132
Miura, alcohol and proteid disintegra-
tion, 120-121
Möbius, excretion of bile pigment, 318
Moddermann, oxalate calculi, 333
Moers, lactic acid in urine, 331
Morgagni, extirpation of spleen, 232
Molisch, iron in vegetable life, 22
Monti, A., milk diet, 384
Moore, B. —

Absorption of fat after extirpation of
pancreas, 166

Reaction of intestinal contents, 152
Moos, S., chlorin in febrile urine, 427
Moscatelli, sugar in urine, 331
Mosetig-Moorhoif, R. v., iodoform in-
jections in goiter, 441
Mosso —

Influence of the nervous system in
fever, 423

Toialbumins, 416
Moussu, G., extirpation of thyroid, 434,

438
Mühll, P. V. d., alcohol, 117, 118
Müller —

Mucin, 179

Poisonous effects of CO2, 268
Müller, Fr., functions of bile, 183
Müller, J. —

Blood coagulation, 202

Ideas of space, 2

Specific energy of the senses, 9
Müller, Max, fever temperature, 421
Müller, W., eflFect of low oxygen ten-
sion, 241
Munk, I —

Alcohol, 121

Fat formation, 360

Lactic acid, 331

Sulphocyanic acid, 330
Muntz, saltpeter, 252
Murisier, artificial gastric digestion, 160
Musculus —

Action of ferments on glycogen, 345

Ammoniacal fermentation, 322

Digestion of starch, 162, 163

Glycuronic acid, 260

NÄGELI, digestion of starch, 162
Napier, influence of thyroidectomy on

metabolism, 443
Nasse, H., analysis of lymph, 225
Nasse, O. —

Digestion of starch, 162

Glycogen, 343
Naunyn, B. —

Diabetic puncture, 395

Glycogen, 345 ; its formation from
proteid, 345

Jaundice, 340

Nitrogenous excretions in fever, 424

Urea excretion and temperature, 424

Uric acid, 306
Nencki, M. —

Anaerobism, 158, 244

Bacterial poisons, 409, 411

Decomposition of fat by pancreatic
ferment, 164; of gelatin, 288

Diabetes, 389

30

Nencki — continued

Hemoglobin, 215

Hydration and fermentation, 159

Indol, 324

Intestinal contents, 168 ; bacteria of,
143 ; reaction of, 152

Lactic and butyric acids, 143

Oxidation of grape sugar, 248

Ozone, 250

Proteid absorption, 192
Neubauer —

Oxalate of lime, 333

Xanthin, 314
Neumann —

Extirpation of spleen, 231

Typhoid bacillus in urine, 426
Neumeister, R. —

Albuminuria, 317

Digestion products, 417

Peptones, formation from proteid,
167 ; nature of, 171
Nicati, comma bacillus, 142
Nieman, cystinuria, 329
Nissen, F., secretion of milk, 113
Norwak, nitrogen in respiration, 237
Nothnagel, H., bacteria of lactic and

butyric fermentations, 142
Notkin, J., active principle of thyroid

gland, 441
Nussbaum, carbonic acid tension, 261

Oeetmann, salt frog, 246
Ogata, M. —

Alcohol, influence on digestion, 121

Stomach, functions of, 140-141
Oliver, G. , suprarenal capsules, 430
Oppel, A., absence of gastric digestion

in vertebrates, 152
Osborne, W. A., invertin, 156
Ord, W. A.—

Influence of thyroidectomy on meta-
bolism, 443

Myxedema, 430-431
O'SuUivan, C, digestion of starch, 162
Ott, J., influence of the nervous system
in fevers, 423

Pacanovpski, H., peptonuria, 199
Pachon, V., partial extirpation of the

stomach, 140
Packard, F. A., pituitary body, 446
Pages —
Blood coagulation, 205
Rennet ferment, 109
Pal, J.—
Extirpation of suprarenal capsules,

429
Sugar in pancreatic blood, 401
Palleske, administration of thyroid,

443
Palma, levulose in diabetes, 393
Panceri, saliva of Dolium Galea, 134,

137
Panum —
Bacterial poisons, 413
Gastric ulcer, 148
Vegetable diet, 71
Park, Mungo, desire for salt among

negroes, 95
Parker, R., administration of thyroid,
444

466

INDEX OF AUTHORS

Parkes, alcohol, 120
Paschutin, V. —
Attempt to isolate three pancreatic

ferments, 161
Influence of nerves on lymph, 318
Pasteur —
Anaerobic fermentation, 158
Influence of heat on bacteria, 420
Paton, N.—
Albuminuria, 53
Biliary fistula, 176
Paul, F. T., pituitary body, 447
Pavy —
Diabetes, 386

Digestion of living tissue, 146-147
Pawlow, J. P. —
Eck's fistula, 296

Reflex secretion of gastric juice, 116
Payen, digestion of starch, 162
Pean, excision of spleen, 233
Pellacani, P., suprarenal capsules,

430
Penzoldt, acids in febrile urine, 425
Peters, E.., rennet ferment, 110
Pettenkofer —
Cutaneous respiration, 272
Fat formation, 359

Influence of work on output of nitro-
gen, 350
Respiratory apparatus, 270
Urea in diabetes, 388
Pfeiffer, analysis of human milk, 104
Pfeffer, iron-salts in oxidation, 254
Pflüger —
Blood, CO2 of, 264, 265 ; gases of, 238
Fat formation, 366
Frog without oxygen, 354
Oxygen, absorption by blood, 243 ; in

saliva, 246
Oxidation in salt frog, 246
Philipeaux, extirpation of thyroid, 436
Piccard —
Nucleins, 77
Protamins, 289
Uric acid, 313
Pick, E. P., conversion of proteid to

peptone, 167
Pinkus, S. N., crystallization of Pro-
teids, 53
Pizzi, A., analysis of rabbit's milk, 104
Planer —
Gases of intestine, 276
Sulphuretted hydrogen, 279
Plateau, F., digestion in higher and

lower animals, 152
Pliny, extirpation of spleen, 229
Plosz, P., peptones, 194, 195
Poehl, A., peptones, 171
Podolinski —
Nitric oxid hemoglobin, 240
Origin of pancreatic ferment, 161
Pohl, J., increase of leucocytes during

digestion, 197-198
Pollitzer, digestion products, 417
Ponfick, burns, 275
Popoff", L., action of lime on bacteria,

156-157
Pouchet, extirpation of the spleen in

fish, 232
Prausnitz, W., absorption of milk, 69
Pregl, Fr., intestinal juice, 173

Preyer, W. —
Blood gases, 238
Digestive glands, action in embryo,

183
Oxyhemoglobin, effect on carbonates,

265
Preusse, cystin, 327
Pribram, A., nitrogen excretion in

fever, 424
Prior, nitric oxid hemoglobin, 240
Pröscher, Fr., milk, analysis of dog's,

104 ; its composition compared with

growth of suckling, 106
Proskauer, bacterial poisons, 414, 415
Prudden, thyroid gland, 431

Quincke, G.—

Alkalies, emulsifying action of, 165

Bilirubin, formation of, 338

Intestinal juice, 172-174

Iron, absorption of, 372
Quervain, Fr. de, thyroidectomy, 434

Radziejewski—
Aspartic acid, 288
Indol, 324

Phosphorescence, 252
Ranke, H., vegetable diet, 70
Ranke J., biliary fistula, 176
Rauschenbach, Fr., blood coagulation,

203
Rechenberg, heat-equivalents of food-
stuffs, 60-62
Redtenbacher, chlorin in febrile urine,

427
Recklinghausen, formation of bile pig-
ment, 338
Rees —
Analysis of chyle, 225
Lactic acid, 331
Uric acid, 306
Regnard, respiration of aquatic ani-
mals, 270
Regnault, 270

Reichert, E. T., toxalbumins, 418
Reihe, conversion of proteid to peptone,

167
Reinbach, G., thyroid administration,

444
Reinhold, administration of thyroid,

443 111
Reiset, 270 ; nitrogen, 237
Reverdin, extirpation of thyroid, 431
Rey-Pailhade, J. de, fermentation, 155
Ribbert, pathogenic bacilli in kidneys,

426
Richter, P., urea excretion, 424
Rieder, non-nitrogenous food, 69
Rietsch, comma bacillus, 142
Ringer, S., metabolism in fever, 424
Ritthausen, crystalline proteid, 49
Robin, hematoidin^ 338
Robitschek, J., nitrogenous excretion

in fever, 424
Robson, M., biliary fistula, 176
Rockwell, J. —

Extirpation of thyroid, 435, 437
Pituitary body, 446
Rockwood, reaction of intestinal con-
tents, 152
Roger, effect of liver on alkaloids, 334

INDEX OF AUTHORS

467

Rogowitsch, pituitary body, 446
Eöhmann, F.—

Bile, functions of, 183

Chlorin in febrile urine, 427
Röhrig, paths of absorption, 187
Eosbach, diabetic coma, 391
Roussy, action of enzymes, 417
Roos, E., influence of thyroid on meta-
bolism, 439
Rosenthal, C, temperature in fever,

423
Roux, bacterial poisons, 411, 413
Roxburgh, R., pituitary body, 447
Rubner —

Absorption of proteid, 69

Animal heat, 34

Digestion of cellulose, 277

Fat formation, 368

Heat-equivalents of food-stuffs, 60-62 ;
regulation, 354

Vegetable diet, 70, 71
Rudel, absorption of calcium com-
pounds, 85
Ruge, intestinal gases, 276, 280

Saae, M. C. du, rennet ferment, 109
Sacharjin, sodium in blood, 208
Sachs, conversion of fats, 346

Influence of the nervous system in
fevers, 423

Silicic acid in plants, 23
Sachsendahl, J., blood coagulation, 203
St. Martin, L., effects of rarefied air, 241
Salomon, urea formation, 294
Salkowski, E. —

Ammoniaj fate of, 291

Hematoidin, 338

Hippuric acid during starvation, 282

Indol, 324

Oxalic acid, 257

Oxidation, 248

Pepsin, 161

Taurin, 182
Sallust, 95
Salvioli, G —

Peptone regeneration, 196

Proteid in lymph, 228

Starvation, 216
Samson-Himmelstjerna, J. v., blood

coagulation, 203
Saury, ozone, 248
Schäfer, E. A —

Blood coagulation, 205

Suprarenal capsules, 430
Schaffer, J. —

Phenol, 257

Thymus, 236
Scharling, respiratory exchanges, 350
Scheremetjewski, decomposition of

sugar, 389
Scherer, analysis of hydrocele, 226
Scheube, uric acid, 381
Schiff, M —

Glycogen, 345

Thyroid, extirpation, 433,434; tran-
plantation, 438
Schimanski, nitrogenous excretion, 424
Schimraelbusch, C, origin of thrombi,

202
Schlatter, C, extirpation of stomach,
142

Schleich, effect of temperature on urea

excretion, 424
Schlösing, saltpeter, 252
Schmidt, A. —

Blood, CO2 of, 2(^4 ; coagulation, 203,
204-205 ; gases, 237 ; reducing sub-
stances in, 243

Pepsin, 161

Rennet ferment, 109
Schmidt, Aug. —

Alcohol, excretion of, 117

Ferments, isolation of, 160
Schmidt, C—

Analyses of transudations, blood
plasma, cerebrospinal fluid, 225-227

Blood, analyses of, 212-215 ; sodium
in, 208

Bile, functions of, 183 ; biliary fistula,
176

Gastric juice, 130 ; HCl in dog's, 132

Iron, absorption of, 372

Pancreatic juice, Na2COs in, 165

Saliva, secretion of, 149 ; amount
secreted in 24 hours, 129

Starvation, 216
Schmidt-Mülheim —

Absorption, paths of, 187

Digestion products, 417

Intestinal contents, amido-acids in,
168 ; reaction of, 152

Peptones, 171, 194, 195

Proteids, absorption, 191 ; conversion
to peptones, 167
Schmiedeberg, O. —

Alcohol, 117, 118

Alkaloids of fly fungus, 76

Bacterial poisons, 409

Cartilage, decomposition products, 56

Chondrin, 179

Crystalloids, 46

Glycuronic acid, 259

Hippuric acid, 284

Oxidation, 248

Proteid, molecular weight of, 47

Thiosulphuric acid, 330
Schnitzler, pituitary body, 446
Schöffer, A. —

Carbonic acid, 261

Ferments, isolation of, 159
Schönbein —

Nitrite of ammonia, formation of, 18

Ozone, 248
Schöndorff, B., influence of thyroid

gland on metabolism, 439
Schöndorff, O., iodin compound in

goiter, 440
Sehönlein, goiter, 445
Schotten, aromatic amido-acids, 257
Schoumoff, C, on alcohol, 121
Schröder, v. —

Ammonia in birds, 309

Caffein as a diuretic, 319

Gastric digestion, 151

Hippuric acid, 256

Kidneys, extirpation of, 293, 309
Schuchardt, extirpation of stomach, 141
Schultze, M.—

Burns, effects of, 275

Oxidation in the glow-organ, 245
Schneider, R., absorption of caffein,

123

468

INDEX OF AUTHORS

Schultzen, 0. —
Aromatic hydrocarbons, 258
Diabetes,_389
Lactic acid, 331
Leukemia, 307
Oxalic acid, 331
Schulze, E. —
Decomposition of proteids, 288
Digestion of starch, 162
Schunek, oxaluric acid, 305
Schütz, E., alcohol, 121
Schützenberger, proteid decomposition,

288
Schutzkwer, absorption of caffein^ 123
Schwann, functions of bile, 183 ; biliary

fistula, 176
Schwarz, L., common salt, 94
Schwarz, R., extirpation of dog's thy-
roid, 435
Schwarzer, Aug., digestion of starch,

162
Schwendener, symbionta, 39
Scriba, removal of dog's stomach, 140
Sczelkow —

Gases of blood, 238 ; of muscle, 350
Tension of CO,, 261
Seegen —
Diabetes, 386

Fats, conversion to sugar, 346
Levulose, 387
Sugar in urine, 331
Seemann, rickets, 85
Seifert, acids in febrile urine, 425
Selig, diabetic puncture, 395
Selmi, F.—
Bacterial poisons, 409
Febrile urine, 426
Semmer, G., granule masses, 204
Senator —
Albuminuria, 317

Fever, metabolism of, 422 ; tempera-
ture of, 423
Sulphuretted hydrogen, effects of,

279
Uric acid, 386
Varnishing skin, 274
Sendtner, J., action of alcohol, 122
Sertoli, proteid as acid, 264
Sieber, N —
Grape sugar, oxidation of, 348
Hemoglobin, 215
HCl as an antiseptic, 131-132
Intestinal contents, 168 ; bacteria in,

143 ; reaction of, 152
Lactic and butyric acids, 143
Proteid, absorption of, 192
Streptococcus pyogenes, 415
Siedamgrotzky, change in the composi-
tion of milk, 107
Silbermann, heat-equivalents of food-
stuffs, 61-62
Silujanoff, metabolism in fever, 422
Simanowskaja, E., reflex secretion of

gastric juice, 116
Simanowski, N. —
Alcohol, 121

Urea, increase in fever, 424
Simon, Th., lactic acid in trichinosis,

331
Simone, de, action of heat on bacteria,
420

Slevogt, F., blood coagulation, 203
Smith, A., alcohol, 117
Smith, E., respiratory exchanges, 350
Smith, R. M., absorption in dog's

stomach, 148
Socin —

Hematogen, 375

Levulose in diabetes, 393
Socoloff, bile acids, 178
Söldner, analysis of human milk, 104
Sonnenburg, administration of thyroid,

Soxhlet, milk, 110
Spallanzani —
Antiseptic action of gastric juice,

132-133
Respiration in amphibia, 271
Speck, C, respiratory exchanges, 350
Spiro—
Bile,_ 182 _
Lactic acid, 355
Stabel, H., administration of thyroid,

444
Städeler, bilirubin, 178
Stadelmann—
Ammonia, 312 ; of urine, 295
Bile pigment, 178
Diabetes, 391 ; diabetic coma, 404
Jaundice, 339
Stadthagen—
Cystin, 327 ; eystinuria, 329
Uric acid in spleen, 307
Xanthin bases, 314
Stammreich, alcohol, 120
Starling, lymph, 218
Steinbach, ideas of space, 2
Steiner, J., emulsifying ,action of alka-
lies, 165
Steinhaus, J., secretion of milk, 113
Stern —
Eck's fistula, 296
Liver, Extirpation of, 335, 336
Natural immunity, 419
Portal vein, ligature of, 810
Stieda, H., pituitary body, 446
Stilling, rickets, 85
Stohmann —

Cellulose, decomposition in the ali-
mentary canal, 163
Heat-equivalents of food-stuffs, 60-62
Stohr, Ph., leucocytes, 223
Stolnikow, Eck's fistula, 296
Storch, phosphorus poisoning, 363
Strassburg, tension of CO2, 261, 267
Strecker, A. —
Bile acids, 177-178
Creatin, 297
Lecithin, 75, 76
Strogonow, N., asphyxial blood, 241
Strohmer fat formation, 367
Strümpell, A. —
Alconol, action of, 122
Pituitary body, 447
Proteid, absorption of, 69
Subbotin, V—
Alcohol excretion, 117
Fat formation, 366
Szabo, D., HCl in gastric juice, 132
Szydlowski, L., rennet ferment, 110
Szymonowicz, L., extirpation of supra-
renals, 429, 430

INDEX OF AUTHORS

469

Tacke, marsh-gas in expired air, 279
Tamburini, A., pituitary body, 447
Tammann, G., fluorin, 24
Tappeiner^ H. —

Absorption in the stomach, 148

Burns, effect of, 275

Cellulose, decomposition in the ali-
mentary canal, 163

Cholalic acid, 177

Hippuric acid, 282

Intestinal gases, 276
Tarchanoflf, hemoglobin in urea, 339
Tauber, phenol, 257
Thanhoffer, L. v., action of bile on fat

absorption, 184
Thierfelder, H —

Glycuronic acid, 259

Hydrolysis of jjroteid, 167
Thiry, intestinal juice, 172-174
Thomsen, J., thermoehemical re-
searches, 135-136
Thudichum, bilirubin, 178
Tiagel, E.—

Blood-serum of snakes, 216

Fibrin, 202
Tieghem, van, proportion of oxygen to

light, 31
Tizzoni —

Bacterial poisons, 411, 413, 414

Extirpation of spleen, 230 ; of supra-
renal capsules, 429

Natural immunity, 419
TolmatschelF—

Cholesterin, 80

Lecithin in milk, 77
Töpfer, iodin in the thyroid gland,

440
Traube, M., oxidation, 244, 250 ; oxy-
gen-carriers, 253
Traube, T., temperature in fever, 422-

423
Trifanowsky, bile, acids of, 178 ; com-
position of, 180
Troschel, saliva of Dolium Galea, 133-

134
Tschervinsky, N., fat formation, 366
Tschiriew —

Nitrogenous excretion, 193

Reducing substances in lymph, 246
Tubby, H., intestinal juice, 173

Udranski, urine, bile acids in, 336;

sugar in, 331
Uffelmann, J., gastric digestion, 151
Ughetti, diet after thyroidectomy, 438
Unruh, E., chlorin in febrile urine,

427

Yaillakd—

Bacterial poisons, 413, 414, 417

Leucocytes, 223
Vas, B., thyroid administration, 444
Vassale, thyroid administration, 443
Vauquelin, allantoin, 304
Velden, v. d., aromatic sulphates, 326
Vella, L., intestinal juice, 173
Vermehren, administration of thyroid,

443, 444
Vierordt, CO2 in expired air, 267

Respiratory exchanges during work,
350

Ville, J., absorption of fat after extir-
pation of pancreas, 166
Vincent —

Bacterial poisons, 413, 414, 417

Leucocytes, 223
Vinke, H. H., administration of thy-
roid, 444
Virchow —

Gastric ulcer, 148

Hematoidin, 338

Origin of thrombi, 202
Vogel, A., nitrogenous excretion in

fever, 421
Voit, C—

Absorption of iron, 372; ofproteid, 192

CaiFein and nitrogen output, 124

Creatin and Creatinin, 125, 128, 297

Fat formation, 358, 359

Food value of gelatin, 57-58

Functions of bile, 183

Glycogen, 345

Meat extracts, 126

Metabolism during work, 349

Nitrogen, in respiration, 237 ; in-
fluence of work on output of, 350

Nitrogenous equilibrium in fasting
dog, 193

Starvation, 216

Sulphur of urine, 321

Urea in diabetes, 388

Urinary sediments, 301
Voit, E., rickets, 85
Voit, Fr.—

Absorption of calcium compounds, 85

Thyroid administration, 439
Volhard, creatin, 297
Vossius, jaundice, 341
Vulpian, suprarenal capsule, 430
Vulpius, extirpation of spleen, 230, 231,
233, 234

Wachsmuth, analysis of liquor peri-
cardii, 226
Walter, Fr.—
Blood gases, 238
Excretion of ammonia, 292
Walter, G., nuclein, 78
Walther, Ch., transplantation of thy-
roid, 442
Warrington, nitrification, 252
Wassermann —
Bacterial poisons, 414, 415
Febrile urine, 426
Weigert, leucocytes, 223
Weir Mitchell, S., toxalbumins, 418
Weiske, H. —
Change in the composition of milk,

107
Cellulose, decomposition in the ali-
mentary canal, 163
Digestion of woody fiber, 71
Weiss, G., origin of pancreatic ferment,

161
Wendelstadt, administration of thyroid,

443
Wenz, J., intestinal juice, 173
Werenskiold, Fr., analysis of reindeer

milk, 104, 105
Wertheim —
Burns, 275
Metabolism of fever, 422

470

INDEX OF AUTHORS

Weyl, bacterial poisons, 411
Wibel, lactic acid, 331
Wiedemann, glycuronic acid, 259
Wieder shi em, intestinal epithelium of

cold-blooded animals, 3
WUliams, F., action of inorganic poi-
sons on the blood, 426
Wilson, G., fluorin, 24
Winogradsky, nitrification, 252
Winston, biliary fistula, 176
Winternitz, varnishing animals, 274
Wislicenus —

Ascent of Faulhorn, 348

Lactic acids, 312
Wissokowitsch, lactic acid, 355
Wistinghausen, action of bile on fat,184
Wittich, v.—

Carmine excretion, 318

Diffusibility of peptones, 166

Ferments, 159
Wöhler —

Allantoin, 304

Hippuric acid, 283

Uric acid, 302
Wolf, K., pituitary body, 446
Wolfers, alcohol, 121
Wolff", M., effect of heat on bacteria

spores, 161
Wolfi"berg, tension of CO2, 261
Wolflfhiigel, eflPect of heat on bacteria

spores, 161
Wolkoff", A. v., kinetic energy and

intensity of light, 30-31
Wolpe —

Acetonuria, 391

Ammonia in diabetes, 312

Butyric acid, 391
Woltering, absorption of iron, 372
Wood, metabolism in fever, 424
Wooldridge, L. C—

Blood coagulation, 203, 204

Wooldridge — continued

Stromata of blood, 206
Worm-Müller —

Diabetes, 392

Oxyhemoglobin dissociation, 242
Wörmser, E., extirpation of thyroid,

435, 440, 441
Woroschiloff—

Diet regulation, 70

Proteid absorption, 69
Wrede, 95
Wroblewski, analysis of human milk,

109
Wurtz, cholin, 75

Yeo, G. F., biliary fistula, 176
Yersin, bacterial poisons, 411, 413

Zabelin, uric acid, 306

Zagen, nitrogen in respiration, 237

Zahn, F. W.—

Blood coagulation, 203

Origin of thrombi, 202
Zaleski —

Carbonic oxid, 255, n. 4

Iron in the liver, 342, n. 5

Uric acid in the kidney, 318
Zawilski —

Absorption of fat, 190

Paths of absorption, 187
Zimmerberg, alcohol, 117, 118
Zinoffsky, O., hemoglobin crystals, 50
Zoja, 52
Zuntz —

Alcohol, 121

CO2 of blood, 263

Cellulose, decomposition in the ali-
mentary canal, 163
Zweifel, embryonic life, bile secretion
in, 183 ; oxidation in, 245

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