Physical chemistry in the service of medicine; seven addresses

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Physical chemistry in the service of med

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WORKS OF DR. M. H. FISCHER

PUBLISHED BY

JOHN WILEY & SONS.

The Physiology of Alimentation.

Large i2mo, viii + 348 pages, 30 figures, cloth,
$2 00 net.

TRANSLATION.

Physical Chemistry in the Service of Medicine.

Seven Addresses by Dr. Wolfgang Pauli, Privat-
docent in Internal Medicine at the University of
Vienna. Authorized Translation lay Dr. Martin
H. Fischer, i2mo, ix+156 pages, cloth, $1.25 net

PHYSICAL CHEMISTRY

SERVICE OF MEDICINE

SEVEN ADDRESSES

Dr. WOLFGANG PAULI

Privatdocent in Internal Medicine at the University of Vienna
AUTHORIZED TRANSLATION BY

Dr. martin H. FISCHER

Professor of Pathology at the Oakland College of Medicine

FIRST EDITION
FIRST THOUSAND

NEW YORK

JOHN WILEY & SONS

London: CHAPMAN & HALL, Limited

1907
5

T?^

Copyright, 1906

BY

MARTIN H. FISCHER

F3X

ROBERT ORUMMOND, PRINTER, NEW YORK

AUTHOR'S PREFACE.

The addresses which have been collected for the
first time in this volume and which were delivered in
the main as summaries of my own special investigations
concern themselves with the application" of physical
chemistry to different fields in medicine as rendered
possible more particularly through advances in the
physics and chemistry of organic colloids. In that
questions in. physiology as well as pathology and
pharmacology are touched upon, it may perhaps be
hoped that different circles of medical men may be
interested in the problems discussed in this volume.
The translated addresses differ in only a few unimpor-
tant abbreviations from the original. The development
of the guiding thought common to all of them stands
out quite clearly. Its foundation is the extensive
parallelism between the laws which govern changes in
the colloidal state in vitro and in the living organism.
Even though the future may become acquaihted with
many a new fact through which the questions discussed
in this volume may be made to appear in a different
light, it will scarcely be possible to belittle the fruitful-
ness of the methods described and the stimulating effect

IV AUTHOR'S PREFACE.

of the results obtained through them. Since all the
results that these methods can yield are as yet by no
means attained it is hoped that the volume may be
looked upon as a modest attempt to win friends capa-
ble of work in this still young field of labor.

Wolfgang Pauli.

Vienna, May i, 1906.

TRANSLATOR'S PREFACE.

It is hoped that the following translation of a few
of Dr. Pauli's papers may render some of the work of
this modest Viennese investigator already famUiar to
a large circle of American and English workers accessi-
ble to yet others. The fundamental character of the
subjects touched upon by the author needs no com-
ment. It is only hoped that the translation may not
have lost too much of the spirit and the letter of the
original German. The volume as a whole represents
another stone in the structure of physical chemistry
in the biological sciences; and while it is not the
tendency of modern times to divide existing sciences
or to create new ones, specialism is followed as a
matter of necessity, so that it wUl not seem strange if
in the near future we shall come to recognize as branches
developing separately from the trunk which all these
sciences have in common, a -physico-chemical physiology
and a physico-chemical pathology.

Martin H. Fischer.

Oakland, California,

y

PREFATORY NOTE TO AMERICAN
EDITION.

The advance of medicine is so dependent upon
progress in the fundamental sciences of physics, chem-
istry, and biology that he who will keep abreast of
modern conceptions in physiology and pathology is
compelled to be more or less conversant with theory
and practice in the basal subjects. When one con-
siders the phenomenal development in recent years,
through the work especially of Willard Gibbs, van't Hoff,
and Arrhenius, in the domain of what is designated
physical chemistry, it is not surprising that attempts
should have been made to apply the new knowledge
gained to the clearing up of some of the problems
which confront the physician. While the application
of stoichiometrical methods in medicine and biology
has led and is leading to fruitful results, it is from
the utilization of the principles of the other great branch
of physical chemistry, that which deals with energy-
relations in chemical processes, that most is to be
hoped; that many of the medical conceptions of the
future are to be colored by the ideas of thermochem-
istry, electrochemistry, chemical kinetics, and chemical
dynamics even those of us who are entirely untrained
in these sciences are compelled to admit. The work
already done on reaction-velocity, catalysis, equilibrium,
viscosity, osmotic pressure, and electrolytic dissocia-

vin PREFATORY NOTE TO AMERICAN EDITION.

tion in the human and animalbody may be regarded
as an earnest-penny of greater good hereafter.

The new medicine will require a new preliminary
training of its workers. A few investigators in biology
and medicine have been wise enough to foresee the
path which future inquiries must follow; we should
be thankful that they have prepared themselves for
the pioneer work of blazing the trail. Notable
among these hardy explorers are some of our fore-
most American workers in physiology. Among Euro-
pean scientists, Dr. W. Pauh of Vienna stands out
prominently as a representative of the forward move-
ment. His researches in physiology and pharmacology
have dealt almost entirely with problems in the solu-
tion of which the methods of physical chemistry have
been applied. In his recent studies in colloidal chem-
istry he has been pr5dng into and attempting to illu-
minate some of the darkest of the regions in which
physiological chemists grope.

The American publishers of Dr. Pauh's papers have
been fortunate in securing the services of Dr. Martin
Fischer as translator. The experience he has gained
by his personal researches in similar fields, and his
familiarity with the bibliography of the whole sub-
ject, especially fit him for the task.

May Dr. Pauli's papers stimulate American stu-
dents to further investigations where they are so much
needed, and may he and they collect speedUy for us
a body of facts which we, as medical men, may utihze
in the diagnosis of disease and the cure of human ills!

Lewellys F. Barker.

Baltimore, Oct. 23, 1906.

CONTENTS.

PAGE

1. On Physico-chemical Methods and Problems in Medi-

cine I

2. The General Physical Chemistry of the Cells and

Tissues 23

3. The Colloidal State and the Reactions that Go on

IN Living Matter 44

4. Therapeutic Studies on Ions 71

S- On the Relation between Physico-chemical Properties

and Medicinal Effects 90

6. Changes Wrought in Pathology through Advances

IN Physical Chemistry loi

7. On the Electrical Charge of Protein and its Signifi-

cance 137

ix

PHYSICAL CHEMISTRY IN THE
SERVICE OF MEDICINE.

X. On Physico-chemical Methods and Problems in
Medicine.*

The last decades have brought with them an amal-
gamation of two sciences, — physics and chemistry, —
which have no doubt always had mutual relations,
although formerly these were not so intimate or extensive
as they are now.

This amalgamation was undoubtedly inaugurated
through physics, and must be attributed primarily to
the stimulus which brought with it the estabhshment of
the laws of thermodynamics.

I cannot here sketch even briefly the development of
thermodynamics. As is well known, the law of the
conservation of energy as most clearly enunciated by
Mayer forms its foundation. The remarkable experi-
ments of Joule next led to an, exact determination

* Tiber physikalisch-chemische Methoden und Probleme in der
Medicin, Wien, igoo, M. Perles. Address delivered to the K. k.
Ceselhchap dfr Aergte, Vienna, November lo, 1899.

2 PHYSICAL CHEMISTRY IN MEDICINE.

of the mechanical equivalent of heat, while through
Helmholtz was developed and executed the most
extensive programme for the application of the law of
energy to all subjects.

The penetrative analysis of thermodynamical phenom-
ena by Clausius and Thomson completed the subject
with the establishment of the so-called chief laws of
thermodynamics.

The transformations in energy in chemical reactions
have in general two sources. As is well known every
change in the state of aggregation is accompanied by
either an absorption or an evolution of heat. Since
changes in physical state often accompany a chemical
reaction, these constitute therefore one of the bources
of the transformations in energy accompanying this
reaction.

A second is found in the chemical reaction itself.
The synthesis or analysis of a substance is accompanied
by a thermal change which may have eiiher a positive
or a negative value. To illustrate this we may cite the
formation of a salt from an acid and a, base with the
development of the so-called heat of neutralization; or
the decomposition of a salt into its components with a
using up of electrical energy.

All these metamorphoses in energy constituted from
the first' a fruitful field for work, in which medicine
also soon took part. While, however, the decrease
in the potential energy of the foodstuffs in the metabolism
of men and the higher animals constitutes one of the
best developed chapters of medicine, calorimetric in-,
vestigations of the culture media of bacteria are still
lacking, and this in spite of the fact that this subject

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 3

promises the solution of an important problem, namely,
the energy of growth;

Further relations between chemical constitution and
physical properties were discovered by the new science,
physical or theoretical chemistry.

Under this heading must be mentioned first of all
the connection discovered between optical asymmetry
(rotation of the plane of polarized light) and asymmetry
in chemical composition. At' almost the same time
Le Bel and van't Hoff discovered that all optically
active substances which in the non-crystalline state
rotate the plane of polarized light contain an asymmetric
carbon atom, the four valencies of which are connected
with four different radicles. If we imagine these four
valencies connected with the corners of a tetrahedron,
the four radicles may be grouped in two different ways
and be symmetrical. The development of this idea,
which constitutes the foundation of stereochemistry, has
been very fruitful.

The doctrine of the asymmetrical carbon atom is
destined to play an important role in biological problems
also, for such essential constituents of protoplasm as the
proteins and many carbohydrates must, to correspond
with their optical activity, contain such an asymmetrical
carbon atom.

The connection between physical changes in state and
chemical constitution was early indicated by the regu-
larity with which bodies of the aliphatic series affect
the boihng-point. More recently a connection between
color and the position of certain groups in the molecule
known as chromophores has been discovered. Similar
conditions exist in the case of fluorescence which is

4 PHYSICAL CHEMISTRY IN MEDICINE.

connected with the existence of fluorophore radicles,
and in the case of antipyretics the effect of which is
intimately associated with their chemical constitution.

The modern theory of solution as harmoniously
enlarged through van't Hoff's conception of the gas-
like condition of the dissolved particles, and Arrhenius's
teaching that electrolytes — salts, acids, and bases — dis-
sociate upon solution into their constituent ions, has
also found extensive scientific application to many
subjects including medicine.

Following the establishment of these fundamental
facts physical chemistry has developed as an independent
science with numerous methods of experiment peculiar
to itself and adapted to its own special purposes.

Medicine has at no time denied its dependence upon
advances in the exact sciences, and so it is not strange
to find that with new ideas in physics there have come
corresponding periods of discovery .in medicine. But
the application of newly discovered facts in physics
to medical problems for the solution of which they were
never intended has as a rule brought it to pass that every
era of progress has been followed by one of disappoint-
ment, a period characterized by an overgrowth of specu-
lation and hypothesis.

The great development of mechanics in the seventeenth
century associated with the names of Stevin, Galilei,
Keplee, Descartes, Huyghens, and many others fruc-
tified the epoch of the iatro-physicists whose accomplish-
ments as evidenced by their work on the mechanics of
joints and the development of Harvey's teaching of the
circulation have lasted into modern times. But even

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 5

as late as the eighteenth century great physicists such as
Johannes Bernoulli attempted the solution of such
subjects as Dissertationes physico-mechanicae de motu
■ musculorum et de effervescentia et fermentatione.

In the first half of the nineteenth century the great
development of physics, more especially electricity,
favored the wonderful development of physical physi-
ology which began its career in Germany.

But both these times physics were insufficient to exhaust
the problem of life, and the fully developed reaction to the
iatro-mechanical school finds counterpart in the reaction
of modern times, the participants of which are divided
between two camps. The belief of one of these, the
neovitalists, can be traced back to the "anima" of
Georg Ernst Stahl. In this teaching vital force
which has been so often pronounced dead is born again.
The second group, not less dangerous than the first,
employs an atomic mechanics for the explanation of life
phenomena, and mistakes the death-dance of the mole-
cules for living reality.

In this time of threatening retrogression the seeds of
modern physical chemistry fall upon that narrow field
of endeavor which we call our own. But if this new
and flourishing science is not also to prove a hindrance
to investigation by exceeding its natural limits, it is well
that we define first of all the boundaries within which its
laws hold in biological questions.

Let us attempt first of all to get a conception of the
significance of the law of the conservation of energy as a
means of biological research. This attempt seems all
the more justified since Ostwald, whose great services
in the development of physical chemistry demand the

6 PHYSICAL CHEMISTRY IN MEDICINE.

widest recognition, has already proclaimed the complete
triumph of the energetische Weltanschauung (energetic
conception of natural phenomena).

According to this conception transformations in energy ■
constitute the kernel of aU phenomena in nature, and
their quantitative determination furnishes at the same
time a complete insight into the course of things.

If this is true, then the reaction of the sensory nerves
is also always a consequence of changes in energy and
these become therefore the means by which sensory
experience is obtained.

An attempt will be made in the following paragraphs
to show that a purely energetic conception of natural
phenomena conceals all the dangers of a too extensive
generalization, as it leads to a one-sided development
of our point of view with all its threatening consequences.

Do transformations in energy really constitute the whole
or even the nucleus of the changes that go on, in and-
about us? Do we really react only in proportion to the
amount of difference in energy ?

Transformations in energy are in fact constant accom-
paniments of all changes in nature, and we could scarcely
possess a simpler picture of nature than one in which all
differences represent only differences in the amount of
of energy. In reality, however, it is only one side of aU
natural phenomena that we are able to include in the
energetic principle, for only for the value of the mechanical
work performed in all changes does the law of its inde-
structibility hold. The energetic analysis of a phe-.
nomenon is, however, so little exhaustive that in physical
realms, such as that of electricity for example, we are
unable to answer the question of the nature of electrical

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 7

phenomena in spite of most extensive utilization of the
Mayer- Joule law.

The energetic principle suffices equally little in bio-
logical questions, and we must regard the attempt of an
excellent investigator to define general physiology as
the' energetics of life phenomena as not sufficiently
comprehensive. Our law determines only the energy value
corresponding with the changes that take place in living
matter; the fundamental question of their nature remains
entirely unanswered.

A picture of natural phenomena which shows only
differences in energy is as incomplete as a photograph
which shows only differences in light and shade.

Upon the second assertion of Ostvv^ald that we react
only in proportion to differences in energy we must also
place certain limitations.

What we designate as external stimuli are changes
which also are connected with variations in energy. The
important point in our question is whether differences
in energy determine quantitatively the excitation value
of a stimulus. If this is true, then electrical, thermal, or
mechanical stimuli having the same energy value ought
to possess the same excitation value. Things are by
no means as simple as this, however. We do not per-
ceive the energy communicated to our sense-organs
directly. What we perceive are only changes in the
state of our sensory nerves, a fact recognized by Descartes
in his day and, as pointed out by Johannes Mltller,
suggested even by Plato.

When MiJLLER postulates in the famous laws which
bear his name qualitatively different changes in state in
each variety of sensory nerve, changes which for different

8 PHYSICAL CHEMISTRY IN MEDICIUE.

stimuli are of the same kind in the same nerve, this is
not at all synonymous with saying: to equal amounts of
energy equal reactions.

At different times and under different conditions we
react differently to the same amount of energy, and
conversely. Stimuli carrying an amount of energy which
normally is not perceived can, as in strychnine poisoning,
bring about most powerful effects. The selective be-
havior of the nervous end-organs must also be attributed
to differences in the stimuli received, which are more
than simple quantitative differences in energy. How
great is the difference between our sensations of noise
and of music! and yet the value of the transmitted energy
in the two cases may be the same.

It would be an easy matter to increase the number
of striking examples indefinitely. They all lead to the
conclusion that the quality of a natural stimulus plays
an important r6le, as well as the amount of its energy.
MuLiER himself is inclined to make a qualitative dis-
tinction between impulses when he speaks of homogeneous
and heterogeneous stimulation of a sense-organ. After
all that has been said the assertion seems justified that
the new energetic world conception will prove to be
scarcely less poor than the mechanical. Did we wish to
go deeper we should have to call the former a purely
mechanical one.

If with this we have to regard as a failure the attempt
to solve from the standpoint of energetics du Bois-
Reymond's famous riddle of the universe, then of what
value are the laws governing energy in the investigation of
biological problems?

If we know from experience or if this leads us to assume

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 9

that two processes influence each other in the way, for
example, that pressure affects the freezing-point of water
or the electric current a magnet, the degree of this action
upon each other can be directly deduced from the laws
of energy.

If in the explanation of a phenomenon we build it
up out of the elements a,b,c,d . . . , then these elementary
processes correspond with a group of transformations in
energy which we will designate by a, ^, f, d . . . The
principle of energetics states that the sum of a +/? + /- +
d . . . must be constant. The attempted analysis of the
phenomenon into a, b, c, d is possible only when it sat-
isfies at the same time, under the most varied circum-
stances, the above condition. The Mayer- Joule law
contains no more than this. But while it itself therefore
gives no positive or complete insight into a phenomenon,
it nevertheless renders possible the exclusion of a whole
series of false interpretations of our observations. It
constitutes, therefore, an indispensable and excellent con-
trol of our suppositions.

This control of our conceptions through the Mayer-
Joule law may be of two kinds. In the one case it will
be able to prove that our assumption is wrong, in another
that it is incomplete. In so far as it points out in the
latter case an as yet undiscovered condition it seems
under these circumstances to lead directly to the dis-
covery of new facts.

But even under these conditions we learn from the
law of energy only that something is to be sought or to
be discovered. What this really is, or what the nature
of the fact that is to be discovered is, can never be learned
except through special investigation. We may say in

10 PHYSICAL CHEMISTRY IN MEDICINE.

consequence that the energetic principle has really only
a formal significance, and can tell us nothing regarding
the quality of the process. This is apparent from its very
nature, namely, that of combining equivalents. With
what the numerical equivalence corresponds in any given
case, of this the law tells us nothing; just as Uttle as
we know from the weight of an amount of gold what
kind of money it is, whether francs, marks, or guldens.

The law of the conservation of energy could not help

. but have from its very beginning an overwhelming

effect upon every investigator, not only because of

its great simplicity but also because of its unhmited

tenability in all subjects.

It can seem little strange, therefore, that its heuristic
value has often been overestimated. It is certainly going
too far when, for example, a recognized medical historian
says of the law, " The discovery of the law of the con-
servation of energy has contributed no mean amount
toward disproving the vitalistic theory, that behef in a
peculiar vital force, and toward proving that the laws
of physics and chemistry sufi&ce to explain all biological
and pathological phenomena."

The darkness which envelops life phenomena cannot
be illuminated through any principle of mechanics.
For the time being, therefore, the behef in a vital' force
must needs continue to exist. As in the case of the
other " forces " it too has had to bow to the law of energy,
but its death-blow will be received only when our knowl-
edge of natural phenomena will have attained a higher
development than at present.

We have in the preceding paragraphs tried to go

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 1 1

back to the very foundations of modern chemistry in
order to obtain a conception of its applicability to biological
questions. In what follows an attempt will be made
to ascertain the value of physico-chemical methods in
special questions in medicine. A division of our sub-
ject might follow either one of two schemes. According
to the first the division would follow that current in
physical chemistry. A second, however, which seems
better adapted to our purposes, takes into consideration
the medical problems that have made use of the new
methods.

We can readily distinguish between two fields of
biochemical research. One in which dead material is
studied and through a discovery of the structure of
chemical substances, such as the proteins and carbo-
hydrates, an explanation of their biological significance
is sought; and a second which approaches the tissues
and their functions directly and endeavors to unveil
their secret vital activity through an investigation of
their constituents and products. Often investigations
that utilize more or less strictly the living organism have
a knowledge of the results obtained in the first field upon
which to base their work. True as seems to be the
assertion that a broad chasm exists between the great
group of proteins and living protoplasm, equally true
is it that a bridge leads across this chasm, even though
investigation has not yet succeeded in recognizing the
nature of this connection. We may therefore expect that
in the chemical and physical reactions of the proteins
there exist even now many of the elements of physiological
and pathological reactions. In fact this expectation
has been fulfilled in great measure more especially

12 PHYSICAL CHEMISTRY IN MEDICINE.

through a utilization of the methods of physical chem-
istry.

The studies of Hofmeister on the protein -precipitating
.power of salts have shown that these arrange themselves
in the same order as they do when arranged according
to their diuretic or cathartic action.

In a study of the condition of swelling which I pub-
lished some time ago a large number of biological rela-
tions were found. Analogies exist, for example, between
the absorption of water by substances capable of swelling
and the absorption of water by the living organism;
and the velocity of swelling and the time of a muscle
contraction are about the same. A continuation of
these experiments along the line of changes in the physical
state of the proteins has led to results whose significance
also extends beyond that for the dead material itself.

As is well known the proteins suffer when subjected to
heat a change in state, a so-called coagulation, which, gen-
erally speaking, is not reversible. The coagulation point,
that is the temperature at which this change takes place,
is, among other things, dependent to a large extent upon
the presence of neutral salts. If M'e employ the neutral
salts in the form of equimolecular solutions, we can
compare their effects on the coagulation-point, which
may vary between more than fifteen degrees centigrade.
If now we plot the concentrations upon the abscissas, the
corresponding coagulation temperatures upon the ordi-
nates, we obtain curves which give a general survey of
the laws governing the process. From these we learn
that with solutions of a medium concentration, the
order in which the different salts follow each other when
arranged according to their different acids is independent

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 13

of the base common to all of them. If the salts are
arranged according to their bases, then they follow each
other in a certain order which is independent of the
acid common to all.

The effect of a salt upon the coagulation temperature
is therefore made up of two components the effect of
the acid and the effect of the basic parts. We call this an
additive ion effect.

The remarkable phenomena observed when two salts
Si and S2 together affect the coagulation-point give us
a deeper insight into the important biological relations
existing between proteins and salts.

If in a protein-salt mixture to which a definite amount
of S2 has been added we allow the salt Si to vary in
concentration, while in a second series of experiments
we repeat this but use a different amount of 52, etc., we
obtain a group of curves. A second series of curves
are obtained by using constant amounts of Si and varying
amounts of 52. In this way we obtain two groups of
curves which illustrate very well the mutual effects
of two salts upon protein coagulation. These curves
show in a very remarkable way points at which they
cross each other, in other words a constancy in the
coagulation-point as soon as certain quantitative rela-
tions exist between the two salts. When this is attained
a change in the concentration of one of the salts which
at other times would bring about a change in the coagu-
lation temperature remains entirely without effect even
when the amount of the change is four or five times as
great.

A point at which the curves cut each other may be
shown also between the combination curve 5i-|-5g and

14 PHYSICAL CHEMISTRY IN MEDICINE.

. the pure 5i curve. In other words in a definite salt-
protein mixture the addition of an indefinite amount
of another salt does not change the coagulation-
point.

These experiments, which are given here only in part,
seem to show for the first time that compounds of a certain
stability are formed when salts are mixed with pro-
teins.

The additive ion effects of the salts show also a depen-
dence upon certain quantitative relations. We must
probably attribute this to an affinity between salt and
protein which, as indicated by other observations, is
of such a character that the metallic ion and the acid
ion of a salt unite with different, asymmetric parts of
the protein molecule.

An investigation of the conditions determining the
solubility of egg globulin has shown that this is dependent
upon the presence of ionized compounds. In even a
highly concentrated solution of dextrose or urea, in other
words substances which do not dissociate into ions,
globulin is precipitated in the same way as in the almost
entirely non-ionized water.

We may point out in passing the biological significance
of these facts which show the importance of the mineral
constitutents of the organism in a new light.

There can be little doubt that ion-protein compounds
are present in the animal organism, in fact we have
every reason for believing that all protein constituents of
the protoplasin enter into the composition of this sub-
stance only in combination with ions.

As shown by numerous observations, the salts are
held fast in the organism with great force. This affinity,

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 15

which until now could scarcely be explained, is an analogue
of the affinity existing between salts and proteins as dis-
cussed above.

The way in which water and the way in which salt are
united M'ith the colloids have many things in common,
for the water and salt mutually affect each other in the
organism, and each of the two is maintained at as constant
a value as possible. If we allow a swollen colloid to
desiccate in an atmosphere which is kept permanently
dry, we find that it loses water in a way analogous to
that in which a protein-salt mixture loses salt when
dialyzed against running water. In either case some
water or some salt remains behind which can be removed
only with the greatest difficulty if it can be removed
at all. The ion-protein compounds show a considerable
stability toward conditions influencing their state of
aggregation in yet another way. The presence of neutral
salts, for example, inhibits the effect of an acid or an alkali
upon the dissolved globulin, while non-ionized substances
do not do this.

We must therefore look upon the ion-protein compounds
as being of importance in the animal body through
their ability to decrease its sensitiveness toward changes
in concentration, changes in temperature, and changes
in alkalinity.

Through the decomposition of the large protein mole-
cules and certain carbohydrates there are produced
during metabolism substances having a low molecular
weight which in many ways have characteristics in
common with those of the salts, — such, for example,
as urea or sugar. All these substances are either not
at all or only slightly ionized in water. They are there-

1 6 PHYSICAL CHEMISTRY IN MEDICINE.

fore not able to replace the salts which in dilute solution
are almost completely ionized.

// is not the salts but the ions of the salts that are essen-
tial to the organism.

Our belief that many reactions of living matter can
be traced back to the properties of the dead ground-
substance itself seems to be true not alone of the proteins
and their closely related bodies.

Emil Fischer has been able to show, for example, that
the fact that enzymes or living organisms split certain
kinds of sugars more easily than others ■ is dependent
upon their structural peculiarities, and has assumed the
existence of a peculiar, stereochemical relation between
the reacting substances.

A remarkable similarity between the reactions in dead
and in living matter has also been proven -to exist for the
fats. If we allow two immiscible liquids, such as oil
and water, to compete for a substance soluble in both,
the amounts of this substance dissolved in the two solvents
bear a definite proportion to each other. Meyer and
his pupil Baum have studied a long series of narcotics
with, reference to their distribution coefficient in the
above mixture, and have been able to point out a far-
reaching parallelism between the distribution coefficient
of a substance and its narcotic effect. This observation
has led Meyer to an interesting theory of narcosis,
based upon the' difference in the distribution of the active
substances between the watery tissue fluids and the fat-
like constituents of nerve tissue.

We will now leave the field of more or less indirect
biochemical investigation and, even though but hastily,
consider the results which have been obtained through

ON PHYSICO-CHEMIC/IL METHODS /IND PROBLEMS. 17

a direct application of the new methods to changes which
go on in the organism. These belong more or less in the
field of special physiology, while the foregoing fall more
naturally into the territory of general physiology.

We have to deal in what follows almost entirely with
the principles of the modern theory of solution, of which
extensive use is made in the explanation of phenomena
of absorption and secretion. •

We must consider it a great advance that we now know
that almost all relations existing between the red blood-
corpuscles and the plasma can be explained by the laws
which govern any solution. The credit of having recog-
nized this fact belongs chiefly to Hamburger and Koppe.
These investigations, it seems to me, are the first to
conclusively do away with any higher life in the blood.
What appears as life in the blood is only a reflection of
those true vital processes which go on in the tissues. All
known changes which take place in the circulating blood
(with the exception of the white blood-corpuscles) are
passive physico-chemical reactions, and are in consequence
independent of nervous influence.

Of special physiological and pathological interest are
the efforts to explain the activities of the kidneys from
these new points of view. The starting-point of these is
furnished by a paper of Dreser, in which this author
develops for the first time the conception of the osmotic
work of the kidneys and calculates this in mechanical
work-units. A detailed study of this fundamental con-
ception is desirable, since in its original form it is neither
entirely clear nor complete.

We can determine the number of particles present in
the unit volume of a solution, the so-called molecular

1 8 PHYSICAL CHEMISTRY IN MEDICINE.

concentration, either through a determination of the
osmotic pressure — the attraction between dissolved par-
ticles and solvents — or the change in the freezing-point
or boiling-point of the solution.

All these values are related in a simple way and are
independent of the nature of the dissolved substances.
If we wish to increase the concentration of an aqueous
solution we must remove a part of its water. It is
immaterial whether we do this through evaporation^
freezing, or expression of the water through a membrane
impermeable to the dissolved substances, or whether this
process takes place in. the kidneys: in every case the
amount of work required must, according to the laws of
energy, be the same. The amount of this work is deter-
mined solely by the original concentration and the change
in concentration finally attained. With these facts in
mind, we will try to formulate the conception of rencd
work more clearly.

While the molecular concentration or the freezing-
point of normal blood has an almost constant value, that
of the urine varies within wide limits. Our kidneys are
able to furnish a secretion the freezing-point of which
may be higher or lower than that of the blood. For the
sake of simplicity, it may be well to consider these two
possibilities separately.

If the kidneys furnish a urine having a higher freezing-
point than that of the blood, then their entire activity
consists in the mere preparation of a dilute urine, and
these organs do their osmotic work by expressing from the
more highly concentrated blood a certain amount of water.
During all this time the osmotic pressure of the blood is
pf course kept at its original height through the tissues,

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 19

The amount of water given o£E can be readily calcu-
lated: it is the amount which must be separated from
the urine in order to change this into a liquid having the
high molecular concentration of the blood.

The calculation of the work necessary to accomplish
this is, however, not as simple as Dreser believes, since
through the transport of the water from the blood to the
urine the concentration of the latter is steadily altered,
a fact which this author has not taken into consideration.

We will look upon the amount of work necessary for
this purpose, which can be determined mathematically
as a measure of the water-secretory function of the kidneys.

The converse of the above would exist when the kidney
has to prepare, from a liquid having the osmotic pressure
of the blood, one having a molecular concentration
greater than the blood. Under these conditions we
should have to add a certain amount of water to the urine
in order to make its osmotic pressure equal to that of the
blood. While in the first case, therefore, the kidneys
have to express water from the blood, this time they
have to express it from the urine and return it to the
blood.

The work corresponding to this, which has been cor-
rectly determined by Dreser, we will have to regard as
a measure of the water-absorption activity of the kidneys.

As we know from numerous facts, this double function
of the kidney is performed by two different parts of the
organ. While the glomeruli probably secrete the water
of the urine, the uriniferous tubules have an antagonistic
function.

The urine which we are able to examine has already
been subjected to hath kinds of work. We are able to

20 PHYSICAL CHEMISTRY IN MEDICINE.

determine from it, by freezing-point determinations, only
the difference between these two values, while the kidney
has in reality performed the sum of the two. All the
measurements of osmotic renal activity made by Dreser
do not take this important fact into consideration. Failure
to consider it must of necessity lead to radically incorrect
conclusions.

The normal human being usually secretes a urine the
freezing-point of which is lower than that of the blood,
because its molecular concentration is greater. By con-
suming much water we are, however, able to raise the
freezing-point of our urine, and it would not be difi&cult
to so regulate by artificial means the amount of water
taken up by the organism that the freezing-point of urine
and blood would be the same. If now we base our cal-
culation of renal work upon the difference between the
freezing-point of the blood and that of the urine, — a
difference which under these circumstances would be
zero, — ^then we would be compelled to conclude that the
secretion of a urine equimolecular with that of the blood
had been accomplished without work, while as an actual
matter of fact it may have demanded a great deal of
work. For after what has been said it is clear that the
osmotic work of water secretion and the osmotic work of
water absorption by the kidneys equal each other in this
case.

A statement which is found in various articles and which
threatens to be adopted by text-books, that the work per-
formed by the kidneys in twenty-four hours normally
varies between 70 and 240 kilogrammeters, has therefore
no real value. After what has been said it will not seem
strange that the attempts to utilize for diagnostic pur-

ON PHYSICO-CHEMICAL METHODS AND PROBLEMS. 2t

poses the work of the kidneys as determined in this way
have failed.

It seems to me that still another point should be noted.
It is readily apparent when one studies the papers that
have followed Dreser's initiative that the method of
measuring the work of the kidneys as criticised above
has been regarded as giving the value of the total work
done. At the best, however, the method determines
only that portion of the work which is necessary to bring
about the secretion of the water of the urine. For our
urine does not represent a concentrated or a diluted
blood, but contains, as we know, the constituents of the
blood in different concentrations, even when we disregard
the osmotically inactive substances (albumin).

If we imagine a certain amount of urine having the
same freezing-point as the blood, separated from this
by a thin permeable membrane, and the blood kept in
circulation and maintaining its original composition as
in the body, an interchange between the diffusible con-
stituents of the urine and those of the blood takes place
until the amount of these is the same on both sides of the
membrane. We will call such an interchange a molecular
interchange, as does Koranyi, because the molecular
concentration of the two fluids remains the same through-
out the experiment. As we do not have to do in this
case with differences in osmotic pressure, the external
work is zero. But a certain amount of internal work
is performed, the direction of which can also be deter-
mined. For substances migrate from regions having a
higher concentration to those having a lower one, through
which a certain amount of osmotic work becomes free
for each of the substances. The sum of all these different

22 PHYSICAL CHEMISTRY IN MEDICINE.

amounts of diffusion work would have to be used in order
to separate the substances again and to bring about the
original differences. This work must also be done by
the kidneys, and in two directions, toward the urine and
toward the blood. The value of this can also be calcu-
lated, a subject which is, however, not within the bounds
of this paper. We may call this the selective work of the
kidneys.

The osmotic work of the kidneys is therefore made
up of three components — the osmotic work of water
secretion, that of water absorption, and that of selection.

Dead material, such as gelatine plates, may also show
a power of selection. For a recognition of this important
fact we are indebted to Hofmeister and his pupil Spiro.
The latter has elucidated these phenomena through
physico-chemical principles.

While, however, a gelatine plate that has absorbed
a salt or a dye remains in equilibrium with its surround-
ings and is not capable of any further selective activity,
the phenomena observed in the kidney are of a dynamic
nature.

The selective function of the kidney is an uninterrupted
process, maintained through the active metabolism of its
living substance.

It is not possible to mention here all the other beautiful
applications that have been made of physical chemistry
to questions in physiology and pathology. Many im-
portant advances besides those already noted might be
brought up here. Pharmacodynamics may also expect
great changes through use of the new theories, as may
be concluded from the attempts which are already being
made to introduce these new methods into this science.

CELLS Ano TISSUES. 23

In fact, no branch of our science will attempt to solve
the new questions presented to it without rich results.

I have arrived at the end of my paper, the purpose of
which was to test the value of the methods of physical
chemistry in questions of medicine. Unquestionably
•they enlarge that territory which the organic and the
inorganic world have in common. The last barriers
between the two cannot as yet be broken down, how-
ever, through the increase in our means of investigation
that we are at present enjoying. There always remains
an unsolved portion, the kernel, as it were, of vital
phenomena.

The cause of the final failure of the new instruments
can rest only in their origin. They have all been evolved
from the study of lifeless matter. For a complete under-
standing of the living the words of a great physiologist
will probably hold:

" Lije can perhaps be completely understood only through
life itself. "

2. The General Physical Chemistry of the Cells and
Tissues.*

A COMPLETE and ordered understanding of all the func-
tions of living matter, independent of its relation to a
definite organism or organ, is the final goal of general
physiology. Free from a one-sided overestimation of any
one system of investigation, it makes use not only of the
methods peculiar to biology, but also of those employed
in physics and chemistry. The methods of chemistry
have attained a special importance in the investigation

* From Ergebnisse der Physiologie, 1902, I, ite Abth,, p. i.

24 PHYSICAL CHEMISTRY IN MEDICINE.

of the metabolic changes that take place in living matter.
This so-called vegetative physiology has been greatly
advanced through the modern development of theoretical
or physical chemistry. It is the purpose of this young
and rapidly growing branch of the inorganic sciences to
establish the general laws governing chemical changes.
Through the stupendous theoretical and experimental
accomplishments of such investigators as van't Hoff,
Arehenius, Gibbs, Hittoef, Kohlrausch, Ostwald,
Nernst, and Planck, our understanding in this direction
has within a comparatively short time been incredibly
increased and deepened. As in every great development
in, the exact sciences, physiology may in this case also
expect to be enriched in no small way, and though it to-
day stands only at the beginning of this wonderful fertil-
ization, the number of workers along special and general
subjects in physiology is daily increasing. In fact, in
the realm of general physiology the physico-chemical
method of looking at things has been the first to make
it possible to ask many questions in a general way and
to answer them according to the present status of physico-
chemical investigation. New analogies and transitions
between phenomena in living and in dead matter have
been discovered; and it has often proved no small task
to discover that side of a phenomenon which charac-
terizes it as a specifically biological one.

Important as many of the advances that have been
made may seem, closer inspection shows that even at
the best we are only beginning to solve the questions before
us.

The development brought about through the seeds of
physical chemistry has as yet not led to an equilibrium

CELLS y4ND TISSUES. *S

between our imagination and fact, due in part to a lack
of chemical data of biological importance, in part to a
lack of that theoretical foundation necessary for special
questions in biology. For this reason the following
fragments of a general presentation of the physical
chemistry of the cells and tissues cannot claim to be
complete or to give a satisfactory account of facts to
which nothing- more will ever be added. It must suffice
if the great importance of physical chemistry in general
physiology is rendered apparent.

I,

All living matter is made up of colloidal and crystal-
loidal material, and there exists no life process that is
not accompanied by changes in the colloidal and crystal-
loidal substances. And the physico-chemical laws which
govern the crystalloids and the colloids reappear in the
numerous properties of living matter.

The colloids have for the most part a high molecular
weight, diffuse only with the greatest difficulty, and do
not pass through animal membranes. Solutions of col-
loids have a scarcely measurable osmotic pressure, and
have in consequence little effect in raising the boiling-
point or depressing the freezing-point. They do not con-
duct the electric current, yet they move, for the most part,
in an electric current.

The crystalloids diffuse easily and pass readily through
animal membranes. Their molecular weight is low,
while their affinity for water, as measured by an in-
crease in the boihng-point or a depression of the freezing-
point of their solutions, is very great. The crystalloids

26 PHYSICAL CHEMISTRY IN MEDICINE.

are divisible into two groups — the electrolytes, which in
(aqueous) solution conduct the electric current, and the
non-electrolytes, which do not. To the first class belong
the salts, acids, and bases; to the latter most of the
organic substances, such as urea and sugar.

Between the two great groups of colloids and crystal-
loids there exists no sharp line, for we are acquainted
with " half -colloids, " which stand midway between these
extremes. But because of the typical differences existing
between the extremes of the whole series, differences
which all substances show more or less perfectly, this
division into colloids and crystalloids is nevertheless of
great value.

The colloids exist in two states, a liquid and a solid
state. In the liquid state they are known as sols (Gra-
ham), in contrast to the solid state, in which they appear
as dry, swollen, coagulated (through heat or ferments),
or precipitated (for example, through electrolytes) masses,
which are known as gels. A question that arises at once
is, Do the colloids of Uving matter exist in the sol or in
the gel state ?

Protoplasm possesses properties which are character-
istic, generally speaking, of both solid and liquid sub-
stances. This peculiarity of living matter has given rise
to great discussions between the behevers in the sohd
and those in the fluid state of aggregation af protoplasm.
The ability to stand alone — in other words, a relative
independence in form, which often expresses itself in the
existence of characteristic cell forms — corresponds with
the properties of the solid state, while an argument for
the liquid state of protoplasm is readily found in the
general and necessary condition that chemical reactions

CELLS AND TISSUES. 27

must be able to take place within the cell and often with
great velocity.

In those cases in which changes in the shape of the
protoplasm under investigation can be easily explained
through the assumption of the existence of a surface
tension, there seems to be no reason for doubting the
fluid nature of the protoplasm, for surface tension is
ordinarily looked upon as a dependable criterion of the
liquid state. The amoeba, which becomes spherical in
a state of rest or when universally excited, or forms
pseudopodia when it suffers a local alteration in surface
tension, may be looked upon as a liquid mass as long as
it has not been possible to demonstrate in it a noticeable
displacement elasticity such as torsion. To prove the
existence of the latter by suitable experiment has never
been attempted, so far as I know. Since the discovery
of the "amoeboid" movements of oil droplets and the
careful physical analysis of this phenomenon by Quincke,
the formation of pseudopodia has been robbed of the
characteristics of a specific life phenomenon, and later
investigators have shown that it is governed in all its
details by the laws of surface tension. The taking up of
food and the process of defecation in rhizopods can
also be easily explained in this way. Rhumbler could
even imitate most cleverly with drops of chloroform and
threads of shellac such apparently complicated phenomena
as the rolling up of algas threads within the body of
Amceba verrucosa. By similar methods he was able to
imitate in a most surprising way the formation of cases
about testaceans by rubbing up fine quartz or glass pow-
der with different kinds of oils or chloroform, and
dusting this into dilute alcohol or water. E. Albrecht,

28 PHY SIC/1 L CHEMISTRY IN MEDICINE.

who has formulated the question of the state of aggre-
gation of living matter in both a penetrating and per-
tinent way and has attacked it with the arriiament of
modern physico-chemical research, could bring about a
separation of droplets within the contents of a number of
cells such as those of the sea-urchin and of the kidney.
Such a separation is dependent upon differences in sur-
face tension, such as can exist apparently only between
fluids. Even before him Berthold had regarded the
normal formation of granules and vacuoles in protoplasm
as a separation of droplets. Jensen has measured the
tensile strength of the pseudopodia of orbitolites and
has found that it about corresponds with the calculated
surface tension. This author has also again pushed into
the foreground the surface-tension properties of liquids
as a means of explaining many mechanical properties of
living matter.

In spite of these results, which are all of them, appar-
ently, capable of only one interpretation, a generalization
in the sense that all living substance must be liquid meets
with difficulties. The maintenance and the individuality
of form in cases in which no supporting framework is
demonstrable would have to be attributed by the believer
in the liquid state of protoplasm to currents that are
able to hold their own against disturbing forces. What
is of static origin in the solid state of aggregation needs
here a dynamic explanation which brings with it the
assumption of a constant expenditure of work. Since
an inner stabile differentiation is impossible in a liquid
(for even the finest particles of matter dissolved or sus-
pended in a liquid endeavor with great force to become
uniformly distributed throughout the whole), the assump-

CELLS AND TISSUES. 29

tion of a liquid state of aggregation for protoplasm meets
in many cases with still greater difficulties than does the
assumption of a solid state. While, for example, all the
different portions of the cell body of an amoeba show
the same behavior, in that any element within the pro-
toplasmic mass may become a surface element, and con-
versely ; in other words, every particle is equally capable
of the functions of assimilation, stimulation, and move-
ment, there exist peculiarities in many of the more highly
developed unicellular organisms, or the individual cells
of higher animals, which can scarcely be interpreted
otherwise than as expressions of polarity. Under this
heading belong, for example, the fact that absorption and
secretion take place predominantly in certain directions,
the dependence of muscular stimulation upon the angle
of the current and the direction of the muscular fibrils,
and the polarity of phenomena of regeneration in plants
and animals. These phenomena, which indicate a per-
sistent inner differentiation, can scarcely be explained
without the assumption of a solid orientation of the par-
ticles of living matter.

A way out of this dilemma, of which the details con-
stitute a literature that cannot be entered into in this
paper, is rendered possible through a study of the colloidal
state.

II.

Those gels which were said above to be swollen or
solidified (for example, ordinary gelatine or agar-agar)
show the properties of both solids and liquids united in
one, in much the same way as protoplasm. They are
capable of existing in all states of aggregation, varying

30 PHYSICAL CHEMISTRY IN MEDICINE.

from the solid to the liquid, depending only upon the
amount of water they have absorbed. Chemical reactions
may take place anywhere in such a medium, and with
almost the same velocity as in the fluid absorbed by the
colloid alone. Such a jelly does not take up any other
colloid which is brought in contact with it (differentiation
between different membraneless cells), and a foreign
colloid imbedded in it does not tend to spread (intra-
cellular differentiation). Such gels undergo most deh-
cately shaded changes in state even without changes in
temperature, through the action of substances which are
present in the living organism. They may be rendered
more solid or more fluid, without suffering a change in
the amount of water which they hold, through the action
of crystalloids, and also through the action of certain
enzymes (partial or complete peptonization).

Such sohd colloids show yet other properties that
have been used as potent arguments in favor of the
entirely fluid character of living matter. If mercury
globules are driven under pressure through a capillary
into solidified gelatine, the gelatine closes in as completely
behind the rapidly moving globules as a hquid itself.
The separation of droplets such as Albrecht has de-
scribed in protoplasm is also possible in solidified gelatine.
In the fluid state, that is to say, above the solidification-
point, gelatine is precipitated by certain electrolytes such
as the sulphates, citrates, and tartrates of the alkali
metals. As can be proved microscopically and mechan-
ically, this precipitation is a separation of droplets —
the appearance of a "phase" richer in gelatine. The
precipitating power of the electrolytes decreases with an
increase in the temperature, that is to say, a more cpo-

CELLS AND TISSUES. 31

centrated salt solution is required to precipitate gelatine
at a higher temperature than at a lower one. Corre-
sponding with this, it is an easy matter to prepare con-
centrations in which a precipitation will not take place
until a temperature below that at which gelatine becomes
solid has been reached. When this temperature has
been reached a precipitate is produced, this time also in
the form of fine droplets, in the solid and originally
entirely clear gelatine. We can therefore not regard
such a separation of droplets as an undeniable proof
of the fluid character of a medium. That, however, the
application of the theory of surface tension to certain
cellular phenomena may be of great service, as shown
by the observations of Albeecht, is of course not ques-
tioned by the above experiment. Nor does anything stand
in the way of looking upon the shrinkage forms of thin
solidified gelatine (Butschli, Pauli) in alcohol, am-
monium sulphate solution, etc., as expressions of sur-
face tension. In fact, the similarity is very great between
such shrinkage forms and the shapes of suspended
("schwerloser") masses of oil (cubes, cylinders, etc.) in
suitable media, as described by Plateau. The diffi-
culties that are encountered in endeavoring to explain,
on the basis of the solid nature of protoplasm, the
unhindered appearance and solution of crystals without
the formation of holes, do not exist in the case of
gels, as experiment has taught. Ludeking has been
able to demonstrate with the polarization microscope the
appearance of ice crystals in the clear substance of thin
slices of deeply cooled (— i8°C.) gelatine. One can
also notice in salt-gelatines in which the crystalloid, such
a,§ ammpnium chloride, shows a great fall in solubility

32 PHYSICAL CHEMISTRY IN MEDICINE.

with a decrease in the temperature, that with a fall in
the temperature supersaturation and finally crystallization
of the salt occurs in the solid gelatine, and that when the
gelatine is warmed once more the crystals disappear
without leaving a trace of their existence behind them;
and all this without a change in the state of aggregation
of the colloid.

A study of gels has disclosed yet other interesting
analogies with living matter. Variations in the degree
of swelling or in the volume of jellies having the approx-
imate size of body cells occur with a velocity the mag-
nitude of which corresponds very well with that observed
in the changes in volume noticed in living matter. Solid
colloids also manifest very extensively a group of phe-
nomena — so-called adsorption phenomena — the simplest
laws of which still demand much study. In these
phenomena a chief role is played by great surfaces which
load themselves (depending upon the pressure, tempera-
ture, etc.), often very rapidly, with different substances.
If one bears in mind the complicated combination exist-
ing in a solidified gel between the colloid and its absorbed
liquid — the water seems to be held in part mechanically,
in part in combinations varying from the most firm to the
loosest, which renders possible true liquid and solid
solutions in addition to pure adsorption — one is impressed
with the great variety of ways in which substances may
be taken up in such colloids. In this way a great selection
in the substances offered them is rendered possible, as
HoFMEiSTER and Spiro were able to illustrate with biolog-
ically instructive examples in gelatine and agar-agar
plates.

Since a part of the imbibition fluid may be mixed

CELLS AND TISSUES. 33

with ether-soluble substances — in the protoplasm these
are such as cholesterin and lecithin, or, as Overton
calls them all, lipoids — these gels are able to take up
substances which are not soluble in water. The man-
ner in which the lipoids are held by the cell plasma,
the nature of which is still unknown, must no doubt be
governed, according to our newer physico-chemical
conceptions, by some property of the lipoids,- such as
their solution affinity. According to the extensive investi-
gations of OvEETON, the ability of many substances
soluble only with difficulty in water ,to enter the living
cell is dependent upon their solubility in the Hpoids.

If by the distribution coefficient of a substance between
two solvents we understand the relation between the
spacial concentrations which exist in these two solvents
after equihbrium has been established, it is fount} that
the distribution coefficient of many narcotics between oil
and water determines also their distribution between
medium (such as blood plasma) and cell contents (such
as the lipoids of the brain), and therefore also their effect
(Meyer, Overton). The investigations of Frieden-
THAL on- absorption by the intestine of substances insol-
uble in water also belong under this heading, which is of
such fundamental importance in many questions in physi-
ology. Spiro has given numerous examples of the gen-
eral significance of the distribution law. No doubt experi-
ments carried out on simple models would bring much
hght into this field.

After what has been said, the similarity in important
physico-chemical properties between Hving matter and
certain gels must be looked upon as an extensive one.
Without doubt a continued investigation of the colloids

34 PHYSICAL CHEMISTRY IN MEDICINE.

is destined to contribute much toward an understanding
of biological problems.

III.

The sols also play an eminent part in life processes.
In contrast to the green plants, which, according to well-
known cultural experiments, are able to obtain their
nourishment from pure crystalloidal solutions, animals
are dependent upon liquid colloidal food. The process
of digestion serves to prepare nutrient sols capable of
absorption, and fluid colloids are mechanically moved
about and distributed throughout the organism to the
nourishing tissue fluids. While exerting only a slight
osmotic pressure, the dissolved colloids are nevertheless
able, 'through their inability to pass through animal
membranes, to exert a resorptive power, which through
a steady change in the osmotically active material, as
maintained by the circulation, finally attains significant
proportions (Okerblom).

As recent investigations have shown, the sols have
several important properties in common with true sus-
pensions of very fine particles. The most important of
these from a biological standpoint is the at times enormous
surface effect of the colloidal particles contained in the
solution. Bredig, who rediscovered the well-known
ferment-like action of metallic surfaces in the enormously
more active colloidal solutions of metals, and investigated
the whole subject quantitatively, has attempted to explain
the importance of the colloidal condition of the enzymes
by the enormous surface effects with which this condition
is combined.

The free surface energy and the osmotic energy seem

CELLS ANt) Tissues. i5

in many ways to bear a reciprocal relation to each other
in the cell. The analysis of the colloidal material
decreases the former while it increases the latter, and
conversely. The metabolic changes which are forever
going on in the hving organ compel us to look upon life
as a dynamic process, and the repeated attempts that
have been made to comprehend life physico-chemically
without taking this fact into consideration could not help
but seem inadequate. To discover the right connection
between this metabolic physiology and physical chemistry
is among the most important of the problems of general
vegetative physiology.

IV.

The biological significance of the crystalloids has until
recently been the main object of research with the
majority of those investigators who have made use of
physico-chemical methods in physiological questions.
Especially has use been made of the theory of solutions.
The great fertility of van't Hoff's teaching of osmotic
pressure had as an immediate consequence its unrestricted
application to all manner of Ufe problems. The cells
were looked upon as liquid masses surrounded by semi-
permeable membranes which were supposed to act as
Pfeffer's well-known model. A relative increase in the
osmotic pressure of the fluids surrounding the cells was
supposed to bring about a shrinkage, while an increase
in the osmotic pressure of the cell contents over that of
the surrounding fluid was supposed to be followed by a
swelling of the cell. This so simple and consequently
so enticing conception of the role of osmotic pressure in the
organism meets, however, when further considered, with

3^ PHYSICAL CHEMlStkY IN MEDICINE.

difl&culties ; nor does it furnish even the possibilities of a
complete understanding of many important phenomena.
In spite of this, however, numerous fundamental investi-
gations, such as those of Hamburger and Koppe, con-
tinue to retain great value, representing as they do the
first experiments undertaken in the study of a nev\f subject.
The principles employed in these investigations approxi-
mate actual conditions only more or less coarsely; they
fail, however, to explain details because conditions for their
employment in the organism are satisfied only in part.
This fact leads, however, to the recognition of new
physico-chemical peculiarities of living matter, as illus-
trated, for example, in such discoveries as the biological
significance of the distribution law.

The osmotic relations between animal cells and their
surrounding media were studied for the most part on
red blood-corpuscles. These give off their red coloring-
matter in dilute salt solutions as soon as the concentration
of the salt drops below a certain value. The lowest con-
centration of different salt solutions which just prevent
the "laking" of blood are said by Hamburger to be
isotonic with each other and are regarded as bringing
about the same degree of swelling in red blood-corpuscles.
Since a determination of the osmotic pressures of such
isotonic salt solutions by physical methods (determina-
tion of the freezing-point) showed them to be about the
same, the "blood-corpuscle method" was looked upon
as a universally applicable procedure for determining
osmotic pressures. An extension of this method to a
large number of crystalloids soon showed, however, that
physical and physiological isotonicity are identical in
only a few substances, the majority showing differences

CELLS /im TISSUES. ii

between the two (Hedin, Geyns). A part of these
exceptions could be explained by Hedin, and more
especially by KOppe, on the ground that the crystalloids
permeate the red blood-corpuscles more or less perfectly.
KoppE has taken the following stand: The solution of a
red blood-corpuscle is analogous to the bursting of a
balloon filled with gas in a rarefied atmosphere. This
bursting will occur also when the space about the balloon
is filled with a gas that can pass through the wall of the
balloon, for it cannot under these circumstances counter-
act the pressure existing within the balloon. In this
way is explained the laking of blood in even the most
concentrated solutions of substances which are able to
pass into the red blood-corpuscles, such as urea.

If this simple conception, deduced from the analogy
between gas pressure and osmotic pressure, is strictly
tenable, then the addition of substances which lake
red blood-corpuscles (such as urea) to salt solutions
having a concentration in which the haemoglobin just
manages not to pass out of the corpuscles should be
without effect, since the relative osmotic conditions
v/ithin and without the cells remain unchanged. This is,
however, not the case ; such solutions also become colored
red. Whenever urea has been added to a NaCl solu-
tion a much higher concentration of the latter is required
to keep the red blood-corpuscles of the horse from losing
their haemoglobin than when pure NaCl is used. The
differences in concentration varied in a series of experi-
ments between 0.005 ^^'^ °-°^ molecular NaCl, and were,
strange to say, not markedly influenced by an increase
in the concentration of the urea from 0.25 to i .00 molecular.

Not until thorough investigations have been made

aS PHYSiCJL CHEMlSTkY IN MEblCiNS.

into the equilibrium between substances that dissolve
and those that inhibit the solution of red blood-corpuscles,
and the reversibility of the migration of color, can we
know in how far haemolysis through crystalloids represents
a single process. The idea that the exit of haemoglobin
from the red blood-corpuscles does not represent a single
change, as rendered apparent through the action of such
various agents as electricity, cold, various poisons, etc.,
has found valuable support in the investigations of
Stewart on the permeability of red blood -corpuscles
to various salts (determination of electrical conductivity
of plasma). Only the failure to recognize this fact is
responsible for the extensive use that has been made of
the determination of the osmotic resistance of the eryth-
rocytes in the solution of questions in the physiology
and pathology of the blood, for which this method was
never adapted. We do not understand the conditions
under which the physiological destruction of the red blood-
corpuscles, with a splitting oil of their coloring-matter,
occurs, and neither the discovery of normal nor of patho-
logical values for their osmotic resistance yields any data
from which conclusions regarding their behavior under
experimental (for example, removal of the spleen) or
pathological conditions (icterus, haemoglobinuria, etc.)
may be drawn. In fact, the beautiful investigations of
BoRDET, Ehrlich, Landsteinee, etc., on the production
of hemolytic substances in the animal body point to a
new field of work entirely outside of the teachings of
osmotic pressure.

There is no objection to saying that several solutions
which have the same osmotic pressure are isotonic, that
is, isosmotic with each other; but to speak of the isoto-

CELLS AND TISSUES. 39

niclty of a single solution is impossible, as Koppe has well
pointed out by indicating the confusion wrought by this
expression. The osmotic effect of a solution may be
expressed in terms of molecular concentration (mol.). The
molecular weight of a non-dissociable substance (such
as cane-sugar), expressed in grams and dissolved in
enough water to make a hter, constitutes the unit of
molecular concentration. Such a solution has an osmotic
pressure of 22.35 atmospheres at 0° C. Isotonic solutions
are equimolecular.

The fact that there exists a difference between physical
and physiological determinations of osmotic pressure is
emphasized all too httle. In the former case the pressure
is measured against the solvent, in the second case the
pressure of a solution against cells or their contents.
Each of these values, differing as it does more or less
from the other, may have its own biological signifi-
cance.

A study of the changes in the volume of cells brought
about through differences in osmotic pressure clearly
shows that the conditions for the unhmited tenabihty of
van't Hoff's laws do not exist in the living organism.
In its simplest form van't Hoff's theory presupposes
two things : impermeability of the separating membrane
for the dissolved substance, and complete freedom of
movement of the solvent throughout the entire medium
contained within the membrane. If these two conditions
existed in the case of cells, then two series of facts should
be found to be true experimentally:

I. A cell should have the same volume in isosmotic
solutions of differerit substances.

II. A cell should show an amount of change in volume

40 PHYSICAL CHEMISTRY IN MEDICINE.

proportional to the amount of change in the osmotic
pressure within or without the cell.

It was soon learned to attribute the exceptions to the
first sentence to the relative permeabiUty of the cells for
certain substances. But this explanation does not suffice
for a large and important number of cases in which the
substance that has entered a cell exists here in a greater
concentration than in the solution surrounding it. These
cases have been explained in part through the distribution
law.

Strange to say, not a single example investigated thus
far has ever brought a confirmation of the second con-
clusion stated above — a change in volume proportional
to the change in osmotic pressure. Koppe, for example,
found that it was the rule to discover very considerable
variations from this law in the red blood-corpuscles.
When the osmotic pressure of the surrounding liquid is
increased, the decrease in the volume of the red blood-
corpuscles is less than calculated, as is true also of the
amount of their swelling when the osmotic pressure in
the surrounding fluid is decreased. In the experiments
carried out by Dueig on the swelling and shrinkage of
frogs great exceptions to the simple laws of osmotic
pressure were found to exist. We seem to have every
reason for believing that freedom of movement and
homogeneousness of solvent, which are demanded for an
immediate application of van't Hoff's theory to the
interchange between the fluids within and without the
cell, do not exist in our tissues. A chief role in this
modification of the solvent will no doubt fall to the part
of the colloidal constituents of living matter.* The

* It does not seem impossible that the relations found to exist here

CELLS AND TISSUES. 4^

fact that protoplasm behaves in many ways as a mixture
of difEerent solvents might also be of importance.

A peculiar and important place biologically is occupied
by those crystalloids which because of their behavior
in the electric current (conductivity and electrolysis) are
called electrolytes. These are substances which in aqueous
solutions (and in certain other solvents) break up into
electrically charged particles, the ions (the electronegative
anion and the electropositive cation). This electrolytic
dissociation, which may in dilute solutions attain a very
high grade, is, however, never complete; beside the ions
there exist also non-dissociated, electrically neutral
molecules. The investigation of the r61e of electrolytes
in life phenomena must be directed toward an under-
standing of the part played by each of these.

Experiment has taught us that there exist physiological
effects -which are attributable solely to ions. The vital
property of the ions to keep in solution the widely
distributed globulins cannot be replaced by any other

may be expressed mathematically. Support for this is found in the
no longer negligible volume of molecules present in colloidal mixtures
which bind the solvent. The vifater found in gels is, moreover, to be
regarded as freely movable only in part, and this part decreases rapidly
with an increase in the amount of shrinkage. In consequence of the
increase in the values of the volume and the attraction of the gas mole-
cules the simple equation pv = R.T. no longer holds, as is well known,

at higher temperatures, but van der Waal's equation ip-\ — A {v—b) =

R.T. Much seems to speak in favor of the idea that the relation
between osmotic pressure and cell volume may be kindred to the latest
modification of the law of Mariotte-Boyle.

42 PHYSICAL CHEMISTRY IN MEDICINE.

kind of dissolved crystalloids (Pauli). The poisonous
effects of water poor in ions upon the human organism
(Koppe) may also belong under this heading.* Differ-
ences in the concentration of ions brought about through
differences in their migration velocities constitute the
source of differences in elettrical potential. Loeb was
probably the first who recognized in such "concentration
chains" the cause of the majority of the electrical phe-
nomena observed in animal organs.

We are far from a satisfactory insight into the nature
of the effects of ions the elements of which may be
electrical in character. Nevertheless, we know enough
to be able to say definitely that a certain effect is quan-
titatively determined by ions, if it follows the general
principles outlined below:

"Since very dilute solutions of electrolytes are almost
completely dissociated, the effects brought about by such
solutions may, as a rule, be looked upon as ion effects,
and the electrically neutral molecules may be neglected
because of their exceedingly small number. A pure ion
effect must parallel the concentration of the ions and not
the concentration of the substance itself; and at the same
concentration of substance be dependent upon the degree
of dissociation, which can be varied, without a change in
volume, through the addition of an electrolyte having a
common or a different ion. When anion and cation

* A specific ion effect is not, strictly speaking, proved by this experi-
ment, because the attempt to do away with the poisonous effects of the
water through the addition of non-ionized substances such as sugar
was not made. Moreover, Nansen and his followers in his polar expe-
dition drank for months without harm the almost ion-free water ob-
tained by melting natural ice.

CELLS /IND TISSUES. 43

both take part in the ion effect it must be possible to
demonstrate the law of additive ion effects. If, however,
the ion effect is connected with but one of the ions,
then it is dependent only upon the concentration of the
effective ion, and a variation in the opposite ion must,
under otherwise unchanged conditions, be indifferent.
The role of the electrically neutral molecules springs
into prominence in proportion as the degree of electro-
lytic dissociation is decreased."

Examples of such ion effects are to be found in the
papers of Dreser on the pharmacology of mercury, of
LoEB on the absorption of water by muscle and in his
much-discussed experiments on artificial parthenogenesis,
of HoBER on the sense of taste, of Spiro with Scheurlen
and Bruns, as well as Paul and Kronig, on the founda-
tions of disinfection, of Pauli on changes in state in the
proteins, etc. The laws governing the simultaneous
action of several electrolytes can also be deduced from
the ionic theory. Pauli and Rona have recently dis-
covered an antagonism between the effects of different
electrolytes and some non-electrolytes on the changes in
state in colloids.

In the living animal we have to deal with complex
mixtures of crystalloids and colloids, between which
there exist relations so varied "that they are in part still
incapable of investigation. Connected with the uninter-
rupted vital activity of the cell, the anabolism and cat-
abolism of its substance, is the conversion of crystalloids
into colloids and colloids into crystalloids, and this at
present still entirely unexplained transformation serves
at one time to protect a substance from oxidation, as in
the conversion of sugar into the colloidal glycogen, while

44 PHYSICAL CHEMISTRY IN MEDICINE.

at another it protects the protoplasm against the poisons
of its own products. Questions in absorption, secretion,
pharmacology, and immunity are connected with these
changes in state, a discovery of the nature of which
must constitute one of the great aims of biochemical
research.

3. The Colloidal State and the Reactions that Go On in
Living Matter.*

I.

Colloidal material enters into the construction of
living matter in two forms — ^first, in the Uquid or solid
state, in Graham's sense of the word, and, second, in
the form of a more or less solid, swollen mass, at
times sufficiently solid to have independent form, at
others, because of its^ approximation to the semi-solid
condition, still subject to the laws of surface tension
governing liquids. We wish to consider in this paper
some of the properties of this swollen (jelly-like) condition
which can be attained not only through the absorption
of the so-called "solvent" by the original solid material —
for example, the absorption of water by dry gelatine — but
also through "gelation" of the liquid colloid. This
gelatinous state is of the greatest interest to the biologist
in that it represents a state of aggregation in which the
properties of a solid and those of a liquid are often united,
a condition which is so frequently necessary in living
matter. For this reason the experiments that have been

* From Naturwissenschaftliche Rundschau, 1902, XVII, p. 312.
Address delivered before the Morphologisch-physiologische Gesellschaft
in Vienna, May 13, 1902,

THE COLLOIDAL STATE. AS

undertaken to obtain a better knowledge of the inner
structure of these jelHes, partly from the standpoint of
the morphologist, partly from that of the physical chemist,
have not remained without influence upon important
problems in general physiology.

The systematic investigations of BtJTSCHLi, extending
over more than a decade, tended to show that a fine
honeycomb structure is present in all jellies, that, for
example, ordinary solid gelatine when it has "set" con-
sists of a framework made up of delicate gelatine walls,
and that in this framework is contained a fluid gelatine
of a low concentration. Expressed physico-chemically,
every such jelly represents, therefore, a diphasic systein,
for we call every physically or chemically homogeneous
constituent of a heterogeneous complexity a phase. Other
investigators looked upon the results they obtained in
expression experiments on jellies as furnishing further
proof for tTie existence in them of a homogeneous fluid
phase beside a solid supporting framework, and this in
spite of variations in the amount of gelatine contained in
the expressed liquid and its dependence upon the amount
of. pressure employed. These observations have led to
the conclusion that living matter, too, is to be looked
upon as made up of a honeycomb structure just as other
colloids — a view which has been more and more adopted
by physiologists and which has been utilized to render
intelligible mechanical and chemical changes which go on
in living matter. Butschli has, for example, used the
radiating figures which appear about gas-bubbles in
gelatine to explain the astrospheres which appear during
cell division, 'for an undisputed similarity exists between
the two pictures. Questions in absorption and the

46 PHYSICAL CHEMISTRY IN MEDICINE.

spacial differentiation of chemical processes have also
seemed capable of a seductively simple solution by belief
in the existence of a finely chambered structure in living
matter.

Against the very considerable evidence that has been
brought forward for the existence of the honeycomb
structure, any other conception of the constitution of
jellies could hope to receive but little attention. Never-
theless, the attempt is once more to be made, in the
following pages to enter into a discussion of this difficult,
but for the biological chemist so important, question of
the structure of jellies. This will be followed by a dis-
cussion of the possibility of explaining certain funda-
mental properties of living matter which have been
looked upon as an expression of its honeycomb structure
independently of such a structure.

II.

Jellies are capable of a separation into two sharply
defined phases ; in other words, they can be precipitated
or coagulated. Such a precipitation can be brought
about, for example, through the addition of the sulphates,
acetates, tartrates, or citrates of the alkali metals. For
the sake of clearness we will base our considerations upon
the behavior of gelatine, which represents one of the
most thoroughly studied among the jellies. The separa-
tion during precipitation of a phase rich in gelatine
from one that is poor can be observed not only micro-
scopically, but also by allowing the precipitate to settle
to the bottom of the vessel while kept in a thermostat,
wben the phase poor in gelatine forms a distinct layer

THE COLLOIDAL STATE. 47

over that rich in gelatine. It will be well to compare first
of all the laws governing this change in state, which is
so well characterized through the formation of two phases,
with the laws governing the solidification or gelation of
colloids, for which, as has already been discussed, a sep-
aration into two phases is also looked upon as a distin-
guishing characteristic.

Investigations which have" been carried on during
past years have, however, disclosed a whole series of
marked differences between these two processes, the
more important of which are now to be briefly touched
upon.

The gelation velocity and the gelation-point of gelatine
are always more or less influenced through the addition
of crystalloids, which at times hasten, at other times inhibit
gelation, when compared with the gelation when pure water
only is used. This influence of the crystalloids is a pro-
gressive one and increases in proportion to the amount
added.

The precipitation of gelatine is, on the other hand,
strictly connected with the addition of definite amounts
of the precipitating agent, amounts less than are sufficient
for actual precipitation being without effect.

While all crystalloids modify the process of gelation,
even though they do this in different degrees and in
different directions, only certain crystalloids are precipi-
tating agents, while the others do not possess this power
even in the most concentrated solutions. Gelatine, for
example, is precipitated only through certain electrolytes,
non-ionized crystalloids being effective at no concentra-
tion. Non-conductors, such as urea and dextrose, can,
however, influence the process of gelation just as effectively

r-f

48 PHYSICAL CHEMISTRY IN MEDICINE.

as electrolytes, and this in both directions. Urea inhibits
gelation, while dextrose favors it.

If gelation consisted fundamentally in the formation
of a phase rich in gelatine, then one would expect to
find all precipitating salts among those substances which
favor gelation. This is true, however, of only a part of
the precipitating agents; the precipitating chlorides of
potassium and sodium exert-even a liquefying action upon
gelatine to a considerable extent.

The following fact also speaks in favor of a strict
separation between the two kinds of changes in the col-
loidal state.

If the gelation-points are plotted as ordinates, the
molecular concentrations of the added crystalloids as
abscissas, one obtains curves which readily indicate the
dependence of the gelation upon the added crystalloid.
These curves show no irregularities throughout their
course, not even when the amounts added approximate
very closely those at which precipitation occurs.

When several substances are allowed to act together, the
differences between the laws governing precipitation and
those governing gelation also evidence themselves. It could
be shown on a large series of crystalloids that when more
than one are allowed to act simultaneously upon a colloid
the effects of the separate crystalloids upon gelation add
themselves algebraically. This summation of the effects
of the individual crystalloids is not altered when electro-
lytes are combined with non-electrolytes, or these with
each other, nor by the fact that through the combination
of electrolytes having a common ion the degree of dis-
sociation is reduced, nor by the valency of the ions.

Put matters are entirely different when the gelatine

THE COLLOIDAL STATE. 49

is precipitated. The meeting of two electrolytes with a
common ion favors precipitation, while certain non-
electrolytes, such as urea and sugar, inhibit through
their presence the precipitating power of electrolytes, and
even cause already existing precipitates to go back into
solution. These differences between the two changes
in state may be made still clearer by citing a few
examples. Thus gelation is greatly inhibited through
the presence of bromides, while precipitation through
electrolytes is markedly increased as soon as the added
bromide contains a common ion. The combination
sodium acetate — sodium bromide with the common Na
ion is in this way a more powerful precipitating agent
than the acetate itself. Again, dextrose favors gelation
in that it elevates the gelation-point and increases the
gelation velocity, and yet it inhibits the formation of a
precipitate through a precipitating electrolyte as soon as
the sugar is present in sufficient amount.

The independence of the two changes in state evidences
itself in this also, that through suitable selection of experi-
mental conditions it is possible to produce precipitates
in a solid and clear gelatine just as in a liquid one, and
this without a change in the state of aggregation of the
solid gelatine.

It seems to me that what has been said proves Mdthout
■ question that between the precipitation and the gelation
of a colloid, at the basis of which fundamentally similar
changes have been supposed to lie, there exist in reality
profound differences through which the assumption of a
related origin of the two phenomena has been rendered
most improbable. In the same direction will be found
to point an analysis of those facts which have always

50 PHYSICAL CHEMISTRY IN MEDICINE.

been considered as sufficient evidence for the primary
coagulation structure of all solid colloids.

III.

The beginning of those investigations of Butschli on
colloidal structures which must be considered in the gen-
eral question that lies before us were observations on
microscopic foams of gelatine and olive-oil, which when
properly prepared furnish a framework of solidified gela-
tine walls in the chambers of which is inclosed the fluid
oil.

BiJTSCHLi found that the structures which can be
obtained through typical coagulation of colloids are also
built according to this plan. Thin layers of egg albumin
coagulated through heat or those precipitating agents
which are generally known as "fixing-agents, " or aca-
cia solutions precipitated with alcohol, precipitated
liquid (peptonized) gelatines, etc., all show under the
microscope the same characteristic, finely honeycomb
structure. Up to this point the conclusions of the Heidel-
berg zoologist, which are of great interest to the molecular
physicist also, show a complete harmony between obser-
vation and interpretation; and the value of Btjtschli's
discoveries for the morphologist who utilizes analogous
methods to render apparent cell structures is not to be
underestimated.

In the further course of his observations on colloids
Butschli later concludes, from a study of substances in
the condition of swelling (jellies), that these also have a
true honeycomb structure identical with that observed
in coagulation foams and in typical coagulations. Only

THE COLLOIDAL STATS. gt

this honeycomb structure is ordinarily not convincingly
demonstrable; it becomes distinctly visible, however,
under certain experimental conditions.

A closer study of the conditions which make apparent
the honeycomb structure teaches us, however, that we
have to deal in every case with the introduction of true
coagulation or precipitation phenomena governed by the
laws already outhned above. By far the most thorough
investigations bearing upon this subject have also been
carried out on solidified gelatine, and upon these Butschli
supports in the main his belief in the primary honey-
comb structure of all swollen media, and consequently
also that of native protoplasm.

But, as has already been pointed out, even though
neither direct observation nor tinctorial methods — and
this in spite of the well-known marked affinity of gelatine
for dyes — have rendered it possible to prove the existence
of a honeycomb structure in untreated gelatines, such a
structure is, nevertheless, supposed to exist in all prob-
ability. The reasons which Butschli has brought for-
ward in support of this idea can only very briefly be given
here and their tenability be tested.

The reason why it is normally impossible to see the
walls constituting the framework of gelatine is, according
to one author, dependent in part upon the fact that they
are pliable and when dried in vacuo, for example, adhere
closely to each other, in part upon the fact that the
difference between the indices of refraction of the walls
of the framework and of the substance found within
them is too little to give distinct pictures. These walls
of the honeycomb structure can, however, be rendered
more solid and dense through the action upon them of

52 PHYSICAL CHEMISTRY IN MEDICINE.

chromic acid, alcohol, or ether, when their optical recog-
nition is made much easier. Any one can at any time
prove to himself that a thin layer of gelatine when treated
with dilute chromic acid according to Butschli's instruc-
tions becomes opaque and white, and shows under the
microscope a very regular, finely chambered structure
entirely identical with the picture found in true coagula-
tions of colloids. But we are supposed to deal here not
with a true coagulation, but, as BiJTSCHLi expresses it
in a by no means clear and unequivocal way, with a
"kind of coagulation" through which a preformed struc-
ture becomes visible.

That structures which have been produced through the
action of alcohol disappear when put into water, to
reappear in exactly the same form when subjected a
second time to the action of alcohol, does not argue at
all in favor of the primary nature of the structure. The
explanation of this phenomenon is easily found in the
well-known properties of the changes in state which
colloids suffer. The change which is brought about in
gelatine through alcohol is, in contrast to that produced
through chromic acid for example, simply reversible.
Since, however, changes in state take place only very
slowly in gels, these are, if at all, only gradually and
scarcely completely reversible. It is readily intelhgible,
therefore, why under these circumstances structures
which have once been produced and which are not
entirely destroyed even through remelting of the gelatine
reappear in their old form.

That a fluid condition of the colloid is necessary for
the production of coagulation structures, as BtrxscHLi
believes, and that these structures must be present

THE COLLOIDAL STATE. S3

as soon as the colloid solidifies, can be readily shown to
be untrue through the production of precipitates in clear,
solidified gelatine. For, since the precipitation limits of
many electrolytes, such as the sulphates, citrates, and
tartrates of the alkali metals, are dependent upon tem-
perature in such a way that they are lowered with a de-
crease in the temperature, it is an easy matter to prepare
salt-gelatines in which heavy precipitates do not appear
until the soHdification temperature has been long passed
■ — in other words, in the clear and solid gelatine. Such
coagulations are subject to the well-defined effects of
coagulation "germs" in the same way as those which
occur in a fluid medium. The beautiful figures which
LiESEGANG has been able to produce in colloids with
the aid of precipitates all rest, in the main, upon the
"germ" action of previously produced coagulations. In
such processes is also found an unforced explanation of
the phenomenon, used by Butschli as an argument in
favor of the existence of a primary honeycomb structure,
that deHcate granules when suspended in gelatine are
always found in the nodal points and walls of the frame-
work. The reason for this is that these foreign bodies
all act as coagulation germs. For the same reason, the
chambers of the honeycomb structure arrange themselves
in rows which correspond with the lines produced on
the sHde in polishing it. And just as little will we be able
to consider it proof of a preformed foam structure that
the coagulations which take place in colloids mirror all
the stresses that appear in it, due in part to shrinkage
while drying, in part to the contraction of cooling air
bubbles.
As further support for belief in a preformed structure,

S4 PHYSICAL CHEMISTRY IN MEDICINE.

observations are utilized which are noticed when delicate
gelatine threads that have been kept in absolute alcohol
or have been dried in the air are subjected to the effects
of tension or pressure. If such threads are stretched or
bent, microscopic examination reveals a cross-striation
upon their surface corresponding with parts of the
threads that have become white and opaque. The cen-
tral portion of the threads may retain its hyaline char-
acter. That we are dealing in this case with more or
less well-marked breaks in continuity is without question
when the manner of their production is considered.
BuTSCHLi explains the regularity of the pictures which
are produced by sayiag that the chambers of the stretched
honeycomb structure of the gelatine give rise to a system
of stripes which cross each other diagonally, just as is
the case with a net when this is pulled in certain direc-
tions. It would be an argument in favor of this explana-
tion if it could be shown that in gelatine threads which
had previously not been treated with fixing-agents the
distance between the stripes is less than the diameter of
one of the honeycomb chambers. This is, however, not
the case. In a large number of measurements Butschli
has determined the diameter of the latter to be 0.7 ji in
gelatine that has been treated with chromic acid or
alcohol, while the distance between the stripes in untreated
gelatine threads is 2.1 to 2.3 /i. That the honeycomb
structure of gelatine threads which have been treated
with precipitating agents is more or less cross-striated
cannot seem strange when the systems of cross-striation
are looked upon as expressions of a definite distribution
of tension and pressure in the threads. As has already
been described above, such stresses may impress them-

The COLLOID/IL statb. ii

selves upon coagulations also, and under favorable con-
ditions may evidence themselves even about fine suspended
granules. A satisfactory explanation of the fact that ten-
sion alone may make a honeycomb-like structure visible,
BuTSCHLi is unable to give, because of lack of observa-
tions directed toward this point. But surface structures
similar to those described above frequently appear, in
different substances that have been stretched or com-
pressed, in part as an expression of the incomplete
mechanical homogeneousness of these bodies. Honey-
comb and fibrillar pictures are found on the surface of
stretched and compressed metals, and we can justly
put into this class also the cross-striated structures ob-
served by BiJTSCHLi on delicate threads of Canada balsam,
without assuming, with this author, that this resin also
possesses a preformed honeycomb structure. Interesting
and worthy of further study as these observations may
be, they furnish conclusive evidence of the primary
honeycomb structure of colloids just as little as the
already described experiments dealing with the question
of rendering this structure visible. That we are dealing
with a true coagulation whenever a structure is rendered
visible, and not, as BiJTSCHLi thinks, with a condensation
of primary supporting walls, in a certain sense a more
advanced stage of simple gelation, is shown by the follow-
ing experiment, which to my mind is conclusive.

In order to recognize its nature, let us recall to mind
the already discussed laws governing coagulation, on the
one hand, and gelation, on the other, under the influence
of combinations of electrolytes and non- electrolytes.
These two classes of substances add themselves alge-
braically in their effect upon gelation, while the coagu-

S6 PHYSICAL CHEMISTRY IN MEDICINE.

lation brought about through electrolytes does not occur
if such non- electrolytes as urea or sugar are present; in
fact, an already existing coagulum is made to go back
into solution when these substances are subsequently
added. If thin layers of gelatine spread upon slides are
introduced for fifteen minutes into a 0.3 per cent, chromic
acid solution kept at an even temperature of about 23° C,
the beautiful coagulation structures are produced which
BtTTSCHLi has described and pictured. As soon, how-
ever, as urea is added to the chromic acid solution in the
concentration of i.o molecular, the gelatine does not
become opaque, and a formation of structure as described
above does not take place, even when everything else in
the experiment is arranged as before. The gelatine
remains clear, and examination with even the highest
powers of the microscope shows it to be homogeneous.
Urea in the concentration of 0.25 molecular is without
effect, while concentrations above 2.0 molecular lead to
excessive swelling and solution of the layer of colloidal
material. That we are dealing in this experiment not
with the inhibiting effects of urea upon gelation, but
with its anti-coagulating effects, is shown by the follow-
ing. Chlorides cause an excessive swelling and prevent
gelation in the same way as urea, a 2.0 molecular sodium
chloride solution being equal to a i.o molecular urea
solution. Yet chlorides have as electrolytes no inhibiting
effect upon coagulation. Corresponding with these facts,
it is found that an addition of sodium chloride to the
chromic acid solution equivalent in effect to an adequate
amount of urea does not at all prevent the formation of
the typical coagulation structures in the gelatine prep-
arations. These experiments prove definitely that in the

THE COLLOIDAL STATE. 57

formation of structures in gels we are dealing with true
coagulations. The experiments may easily be varied and
similar results be obtained by using other fixing agents and
non-electrolytes. It may be pointed out, in passing, that
histology could easily employ to advantage this property
of the non-electrolytes, especially that of urea, for obtain-
ing a finer gradation in its methods of hardening and
fixing tissues, as well as for causing changes brought
about through these methods to disappear more or less
perfectly.

All physico-chemical investigations that have been de-
scribed here indicate, therefore, that the condition of
swelling in colloids is not to he looked upon as a diphasic
one, and that the reasons which have thus far been
advanced in favor of such an assumption do not bear
careful criticism. We can therefore find in the prop-
erties of the jellies no arguments for believing that proto-
plasm is a strictly diphasic system having a finely
honeycomb structure. No doubt the substance of the
cell may, in those instances in which we have to deal
with inclusions of such substances as colloidal carbo-
hydrates or fats, represent a heterogeneous complexity
with phases the relations of which to each other are
subject to the laws of chemical equilibrium. In general,
however, such inclusions take part only indirectly in the
actual life processes of the cell. At present no cogent
reason exists for not believing that the mass which is
looked upon as the bearer of life processes may not well
be monophasic in structure.

According to a view expressed years ago and based on
studies of the vi^ay in which water is held in gels, the
colloidal particles of the latter are believed to contain

58 PHYS1C/1L CHEMISTRY IN MEDICINE.

the liquid producing the swelling in combinations vary-
ing from those that are exceedingly loose to those that
are very firm. In this way is rendered possible a great
diversity in absorption phenomena as well as the formation
of solid and liquid solutions. From this metastabile con-
dition of equilibrium the gel gradually endeavors to
attain one in which all the colloidal particles are swollen
to the same degree. In living matter colloidal material
is being constantly broken down and built up anew, and
in this way the progress toward a final condition of
equilibrium in the molecular disposition of the liquid
producing the swelling is steadily destroyed.

, IV.

The colloidal constitution of living matter is intimately
connected with one of the most important problems in
biological chemistry, i.e., with the question of the spacial
differentiation of the chemical reactions in protoplasm.
Since colloids resist the diffusion into them of other col-
loids, it is self-evident that through the presence of
different colloids within a cell as many different localities
are provided in which chemical reactions having a more
or less different course may take place.* With the
exception of these coarser divisions between chemical
reactions, physiological experience compels us to believe
that chemical reactions of the most different kinds are
simultaneously possible in the homogeneous, colloidal
ground-substance of the cell. In even the smallest par-

* The great importance of the differentiation of the cell into nucleus
and cell body has been proven beyond question. Reactions that are
connected with the heterogeneous constitution of the cell no longer
take place when the cell is destroyed mechanically.

THE COLLOIDAL STATE. 59

tides of protoplasm antagonistic chemical reactions, such
as oxidation and reduction, hydration and loss of water,
condensation, polymerization, synthesis, and their oppo-
sites, or, generally speaking, as Hering puts it, assimila-
tion and dissimilation, are able to occur through and
beside each other.

In a suggestive lecture on the phemical organization
of the cell, one of the greatest of present-day biochemical
investigators has thrown much light on this important
problem and has assumed for its solution the existence
of a finely chambered structure in colloids and the im-
permeability of the colloidal walls.* Just as the chemist
allows different chemical reactions to take place in different
vessels, the cell is believed to utilize the different chambers
of its honeycomb structure and, with the help of the
colloidal ferments, the number and knowledge of which
is daily growing, allow the necessary reactions to go on
independently of each other.

As the considerations outlined above have shown that
we lack at present any adequate foundation for believing
that living matter has a honeycomb structure, the ques-
tion arises whether it is possible for antagonistic chemical
reactions to take place in exceedingly small spaces with-
out the help of any structure. An analysis of such
antagonistic reactions brings with it, I believe, their
satisfactory explanation, based upon numerous facts and
teachings of physical chemistry.

* HOJMEISTER (Naturw. Rundschau, 1901, XVI, p.s8i) supports the
hypothesis of a finely chambered structure in protoplasm upon chemical
grounds which need not be discussed here. We have first to settle
the question whether antagonistic reactions can at ^11 take place in a
liomogeneoijs subsfratp.

6o PHYSICAL CHEMISTRY IN MEDICINE.

The chemical reaction
CH3COOH + C2H50H<=iCH3COOC2H5+H20

Acetic acid Ethyl alcohol Ethyl acetate Water

furnishes a picture of a simple reaction which may take
place in either direction. If we begin with a mixture of
chemically equivalent amounts of acetic acid and ethyl
alcohol, the reaction takes place from left to right, with
the formation of ethyl acetate and water; and conversely,
if the latter are added to each other, the reaction takes
place in the reverse direction. Whatever the starting-
point, the final result is a definite state of equilibrium
between all the end products. Depending upon the
direction toward which the equilibrium-point is pushed,
at one time the one reaction, at another time the other,
may have the upper hand. The manner in which such
an equilibrium-point can be displaced is illustrated by
the change that systems such as the above suffer under
the influence of an increase in temperature. According
to a well-known law, an increase in temperature pushes
the equilibrium toward the side of the endothermic reac-
tion.

The following equations, in which letters have been
used in place of different chemical formulas, illustrate
some types of such reactions which in practice take
place only in the one or in the opposite direction:

A->rm=B
B—m=A

(a4-/3-l-r+ ...)-m=M \

THE COLLOIDAL STATE. 6 1

One can at any time imagine either O or H2O written
into equation I instead of m, and so obtain the picture
of a simple reversible reaction — an oxidation and a reduc-
tion, or a hydration and a loss of water, following the
type of a simple reaction which may take place in either
direction; or in equation II a condensation or a hydro-
lytic cleavage. General biochemistry has until now
taken notice of only this type of antagonistic reaction,
that is to say, reactions which counteract each other in
the sense of positive and negative values.

There exists, however, among the reaction chains in
the body a second apparently very common type of
antagonistic reaction, the nature of which can be best
illustrated by certain changes in physical state that
colloids are capable of suffering.

It is a well-known fact that with the customary methods
of investigation it is found that the melting-point and
the solidification- point of the crystalloids coincide. It
is different, however, in the case of the colloids, in which
these two points may lie some distance apart, even when
the changes in temperature are brought about most care-
fully. In consequence of the indolence with which
changes take place in colloids, superheating and under-
cooling are the rule. A gelatine the temperature of
which lies between the melting-point and the gelation-
point shows in consequence a peculiar behavior. If such
a gelatine is cooled to beyond the gelation-point and is
then carefully warmed back to the original temperature,
the gelatine remains solid; if, however, the gelatine is
heated to beyond the melting-point and is then carefully
cooled down to the starting temperature, it remains
liquid. . A change in state, therefore, impresses itself upon

62 PHYSIC/IL CHEMISTRY IN MEDICINE.

the colloid and determines the condition in which the
colloid will ultimately be found. In other words, a colloid
seems to remember more or less perfectly a change that
it has suffered, just as does living matter. If gelation
and melting followed the same course, only in opposite
directions, then a gelatine, when it has returned to its
original temperature, should also be existing in its original
state, no matter in which direction it had previously
suffered a change in temperature. That we have to do
in this case with reversible changes that follow different
paths is evidenced by another property of this change
in state. If one compares the curves indicating the
melting- and gelation-points of gelatines of different
concentrations, obtained by plotting the concentrations
upon the abscissas and the corresponding melting- and
gelation-points upon the ordinates, it is seen that the
two processes are dependent in different ways upon the
concentration of the gelatine. The gelation curves follow
an approximately straight line; the melting curves, on
the other hand, rise gradually, but in a decreasing degree,
above the abscissa.

In contrast to the previously described simple or homo-
drome antagonistic reactions, which follow the same
course in either direction and which behave at any stage
as mathematical values having different signs, we are
dealing in this case with complex or heterodrome antag-
onistic reactions, which reach their respective end states
along different paths. (See Figs, i and 2.)

In what follows we will make use of these simple dia-
grams in characterizing the antagonistic reactions.

Heterodrome reactions of a chemical nature play
an important rple in the changes that go on in living

THE COLLOIDAL STATE. 63

matter. They may be readily illustrated by a few
examples.
The equations

A-\-m
B—ml

^=■8 It

A=l-\-m+n+ . . .)

represent, when m and m' indicate differently placed
O or H2O groups, cases in which, as in la, oxidation

'lllllliliiiiiiiiiiiiiiiiiiiiii ^ "^ "^

Fig. I. Fig. z.

and reduction, or hydration and splitting off of water,
follow a heterodrome course; or, as in Ila, cases in which
the decomposition products are different from the sub-
stances employed in the synthesis.

The principle of antagonistic reactions remains the
same whether they take place under the influence of
substances that increase the velocity of the reactions, so-
called catalyzers,* or not. In the organism we have
acting as such catalytic agents mostly ferments, which
are capable of acting only upon certain substances, and

* No doubt the catalyzers determine also the direction of a reaction, in
that the reaction follows a qualitatively different course under the influence
of different catalytic substances. If one holds fast to the above-mentioned
(Ostwald's) definition of catalysis, then we would be dealing in this
case with several simultaneously possible reactions, of which different
ones are accelerated hy diffprpnt catalyzers, while the jrest remain not
(lijcpverablpr

64 PHYSIC/1 L CHEMISTRY IN MEDICINE.

playing a r61e, therefore, only when these substances
appear in the organism.

Such catalyzers can act, as was first pointed out by
VAn't Hoff, in two directions, depending upon the
relations existing between the substances originally present
and those formed. In this way, as has recently been
shown, amygdalin cannot only be split into amygdalic
nitrilglucoside and glucose under the influence of yeast
maltase, but also be formed synthetically from these two
substances with the help of the same enzyme. One and
the same enzyme can, according to conditions, accelerate
the one or the other homodrome antagonistic reaction.
In the animal organism the synthesis of glycogen from
dextrose and the sphtting of glycogen into dextrose might
in part, at least, represent a simple antagonistic reaction
governed by a single eazyme; while the synthesis of
starch in plants and its diastatic splitting into glucose
or maltose represents a heterodrome antagonistic reaction
in which the synthesis has the upper hand by day and
the analysis by night.

It is also possible, however, that two catalyzers may
act in such a way upon a homodrome antagonistic reac-
tion that the one accelerates the conversion of the system
in the one direction, while the other does it in the opposite
direction. This is the case when the two catalyses go
hand in hand with different equilibrium-points in the
two reactions that constitute the simple antagonistic
reaction. An example of this sort will be given later.
The deposition and solution of the calcium salts of the
bone represents a simple reversible reaction which, with
the aid of special cells, the osteoblasts and osteoclasts,
can, according to physiological needs, be divided, and

THE COLLOIDAL STATE. 65

the two reactions occur independently of each other in
entirely separate localities.

In heterodrome antagonistic reactions the acceleration
of the two reactions by one and the same catalyzer is
impossible; one catalyzer can be effective in only one of
the two reactions. A reaction can take place in one
direction, and at a certain stage — for example, after a
condensation or polymerization through one enzyme — be
switched into another direction; or the components of
the complex antagonistic reaction may be influenced
through two different catalyzers. Between two catalyzers
which displace the equilibrium of a homodrome antag-
onistic reaction in opposite directions, there exists a true
antagonism, while a complex antagonistic effect exists
where the two components of a heterodrome reversible
reaction are governed by two catalyzers. We may ther£-
fore distinguish also bety^een simple and complex antag-
onistic ferments.

A suitable example of a heterodrome antagonistic re-
action in metabolism is furnished by the formation and
destruction of uric acid in the animal body. The funda-
mental investigations of H. Wiener have thrown light
upon this subject. Wiener found that the " surviving"
ground-up pulp of different animal organs has the power
of both forming and destroying uric acid. In the liver
of the ox the two processes can take place simultaneously
and are, no doubt, dependent upon the activities of two
different catalyzers. As the sensitiveness of . the two
catalytically acting substances toward heat is different,
the two chemical changes can be separated from each
other, the power to decompose uric acid being lost later
than the power to form it. That we have to do here

66 PHYSICAL CHEMISTRY IN MEDICINE.

with a heterodrome reaction is indicated by the fact that
none of the substances which are formed in the destruc-
tion of the uric acid can be built up into the original
uric acid.

It would lead us too far afield to discuss further the
fate of the different substances that enter into the metab-
olism of the organism in the light of our conception of
antagonistic reactions which can be combined among
themselves in the greatest variety of ways. In the last
analysis, no doubt, it is because the reaction is a hetero-
drome one that no path exists in the animal body over
which urea can- again be built up into protein.

The two components of an antagonistic reaction are
dependent upon each other only in so far as the one
furnishes the material necessary for the other. We can
easily see how in the fact that they can follow different
courses there resides the possibility that they can take
place simultaneously and side by side. This explains
also why ferments acting in opposite directions can
exhibit their characteristic effects without the presence
of separating walls — in molecular proximity to each
other, as it were.

Such reactions can without mutual interference take place
side by side, just as sound, light, and electric waves, or
currents oj heat, electricity, and diffusion, can pass through
a medium simultaneously.

The idea of homodrome and heterodrome antagonistic
reactions, as deduced from a consideration of changes
jO th^ colloidal state ^nd in metabolism, is closely related

THE COLLOlD/tL ST/lTB. 67

to facts which furnish a welcome support of this concep-
tion in the physiology of the senses.

As early as 1865, through his complete recognition of the
relation between the physical and psychic elements of a
sensation and through the assumption that every quality of
a sensation has lying at the bottom of it a specific change
in the substance of the nerve, which for the same sensation
is the same, and for similar sensations partly identical.
E. Mach laid the foundations from which, through an
analysis of the sensations, a knowledge of the changes
that go on in living matter has been obtained. In his
hands and through the work of E. Hering, who, some-
what later and independently of Mach, set up the same
principle of research, this led to a great enrichment of
the physiology of the senses. Upon these same founda-
tions Hering has built up his famous theories of the
sense of light and color, a theory of the temperature sense,
and finally a general theory of the changes that go on in
living matter. The great and fruitful significance that
these principles possess, not only for questions in the
physiology of the senses, but also for general physiology
and for a recognition of the aims and limits of scientific
research in general, could only temporarily be belittled,
through the mighty authority of a Helmholtz. To-day
when this combat is a thing of the past and the teaching
of Mach and Hering has made itself felt in the most
varied branches of science, we recognize that in decades
general physiology has enjoyed no such significant increase
in enlightenment as has been furnished by the Mach-
Hering analysis of the sensations and the physical changes
that lie at the bottom of these sensations.

We will enter into this physiology of the senses only

63 PHYSICAL CHEMISTRY IN MEDICINE.

far enough to show that it contains all those elements
which we discovered in the discussion of another subject.
The idea that antagonistic reactions must be possible
in even the smallest particles of protoplasm we meet in
Hering's theory of the changes that go on in living matter.
In the discussion of assimilation and dissimilation, he
writes :

" But in separating the mental conceptions of these
two processes we must not be misled into thinking of
them as two processes which, while they go on side by
side, are really separated, and into imagining living sub-
stance to be within itself a resting mass that on one side
only analyzes matter and on the other only synthesizes
it ; but rather as a copper wire dipping with both its ends
into copper sulphate, which when it is traversed by an
electric current suffers at one end a loss of copper by
going- into solution, while at the other end it has copper
deposited upon it. We must rather imagine assimilation
and dissirriilation as two closely interwoven processes which
constitute the still unknown metabolism of living matter,
and which take place simultaneously in even the smallest
particles of living matter, for living matter represents not
something fixed or resting, but something more or less
labile."

The investigations of Hering on the sensations of
light and color led him to the assumption of three kinds
of antagonistic processes in the visual substance, corre-
sponding with the three pairs of sensations, red-green,
yellow-blue, and black-white. The red-green and the
yellow-blue reactions each constitute a pair of antagonists
which mutually destroy each other, so that only the
simultaneous black-white reaction remains. Red and

THE COLLOIDAL STATE. 69

green or yellow and blue cannot be perceived at the
same time, while black and white can be perceived simul-
taneously and can be mixed in different proportions in
the gray sensations. That we are deahng in this case
with two kinds of antagonistic processes has been suf-
ficiently emphasized by Hering.

Mach has also pointed out in a general way the
essential difference between the two kinds of antagonistic
processes in his doctrine of the sensations of motion.
While criticising Plateau's' oscillation theory Mach
writes :

" When two things, A and B, are designated as positive
and negative with regard to each other, one understands
thereby that A can, through the addition of B, be in
part or entirely destroyed. This relation exists between
many sensations and their after-images, but not be-
tween all. It exists, for example, between the percep-
tion of a movement and its after-iinage, which is an
entirely similar movement, but of an opposite character.
It does not exist, however, between the sensations black
and white, of which the one may also be the after-image
of the other. Both sensations are entirely different from
each other, and the two together do not annihilate each
other, but produce, as do two different colors, a mixed
color, namely, gray. In this case, therefore, the terms
positive and negative are not appropriately applied."

According to our conception, those antagonistic reactions
that behave as positive and negative values are homo-
drome, the other heterodrome reactions.

Nothing stands in the way of regarding the individual
kinds of light as catalyzers of antagonistic reactions.
.Corresponding with this idea, we would pronounce the

70 PHYSICAL CHEMISTRY IN MEDICINE.

red-green reaction and the yellow-blue reaction as homo-
drome antagonistic ones, the mobile equilibria of which
can be pushed in opposite directions under the influence
of two catalyzers. But these reactions may at one time
take place in the one direction, at another in the opposite
direction, so that red and green can never be simultaneously
discovered in a color, no more than blue and yellow. The
black-white sensation would, on the other hand, represent
a heterodrome antagonistic reaction which, under the
influence of white light, moves along one course, but en-
deavors spontaneously to move back along another. As
these oppositely running components of the antagonistic
reaction can occur side by side, black and white can
be perceived simultaneously.

With this we will bring our consideration of antag-
onistic reactions in living matter to an end. A more
detailed study of the questions which are involved is
reserved for a future paper.

If, in conclusion, we look back once more over the
path that has been traversed, every step seems to indicate
that physico-chemical investigations of a substance that '
is closely related to living matter are able to throw much
light upon the conditions that exist in living matter. In
fact, we see that the experimental results obtained in
this way pass over to meet those which direct observation
of the changes that go on in living matter yields.

Investigations of this kind are well suited to show how
all biological methods are of the same value, in that
they leave no room for strictly mechanistic or vitalistic
tendencies. They form a mighty support for the true
scientific monism. The investigator, however, they fill
with a conception of those overpowering feelings of the

THERAPEUTIC STUDIES ON IONS. 71

explorer who imagines himself upon an island until he
discovers a connection with the scarcely measurable
continent beyond.

4. Therapeutic Studies on Ions.*

"The acquisition of a new truth is like the acquisition
of a new sense, which renders a man capable of perceiving
and recognizing a large number of phenomena that are
invisible and hidden from another, as they were from him
originally." — Chemische Briefe.

With scarcely more fitting words than these of the old
master Liebig can we characterize the increase in scien-
tific knowledge and the establishment of new methods
of work and points of view for which we are indebted
to the application of the laws of physical chemistry to
questions in biology and even in practical medicine. If
we try to determine, from the varied and many advances
that have been made, along what lines these were made,
it can be easily shown that the application of three es-
pecially of the fundamental laws of physical chemistry to
biological problems has been most fruitful. These are
the law of chemical mass action of Guldberg and Waage,
which permits of an insight into the course, the velocity,
and the ultimate equilibrium of chemical reactions; the
theory 0} osmetic pressure, which has discovered to us
the common properties possessed by any series of solutions
independently of the nature of the dissolved substances;
and the theory of the electrolytic dissociation of certain
dissolved substances, the foundation of which resides

* From Miinchener medizinalische Wochenschrift, 1903, p. 153. Ad-
dress delivered before the K. k. Gesellschaft der Aerzte, Vienna.

72 PHYSICAL CHEMISTRY IN MEDICINE.

in the partial dissociation into electrically charged ions
which salts, acids and bases suffer when dissolved in
certain solvents, especially water.

The effects of salts within and without the organism
must all be treated from the standpoint of how far the
electrically charged ions or the electrically neutral mole-
cules play a part. Such an investigation, carried out
from both a theoretical and a practical point of view, is
to form the subject of my address to-day.

It is evident that there exist different ways in which
the unknown pharmacological properties of a substance
may be studied. As least practical and economical would
to-day be the attempt to employ the substance directly
in cases of illness. The animal experiment is little better,
and is of use only when it is possible to reproduce the
disease artificially in a more or less perfect way, as in
the case of the infectious diseases. Modern pharma-
cology has been very successful in predicting the nature
of the therapeutic effect of newly discovered chemical
compounds from their chemical constitution. There
exists, however, another way which, though still but
little used, renders it possible under suitable conditions
to discover unsuspected pharmacodynamic relations.
This is the application of a principle which I published
years ago, and which has since then rendered possible
the solution of difi&cult problems in physiology. This
may be called the principle of the manifold analogies
which exist between the changes in state suffered by colloids
and the changes thai take place in living matter. In

THERAPEUTIC STUDIES ON IONS.

73

attempting to apply this principle, let us discuss first
of all the mutual effects of proteins and salts upon each
other.

As is well known, proteins suffer a change in state, in
the presence of many salts — they are precipitated in solid
form. In the case of the salts of the alkali metals and
magnesium this precipitation does not occur until a cer-
tain, fairly high concentration has been reached. The
precipitate redissolves when the solution is diluted; the
process is, in other words, reversible. We will discuss
first of all the laws governing these reversible precipi-
tations.

If the salts are arranged according to their power of
precipitating protein (as determined by the use of chem-
ically equivalent solutions), the following table is ob-
tained. -I- indicates that the protein is precipitated,—
that it is not, n. s. that the salt has not been studied.

Cations. The precipitating power increases-

I. Fluoride

II. Sulphate

III. Phosphate

IV. Citrate

V. Tartrate

VI. Acetate

VII. Chloride

VIII. Nitrate

IX. Bromide.

X. Iodide

XI. Sulphocyanate. .

I

a

3

4

Mg

NH4

K

Na

n. s.

+

+

+

+

+

+

+

n. s.

+

+

+

il. E>.

+

+

+

n. s.

+

+

+

—

—

+

+

—

—

+

+

—

—

—

-t-

n. s.

—

—

—

~

~

~

~

s

Li

n. a.

4-
n. s.
n. s.

XI. a.

n. s.

-I-

-1-

+
n. s.
n. s.

For one and the same anion the precipitating power
increases from magnesium toward lithium, and for each

74 PHYSICAL CHEMISTRY IN MEDICINE.

metallic ion the precipitating power decreases in the
direction from fluoride toward bromide. No matter which
anion we take, therefore, we find that the cations always
follow the same order when arranged according to their
precipitating power, and, conversely, that with any cation
the anions always follow the same order when they are
arranged according to their precipitating power. This
law may also be stated thus: The precipitating power
of a salt is determined by the sum of the powers of its
individual ions, which act in large part independently
of each other.

In what way, now, do the anions and the cations act ?
It might be thought, first of all, that both the metallic
and the acid ions of a salt have a specific precipitating
effect, and that the sum of these two positive values
constitutes the precipitating power of an electroljrte.
According to this conception, the precipitating power
of sodium acetate would be made up of the precipitating
effect of the sodium ion plus that of the acetic acid ion.
Many salts are known, however, which in spite of their
ready solubility precipitate protein in no concentration,
so that the above explanation does not hold at all in
these cases. Ammonium acetate, for example, does not
precipitate protein in any concentration, while the acetic
acid ion of sodium acetate and the ammonium ion of
ammonium sulphate are both strong precipitants. An
explanation without contradictions is offered by the fol-
lowing experimentally supported conception. Only the
metallic ions, or cations, act as the precipitating constituents
of the salts, and the oppositely charged anions inhibit
this precipitating property.
It is self-evident that only those salts will precipitate

THERAPEUTIC STUDIES ON IONS. 75

protein in which the precipitating power of the cations
exceeds the inhibiting effects of the anions. Let us
study the above table with this idea in mind. The table
shows along the horizontal the metaUic ions arranged
in the order of their precipitating power, along the vertical
the anions arranged iri the order of their inhibiting effect.
It is now at once intelligible why sodium nitrate, with
its powerful precipitating sodium ion, coagulates protein,
while the weaker precipitants, K, NH4, and Mg ions,
are overcome in their effects by the antagonistic NO 3
ion. Only the Uthium salt of the bromides precipitates,
and so we might go on.

The table discloses yet other facts. If it is true that
the effect of salts upon proteins is determined through
the antagonistic properties of their ions, then there must
exist not only salts which precipitate protein or are in-
different, but also such as prevent precipitation or dis.
solve already existing precipitates. Observation has con-
firmed this important conclusion. When it has been
determined experimentally that a certain salt behaves
indifferently toward protein, then it will be found that
all other salts found to the right and above the point
occupied by this salt in the table will have precipitating
properties, while salts found to the left and below this
point wiU inhibit protein precipitation. The fact that
it has been the protein-precipitating salts which have
until now chiefly held the attention of investigators has
prevented the recognition of this conspicuous phenom-
enon.

An experiment wiU best illustrate what has been said.
Each of this series of test-tubes contains the same amount
of solvent, and neutral potassium tartrate in sufficient

76 PHYSICAL CHEMISTRY IN MEDICINE.

amount to precipitate protein. With the exception of the
first tube, they all contain in addition different ammonium
salts in chemically equivalent concentrations arranged
in the order given in the table. As can be readily seen,
the fluoride and sulphate increase the precipitate, the
chloride is practically indifferent, while the bromide,
iodide, and sulphocyanate hinder in increasing degree
the coagulation through the potassium tartrate.

From a large number of similar experiments it has
been possible to deduce the following laws, which will
be utilized as the foundation for what is to follow:

1. The effect of a salt upon a protein is made up, in
the main, of the algebraic sum of the effects of the in-
dividual ions.

2. Anions and cations antagonize each other — the
cations precipitate, the anions inhibit precipitation; there
results in this way a definite grouping of the ions according
to the intensity of their actions.

I wish to add that an analogous table of ions has been

■ constructed for the salts of the alkaline earths and the

heavy metals, though an investigation of the protein

precipitates brought about by these salts is attended

by many complicating circumstances.

II.

With the exception of the beautiful studies of Dreser
on the toxicity of mercury salts and scattered investiga-
tions on the effects of electrolytes on unicellular organisms,
there exist but few attempts to apply the ionic theory
to the pharmacology of salts. One cannot even say that
the conception of the general effects of salts the basis

THER/IPEUTIC STUDIES ON IONS. 7?

of which is often sought in the theory of osmotic pressure
is entirely clear. The introduction of the ionic theory
may perhaps be the first means of bringing a better
understanding into this field also. Under these conditions
it is readily intelhgible that from a classification of the
ions won through a study of the changes in state of pro-
teins only broad generahzations can be made. These
have, however, shown themselves valuable in pointing
out the direction which further investigations must take.

The relation between the cathartic effects of salts and
their power to precipitate protein has been recognized
for a long time, more especially through the fundamental
investigations of Hofmeister. If we bear in mind what
has been said above, that the power of precipitating pro-
tein is a property of th.6 metallic ions, then we will also
have to attribute the transitory purgative action of the
alkali salts to their cations. This faculty is, in fact,
seen to reappear, only accentuated to an extreme, in the
case of the heavy metals, which, it is well known, are
able to coagulate protein in even the weakest concen-
tration. The mild contractile and purgative action cor-
responds in the latter case to the erosion and severe
gastro-enteritis of the toxic picture. Most of the metallic
ions also influence more or less markedly the irritability
of the nervous system, the heavy metals producing in-
flammation and degeneration.

The anions also appear as mighty carriers of pharma-
cological properties. This is especially true of the end
members of one series — the nitrates, bromides, and iodides.
They are all readily absorbed and bring about a lower-
ing of the blood-pressure. The Br ion shows a much-
utilized sedative action, while the I ion belongs among

78 PHYSICAL CHEMISTRY IN MEDICINE.

those therapeutic agents that have a multiplicity of
effects. Besides its specific relation to the metabolism
of the thyroid gland, it is employed for its power of
lowering blood-pressure in arteriosclerosis and for its
absorptive effect upon the most varied products of chronic
inflammation, more especially the late forms of syphilis.
Readily as one can recognize in these general consid-
erations how the effects of the ions of a salt are independent
of each other, and how there exists an antagonism between
cations and anions, the grouping given above suggests
something which leads us still further. Even if we pro-
ceed most carefully in the extension of our analogy, it
must be apparent to every one that the sulphocyanate
ion, which antagonizes precipitation most powerfully,
constitutes the end member of a series of pharmaco-
logically most active substances, and so the question
arises whether this ion does not possess some peculiar
medicinal effect. The direction in which such an effect
is to be sought is also indicated by the position of this
ion in our scale.

m.

So far as I know, there exist no therapeutic experi-
ments on sulphocyanate compounds. At any rate,
nothing definite can be found in large handbooks on
therapy or in very complete text -books on pharmacology.
The r6le of sulphocyanate in metabolism has absorbed
the attention of many investigators since its discovery
as a normal constituent of the saliva by Treviranus,
TiEDEMANN and Gmklin. As Gscheidlen and Munk
discovered independently of each other, sulphocyanate

THERAPEUTIC STUDIES ON JONS. 79

occurs also in the urine. The sulphocyanate of the
urine might well, however, be absorbed from the saliva,
for, according to Gscheidlen, it disappears entirely from
the urine of the dog as soon as the excretory ducts of the
salivary glands are turned outward.

As to where in the body sulphocyanate is formed, is
still unsettled; we know something, however, of the
manner in which it is produced. S. Lang has shown
that all cyanides and nitrils are converted into sulpho-
cyanates in the organism. This change probably occurs
through a process of association with the neutral sulphur
of the proteins, for I succeeded in bringing about such
a synthesis years ago in Hofmeister's laboratory with
proteins and" their derivatives, provided they had not first
been robbed of their readily removable sulphur group.

Recent experiments of Bruylants indicate that a
relation exists between the metabolism of the sulpho-
cyanates and that of the purin bodies. In an investiga-
tion characterized by originality and far-sightedness, and
carried on in 1853 in the Wiener Institut fiir patho-
logische Chemie, Kletzinsky made valuable contribu-
tions to our knowledge of the excretion of sulphocyanate
in healthy and diseased su jects, which have in the main
been corroborated, most recently by Grober. The
intoxication after large subcutaneous doses of sulpho-
cyanate was studied twenty-seven years ago by Paschkis
on dogs, rabbits, and frogs. Valuable experiments on
the effect of sulphocyanate on the metabolism of man
and animals have in recent years been made by Treupel
and Edinger. Muck recently discovered sulphocyanate
as a separate secretory product in the conjunctival and
plfactory secretions.

So PHYSICAL CHEMISTRY IN MEDICINE.

Of primary interest for us is the proof that iodine and
sulphocyanate are excreted in the same places in the
organism, that sulphocyanates do not pass through the
body in even small doses without altering the metabolism,
and that a single dose of sulphocyanate, as discovered
by MuNK in 1877, still brings about an increased secretion
of. this substance a week later. As was recognized by
even the earliest workers in this field, the excretion of
sulphocyanate is decreased when iodine is taken, and
completely stopped when iodism is produced. When
this condition exists, Grober found that even concen-
trated saliva gives no sulphocyanate reaction.

We are acquainted, therefore, with isolated facts in
the physiology and the pathology of sulphocyanate ex-
cretion which indicate that a relationship exists between
sulphocyanate^ and iodides.

IV.

The following report on therapeutic experiments with
sulphocyanate ions is based upon a rather small amount
of material. If we exclude the orientation experiments
to determine how much of the substance can be borne
and how it is excreted, there are thirty-five cases in all
in which careful observations were made and registered,
the possibility that other curative agencies were simul-
taneously active taken into consideration, and these
results controlled as far as possible by omitting the
sulphocyanate or using other remedies. Since sodium
ions are, as far as we know, the most indifferent of the
metallic ions from a pharmacological standpoint, sodium
sulphocyanate was employed, and this in the maximal

THERAPEUTIC STUDIES ON IONS. 8l

daily dose of one gram. The excretion of the sulpho-
cyanate was studied in the saliva and urine.

The existence of a sedative action was tested on a
series of neuroses and organic nervous diseases in which
the signs of an increased excitability, such as fear, irri-
tability, sleeplessness, increased reflexes, tremors, etc.,
existed. Ten cases in all were studied : 2 cardiac neuroses,
with signs of general neurasthenia, 3 neurasthenics, 2
general paretics, and i tabes dorsalis, with increased
irritability, and 2 climacteric neuroses. In nine of the
cases positive results were obtained. Within two to five
days the patients became much quieter, and with further
use of the drug a very decided improvement in even the
most disturbing symptoms took place. The fear, rest-
less sleep, headache, and dizziness became less, the
troublesome congestions of the climacteric women passed
away, and a sense of rest repeatedly took the place of
weariness in the patient. Only in one case did the
original neurasthenic symptoms return after being absent
for some days. These were connected with periodic
pains in the splenic region, which radiated toward the
epigastrium, the pathology of which remained obscure.
A subsequent use of bromides was also without effect
in this case. The fact that the symptoms of increased
excitability in organic and functional nervous diseases
began to disappear a short time after taking sulpho-
cyanate and continued to improve as time went on, that
the old symptoms reappeared when the drug was no
longer given, especially when it was taken away shortly
after its use had been begun, that previous indifferent
methods of treatment had brought no great change in
the patients' condition, and that, finally, unprejudiced

82 PHYSICAL CHEMISTRY IN MEDICINE.

observers as well as the patients themselves felt convinced
of the immediate good effects of the drug, seems to justify
the conclusion that sulphocyanate possesses, as a rule, a
well-marked sedative action upon the pathologically
excited nervous system.

" The experiments with sulphocyanates were then ex-
tended to a group of diseases which have one symptom
in common, namely, an increase in the blood-pressure.
These included arteriosclerosis, aortic insufficiency, and
chronic nephritis. From the large number of patients
with circulatory disturbances in Professor v. Basch's
wards, eleven cases of arteriosclerosis were chosen, nine of
which showed tortuosity and great pulsation of the blood-
vessels, hypertrophy of the left ventricle, accentuation of
the second aortic sound (usually with an increase in the
intensity of the apex-beat), and marked increase in the
blood-pressure, besides a number of subjective symptoms.
These consisted of pains in the chest, a feeling of pressure
and shortness of breath on exertion, especially after meals
or at night, a sense of fear and disturbed sleep, while
two of them showed, in addition, attacks of dizziness
and ringing in the ears.

Corresponding with the uniformity in clinical material,
the drug also showed a uniformity in action. The sense
of fear disappeared; the attacks diminished within a few
days, to return later only under special provocation.
Disturbances which had existed for months, such as
ringing in the ears and attacks of dizziness disappeared,
not to return. In most of the patients systematic blood-
pressure determinations were made with v. Basch's
sphygmomanometer by Dr. S. Kornfeld, who very
generously gave me the benefit of his years of experience

THEk/IPEUTIC STUDIES ON IONS. 83

in this field. A steady drop in blood-pressure, amounting
from 10 to 25 per cent, of the original value, could beob
served within a few days in all the cases studied. As soon
as the drug was stopped the blood-pressure rose again,
often to the original height within three to four days. Ac-
companying this, there was also a return of some of the
previous symptoms. Of interest are two further cases
of sclerosis of the larger arteries. One of these was a
female patient with sclerosis of the abdominal aorta, which
could with its large branches be readily palpated and
which gave rise to severe attacks of pain in the abdomen;
the other, a woman with all the signs of an advanced
arteriosclerosis, who had suffered for months with pain
and weakness in the right arm, which appeared on the
slightest exertion or when the arm was allowed to hang
by the side for some time. Besides this there existed
a so intense and painful sense of cold in the diseased
extremity, which corresponded with a very noticeable
decrease in the temperature of the skin, that the lower
arm and the right hand had always to be wrapped in
thick cloths. After a test had been made with sodium
bromide and aspirin, and these had proved entirely with-
out effect, the pains diminished very markedly after an
eight days' use of diuretin. After taking sodium sulpho-
cyanate for a number of weeks the sensation of cold
gradually disappeared, the hand no longer needed to
be wrapped in cloths, and the weakness in the ex-
tremity disappeared sufficiently so that the patient, who
had been under observation for eight months, was able
to do light work about the house. The blood-pressure
fell during this time from 210 to 160 mm. of mercury.
The patient with arteriosclerotic pains in the splanchnic

84 PHYSICAL CHEMISTRY IN MEDICINE.

region was much relieved, especially during the first
weeks, by the sulphocyanate treatment, while other
methods had been without effect. Whenever the sulpho-
cyanate administration was interrupted, the blood-pressure
rose, and with it returned the old symptoms.

Besides the decrease in the blood-pressure, a sedative
action may also play a role in the medicinal effects of
sulphocyanates. It is possible that yet another factor
plays a r61e, which can, however, only be touched upon
here. In investigations carried on during the past two
years with Dr. Peter Rona on the relation between the
effects of iodides and sulphocyanates and the effects of
salts of the heavy metals and the alkahne earths, the
following has been found:

It has been definitely established through exact ob-
servation and experiment that the iodides bring about
and favor the excretion of the ions of the heavy metals,
such as lead and mercury, in cases of chronic intoxication.
The explanation of this fact, which has been utihzed
therapeutically, has been sought in the formation of
soluble albuminates, which the iodides have been sup-
posed to bring about.

When quantitative experimens on protein precipita-
tion are made, it is found that the heavy metals show
at first a rapid increase in the precipitation value, with
an increase in the concentration of the salt, which later
however, as in the case of zinc, gradually falls to zero.
When the concentration of the salt is still fiirther increased,
a precipitate appears a second time, which is very heavy
and which also is again soluble. Curves in which the
ordinates indicate the degree of precipitating power, the
abscissas the amount ,of salt of a heavy metal employed,

THlSRAPEUTtC sruDlBS ON IONS. ^S

can "be constructed to give a graphic survey of these
relations. Such precipitation curves suffer a great change
upon the addition of iodides or sulphocyahates. If the
ions of the heavy metals are present in a low concentra-
tion, the precipitation of the protein is prevented alto-
gether; if present in larger amounts, the protein precipita-
tion is markedly increased. In the case of living animals
only the former possibility, that of the presence of but
a low concentration of poisonous ions, comes into con-
sideration. The iodides and still more the sulphocyanates
do in fact act under these circumstances as substances
which favor the formation of readily soluble protein
compounds, through, which an elimination of the heavy
metals is greatly aided. Conditions in the test-tube and
in the animal body are here, in the main, identical.

The relation of the metals calcium, barium, and stron-
tium to the proteins is somewhat different, a fact of
interest because of the important r61e of the calcium
ions in physiological and pathological questions. These
metals' stand in many ways between the alkali metals
and the true heavy metals. They have, in common with
the former, a high precipitation limit; with the latter, the
fact that the combination between protein and metal is a
firm one, and once produced continues even upon the ad-
dition of water to the solution. The power of depressing
most markedly the precipitation limit of the earthy metals
is possessed to a slight degree by the Br ion, in greater
degree by the I ion, and most powerfully by the sulpho-
cyanate ion. In the presence of sulphocyanate ions,
calcium, strontium, and barium chloride will precipitate
protein when present in simple normal solution and even
below this, while under ordinary circumstances the two

86 PHYSICAL CHEMISTRY M MEDICINE.

latter will not coagulate in any concentration, and calcium
chloride only when present in nine times the concentra-
tion given above. This formation of a solid protein
compound is always preceded by a state in which an
intimate combination between the protein and the metallic
ion occurs even before the precipitation limit is reached.
It can readily be seen that, through the establishment of
a firmer combination between protein and calcium ions
in the presence of a few iodide or sulphocyanate ions,
the formation of other insoluble calcium salts can be
inhibited, and the excretion of calcium be increased in
this way. The therapy of arteriosclerosis has within
recent years been directed in no small degree against the
calcification process itself. It seems to me that what
has been said above serves as a theoretical basis for the
clinical experience of the best observers in this field, that
the continued use of iodides is able to retard the course of
arteriosclerosis. For reasons which will become clearer
later, the use of sulphocyanates in these cases would
represent a therapeutic advance.

To the series of cases of arteriosclerosis there belong
two cases of aortic insufficiency with palpitation, dizzi-
ness, headache, a feeling of fear, and increased blood-
pressure. In one of these permanent relief from all
symptoms was achieved, in the other a temporary one,
as the therapy had to be interrupted after eight days.

Four patients with chronic Bright's disease, hyper-
trophy of the heart, and pallor showed a rapid better-
ment of their subjective symptoms, consisting of back-
ache, neuralgias, and sleeplessness, when put on a milk
diet and sulphocyanate. Without attributing the better-
ment to the sulphocyanate, it could be shown in these

THERAPEUTIC STUDIES ON IONS. 87

cases that an existing chronic albuminuria does not
contraindicate the use of the drug.

My last observations are taken from a group of patients
with syphilitic headaches — two men and two women.
In the men there was a history of syphilitic infection; in
the women abortions and still-births had occurred. One
rhan and one woman had a year previously suffered from
the same symptoms, which had promptly disappeared
after the use of iodides, and only after these. The head-
aches were in all cases very severe, and in three of them
typically nocturnal in character, particularly during the
weeks when this symptom first developed. Sensitiveness
of the skull upon percussion also existed.

The syphilitic character of the pains was therefore
definitely established in these cases, so far as this is
clinically possible. This diagnosis was further strength-
ened by the uselessness clinically of physical healing
methods and antineuralgic remedies.

The effect of the sulphocyanate in these cases was so
prompt and so clearly beneficent, even in the first few
days after administration, that its medicinal properties
cannot be doubted.* The effect upon the patients
proved in all cases to be a lasting one. The two patients
who had for similar symptoms previously undergone a
treatment with iodides agreed that the feeling of relief
had this time come much more promptly. In one of
the patients, who could tolerate drugs only badly and
who had a year previously suffered from severe iodism.

* I do not, of course, on the basis of these few observations on a
special form of late syphihs, want to look upon the question of the
specific effects of a sulphocyanate therapy in syphilis as settled.

88 PHYSICAL CHEMISTRY IN MEDICINE.

the sulphocyanate was administered in two small enemas
daily.

This constitutes a summary of my experiences thus
far. They were obtained for purposes of general
orientation on patients of whom each group presented a
great, almost monotonous similarity in symptoms. When
the careful choice of cases is taken into consideration,
it can scarcely seem strange that the effect of the drug
should have been so uniform. In passing it must have
been apparent what small doses of sodium sulphocyanate
proved remedially effective. The explanation of this
fact lies in part in the low molecular weight of the sub-
stance, for i.o gram sodium sulphocyanate is equal to
2.15 grams sodium bromide or 2.82 grams sodium
iodide.

But a close relationship between these substances
shows itself not only in the harmony of their advantages,
but also in the harmony of their disadvantages. There
exists a sulphocyanate acne and a sulphocyanate rhinitis.
The latter is the commoner. Twice a mere sugges-
tion of it occurred, in one of these cases only once toward
evening. In two other cases copious secretion from
the nose and eyes set in, which disappeared, however,
within two to three days after the administration of
sulphocyanate was stopped. In only one patient with a
sensitive skin, which had some months previously been
the seat of a bromide exanthem, a sulphocyanate acne
appeared, consisting of small nodules, most numerous
in the face and sparingly distributed over the trunk and
extremities, which did not, however, give any further
trouble. It disappeared a few days after the medication
was stopped. Gastric disturbances never appeared, even

THERAPEUTIC STUDIES ON IONS S9

after the remedy had been used for months. While a
great similarity, in part even an identity, seems to exist
between the iodides and the sulphocyanates, the latter
do not possess the specific effect upon the thyroid gland.
The use of the drug even for months does not affect a
parenchymatous goitre. This fact might well at times
prove of therapeutic advantage.

Therapeutics still continues to count the salts among
the "alterants" and the "resolvents." Both of these
properties of " changing the course of k disease" and
" bringing about a resolution" the sulphocyanate ions
possess in rich part, as shown by our own observations.
From the versatility and intensity of their action we are
presumably correct in putting them beside the iodide ions.

I do not wish to bring this paper to a close without
adding a few general remarks on the principle which
prompted it.

This leads, first of all, to a conception of the way in
which the salts act upon the organism, which, though
still hypothetical', encounters at present nothing which
speaks against it. Just as a large group of non-ionized
narcotics bear an intimate relation, according to H.
Meyer's and Overton's beautiful discoveries, to the
lipoids of the cell, the ionized compounds might find
their point of attack in the protein constituents of the
protoplasm. A difference in the distribution, or a re-
placement of the normal ions of the cell, would be con-
nected with changes in the state of the colloids and con-
sequently also changes in function. If the application
of our principle extends, on the one hand, almost to the
chain of psychophysical processes, it has its limitations,

90 PHYSICAL CHEMISTRY IN MEDICINE.

on the other, which are inherent in the nature of such a
method itself.

When we speak of the great analogy between changes
in state in organic colloids and life phenomena, we are
dealing, to use the words .of Maxwell, " with that
partial similarity between the laws of one series of phe-
nomena and those of another, in consequence of which
the one comes to illustrate the other. " Besides a limited
identity, extensive differences may therefore exist, many
of which are still beyond our understanding. This holds
also for the great differences known to exist in the toxicity
of ions in animal experiments. We are at present still
much . inclined to attribute, qualitatively at least, great
importance to the value of animal experiments for settling
such a question as the one before us. This we do un-
justly, I believe. Clinical therapeutic experience must be
gotten by itself. The animal experiment brings in this
case also only an analogy; at the best it serves only to
stimulate further work.

S. On the Relation between Physico-chemical Properties
and Medicinal Effects.*

In the consideration of questions in pharmacody-
namics, from the point of view of physical chemistry, a
scarcely measurable field lies before us, into only a small
part of which, however, paths lead at present. If under
these conditions I attempt to speak before a body of
clinical men on some questions which belong in this
realm and which have interested me for several years, I

* From Verhandlungen des XXI. Congresses fiir innere Medicin
in Leipzig, 1904.

PHYSICO-CHEMICAL PROPERTIES. 91

can give many good reasons for doing so. As is evidenced
by the studies of H. Meyer and Overton on the theory
of narcosis, and by the work of Straub on the tenability
of the law of mass action for the distribution of certain
poisons in the organism, so our work, too, has clearly
shown that only the use of physico-chemical methods
renders possible a deeper understanding of medicinal
effects. To this there comes the well-founded feeling
that in this way explanations of the nature of the im-
portant phenomena accompanying constitutional changes
may also be obtained, a problem which has long been
a favorite one with the internal clinicist.

This paper will be limited to a discussion of the r6le
of ions, those electrically charged dissociation products
of acids, bases, and salts which are produced when these
substances are dissolved in water. We know that the
mineral constituents of the body are, in the concentration
in which they are present, almost completely dissociated.
This is true also of the metallic and alkaloidal salts
which are introduced into the body for medicinal pur-
poses. Other pharmacologically active substances which
scarcely ionize on solution in water, such as the esters,
may be converted into ionizable compounds in the body.
Because of this many-sided importance of the omni-
present ions, it seemed of value first of all to get an
experimentally demonstrable conception of the mode of
action of the ions in the animal body. Of all the con-
stituents of the protoplasm, the proteins show the most
intimate relation to the salts. Their most varied changes
in state, such as solution, precipitation, and coagulation
through heat, are all connected with the cooperation of
salts, and it seemed necessary therefore to obtain first

92 PHYSICAL CHEMISTRY IN MEDICINE.

of all a more intimate knowledge of the significance of
the ions for these changes in state.

The neutral salts of ammonium, magnesium, and the
alkali metals are best adapted to such a study, as the pro-
tein precipitates produced by them can be reobtained in an
almost unaltered condition through dialysis of the salt.
The most important laws governing this reversible change
in state are the following: If the salts are arranged
according to their precipitating power, the acid ions (or
anions) always follow each other in the same order with
any given metaUic ion, and, conversely, with any acid
ion the metallic ions (or cations) always follow each other
in the same order. The precipitating power of a,ny
salt represents, therefore, the product of the effects of
its constituent ions, and the properties of these ions are
to a large extent independent of each other.

A second law governs the character of the ionic effects.
It was found that the ions of a salt antagonize each other
in bringing about changes in the physical state of a colloid,
for the one ion has a precipitating action, while the other
has a solvent action, and, as the one or the other ion has
the upper hand, the salt under consideration either pre-
cipitates or prevents the precipitation of protein. The
effectiveness of ions is expressed in the following series:

Cations arranged in the order of their precipitating
power. The most powerful comes first: sodium, potas-
sium, ammonium, magnesium.

Anions arranged in the order in which they prevent
precipitation. The most powerful comes last: sulphate,
citrate, tartrate, acetate, chloride, nitrate, bromide, iodide,
sulpkocyanate.

To render what follows more intelligible it is necessary

PHYSICO-CHEMICAL PROPERTIES. 93

to touch upon the relation of the alkahne earths to the
proteins.

The protein precipitates produced through the action
of the alkahne earths are irreversible in so far as the solu-
tion of a precipitate that has once been produced is
difficult and scarcely leads to the restitution of an un-
changed protein. The effects of calcium, strontium, and
barium are determined to a large extent through the
presence of other ions simultaneously present. Under
these circumstances the effects of the ions of a salt of
an alkaH metal also antagonize each other, only in a way
opposite to that observed in precipitations produced
through pure neutral salts. The formation of a pre-
cipitate in a solution of native protein through the alkaline
earths is favored by anions and inhibited by cations. The
anions under these circumstances arrange themselves
in the following order, in which the most powerful pre-
cipitants come first :

Acetate, chloride, nitrate, bromide, iodide, sulphocyanate.

The cations arrange themselves in the following order
in which the greatest inhibitor of precipitation is put
first:

Magnesium, ammonium, potassium, sodium.

Nothing stands against the assumption that it is the
protein constituents of protoplasm that constitute the point
of attack of the ions in the organism, and this behef
cannot only be supported by experiment, but is also of
heuristic value.

The two chief laws of protein precipitation, the additive

and the antagonistic effects of ions, hold also for the

physiological properties of ions. All cations, for example,

"have certain. physiological characteristics in common, in

94 PHYSICAL CHEMISTRY IN MEDICINE.

that they increase more or less the irritabihty of nerves
and muscles, excite intestinal activity even to the point
of producing a gastro- enteritis, and usually increase blood-
pressure. The solvent action upon protein and, running
parallel with it, the physiological effects of the anions
are the more pronounced the further we pass along the
series of anions given above. The protein precipitating
salts, such as the sulphates, citrates, and tartrates, when
these are connected with the overbalancing properties
of the metallic ions, are all cathartics. The salts which
follow these, more especially the nitrates, bromides, io-
dides, and sulphocyanates, show the characteristics of the
anions; they are sedative in their action and decrease
blood-pressure. The relationship between them is in-
dicated also in the similarity with which they bring about
an acne and coryza. For the sulphocyanates these
pharmacological properties were deduced from the group-
ing given above and verified on patients.

The experimental study of the effects of sulphocyanates
has proved fruitful in yet another way, in that the sulpho-
cyanate anions, representing as they do the last members
of the anion series, allow one to study the proper-
ties of anions in a particularly pure foirm. Sulpho-
cyanates can be used first of all in order to ascertain
more accurately the physiological relations between salts
and esters. Between the strongly ionized salts and the
scarcely dissociable esters (which represent combinations
between alcohols and acids) there exists a great difference
in their power of penetrating a cell. While the latter,
according to the extensive investigations of Overton,
readily enter a cell because of their solubility in its lipoids,
— ^lecithin, cholesterin, cerebrin, etc.^ — the salts enter the

PHYSICO-CHEMICyiL PROPERTIES. 95

protoplasm only with difficulty. Since, however, the
esters are saponified in the organism, in consequence of
which the anions of the acids become free, a physiological
ion effect might nevertheless be expected under favor-
able conditions, even after the administration of esters.
Such an effect will become apparent, however, only when
in a readily dissociated ester some anion is present that
has characteristic physiological properties and is suf-
ficiently active physiologically to show itself, otherwise
the narcotic and circulatory effects common to all esters
conceal the intoxication picture. If for purposes of
comparison experiments are made with sodium sulpho-
cyanate and the amyl ester of sulphocyanic acid, atypical
sulphocyanate intoxication occurs in both cases. Careful
analysis shows that this consists in a fall in blood-pressure
brought about through a decrease in the energy of the
heart muscle, a subsequent increase in pressure through
stimulation of the vascular centres and great, principally
central, stimulation of the vagus. While, however, the
intravenous injection of two to three drops of the ester
suffice to bring about a rapid and fatal intoxication in
a medium-sized dog, eight to ten grams of sodium sulpho-
cyanate must be introduced intravenously to bring about
the same effect. This enormous difference in toxicity
shows that in the amyl-sulphocyanate intoxication the
ester readily enters the cells, because of its solubility in
the lipoids, and that not until it has arrived in the cells
are its anions set free. These same ions, when already
formed, enter the cells only with difficulty, in consequence
of which the body must be charged with a great excess
of sodium sulphocyanate in order to bring about the
same degree of intoxication.

96 PHYSICAL CHEMISTRY IN MEDICINE.

Numerous instances in pharmacology, in which any
, alcoholic radicle in an ester- like combination with an acid
is required to bring about any specific effect, can, I be-
lieve, be explained in the same way. The alcohol radicle
only renders possible the ready absorption of the substance
by the cell; the anion connected with it is the really
active principle. Cocaine is, for example, a me.thyl ester
of benzoylecgonin, a substituted tropincarbonic acid.
The benzoylecgonin, the real carrier of the medicinal
properties, is however twenty times less poisonous than
its ester, cocaine, and does not possess the anaesthetic
properties of the latter. Only after being converted into
an ester, through any alcohol whatsoever, is the cocaine
effect produced. Existence in the form of an ester is
apparently always the sine qua non of a useful local '
ancBsthetic whose active anion must enter the endings of
the sensory nerves. Eesthorn has found that a large
number of cyclic and heterocyclic esters are able to bring
about a local anaesthesia, and has been able to discover
valuable substitutes for cocaine in the orthoforms, which
represent methyl esters of amido-oxybenzoic acid, and in
nirvanin, a diethylglycocoll compound of orthoform-
Eucaine and ansesthesin are also esters, the latter one
of p-amido-benzoic acid. Without being directly con-
cerned in the physiological effect produced, the presence
of an alcohol radicle in the compound first renders such
an effect possible, for only under these circumstances is
the active acid ion' present in sufficient concentration at
its point of physiological attack. Arecaidin, which
chemically represents a methyltetrahydronicotinic acid,
is scarcely active physiologically, while its methyl ester,
arecolin, represents the toxic principle of the areca-nut.

PHYSICO-CHEMICAL PROPERTIES. 97

The number of these illustrations might easily be
multipUed. In passing I only wish to point out that the
activity of the metallic ions can be increased through
combination with an alcohol radicle in the same way as
the activity of the acid ions. It is possible in this way
to bring about in animals most acute metallic intoxica-
tions with the ethylic compounds of zinc, mercury, and
lead.

Besides this influence upon the effects of ions, brought
about through combination with alcoholic radicles, de-
pendent upon the fact that protoplasm is made up of
lipoidal and proteoidal material, there still exists another
way in which the specific effects of many ions can be
increased or decreased, namely, through combination
with other ions. As an example of this we may take
the behavior of the alkaUne earths toward protein in the
presence of neutral salts of the alkali metals. As a glance
at the lists of ions given above shows, the protein precipi-
tations brought about through the alkaline earths can
be inhibited through the addition of ions of the alkali
metals, or hastened through the addition of anions, most
powerful of which is the sulphocyanate anion." It seemed
possible, therefore, that through proper experiments a
physiological antagonism could be discovered to exist
between monovalent cations and the alkaline earths, as
well as a synergistic increase in the effect of anions
through the cations calcium, strontium, and barium.
This suspicion, prompted by analogies existing between
experiments carried on in vitro and certain phenomena
observed in vivo, could be shown to be correct by animal
experiments.

If animals are kept in a half-intoxicated state with

gS' PHYSICAL CHEMISTRY IN MEDICINE.

sulphocyanate — a state which is characterized by a strong,
steady heart action and stimulation of the vagus nerve
and vascular centres — it is possible to bring about an
immediate standstill of the heart, not preceded by an in-
crease in blood-pressure, by injecting an amount of a
barium salt which, under ordinary circumstances, scarcely
affects the heart at all, or, if it does, only stimulates it.
Such a heart-failure may under circumstances occur
after the injection of five milUgrams of barium chloride
into a medium-sized dog. Since this effect can be ob-
tained even in a completely atropinized heart, or after
the exclusion of the greater circulation and the nerve-
centres, it is probable that the salt afiects the heart
directly. Just as in test-tube experiments with protein,
barium, which is characterized by a remarkable af&nity
for the musculature of the heart and the blood-vessels,
is able to join such large amounts of neighboring sulpho-
cyanate ions to the heart muscle in such remarkably
short time that an acute, deadly sulphocyanate intoxi-
cation results. How small amounts of sulphocyanate
suf&ce in order to bring about a heart failure, if only it
reaches its point of attack within the cells, was indicated
in the experiments described above with sulphocyanate
esters. Calcium and strontium act in the same way as
barium, only, because of their lesser affinity for the
musculature of the heart, larger doses are required
(Pauli and A. Frohlich).

The physiological antagonism between many ions which
we supposed to exist from a certain parallelism between
the behavior of dead and of living protein, and which has
been proved to exist experimentally, had been previously
discovered in another way by the well-known American

PHYSlCO-CHBMlC/lL PROfeRTlBS. 09

physiologist J. Loeb, and rediscovered under the most
varied conditions by his numerous pupils. We can only
touch upon these investigations here. That they har-
monize with our own findings and represent only an ex-
pression of the general principle common to them all
is, however, readily discernible. The starting-point of
Loeb's investigations is the question of the significance
of the different ions of sea-water for the life processes of
marine animals. A great similarity was found to exist
between the effects of various ions upon phenomena of
development and upon the activities of muscle and nerve.
An interesting example is furnished by the development
of the eggs of Fundulus, a small bony fish. These fish
are able to develop not only in sea-water but also in dis-
tilled water. If immediately after fertilization these eggs
are introduced into a sodium chloride solution of the
concentration of the sea-water they all die in the course
of a few hours without developing any further. If,
however, a small amount of calcium, which also represents
a constituent of the sea-water, is added to the sodium
chloride solution, normal embryos are produced. A
pure sodium chloride solution is poisonous also for the
adult animals, but this toxicity, too, is done away with
upon the addition of a little calcium. Instructive also
are the effects of ions on the rhythmical contractions of
the swimming-bell of medusae. After removal of the
central nervous system in these animals the bell still con-
tracts rhythmically in a pure sodium chloride solution.
These contractions cease, however, as soon as certain
cations, such as calcium and strontium, are added to the
solution, just as they cease in sea-water. In a similar
way, the poisonous effects of pure sodium chloride on

too PHYSICAL CHEMISTRY IN MEDICJNE.

heart muscle or its stimulating effects upon the excised
gastrocnemius of the frog are also done away with through
the addition of calcium or strontium.

Ralph S. Lillie demonstrated an analogous antag-
onism between the effects of cations on ciliary movement.
MacCallum showed in animal experiments that the
effect of cathartic sodium salts, which is to be looked
upon as an expression of the activity of the metallic
ions, can be inhibited through administration of calcium.
Martin H. Fischer was able to demonstrate that a
glycosuria, brought about through the injection of sodium
salts into rabbits, can be suppressed through calcium,
and, according to Brown who discovered the same fact
independently, also through strontium.

That the relations between anions are governed by
similar laws within and without the organism is apparent
from the investigations of Torald Sollmann. As this
author was able to show in his studies on diuresis, the
urinary excretion of chlorine ions from the body under
the influence of other ions is to a large extent independent
of the amount of water secreted along with them. The
per cent, of chlorides in the urine is increased through
administration of nitrates, iodides, and sulphocyanates,
decreased through acetates, phosphates, and sulphates.
It is not difficult to recognize in this grouping the order
in which the anions act upon the proteins. The second
group acts less powerfully, the former more powerfully
than the chlorine ions in the effect of the ions of the
alkali metals upon proteins.

After what has been said it will no doubt be admitted
that a considerable material is already at hand which lends
further support to the principle of the many analogies

CHANGES IVROUGHt IN PATHOLOGY. 101

between changes in the physical state oj colloids and the
changes which go on in living matter. It would, however,
be unfair to expect such a principle to hold quantitatively
for every biological detail. It is subject rather to the
various changes brought about through differences in
living matter which vary with different kinds of animals
and with different kinds of organs. While calcium,
strontium, and barium have an almost equal effect in
■the presence of sulphocyanates on egg albumin in a
test-tube, the synergistic function of the barium is the
most apparent of the three in a physiological experiment
on the heart. In a similar way Loeb and Herbst
found that individual differences exist between ions in
their effect upon different marine animals. Nevertheless,
the general law governing all these phenomena appears
everywhere, at one time more, at another time less dis-
tinctly, just as in a musical composition the theme is
heard at all times by him who has once learned it among
the infinite number of its variations.

6. Changes Wrought in Pathology through Advances
in Physical Chemistry.*

Not until it has been found possible to explain the
anomalies in the functions of the organism through
changes in the form and in the composition of its constit-
uents can pathology consider its task completed. Its field
of knowledge grows in three ways: through the experi-

* Wandlungen in der Pathologie durch die Fortschritte der all-
gemeinen Chemie, Wien, 1905. Festival address at the third aniiual
meeting of the K. k. Gesellschaft der Aerzte in Vienna, March 24, 1905.

toi PHYSICAL CHEMISTRY IN MEDICINE.

mental determination of the degree and the direction of
changes in function; through a study of the morphological
and through a study of the chemical deviations from the
normal lying at the basis of these changes in function.
When one studies the development and the present
status of pathology one soon sees that this science has
not grown with the same rapidity, nor equally well in
all three directions. It has developed most markedly
toward the morphological side, least of all toward the
chemical side. This difference is still more apparent
when we study more particularly the part that the Vienna
School has played during the past century in the develop-
ment of pathology. Chemical methods have scarcely
at all been employed, except in the last ten years, while
the morphological investigations carried on in Vienna
during this same century have been truly brilliant.

It may not be without interest to touch upon some
of the reasons that have brought about such a noticeable
difference in the pursuit of these two branches in our
school. It was, of course, but natural that the con-
ceptions of the famous men of the second great period
of the Vienna School should have determined for a
long time to come the course which further development
in the past century took. If this development was chiefly
morphological in character, then this depended in large
measure upon the state of chemistry in Austria at that
time. For the education and the first efforts of those
pioneers occurred during an epoch when chemistry was
most deplorably represented in Austria, followed and
taught as it was, not experimentally, but sf)eculatively.
A classical document describes conditions as they were
in those days. In one of his memorable addresses Liebig,

CHANGES IVROUGHT IN PATHOLOGY. 103

in 1837, so frankly and mercilessly criticised the condi-
tion of chemistry in Austria that it seems small wonder
that the succeeding generation of medical men, mightily
influenced through the labors of such as Corvisart,
Laennec, and Bretonneau, dedicated themselves chiefly
to morphology, which promised so much. The experi-
ences of medicine with a chemistry which had been in the
main of a speculative character no doubt also contributed
to this end. The birth of iatro-chemistry, which through
Paracelsus, Helmont, and Sylvius ruled medicine in
the seventeenth century, met a just and fruitful opposition
through the morphological workers. Later Boerhave,
with whose entry the first brilliant epoch in medicine is
intimately connected, most emphatically emphasized the
great importance of chemical research in pathology, but
because of its insufficient development chemistry could
offer too Uttle at that time to fulfil his promises.

Not until the wonderful development of organic and
appUed chemistry as introduced in the middle of the
last century, more especially by Liebig, did new paths
open up before pathology. In the meantime, however,
the morphological tendency in Vienna had, under the
tremendous influence of its illustrious exponents, obtained
the upper hand, a fact which helped to determine also
the nature of the increase in the faculty. Into the circle
of their influence were drawn the majority of the younger
men of talent and permanently kept there. For it resides
in the nature of morphological research that it is admirably
adapted for the introduction of the beginner to science, in
that it offers a large number of simple problems which
may be solved without drawing upon a larger number of
accessory sciences, while its results, which usually repre-

104 PHYSICAL CHEMISTRY M MEDICINE.

sent a truthful description of what has been seen, give
a feeling of great security.

The far-reaching results of chemical research in the
last decade have brought to us also a gradual increase
in the general interest taken in the chemical aspects of
pathology, and so it has been no accident that this altered
point of view has found an expression in the change in
the character of the annual addresses made before our
society. Three years ago we enjoyed an inspiring pres-
entation of the pathology of metabolism, and last year
brought us a sharply defined discussion of the protein
question, such as only ripe experience, hand in hand
with critical judgment, can produce. If I to-day find
myself once more face to face with the problem of bring-
ing before you in our annual meeting another chapter
from the realm of chemistry as applied to medicine, I
must attribute this honor first of all to that great
new interest taken in this subject. This subject is, in
fact, worthy of your greatest attention, for we stand at
present in the midst of an undreamed-of improvement
and development in our point of view in physiology and
pathology, and this strange and sudden change is based
in particular upon advances in general or physical chem-
istry. This science has acquainted us with a series of
fundamental laws that govern chemical reactions, whose
validity, influenced more or less through special circum-
stances, extends also to the changes that go on in living
organisms.

It was probably the first important step for the physico-
chemical characterization of living matter when Graham
divided all bodies into colloids and crystalloids, according

CHANGES IVROUGHT IN PATHOLOGY. 10$

to the behavior of certain typical substances. For from,
this division there has arisen the conception that all
living matter is of necessity connected with the existence
of a colloidal ground-substance in which all changes
take place. Nevertheless, more than twenty years were
necessary before a systematic attempt was made to obtain
a conception of the changes that go on in living matter
from a study of changes in the state of colloids. In the
three years from 1888 to 1891 Hofmeister took the first
step in this direction, in that, in attempting to explain
the physiological effects of salts, he compared the effect of
salts upon colloids in a test-tube with the effect of these
salts upon the animal organism. During the last decade
similar investigations have been carried on with the
means offered by physical chemistry, which has during
that time enjoyed most rapid growth, and have, in con-
junction with the investigations of chemists on inorganic
colloids, furnished so abundant a material that the time
for a broad alliance between biology and colloidal chem-
istry seems to have come. From this most promising
section of appUed chemistry I would to-day like to take
a few facts which to all appearances seem to be of funda^
mental biological importance.

The colloidal substances are present in two forms in
the body — in a more or less jelly-like condition in the
cells, and in a fluid condition in the blood and the tissue
juices. The laws of colloid chemistry govern the changes
that go on in the cells, only these laws are modified
through the metabolism of living matter, the character-
istics of which we do not as yet understand. The behavior
of the extracellular material is, however, of a much
simpler character. In the former case there exists only

io6" PHYSICAL CHEMISTRY M MEDICINE;

a certain parallelism between changes in colloids and
many manifestations of cell life; in the second, however,
we are dealing with a direct applicability of the laws of
colloid chemistry, controllable at any time by experiment.
We will to-day discuss only these last-named phenomena,
the importance of which has recently been pushed into
the scientific foreground, more especially through the
modern development of the teachings of immunity.

Before attempting an explanation of the significance
of the phenomena which interest us especially, it is
necessary to obtain a clear conception of the characteristic
properties of the colloidal condition. These character-
istics are best illustrated by the properties of the colloidal
solutions of metals, from which a gradual transition to
the biologically important colloids occurs.

If a clean metal plate, such as platinum, is put into
water it assumes a weak electric — in this case negative- —
charge, while the fluid surrounding it becomes electro-
positive. According to the fruitful conceptions which
Nernst has developed of the source of galvanic currents,
we have to deal with the following process : Just as after
the solution of a salt — such as sodium chloride — in
water the metallic portion is present in the form of
electropositive particles, the acid portion in the form of
electronegative particles or ions, a metal when dropped
into water also goes into solution in traces to form
electropositive metallic ions, while the metal itself be-
comes a negative electrode. A proper combination of
such metals having different solution tensions then con-
stitutes a galvanic element. If now we imagine such
a metal divided under water into smaller and smaller
particles until this metallic dust is able by virtue of its

CHANGES IVROUGHT IN PATHOLOGY. ■ 107

minuteness to remain suspended in the liquid an in-
definite length of time, then we have a colloidal solution
before us. Such a solution is perfectly clear and passes
unchanged through the finest filter. We can deduce
from the manner of its origin its characteristic properties
— such a solution represents a suspension of fine elec-
trically charged particles, in other words minute elec- ,
trodes. If two gold electrodes connected with a strong
electric current are introduced, according to the direc-
tions given by Bredig, into pure water cooled by ice and
then are carefully separated until a tiny arc appears,
purplisb^red clouds begin to emanate from the negative
electrode as this goes into solution in the form of fine
dust particles, and the result is the production of the
beautiful colloidal gold solution which Zsigmondy pre-
pared previously by chemical means through careful
reduction of a gold chloride solution. Partially through
use of the chemical method, partially through use of
the electrical method, a large number of inorganic
colloids have been produced, which have, since Gra-
ham's fundamental work, formed a much-cherished ob-
ject of investigation. But not until recently has it
been possible to deduce in a satisfactory way the laws
governing their varied behavior from variations in a
few characteristics. By utilizing the fundamental work
of such investigators as Lixstder, Picton, Hardy, and
Bredig, and many of his own experiments, J. Billitzer,
a Vienna chemist, has been able to show that the chief
laws governing and the differences existing between col-
loids can all be explained by variations in only three
values, namely, the number, size, and electrical charge
of the suspended particles. This conception, which

lo8 PHYSICy4L CHEMISTRY IN MEDICINE.

allows not only a survey of what has been accomplished,
but also allows us to state in advance what naay be ex-
pected to happen in colloidal solutions, has, moreover,
the advantage that its suppositions are capable of being
tested experimentally — in fact, have already been tested
in many cases.

We have optical means at our disposal, for example,
by which we can determine the number and the size of
the colloidal particles. If a colloidal solution is placed
in a bundle of intense light rays, the fine particles of the
solution reflect the light in part, as can be determined
through its polarization. The absorption of different
portions of the spectrum may also give a clue regarding
the size of the particles. Finally, Siedentopf and
ZsiGMONDY have made it possible with their ingenious
ultramicroscope to determine the number and size of the
colloidal particles. The electrical condition of the sus-
pended particles we can recognize from their behavior
in the electric current, in that they migrate, according to
their electrical charge, either toward the positive pole
when they are negatively charged, or toward the negative
pole when they are positively charged.

These facts allow us to understand a process which
has long served as the prototype of most of the colloid
reactions and which explains many important questions
in physiology and pathology, namely, the precipitation of
colloids.

It has already been pointed out that the salts, acids,
and bases dissociate in part in aqueous solution into
their oppositely charged constituents, the ions. Let us
suppose now that a sufficient number of such ions are
introduced into a colloidal solution of a metal which

CHANGES IVROUGHT IN PATHOLOGY. 109

represents a suspension of weakly charged electronegative
particles. In consequence of 'electrical attraction, the
negative colloidal particles will collect about the electro-
positive ions, until through the heaping up of a suffi-
cient number of such particles the collecting ion will
be electrically neutralized. When the aggregates thus
formed have reached a sufficient size, the solution
becomes turbid, and finally a precipitate drops to the
bottom.

We are able to foretell the possibilities which result
from a change in the number, size, and electrical charge
of the particles of a colloid, all of which can be proved by
experiment. When the number of particles is decreased,
the probability that a sufficient number will be collected
together through added ions for the formation of large
aggregates is also decreased, and finally a stage is
reached in the concentration of the colloid below which
precipitation does not occur. The precipitation is also
rendered difficult when the particles are very small and
carry, but a weak charge, because under these circum-
stances too large a number of the particles have to be
collected together. If, on the other hand, the electrical
charge of the particles is too great, then too few suffice
to neutralize the oppositely charged ions, and the aggre-
gates formed are too small to settle to the bottom. A
medium charge, a sufi&cient number, and a sufficiently
large size of the colloidal particles constitute, therefore,
the optimum for precipitation. Just as we have electro-
negative metallic colloids, we have also electropositive
colloids. Oppositely charged colloids precipitate each
other in the same way as the. ions of salts precipitate a
Cplloid, only in consequence of the size of the reacting

110 PHYSICAL CHEMISTRY IN MEDICINE.

particles the conditions for the formation of large aggre-
gates are especially favorable.

We have yet to speak of a few typical observations on
the precipitation of colloids that have become of great
importance for certain questions in biology. Such, for
example, is the often-observed variability in colloids. This
variability often does not attain a stabile end state until
after a very long time. It has been found that this origi-
nal instability is dependent chiefly upon the presence of
impurities introduced during the preparation of the
colloid, which because of their slight amount do not
make themselves felt until a long time has passed. As
soon as this slow process of neutralization has come to
an end, the colloid is in a stabile condition.

A further very important observation is the great
influence that time has upon the formation of a precipitate.
We usually require very different amounts of a precipi-
tating salt or a colloid, depending upon whether the
precipitate is to be brought down at once or more slowly.
Not rarely the amount of precipitating substance used
in the second case is larger than in the former. This
is dependent upon the following fact: If the precipitating
colloid A is at once added to the colloid B, the particles
are present everywhere in the mixture in the size and
with the electrical charge which they possess in the
unmixed individual colloids. A and B. Things are
different, however, when small portions of B are added
one after the other to A. Under these circumstance.s, if
the reaction does not take place too rapidly, new aggre-
gates of B and A are formed upon the addition of the
first amount of colloid, which are not entirely neutral
and which differ in size and charge from the original

CHANGES JVROUGHT IN PATHOLOGY. Ill

particles of A. Every new addition of B will encounter
new conditions in this regard, and, as experience has
taught, usually conditions less favorable so far as pre-
cipitation is concerned. The result is that under these
conditions of partial saturation more precipitating ma-
terial is used up than when all is added at once, and
that a series of intermediate bodies between the pure
substances A and B and the fully neutralized mixture
AB are formed. These intermediate bodies are built
according to the type xAyB, in which x and y vary
within certain Hmits.

A third possibility that interests us is the following.
The aggregates formed through neutralization of the par-
ticles of two oppositely charged colloids are often held
loosely together through slight electric forces. If an
excess of one or the other colloid is added to such a
precipitate, the new particles will, because of their elec-
trical charge, enter into competition with the attraction
forces existing in the neutral aggregates, and by diminishing
their size and electrifying the particles cause the • pre-
cipitate to go back into solution. As soon as a certain
quantitative relation exists between the two colloids, the
precipitate will therefore attain a maximum and will go
back into solution as soon as one or the other colloid
is present in excess. This is a familiar and well-studied
relation existing between colloids.

The experimental facts that have just been recited
were arranged so as to be ready for immediate application
to one of the most important and interesting chapters
of medicine, the immunity reactions. We shall deal
more ■ particularly with that difficult and much-argued
relation between toxin and antitoxin. On thiss ubject

112 PHYSICAL CHEMISTRY IN MEDICINE.

there exist a large number of valuable quantitative
investigations, of which must be mentioned in particular
the fundamental work of Ehrlich on diphtheria toxin.

I may perhaps be allowed, before entering into details,
to touch upon those few leading points which render
possible a simpler and more satisfactory conception of
the relation of toxin to antitoxin than has until now
been possible. Two assumptions sufhce, both of which
rest upon a fully established experimental basis and are
generally accepted without contradiction: the colloidal
constitution of toxins and antitoxins, and their ability
to neutralize each other. Through these suppositions
is rendered possible the extension to the dark relations
existing between toxin and antitoxin of our advanced
insight into the process of colloidal precipitation. As an
actual matter of fact, we are dealing in both cases with a
neutralization of colloids, only the criterion which exists to
show that such a neutralization has occurred is different in
the two cases. For in the first case this consists in the
production of macroscopically visible aggregates, in the
second in the formation of non-poisonous ones. The
similarity between the general laws governing the two
sets of phenomena is, in truth, striking.

It is a well-known fact, for example, that especially diph-
theria toxin when kept for longer periods of time under-
goes changes which are attributed to the formation of
various complexes from the originally simple toxin. An
analogous phenomenon is counted among the first-observed
and best-known facts of colloids in general. It is de-
pendent upon the presence of neutralizing impurities
which are in the course of time able to render manifest
their effect in the production of aggregates. The more

CH/tNGES ly ROUGH T IN PATHOLOGY. 113

concentrated a colloidal solution, the richer it is, other
things being equal, in impurities, and the less stabile in
consequence. In the course of time the process of
neutraUzation in the colloidal solution comes to an
end, after which it remains stabile. Ehrlich has
been able to observe similar facts in the case- of
diphtheria toxin which is kept a sufficiently long time.
And we know from the observations of Paltauf on
the loss in strength of stored immune sera, and a recent
excellent investigation of Pick and Schwoner, that in
antitoxin, especially in the case of the high-potency
sera, the tendency to form aggregates is very great. That
this tendency toward the formation of aggregates must
be subject to the greatest variations under our present
system of obtaining the impure toxin and antitoxin
solutions is readily intelligible. In the preparation of
inorganic colloids we have also only lately and by no
means in all cases succeeded in obtaining stabile and
uniform solutions, through perfection of technic and
ideal cleanliness of material.

Upon the variations in the original properties of colloids
are also dependent the variations in the colloidal mix-
tures. This explains that variability which has been
observed in the behavior of toxin-antitoxin mixtures
and which originally wrought great confusion in this
question. We have already touched upon the great
differences shown in the behavior of colloidal mixtures,
depending upon whether they are precipitated at once
or in fractions. It is of value to enter a little into the
details of the relations existing when toxin and antitoxin
are mixed together, for the observations of Ehrlich
pri the fractional saturation of toxin constitute the

114 PHYSICAL CHEMISTRY IN MEDICINE.

foundation of our modern (Conceptions of its nature. If
we add to a certain amount of a colloid A a much smaller
amount of a neutralizing colloid B, then, generally
speaking,* a part of A is not completely neutralized, while
the remaining part remains free, but B is distributed
over and combines with as large a number of the colloidal
particles of A as is possible. As a result, new, incom-
pletely neutralized aggregates are formed. By this means
the number, size, and electrical condition of the particles
become changed, and it depends entirely upon the char-
acter of these new values whether the tendency toward
a formation of further aggregates upon the addition of
a second portion of B is favored or inhibited. When
such a second addition is made, new aggregates with
new properties are again produced. If we have deter-
mined the amount of antitoxin necessary to just neu-
tralize a lethal dose of toxin, we will need w times this
amount to neutralize an w-times dose of toxin. Things
are different, however, as soon as we try to saturate
gradually, through the addition of succeeding small
amounts of antitoxin, an n dose of toxin, as Ehrlich
has done. Under these circumstances we can get only

* It cannot be discussed in this paper in how far neutralization
velocity and reversibility of the formation of aggregates determine the
character of the course of the reaction. The more important instances
can, however, be reviewed. Reversibility is always only partial, and
decreases steadily from the moment of neutralization. Even such
stabile colloidal changes as the coagulation of egg albumin through
heat or concentrated mineral acids are reversible at the moment that
they are brought about. In the precipitation of protein through phenol,
alcohol, or neutral salts the eSect of time and the degree of reversibility
increase from the first toward the last. This general property of
colloids has in recent discussions of immunity assumed an important
part under the heading of secondary fixation of toxin-antitoxin.

CH/tNGBS IVROUGHT IN PATHOLOGY. Ii5

those transitional toxin-antitoxin compounds which show
great variations in their reactions. This phenomenon
has been responsible for the development of a rich
noilienclature. All the relations between toxin and
antitoxin, are much complicated by the fact that diph-
theria toxin, as has already, been pointed out, may from
the start enter into a reaction with antitoxin, with aggre-
gates which are by no means all alike. To this is still
to be added the following fundamental peculiarity in the
reactions of the toxin. The toxicity of diphtheria toxin
and its relations to antitoxin are able to vary independ-
ently of each other, a behavior which finds expression, for
example, in the fact that a toxin requires approximately
the^same amount of antitoxin for neutrahzation no mat-
ter whether its toxicity is high or diminished through age.
This phenomenon, which represents another of Ehrlich's
discoveries, was explained by assuming that the toxin
is composed of a haptophore, or binding group, and a
toxophore, or poison-bearing group. We must not fail
to consider, however, that we are dealing with a reaction
of the colloidal toxin with two different kinds of colloids
— with the antitoxin and with the constituents of the
cell.

Slight changes in the colloidal properties of a body
are, however, able to affect one part of its reactions and
leave another part free. An interesting example of this
is furnished by the behavior of colloidal gold toward
mercury, which I introduce because we are dealing under
these circumstances with reactions between elements,
reactions which no one will be inclined to attribute to
properties of special atomic groups. Colloidal gold
shows the properties of the pure metal, except that it

II 6 PHYSIC/IL CHEMISTRY IN MEDICINE.

does not form an amalgam with mercury. A similar
behavior can be mimicked in immunity reactions when
the haptophore groups are lost while the ergophore
groups are retained, or conversely. According to Bil-
LITZEr's observations, it is the fact that both metals
possess the same electrical charge which prevents the
formation of an amalgam. How easily, however, it may
be concluded from work with colloidal mixtures that
new chemical compounds have been produced is indicated
by the interesting fact that no less a man than Berzelius
did this in a study of colloidal gold and came to similar
conclusions, as did Ehrlich in a study of toxin-anti-
toxin mixtures. In gold-purple, which has been recog-
nized through an excellent investigation of Zsigmondy
as a mixture of colloidal gold and colloidal stannic acid,
the gold shows some variations in reaction. Misled
by this fact, Berzelius drew the conclusion that gold
exists in gold-purple as the oxide. It is a fact of great
importance that, in a mixture of two colloids A and B,
the properties of A disappear for many reactions, while for
others those of B disappear. According to the beautiful
experiments of Zsigmondy, in a mixture of orthostannic
and metastannic acids certain of the chemical properties
of the metastannic acid are concealed by the ortho-com-
pound, while toward other reagents the properties of the
ortho-compounds fall entirely into the background. Every
species of animal represents a different reagent toward
the same mixture of toxin and antitoxin, in which at one
time the effect of the toxine, at another that of the anti-
toxin, may hold the upper hand. Besides the phenom-
ena of neutralization, this fact has done most to sup-
port the belief in the existence of toxins having different

CH/1NGES H^ROUGHT IM PylTHOLOGY. Xi7

chemical compositions. We are able to recognize in this
only a general property of colloidal mixtures, the laws
governing which Zsigmondy has formulated in his inves-
tigations on Cassius's gold-purple in the following way:

" As most important I consider the recognition of the
fact that a mixture of colloids may, under certain circum-
stances, behave as a chemical compound, and that the
properties of one of the constituents of such a mixture
may be concealed through those of another. "

An especially remarkable illustration of the identity
of the neutralization of toxin with antitoxin and the
neutralization of two colloids is furnished by a phenomenon
which has also been discovered by Ehrlich, and a de-
scription of which we will introduce, with a few figures.

As the standard of a lethal dose of diphtheria toxin
is taken the amount which will kill a guinea-pig of 250
grams in from four to five days. Ehrlich added to one
immunity unit — that is, one cubic centimeter of antitoxin
serum, capable of counteracting the poisonous effects of
100 simple lethal doses — enough diphtheria toxin until
the mixture showed no toxic properties and indicated
the amount of toxin necessary to accomplish this by
Lq. This is usually less than one hundred, for the neu-
tralizing toxin has, as a rule, stronger neutraUzing than
toxic properties. Without a knowledge of the properties
of colloids one would expect that through the addition of
a simple toxic dose to the approximately neutralized mix-
ture Lo one would obtain a product capable of killing
a normal guinea-pig in from four to five days. Ehrlich
found, however, that several simple toxic doses have to
be added before the mixture again assumes the effect of
a free lethal dose. From our knowledge of the formation

Il8 PHYSICAL CHEMISTRY IN MEDICINE.

of aggregates in the process of colloidal precipitation, this
result was to be expected, for each of the toxin doses
added to Lo distributes itself over all the aggregates already
present, in consequence of which the mixture can attain
the unit toxicity only after several doses have been added
to it.

Through an investigation carried out by the chemist
BiLTZ, who has brought much light into this field, we
are famihar with phenomena observed upon inorganic
colloids that are entirely analogous to the Ehrlich
phenomena just described. Biltz studied quantitatively
the neutrahzation of arsenious acid by its well-known
antidote, iron hydroxide, of which the former represents
an electronegative radicle, the latter an electropositive
colloid. These investigations showed that a neutralized
mixture of the two — that is, one corresponding with the Lq
toxin-antitoxin mixture, therefore — still has the power of
uniting with arsenious acid and rendering several poison-
ous single doses harmless. A certain analogue of the
Ehrlich phenomenon in the field of precipitation is per-
haps to be found in the following. It is often possible, as
has already been pointed out, to dissolve a precipitated
colloid in an excess of the precipitating colloid. If the
addition of a colloidal solution to a neutralized precipitated
mixture corresponding with the Lq value of Ehrlich is
continued until the precipitate is redissolved, much more
of this colloid is required for this purpose than when a
colloid has added to it all at once an excess of a second
colloid. The intimate connection between this phenom-
enon and the behavior of a colloid when precipitated
through the addition of successive small doses of a second
colloid can readily be seen. The procedure is the same,

CHANGES BROUGHT IN PATHOLOGY. U4

only it is executed in different time and follows a different
scale.

We still have to consider a few possibilities which can
be deduced from the properties of differently charged
colloids and which are realized in the phenomena of
precipitation and in the phenomena of neutralizing a
toxin. One of these is the antagonistic effects that
small and large amounts of one colloid may have upon
a second. Number, size, and charge of the particles
of a colloid need not at all be related to each other in
such a way as to best favor neutralization. For this
reason different colloids are not precipitated with the same
ease. Under certain circumstances a decrease in the
electrical charge with a slight change in the size of the
particles may make a colloid more stabile. This may
be brought about through the addition of the right
amount of a neutralizing colloid. Gelatine in small
amounts may, for example, protect another colloid against
a precipitation which at a greater concentration it itself
brings about. A striking example, which until now has
been regarded only as a curiosity, of such an antagonistic
effect of one and the same colloid has been studied by
Jacoby, who found that the toxicity of crotin is increased
through the addition of small amounts of antitoxin, while
it is decreased and neutralized through the addition of
larger amounts.

A well-recognized conclusion to be drawn from the
behavior of colloids toward each other is the following:
It is by no means immaterial whether a colloid A has
small amounts of a colloid B added to it, or whether B
has small amounts of A added to it, and the aggregates
formed in the two cases wiU, in general, be different

120 PHYSICAL CHEMISTRY IN MEDICINE.

from each other. If we begin with an excess of toxin
to which successive small amounts of antitoxin are added,
the formation of aggregates will be able to follow a
different course than when the reverse is the case, when
we start with an excess of antitoxin. Ehrlich has
worked according to the first method, while Pick and
ScHWONER utilized the second method and came to the
conclusion that the laws governing the combination
between toxin and antitoxin were totally different from
those discovered by Ehrlich.* It can easily be seen
how through changes in only a few conditions an enormous
variety in the character of the colloidal reactions is
brought about, a behavior which is rendered apparent
through a consideration of the numerous well-studied
transitions existing between colloids and crystalloids.
A colloidal solution consists of a suspension of fine par-
ticles which have assumed an electrical charge through
giving off ions, just as have electrodes. If now the
suspended particles become steadily smaller, while at the
same time their electrical charge grows, they approximate
more and more the behavior of ions, until finally the
colloid passes over into a crystalloid, which dissociates

* The relations existing here can be illustrated also by examples of
protein precipitation. The precipitation of protein through the heavy
metals is dependent upon the neutralization of the negative protein
through the positive colloidal metallic hydroxide. The precipitates
formed are, however, not soluble to the same extent In excesses of the
individual colloids. The silver-protein precipitate is, for example, soluble
in an excess of protein, but not in an excess of the silver salt. In th^
former case we have to do with the formation of variable aggregates'
in the second with simple neutralization according to the manner
observed by Pick on his toxostabile sera when large amounts of anti-
toxin have toxin added to them.

CHANGES IVHOUGHT IN PATHOLOGY. 121

in aqueous solution into its strongly charged ions. In
this way mixtures of antagonistic colloids may approx-
imate in their properties salts that have arisen from
combinations between weak acids and weak bases.
Strictly speaking, we are compelled to assume the existence
of at least traces of such a similarity in order to account
for the traces of the free substances which we find beside
the aggregates in toxin-antitoxin mixtures. Some toxin-
antitoxin mixtures might, finally, because of their close
relationship to the crystalloid salts, contain the free sub-
stances beside completely neutralized aggregates. Accord-
ing to the investigations of Arrhenius and Madsen,
it is not impossible that such a state of affairs exists
in the case of their tetanolysin. We are acquainted with
an excellent experimental procedure for analyzing col-
loidal mixtures which Billitzer has employed in a study
of the relations existing in mixtures of the electropositive
red iron hydroxide and the electronegative yellow arsenious
sulphide. If an electric current is sent through such
a mixture, the completely neutralized aggregates do not
move, while the unneutralized aggregates, which carry
the electric charge of the colloid that is present in excess,
are slowly carried to the oppositely charged pole. The
traces of free colloid still present move most rapidly
and to opposite poles, where they evidence themselves
in this case through differences in color.

The transition from the complicated conditions exist-
ing in the case of the toxins to the more simple ones
in the case of the precipitating and agglutinating sub-
stances is rendered easy through the fact that in the
latter case we are dealing with the reactions of the rela-
tively well-understood proteins, or substances closely

t22 PHYSIC/IL CHEMISTRV IN MEDICINE.

related to them. With this we come to the question of
the colloidal properties of the proteins.

If an electric current is carefully sent through a solution
of egg albumin poor in salts, the protein migrates, as
shown by chemical analysis, to the positive pole. This
migration is very slight, and, since the protein particles
have been by optical means proved to be very smaU,
must be attributed to a weak electronegative charge
which they carry. A current of 250 volts for twenty-four
hours is required to render evident this migration of the
protein. The slight charge and the minuteness of the
particles explain the very considerable stability of the
protein toward precipitating ions. While the more
strongly charged colloidal metals and the majority of
the inorganic colloids are precipitated in weak salt solu-
tions, this is not true of protein. Through this fact is
rendered possible the vitally important existence of salts
and protein side by side. If the protein particles are
given a greater charge than they possess normally,
they are readily precipitable. In the presence of acids,
for example, the proteins assume a strong electropositive
charge, as evidenced by their very considerable migration
toward the negative pole, and are now readily precipitable
through electronegative colloids. We make clinical use
of this procedure daily when we first give dilute protein
solutions a positive charge through the addition of acetic
acid, after which, upon the addition of potassium ferro-
cyanide, they produce the well-known precipitate with
the colloidal negative ferrocyanic acid. In fact, in the
majority of the sensitive reactions for albumin, we have
to do with the effect of an oppositely charged colloid
upon a suitably electrified albumin.

CHANGES IVROUGHT IN PATHOLOGY. 123

The phenomena observed in precipitin and agglu-
tinin reactions are explained in a similar way. These
precipitations are possible only in the presence of salts.
If the protein or the bacteria under investigation are
mixed with the specific substances in a salt-free condition,
no reaction occurs. These specific substances may,
therefore, be looked upon as giving the colloidal proteins
the properties of sensitive colloids, that of being pre-
cipitated through small amounts of salt ions. According
to BiLLiTZER the specific substances serve in this case
only to give the coUoidal particles the charge and size
necessary for precipitation. Apparently all " sensitizing "
reactions encountered in the realm of the immune-body
reactions are explainable in a similar way.

A phenomenon frequently observed is furnished by the
above-mentioned tendency of colloids to show an opti-
mum proportion in which the two reacting colloids must
be mixed in order that they may be precipitated, and by
the inhibition of the reaction when an excess of the one is
present. Biltz has already pointed out the existence of
this generalized phenomenon of colloids in agglutination;
analogous phenomena may, however, be observed in
nearly all immune-body reactions. A remarkable exam-
ple of this kind is furnished by the " complement diver-
sion " (Komplemeniablenkung) observed by Neisser and
Wechsberg. These authors showed that bactericidal
immune sera showed a maximum effect, under other-
wise similar conditions, when they contained a medium
amount of immune substance. No doubt we can with'
profit now express the description of this phenomenon
in the smoother language of colloid chemistry. The com-
plex relations existing in the case of haemolysis, which

124 PHYSIC/IL CHEMISTRY IN MEDICINE.

may be brought about in a great variety of ways, also
seem clearer as soon as the exit of the coloring-matter
from the blood-corpuscles is looked upon as a rupture
of the colloidal haemoglobin-stroma compound. There
seem to exist, therefore, a large number of light-bringing
relations between immunity phenomena and phenomena
in colloid chemistry. Landsteiner in conjunction with
Jagic have been able to show the identity existing between
the mechanism of the haemolysis (studied by Kyes and
Sachs) brought about through the unknown cobra poison
and the mechanism of the haemolytic effect of colloidal
silicic acid. In this case a structurally uniform inorganic
colloid behaves like the hcemolytic amboceptor of the
side chain theory.

We are indebted to the same investigator for recog-
nizing a fact of still more general significance. The
proteins, and from many facts at our disposal the immune
bodies also, represent so-called amphoteric electrolytes;
in other words, substances which assume basic properties
in acid solutions and acid properties in alkaline solutions;
or, as shown by experiment, change the sign of their
electric charge with a change in reaction. There exists,
however, a zone between the extreme changes in the
sign of the electrical charge in which these hermaphrodite-
like substances respond to the slightest change in their
surroundings with an alteration in their electrical char-
acter, through which the existence of a large number of
finely graded relations between amphoteric electrolytes
differing only slightly from each other is rendered pos-
sible. This enormously changeable sensitiveness of such
substances, which may, according to circumstances, act
at one time as colloids having one kind of electrical

CHANGES IVROUGHT IN PATHOLOGY. 125

charge, at another time an opposite charge, is evidenced
by a large number of facts. With this conception of
the r6le of amphoteric substances, Landsteiner has
made the first rational attempt to explain the specificity
of the immune substances.

The chemistry of the colloids also allows us to
assume a freer position regarding the hypotheses
governing investigations in immunity. We can, how-
ever, touch upon this subject only briefly here, and
must limit ourselves to the question of toxins and anti-
toxins.

Every one is familiar with the dominating influence
which those views have at present attained that Ehrlich
has developed under the name of the side chain theory,
views which have not, of course, remained without con-
tradiction. The opposition which this theory has encoun-
tered has evidenced itself silently in the fact that a number
of investigators have continued to work independently
and without using it, and audibly through the ex-
pressions of various authors, more particularly Max
Grubee, who delivered an address in Vienna several
years ago.

As already stated, Ehrlich has, among others, utilized
the fact that the affinity of toxin for antitoxin and the
toxicity of toxin may vary independently of each other
to support the idea that two different groups, a hapto-
phore and a toxophore, exist in a toxin. These are
supposed to furnish the material substrate for the different
reactions of which one and the same substance is capable.
Ehrlich has at the same time distinguished between
different varieties of a toxin, originating in part from the
bacteria themselves, such as the toxones, and in part the

126 PHYSICAL CHEMISTRY IN MEDICINE.

product of time when the toxin is kept for a long time, such
as the toxoids. The differences observed in the toxicities
of a toxin when only partially saturated with antitoxin,
and those observed in the behavior of different animals
toward the neutralized toxins, all furnish important
support for these assumptions. But we must look upon
it as a fact well estabhshed through investigations on
colloids, that in their changes in state a part of their
reactions may be influenced, while another part may
remain untouched; that through the mixture of colloids
which neutralize each other manifold new, in no sense
preformed, aggregates can be produced, and that such
aggregates may at one time allow the effect of the one
colloid, — in this case the toxin, — at another time the other,
— the antitoxin, — to become apparent. Great differences
must in consequence result in the intensity and in the
picture of the intoxication in different animals. Against
Ehrlich's theory Arehenius and Madsen, as well as
Gruber and Pirquet, have set up the idea that in
toxin-antitoxin mixtures we always have to do with a
dissociation of compounds having only a weak affinity
for each other. This conception, which originated from
a top far-reaching generalization of a special case, allows
only of the existence of completely neutralized aggregates,
beside traces of their components, and is, therefore, in-
capable of explaining the multitude of experimental facts
which have been obtained in the study of different toxins,
more especially diphtheria toxin. Against this inade-
quate assumption arose the strength of the Ehrlich
theory, which has rendered the great service of having
been the first to fix in the minds of investigators the
newly discovered and scarcely calculable varieties of

CHANGES IVROUGHT IN PATHOLOGY. 127

facts won through a study of immunity. But the facts
of colloidal chemistry, together with advances in the
investigation of immunity, show clearly, it seems to me,
that the Ehrlich assumptions, in spite of the many
variables introduced into them, do not at all suffice to
explain the phenomena actually observed.

It is, for example, an easy matter to foretell even now
that through changes in the manner and the rapidity with
which toxin and antitoxin are mixed, and through a
proper choice of animals, the varieties of toxins that
have been assumed to exist by Ehrlich might easily be
increased indefinitely.

It can be readily seen, too, how difficulties arise in the
expansion of any theory that is based upon crystalloidal
cjiemistry. With Ehrlich it is the application of syn-
thetic organic chemistry, with his opponents, the appli-
cation of a special case of the dissociation of salts that
iinally constitutes too narrow a frame to receive the
entire picture of facts. Insufficient also was the attempt
of Danysz and Bordet to explain the behavior of toxins.
The latter especially tried in his brilliant way to sup-
port his theory through an analogy with the process of
dyeing, which we now know to be a colloidal reaction.
In this theory the correct assumption that toxin and
antitoxin are able to unite in different proportions was
made; it could, however, be of value only as a hypo-
thetical objection, as it included only some of the possi-
bihties and was unable to explain, while lacking the broad
base of other facts in colloidal chemistry, the variety of
observations made on toxins. If we disregard my first
brief suggestion, pointing out the relation between im-
munity reactions and colloidal changes in state, Lanp-

128 PHYSIC/iL CHEMISTRY IN MEDICINE.

STEINER was the first who independently, and recogniz-
ing the goal toward which he was travelhng, studied this
connection between immunity and colloidal reactions
experimentally. Landsteiner has done this more espe-
cially for agglutination and haemolysis, while I have
attempted to do it for the true toxins and their anti-
toxins.*

The extensive importance of colloidal chemistry for
biology is by no means limited to the highly interesting
field of immunity. This can be shown to be true to-
day, however, on only a few examples.

We are acquainted with a remarkable kind of separa-
tion of solid colloids through the action of surface tension,
an understanding of which is of importance in many
problems of pathology.

The nature of these forces which evidence themselves

* I am, of course, aware that valuable beginnings have already been
made to apply the facts of colloidal chemistry to the teachings of toxins
and antitoxins, and nothing is further from my mind than to disregard
the great credit which more especially BiLTZ deserves in this respect. I
would, nevertheless, like to emphasize that my conceptions are inde-
pendent ones which developed gradually — as such things must — in
the course of my investigations of organic colloids. They form only
a special case of the analogy which I have for more than a decade
tried to show exists in the most varied subjects between changes in the
state of colloids and the processes that go on in living matter. My
treatment of the subject is, moreover, directed toward numerous until
now scarcely prized, but apparently most important, sections of the
problem.

For the parallelism between the precipitation of a colloid and the
neutralization of a toxin by an antitoxin which I have given above,
the experiments of Coehn, according to whom toxin and antitoxin
wander toward the same side in the electric current, are of no importance,
as I have been able to show in my unequivocal investigations,

CHANGES fVROUGHT IN PATHOLOGY. 129

at the surfaces of all liquids is familiar to every one.
While the particles within the liquid are surrounded on
all sides by particles of the same kind and are in con-
sequence in a state of equilibrium through the uniform
distribution of the attractive forces about them, this is
not the case with the surface particles. For here the
forces which act upon the particles and are directed
toward the centre of the liquid encounter no correspond-
ing antagonistic force. In consequence of the effort of
the surface particles to follow the attraction toward the
centre, the surface endeavors to become as small as
conditions will permit. Many substances are able
through solution in a solvent to bring about a decrease
in its surface tension. Under these circumstances the
liquid may follow its tendency to decrease its surface as
much as possible by allowing the particles of the sub-
stance which decrease the surface tension to take the
place of the particles of the liquid which are being pulled
toward the centre. In this way the surface becomes
gradually richer in the dissolved substance. In the end
the concentration of the sohd particles at the surface
becomes so great that a film is formed which may be
removed and which is renewed after each removal. This
behavior, which has been studied in great detail by
Ramsden, is shown chiefly by the colloids, more especially
protein solutions. If such solutions are shaken together
with air or immiscible liquids, such as oil, chloroform, or
mercury, all the dissolved colloid can finally be precipi-
tated through the surfaces which are constantly re-
newed.

That this process should be demonstrable most clearly
on colloids and especially on protein solutions is due to

13° PHYSICAL CHEMISTRY IN MEDICINE.

two still other conditions, according to our judgment.
If the coagulation through surface tension is studied in
detail we find that we have to do with an extreme increase
in the concentration of a solution, or, what amounts to
the same thing, with the expression of the solvent from
such a solution. The energy necessary for this, which,
as is well known, expresses itself in osmotic pressure, is,
however, in the case of the colloidal substances, exceed-
ingly small in contrast to that observed in crystalloidal
substances. And so it is that the colloids are especially
well able to form solid surface films quickly and exten-
sively.

A second important condition is the electrical charge
of the colloidal particles. The greater this is, the
more powerful are the repellent forces between the sim-
ilarly charged particles that antagonize the surface ten-
sion, which tends to crowd them together. The proteins,
as we know, carry only weak charges of electricity and
furnish in consequence favorable conditions for the col-
lection of the particles on free surfaces. To the formation
of such solid protein films Ramsden attributes the well-
known formation of a film on milk and the behavior of
the fat droplets of milk, which have long been imagined,
from their physical and chemical reactions, to be sur-
rounded by a denser film of protein. In pathology similar
phenomena might play an accessory part in air and fat
embolism. It can readily be shown experimentally that
the migration of air bubbles in tubes which are filled
with protein solutions meets with unexpectedly great
difficulties. In the living organism the danger of the
entrance'of air bubbles or fat droplets into the circulation
is dependent, at least in part, upon similar processes.

CHANClES U^ROUGHT IN PATHOLOGY. t^i

In both cases we have to do with a soHdification of their
surfaces which makes the emboh behave, in spite of their
gaseous or Uquid character, Hke solid obstructions to the
circulation.

In a new light appear also, through a study of the
colloids, the extracellular phenomena observed in the
development of solid supporting substances, such as car-
tilage and bone, and the precipitation of crystalloidal sub-
stances in the tissues connected with them. The latter
question, which is also of great pathological importance,
has aroused much interest in the past decade, but it does
not seem to have been possible to get far beyond the
recognition of the difficulties which the solution of the
problem encounters. The nucleus of the question seems
to lie in the fact that we are dealing, on the one hand,
with simple processes of crystallization, while, on the
other hand, formative influences on the part of the cells
and functional adaptations to the forces destined to act
upon them seem to be clearly discernible in the arrange-
ment of the crystallization. Besides the studies of nu-
merous investigators on the process of ossification, it has
been Biedermann, more especially within recent years,
who, through his excellent work on the shells of molluscs,
crustaceans, and insects, has furnished much important
experimental material.

The importance of colloidal chemistry in these prob-
lems evidences itself at once in that first and most important
question of the conditions under which the scarcely
soluble salts are kept in solution and precipitated in
suitable places. The colloids constitute, as shown by
many experiments, an excellent means under certain
.circumstances of keeping slightly soluble salts in solution,

t3* PHYSICAL CHEMISTRY IN MEDICINE.

in that they themselves unite with the salt ions and form
aggregates without necessarily being precipitated, when
the size and charge of the particles, as in the case of
protein, are small. It is, for example, an easy matter
to show that by no means inconsiderable amounts of
barium sulphate, one of the least soluble of substances,
can be kept in solution in serum. If now, through the
metabolism of the cells, the dissolving colloids are de-
stroyed and not replaced, supersaturation and finally
precipitation of the crystalloidal material can easily be
brought about, after which, as is so often the case, crystals
that have once been formed may serve as centres for
further crystallization. This conception seems to make
clear the connection between crystallization and the vital
activities of the cells, as evidenced by the organization
of the supporting tissues. It renders intelligible also the
regularly observed phenomenon that a small portion of
colloidal material, which is no longer able alone to keep
the salts in solution, always crystallizes out with them.
In this same direction is to be sought the connection
between pathological processes of calcification, deposition
of uric acid, and tissue metabolism. If the beautiful
investigations of Paul and His on the conditions deter-
mining the solubility of uric acid are not of that im-
portance for the pathogenesis of gout which they had
hoped, then this is dependent primarily upon the fact
that the same conditions of equilibrium which exist in
the organism in the presence of colloids were not estab-
lished in their experiment.

A special problem is presented by the origin of the
great solidity of cartilage and bone, or rather their
peculiar colloidal intercellular substance. These tissues

CHANGES IVROUGHT IN P/itHOLOGY 133

possess a characteristic, highly concentrated ground sub-
stance, connected with structures which represent, in
the main, thin layers deposited abcut the formative cells
or their delicate protoplasmic extensions. A very in-
structive example of this kind is furnished by the exceed-
ingly hard cartilage of myxina, in which Schaffer was
recently ab^ to demonstrate layers of great dehcacy sur-
rounding the cartilage cells. In such thin precipitation
layers there can arise, when they absorb or gradually
give off water, tremendous pressures which might well be
of great importance in hardening the entire mass. Ac-
cording to experiments which I have carried out in conjunc-
tion with Dr. LuDWiG Mach, it is an easy matter to give
protein a bony hardness by pressing it into a steel tube
and heating it almost to its decomposition temperature.
Interestingly enough, this ability to form a material
sufficiently hard to be worked with instruments is con-
nected with a certain integrity of the albuminous sub-
stance and is lost entirely when the albumin is decomposed
beyond the albumose stage. By mixing with the protein
the fine dust of insoluble calcium salts in the proportion
in which these are found in bone, the solidity of the prod-
uct can be markedly increased.

The pressures exerted by thin layers of colloid under
suitable circumstances cannot well be determined. That
these may attain high value is shown by experiments of
Cailletet, who was able to render glass permanently
doubly refracting through thin layers of gelatine which
were allowed to dry upon its surface.

With this example, to which many others might be
added, illustrating the connection between physico-
chemical investigations and morphology, I shall close

t34 PHYSICAL CHEMiSTkY Ihl MEDICINE.

what I intended to offer in tlie line of experimental
facts.

If I have succeeded, as I hope, in convincing you also
that the application of colloidal chemistry to physiology
and pathology justifies great expectations, it might be well,
in conclusion, to seek in the development and the present
state of the colloid problem a measure for our faith in
its future contributions.

As is well known, the difference between crystalloids
and colloids appeared to be so radical a one to Graham
that to characterize it he wrote the following oft-quoted
sentence :

" The difference between these two kinds of matter is
like that which exists between the material found in a
mineral and that found in an organized mass."

The discoverer of the colloidal world has since been
reproached, and certainly unjustly, for having so strongly
emphasized the differences between crystalloids and col-
loids. For every discovery depends primarily upon a
recognition of the most apparent differences between the
new phenomenon and the facts well known at the time.
This contrast is the most powerful stimulus to investi-
gation. It is the source of the problem, which is not
solved until the apparent contradictions to it have been
set aside and those fine threads have been unravelled
which connect the newly found with the old. Our prob-
lem also developed in this way, and we have seen how
the connection between colloids and crystalloids was
established through a recognition of their principal
characteristics and their gradations. One is almost
inclined to believe that the possibility of explaining

CHANGES iVROUGHT IN PATHOLOGY 13S

organized living matter through his colloidal condition
seemed close at hand even to Graham.

The continued application of colloidal chemistry to
biological problems soon shows, however, the limits which
are set upon it. We are able to see this in the case of
the antibodies also. How much a knowledge of the
colloids contributes toward an understanding of their
varied reactions and even the solution of the riddle of
their specific sensitiveness toward each other seems most
apparent. Our new methods are of no use, however,
as soon as we try to discover the secret mechanism by
means of which the cells produce a suitable antitoxin
against any definite toxin. To repeat the words of
Gruber: " Whence comes this astonishing purposeful-
ness, this predetermined harmony, this specific adapta-
tion, of substance to antisubstance, which one would
a priori consider entirely impossible?"

It must seem remarkable that, instead of exhausting
one's self in chemical analogies, one has not sought a more
intimate connection * with those phenomena which arise
from a direct observation of living matter. Beginning
with his classical investigations of the physiology of the
senses, Ewald Hering has developed a theory of the
changes that go on in living matter, which through abun-
dant use of the principle of mobile equilibrium has fore-
shadowed modern chemical dynamics. We need only to
recall how, according to Hering, the^ sensations of
antagonistic colors correspond with antagonistic reactions
in the visual substance which mutually suppress each
other. When we consider that the substances of the

* Only Landsteiner makes a similar suggestion.

136 PHYSlC/iL CHEMISTRY IN MEDICINE.

red process produce in their surroundings or after them
the antibodies of the green pirocess,* and that these prod-
ucts neutralize each other physiologically, just as do toxin
and antitoxin, the analogy between the two phenomena
becomes very apparent.

In spite of a few differences, are not the chemical phe-
nomena of the production of a lasting complementary
after-image and the formation of an antitoxin essentially
the same? Even in Ehrlich's bold conception of the
regenerative hyperplasia of the side chains, there seems
to be mirrored only a part of that truth which Hering
grasped so deeply.

No doubt every attempt to follow these questions
further soon brings us to the solid barriers of our present
knowledge, which do not open even to the storm of
physical chemistry. And if some investigators, such as
the followers of the energetic school, carried away by
physical chemistry, have believed that they had hoisted
their flag upon the outermost pole of biology, it has
always been found that this was due to a failure to dis-
criminate between the boundaries of the known and the
unknown. We have therefore learned to be satisfied
with having arrived at a clear conception of the problem
before us, just as the chemist who must first carefully
free an unknown substance of all its impurities before
he holds the pure crystal in his hands. As yet the way

* For comparison the white-black process might better be used, because
this leads to black in only one direction, namely, over white to black.
In the case of the antibodies also we obtain the antibody only by way
of the toxin and not conversely. The exceptions mentioned in the
sentence following the one to which this note refers have to do with
another point which will be discussed in detail at some future time.

On the electrical charge of protein. I'il

is not apparent along which it will one day become
possible to discover its structure.

7, On the Electrical Charge of Protein and its
Significance.*

The surprising development of the chemistry of the
colloids, which in no small part has been incited through
its great biological importance, has reacted most benef-
icently upon the latter science and many problems in
general physiology. I have repeatedly had the honor
of bringing before this society reports of that daily
increasing territory in which the study of colloidal reac-
tions touches upon or coincides with that of the struc-
ture and changes in state, and in consequence the func-
tions of the cells and fluids of the organism.

If one attempts to survey the long series of colloidal
substances and to study along the lines common to all,
it must become apparent to every one how markedly
their typical properties vary in degree in spite of a certain
identity in behavior in the matter of diffusion, for example;
and how the presence or entire absence of certain prop-
erties changes the whole character of a colloidal reaction.
This holds not only for the fundamental differences
between the solid and jelly-like colloids, or gels, and the
liquid colloids, or sols, but also for the individual mem-
bers of each of these groups. In fact, we see that among
the sols the proteins constitute an almost independent

* From Naturwissenschaftliche Rundschau, 1906, XXI, p. 3. Ad-
dress delivered before the Morphologisch-physiologische Gesellschaft in
Vienna, December 5, 1905.

13^ PHYSICAL CHEMISTRY IN MEDICINE.

group because of numerous properties that they have
in common. This behavior will, no doubt, have to be
taken into consideration by any one who attempts to
extend the analogy of the behavior of colloids in general
to that of the colloidal substances in the fluids and tissues
of the organism. For it has been found that the reactions
of all colloids do not approximate the reactions that
occur in the living body, in consequence of which it has
proved necessary, in the attempt to discover such anal-
ogies, to cling to the colloidal products of living matter
itself, namely, to the proteins.

The value of an accurate knowledge of the proteins
as a means of understanding the inner workings of life
phenomena has at different times been differently
estimated by physiologists. While a time once existed
when many believed that a knowledge of protein structure
would by itself give us an explanation of the peculiar
metabolism of living matter, we have to-day, when the
beginnings of a protein synthesis are apparent and many
important constituents of the protein molecule have been
isolated, become quieter and soberer in our expectations.
Largely independent of a complete insight into the
chemical composition of the proteins is the knowledge
of their physico-chemical properties, which can only be
obtained through utilization of different methods. This
knowledge gives us an immediate understanding of the
majority of the general properties and functions of the
tissue fluids, and is applicable without reserve to those
cases also in which no longer living but more or less
coagulated cell material serves as an object of research.
In the end, however, such a knowledge also renders easy
an insight into the changes that take place in living

ON THE ELECTRICAL CHARGE OF PROTEIN. 139

cells in consequence of the frequently recognizable paral-
lelism between changes in state in colloids and changes
in physiological function. This is no doubt dependent
upon the fact that the colloidal constituents of living
matter show, at least in part, a physico-chemical identity
with the properties of isolated proteins.

It is our purpose to-day to give as far as possible a
survey, based on the personal investigations of many years,
of the more important physico-chemical properties of the
proteins, and to point out, at least in a cursory way, the
relation between these properties and many biological
phenomena.

II.

As in the case of crystalloids, so both the behavior in
solution and the behavior in the solid precipitate serve
to characterize the colloids. An accurate knowledge of
the conditions which determine their precipitation has
recently assumed great importance in the study of the
colloids.

We can to-day regard it as settled that between a true
■suspension and a colloidal solution there exists only a
difference in the size of the suspended particles. In a
colloidal solution they are always so small that through
their friction upon each other they are kept in suspension.
The colloidal particles seem, therefore, to be no longer
affected by the force of gravity, just as is the case with
those smallest dust particles in the air that become visible
only in the sunlight. The colloidal particles can also be
rendered visible in many cases by utilizing intense illu-
mination methods. Even though gravity is unable to
cause a clumping of the colloidal particles, other forces

140 PHYSIC/IL CHEMISTRY IN MEDICINE.

are readily able to do so, especially electrostatic forces,
with which we are going to deal chiefly to-day.

As is well known, many crystalloids, such as salts, acids,
and bases, give off their constituents at the electrodes
when a current is sent through them. We call such sub-
stances electrolytes, and a much-used theory assumes, as
is well known, that there exist in aqueous solutions of
electrolytes, besides the electrically neutral molecules, the
electrically charged dissociation products, the so-called
ions. Upon the migration of these ions toward the
electrodes is dependent the conduction of electricity. The
ions are said to be positive when they wander to the
negative pole to be discharged and deposited, and negative
vv'hen they wander to the positive pole. In this way the
H ion, which all acids have in common, is electropositive,
the remaining portion of the molecule electronegative,
In the same way the OH ion, which all alkalies have in
common, is electronegative. The strength of an acid
or a base is determined by the concentration of these
ions.

Colloids behave in an entirely diflEerent way. If an
electric current is sent through a pure colloidal solution,
the colloidal particles move, in contrast to the electrolytes,
in only one direction. They accumulate at either the
positive or negative electrode, from which we conclude
that they have either a negative or a positive charge. A
connection has shown itself to exist between this electrical
charge and the process of precipitation. Several inves-
tigators, more especially Biltz, have shown that only
oppositely charged colloids mutually precipitate each
other, and that the entirely precipitated colloidal material
no longer has an electrical charge, that is to say, no

ON THE ELECTRICAL CHARGE OF PROTEIN. 141

longer moves with the electric current. Even before
BiLTz's work other observations had indicated the impor-
tance of electrical conditions for colloidal precipitations
and had formed the starting-point of theoretical explana-
tions. The colloids seem, in general, to be precipitable
only through electrolytes ; non-electrolytes such as sugar
or urea have no precipitatiag effect even upon very un-
stabile colloids. Hardy and Bredig have, in accord with
the theory of electrocapillary phenomena, developed the
idea that there exists an antagonism between the forces
of surface tension, which, according to Bredig, cause
the colloidal particles to coalesce, and the electrical charges
that the colloidal particles carry, in such a way that only
after the electrical charge which causes the particles .to
repel each other has been removed can the surface tension
attain its maximum. If a discharge of the colloidal
particles is brought about through the addition of the
oppositely charged ions of electrolytes, then the optimum
of precipitability is produced at the same time, and a
precipitate is formed.

According to a different theory developed by Billitzer,
surface tension does not play the role attributed to it by
Hardy and Bredig. If oppositely charged ions are
added to a colloid, the colloidal particles collect about
these ions through electrostatic attraction. In this way
aggregates are finally formed of sufficient size to fall to
the bottom. According to this view, with which many
facts agree that contradict the first-mentioned theory, a
colloid carrying no electrical charge should be capable
of precipitation only with difficulty, as its particles exert
no electrostatic forces. One can regard these theories
as one pleases; no doubt the necessity of testing the

142 PHYSICAL CHEMISTRY IN MEDICINE.

electrical behavior of dissolved protein in order to obtain
a better insight into its colloidal reactions will be apparent
to every one. I planned, therefore, to obtain, first of all,
native protein as free from electrolytes as possible in
order to have a stock material for testing the effect of
different conditions upon the electrical behavior of pro-
tein. From the standpoint of general technic, moreover,
it seemed of great value to use a material which through
extreme dialysis, or this in combination with repeated
freezing, had been rendered as free from salts as possible.
The electrical conductivity rendered possible through
the presence of ions is very great when compared with
that produced through the migration of colloids. In
order to render the latter apparent, very strong currents
must therefore be used, which in the presence of salts
lead to a great heating of the solution and also to a
masking of the phenomenon sought for through the
action of the products of electrolysis. In our experiments
we used, for example, a current of 250 volts and 6 amperes.
In this current ordinary blood serum burns, while our
salt-free serum allowed only a few millionths of the
current to pass through it. To test the migration of the
colloid in the electrical current we utilized an apparatus
similar to the one successfully used by Billitzer in his
beautiful experiments. Three beakers of uniform size
were connected with each other by means of siphons.
The electrodes dipped into the two outer beakers, while
the middle one served as a control, the contents of which
should, of course, not vary. At the conclusion of the
experiment the nitrogen in all three of the vessels was
determined by Kjeldahl's method.

The results of a long series of electrical convection

ON THE ELECTRICAL CHARGE OF PROTEIN. I43

tests, in which the effect of concentration and other con-
ditions was also determined quantitatively, may be thus
summarized :

1. A protein which has been carefully freed from
electrolytes shows no recognizable electrical charge and
does not wander toward one of the two electrodes, even
when subjected to an electric current for twenty-four
hours.

2. Each of the albuminous constituents of the serum —
serum albumin, pseudoglobulin, euglobulin — shows no
electrical charge in the absence of electrolytes.

3. The addition of neutral salts of the alkalies or the
alkaline earths does not impart an electrical charge to
the uncharged protein.

4. Traces of acids impart a positive charge to protein
through their positively charged hydrogen ions; alkalies
a negative charge through their hydroxyl ions.

5. Salts with an alkaline reaction toward litmus, such
as carbonates and the secondary and tertiary phosphates
of the alkali metals, render protein electronegative; acid
salts give it a positive charge.

6. This charge is independent of the end reaction of
the medium. A proper mixture of protein and sodium
bicarbonate is faintly acid toward phenolphthalein, neutral
toward litmus; the protein has, however, a strongly
negative charge.

III.

Let us consider, first of all, the fact that our salt-free
protein carries no electrical charge. How does it behave
toward the salts of the heavy metals, such as Cu, Fe, Zn,
Pb, Hg, which are all regarded as general precipitants of

144 PHYSICAL CHEMISTRY IN MEDICINE.

protein in even very dilute solutions ? All these salts are
characterized by the fact that they undergo great hydro-
lytic dissociation in dilute solution — in other words, take
up water and break up into their metallic hydroxide and
their acid. According to different investigations which
agree in their conclusions, the dissolved colloidal electro-
positive metallic hydroxide is the real protein-precipi-
tating constituent. If now it is true that colloids mutually
precipitate each other only through the opposite electrical
charges which they carry, then the uncharged protein
should in general not be precipitable through electro-
positive heavy metals. It can be easily shown that our
uncharged protein, in contrast to native protein, cannot
be precipitated through salts of Fe, Cu, Hg, Pb, and Zn.
This experiment harmonizes, therefore, with Billitzer's
theory, according to which protein is very stabile in the
uncharged state.

Let us now turn to something else. As is well known,
alcohol is an excellent precipitant for proteins. Since
alcohol as a non-electrolyte furnishes practically no ions
in aqueous solution, its precipitating power cannot rest
upon electrical grounds. The matter may be explained
in the following way: Proteins are not soluble in alcohol,
but they are readily miscible with water. The proteins
are therefore crowded out of their solvent through the
addition of much alcohol, in the course of which their
small particles, by virtue of their surface tension, coalesce
into larger aggregates in a way similar to the clumping of
the particles of a fresh, fine precipitate into larger masses
with time. We will therefore not be surprised to see
that our uncharged protein is readily precipitated by
alcohol, ■ But what will happen if we first give this protein

ON THE ELECTRICAL CHARGE OF PROTEIN. 14S

a positive or a negative charge? We create in this way
repellent electrical forces between the smallest particles
of colloidal material, which will work against the surface
tension, which tends to make them coalesce and pre-
cipitate. If the protein is given an electrical charge
through the addition of a little acid or alkali, then, as
experiment shows, its precipitation through alcohol is
inhibited or entirely prevented. We may imagine from
this that for precipitation through non-electric forces
conditions must exist somewhat similar to those which
Hardy and Bredig believed to exist for electrolytes.

In passing it may be mentioned that our uncharged
protein is readily coagulable through heat and, as may
be imagined, through acetic acid-potassium ferrocyanide,
phosphotungstic acid, and phosphomolybdic acid. In
the first case we are dealing with an as yet not entirely
understood chemical change in the protein brought about
through the high temperature. In the second case the
protein is first charged positively through the acetic acid,
to be precipitated later by the various oppositely charged,
probably colloidal, acid ions.

These conversion and* precipitation experiments are
able to answer the question. In what electrical condition
do the proteins exist in the blood and the tissue fluids?
Since alkalies impart a negative, acids a strongly positive,
reaction to proteins, one is able to draw conclusions from
the reactions of animal fluids as to the charge of the
proteins contained in them. Modern investigations have
solved for us the question of the reaction of the tissue
fluids, or, to put it more accurately, the relation between
their content of H and OH ions. According to these
investigations, the body fluids are neutral. The free

146 PHYSICAL CHEMISTRY IN MEDICINE.

hydrogen and hydroxyl ions exist in them in the same
proportion as in water. This is shown most harmoni-
ously not only through tests with proper indicators,
such as phenolphthalein, but also through electrical
measurements. Litmus, which was formerly employed
as an indicator, is itself too strong an acid to show
the presence of the weak acids of the tissue fluids,
and indicates therefore an alkaline color reaction. If
we remember that uncharged protein cannot be pre-
cipitated through the positively charged heavy metals,
while the proteins of the tissue fluids can at once be
precipitated by them, the conclusion is inevitable that
native protein carries a negative charge. This charge
can be derived only from the hydroxyl ions that are split
off from the salts of the serum, which, in harmony with
the above-described experiments, must be the carbonates
and phosphates. If sodium bicarbonate is added to fresh
non-charged protein, this assumes a strong negative
charge even though the resulting mixture is neutral
toward litmus and acid toward phenolphthalein. In an
experiment conducted with such a sodium bicarbonate-
protqin, it was found that the relation of nitrogen at the
cathode was to that at the anode as 3:5; while the
nitrogen content of the middle beaker was expressed by 4.

IV.

We are now acquainted with sufficient facts to study
more closely the conditions for the precipitation of
native electronegative protein, and to compare these
whenever necessary with those of uncharged or artificially
charged protein.

ON THE ELECTRICAL CHARGE OE PROTEIN. I4?

Let us consider, first of all, the precipitation of native
protein through neutral salts of the alkali metals and see
in how far the ions play an immediate r6le. The follow-
ing table, in which + indicates that the protein is pre-
cipitated, — that it is not precipitated, gives a good survey
of these relations.

In the vertical row of the table are arranged the positive
ions in the order of their decreasing power to precipitate
protein; in the horizontal row are arranged the negative
ions in the order in which they inhibit the precipitation.

S" — > Increase in inhibition.

OJ o

a

u

p

i

SO4

CjHaOz

01

NO,

Br

I

CNS

Li

+

+

• +

-1-

Na

.+

+

+

+

-

-

-

K

+

+

+

-

-

-

"-

NH,

+

-

-

-

-

-

-

The antagonism between cation and anion is indicated
by the appearance of one and the same ion in salts which
precipitate and those which do not precipitate protein —
for example, sodium as the sulphate and as the bromide;
and if we go along still further in the sodium series the in-
hibiting effects of iodide and sulphocyanate ions have so
much the upper hand that the presence of these salts pre-
vents the precipitation of protein through other salts. As
an actual matter of fact, the inhibiting salts were discov-
ered as a consequence of the assumption of antagonistic
ion effects. That it is the positive metallic ions which are
the bearers of the precipitating power may be concluded
from the fact that native protein carries a negative charge.

14^ PMYSIC/iL CHEMISTRY IN MEDICINE.

Let us now ask what will happen when we try to pre-
cipitate with neutratl salts protein that has been rendered
electropositive through the addition of an acid. Theoret-
ically we would expect that under these circumstances
the negative ions of the salts would precipitate the pro-
tein, while the metallic ions would have an inhibiting effect.
And as an actual matter of fact, we find that when the
protein has been acidulated the formerly inhibiting
bromides, iodides, and sulphocyanates become powerful
precipitants, and those salts which formerly precipitated
now inhibit. In other words, the signs cf the above table
are reversed; only the precipitating effect of the negative
ions increases in the same order as their inhibiting effect
did formerly, while the order of the now inhibiting
positive ions is just the reverse of that given in the table.

The following interesting fact has ' also been found.
The same reversal in ionic effects as is brought about
through acids can also be brought about through the
addition of the salts of the alkaline earths, Ca, Ba, and
Sr, to the native protein. One may conclude from this
that a change in the sign of the charge of the protein
solution from the negative to the positive occurs in this
case also. According to our conversion experiments,
however, uncharged protein does not assume an electrical
charge through the presence of the neutral salts of the
alkaKne earths, and in consequence we have to discover
whether these do not bring about an acid reaction by
meeting with the salts contained in the animal fluids.
In order to answer this question, let us consider the
changes that are brought about through the addition of
calcium chloride to a solution of sodium bicarbonate
or disodium phosphate. As is well known, the two salts

ON THE ELECTRICAL CHARGE OF PROTEIN. I49

last mentioned have an alkaline reaction in that upon
solution in water they increase the number of OH ions
present in it. This is brought about through the fact
that they combine with water and spHt hydrolytically into
sodium hydroxide and carbonic and phosphoric acids.
Since, however, sodium hydroxide is a stronger base than
carbonic and phosphoric acids are acids, more OH ions
exist in solution than H ions. If now we imagine the
sodium hydroxide to be replaced by the much weaker
calcium hydroxide, then the concentration of the free
OH ions will fall immediately. The chemical reaction
between the alkaline earths added to an animal fluid
and the phosphates and carbonates contained in it must
also act in this way — in other words, toward the establish-
ment of an acid reaction in the fluid. It can readily be
shown even in an experiment with native protein to which
an alkali has been added and which reddens phenol-
phthalein very strongly that an acid reaction is produced
in the mixture as soon as calcium chloride is added to
it, as indicated by disappearance of the red color. In
this way the identical effects of acids and alkaline earths
upon negatively charged protein have found a ready
explanation.

That the alkaline earths can act only indirectly through
their effects upon the salts of the serum is shown most
strikingly by an experiment in which calcium chloride is
added to salt-free serum. If sodium iodide or sodium
sulphocyanate is added to this mixture, no precipitate is
produced. If, however, the protein is rendered electro-
positive through the addition of a little acid, then the
sulphocyanate at once brings about a coarsely flocculent
precipitate.

15° PHYSICAL CHEMISTRY IN MEDICINE.

We will end with this our discussion of observations
which indicate unequivocally the great importance of
the electrical condition of the proteins for their reactions.
Since this electrical condition of the proteins is deter-
mined solely through the non-neutral salts of the tissue
fluids, we can readily see how important a proper balance
of these salts must be for the organism. One will not
err, therefore, in discovering, in the purposeful arrange-
rrients existing in the animal body against the presence of
too large amounts of acid, instruments of protection for
the proper physiological electrical charge of the proteins.

We are, no doubt, justified in presupposing that con-
ditions within the cell are very analogous to those found
in the tissue fluids. Hober, for example, has found in
an excellently arranged experiment that the red blood-
corpuscles move to the anode — in other words, are nega-
tively charged under normal circumstances and retain
this charge under a great variety of conditions. If they '
possess in this wise an electrical charge which is similar
to that of the blood serum, they can nevertheless show
variations in their behavior, as, for example, under the
influence of acids. In an isotonic cane sugar-sodium
chloride mixture they become electropositive under the
influence of carbonic acid, a change that is again reversed
when the carbonic acid is removed. It seems, therefore,
as though the red blood-corpuscles suffer a complete
change in electrical reaction when they pass through
the pulmonary circuit.

The essence of the electrical condition of cells can be

ON THE ELECTRIC/1 L CH/IRGE OF PROTEIN. 151

demonstrated without difficulty on the electrical properties
of the proteins. Every attempt to explain the phenomena
observed ends with the question, How does a protein
particle floating about, for example, in a dilute hydro-
chloric acid assume an electropositive charge when the
acid contains, as we know, an equal number of positive
H ions and negative CI ions ? It is evident that this is only
possible when protein takes up more positive H ions than
negative CI ions, or, as it is ordinarily stated, when the
protein is semi-permeable to ions. The same holds in
the case of alkalies for the OH ions. Many cells seem
to have this same power, and Hober has rendered it
probable that red blood-corpuscles become positive when
treated with carbonic acid, because they become per-
meable for some of the negative ions which they contain
and which leave the red blood-corpuscles, thereby allowing
an excess of positive ions to remain behind.

OsTWALD was no doubt the first to try to discover
in the semi-permeability for ions the cause of the electrical
phenomena observed in animal cells, and this suspicion
has recently attained a very considerable degree of proba-
bility. Oker-Blom and later Bernstein have further
developed this idea for the electrical phenomena observed
in muscle and nerve, and sought experimental evidence
for its support. If we imagine the surface of the muscle
fibril to be more permeable for the positive ions than for
the negative ions contained in the muscle, then the muscle
must carry a positive charge externally and a negative
one within. When two electrodes are laid upon the
surface of an uninjured musck, points having a different
electrical potential are not touched, and the muscle
shows no current.

IS2 PHYSICAL CHEMISTRY IN MEDICINE.

As soon, however, as the one electrode is placed upon
an artificially produced cross-section of a muscle — in other
words, along the contents of the fibrils — ^the well-known
current of rest passes in the outer circuit toward the
negative exposed portions of the muscle plasma. The
experiments of Bernstein have shown that this current
follows very accurately the typical laws governing ionic
concentration chains. The same holds for the current
of rest in nerves. Stimulation of the nerve brings about
the well-known phenomenon of negative variation, in
that it alters the permeability for ions.

Similar phenomena are observed in the electric organ
of the torpedo, which has been studied by Bernstein
and TscHERMAE. This organ consists - of numerous
plate-like cells arranged upon each other in a way similar
to the plates of a voltaic pile and possessing a nervous
end brush upon one side only.

When through nervous stimulation this side becomes
more permeable for negative ions, an electric shock is
produced through summation of the charges of the single
cells, the intensity of which does not need to exceed that
of a muscle current. As measurements indicate, the pro-
duction of electricity in the electric organ seems also to
follow in the main the thermodynamic laws governing
concentration chains.

Let us return once more to the current of rest in muscle,
which we have attributed to the semi-permeability of the
plasma membranes for ions. If we imagine the per-
meability of this plasma membrane to be altered through
some agency that precipitates protein or causes it to go
into solution, then we may expect parallel variations in
the current of rest. When Hober dipped the surface of

ON THE ELECTRICAL CHARGE OF PROTEIN. igS

freshly cut frog's muscles into salt solutions of various
kinds and measured the current of rest, he found that
the effects of the different salts in this regard arrange
themselves into a table similar to that given above for
the precipitation of electropositive protein. The sign
indicating a precipitation corresponds with a reversal
in the current of rest, while that indicating a solution
with the normal current of rest.

The electrical behavior of proteins is of importance to
the histologist also for a proper understanding of the
important cellular reactions which take place in fixation
and staining. In spite of the fact that all the different
portions of the cell are exposed to the same action of
the fixing-agent, be this an indifferent substance, such as
alcohol, or one imposing a positive 'charge, such as a
solution of an acid or a heavy metal, the separate con-
stituents of the cell react differently toward acid and
basic dyes. Through the investigations of Biltz in par-
ticular, the identity of the process of dyeing and colloidal
reactions seems to be well established, so that we may
assume that different portions of a cell may show different
electrical states when exposed to the same external con-
ditions. We will carry this discussion no further, but
will only draw attention to an observation which is
intimately connected with our own. E. Mayr (Graz)
has studied under Bethe's direction the influence of
salts upon the fixation and precipitation of nervous tissue.
These studies have shown that the effects of ions upon the
preservation and staining qualities of nerve fibres arrange
themselves in a way similar to the table given on page 147
for the precipitation of electronegative protein, while the
order of the ions is just the reverse and corresponds, in

1 54 PHYSICAL CHEMISTRY IN MEDICINE.

the main, with that for the precipitation of electropositive
protein when the ions are arranged in the order in which
they render visible certain elements of the ganglion cells,
such as NissL bodies and nucleoli.

But that an electrical difference exists between nuclear
substance and cell protoplasm even in the living cell is
rendered probable through many facts. Ralph Lillie
found a difference in the direction in which spermatozoa
and cells rich in protoplasm move in the electric current,
and Martin H. Fischer and Wolfgang Ostwald
have already tried to give a physico-chemical theory of
fertilization. However imperfect these attempts must
of necessity seem, the successful establishment of a certain
parallelism between those factors which, on the one hand,
bring about artificial parthenogenesis and, on the other,
cause a precipitation of solid colloids is of permanent
value. The similarity of the formation of the astrosphere
about the spermatozoon which has entered an egg with
certain precipitations produced in colloids has been re-
peatedly noticed by investigators.

But we will keep from entering fields which have
as yet been but little opened experimentally, and in closing
point out a relation which by itself is not without general
interest and which may also be of service to the investigator.

Between the reactions of colloids which take place
with an equalization of electrical differences and the
reactions of the immune bodies there exists a relation
which is as intimate as anything can be, an idea which
has already been illustrated in another place. More-
over, a more than accidental similarity seems to exist
between immune reactions and the changes which take
place in the process of fertilization.

ON THE ELECTRICAL CHARGE OF PROTEIN. rSS

We know that the spermatozoon reacts specifically with
the egg, that this specificity is, however, not absolute,
as shown by the production of bastards. This specificity
can also be altered through different chemicals, as shown
by the remarkable hybridization experiments of Loeb.
We see further that the spermatozoon becomes immo-
bilized within the egg, in that a kind of precipitation, the
formation of the astrosphere, a characteristic morpho-
logical sign of fertilization, starts from the spermatozoon.

Let us compare with this picture such a process as the
agglutination of bacteria through immune serum. Here
also there exists a specificity which is, however, by no
means absolute, and here also an immobilization in the
serum of the mobile bacterium. According to the
pleasing idea of Paltauf, we are dealing in this case
with the formation of a precipitate about the capsule of
the bacterium, something similar, therefore, to the change
which occurs about the spermatozoon which has pene-
trated an egg. The specific effects of the immune bodies
can also be altered through chemicals.

They are always associated problems, therefore, which
arise in this or the other illustration used, and they all
spring from the manifold similarity which exists between
the colloids of the organism within and without the cells
and which is determined to so great a degree by the
electrical properties of the colloids.

There can be little doubt that out of the study of the
physico-chemical properties of the colloids there will
spring a new bud of physical physiology in which the
application of the modern teachings of electricity will
play a primary r61e. The physiology which recognizes

IS^ PHYSICAL CHEMISTRY IN MEDICINE.

in the neighboring sciences of physics and chemistry that
profound revolutionizing influence of the newer electrical
investigations, which do not stop before even the most
sacred and fundamental conceptions of this subject, must
consider it as a next most worthy task to guarantee itself
its share in the new conquests of scientific knowledge.

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Howe's Retaining Walls for Earth i2mo, i 35

Johnson's (J. B.) Theory and Practice of Surveying Small 8vo, 4 00

Johnson's (L. J.) Statics by Algebraic and Graphic Methods 8vo, 2 00

Laplace's Philosophical Essay on Probabilities. (Tniscott and Emory.) . i2mo, 2 00
Mahan's Treatise on Civil Engineering. (1873.) CWood.) 8vo, 5 00

* Descriptive Geometry. 8vo,

Merriman's Elements of Precise Surveying and Geodesy 8vo,

Elements of Sanitary Engineering 8vo,

Merriman and Brooks's Handbook for Surveyors i6moi morocco,

Hugent's Plane Surveying 8vo,

Ogden's Sewer Design lamo,

Patton's Treatise on Civil Engineering 8vo half leather,

Keed's Topographical Drawing and Sketching .4to,

Rideal's Sewage and the Bacterial Purification of Sewage. 8vo»

Siebert and Biggin's Modern Stone-cutting and Masonry « 8vo,

Smith's Manual of Topographical Drawing. (McMillan.) 8vo,

Sondericker's Graphic Statics, with Applications to Trusses, Beams, and Arches.

8vo,
Taylor and Thompson's Treatise on Concrete, Plain and Reinforced 8vo,

* Trautwine's Civil Engineer's Pocket-book i6mo, morocco.

Wait's Engineering and Architectural Jurisprudence 8vo,

Sheep,
Law of Operations Preliminary to Construction in Engineering and Archi-
tecture 8vo,

Sheep,

Law of Contracts 8vo,

Warren's Stereotomy — Problems in Stone-cutting 8vo,

Webb's Problems in the Use and Adjustment of Engineering Instruments.

i6mo, morocco,

* Wheeler s Elementary Course of Civil Engineering 8vo,

Wilson's Topographic Surveying. 8vo,

BRIDGES AND ROOFS.

Boiler's Practical Treatise on the Construction of Iron Highway Bridges. .Svo,

* Thames River Bridge 4to, paper,

Burr's Course on the Stresses in Bridges and Roof Trusses, Arched Ribs, and

Suspension Bridges 8vo,

Burr and Falk's Influence Lines for Bridge and Roof Computations. . . .8vo,

Du Bois's Mechanics of Engineering. Vol. II Small 4to, :

Foster's Treatise on Wooden Trestle Bridges 4to,

Fowler's Ordinary Foundations 8vo,

Greene's Roof Trusses Svo,

Bridge Trusses 8vo,

Arches in Wood, Iron, and Stone 8vo,

Howe's Treatise on Arches Svo, 4 00

Design of Simple Roof-trusses in Wood and Steel 8vo, 2 00

Johnson, Bryan, and Turneaure's Theory and Practice in the Designing of

Modern Framed Structures Small 4to, 10 00

Merriman and Jacoby's Text-book on Roofs and Bridges :

Part I. Sb'esses in Simple Trusses 8vo, 2 50

Part n. Graphic Statics 8vo, 2 50

Part HI. Bridge Design 8vo, 2 50

Part IV. Higher Structures Svo, -^ 50

Slorison's Memphis Bridge .^ 4to, 10 00

Waddell's De Ponilbus, a Pocket-book for Bridge Engineers. . i6mo, morocco, 3 00

Specifications for Steel Bridges i2mo, i 25

Wood's Treatise on the Theory of the Construction of Bridges and Roofs. .Svo, 2 c?
Wright's Designing of Draw-spans :

Part I. Plate-girder Draws Svo, 2 50

Part n. Riveted-truss and Pin-connected Long-span Draws Svo, 2 50

Two parts in one volume Svo, 3 50

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HYDRAULICS.

Bazin's Experiments upon the Contraction of the Liquid Vein Issuing from

an Orifice. (Trautwine.) 8vo, 2 00

Bovey's Treatise on Hydraulics 8vo, 5 00

Church*s Mechanics of Engineering 8vo, 6 00

Diagrams of Mean Velocity of Water in Open Channels paper, i 50

CofiSn's Graphical Solution of Hydraulic Problems i6mo, morocco, 2 50

Flather*s Dynamometers, and the Measurement of Power i2mo, 3 00

Folwell*s Water-supply Engineering 8vo, 4 00

Frizell's Water-power 8vo, 5 o'»

Puertes's Water and Public Health i2mo, i 50

Water-filtration Works i2mo, 2 50

Oangulllet and Kutter's General Formula for the Uniform Flow of Water in

Rivers and Other Channels. (Hering and Trau Tine.) 8vo 4 00

Hazen's Filtration of Public Water-supply 8vo, 3 00

Hazlehurst's Towers and Tanks for Water-works 8vo, 2 50

Herschel's 115 Experiments on the Carrying Capacity of Large, Kiveted, Metal

Conduits 8vo, ^ 00

Mason's Water-supply. (Considered Principally from a Sanitary Standpoint.)

8vo.

Merriman's Treatise on Hydraulics. 8vo,

* Michie's Elements of Anal3rtical Mechanics 8vo,

Schuyler's Reservoirs ^or Irrigation, Water-power, and Domestic Water-
supply Large 8vo,

** Thomas and Watt's Improvement of Rivers. (Post., 44c. additional.). 4to,

Tumeaure and Russell's Public Water-supplies , 8v6,

Wegmanu's Design and Construction of Dams 4to,

Water-supply of the City of New York from 1658 to 189s 4to,

Wilson's Irrigation Engineering Small 8vo,

Wolff's Windmill as a Prime Mover 8vo,

Wood's Turbines 8vo,

Elements of Analytical Mechanics , ^ Svo,

MCATERULS OF ENGINEERING.

Baker's Treatise on Masonry Construction , . . Svo,

Roads and Pavements .8vo,

Black's United States Public Works Oblong 4to9

Bovey's Strength of Materials and Theory of Structures. 8vo,

Burr's Elasticity and Resistance of the Materials of Engineering 8to,

Byrne's Highway Construction Svo,

Inspection of the Materials and Workmanship Employed in Construction.

i6mo,

Church's Mechanics of Engineering. , Svo,

Du Bois's Mechanics of Engineering. Vol. I Small 4to,

Johnson's Materials of Construction Large Svo,

Fowler's Ordinary Foundations Svo,

Keep's Cast Iron Svo,

Lanza's Applied Mechanics Svo,

Marten's Handbook on Testing Materials. (Henning.) 2 vote Svo,

Merrill's Stones for Building and Decoration Svo,

Merriman's Text-book on the Mechanics of Materials ;8vo.

Strength of Materials i2mo,

Metcalf's Steel. A Manual for Steel-users i2mo,

Patton's Practical Treatise on Foundations - .-8vo,

Richardson's Modern Asphalt Pavements 8to,

Richey's Handbook for Superintendents of Construction lOmo, mor.,

Rockwell's Roads and Pavements in France ^ z2mo,

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Sabin's Industrial and Artistic Technology of Paints and Varnish 8vo,

Smith's Materials of Machines i2mo.

Snow's Principal Species of Wood 8vo,

Spalding's Hydraulic Cement i2mo,

Text-book on Roads and Pavements i2mo,

Taylor and Thompson's Treatise on Concrete, Plain and Reinforced 8vo,

Thurston's Materials of Engineering. 3 Parts 8vo,

Part I. Non-metallic Materials of Engineering and Metallurgy 8vo,

Part II. Iron and Steel 8vo,

Part III. A Treatise on Brasses, Bronzes, and Other Alloys and their

Constituents 8vo,

Thurston's Text-book of the Materials of Construction Svo,

Tillson's Street Pavements and Paving Materials Svo,

Waddell's De Pontibus. (A Pocket-book for Bridge Engineers.) . . z6mo, mor..

Specifications for Steel Bridges i2mo,

"Wood's (De V.) Treatise on the Resistance of Materials, and an Appendix on

the Preservation of Timber Svo, 2 00

Wood's (De V.) Elements of Analytical Mechanics Svo, 3 00

Wood's (M. P.) Rustless Coatings: Corrosion and Electrolysis of Iron and

Steel Svo, 4 00

RAILWAY ENGINEERING.

Andrew's Handbook for Street Railway Engineers 315 inches, morocco, i 25

Berg's Buildings and Structures of American Railroads 4to, 5 00

Brook's Handbook of Street Raihoad Location i6mo, morocco, i 50

Butt's Civil Engineer's Field-book i6mo, morocco, 2 50

Crandall's Transition Curve i6mo, morocco, i 30

Railway and Other Earthwork Tables Svo, r 50

Dawson's "Engineering" and Electric Traction Pocket-book. . i6mo, morocco, s 00

Dredge's History of the Pennsylvania Railroad: (1879) Paper, 5 00

* Drinker's Tunnelling, Explosive Compounds, and Rock Drills. 4to, half mor., 25 00

Fisher's Table of Cubic Yards Cardboard, 25

Godwin's Railroad Engineers' Field-book and Explorers' Guide. . . i6nio, mor., 2 50

Howard's Transition Curve Field-book i6mo, morocco, i 30

Hudson's Tables for Calculating the Cubic Contents of Excavations and Em-
bankments Svo, I 00

Molitor and Beard's Manual for Resident Engineers i6mo, i 00

Nagle's Field Manual for Railroad Engineers i6mo, morocco, 3 00

Philbrick's Field Manual for Engineers i6mo, morocco, 3 00

Searles's Field Engineering i6uio, morocco, 3 00

Railroad Spiral i6mo, morocco, i 50

Taylor's Prismoidal Formulae and Earthwork Svo, i 50

* Trautwine's Method of Calculating the Cube Contents of Excavations and

Embankments by the Aid of Diagrams Svo, 2 00

The Field Practice of Laying Out Circular Curves for Railroads.

i2mo, morocco, 2 30

Cross-section Sheet Paper, 23

Webb's Railroad Construction i6mo, morocco, s 00

Wellington's Economic Theory of the Location of Railways Small Svo, 5 00

DRAWING.

Barr's Kinematics of Machinery Svo, 2 so

* Bartlett's Mechanical Drawing Svo, 3 00

* " " " Abridged Ed Svo, 150

Coolidge's Manual of Drawing Svo, paper i oo

Coolidge and Freeman's Elements of General Drafting for Mechanical Engi-
neers Oblong 4to, 2 50

Durley's Kinematics of Machines Svo, 4 00

Emch's Introduction to Projective Geometry and its Applications Svo. z 30

8

Hill's Text-book on Shades and Shadows, and Perspective Svo, 2 00

Jamison's Elements of Mechanical Drawing , 8vo, 2 so

Jones's Machine Design :

Part I. Kinematics of Machinery. 8vo, i 50

Part n. Form, Strength, and Proportions of Parts 8vo, 3 00

MacCord's Elements of Descriptive Geometry. 8vo, 3 00

Kinematics; or. Practical Mechanism 8vo, 5 00

Mechanical Drawing 4to, 4 00

Velocity Diagrams 8vo. 1 50

* Mahan's Descriptive Geometry and Stone-cutting. 8vo, i 50

Industrial Drawing. (Thompson.) 8vo» 3 50

Moyer's Descriptive Geometry 8vo, 2 00

Reed's Topographical Drawing and Sketching 4to, 5 00

Reid's Course in Mechanical Drawing 8vo, 2 00

Text-book of Mechanical Drawing and Elementary Machine Design. 8vo, 3 00

Robinson's Principles of Mechanism. ^ 8vo, 3 00

Schwamb and Merrill's Elements of Mechanism 8vo, 3 00

Smith's Manual of Topographical Drawing. (McMillan.) Svo, 2 50

Warren's Elements of Plane and Solid Free-hand Geometrical Drawing. i2mo, i 00

Drafting Instruments and Operations i2mo^ i 25

Manual of Elementary Projection Drawing i2mo, i 5%

Manual of Elementary Problems in the Linear Perspective of Form and

Shadow i2mo, i 00

Plane Problems in Elementary Geometry i2mo, i 25

Primary Geometry i2mo, 75

Elements of Descriptive Geometry, Shadows, and Perspective Svo, 3 50

General Problems of S^des and Shadows Svo, 3 00

Elements of Machine Construction and Drawing Svo, 7 50

Problems, Theorems, and Examples in Descriptive Geometry. Svo, 2 50

Weisbach's Kinematics and Power of Transmission. (Hermann and Klein)8vo, 5 00

Whelpley's Practical Instruction in the Ait of Letter Engraving i2mo, 2 00

Wilson's (H. M.) Topographic Surveying Svo, 3 50

Wilson's (V, T.) Free-hand Perspective Svo, 2 50

Wilson's (V. T.) Free-hand Lettering Svo, i 00

Woolf's Elementary Course in Descriptive Geometry. Large Svo, 3 00

ELECTRICITY AND PHYSICS.

Anthony and Brackett's Text-book of Physics. (Magie.) Small Svo,

Anthony's Lecture-notes on the Theory of Electrical Measurements i2mo,

Benjamin's History of Electricity Svo,

Voltaic CeU. Svo,

Classen's Quantitative Chemical Analysis by Electrolysis. (Boltwood.).Svo,

Crehore and Squier's Polarizing Photo-chronograph Svo,

Dawson's "Engineering" and Electric Traction Pocket-book. i6mo, morocco,
Dolezalek's Theory of the Lead Accumulator (Storage Battery), (Von

Ende.) i2mo,

Duhem's Thermodynamics and Chemistry. (Burgess.) Svo,

Flather's Dynamometers, and the Measurement of Power z2mo,

Gilbert's De Magnete. (Mottelay.) Svo,

Hanchett's Alternating Currents Explained i2mo,

Bering's Ready Reference Tables (Conversion Factors) z6mo, morocco,

Holman's Precision of Measurements Svo,

Telescopic Mirror-scale Method, Adjustments, and Tests. .. .Large Svo,

Kinzbrunner's Testing of Continuous-Current Machines Svo,

Landauer's Spectrum Analysis. (Tingle.) Svo,

Le Chatelien's High-temperature Measurements. (Boudouard — Burgess.) i2mo.
Lob's Electrolysis and Electrosynthesis of Organic Compounds. (Lorenz.) i2mo,

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■^ Lyons's Treatise. on Electromagnetic Phenomena. Vols. I. and II. 8vo, each, 6 oo

* Michie*s Elements of Wave Motion Relating to Sound and Light. 8vo, 4 00

Ifiaudet's Elementary Treatise on Electric Batteries. (Fishback.) i2mo, 2 50

* Rosenberg's Electrical Engineering. (Haldane Gee — Kinzbranner.). . .8vo, i 50

Ryan, Norris, and Hoxie's Electrical Machinery. VoL 1 8vo, 2 50

Thurston's Stationary Steam-engines 8vo, 2 50

* Tillman's Elementary Lessons in Heat 8vo, 1 50

Tory and Pitcher's Manual of Laboratory Physics Small 8vo, 2 00

TTIke's Modern Electrolytic Copper Refining 8vo, 3 00

LAW.

* Davis's Elements of Law 8vo, 2 50

* Treatise on the Military Law of United States 8vo, 7 oo

=" Sheep, 7 SO

Manual for Courts-martial i6mo, morocco, i so

"Wait's Engineering and Architectural Jurisprudence 8vo, 6 00

Sheep, 6 50
Law of Operations Preliminary to Construction in Engineering and Archi-
tecture 8vo, 5 00

Sheep, 5 50

Law of Contracts 8vo, 3 00

Winthrop's Abridgment of Military Law i2mo, 2 50

MANUFACTURES.

Bernadou's Smokeless Powder — Nitro-cellulose and Theory of the Cellulose

Molecule i2mo, 2 50

Bolland's Iron Founder , i2nio, 2 50

"The Iron Founder," Supplement i2mo, 2 50

Encyclopedia of Founding and Dictionary of Foundry Terms Used in the

Practice of Moulding r2mo, 3 00

Eissler's Modem High Explosives 8vo» 4 00

Effront's Enzymes and their Applications. (Prescott.) 8vo, 3 00

Pitzgerald's Boston Machinist i2mo, i 00

Ford's Boiler Making for Boiler Makers i8mo, i 00

Hopkin's Oil-chemists* Handbook 8vo, 3 00

Xeep's Cast Iron 8vo, 2 50

Leach's The inspection and Analysis of Food with SpecAl Reference to State

ControL Large 8vo, 7 so

Matthews's The Textile Fibres 8vo, 3 so

Metcalf's Steel. A Manual for Steel-users i2mot 2 00

Metcalfe's Cost of Manufactures — And the Administration of Workshops. 8vo, s 00

Meyer's Modern Locomotive Construction 4to, 10 00

Morse's Calculations used in Cane-sugar Factories i6mo, morocco, i 50

* Reisig's Guide to Piece-dyeing 8vo, 25 00

Cabin's Industrial and Artistic Technology of Paints and Varnish 8vo, 3 00

Smith's Press-working of Metals 8vo, 3 00

Spalding's Hydraulic Cement i2mo, 2 00

Spencer's Handbook for Chemists of Beet-sugar Houses. ... x6mo, morocco, 3 00

Handbook for Sugar Manufacturers and their Chemists. .i6mo, morocco, 2 om

Taylor and Thompson's Treatise on Concrete, Plain and Reinforced Svo, 5 00

Thurston's Manual of Steam-boilers, their Designs, Construction and Opera-
tion Svo, 5 00

* Walke's Lectures on Explosives Svo, 4 00

Ware's Manufacture of Sugar. (In press.)

West's American Foundry Practice .' x2mo, 2 50

Moulder's Text-book i2mo, 2 s©

10

"Wolff's Windmill as a Prime Mover 8vo, 3 00

Wood's Rustless Coatings: Corrosion and Electrolysis of Iron and Steel. .8vo, 4 00

MATHEMATICS.

Baker's Elliptic Functions 8vo,

* Bass's Elements of Differential Calculus i2mo,

Briggs's Elements of Plane Analytic Geometry i2mo,

Com.pton's Manual of Logarithmic Computations i2mo,

Davis's Introduction to the Logic of Algebra 8vo,

* Dickson's College Algebra Large z2mo»

* Introduction to the Theory of Algebraic Equations Large i2mo»

Emch's Introduction to Projective Geometry and its Applications 8vo,

Halsted's Elements of Geometry 8vo,

Elementary Synthetic Geometry 8vo,

Rational Geometry. i2mo,

♦^Johnson's (J, B.) Three-place Logarithmic Tables: Vest-pocket size. paper,

100 copies for

* Mounted on heavy cardboard, 8X 10 inches,

10 copies for
Johnson's (W. W.) Elementary Treatise on Differential Calculus. .Small 8vo,
Johnson's (W, W.) Elementary Treatise on the Integral Calculus. Small 8vo,

Johnson's (W. W.) Curve Tracing in Cartesian Co-ordinates i2mo,

Johnson's (W. W.) Treatise on Ordinary and Partial Differential Equations.

Small 8vo,
Johnson's (W. W.) Theory of Errors and the Method of Least Squares. i2mo,

* Johnson's (W. W.) Theoretical Mechanics i2mo,

Laplace's Philosophical Essay on Probabilities. (Truscott and Emory.) . i2mo,
"* Ludlow and Bass. Elements of Trigonometry and Logarithmic and Other

Tables 8vo.

Trigonometry and Tables published separately Each,

* Ludlow's Logarithmic and Trigonometric Tables 8vo,

IHaurer's Technical Mechanics S . , ,

Dllerriman and Woodward's Higher Mathematics > 8vo ,

Dferriman's Method of Least Squares 8vo,

Rice and Johnson's Elementary Treatise on the Differential Calculus. . Sm. Svo,

Differential and Integral Calculus. 2 vols, in one Small Svo,

Wood's Elements of Co-ordinate Geometry Svo,

Trigonometry: Analytical, Plane, and Spherical i2mo.

MECHANICAL ENGINEERING.

MATERIALS OF ENGmEERING, STEAM-ENGINES AND BOILERS.

Bacon's Forge Practice i2mo,

Baldwin's Steam Heating for Buildings i2mo,

Barr's Kinematics of Machinery. Svo,

=*= Bartlett's Mechanical Drawihg Svo,

* " " " Abridged Ed Svo,

Benjamin's Wrinkles and Recipes i2mo,

Carpenter's Experimental Engineering' Svo,

Heating and Ventilating Buildings Svo,

Cary's Smoke Suppression in Plants using Bituminous Coal. (In Prepara-
tion.)

Clerk's Gas and Oil Engine Small Svo,

Coolidge's Manual of Drawing. Svo, paper,

Coohdge and Freeman's Elements of General Drafting for Mechanical En-
gineers, , , Oblong 4to, 2 50

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Cromweirs Treatise on Toothed Gearing i2mo, x 50

Treatise on Belts and Pulleys I2ni0t i 5°

Durley's Kinematics of Machines 8to, 4 00

riather's Dynamometers and the Measurement of Power. i2mo, 3 00

"* Rope Driving i2mo, 2 V)o

Gill's Gas and Fuel Analysis for Engineers i2mo, i 25

Hall's Car Lubrication i2mo, i 00

Bering's Ready Reference Tables (Conversion Factors) i6mo, morocco, 2 50

Button's The Gas Engine 8vo, 5 00

Jamison's Mechanical Drawing 8vo, 2 50

Jones's Machine Design:

Part I. Kinematics of Machinery. Svo, i 5©

Part n. Form, Strength, and Proportions of Parts Svo, 3 00

Kent's Mechanical Engineers* Pocket-book i6mo, morocco, 5 00

Kerr's Power and Power Transmission Svo, 2 00

Leonard's Machine Shop, Tools, and Methods. (In press.)

Lorenz's Modern Refrigerating Machinery. (Pope, Baven, and Dean.) (In press.)

HacCord's Kinematics; or. Practical Mechanism Svo, 5 00

Mechanical Drawing 4to, 4 00

Velocity Diagrams Svo, i 50

Mahan's Industrial Drawing. (Thompson.) Svo, 3 50

Poole's Calorifi.c Power of Fuels Svo, 3 00

Raid's Course in Mechanical Drawing Svo, 2 00

Text-book of Mechanical Drawing and Elementary Machine Design. Svo, 3 00

Richard's Compressed Air i2mo, i so

Robinson's Principles of Mechanism Svo, 3 00

Schwamb and Merrill's Elements of Mechanism Svo, 3 00

Smith's Press-working of Metals Svo, 3 00

Thurston's Treatise on Friction and Lost Work in Machinery and Mill

Work Svo, 3 00

Animal as a Machine and Prime Motor, and the Laws of Energetics . i2mo, i 00

Warren's Elements of Machine Construction and Drawing , . . .Svo, 7 so

Weisbach's Kinematics and the Power of Transmission. (Herrmann —

Klein.) Svo, s 00

Machinery of Transmission and Governors. (Herrmann — Klein.). .Svo, 5 00

Wolff's Windmill as a Prime Mover Svo, 3 00

Wood's Turbines Svo, 2 50

MATERIALS OF ENGINEERING.

Bovey's Strength of Materials and Theory of Structures Svo, 7 so

Burr's Elasticity and Resistance of the Materials of Engineering. 6th Edition.

Reset Svo, 7 50

Church's Mechanics of Engineering Svo, 6 00

Johnson's Materials of Construction Svo, 6 00

Keep's Cast Iron Svo, 2 50

Lanza's Applied Mechanics Svo, 7 so

Martens's Handbook on Testing Materials. (Henning.) Svo, 7 50

Merriman's Text-book on the Mechanics of Ma,teriab Svo, 4 00

Strength of Materials -. i2mo, i 00

Metcalf's Steel. A manual for Steel-users z2mo, 2 00

Sabin's Industrial and Artistic Technology of Paints and Varnish Svo, 3 00

Smith's Materials of Machines i2mo, i 00

trturston's Materials of Engineering 3 vols., Svo, 8 00

Part n. Iron and Steel Svo, 3 50

Part in. A Treatise on Brasses, Bronzes, and Other Allo3rs and their

Constituents 8™» 2 S»

Text-book of the Materials of Construction * Svo, 3 o»

12

Wood's (De V.) Treatise on the Resistance of Materials and an Appendix on

the Preservation of Timber 8vo, 2 00

Wood's (De V.) Elements of Analytical Mechanics 8vo» 3 00

food's (M. P.) Rustless Coatings: Corrosion and Electrolysis of Iron and

Steel. 8vo, 4 00

STEAM-ENGINES AND BOILERS.

Berry's Temperature-entropy Diagram., ^,..,>.^ i2mo, i 25

Camot's Reflections on the Motive Powei: of Heat . (Thurston.) i2mo, i 50

Dawson's "Engineering" and Electric TractionPocket-book. ...l6mo, mor., 5 00

Ford's Boiler Making for Boiler Makers i8mo, i 00

Goss's Locomotive Sparks 8vo, 2 00

Hemenway's Indicator Practice and- Steam-engine Economy z2mot 2 00

Hutton's Mechanical Bngineering of Power Plants 8tOi 5 00

Heat and Heat-engines Svo, 5 00

Kent's Steam boiler Economy , 8vo, 4 00

Slneass's Practice and Theory of the Injector. 8vo, i 50

MacCord's Slide-valves , . , 8vo, 2 00

Meyer's Modem Locomotive Construction .' 4to, zo 00

Peabody's Manual of the Steam-engine Indicator z2nio, i 50

Tables of the Properties of Saturated Steam and Other Vapors 8vo, i 00

Thermodynamics of the Steam-engine and Other Heat-engines Svo, 5 00

Valve-gears for Steam-engines Svo, 2 50

Peabody and Miller's Steam-boilers 8vo, 4 00

Pray's Twenty Years with the Indicator Large Svo, 2 50

Pupin's Thermodynamics of Reversible Cycles in Gases and Saturated Vapors.

(Osterberg.) i2mo, 1 25

Reagan's Locomotives: Simple Compound, and Electric i2mo, 2 50

Rontgen's Principles of Thermodynamics. (Du Bois.)< • Svo, s 00

Sinclair's Locomotive Engine Running and Management i2mo, 2 00

Smart's Handbook of Engineering Laboratory Practice i2mo, 2 50

%iow's Steam-boiler Practice Svo, 3 00

Spangler's Valve-gears Svo, 2 50

Notes on Thermodynamics i2nio, i 00

Spangler, Greene, and Marshall's Elements of Steam-engineering Svo, 3 00

Thurston's Handy Tables Svo, 1 50

Manual of the Steam-engine 2 vols., Svo, 10 00

Part I. History, Structure, and Theory Svo, 6 00

Part n. Design, Construction, and Operation Svo, 6 00

Handbook of Engine and Boiler Trials, and the Use of the Indicator and

the Prony Brake Svo, 5 00

Stationary Steam-engines Svo, 2 so

Steam-boiler Explosions in Theory and in Practice i2mo, i 50

Manual of Steam-boilers, their Designs, Construction, and Operation Svo. 5 00

Weisbach's Heat, Steam, and Steam-engines. (Du Bois.) Svo, s 00

Whitham's Steam-engine Design Svo, 5 00

Wilson's Treatise on Steam-boilers. (Elather.) i6mo, 2 50

Wood's Thermodynamics. Heat Motors, and Refrigerating Machines. . .Svo, 4 00

MECHANICS AND MACHINERY.

Barr's Kinematics of Machinery Svo, 2 50

BoTey's Strength of Materials and Theory of Structures Svo, 7 50

Chase's The Art of Pattern-making i2mo, 2 50

Church's Mechanics of Engineering. Svo, 6 00

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Chiirch's Notes and Examples in Mechanics Svo, 2 00

Compton*s First Lessons in M^etal-working ,^» izmo, z 50

Compton and De Groodt's The Speed Lathe * i2mo, i 50

Cromwell's Treatise on Toothed Gearing i2mo, * 50

Treatise on Belts and Pulleys i2mo, i 50

Dana's Text-book of Elementary Mechanics for Colleges and Schools. . i2mo, i 50

Dingey's Machinery Pattern Making i2mo, 2 00

Dredge's Record of the Transportation Exhibits Building of the World's

Columbian Exposition of 1893 4to half morocco, 5 00

Du Bois's Elementary Principles of Mechanics:

Vol I. Kinematics 8vo» 3 50

Vol. n. Statics 8vo, 4 00

Vol. in. Kinetics 8vo, 3 5o

Mechanics of Engineering. Vol. I Small 4to, 7 So

Vol. II Small 4to, 10 00

Durley's Kinematics of Machines 8vo, 4 00

Pitzgerald's Boston Machinist i6mo, i 00

Elather's Dynamometers, and the Measurement of Power. i2mo, 3 00

Rope Driving. i2mo, 2 00

Goss's Locomotive Sparks 8vo, 2 00

Hall's Car Lubrication i2mo, i 00

Holly's Art of Saw Filing iSmo, 75

James's Kinematics of a Point and the Rational Mechanics of a Particle. Sm.8vo,2 00

* Johnson's (W. W.) Theoretical Mechanics i2mo, 3 00

Johnson's (L. J.) Statics by Graphic and Algebraic Methods 8vo, 2 00

Jones's Machine Design:

Part I. Kinematics of Machinery 8vo, i 50

Part n. Form, Strength, and Proportions of Parts 8vo, 3 00

Kerr's Power and Power Transmission 8vo, 2 00

Xanza's Applied Mechanics 8vo, 7 50

Xeonard's Machine Shop, Tools, 'and Methods. (In press.)

I/Orenz's Modem Refrigerating Machinery. (Pope, Haven, and Dean.) (In press.)

MacCord's Kinematics; or, Practical Mechanism 8vo, s 00

Velocity Diagrams 8vo, i 50

Maurer's Technical Mechanics 8vo, 4 00

3Ierriman's Text-book on the Mechanics of Materials 8vo, 4 00

* Elements of Mechanics i2mo, i 00

4 Michie's Elements of Analytical Mechanics 8vo, 4 00

P.eagan's Locomotives: Simple, Compound, and Electric i2nio, 2 50

Heid's Course in Mechanical Drawing .8vo, z 00

Text-book of Mechanical Drawing and Elementary Machine Design. 8vo, 3 00

lUchards's Compressed Air i2mo, i 50

Hobinson's Principles of Mechanism 8vo, 3 00

Hyan, Norris, and Hoxie's Electrical Machinery. Vol. 1 8vo, 2 50

Schwamb and Merrill's Elements of Mechanism 8vo, 3 00

Sinclair's Locomotive-engine Rimning and Management. i2mo, 2 00

Smith's (0.) Press-working of Metals- .' 8vo, 3 00

Smith's (A. W.) Materials of Machines i2mo, x 00

Spangler, Greene, and Marshall's Elements of Steam-engineering 8vo, 3 oa

Thurston's Treatise on Friction and Lost ■\7ork in Machinery and Mill

Work 8vo, 3 00

Animal as a Machine and Prime Motor, and the Laws of Energetics.

i2mo, I 00

Warren's Elements of Machine Construction and Drawing 8vo, 7 so

Weisbach's Kinematics and Power of Transmission. (Herrmann — Klein. ).8vo, 5 00

Machinery of Transmission and Governors. (Herrmann — Klein.). 8vo, 5 00

Wood's Elements of Analytical Mechanics 8vo, 3 00

Principles of Elementary Mechanics i2mo, i 25

Turbines 8vo, 2 50

The World's Columbian Eaposition of 1893 4to, 1 00

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METALLURGY.

Egleston's Metallurgy of Silver, Gold, and Mercury:

Vol. I. Silver 8vo, 75a

VoL II. Gold and Mercury 8vo, 7 So

** lles's Lead-smelting. (Postage 9 cents additionaL) i2mo, 2 50

Keep's Cast Iron 8vo, 2 B**

Kunhardt's Practice of Ore Dressing in Europe 8vo, j go

Le Chatelier's High-temperature Measuremepts. (Boudouard — Burgess. )i2mo, 3 o&

Metcalf 's Steel. A Manual for Steel-users' i2mo, 2 oo

Smith's Materials of Machines i2mo, i oo

Thurston's Materials of Engineering. In Three Parts 8vo, 8 00

Part II. Iron and Steel Svo, 3 So

Part III. A Treatise on Brasses, Bronzes, and Other Alloys and their

Constituents Svo, 2 s<>

Ulke's Modern Electrolytic Copper Refining Svo, 3 00

MINERALOGY.

Barringer's Description of Minerals of Commercial Value. Oblong, morocco, 2 50

Boyd's Resoiurces of Southwest Virginia Svo 3 oo

Map of Southwest Virignia Pocket-book form. 2 oo-

Brush's Manual of Determinative Mineralogy. (Penfield.) Svo, 4 00

Chester's Catalogue of Minerals Svo, paper, i oo

Cloth, I 25

Dictionary of the Names of Minerals Svo, 3 50

Dana's System of Mineralogy Large Svo, half leather, 12 so

First Appendix to Dana's New " System of Mineralogy." Large Svo, i 00

Text-book of Mineralogy Svo, 4 00

Minerals and How to Study Them z2mo, i 50

Catalogue of American Localities of Minerals Large Svo, i 00

Manual of Mineralogy and Petrography i2mo, 2 00

Douglas's Untechnical Addresses on Technical Subjects i2mo, i 00

Eakle's Mineral Tables Svo, i 23

Egleston's Catalogue of Minerals and Synonyms Svo, 2 so

Hussak's The Determination of Rock-forming Minerals. (Smith.). Small Svo, 2 00

Merrill's Non-metallic Minerals: Their Occurrence and Uses Svo, 4 00

* Ptnfield's Notes on Determinative Mineralogy and Record of Mineral Tests.

Svo. paper, o so
Roscttbusch's Microscopical Physiography of the Rock-making Minerals.

(Iddings.) Svo. s 00

* Tillman's Text-book of Important Minerals and Rocks Svo, 2 00

Willifttns's Manual of Lithology Svo, 3 00

MINING.

beard's Ventilation of Mines I2mo, 2 50

Boyd's Resources of Southwest Virginia Svo, 3 00

Map of Southwest Virginia Pocket-book form, 2 00

Douglao's Untechnical Addresses on Technical Subjects i2mo. i 00

* Drinker's Tunneling, Explosive Compounds, and Rock Drills. .4to,hf. mor., 25 00

Eissler's Modem High Explosives Svo, 4 00

Fowler's Sewage Works Analyses i2mo . 2 00

Goodyear's Coal-mines of the Western Coast of the* United States i2mo. 2 50

Ihlseng's Manual of Mining Svoi 5 00

** lles's Lead-smelting. (Postage 9c. additionaL) i2mo. 2 50

Kunhardt's Practice of Ore Dressing in Europe Svo, i 50

O'Driscoll's Notes on the Treatment of Gold Ores Svo, 2 00

* Walke's Lectures on Explosives Svo, 4 00

Wilson's Cyanide Processes i2mo, t 50

Chleciination Process lamo, i 50

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Wilson's HydrauL^, and ±»lacer Mining lamo, 2 00

Treatise on Practical and Theoretical Mine Ventilation t2mo, i 25

SANITARY SCIENCE.

Folwell*s Sewerage. (Designing, Construction, and Maintenance.) 8vo, 3 Off

Water-supply Engineering 8to, 4 o©

Fuertes's Water and Public Health i2mo. i 50

Water-filtration Works i2mo, 2 50

Gerhard's Guide to Sanitary House-inspection x6ino, i 00

Goodrich's Economic Disposal of Town's Refuse Demy 8vo, 3 so

Hazen's Filtration of Public Water-supplies Svo, 3 00

Leach's The Inspection and Analysis of Food with Special Reference to State

Control Svo, 7 50

Mason's Water-supply. (Considered principally from a Sanitary Standpoint) Svo, 4 00

Examination of Water. (Chemical and Bacteriological.) i2mo, i 25

Merriman's Elements of Sanitary Engineering Svo, 2 00

Ogden's Sewer Design i2mo, 2 00

Prescott and Winslow*s Elements of Water Bacteriology, with Special Refer-
ence to Sanitary Water Analysis i2mo, i 25

* Price's Handbook on Sanitation i2mo, i 50

Richards's Cost of Food. A Study in Di«taries i2mo, i 00

Cost of Living as Modified by Sanitaiy Science i2mo, i 00

Richards and Woodman's Air, Water, and Food from a Sanitary Stand-
point Svo, 2 00

* Richards and Williams's The Dietary Computer Svo, i 50

Rideal's Sewage and Bacterial Purification of Sewage Svo, 3 50

Tumeaure and Russell's PubUc Water-supplies Svo, 5 00

Von Behring's Suppression of Tuberculosis. (Boldiian.) i2mo, i 00

Whipple's Microscopy of Drinking-water Svo, 3 50

Woodhull's Notes on Military Hygiene i6mo, i 50

MISCELLANEOUS.

De Fursac's Manual of Psychiatry. (Rosanoff and Collins.). ■ - .Large i2mo, 2 50
Emmons's Geological Guide-book of the Rocky Mountain Excursion of the

International Congress of Geologists Large Svo, i $0

Ferrel's Popular Treatise on the Winds Svo. 4 00

Haines's American Railway Management i2mo, 2 50

Mott's Composition, Digestibility, and Nutritive Value of Food. Mounted chart, 1 25

Fallacy of the Present Theory of Sound i6mo, i 00

Ricketts's History of Rensselaer Polytechnic Institute, 1824-1894. . Small Svo, 3 00

Rostoski's Serum Diagnosis. (Bolduan.) i2mov i 00

Rotherham's Emphasized New Testament Large Svo, 2 00

Steel's Treatise on the Diseases of the Dog Svo, 3 50

Totten's Important Question in Metrology Svo, 2 50

The World's Columbian Exposition of 1893 4to, i 00

Von Behring's Suppression of Tuberculosis. (Bolduan.) i2mo, i 00

Winslow's Elements of Applied Microscopy i2mo, i 50

Worcester and Atkinson. Small Hospitals, Establishment and Maintenance;

Suggestions for Hospital Architecture : Plans for Small Hospital. i2mo, i 25

HEBREW AND CHALDEE TEXT-BOOKS.

Green's Elementary Hebrew Grammar i2mo, i 25

Hebrew Chrestomathy Svo, 2 00

Gesenius's Hebrew and Chaldee Lexicon t© the Old Testament Scriptures.

(Tregelles.) Small 4to, half morocco, 5 00

LetteMs's Hebrew Bible 8vo, 2 25

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