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LIFE

Its Nature and Origin

by

JEROME ALEXANDER

REINHOLD PUBLISHING CORPORATION
330 West Forty-Second St., New York 18, U. S. A.

1948

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Copyright 1948 by
REINHOLD PUBLISHING CORP.

All rights reserved

Printed in U.S.A. by
The Haddon Craftsmen, Inc.

Preface

The mystery of life, so long unsolved, and by many regarded as
beyond human understanding, has been slowly revealing itself
in the light of scientific investigation. The purpose of this book
is to present in coherent order sufficient facts regarding material
biological phenomena to show that life is dominated by catalysis —
the direction of chemical change by surface areas of specific struc-
ture and efficiency. Catalysts not only direct the chemical changes
essential to life, but some of these catalysts actually are the ulti-
mate living units.

Since matter is the physical basis of life, its successive structural
levels are first considered, and then the ways in which atoms and
molecules aggregate into masses, and the consequences of the
intermixture of substances, even though some are present in mere
traces. The nature of living units is next discussed, together with
the catalytic mechanism whereby life exists, persists, and proceeds.
Immunology, genetics, embryology, diseases and drugs and evolu-
tion are then reviewed, and some speculations as to the origin of
life are outlined. Since the mental and spiritual aspects of life
are quite as real as the material, the last chapter deals with the
equally real interrelation between them, even though its basis is
unknown.

Each chapter should be considered as part of the whole general
picture of life presented, rather than as a separate, isolated entity.
Each topic is treated in as simple and elementary a manner as
justice to the facts of nature will permit. However, experts in the
various fields are aware that no chapter in a book like this can
adequately cover their several specialities. It is felt that this out-
line approach will help the general reader, who is suddenly
confronted with so many diverse and puzzling biological problems.

A word about my personal interest in these problems will be
found on page 277.

This book represents my reactions to enormous advances in all
branches of science for more than half a century. In the attempt
to sketch a coherent picture of life processes, I have freely drawn
upon the recorded mass of scientific data, with references to origi-

iii

iv PREFACE

nal publications where feasible. My thanks are due to many pub-
lishers, institutions, and individuals for information supplied;
acknowledgments for quotations and illustrations are given in
appropriate places.

Jerome Alexander
New York, N. Y.
June 16, 1947

Introduction

The transformation of non-living matter into the multitudinous
forms of living plants and animals, from the visible to the ultra-
microscopic, is one of the least comprehensible of all natural
phenomena. In this book an attempt is made to explain the basic
mechanism of life and its processes in terms of better known and
more readily grasped concepts. Life is so usual, so widespread, so
persistent, that it peculiarly justifies the motto which hangs on the
wall of a large research laboratory:

THIS PROBLEM, WHEN SOLVED, WILL BE SIMPLE

For nature, not limited by our experimental or mental capabili-
ties, solves directly and with ease the most complicated problems
submitted to her. Man spends years in endeavoring to discover
and comprehend her operative mechanisms, in the hope that he
may mold them nearer to the heart's desire.

Though science properly demands that we should accept only
what we can unequivocally demonstrate, it is unscientific to con-
demn a view simply because we cannot check it experimentally
with methods at present known. The future has always brought
new methods, new light, new insight. Napoleon's clever but
sometimes untrue statement — history is a lie, agreed upon —
points up the fact that science has sometimes accepted, taught and
dignified notions later proven to be erroneous — for example, the
indivisibility of the atom, and the belief that all atoms of every
element are precisely alike.

The chemist and the physicist, starting with the many kinds of
atoms and more recently with the fewer kinds of sub-atomic par-
ticles, have been working their way upward into larger aggrega-
tion units, the molecules, and into the still larger macro-molecules,
chain-molecules, molecular groups, and colloidal particles. On
the other hand, biologists in their various fields have been steadily
working downward to smaller and still smaller units in the cell
and "protoplasm," once naively spoken of as "the living jelly."
These two groups of investigators have been drilling a tunnel
through the mountain of ignorance from opposite directions, and

vi INTRODUCTION

though the composite terms "biochemistry" and "biophysics" indi-
cate that they have "holed through," it is no simple task to make a
perfect joining of the two shafts.

Our endeavor will force us to consider facts in many scientific
fields which, for pedagogical convenience, are usually separated
into different areas or disciplines, whose frontiers are often jeal-
ously guarded or at least respected by teachers. Naturally no
attempt is made to give a complete picture of any field or to
include every aspect or detail having a bearing on the problem.
Since What is right? is a more important question than Who was
first? no attempt will be made to settle questions of priority. Nor
is it possible to refer to all pertinent publications; it frequently
happens that the same ideas are independently reached by several
investigators, and the literature is so vast that reference can be
made to only a few publications in the many fields considered.

The last half century has seen such fundamental advances in
science that text-books in actual use are often far behind. This
institutional time lag requires alertness on the part of teachers if
their students are to be kept properly informed. And graduates
must remember that no college or university degree stops the
progress of science. It is hoped that some of the details included
here will prove interesting and helpful to those who, for any
reason, have failed to become acquainted with them, or with their
interrelations. This interest may stimulate readers to seek out
more detailed reviews in the various fields, and thus be led to the
multitude of researches reported in scientific journals throughout
the world.

Newton, with true humility, said that he was able to see so far
because he stood on the shoulders of giants. The real scientific
spirit is not exemplified by the few more selfish but less worthy
scientists who, basking in the spotlight of ephemeral publicity,
forget or ignore what they owe to dead or even to contemporary
colleagues. As the great Lord Rutherford so well said in his last
address: "... it is not in the nature of things for any one man to
make a sudden violent discovery; science goes step by step, and
every man depends on the work of his predecessors. When you
hear of a sudden unexpected discovery — a bolt from the blue, as it
were — you can always be sure that it has grown up by the influence
of one man on another, and it is this influence which makes the
enormous possibility of scientific advance. Scientists are not
dependent upon the ideas of a single man, but on the combined

INTRODUCTION

Vll

wisdom of thousands of men, all thinking of the same problem,
and each doing his little bit to add to the great structure of knowl-
edge which is gradually being erected."1

1 "Background to Modern Science," The Macmillan Co. (N.Y.) and the Uni-
versity Press (Cambridge, Eng.) 1936.

"Books must follow sciences, and not sciences books." — Sir Francis
Bacon, "Of Studies".

Contents

PAGE

Preface iii

Introduction ... v

CHAPTER

1. How Did Life Originate? 1

2. The Smallest Particles of Matter 9

3. How Molecules Make Masses 41

4. The Importance of "Impurities" and Trace Sub-

stances 64

5. What Are Living Units? 79

6. Catalysis, The Guide of Life 90

7. Immunology and Self-Saving Catalysts 140

8. Genetics: The Heritable Transmission of Catalysts 154

9. The Catalyst Entelechy in Differentiation and

Morphogenesis 179

10. Some Catalytic Aspects of Disease and Drugs 215

1 1 . Catalysis As the Efficient Cause of Evolution .... 246

12. Philosophy, the Guide of Mental Life 259

Author's Note 277

Author Index 279

Subject Index 286

62151

Chapter 1

How Did Life Originate?

Regardless of how greatly we may differ as to explanations of
its origin, life is an accomplished fact. H. E. Richter1 and Svante
Arrhenius,2 dodged the whole question of the origin of life by
suggesting that living spores — "seeds of being," Arrhenius called
them — reached the earth from outer space, impelled by "light-
pressure" which James Clerk Maxwell had shown to be an impor-
tant factor affecting the tails of comets. E. Pfiuger3 pointed out
the analogies between proteins and cyanogen compounds, and
suggested that living matter (protoplasm) arose from cyanogen and
other carbon compounds, which formed as the earth cooled. The
view is even now commonly expressed that "protoplasm" arose in
the "primordial oceanic ooze," when the warm oceans were blan-
keted by heavy mists and an atmosphere rich in carbon dioxide.

The following definition of protoplasm appeared in "Encyclo-
pedia Britannica:"4 "A substance, composing wholly or in part
all living cells, tissues or organisms of any kind, and hence re-
garded as the primary living substance, the physical and material
basis of life. ... A living organism of any kind whatsoever may be
regarded as composed of (1) protoplasm, (2) substances or struc-
tures produced by this protoplasm, either by differentiation of the
protoplasm itself, or by the excretory or secretory activity of living
substance." The total inadequacy of this definition led me to
remark:5 "Although isolated protoplasm may maintain activity
for a short time under suitable conditions, it is incapable of self-
reproduction, and should be regarded rather as a highly specific
milieu in which the real, living self-reproductive units of cells
exist and function. The concept of protoplasm as the ultimate
'living jelly' is a relic of antiquated text-books and should be
definitely abandoned. The modern concept of protoplasm em-
braces the cytoplasm with its included nuclear and other par-
ticulate units."

2 LIFE: ITS NATURE AND ORIGIN

"Although the gene is the simplest vital unit definitely known,*
it is possible that in some cases the gene itself is an aggregate of
simpler units which have been called 'gene elements,' or 'genels.'
The hypothetical lower limit of vital units is in the molecular
order, for nothing simpler than a molecule, for example an atom,
depends for its increase in numbers upon forces contained only
within the unit itself.

"The question arises: is there in nature any free-living unit of
the grade of organization and properties of the gene? It has been
suggested that in the bacteriophage and similar ultrafiltrable
particles we are dealing with living units (bionts) which either
are actually of this degree of simplicity or approach it closely.

"Considering briefly the bearing of these ideas on the origin of
life — a very speculative endeavor — it would seem that no biont
as complex in its order of aggregation as a cell, or even a bac-
terium, could have been an initial form of life. The structure of
a cell is a box-within-box series of units, of successively simpler
orders of aggregation, and it seems reasonable to suppose that the
simplest of these units was the first to appear in evolution."6

To the primal living unit, the cooling earth was in effect a
vast sterile, culture medium, and there existed none of the in-
numerable and omnipresent mold spores, bacteria, and other
contaminants that are now the bane of bacteriologists. On the
other hand, while free from competitors and predators, the origi-
nal biont had at its disposal only such molecules as chance for-
mation gave it.

But matter itself is pregnant with the possibility of life. Once
a self-producing unit was formed, its speedy spread was limited
only by the then-existing chemical and physical conditions. From
such a unit, its later analogs, and their modified forms and ever-
varying progeny, there emerged the enormous numbers and varie-
ties of organic molecules now widely available for, and in many
cases essential to the life of present-day organisms. Plants and
animals surviving under present conditions are adapted to world-
wide chemical and physical life with each other, and are in most
cases so interdependent that they no longer possess the ability to
synthesize all the molecules which they need to live and to propa-

* According to the criteria of "living" given later in this volume, ultrafiltrable
viruses and bacteriophages are vital units, and many of them are resolvable in the
electron microscope.

HOW DID LIFE ORIGINATE? 3

gate. In view of changed conditions, if a primal biont were now
re-formed, we could hardly expect it to survive.

Considering the origin of life on the basis of mathematical
probability alone, the chances that atoms and molecules, in suffi-
cient numbers and variety, would gather together to form the
relatively enormous mass and exceedingly complicated structure
of an elephant, a man, a flea, or even an ameba, are so remote
as to be practically nil. But the smaller and simpler the living
unit considered, the greater the probability that the atomic and
molecular units comprising it might have come together by mere
chance. The simplest conceivable living unit, or biont, should
therefore be considered as the type most likely to have begun the
wonderful development of plants and animals which teem in sea,
air, and earth.5

But unrestricted probability calculations cannot be applied to
a case like this. We have ample evidence from chemistry and
physics that only some of the calculable combinations of atoms
yield molecules that are both possible and persistent. The work
of Svedberg indicates that with larger molecular aggregates, only
a few of the many possibilities exist in organisms, the others
apparently being impossible or unstable. The physical structure
of matter thus weights or "loads" the atomic and molecular "dice"
so that only certain combinations actually come into existence.
"Out of the inconceivably great number of possibilities in life
processes, only relatively few regularly develop, because the
results forthcoming are made vastly more probable by factors
often going down to the very electronic configurations of atoms
themselves.'"7

Such considerations call for a modification of the conclusions
which Dr. P. Lecomte du Noiiy8 draws from the probability cal-
culations of Professor Charles-Eugene Guye. Since the original
living catalyst was able to initiate its own duplication, there is no
need to assume the "compound probability" which plagues
du Noiiy when he considers the necessity of hundreds of millions
of identical molecules.

What is the probability that a well-shuffled deck of cards will
be found to have all the hearts, spades, diamonds, and clubs in
perfect sequence, and in the suit order named? Vanishingly small,
according to mathematical probability calculations. But a like
factor of improbability will also apply to any particular sequence
that actually does appear. In the case of our hypothetical primary

4 LIFE: ITS NATURE AND ORIGIN

living unit, the probability of its appearance is vastly increased by
three factors:

(1) the enormous numbers of "card packs" (i.e., mixtures of
atoms and molecules) experimented with over the whole
earth;

(2) the equally large numbers of "shufflings" of these molecular
mixtures over geological epochs, and at high rates of speed;

(3) the inherent structure of material units, which rules out
many, if not most, of the theoretically calculable possibilities.

But the fact remains that living units did arise and undergo
evolution in a most marvelous manner, even though scientists,
gradually emerging from ignorance, are unable in their few
human generations to understand all the biological details of the
past, much less to duplicate them experimentally. We have not
yet discovered a synthetic medium in which to grow viruses or
even the leprosy bacillus, although the latter is closely related to
the tubercle bacillus which grows well in Long's synthetic
medium.

The probability that any living unit will originate spontane-
ously increases enormously with its simplicity. Since we know
neither the nature of the hypothetical first living unit, the nature
of the then-existing milieu, nor the value of the three factors
mentioned above, we have slight basis for calculating the proba-
bility for the chance formation of such a unit. We cannot, even
in imagination, construct a complete picture of terrestrial con-
ditions when life first appeared, say a billion or more years ago.
The composition of the earth's atmosphere; solar radiation and
its ability to reach the earth's surface; the alpha, beta, and gamma
radiations from radioactive atoms — all must have been quite dif-
ferent from what they are at present. Other factors may be
unknown or unweighted; for instance, fourteen hundred million
years ago the amount of uranium isotope 235 was about four
times what it is now.

When once formed, a "living molecule" could serve as a mold
or template for the production, not only of incalculable numbers
of like molecules but also of new types arising from modifications
of the older ones. The initial absence of predators must have
been a most favorable factor; for though the spontaneous gener-
ation of living units may even now be continually occurring at
the ultramicroscopic level, existing and well-established forms of
life make their chance of persistence very slight, either by devour-

HOW DID LIFE ORIGINATE? 5

ing them or by depriving them of nourishment. Furthermore,
the chance of locating such a new living unit in this low size
bracket, of perhaps transient existence, and at unknown place of
origin^ would be very slight.

If a new or a modified self-duplicating agency arises in a cell,
it may persist there, and its presence may lead to chemical conse-
quences which are beneficial to the cell or to the organism of
which the cell is part. If it is carried on to succeeding genera-
tions, it may result in evolutionary advance or retrogression (see
Chapter 11). Where the chemical consequences of the new agency
are harmful to the cell or its organism, they may cause disease or
death (see Chapter 10). The cell or its organism may respond by
forming a specific antibody which will destroy or inhibit the new
agent or its harmful products, just as may happen to any antigen
(see Chapters 7 and 8).

The formation and establishment of a new or a modified self-
duplicating mechanism in any cell or organism is, in effect, the
creation of a new living unit at or near the molecular level. Such
a process may well be of common occurrence, even though the
new units thus formed may not be able to survive if removed from
the special milieu in which they appear. Units like mitochondria
and viruses may thus be formed de novo, even though they may
also be formed by the degeneration of parasitic or symbionic
invaders, along the lines suggested by Prof. Robert H. Green.
But whatever was the structure of the original living unit which
initiated life on this earth, it must have been able to start life
and to persist on the basis of what inanimate nature could then
supply. The origin of new units, or the modification of some of
the existing units, would greatly add to the evolutionary possi-
bilities.

Professor Michael I. Pupin of Columbia University thus con-
cluded an address at a dinner in honor of Sir James Hopwood
Jeans, Professor of Astronomy at The Royal Institution:9

"Science cannot penetrate the mysterious veil which covers the
face of the space-time entity, separating the world of ultimate
reality from the world presented to our senses and interpreted
by mere pictures of mathematical symbols. Faith alone pene-
trates it and finds behind it the throne of the divinity which cre-
ated that space-time entity and filled it with electrons and protons,
and with their offspring, the omnipresent photons, the tiniest and
liveliest energy granules in the ever-expanding interstellar space.

6 LIFE: ITS NATURE AND ORIGIN

One cannot resist the hope that some day, perhaps, we may dis-
cover that these ultra-refined energy granules are responsible for
the first beginning of life and for its never-ending evolution."

But Professor Pupin offered no suggestion as to the kind of
mechanism whereby photons could initiate life. The most reason-
able view, in the light of present knowledge, is that life began
with the chance formation of a self-reproducing unit of molecular
or near-molecular complexity.

Faith

What most persons consider the greatest of all human problems,
survival after death, is one to which we have no direct experi-
mental approach. We treasure memories, mementoes and pic-
tures of those we have loved and lost; we dream of them and yearn
for them, recalling the poignant line of Virgil:

Tendebant manus, ripae ulterioris amore.*

But we face the tragic and inexorable fact so concisely stated by
Omar:

Strange, is it not, that of the myriads who
Before us pass'd the door of Darkness through,
Not one returns to tell us of the Road,
Which to discover xce must travel too?

It is interesting to note that Edgar Allan Poe's "The Raven,"
which depicts the torturing doubts of a bereaved husband, stimu-
lated Dante Gabriel Rossetti to write "The Blessed Damozel,"
which stresses faith in reunion.

Faith involves no compelling necessity for believing that divine
interposition guides every detail of mental and material activity.
Whatever occurs in nature was already inherently possible when
matter came into being. Tyndall said: "I see in matter the poten-
tiality and possibility of all life." This view simply pushes back
the mysteries of life to the creation of matter, a still more remote
mystery not open to experimental attack. But no one doubts the
existence of matter, the forces affecting it, and the fact that living,
thinking beings are continually emerging from it. Yet it requires
even more faith to believe in the reality of matter, which we know
of only indirectly through our senses, than it does to believe in

* "They stretched their hands, yearning for the farther shore." (Aeneid, Book VI).

HOW DID LIFE ORIGINATE? 7

the reality of our mind, with which we are in much more direct
contact.

Just as physicists have been forced to have faith in the existence
of unobservables, as being in the nature of things, so we are forced
to have faith in the reality of "unobservable"* mental and spiritual
phenomena. This philosophical point of view has, of course,
nothing in common with numerous mercenary frauds, or with
delusions based on wishful thinking, or with "mediums," "psy-
chics," "spiritualists," and even some "religions."

Applying Herbert Spencer's criterion of truth — the inconceiva-
bility of the opposite — we are led by faith to believe that life has
some future significance and meaning, even though we are and
must be ignorant of just what it is. Nothing is more real to us
than our own personality, even though we cannot understand its
basis. Most religions and creeds have been formed about this
basic kernel of faith, which, despite uncertainties and fears, re-
mains mankind's greatest comfort; for it involves the hope and
expectation that we shall, in some way, admittedly unknown, be
reunited with those we love. Some accept faith in the persistence
of mind or soul from formal creeds; others are led to this view
by philosophical consideration of the material and spiritual facts
of life. Nevertheless, despite differences of opinion as to matters
within our control, and as to those at present beyond it, we carry
on to serve our living fellows. The following lines expressing
this view have been called "A Scientist's Psalm":

Almighty Power! Too vast to be
Compassed by human mind or hand,
With loving awe we reverence Thee,
Striving to see and understand.

Within the atom's ordered maze,
Earth's lumined book, writ to be read,
Beyond the star-dust's far flung haze,
We seek Thy works with joy, not dread.

Our souls, which by Thy richest grace,
Have waked to justice, mercy, love,
Find in humanity Thy face,
And serving men, serve Thee above.

* Perhaps they should be termed "directly observable."

LIFE: ITS NATURE AND ORIGIN

REFERENCES

*"Zur Darwin'schen Lehre," in Schmidt's Jahrb. d. ges. Med. (1865) 126, 243;
"Bericht iiber medicinische Meteorologie und Klimatologie," ibid. (1870) 147, 57;
"Die neueren Kenntnisse von den krankmachenden Schmarotzerpilzen," ibid (1871)
151, 313.

2 "Worlds in the Making," 1908, pp. 212-231.

3"Ueber die physiologische Verbrennung in den lebendigen Organismen," Arch,
ges. Physiol. (1875) 10, 251.

Mlth ed. (1916) 21,477.

5 Scientia, Oct., 1933, p. 253.

6 Paper presented before the American Association for the Advancement of
Science Dec. 28, 1928 [Science (1929) 70, 508-10] by J. Alexander and C. B. Bridges.

7 "Colloid Chemistry," Vol. II, p. 1, New York, Reinhold Publishing Corp., 1928.

8 "Human Destiny," p. 34, Longmans, Green & Co., 1947.

9 Scientific Monthly, July, 1931, p. 11.

"A little philosophy inclineth man's mind to atheism, but depth in
philosophy bringeth men's minds about to religion." — Sir Francis
Bacon, "Of Atheism".

Chapter 2

The Smallest Particles of Matter

Until comparatively recently, atoms were thought to be the
smallest units of matter. In fact, the word atom, derived from
the Greek, literally means "that which cannot be cut." About 380
B.C. Greek philosopher Democritus, allowing his imagination to
outrun his senses and all means of observation then known, main-
tained that infinite space is populated by an infinite number of
atoms which he conceived to be eternal, homogeneous, invisible,
and indivisible. The smooth, round atoms of water were supposed
to roll readily past each other, whereas the jagged atoms of iron
hooked tightly together. Democritus regarded the soul as consist-
ing of round, smooth and exceptionally mobile atoms which in the
head, control reason; in the heart, anger; in the liver, desire. Life,
he thought, requires the inhalation of fresh atoms to replace those
lost by exhalation; so that when respiration ceases, death results,
and the soul perishes with the body.

To explain nature, Plato and Aristotle invoked human reason
and reactions, rather than matter and experiment. Aristotle con-
sidered that four primary qualities — hotness and coldness, wetness
and dryness — combined in pairs to form the four "elements,"
earth, air, fire and water. These "elements," described essentially
by human reactions, united in various proportions to make up
various kinds of matter.

The atomic views of Democritus were temporarily revived by
Epicurus (341-270 B.C.) and Lucretius (95-51 ? B.C.); but during
the Middle Ages the ideas of Aristotle prevailed, even though his
four elements competed with a subsequent alchemistic notion that
salt, sulfur and mercury are the basic "principles" or "essences."
Thus Chaucer (1340-1400) wrote of the Clerk of Oxenford:

For hym was levere have at his beddes heed
Twenty bookes clad in blak or reed
Of Aristotle and his philosophy,
Than robes riche or fithele or gay sautrie.

9

10 LIFE: ITS NATURE AND ORIGIN

Faith in experiment developed, however, and Leonardo da
Vinci, Copernicus and Galileo are among the predecessors of Rob-
ert Boyle (1627-1691) who, in his book "The Sceptical Chymist"
(1661), espoused the view that unalterable atoms exist, which sur-
vive in various chemical combinations.1

The Electron

Sir William Crookes' electric experiments with vacuum tubes,
together with the work of Hittorf, Goldstein, Varley, and others,
helped develop the concept of radiant energy as a "fourth state
of matter." This resulted in the modern concept of the electron,
a term suggested in 1891 by Dr. G. Johnstone Stoney for the
natural unit of electricity to which he had called attention in
1874.2

The name electron was later applied to subatomic particles
having negative electric charges. Sir J. J. Thomson (Nobel prize,
1891) first called them "corpuscles," when in 1897 he proved them
to be constituents of cathode rays, so named by Goldstein in 1876.
This led to the conception of an electric current as a stream of
electrons.

Professor Robert A. Millikan (Nobel prize, 1917) actually weighed
single electrons and showed that they are all of identical mass — that is
that they all contain the same quantity of matter. In principle, his
method is quite simple. He caught electrons on tiny ultramicroscopic
oil droplets, and observed how much faster a droplet would fall in still
air when one or more electrons were added to the drop. On some
droplets he had as many as 150 electrons, stuck like currents on a bun,
and each of them added the same increment of fall. Millikan's "elec-
trical balance" could weigh accurately and easily to one ten-billionth
of a milligram, whereas the quartz-fiber balance of Ramsay and
Spencer, in a vacuum, was 10,000 times less sensitive. The most deli-
cate chemical balance of fifty years ago could weigh only about 1/100
milligram — for example, your pencilled signature on a card. Accord-
ing to Millikan's estimate, the number of electrons contained in the
1/100,000 of a cent's worth of electricity passing in one second through
a 16-candlepower carbon-filament incandescent lamp is so enormous
that if the (then) 2^ million inhabitants of Chicago were to count
them at the rate of two per second, and were to keep counting steadily
day and night, they would take 20,000 years to finish the count.

Roentgen and X-rays

In 1895 Professor Wilhelm Konrad Roentgen (Nobel prize,
1901) of Wurtzberg found that when the cathode rays in a Crookes

THE SMALLEST PARTICLES OF MATTER 11

tube strike a metal target within the tube, an intensely pene-
trating form of radiant energy emerges. This is known as x-rays
or Roentgen rays; they cause fluorescence in many substances,
and affect photographic plates. I well remember the thrill we
students got when, soon after Roentgen's discovery, Dr. L. H.
Friedburg showed us a photograph of the bones of his hand which
he had taken by means of x-rays emitted by one of the Crookes
tubes in the laboratory of Professor R. Ogden Doremus at the
College of the City of New York.

Becquerel and Radioactivity

Important consequences followed quickly upon Roentgen's dis-
covery. Professor Henri Antoine Becquerel of Paris (Nobel prize,
1903) had developed an interest in fluorescence and phosphores-
cence from his father, also a professor at Paris. In 1880, he had
prepared crystals of the double sulfate of potassium and uranium,
which glow beautfully when exposed to light. To see what con-
nection there might be between phosphorescence and x-rays, Bec-
querel wrapped a number of phosphorescent substances in ample
folds of black paper and placed them on photographic plate
holders. No effect was registered. Recalling his uranium salt, he
tried some that had been illuminated, and obtained a noticeable
photographic effect, which also appeared when he interposed a
thin glass plate to stop possible vapors. At first Becquerel thought
that this was due to phosphorescence; but later he found that the
photographic image was just as marked when the uranium salt
had been kept for weeks in a dark drawer. He also noted that, if
uranium salts are placed near a charged gold-leaf electroscope,
the uranium rays ionize the air and increase its electrical conduc-
tivity. As a result, the charge leaks away more rapidly and the
strips of gold leaf quickly fall together. Becquerel thus discov-
ered the phenomenon of radioactivity, and this had prompt and
extremely important repercussions in many fields of science.

The Curies and Radium

Marie Skladovska Curie (Nobel prize, 1903 and 1911), while
working for her Doctor's degree in Paris, began measuring with a
gold-leaf electroscope the relative radioactivity of various uranium
salts. She quickly found that the radioactivity is proportional to
the amount of uranium present, irrespective of its mode of chem-
ical combination. This indicated that radioactivity is property
of atoms. Thorium, too, was later found to be radioactive. For-

12 LIFE: ITS NATURE AND ORIGIN

tunately, Mme. Curie also tested the original ores (pitchblende
and carnotite) from which uranium is extracted. To her astonish-
ment, they showed much greater radioactivity than pure uranium.
The conclusion was obvious: the ores must contain some substance
or substances more strongly radioactive than uranium.

With her husband, Professor Pierre Curie (Nobel prize, 1903)
she began the exhausting task of trying to isolate this important
"impurity." Their first paper (1898)3 stated: "We believe the
substance we have extracted from pitchblende contains a metal
not yet observed related to bismuth in its analytical properties.
If the existence of this new metal is confirmed we propose to call
it polonium from the name of the original country of one of us."

A few months later came the announcement of radium, the
radioactivity of which is actually about 2,000,000 times that of
uranium. The Curies wrote: "The new radioactive substance
contains a very strong proportion of barium; in spite of this its
radioactivity is considerable. The radioactivity of radium there-
fore must be enormous."

To show the difficulties overcome by these great French scien-
tists in making their epoch-making discoveries, the following is
quoted from "Madame Curie — A Biography," by Eve Curie, her
daughter:4

"It was necessary, of course, to buy this crude material and to pay
for its transportation to Paris. Pierre and Marie appropriated the
required sum from their very slight savings. They were not foolish
enough to ask for official credits. ... If two physicists on the scent of
an immense discovery had asked the University of Paris or the French
Government for a grant to buy pitchblende residues they would have
been laughed at. In any case their letter would have been lost in the
files of some office, and they would have had to wait for months for a
reply, probably unfavorable in the end. Out of the traditions and
principles of the French Revolution, which created the metric system,
founded the Normal School, and encouraged science in many circum-
stances, the State seemed to have retained, after more than a century,
only the deplorable words pronounced by Fouquier-Tinville at the
trial in which Lavoisier was condemned to the guillotine: 'The Repub-
lic has no need for scientists.' "

Rutherford and Radiations

In 1895 Ernest Rutherford began work in the Cavendish Lab-
oratory at Cambridge (England) on the ionization of gases by
x-rays. Reading of Becquerel's work, he made a systematic exami-

THE SMALLEST PARTICLES OF MATTER 13

nation of uranium radiations, and found that there are two types:

(1) alpha rays, now known to be helium nuclei, which produce
intense ionization but are absorbed in a few centimeters of air;

(2) beta rays, now known to be high-speed electrons, which pro-
duce less ionization, but are more penetrating. The still more
penetrating gamma rays, now known to be "hard" or short-wave
length x-rays, were discovered by Villard in 1898. Rutherford,
then at McGill University in Montreal, found that thorium gives
off a material "emanation," which passes through paper but is held
back by a thin sheet of mica. When in contact with substances,
this "emanation" made them radioactive. Radon, the gaseous
emanation from radium, is nowadays collected in tiny tubes which
may be inserted into cancerous growths; it loses half of its radio-
activity in 3.823 days and emits alpha particles at about b\ million
electron-volts.

Ramsay and Helium

A few years later (1903) Sir William Ramsay (Nobel prize,
1904), who had discovered the inert rare gases of the atmosphere
(argon, krypton, xenon, neon, now used in red electric lamps, and
helium, identified in the sun by Sir Joseph N. Lockyer in 1868),
showed that helium is being continuously formed in radioactive
minerals in amounts that can be recognized in a spectrograph, and
that it is another product of radioactive transformations. Alpha
particles are helium nuclei carrying two positive charges.

The rare gases of the atmosphere had actually been isolated by the
distinguished chemist and physicist Henry Cavendish (1731-1810), who
demonstrated the composition of air in 1793 and of water a year later.
But he failed to discover why a tiny residue of "nitrogen" could not be
oxidized: it consisted of the rare atmospheric gases. Much later the
distinguished American chemist, W. F. Hillebrand,5 in the course of
his analysis of the mineral Cleveite, a variety of uraninite rich in
uranium oxide, isolated a small quantity of a gas which, from its inert-
ness, he assumed to be nitrogen. Spectrographic examination would
have proved it to be helium, as Ramsay later found. Actually, Dr. A.
P. Hallock, later Professor of Physics at Columbia University, did
make a spectrographic examination of Hillebrand's "nitrogen" and
observed in it the bright yellow spectral lines of helium. But he, too,
was outfaced from his prize by the skepticism then prevailing against
"new elements." Dean George B. Pegram, Professor of Physics at
Columbia University, informs me that Professor Hallock often spoke

14 LIFE: ITS NATURE AND ORIGIN

with philosophic chagrin of his failure to insist on the significance of
his finding.

All the evidence indicated that radioactive atoms are continu-
ously and spontaneously decomposing — giving off material par-
ticles and powerful radiations; but the precise origin of the matter
and the energy was still unknown.

Soddy and the Periodic Table of the Elements

Frederick Soddy (Nobel prize, 1921) investigated the chemical
properties of the substances released by successive radioactive
transformations, and observed a simple relation, in the Periodic
Table of the elements constructed by Mendeleef and Newlands,
between the position of the original and the final elements in-
volved in a radioactive disintegration series. Almost simultane-
ously Dr. A. S. Russell, Professor K. Fajans, and Dr. Soddy
announced the "displacement law": when a substance emits an
alpha particle (helium nucleus) it moves two places down in the
atomic table; but it moves one place up when it emits a beta
particle (electron). Later on, we shall see the importance of this
in the transformation of uranium 238 into neptunium and plu-
tonium.

In 1906 Boltwood observed that his newly discovered radioactive
element ionium (atomic weight 230) was chemically so similar to
radium (atomic weight 226), that he was unable to separate their salts,
once they were mixed. On the basis of this and similar facts, Soddy
stated (1910): "These regularities may prove to be the beginning of
some embracing generalization, which will throw light not only on
radioactive processes, but on elements in general and the Periodic
Law . . . Chemical homogeneity is no longer a guarantee that any sup-
posed element is not a mixture of several different atomic weights, or
that any atomic weight is not merely a mean number." Professor
Theodore W. Richards of Harvard University (Nobel prize, 1914), in
making extremely accurate determinations of atomic weights, had
found marked differences in the atomic weights of lead from different
sources. Soddy further wrote: "The same algebraic sum of the posi-
tive and negative charges in the nucleus when the arithmetical sum is
different, gives what I call 'isotopes' or 'isotopic elements,' because
they occupy the same place in the Periodic Table. They are chemi-
cally identical, and save only as regards the relatively few physical
properties which depend upon atomic mass directly, physically iden-
tical also."5a

THE SMALLEST PARTICLES OF MATTER 15

Emptiness in the Atom

In connection with cathode-ray experiments conducted with
Heinrich Hertz of radio-wave fame, Phillip Lenard (Nobel prize,
1905) observed that cathode rays could pass through a "window"
of thin aluminum foil and still retain sufficient energy to cause
fluorescence and phosphorescence. Lenard concluded that the
atoms in the foil must have a very open structure, and also that
they might have localized positive and negative electric charges.
Sir J. J. Thomson, in developing this idea, calculated how nega-
tive electrons would be distributed in a sphere of positive charge,
a matter of importance in understanding the Periodic Table.
Professors William Draper Harkins (Chicago), Gilbert N. Lewis
(California), and Dr. Irving Langmuir (Nobel prize, 1928), also
contributed much to establishing how electrons are distributed in
atoms.

Meanwhile, Rutherford had been investigating scattering of
alpha particles by atoms; but his assistant, Dr. E. Geiger, had
observed only small scattering (about one degree) in thin pieces
of heavy metal. However, Rutherford set Geiger and a young stu-
dent, E. Marston, the task of finding out whether any alpha
particles could be scattered through a large angle by impact upon
an atom. Within a few days, to their great astonishment, they
observed some alpha particles coming backward. In a lecture
given shortly before his death, Lord Rutherford said:

"It was quite the most incredible event that has ever happened to
me in my life. It was almost as incredible as if you fired a 15-inch
shell at a piece of tissue paper and it came back and hit you. On
consideration I realized that this scattering backwards must be the
result of a single collision; and when I made calculations I saw that
it was impossible to get anything of that order of magnitude unless
you took a system in which the greater part of the mass of the atom
was concentrated in a minute nucleus. It was then that I had the
idea of an atom with a minute massive centre carrying a charge. I
worked out mathematically what laws the scattering should obey, and
I found that the number of particles scattered through a given angle
should be proportional to the thickness of the scattering foil, the
square of the nuclear charge, and inversely proportional to the fourth
power of the velocity. These deductions were later verified by Geiger
and Marsden in a series of beautiful experiments."

The extent of the "wide open spaces" in atoms is shown in the
following comparison: If the tiny proton nucleus of a hydrogen

16 LIFE: ITS NATURE AND ORIGIN

atom be represented by a period on this printed page, its satellite
electron would be represented by a small pea about 50 miles
away. Some notion as to the immensity of the numbers of atoms
and molecules is given by this estimate of Professor Herbert
Freundlich: Imagine each water molecule in a liter of water
marked for identification, and the whole lot uniformly mixed
throughout all the waters of all the seas and oceans, down to the
lowest depths. Suppose, thereafter, that a liter of water is taken
at random, anywhere in the oceans of the world; it would contain
approximately 25,000 of the original marked molecules.

Isotopes — a New Concept of the Elements

Shortly before World War I, Sir J. J. Thomson developed the
mass spectrograph, an instrument in which positively charged ions
of elements (or of compounds) in motion are subjected to the pull
of magnetic or electric fields and are diverted from their course
in proportion to their mass. On examining (1912) the rare gas
neon, he found that it gave two parabolas, one corresponding to
particles with a mass of 20, the other to particles with a mass of
22; that is, neon has two kinds of atoms. In 1919 Francis William
Aston of Cambridge University (Nobel prize, 1922) using im-
proved apparatus, confirmed Thomson's work and found that most
elements have atoms of different atomic weights, though all atoms
of the same element have the same chemical properties.

Thus fell another dogma of chemistry — the notion that all
atoms of each element are precisely alike. Even in the cases of
the relatively few natural elements where this is so (e.g., beryllium,
fluorine, sodium, argon, phosphorus, manganese, cobalt, arsenic,
iodine, molybdenum, and gold), new man-made radioactive iso-
topes, usually of transient life, have been created.

Some of our natural elements have quite a number of isotopes, all
chemically the same because they have the same net positive nuclear
charge and therefore the same number of planetary electrons; but the
masses of the isotopes may differ considerably. It is the exterior
electron rings which determine the chemical properties of an atom,
recalling the saying that beauty is only skin deep. In the case of the
metal tin, nine radioactive isotopes have been made synthetically,
with half-lives running from 9 minutes to 400 days; but the natural
metal consists of ten isotopes whose atomic weights range from 112
to 124.6 Chemists use the average, 118.70 as the atomic weight of tin;
for though the mass of the individual atoms varies, the natural average
is practically constant, and all the atoms act chemically like tin.

THE SMALLEST PARTICLES OF MATTER 17

The question of isotopes is no longer academic. In order to
make the first of the "atomic bombs" tested at Alamogordo, New
Mexico, and later used at Hiroshima, the fissionable uranium
isotope 235 had to be separated from the non-fissionable isotope
238 by an ingenious application of the process of differential dif-
fusion of uranium hexafluoride. This work was based on the
pioneer diffusion experiments of Thomas Graham, in the course
of which he coined the word "colloid" and established much of
the nomenclature of colloid chemistry. The bomb dropped on
Nagasaki was of the new fissionable material plutonium, synthe-
sized (indirectly) by bombarding the isotope U238 with neutrons.

Another outstanding case of the importance of isotopes is found
in our lightest element, hydrogen. The discovery by Professor
Harold C. Urey (Nobel prize, 1934) that common water contains a
"heavy" fraction, was quickly followed by the isolation of deu-
terium, whose atomic weight is double that of hydrogen. Natural
hydrogen contains 0.02 per cent of deuterium, whose nuclei con-
tain one proton and one neutron, and have a net nuclear charge
of one. Triple hydrogen, called tritium, with a radioactive half-
life of about 30 years, has been artificially produced; it may be
readily stored by combining it with lithium as lithium tritide.

Moseley and X-ray Spectra

Henry G. Moseley was killed at Gallipoli in 1915 at the age of
28 as a result of the unwise drafting of highly trained scientists;
his death was both a calamity and a disgrace. He had already
brilliantly begun investigating the relation between nuclear charge
and atomic number — the property which fixes the position of an
element in the Periodic Table. Moseley used the crystal spec-
trometer developed by Sir William H. Bragg and his son, Sir
Lawrence Bragg, who jointly received the Nobel prize in 1915. A
direct correlation was discovered between the wave lengths of
x-rays emitted where different metals were used as targets in the
x-ray tubes, and the atomic number of the metal. The x-ray
spectra varied uniformly and regularly, all the lines being similar;
but they shifted in frequency in passing from one element to the
next, because they all depend upon the number and arrangement
of the planetary electrons circulating about the nucleus, whose net
positive charge Moseley supposed to be identical with the atomic
number. This was later proved by Sir James Chadwick (Nobel
prize, 1935).

18 LIFE: ITS NATURE AND ORIGIN

Then Dr. Niels Bohr (Nobel prize, 1922) developed his quan-
tum theory of spectra, referred to by Rutherford as one of the
greatest triumphs of the human mind. Within ten years all the
main features of optical spectra were understood, largely helped
by the application of wave mechanics by Werner Heisenberg
(Nobel prize, 1932), Erwin Schrodinger (Nobel prize, 1933), and
P. A. M. Dirac (Nobel prize, 1933).

Rutherford and Atomic Transmutation

In 1919 Rutherford made the astounding discovery that when
light atoms are bombarded by alpha particles shot out at very high
speeds from radioactive substances, scintillations could be detected
in a device called a "cloud chamber." When nitrogen was the
gas bombarded, these scintillations struck out 40 centimeters or
more. By subjecting these new "rays" to the action of a magnetic
field and observing their deflection, Rutherford found that they
had the mass and charge of protons — that is, they were hydrogen
nuclei. His explanation was that when the helium nucleus (alpha
particle) enters the nucleus of a nitrogen atom, the nitrogen
nucleus is forced to eject a proton. The final result is a nucleus
with a positive charge of 8 and a mass of 17 — one of the isotopes
of oxygen.

Professor Harvey E. White writes:7 "The discovery of the dis-
integration and transmutation of stable elements by controlled
experiments is attributed to the great experimental genius, Sir
Ernest Rutherford. Outsiders might say the discovery was an
accident, but to those who knew him well it was the result of a
long series of well-planned experiments. True, he did not pre-
dict the phenomenon and then discover it, but his long experi-
ence with radioactivity and his keen insight enabled him to
recognize the meaning and importance of the phenomenon when
it was first observed. Due credit must also be given to the admir-
able work of his collaborators and to experimenters in other
laboratories who have since carried the work much further."

And I cannot refrain from repeating here what some scientific
wag wrote of Rutherford:

He made plain the invisible;
He broke up the indivisible;
He changed the immutable;
And he unscrewed the inscrutable.

THE SMALLEST PARTICLES OF MATTER

19

Professor William D. Harkins and his collaborators, who were
for fifteen years (1913-1928) the only scientists in America en-
gaged in work on the structure of the atomic nucleus, advanced
the idea that an intermediate compound nucleus of short life was
formed by the impact of the alpha particle.8 He came to this
conclusion soon after Rutherford's 1919 experiment, and repre-
sents the transmutation of N14 into O17 by the following diagram:

The almost incredible density of atomic nuclei appears from the
following quotation from Harkins' paper: "The electron, or elec-

projectile;

PRODUCTS

Figure 1. Formation of oxygen 17 and hydrogen 1 by the disintegration of
fluorine 18, the intermediate nucleus formed by the impact of helium 4 with nitro-
gen 14. Open circles = neutrons. Circles with plus signs=protons. At higher
energies the excited fluorine nucleus disintegrates in two ways: (1) that given in
the diagram, and (2) to give a neutron and positive electron in place of a proton
(=hydrogen 1). [Courtesy Science, Vol. 103, No. 2671 (1946)]

trons, may be considered to move around the nucleus, where they form
a cloud which is exceedingly tenuous, when considered in comparison
with the high density of the nucleus. The mass of the proton is
1.672 x 10"24 gram. If this is contained in the 1.4 x 10~38 cc. consid-
ered as its volume, the density is 1.2 X 1014 grams, or 130 million tons
per cc. Thus, the whole earth would have a diameter of only 460
meters, or less than a third of a mile (0.286 mile) if its whole mass
were present as protons and neutrons packed as they are in the nucleus
of an atom. The presence of electrons, however, reduces the density
from 1.2 x 1014 g. per cc. to that of the earth (5.522 g. per cc.) which
is 20 million million times smaller."

Neutrons and Positrons

Though both Rutherford and Harkins independently assumed
as early as 1920 that the neutron exists, it was not discovered until

20 LIFE: ITS NATURE AND ORIGIN

1932 by Sir James Chadwick (Nobel prize, 1935). This opened
the way for understanding how the heavy proton and the agile
electron can be associated with still other particles in atomic
nuclei. In 1932 Carl David Anderson (Nobel prize, 1936) dis-
covered the positron, or "positive electron." We have as yet no
complete explanation of how, under sufficient impact or excita-
tion, electrons (beta rays) and positrons may emerge from atomic
nuclei. Rutherford suggested that within the confines of the
nucleus where particles are at close grips and subject to enormous
forces, protons may change to neutrons, and vice versa. P. A. M.
Dirac (Nobel prize, 1933), predicted that if a high frequency
gamma ray (a high-energy photon) were to pass near enough to
an atomic nucleus, the powerful nuclear field would "annihilate"
the gamma ray, and "create" a pair of particles, an electron and a
positron. This phenomenon, known to physicists as pair produc-
tion, was soon observed by P. M. S. Blackett and others.9

Joliot and Induced Radioactivity

In 1934, Jean Frederick Joliot and his wife Irene Curie-Joliot
(Nobel prize, 1945) while bombarding aluminum with alpha par-
ticles from polonium, found that even after the polonium emitter
had been removed, the aluminum still continued to emit radia-
tion— that is, it had become radioactive. What happened may be
understood from the following:

jHe<+uAl" ,16p30+onl

\

MSi3°+_ie0

The entering alpha particle had changed the aluminum into an
unstable isotope of phosphorus with the ejection of a high-speed
neutron; and the phosphorus nucleus (half-life 2.55 min.) gradu-
ally changed into a stable isotope of silicon. On dissolving the
radiated aluminum in HC1, adding some ordinary inactive phos-
phorus-containing salt, and then carrying out an ordinary analyt-
ical group separation, the radioactivity followed the phosphorus.

Ernest O. Lawrence and the Cyclotron

In 1932, Professor Ernest O. Lawrence of Univ. of California
(Nobel prize, 1940) announced the cyclotron. Hundreds of syn-
thetic isotopes have been recognized, and these have been mainly
produced by use of the cyclotron. Following the announcement

THE SMALLEST PARTICLES OF MATTER 21

of the Curie-Joliot discovery, Lawrence bombarded sodium with
2 mev (million electron-volt) deuterons, from his cyclotron, and
found that it became radioactive. The radio-sodium formed has
a half-life of only 15 hours; it changes into a stable isotope of
magnesium, giving off an electron and a gamma ray.

When a high-speed deuteron from the cyclotron crashes into a beryl-
lium nucleus, an unstable, radioactive isotope of boron is formed,
which becomes a stable isotope of boron by ejecting a neutron of
21 mev energy. Unstable nuclei are also capable of undergoing
multiple and branch disintegrations. For example, when boron is
bombarded by protons it forms an unstable carbon nucleus, 6C12, which
breaks down in steps into three helium nuclei; and on bombarding
lithium with deuterons, the unstable 3Li6 formed may break down
either into 3Lit + 1Hx, or into 2He4 + 2He4.

Professor Glenn T. Seaborg (California) has described10 the trans-
uranium elements thus far produced, as well as the astonishing ultra-
microchemical methods used in following the work, including the use
of quartz fiber microbalances with a sensitivity of 0.02 ^g. The new
elements are neptunium (Np239, half-life 2.3 days), plutonium (Pu239,
half-life 24,000 years), americum (Am95, half-life 500 years) and curium
Cm96, half-life of isotope 240, one month; of isotope 242, five months).
Both neptunium and plutonium have other isotopes than the main
ones above indicated. On Aug. 18, 1942 the first pure chemical com-
pound of plutonium was produced, and Seaborg states: "This memor-
able day will go down in scientific history to mark the first sight of a
synthetic element and the first isolation of a weighable amount of an
artificially produced isotope of any element."

Enrico Fermi and Nuclear Fission

Shortly after Chadwick had discovered the neutron, Professor
Enrico Fermi (Nobel prize, 1938) made a number of new radio-
active isotopes by exposing various elements to this uncharged
missile. Usually the nucleus would capture the neutron, and
often the atom would return to a stable state by emitting a beta
ray, thereby yielding an element having an atomic number one
unit higher in the Periodic Table than the parent atom. Fermi
wanted to see what would happen in the case of uranium, the last
element in the atomic table with an atomic number of 92. After
prolonged exposure to neutron bombardment, the activity showed
the existence of particles with jour half-lives, and indications of
others; but natural uranium has only three isotopes. This led to
the notion that one of the supernumerary activities might be due

22 LIFE: ITS NATURE AND ORIGIN

to a newly formed transuranic element 93, which ought to appear
in the Periodic Table in the same column with manganese. So
the irradiated uranium was dissolved with a manganese salt, and
the manganese was precipitated as Mn02. This precipitate carried
with it part of the 13-minute and 90-minute activity, and many
scientists took up the quest for transuranic elements.

In Germany, Otto Hahn (Nobel prize, 1946) and F. Strassman
made careful chemical separations of the dissolved uranium, and
were astonished to find radioactive atoms belonging to a number
of different elements, mostly those about the center of the Periodic
Table. These results were passed to Professor Niels Bohr, then
at Princeton University, reaching him at a meeting of the Ameri-
can Philosophical Society; and many nuclear physicists who
attended the meeting confirmed the results.11 Professor Henry D.
Smyth states:12 "Just before Bohr left Denmark, two of his col-
leagues, O. R. Frisch and Liese Meitner (both refugees from
Germany) had told him of their guess that the absorption of a
neutron by a uranium nucleus sometimes caused that nucleus to
split with the release of enormous quantities of energy, a process
that soon became known as 'nuclear fission.' Before considering
further details about the "atomic bomb," let us see whence comes
the huge amounts of energy released by nuclear fission.

Albert Einstein and the Relation Between Mass and Energy

About the end of the last century, Hendrik Antoon Lorentz
(Nobel prize, 1902) in developing an electron theory of matter,
assumed that the mass of an electron increases with increase in
its velocity;123 but if the velocity could be equal to the speed of light
(186,000 miles a second) the mass would be infinite. Therefore, no
material body, as we know matter, can travel with the speed of
light.13 Measurements on electrons emitted at high speeds from
radioactive elements indicate that those with velocities of 1 per cent
of the velocity of light (i.e., 1,860 miles per second) show no
appreciable increase in mass; at 50 per cent of the velocity of light
the mass increases 15 per cent, while at 99 per cent of the velocity
of light the electron showed more than seven times its mass when
at rest.

Albert Einstein (Nobel prize, 1921) derived from his restricted
theory of relativity an equation similar to that of Lorentz. Ein-
stein also derived what is known as the mass-energy equation,
E = mc2, where E is the energy equivalent of mass, c the velocity

THE SMALLEST PARTICLES OF MATTER 23

of light, and m the mass. This means that if one pound of matter
could be entirely converted into energy, it would yield 1 X (186,000
x5,280)2 foot-pounds of energy, or nearly 11£ billion kilowatt
hours of energy, an amount nearly equal to the total monthly
output of the electric power industry in the United States as of
1939. In the fission of the U235 nucleus it is estimated that only
one-tenth of one per cent of the total mass-energy is released,
i.e., 11-J million kilowatt hours per pound.

Experimental Proof of the Equivalence of Mass and Energy

Proof that Einstein's equation satisfactorily expresses the relation
between mass and energy is concisely stated by Professor H. D. Smyth12
about as follows: Gradual improvement in high-voltage technique
made it possible to substitute artificially produced high-speed ions of
hydrogen or helium for natural alpha particles. J. D. Cockcroft and
E. T. S. Walton in Rutherford's laboratory were the first to succeed
in producing nuclear changes by such methods. In 1932 they bom-
barded a target of lithium with protons of 700 kilovolts energy and
found that alpha particles were ejected from the target as a result of
the bombardment. The nuclear reaction which occurred can be
written symbolically as

3Li7+1H1-^2He<+2He*
where the subscript represents the positive charge on the nucleus
(atomic number, generally represented by Z, the number of nuclear
protons), and the superscript is the number of massive particles in the
nucleus (??iass number, which is the sum of the number of protons and
neutrons, but which omits the tiny masses of any electrons, positrons,
or other particles which may be present).

The above equation, like most chemical equations, does not include
anything relative to mass or energy, but merely indicates a redistribu-
tion, in nuclei, of protons and neutrons. Since both mass and energy
are indestructible, their sums should be the same before and after the
reaction. The masses of Li7 and H1, as determined from mass spectra,
total 8.0241, while the mass of 2He4 is 8.0056. Therefore 0.0185 unit
of mass "disappeared" in the reaction.

The experimentally determined energies of the alpha particles (2He)
was approximately 8.5 million electron-volts each — a figure so great
that the kinetic energy of the incident proton which caused the change
may be neglected. That is, 0.0185 unit of mass had disappeared and
17 mev of energy had appeared. To convert these figures into quanti-
ties we can use in the Einstein equation, we must remember that in
atomic and nuclear physics the unit of mass is one-sixteenth of the
mass of the predominant oxygen isotope, O16, which is equal to

24 LIFE: ITS NATURE AND ORIGIN

1.6603 x 10"24 gram. The unit of electric charge used is the positive
charge of the proton, which is equal in magnitude but opposite in sign
to the charge on the electron, and is often called the electronic charge;
its value is 1.60xl0-19 coulomb. The energy unit used in nuclear
physics is the electron-volt, denned as equal to the kinetic energy which
a particle carrying one electronic charge will acquire in falling freely
through a potential drop of one volt. Since this is so tiny, the million
electron volt unit (mev) is commonly used.

Returning now to the experimental results, 0.0185 mass unit is
3.07 x 10-26 gram, 17 mev is 27.2 x 10-6 erg, and c (the velocity of light)
is 3xl010 cm per second. On substituting these values in Einstein's
equation, E = mc2, we have

27.2xl0-c erg = 27.6xl0-6 erg
which is quite a good approximation to the equality of both sides.

Source of the Sun's Radiant Energy

According to C. G. Abbott, the energy received by the earth
from the sun is about 1.7 horsepower per square yard (1.47 kw
per square mile). This indicates an emission by the sun's surface
of 7.88 X 104 horsepower per square yard (6.79 X 104 kw per square
meter), which is heat enough to melt 39.6 feet of ice or to vaporize
5.92 feet of water per minute. Together, all the planets receive
less than 1/1 20th of one-millionth part of this tremendous energy,
which the sun has been pouring out for at least several billion
years. Apart from the fact that solar temperatures enormously
exceed those of any known chemical reaction, a sphere of coal the
size of the sun, burning in pure oxygen, would be entirely com-
sumed in about 6,000 years. The notion that meteoric matter,
falling into the sun, is a material factor in maintaining its heat
has long ago been dismissed, as has also the notion of Helmholtz
that solar contraction can account for the maintenance of solar
heat.

The discovery of radioactivity, however, opened the door to new
vistas. Thus R. A. Sampson14 stated: ". . . if the sources of energy
within the atom can be drawn upon, there is here an incalculable
source of heat which takes the cogency out of any calculation
respecting the sources of maintaining the sun's radiation. An
equivalent statement of the same conclusion may be put thus.
Supposing a gaseous nebula is destined to condense into a sun: the
elementary matter of which it is composed will develop in the
process into our known terrestrial and solar elements, parting
with energy as it does so."

THE SMALLEST PARTICLES OF MATTER 25

In 1897 Lord Kelvin advanced views as to the age of the earth,
based on Helmholtz' contraction theory.15 Professor T. C. Cham-
berlin (Chicago) replied thus to Kelvin's statements:10

"What the internal constitution of the atoms may be is still an open
question. It is not improbable that they are complex organizations
and seats of enormous energies. Certainly, no careful chemist would
affirm either that atoms are really elementary or that there may not be
locked up in them energies of the first order of magnitude. No
cautious chemist would probably venture to assert that the component
atomolecules, to use a convenient phrase, may not have energies of
rotation, revolution, position and be otherwise comparable in kind
and proportion to those of a planetary system. Nor would he prob-
ably be prepared to affirm or deny that the extraordinary conditions
which reside in the center of the sun may not set free a portion of
this energy. The Helmholtzian theory takes no cognizance of latent
and occluded enemies of an atomic or ultra-atomic nature."

Professor H. A. Bethe of Cornell has advanced17 a theory, now
generally regarded as reasonable, that the heat radiated by the sun
is mainly due to a series of nuclear transformations which may be
indicated thus:

13

(1) 6V* + JV >7N

(2) 7N" >6C13+1e°

(3) .C^H1 >7N"

(4) 7N"+1H1-

8v-'

,0

(5) 8015 >7N13+ie°

(6) 7N,5+1H1 ^C^+oHe4

The final result of these changes is the transformation of hydro-
gen into helium and positrons (ie°), with the release of about
thirty million electron volts. We know nothing of what is hap-
pening within the body of the sun, but to maintain its high rate
of radiation, it must be losing mass at the rate of about 4,000,000
tons per second. It is consoling to remember that since the total
mass of the sun is estimated to be 2.2 X 1027 tons, it would require
about a million years for the sun to lose one ten-millionth of its
mass, provided that nothing fell into it.

So terrific is the development of solar energy, that apart from
the gigantic craters which we call "sun-spots," huge bursts of incan-
descent matter are being continually ejected from the sun's sur-
face at the rate of thousands of miles per hour, and some of these
"prominences" jump half a million or more miles outward.
During the total eclipse of 1919 (see Figure 2) there was seen a

26 LIFE: ITS NATURE AND ORIGIN

gigantic prominence resembling an ant-eater, 350,000 miles from
snout to tail. Before setting of the sun removed it from visibility,
it rose about 475,000 miles above the sun's surface.18

Figure 2. The Ant-eater prominence (May 29, 1919). The whole length of this
prominence was ahout 350,000 miles. (Courtesy A. C. Crommelin, Greenwich Ob-
servatory; from "The Stars in Their Courses" by J. Jeans, The Macmillan Co., N. Y.)

The following comparison between chemical and nuclear heat

is of interest, the chemical example representing an oxy-hydrogen

flame:

4 grams H + 32 grams 0 = 36 grams FLO+ 136,000 calories
1 gram H + 7 grams sLi7^8 grams 2He4 + 5 billion calories.

The "annihilation energy" of one electron is 0.5 mev, while that

of one mass unit is 931 mev.

THE SMALLEST PARTICLES OF MATTER 27

Origin of the Solar System and the Age of the Earth

The Planetesimal Hypothesis of Professors T. C. Chamberlin
and F. R. Moulton early in this century advanced the view that
some ten or twenty billion years ago the sun passed sufficiently
close to another star to raise vast tides and to stimulate greatly the
sun's internal activities, so that vast streams of matter were ejected,
both toward and away from the visiting star. While most of this
matter fell back into the sun, about one-seventh of one per cent
of the sun's mass remained swirling about the sun, all in one direc-
tion. The larger masses served as nuclei upon which the smaller
ones collected into planets and their satellites. (Despite its nine
moons, Saturn still has two rings, apparently consisting of unaggre-
gated particles.) This hypothesis accounts well for the fact that
all the planets and most of their satellites move in the same direc-
tion and approximately in the plane of the ecliptic. The few
retrograde bodies may represent "captures," e.g., of some cometary
body.

Professor Lyman Spitzer, Jr.,19 has attacked this hypothesis, and
holds that material ejected by the sun or by a star would be too
hot to condense to form separate bodies, but would dissipate into
space.20 Astrophysicists face conditions not found on our earth.
Thus in some stars, for example, the "dark" companion of Sirius,
atomic fragments are so closely packed that a single quart has an
estimated mass of about 40 tons. On the other hand, atomic
nuclei are much denser, as appears from the statement of Professor
W. D. Harkins, quoted above.

As to the probable age of the earth, there is more agreement.
According to Professor Louis B. Slichter,21 geophysicists recognize
three major divisions of the earth: (1) a heavy core with a mean
density of 10.7, apparently fluid and possibly consisting of a mix-
ture of nickel and iron; (2) a thick but much lighter mantle
(density, 3.4 to 5.7) overlying the core and composed of ultrabasic
rocks, the iron content increasing with depth; (3) the thin crust
above the mantle (total thickness about 20 to 60 kilometers), con-
sisting of several layers of lighter rocks. "It has long been recog-
nized that the radioactive heat being generated in rocks is large
enough to be a major influence in the earth's thermal history . . .
Radioactive determinations of old crustal rocks indicate that the
time which has elapsed since the solidification of the oldest rocks
is about H to 2 billion years."22

28 LIFE: ITS NATURE AND ORIGIN

While some helium is probably lost, determinations on rocks
preceding the Cambrian indicate an age for the solid earth of
about 1,830 million years, and this checks fairly well with a "lead"
age calculation as determined on uraninite found in Russia.23

Volcanism and Nuclear Energy

At Paricutin (Mexico) we have been witnessing the birth and
formation of a volcano in what had been flat farming country.
After three years the cone has reached a height of over three thou-
sand feet, and in the fall of 1946 two new craters were reported
emitting floods of lava. Professor Wilbur A. Nelson (Virginia)
estimated that during the Cretaceous period a Tennessee volcano
spat up over fifty cubic miles of material, part of which settled
down to form beds of bentonite clay extending nearly 500 miles
north and south, and nearly 400 miles east and west. But the
Paricutin manifestations are trivial compared with what happened
at Krakatoa within the memory of many now living.

Krakatoa is a small volcanic island in Sunda Strait between Java
and Sumatra. A prehistoric explosion had blown away some old
volcano, leaving an outer ring of islands outlining its huge crater.
Later, the main cone, built up by subsequent eruptions, rose over
2,600 feet above sea level. About 1877 earthquakes began, and
on Aug. 26th, 1883, came a series of gigantic explosions lasting
three days, which blew away the entire north and lower portion
of the island, leaving a bare vertical cliff which revealed the
interior of the volcanic cone Rakata. It replaced heights of from
300 to 1,400 feet with submarine cavities 1,000 feet deep in some
places. The huge amount of matter cast out to an estimated
height of 17 miles gave off a colloidally dispersed dust cloud, or
aerosol, which travelled to Europe, Asia, Africa, North and South
America, and throughout Australasia. This cloud reached north-
ern Scandanavia and the Cape of Good Hope, and caused brilliant
sunsets for several years. Pumice floated for hundreds of miles,
and ocean waves, some 50 feet high, reached Cape Horn (nearly
8,000 miles) and perhaps the English Channel (11,000 miles).
More than 36,000 people were killed. The sound of the explo-
sions carried nearly 3,000 miles, being heard in the Philippines,
Ceylon, and in South and West Australia — by far the greatest dis-
tance sound has been known to travel. On the morning of
Aug. 27th, a most powerful explosion originated an atmospheric
wave which, being reflected or reproduced at the antipodes to

THE SMALLEST PARTICLES OF MATTER 29

Krakatoa, "was observed not fewer than seven times at many of
the stations, four passages having been those on the wave travelling
from Krakatoa and three those of the wave travelling from its
antipodes, after which its traces were lost" (Sir R. Strachy).

The comparatively recent eruption of Mont Pele, Martinique,
was much milder and more akin to the "atomic bomb." On
April 25th, 1902, there was a discharge of ashes, and a heavy
flow of lava occurred on May 2nd and 3rd. On May 8th a sudden
explosion tore away the whole side of the mountain — the gash
was clearly visible in 1939 — and released what Zsigmondy called
a nuee ardente — a cloud of superheated steam, gases, and col-
loidally dispersed particles of rock. About 40,000 persons perished,
and all ships in the harbor, except the Roddam, were destroyed.
Metal work on the Rodda?n was melted by the blast; but a pris-
oner in a dungeon cell in the town was later found alive, though
spoons and glass goblets in the room above his cell had been
melted. This bespeaks the intense but short-lived heat. It is
known that under heat and pressure water "dissolves" in silicates,
and the effects may have been due to the sudden explosive release
of such a superheated mass, with atomization of the hot rock.

Dr. Leason H. Adams24 has advanced the view that volcanism is
based on radioactivity, and I give below a note of his theory which he
kindly prepared at my request:

"The central problem of volcanism is to devise a mechanism which
will explain the existence of local hot spots in the Earth's crust,25
whereby at present, as during past geological epochs, eruptions of
molten lava and hot gases may take place in localized areas. Volcanism
is still a highly controversial subject among geologists and geophysi-
cists, though many attempts have been made to explain it. A theory
which has appealed to some of those who have given much attention
to the subject attributes the local heating to slight variations in the
average radioactive content of the rocks forming the crust in the active
area. The theory is based on the following considerations:

"(1) The rocks of the Earth's crust contain a minute but very
important amount of uranium and its disintegration products, includ-
ing radium. In terms of radium, the amount of radioactive material
in the usual igneous rocks is of the order of magnitude of one part in
a million million; but the heat generated by even this minute amount
of radium in a volume of rock measured in cubic miles, is very con-
siderable.

"(2) The temperature gradient in the crust of the Earth (now judged
to be more than 2,000,000,000 years old) is profoundly affected by

30 LIFE: ITS NATURE AND ORIGIN

radioactive heat generated in the crust. Something like three-fourths
of the present thermal gradient may be attributed to radioactive heat,
and the balance to the residual heat of the originally molten globe.

"(3) Any reasonable interpretation of the laws of heat conduction
leads to the conclusion that at moderate depths within the Earth's
crust, say a few tens of miles, the temperatures are still very close to
the melting points of the rocks at the particular depths.

"(4) From the foregoing it may be concluded that a relatively small
increase in the radioactive content of the Earth's crust at a particular
locality will raise significantly the temperatures of the rocks at depths
miles below the surface, and may easily bring the temperatures above
the melting point, thus maintaining a lava reservoir in that region.
In other words, a somewhat greater amount of radium averaged
through the vertical extent of the crust (but still very small in absolute
magnitude), could account for the existence of a volcanic region.

"Against this theory, it has been urged that examinations of volcanic
lavas and emanations have failed to reveal any striking increase in
radioactive elements. It must be noted, however, that since the excess
of radium required to produce a volcanic region is proportionally so
small in amount, it would be difficult to establish experimentally,
without careful sampling; and particularly that the examination of a
few samples of rocks would not be conclusive as to the local average
radioactive content in a particular region.

"It must be admitted that the explanation of volcanism on radio-
active grounds has not been generally accepted, though some thought-
ful geologists and geophysicists have been impressed with the idea. An
alternative theory explains volcanism, in part at least, by chemical
reactions taking place in the rising lava column. Perhaps the radio-
active theory should best be regarded as a subject for further observa-
tion and analysis."26

The "Atomic Bomb"

The term "atomic bomb" is a mumpsimus — a Latin word intro-
duced into the English language to indicate persistence in obvious
error;* it originated in the fact that an old priest who had for
forty or more years used this word, refused to change to sump-
simus, even when shown the correct word in the prayer book.
The correct term is "nuclear fission" bomb.

It is fortunate for the world and for civilization that we were
able to win the feverish race to produce the "atomic bomb"; for
our enemies had been making desperate efforts to accomplish this
difficult task and to use against us and our allies this most potent

* Abandonment of such an error is now termed a sumpsimus.

THE SMALLEST PARTICLES OF MATTER 31

of all explosive weapons. We read the Smyth Report with
mingled feelings — pride in the splendid scientific achievements
revealed; joy for the speedy and enforced surrender of those who
had set out to enslave the world, and for the saving of millions
of lives on both sides — both soldiers and civilians — who would
otherwise have perished had the war been continued; sorrow for
the much lesser number who died in the nuclear explosions, and
for the fact that these epoch-making scientific discoveries were
prostituted to military uses, instead of being devoted to the
benefit of humantiy.

It was already known that the isotope U235 would undergo nuclear
fission by slow or thermal neutrons; but natural uranium contains
only about 0.71 per cent of this isotope (AcU235), 0.006 per cent of
isotope 92UII234, but 99.28 per cent of isotope 92UI238. So besides
rinding out how to separate the isotope 235 for immediate use, a
major problem was to find a way to utilize the major portion of the
natural metal, bv converting: the U238 into something: fissionable.
Thomas Graham had developed the mathematical expression or "law"
regarding gaseous diffusion, and though many other methods were
investigated, the separation was successfully made by differential dif-
fusion of uranium hexafluoride, UF6. Since the rate of diffusion of
gases through chemically indifferent septa is inversely proportional to
the square roots of their molecular weights, the difference in the rate
of diffusion between U235F6 and U238F6, whose molecular weights are
349 and 352 respectively, is very slight indeed. Immense technical
difficulties had to be overcome in handling so corrosive and dangerous
a substance during the 4000 diffusion cycles necessary.27

Meanwhile, it had been found that by radiating 92U238 with neu-
trons, it could be transformed into 92U239, by taking the neutron into
its nucleus and emitting /3-radiation. This new 239 isotope of ura-
nium has a half-life of only 23 minutes; it emits an electron and
becomes an entirely new element, neptunium, 93Np239, which has a
half-life of 2.3 days. Neptunium, in turn emits an electron and
becomes another new element, plutonium 94Pu239, which is relatively
stable, having a half-life of 24,000 years, and emits alpha rays (helium
nuclei).

Plutonium was "manufactured" in a "pile," consisting of a
matrix of highly purified graphite with tubular passages into
which were inserted aluminum "cans" containing uranium rods,
protected from the cooling water needed to carry off the intense
heat generated; for the production of 1 gram of plutonium per
day involves liberation of energy at the rate of 500 to 1,500 kilo-

32 LIFE: ITS NATURE AND ORIGIN

watts. The graphite matrix is needed to slow down high-speed
neutrons sufficiently to obtain the desired fission effect. The
intense radiation fields of the pile changed the electric resistance,
the heat conductivity, and the elasticity of the graphite.

To maintain the pile in operation, conditions had to be chosen so
as to maintain a "chain reaction" by continuous formation of sufficient
neutrons, allowing always for the waste due to non-effective neutron
collisions, absorption of neutrons by impurities, and escape of neutrons
from the pile. Since the object of the pile is to produce plutonium
by chain reaction, it is desirable to absorb all excess neutrons in U238,
leaving just enough neutrons available to maintain the chain by their
action on U235, aided by high-energy fission of U238 and thermal fission
of Pu239. While collisions between neutrons and U238 occur with
neutrons of all energies, they are most probable with those whose
energies lie in the "resonance" region, located somewhat above ther-
mal energies. So great is the tendency of the dominant isotope U238
to absorb neutrons compared to their tendency to cause fission of the
140 times less numerous U235 atoms, that this fission had to be favored
by use of materials of high purity, by a suitable lattice, use of a
moderator, etc.

After sufficient plutonium had been produced in the pile, the
slugs of uranium were withdrawn and dissolved, and the plu-
tonium was separated by co-precipitation with some other ele-
ment, an expedient common in radioactive chemistry. The chem-
istry of plutonium had been worked out previously, on an ultra-
microchemical scale.

Because of the extremely dangerous radiations emitted through-
out the several processes, they must all be operated by remote
control, the personnel being shielded by heavy concrete and metal
walls. Smyth states that plutonium is one of the most dangerous
substances known if it gets into the body; and the fission products,
which include some thirty elements, are also very active and
troublesome. These major fragments of the fission of uranium
are released in considerable quantity when the slugs of uranium
are dissolved, and high stacks had to be built to carry off the
deadly gases without endangering the surrounding countryside.

Most of the technical difficulties involved in assembling the
"atomic bomb" arose from the fact that the time interval between
the beginning and the end of a chain reaction is extremely short.
The efficiency of the bomb depends on the ratio of (a) the speed
with which neutrons emitted by the first fissions can get to other

THE SMALLEST PARTICLES OF MATTER 33

nuclei and produce further fission, and (b) the speed with which
the material of the bomb flies apart. Since a mass of plutonium
or of U235 above a critical size would spontaneously undergo
explosive fission, to produce satisfactory detonation the bomb
must consist of separate pieces so small that they are incapable of
doing this. These are shot together to create the explosion.

This "critical size factor" is one of the most amazing properties
of fissionable materials. The "critical mass" necessary for explo-
sion is guessed to be from five to fifteen pounds.

The Successive Levels of Material Structure

The accompanying table shows the various material units at
present recognized, and their position in order of size and mass
relative to units which are generally known. It must not be
assumed, however, that our present inability to break up the
"ultimate" units, e.g., protons, electrons, etc. represented on the
diagram as of zero order of complexity, is to be considered as final
evidence of their actual simplicity. In fact, the "spin" of an elec-
tron is a factor well recognized in atomic and nuclear physics, and
this may be due to some kind of complexity. Besides, we cannot,
even in imagination, go down to the ultimate particle or particles
of matter, even though we recognize the realities which emerge
from them.

In order to locate man and biological happenings in their rela-
tive position in universe, especially introducing the essential time
factor so often omitted from consideration, there is also given a
table showing measurements in space, mass, and time, reaching in
each case from the greatest to the smallest known or readily
calculable "unit."

Dr. Edwin Hubble (Mt. Wilson Observatory, Carnegie Institu-
tion) compares our stellar system to a drifting swarm of bees, the
sun, with its relatively insignificant family of planets, being a fairly
small star in the swarm. Astronomers, peering out into the vast
emptiness of space, see other stellar systems so distant that they
appear merely as unresolvable patches of light, and are therefore
called nebulas. The "observable region" is a sphere, roughly
600 million light-years in diameter, within which are scattered
about 100 million nebulas, averaging 1| million light-years apart,
80 million times brighter than the sun, and 800 million times
greater in mass. The faintest nebulas that our present telescopes
can detect lie at the peripheral surface of this sphere. Whatever

34

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LIFE: ITS NATURE AND ORIGIN

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THE SMALLEST PARTICLES OF MATTER 37

matter may be scattered in space between the nebulas does not
dim appreciably the most distant ones now visible. Dropping this
from consideration, the concentration of matter in the visible
region figures out to about one gram per 1030 cubic centimeters,
which is equivalent to one grain of sand in each volume of space
equal to that of the earth.28

Plummeting down to our own tiny but (to us) important levels,
we find that life depends upon a great variety of ordered chemical
reactions which are rather limited in space, mass, and time. Living
units have masses ranging from the molecular or near-molecular
up to the immense bulk of the whale or elephant. The chief
chemical elements involved are carbon, hydrogen, oxygen, nitro-
gen, phosphorus, sulfur, sodium, potassium, calcium, iron, mag-
nesium, and manganese; but quite a number of other elements
are also essential or incidental, in amounts small in percentage but
large in numbers of atoms, e.g., copper, zinc, fluorine, vanadium
and molybdenum. From this quintessence of dust, living units
have emerged on our tiny planet which in the slow course of time
developed brains and bodies with which they can receive and
order sense impressions, remember, think, and reason. How all
this happens, no one knows; but the result is undoubted, irrespec-
tive of what words are used to describe it — mind, psyche, soul, etc.
It is recognized in our laws, is studied by psychologists, psychia-
trists, sociologists, and teachers, and dominates the daily life of
every one of us.

In a biographical sketch of Emil Dubois-Reymond, apparently
written by Sir Michael Foster,29 the following is quoted as the
dominant note of "Elements of Physiology" by Johannes Miiller,
central figure of modern physiology:

"Though there appears to be something in the phenomena of
living beings which cannot be explained by ordinary mechanical,
physical or chemical laws, much may be so explained, and we may
without fear push these explanations as far as we can, so long as
we keep to the solid ground of observation and experiment."

Since we now have a continuity of successive levels of material
structure down to the nuclear level, there is no longer any "no-
man's land" where material mysteries of life can escape scientific
investigation. Our present knowledge, based on observation and
experiment, indicates that the simplest living units are in the
molecular or near-molecular range. The information assembled
in this book indicates that many, if not all the basic material facts

38 LIFE: ITS NATURE AND ORIGIN

of life are understandable on catalytic principles, including selec-
tive adsorption and differential diffusion. But the mental and
spiritual phenomena which emerge, and which are just as real as
the material ones, are as inscrutable as ever.

REFERENCES

1 For further historical aspects, reference must be made to books on the history of
science, e.g., that of Sir William C. Dampier (3rd ed., Macmillan Co., New York,
1944).

-'Stoney's original papers are in Proc. Brit. Assoc. Adv. Science, Belfast meeting,
1874, and in Trans. Roy. Dublin Soc, (1891), 4, 583. See also "The Electron Theory"
by Fournier d'Albe, London, 1907.

3 Comptes rendus, July, 1898, "On a New Radioactive Substance Contained in
Pitchblende."

4 English translation by Victor Sheean, Doubleday, Doran & Co., Inc., 1937.

5 "On the Occurrence of Nitrogen in Uraninite and on the Composition of
Uraninite in General," U. S. Geol. Bull., 78, 43-79 (1889-90).

5a About 1865 the great Belgian chemist Jean Servais Stas wrote: "I have arrived
at the absolute conviction, the complete certainty, so far as is possible for a human
being to attain to certainty in such matters, that the law of Prout is nothing but
an illusion, a mere speculation definitely contradicted by experience." (It should
be stated, however, that shortly before his death in 1891, on noting the close
approximation to integers shown by a number of atomic weights when hydrogen
is taken as unity, Stas remarked: "II faut croire qu'il y a quelque chose la-dessous.")
But in 1932 Soddy wrote: "After many vicissitudes and the most convincing apparent
disproofs, the hypothesis thrown out so lightly in 1815 by Prout, an Edinburgh
physician, has a century later become the corner-stone of modern theories of the
structure of atoms. There is something surely akin to, if not transcending tragedy
in the fate that has overtaken the life work of that distinguished galaxy of
nineteenth century chemists, rightly revered by their contemporaries as representing
the crown and perfection of accurate scientific measurement. Their hard-won
results, for the moment at least, appear as of little interest and significance as the
determination of the average weight of a collection of bottles, some of them full
and some of them more or less empty."

6 Isotopes of tin:

tomic Wt.

Percentage

112

—

1.1

114

—

0.8

115

—

0.4

116

—

15.5

117

—

9.1

118

—

22.5

119

—

9.8

120

—

28.5

122

—

5.5

124

—

6.8

7 In his book "Classical and Modern Physics" p. 564, New York, D. Van Nostrand
Co., 1940.

8 See his extensive historical review in Science, 1946, 103, 289-302.

9 The reader must consult special books and journal articles regarding these
matters, and also about mesons, cosmic rays, and other developments.

THE SMALLEST PARTICLES OF MATTER 39

10 Science, Oct. 25th, 1946.

"See Physical Review, Jan. 15th and Feb. 15th, 1939.

12 "A General Account of the Development of Methods of Using Atomic Energy

for Military Purposes," (Princeton Univ. Press, 1945).

12a Lorentz, equation is

mo
m =-

1-

a

where m is the mass of the moving electron, mQ its mass when at rest, v its velocity,
and c the velocity of light in a vacuum.

13 In Nature, Nov. 1913, F. Soddy suggested that while the principle of relativity
indicates that relative velocities greater than that of light are physically impossible,
yet there is an actual possibility of observing in nature a relative velocity con-
siderably greater. Thus if two /3-particles are shot out by a radioactive body in
opposite directions, each with a velocity nine-tenths that of light, their actual
relative velocities would be 1.8c. Regarding this E. Cunningham ("Relativity and
the Electron Theory," Longmans, Green & Co., London, 1915) states (p. 40): "This
is quite true, and the principle of relativity has nothing to say against it. The
principle maintains that a velocity greater than c relative to the observer cannot be
observed. . . . The position is not that velocities greater than c are not conceivable,
but that real bodies become illusory in observation if they are conceived to be
moving faster than light. We shall also see later that the electrical constitution of
matter seems to indicate that a body would suffer dissolution if it were accelerated
so that its velocity were made greater than c."

14Enc. Brit., 11th ed., 1910.

15 One of his addresses on this topic appeared in Science, 1899, 9, 666-74, 704-11.

16 Science, 1899, 9, 889-901, and 10, 11-18.

17 Astrophysical Jour., 1940, 92, 118.

18 The late Dr. W. S. Andrews (General Electric Co.) published in Scientific
Monthly, Dec, 1928, 27, pp. 535-8, a paper entitled: "Hypon — A Hypothetical
Element and a Possible Source of Stellar Energy," in which he suggested the
possibility that what astronomers call novae are due to the sudden and terrific
explosion of "hypon," mass 118. He gave the following table, showing the
position of this hypothetical "element," which we would now speak of as
"transuranic":

Helium 2(F) 2

Neon 2(l2+22) 10

Argon 2(l2+22+22) 18

Krypton 2(12+ 22+22+32) 36

Xenon 2(l2+22+22+32+32) 54

Radon 2(l2+22+22+ 32+32+42) 86

"Hypon" 2(l2+22+22+32+32+42+42) 118

19 Astrophysical Jour., 1939, 90, 675-88.

20 C. S. von Weizsaker (Astrophysical Journal, March, 1945) proposed a different
hypothesis, and still others are discussed in "The Observatory" for August, 1945.
Evidently there is no agreement as to the mode of origin of the solar system.

21 Bull. Geological Soc. of America, April 1, 1941, pp. 562-99.

22 Since ^UI238, ^AcV^33, and ^Th232 are continuously degenerating at constant
speed into ^Pb206, gaPb207, and ^Pb208, with the respective liberation of 8, 7, and 6
helium nuclei, geophysicists use an "age equation" of the following form:

Amount of disintegration product

Affe — — — —

Rate of production of disintegration product

40 LIFE: ITS NATURE AND ORIGIN

"Age" means the time elapsed since the final solidification of the rock or mineral
containing the radioactive element.

23 For further details, see a paper by Professors Clark Goodman and Robley D.
Evans (M.I.T.), Bull. Geol. Soc. of America, April 1st, 1941, pp. 492-541.

24 /. Wash. Acad. Sci., 1924, 14, 459-472; Trans. Am. Geophys. Union, 1930,
pp. 309-41.

25 The Byrd expedition reported (1947) the presence of two "oases" in Antarctica.
Coal is mined in Spitsbergen, only ten degrees from the North Pole. About li/2
billion years ago radioactivity from TJ235 alone was four times what it is at present.
J. A.

26 See also A. Knopf, in "A Textbook of Geology," by Longwell, Knopf and Flint,
Part I, 2nd ed., J. Wiley & Sons, Inc., New York, 1939.

27 For further details, see W. D. Harkins, Science, March 8th, 1946, p. 293, and
Smyth Report, 9.14.

28 Scientific Monthly, Sept., 1934.
^Encylo. Brit., 11th ed., 1910, 8, 626.

Chapter 3

How Molecules Make Masses

Atoms and molecules are so tiny that they seem quite remote.
Only under unusual experimental conditions do we deal with the
effects which they produce as individual bodies of matter. In the
practical affairs of life and in most scientific investigations as well
we are concerned with large numbers of atoms or molecules
which, when gathered together, form masses large enough to be
experimented upon, or even to become microscopically visible.
The smallest particle we can distinguish or "resolve" in micro-
scopes may contain many millions of the smaller molecules, or a
great number of macromolecules.

The convenient shorthand used by chemists to describe a com-
pound, generally called its formula (little or concise form) is far
removed from what that molecule may actually be like under
natural conditions. When Ira Remsen of Johns Hopkins Uni-
versity presented his students with the customary formula for a
double salt, e.g., PtCl4 . 2KC1, he would point to the period in the
formula and remark with a twinkle in his eye, "That period has
for many years been a full stop to thought. Don't let such devices
keep you from trying to find out what lies behind them." Even
the more informative "structural formulas" are only static dia-
grams, which give no indication of the dynamics of atomic and
molecular structure, though in some cases straight or curved arrows
are added to indicate oscillatory or resonance changes.1

Though three-dimensional isomers (stereoisomers) have been known
since the discovery by Pasteur of right- and left-handed tartaric acids,
the extent of this phenomenon and its biological importance are only
now being increasingly recognized. For example, Professor L. Zech-
meister of the California Institute of Technology1 gives skeleton
models of the twenty stereoisomers of beta carotene. (See Figure 3).
Many of the naturally occurring carotenoids have a much larger
number of calculable stereoisomers, two having as many as 128.

41

42

LIFE: ITS NATURE AND ORIGIN

n

ID

!?

I?

>r\

ffi

xx

Figure 3. Skeleton models of the twenty possible stereoisomers of /3-carotene:
all -^ram-/3-carotene, three mono-c/s-/3-carotenes, six di-ciV/3-carotenes, six tri-cis-/3-
carotenes, three tetra-ci's-/3-carotenes, and all-cfs-/3-carotene. (Courtesy Chemical Re-
views)

HOW MOLECULES MAKE MASSES 43

Crystals and Colloids

Water is commonly referred to as H20, and many know that
there are also present a small number of molecules of "heavy
water" (deuterium oxide, D20), the average ratio being one mole-
cule of deuterium to 6,500 of hydrogen. The physical chemist,
however, is aware that under ordinary conditions water molecules
undergo dissociation into H+ and OH", with recombination at such
a rate that with very pure water at 22° C we have at any instant a
concentration of these oppositely charged ions of 1/10,000,000

mole per liter, which equals — - or 10 7 mole per liter. This is

commonly expressed by saying that pure water has a pH of 7,
which means that its concentration of hydrogen ions is expressed
by the mathematical exponent 7, deprived of its minus sign.
The French expression first used by S0rensen was "pouvior hydro-
gene," or hydrogen power (in the mathematical sense of the word
"power"). As a consequence, the intervals on the pH scale, being
exponential, are vastly wider than the figures themselves might
indicate. This may be seen from the following table:

pH Number of times H+ or OH- concentration

exceeds that of pure water at 22° C

1 1,000,000

2 100,000

Acid side 3 10,000

(excess of H + ions) 4 1 ,000

5 100

6 10

Neutrality > 7 0

8 10

9 100

Alkaline side 10 1,000

(excess of OH- ions) 11 10,000

12 100,000

13 1,000,000

In most living units the pH hovers near neutrality, the pH of the
blood in man ranging from 7.30 to 7.45, the former approaching
"acidosis" which is really a dimished alkalinity. The cytoplasm of
immature starfish eggs shows a pH of about 6.6 to 6.8, while that of the
nucleus is 7.6 to 7.8. However, the skin is usually quite acid (about pH
4.2 to 5.6) and Professor Frank C. Combes states2 that this acid mantle
is an important factor in the protection of the organism against
invasion by bacteria and fungi.

In certain protected spots, (e.g., the axilla and between the smaller

44 LIFE: ITS NATURE AND ORIGIN

toes), the pH may be closer to alkalinity and become favorable to the
growth of some micro-organisms. Thus, the fungus Tinea, which
causes "athlete's foot" commonly grows between the toes, and may be
combatted by acid germicidal ointments containing, e.g., salicylic acid
and sulfur; and the highly acid sulfate of alumina is the basis of most
cosmetics used to combat under-arm odor. So old is this custom that
the elder Pliny (Gaius Plinius Secundus), the Roman encyclopedist
who perished while investigating the great eruption of Vesuvius which
buried Pompeii and Herculanium in 79 A.D., mentions in his "Natural
History"3 that "alum is used for offensive odors in the axilla." In the
stomach the gastric juice has an acidity of between pH2 and 3, corre-
sponding to about 0.1 to 0.2 per cent hydrochloric acid. In some
snails and ascidians (e.g., Phallusia), the blood may be quite acid.

Water has one other peculiarity which is generally overlooked,
namely, the tendency of its molecules to form groups, probably in
part through hydrogen bonds. This phenomenon, common to
many other substances4 is known as molecular association; and
water contains double and triple molecules (dihydrol and tri-
hydrol) whose percentages vary with conditions. According to
N.E. Dorsey,5 many accept the quasi-crystalline theory of water
structure sponsored by J. D. Bernal and R. H. Fowler6 and M. L.
Huggins,7 which demands a fairly rigid structure for water. But
it must be remembered that, apart from whatever structure water
may assume as the result of a kinetic equilibrium of its ions and
molecules, a supermolecular structure may at times appear at
levels higher than those before mentioned. Thus Professor H. T.
Barnes of McGill University, in speaking of frazil — a type of ice
occasionally giving much trouble to users of hydraulic power
by obstructing the flow of water like the slimy precipitates met
with in chemical analysis — says that when first formed it is too
fine to be seen by the eye, apart from its action on the color of the
water. But it soon agglomerates into spongy masses of loose tex-
ture, which readily catch onto subjects in the water, and quickly
build large masses. The slightest drop in temperature below
0° C may cause frazil to appear. "The balance is so delicate that
it will escape detection by the most sensitive thermometer and the
first indication that a drop has occurred will be the appearance of
ice." The action of frazil on the appearance of the water brings
to mind the familiar glooming or darkening of clouds when rain
impends.

It is pertinent here to quote the remarks of Thomas Graham (1861):
"Ice itself presents colloidal characters at or near its melting point,

HOW MOLECULES MAKE MASSES 45

paradoxical though the statement may appear. When ice is formed at
temperatures a few degrees under 0° C, it has a well-marked crystalline
structure, as is seen in water frozen from a state of vapor in the form
of flakes of snow and hoar-frost, or in water frozen from dilute sul-
furic acid, as observed by Mr. Faraday. But ice formed on contact
with water at 0° C is a plain, homogeneous mass with a vitreous frac-
ture, exhibiting no facets or angles. This must appear singular when
it is considered how favorable to crystallation are the circumstances in
which a sheet of ice is slowly produced in the freezing of a lake or
river. The continued extraction of latent heat by ice as it is cooled
a few degrees below 0° C, observed by Mr. Persons, appears also to
indicate a molecular change subsequent to the first freezing.

"Further, ice, although exhibiting none of the viscous softness of
pitch, has the elasticity and tendency to rend seen in colloids. In the
properties last mentioned it suggests a distant analogy to gum incom-
pletely dried, to glue or any other firm jelly.

"Ice further appears to be of the class of adhesive colloids. The
reintegration (regelation of Faraday) of masses of melting ice when
placed in contact has much of a colloidal character. The colloidal
view of the plasticity of ice demonstrated in glacial movement will
readily develop itself.

"A similar extreme departure from the normal appears to be pre-
sented by a colloid holding so high a place in its class as albumen. In
the so-called blood-crystals of Funke, a soft gelatinous, albumenoid
body is seen to assume a crystalline contour.

"Can any facts more strikingly illustrate the maxim that in nature
there are no abrupt transitions, and that distinctions of class are never
absolute?"

It is of interest to note that the word "crystal" arose from the notion
that rock crystal (clear, transparent quartz obtained from the Alps in
ancient times), had been formed from water by intense cold. The
word is derived from the Latin crystallum (clear ice) or the Greek
krystallos, (from kryos, frost). Not until the 17th century was the
word extended to the crystals familiar to all of us. In fact, the Romans
called many crystals glasses (vitrum), and this survives in such expres-
sions as blue vitriol (copper sulfate crystals), white vitriol (zinc sulfate),
and green vitriol (ferrous sulfate). The corrosive, oily liquid obtained
by distilling "green vitriol" was called "oil of vitriol."

While there is no space here to consider the experimental and
theoretical aspects of crystals and crystallization, a few popular
misconceptions should be set straight. First, Thomas Graham,
the father of colloid chemistry, was well aware of the fact that the
same substance may exist either in the colloidal or the crystalloidal

46 LIFE: ITS NATURE AND ORIGIN

state. He wrote:8 "For the mineral forms of silicic acid, deposited
from water, such as flint, are often found to have passed, during
the geological ages of their existence, from the vitreous or colloidal
into the crystalline condition (H. Rose). The colloidal is, in fact,
a dynamical state, the crystalloidal being the statical condition."

We now know that the basis of colloidality is degree of dispersion
(size or dimension of particulate units), and that many colloidal or
"amorphous" substances contain crystals or colloidal dimensions,
though non-crystalline aggregates may also be present. In the early
part of this century, P. P. von Weimarn showed that any substance may
be obtained either in the colloidal or the crystalline state, depending
on conditions of its formation.9 Recently, rubber hydrocarbons and
viruses have been crystallized. The devitrification of glass by slow
crystallization may make it turbid and brittle, a condition sometimes
noticed in old chemical glassware and tubing. Professor Alexander
Silverman of the University of Pittsburgh kindly gave me a well-
developed crystalline globulite obtained from a tank of glass that had
cooled slowly when a factory suddenly shut down and was later aban-
doned. I have seen a similar globulite said to have been found in an
ancient Mesopotamian glass furnace.

What may happen, if we wait long enough for results, is also
shown by the huge deposit of travertine (a calcareous rock), at
Mammoth Hot Springs, Yellowstone National Park, Wyoming.
Owing to the sudden release from solution and loss of carbon
dioxide, and assisted by the crystal-inhibiting action of the colloidal
algae which grow on the overflow surfaces, the freshly deposited
travertine has a filamentous or or cryptocrystalline structure. The
older deposits show increasing evidence of crystallinity, and in the
oldest deposits at the top of the terrace-hill, estimated by geologists
to have been laid down twenty to thirty thousand years ago, good-
sized, sparkling crystals are found, which still maintain the rhyth-
mic rings of the original deposit.

Graham had remarked: "The formation of quartz crystals at low
temperature, of so frequent occurrence in nature, remains still a
mystery. I can only imagine that such crystals are formed at an
inconceivably slow rate, and from solutions of silicic acid which are
extremely dilute. Dilution no doubt weakens the colloidal char-
acter of substances, and may therefore allow their crystallizing
tendency to gain ground and develop itself, particularly where the
crystal, once formed, is completely insoluble, as with quartz." We
must consider, however, another mode of crystal formation, which,

HOW MOLECULES MAKE MASSES 47

though it may not be true of quartz, should clarify the mystery
Graham refers to.

Petrographers have long noticed the incipient crystal forms
(crystallites) which appear in media where high viscosity and quick
cooling oppose crystallization, as in obsidian, pitchstone, etc.
Such forms can be obtained artificially from a solution of sulfur
in carbon disulfide, made viscous by the addition of some Canada
balsam. If a drop of this solution is rubbed out on a microscope
slide and blown upon to speed the evaporation of the solvent, any
or all of the following stages may be seen on microscopic examina-
tion: (1) tiny globules (possibly containing ultramicroscopic crys-
tals); (2) aggregations of these globules into bead-like strings or
margarites (Greek, margaritis, a pearl), or into geometrical groups;
and (3) tiny crystals surrounded by empty spaces or lacunae, indi-
cating that the surrounding material had gone to make up the
crystal.10

The various intermediate steps in the formation of visible
crystals are very often observable in window-pane ice, when con-
ditions are right. In fact, during a half-hour ride in a Fifth
Avenue bus in New York City on a very cold day, the transition
from the "ground-glass" effect of globules, to dendrites (tree or
fern-like formations), and ice-crystals with lacunae, took place be-
fore my eyes. Mr. Wilson A. Bentley of Jericho, Vermont, had
for years made photographs of a great many varieties of the frozen
forms of water, including snow, hoar-frost, hail, and window-pane
ice. On seeing some of these printed in the National Geographic
Magazine of 1923, and later in a copy of the Monthly Weather
Review for Nov. 1907, which Mr. Bentley kindly sent me, I recog-
nized each of the phenomena above mentioned. Besides, there
were a number of cases where specific dendritic forms indicated
the presence on the glass of sodium chloride and some protective
colloid, both perhaps coming from the soap used to clean the
window-pane.

The usual course of crystallization seems to proceed in the fol-
lowing steps: (1) as drop in temperature or loss of solvent lessens
the capacity of the magma or solvent mass to hold the atoms, ions,
or molecules of the dispersed substance in true solution, they form
groups which clump together into tiny crystals or amorphous
heaps (crystallogens); (2) when these clumps become large enough,
their kinetic activity drops, and they are aggregated by surface
forces into spherulites; (3) the spherulites then unite to form

48 LIFE: ITS NATURE AND ORIGIN

dendritic or larger groups; (4) the tiny units now slip, snap, or re-
orient to form large crystals, which are usually full of tiny im-
perfections, as many, including Sir William H. Bragg, Smekal,
and Zwicky have noted.

According to Professor G. W. Stewart11 x-ray and other evidence
indicate that the molecules within a liquid fall roughly into two
classes: (1) those comparatively free; (2) those in semi-orderly array.
He terms these fluctuating molecular "mobs" cybotactic groups, which
in the case of liquid para-azoxyanisol, may consist of perhaps 100 to
1,000 molecules. In a liquid crystal of this substance these companies
are ordered into regiments composed of perhaps millions of mole-
cules. In the case of numerous kinds of liquid crystals (O. Lehmann,
1889), these "regiments" form still larger groups of various kinds,
some smectic (soap-like), others nematic (worm-like).12

In 1907, I independently observed the effects of colloids on
crystallization. But the phenomenon has been repeatedly noted
by others.13 Many artifacts, bearing remarkable resemblances to
structures developed by living units, have been produced by forma-
tion in the presence of colloids.14 In 1925 I drew special atten-
tion15 to a most remarkable but unappreciated book by Dr. Wil-
liam M. Ord.16 This book, which I first chanced to see adver-
tised in a second-hand dealer's catalog, sums up the work done by
Ord, George Rainey of St. Thomas' Hospital, Professor Hartung
of Utrecht, and others, much of which is buried in oubliette
journals. Of the many interesting observations (e.g., the use of
double colloidal protection) I here give the following excerpt

17

"It will be useful first to review the more important of the processes
by which the modification of the crystalloid to the spheroidal form is
effected.

"(1) A new salt is formed by decomposition, and caused to combine
in its nascent state with the colloid . . . The colloid may be of the
proteid or the gelatinous kind, or amyloid, or pectous, or an isomeric
modification of an organic crystalloid, as uric acid, or of an inorganic
crystalloid, as silicic acid, peroxide of iron, etc. Thus Mr. Rainey
mixes two gummy solutions of the reacting salts;* Professor Hartung
places solid salts at different points of an albuminous solution; in
my own plugged tubes the reacting solutions are placed on opposite
sides of a thick colloid dialyzer, within which they meet and undergo
mutual decomposition. A modification of this condition is employed
when urate of soda is formed by boiling uric acid with strong solutions

* This is actually double colloidal protection. J. A.

HOW MOLECULES MAKE MASSES 49

of chloride of sodium or phosphate of sodium. The urate comes down
in a colloidal state, and affects included crystals as any other colloid
would.

"(2) A crystalloid is deposited from solution in the presence of a
colloid. This occurs in Dr. Guthrie's experiment with sulfate of
copper and gelatin, in uric acid and urates mixed with albuminous
urine.

"(3) Crystals are broken down and turned into spheres or spheroids
or molecules, by the action of colloids into which they are introduced
— a condition constantly seen in microscopical preparations. Crystals
of uric acid, carbonate or oxalate of lime, etc., when preserved in
gelatin or glycerine or glycerine-jelly, speedily lose their transparency,
lose their sharp outlines, and progress in various degrees towards
sphericity. I have drawn attention to this in respect of glycerine in
particular, in the Quarterly Journal of Microscopic Science for 1873.
The transformation of crystals of murexide put up in glycerine is a
particularly beautiful phenomenon, exquisite tufts of black-looking
needles growing at the expense of the brilliant purple prisms.

"When we seek the causes of the spheroidal modification, several
possible influences present themselves for consideration.

"(1) The 'Nascent' State ... a review of the behavior of the various
salts and matrices favors the idea that the nascent modification of sub-
stances is an important element in the production of changes of form.
This I have pointed out in earlier papers in relation to uric acid,
which is certainly precipitated in colloid form when freshly dis-
possessed of its combinations by other acids. The colloid state has
been called its hydrate by Prout; and, while in aqueous solutions it is
short-lived, in colloidal solutions or mixtures it endures for a long
time. An analysis of the phenomena in a great number of experi-
ments made with various media makes me inclined to believe that
hydrated colloids and very strong solutions of very soluble salts have
the power of prolonging the colloid state of certain crystals. In respect
of the present inquiry, any prolongation of the colloidal state in sub-
stances precipitated must favor the production of spheroidal forms.
Our knowledge, indeed, of the ways of higher colloids must be
admitted to be elementary. Of the albumens, for instance, we know
really little more than their rough chemical reactions; and though the
reports of various societies embalm fragments of what may be more
properly called their natural history, most of these fragments remain
unnoticed or useless. Whenever these fragments shall be put together
and supplemented by further investigation, the connection between
colloidality and hydration will be required to be carefully worked out.
With this the meaning of the 'nascent' state of substances will form a
congenial subject of inquiry; and at present the probability suggests

50 LIFE: ITS NATURE AND ORIGIN

itself to me that the nascent state is allied to or even identical with
the colloid state of matters. Just as chemical substances may be either
gaseous, fluid, or solid, as some are commonly seen in all states, some
only in one, while many which we are accustomed to see in only one
may by special experiments be brought into the other forms, so it
seems to me probable that all matters, when deposited from solution,
or otherwise assuming a solid form, a liquid or gaseous form, have, or
tend to have, a colloid and a crystalloid stage, both of which may be
well marked, as in silica, or one of which may be more marked than
the other, as in uric acid or only one of which may at present be
recognized, as in chloride or zinc on one side, in albumen on the
other. . . .

"(2) Hydration. Professor Guthrie . . . throws out a suggestion that
the partial dehydration of sulfate of copper has to do with the forms
found in the evaporated gelatine solution . . . But . . . sulfate of
barium contains no water, yet undergoes the spheroidal change in the
most complete way. The same may be said of carbonate of barium, of
carbonate and sulfate of strontium, and of cholesterin, all of which
readily form spheres. . . . Dehydration, partial or complete, can cover,
therefore, only part of the facts.

"(3) Crystalline Form. I have sought in vain for any indications of
any difference in the tendency to sphericity, or in the modifications
of spheroidal form assumed by different substances, which might be
attributed to their belonging to one or other group of crystalline
forms.

"(4) Relative Solubility. The best spheres are certainly obtained
when substances of little or no solubility are deposited by double
decomposition; and when a very moderate degree of insolubility is
reached, as in triple phosphate, spheroidal forms are only with great
difficulty obtained by that process. But by evaporation (Guthrie), and
by deposition from hot, concentrated solutions (nitrate of urea, ferro-
cyanide of potassium) very soluble matters may be made spheroidal. . . .

"(5) Influence of the Colloid. . . . The assumption of the spheroidal
state, and the throwing off of the crystalline state, are both consistent
with the idea of a state of movement possessing the molecules, engross-
ing them so fully as to render them insusceptible to attractions by
which, being at rest, they would be held and controlled. . . .

"Graham has spoken of colloid as the dynamic form of matter. The
constituents of their large molecules are in a perpetual movement or
strain tending to ultimate rest in crystallinity, either by isomeric
change or by decomposition. The viscosity characteristic of them in
their most perfect state, instead of appearing to me as a peculiarity
related to their animal and vegetable origin, is partly due to the size
and immobility of their chemical molecule, partly also to their intes-

HOW MOLECULES MAKE MASSES 51

tinal* movements, belonging so far to the same class of conditions as
the spheroidal state of water. . . .

"The idea of a 'combination' between the colloid and the crystalloid
as constituting an essential part of the whole phenomenon is insisted
upon by both Mr. Rainey and Professor Hartung. If by this is meant
chemical combination, the idea does not seem to be to be well founded.
The observation of Professor Hartung that albumen undergoes a chem-
ical change where the spheres are formed — an observation which
agrees with what occurs in urinary calculi — does indeed go to show
that a chemical interaction goes on between the two substances. This
might be expected to occur when they have been so intimately
commingled. But the fact that variations in the density of the colloid
solutions produce the phenomena of molecular disintegration alone
shows the union to be of physical and not of chemical nature; the
history of long-formed spheres, of urinary and of cholesterin calculi in
particular, shows that in process of time there is an actual mechanical
separation of the colloid from the crystalloid within the substance of
the spheres, without loss of the spherical form, so far as it is possessed
by the whole mass. . . .f The quantity also of colloid present in a
sphere is extremely small in proportion to the crystalloid . . . Such a
fact, it is true, is not decisive, but it is at least opposed to the ordinary
laws of combination between colloids and crystalloids, a small pro-
portion of the latter usually combining with a large proportion of the
former. And, if a combination takes place, why is it limited only to
an area of the colloid collimitary with the area of the densely-packed
saline matter?"

Dr. Ord then suggests that the relative compactness of bone in dif-
ferent classes of vertebrates depends upon three factors: (a) the nature
of the colloid matrix; (b) the nature of the earthy salts; (c) the tem-
perature of the body. Greatest compaction is obtained with albu-
minous matrix, with a mixture of calcium carbonate and phosphate,
and with the highest temperature, as in birds. He adds that bone
"may be excavated by a process of molecular disintegration set going
by a variation in the constitution of the colloid matrix." (This sug-
gests that enzymic attack on bone collagen might be involved in
osteomalacia and pregnancy.)

My own early experiments (1907) speedily showed that the na-
ture of the form developed by any salt depends greatly upon the
kind of colloid admixed with its solution, and that with the same
colloid different salts give different forms. Thus a solution of
one part of sodium chloride, one part of sodium carbonate, and

* This word means "of or belonging to the inner parts." J. A.
f See paper on concretions by Dr. L. Lichtwitz, in Alexander's "Colloid Chem-
istry," Vol. V, Reinhold Publishing Corp., 1944.

52 LIFE: ITS NATURE AND ORIGIN

one-tenth part of gum arabic in ten parts of water, when spread
on a microscope slide and allowed to dry, showed in some places a
"flowering plant," with graceful stems (carbonate) and character-
istic four-petalled flowers (chloride). These colloid-crystal effects
have been suggested as aids in diagnosis, because subtle changes in
body fluids often affect protective action. This principle is the
basis of the Lange colloidal gold test for syphilis, which registers
differences in the protective action of spinal fluid on highly sensi-
tive gold hydrosols.18 Dr. Karl Landsteiner (Nobel prize, 1930)
begins his book "The Specificity of Serological Reactions" (1936)
as follows: "The morphological aspects of plant and animal species
form the chief subject of the natural sciences and are the criteria
for their classification. But not until recently has it been recog-
nized that in living organisms, as in the realm of crystals, chemical
differences parallel the variations in structure."

Colloidal Protection

This important principle has been utilized from remote anti-
quity by practical people who, unhandicapped by teachings of
what is orthodox to do or to observe, frequently make discoveries
that surprise scientists and theorists. The late Dr. Edward G.
Acheson put it about like this: "It is often the man that does not
know any better who does the thing that can't be done. The poor
fool does not know that it can't be done — so he goes ahead and
does it." The percentage of success of the practical man is com-
monly below that of the trained scientist; but because of close
daily contact with practical problems of life, and also their tre-
mendous numerical superiority, practical men, in the aggregate,
have in many cases made important advances, which later became
of theoretical value. When Lord Kelvin's son drove a golf ball
farther than theoretical calculations would allow, his father was
led to consider the overlooked factor of the spin of the ball.

From time immemorial the highly effective protective colloid
gelatin (or glue) has been used to deflocculate the carbon in Indian
or Chinese ink — because it worked. We have recently synthesized
ephedrine, which we used to secure from Ma-Huang, a plant illus-
trated in the ancient Chinese pharmacopeia.19 The ancient Egyp-
tians, whose extensive technological knowledge was outlined, e.g.,
by Sir John Gardner Wilkinson nearly a century ago,20 used gum
(probably acacia) for making their water inks; they also made their
clay workable, like that of Babylonia, by infusions of straw, as

HOW MOLECULES MAKE MASSES 53

indicated in Exodus V. Philippine natives, when panning for
gold, often squirt the juice of "gogo bark," which they chew, into
the pan to deflocculate and wash away the accompanying clay.
About forty years ago, E. G. Acheson obtained patents for "Egyp-
tianizing" clay by using alkaline tannin solutions, etc. The aurum
potabile of the alchemists was made by reducing solutions of gold
(chloride) in the presence of stabilizing ethereal oils, and as early
as 1794 silk was dyed with colloidal gold. In his "Lehrbuch"
(1844) Berzelius gives recipes for making several shades of col-
loidal gold; and as early as 1821 isinglass, egg albumen, and
starch were used for this purpose.

What Professor Richard Zsigmondy (Nobel prize, 1927) considered
to be the first example of protective action, recognized as such,21 was
referred to by Thomas Graham.22 He stated that crude caramel, por-
duced by heating raw sugar to 210-220° C, when dialyzed, allows a
colored substance to pass through, while the material richest in carbon
remains behind in the dialyzer. A 10 per cent solution of this residue
is gum-like and forms a weak jelly, which is completely soluble in
water. Evaporated in a vacuum, it yields a tough, black, elastic,
shining mass, which, when thoroughly dry, can be heated to 120° C
and still remain completely soluble. If, however, the first solution is
evaporated to dryness on a water bath, it becomes insoluble. Both
the soluble and the insoluble caramel have the same empirical for-
mula. Liquid caramel is tasteless, neutral in reaction, and extremely
sensitive to crystalloid reagents. Traces of mineral acids, alkali salts,
and alcohol make it pectous, and the brownish-black, powdery sub-
stance yielded by the precipitated caramel is insoluble in both hot
and cold water, though it may be rendered soluble again by dilute
potash.

Graham then states: "The presence of sugar and of the intermediate
brown substances protects the liquid caramel in a remarkable degree
from the action of crystalloids and accounts for the preceding prop-
erties not being observed in crude caramel." Incidentally, Graham
refers to the analogy between caramel and anthracite: "Caramelization
appears to be the first step in that direction — the beginning of a col-
loidal transformation to be consummated in the slow lapse of geo-
logical ages." This recalls Dopplerite, a brown, amorphous, elastic
or jelly-like substance found in peat-beds, and also the so-called
"mother-of-coal" sometimes found in mines.

In 1856 Michael Faraday23 reported the discovery of "jelly"
(evidently gelatin or isinglass) as a protective colloid for colloidal
gold; and in 1898, Zsigmondy,21 then unaware of the preceding

54 LIFE: ITS NATURE AND ORIGIN

work, rediscovered gold sols and used them to measure the relative
protective power of various colloids. The "gold number" repre-
sents the number of milligrams of protector which just fails to pre-
vent the coagulative color change, from red to violet, of 10 cc of
an extremely pure and highly sensitive colloidal gold solution,
upon the addition of 1 cc of a 10 per cent solution of sodium
chloride. The use of these sols in the Lange test has been men-
tioned above. The gold numbers of a few protectors is given
herewith:

Substance

Gold Nu

mber

Gelatin

0.005

to

0.01

Amorphous egg albumen

0.03

to

0.06

Crystallized egg albumen

2.0

to

8.0

Fresh egg — white

0.08

to

0.15

Gum arabic

0.5

to

4.0

Dextrin

6.0

to

20.0

Sodium oleate

0.4

to

1.0

Sodium stearate at 100°C

0.01

Sodium stearate at 60°

10.0

Cane sugar

oo

The generally accepted explanation of the mechanism of prot-
tection is that advanced by H. Bechhold,24 i.e. that the protector
is adsorbed at the surface of the protected particle. The nature of
the outwardly directed electronic fields is evidently an important
factor also, for Bechhold later found that certain minimal quanti-
ties of protectors sensitize rather than protect. Thus 0.0003 to
0.0001 part of gelatin per million will flocculate gold sols and oil
emulsions. This principle is used in the mining industry (flota-
tion processes), and also to flocculate coal slurries.25 The work
of J. Billiter26 indicates that these traces of protector may bring
the colloid particles to the isoelectric point, where, as Sir William
B. Hardy has shown they are especially susceptible to flocculation.

Another curious quirk in the effects of adsorbed surface layers
becomes evident in other cases where the newly formed surfaces attract
each other strongly and stick together. Alexander27 considered starches
as a mixture of substances: (1) amylopectin, the more coherent, less
dispersible gel-like portion (now known to contain branched mole-
cules), and (2) amylose, the more soluble or dispersible portion, now
known to contain unbranched molecules.28 In discussing colloidal
protection as a factor in the behavior of starches, it was pointed out
that the behavior of a substance or a mixture of substances depends
largely on the nature and relative proportions of its aggregating and
its protective fractions. The term cohesive colloid was suggested for

HOW MOLECULES MAKE MASSES 55

substances where adsorbed layers cause particles to cohere. In starch
grains, the less soluble amylopectin seems to coat over the more soluble
amylose; but the resolubility of dried boiled starch paste indicates that
there conditions are reversed.

Calcium seems to play an important role in establishing the co-
herence of particles in aqueous media. Thus lime in soils aids in
bringing them into a condition of good tilth, described by Sir. E. J.
Russell as that "nice crumbly condition suitable for a seed bed."
On the other hand, alkaline soils dcflocculate and puddle badly.
Calcium humate appears to act as a cohesive colloid, especially
when the soil dries out, and thus incidentally prevents the winds
from blowing away the valuable top soil. The economy of China
is affected by such losses, and "Peiping throat" is caused by breath-
ing the begrimed air. A great dust storm swept over New York
on May 12th, 1934; and it is estimated that 300,000,000 tons of
soil were lifted from drought-parched Western States by a strong
northwest wind, and scattered over half of the United States.
It must also be recalled that Professor C. Herbst (Heidelberg),
who died in 1946 at the age of 80, had found many years ago that,
in the absence of calcium, the cells developing from fertilized
sea-urchin eggs fail to cohere, and normal development is frus-
trated.

The work of Wanda K. Farr and collaborators29 indicates that
cellulose contains ellipsoidal crystallites about 1.5 microns long
and 1.1 microns wide, cemented together by a pectinous material.
The passage of the much-needed and beneficial Pure Food and
Drugs Act in 1906 was largely due to the efforts of Dr. Harvey W.
Wiley, Chief Chemist of the U.S. Department of Agriculture.
Flushed with deserved victory, he began soon thereafter to issue
what he considered to be "standards" for many foods. He ex-
tended these rulings to such confections as ice cream, which he
declared should contain nothing but cream, sugar and flavor, the
latter including fruits and nuts. Faced with the fact that pro-
tective colloids (eggs, gelatin, gum, etc.) had commonly been
used in making satisfactory ice cream, and also in candies like gum-
drops, Wiley held that French ice-cream, always made with eggs,
should be sold under the name "frozen custard." He then insti-
gated a test case against a small ice-cream maker in Washington,
which was defended by the National Association of Ice Cream
Manufacturers. After hearing the evidence on both sides, the
Court directed a verdict of "not guilty" in what I am told was the

56 LIFE: ITS NATURE AND ORIGIN

first defeat for the Government under this Act. In this case I
had volunteered my services as expert because I was then inter-
ested in gelatin and its uses, and furthermore because my investiga-
tions had shown me not only the justice of the manufacturers'
position, but also certain scientific data which had an important
bearing on the matter.30

At that time I had begun to make experiments with protective
colloids, and soon noticed the powerful effect of gelatin on crystal-
lization, e.g., on plaster of Paris.31 Experiments with cow's milk
showed that gelatin and gum arabic stabilize it against coagulation
by acid and rennin, and ultramicroscopic examination checked
the results. On comparing the composition of cow's milk with
that of human milk, and separating the "total protein" figure,
commonly used, into casein and lactalbumin, the superiority of
human milk in the protective colloid lactalbumin became mani-
fest. The fact that cow's milk can be stabilized by protectors is of
importance, because large curds, though suitable for a calf, are
not readily handled by an infant; and furthermore, casein entraps
the fat globules when coagulating, giving greasy curds which are
very hard for an infant to digest.32

The literature showed that many types of protective colloids
have been used for years in many countries in adapting cow's milk
to infant feeding. Professor Abraham Jacobi, later President of
the American Medical Association, had long advocated33 the use of
gelatin and gum arabic, and stated that asses' milk is "a refuge
to which mothers fly when other milk or mixtures are not toler-
ated." Cereal gruels, dextrinized starch, seaweed (Irish moss),
lichens (Iceland moss), and beer (the dark dextrinous beer of
Bavaria) are among the many protectors used, and at present, com-
mercial dextrose, and maltose quite high in dextrin content are
popular. With milk mixtures high in fat, like ice cream, colloidal
protectors are desirable from the digestive standpoint; and many
can tolerate an eggnog better than raw milk, with or without the
alcoholic noggin.

In the course of these experiments, an attempt was made to simulate
milk by forming a precipitate of calcium phosphate in the presence of
colloidal protectors. Protected sodium phosphate was mixed with
calcium chloride, and vice versa, but a stable sol did not result. In
following mentally what must take place in the mammary gland, it was
realized that as all body fluids contain protectors, both of the reacting
solutions should contain protectors. Thus was born the concept of

HOW MOLECULES MAKE MASSES 57

double and plural colloidal protection. The doubly protected solu-
tions gave a stable calcium phosphate sol, precipitable with acid and
with rennin (1908).34

Although U. S. Patent No. 1,259,708 was obtained to cover multiple
colloidal protection, it was later found that double protection had
been used empirically — in fact, it is referred to in the foregoing quo-
tation from Ord's book. The so-called "grainless" photographic emul-
sion of G. Lippmann (Nobel prize, 1908) is made by dividing the
protective gelatin equally between the silver nitrate and the halide
solutions. M. Carey Lea produced some of his silver "photohaloids"
in a similar manner, and Lobry de Bruyn35 also used gelatin in both
reacting solutions.

Plural protection is illustrated in the gluten of wheat flour, which
contains a protective colloidal system consisting mainly of the fol-
lowing:

Gliadin, which forms an opalescent colloidal solution in water,

precipitated by sodium chloride;
Glutenin, which is insoluble in water or saline solutions, but dis-
solves in weak acid or alkali, and reprecipitates on neutral-
ization;
Globulin and albumin, which are soluble in sodium chloride
solutions.
Salt, used from time immemorial in making bread, and the feeble
acidity developed by the yeast help to produce desirable bread-making
properties in the protective colloids present by means of what may be
called a cumulative protective system or mixture. Hard water (sul-
fates) hardens the gluten, while alkaline water disintegrates it and
destroys its elasticity. Even distilled water yields a sticky dough.

The multiform effects arising from the interplay of crystalliza-
tion forces and specific colloids lead one to suspect that the size,
shape, and nature of many biological structures are thus domi-
nated.36 Plant and animal cells and circulating fluids abound in
substances which are capable of acting as protectors. As a result,
any precipitate forming by reactions between fluids, or even by
catalysis at specific surfaces, would tend to be highly colloidal be-
cause of double or multiple colloidal protection, and to remain so
unless the adsorbed layers function as cohesive colloids, in which
case particulate units (e.g., starch grains, cellulose units and fibers)
or tissue structures (e.g., wood, fibrous tissue) may emerge.
Naturally, the formation of such structures may also involve other
factors — enzymes, for example. J. Wolf and A. Fernbach37 ex-
tracted from green cereals an enzyme, coagulase, capable of pre-
cipitating starch from its solutions.

58 LIFE: ITS NATURE AND ORIGIN

Mixtures vs. Pure Substances

Apart from the effects of colloidal protection, mixtures of sub-
stances often show surprising properties. A small percentage of
carbon (probably forming iron carbide) converts iron into steel.
Though pure tin melts at 232° C and pure lead at 327° C "half-
and-half" solder melts at 220° C. Very pure iron and vanadium
have properties quite different from those tabulated for the
ordinary "chemically pure" elements.

H. G. Bungenburg de Jong and H. R. Kruyt38 found that when
certain hydrophilic sols are precipitated by a variety of methods,
e.g., by salts, by removal of solubilizing salts, by temperature
change, and especially by addition of oppositely charged sols, the
"precipitate" often forms viscous droplets which aggregate into a
fluid mass called a coacervate, instead of forming a solid phase.
The phenomenon, termed coacervation, had been observed by F.
W. Tiebackx,39 who remarked that the gelatin/gum arabic coagula
resembled casein. Strongly adsorbed shells of water are supposed
to surround the droplets and to prevent their aggregation. In
the water-dispersible emulsions of asphalt now much used in road
and airfield construction, the protective aqueous films commonly
consist of dispersions of soaps or of colloidal clays.40

Practical cooks know that by working butter, lard, or hydro-
genated oil into baked goods (pie crusts, cookies, etc.) they are
made "short" or tender; and the fats are known as "shortening."
The fat gets in between the layers of flour dough and so weakens
the final product that it breaks off "short," or is flaky, the latter
being especially desirable in pie crust. On the other hand, tech-
nologists often use a colloidal substance to make a mixture
stronger or more cohesive, e.g., starch, glue, or rosin size in paper.
B. W. Zweifach reported41 that cells in the walls of capillaries are
bound together by a calcium protein compound, and that diffu-
sion takes place through this intercellular cement rather than
through the cells themselves.

Development of Structures in Living Units (Bionts)

Even in a single cell numerous chemical substances are being
produced catalytically, and as these are liberated in the nascent
state they are likely to be affected by other newly formed neigh-
bor substances, or by other molecules or particulate units afloat
in the cytoplasm of the cell. The chemical or physical combina-

HOW MOLECCEES MAKE MASSES

59

. -•■

^r

%

Figure 4a. Collagen fibril from
human skin corium shadowed with
chromium, (x 111,000) [Courtesy
Prof. Francis O. Schmitt, M.I.T.]

Figure 4b. Collagen fibril from
rat tail tendon, stretched by peeling
back of collodion supporting film.
(X 21,000) [Ref: Schmitt, Hall and
fakus, /. Cell, and Comp. Physiol.,
20, 11 (1942)]

60 LIFE: ITS NATURE AND ORIGIN

tions that result go to make up the various characteristic struc-
tures we recognize at higher structural levels, many of which have
long been the wonder of microscopists because of the meticulous
accuracy of their formation. The electron microscope reveals
some of these "vestiges of molecular creation" at submicroscopic
levels, as may be seen in Fig. 4, micrographs of collagen. It
reveals that this supposedly "homogeneous" substance, in the
specimens examined, consists of two substances in regular forma-
tion, one of which is more readily stretched than the other. This
causes the striations so apparent in the picture. The biocatalysts
determine where and what substances shall be formed, and the
formation rates; and the subsequent mutual reactions of the sub-
stances largely determine what superior structures will emerge.

Some insight as to the further complications that arise at a still
higher structural level when numerous cells get together is given
by the slime molds. When plenty of food is available, they live
singly and divide by fission. After this vegetative stage, the cells
gather together in masses, which may number as high as 150,000
cells, and form what is termed a pseudoplasmodium, which moves
about as though it were an individual unit. In the case of
Dictyostelium discoideum42 the migrating unit stops just before
the formation of a spore-bearing stalk (sorocarp). After aggrega-
tion of the individual cells (myxameboe) there is no further
increase in their number or size; but all further development
consists entirely in the integration and subsequent differentiation
of the myxameboe already present, which may be of wholly differ-
ent spore origin and of initially equal potentialities. If the cell
masses are broken up in the presence of food (bacteria), they re-
turn to the vegetative self-reproducing stage; but if no bacterial
food is present, they re-aggregate and develop fruiting structures
whose pattern is constant, though the size is in proportion to the
cell mass. Different species, thoroughly intermixed in the vegeta-
tive stage, aggregate to separate and distinct centers. Though
two species of Dictyostelium may initially enter the same fruiting
organization, they later draw apart and form separate sorocarps,
which have a distinctive form for each species. "What is inherited
is not a specific type of structure, but the ability of like but discrete
and independent units to cooperate in the formation of such a
structure."

Just as slowly grown crystals tend to "purify" themselves by
elimination of stranger ions or molecules from their space lattices,

HOW MOLECULES MAKE MASSES 61

so cells of like species tend to segregate, as has so ably been dem-
onstrated by Professor Herbert S. Jennings.43 When a hetero-
geneous mixture of bacteria is agglutinated by a heterogeneous
mixture of specific antisera, each cluster of bacteria is homo-
geneous. Apparently each bacterium selectively adsorbs a layer
of its own specific antibody, and the bacteria so conditioned
cohere or "crystallize" into lattices or clumps because of the specific
unions of their new surfaces. The adsorbed antibody appears to
act like a cohesive colloid.44, 45

REFERENCES

1 Zechmeister's paper entitled Cis-Trans Isomerization and Stereochemistry of
Carotenoids and Diphenylpolyenes, Chemical Reviews (1944), 34, 267-334.

2 "Colloid Chemistry," Vol. VI, p. 748, New York, Reinhold Pub. Corp., 1946.

3 Liher XXXV, Par. 185: Virus alarum sudoresque sedat.

4 See, e.g., "Molecular Association," by W. E. S. Turner, in "Colloid Chemistry,"
Vol. I, pp. 278-287, New York, Reinhold, 1926.

5 "Properties of Ordinary Water-substance in All Its Phases," A. C. S. Monograph,
Reinhold Publishing Corp., 1940.

6 /. Chem. Physics, 1933.

7 /. Phys. Chem., 1936.

&Phil. Trans. Roy. Soc, 1861, 151, 184.

9 His original papers were printed in the Journal of the Russian Chemical Society,
1906-1908, and a comprehensive paper by him appeared in "Colloid Chemistry,
Theoretical and Applied," Vol. I, pp. 27-101, New York, Reinhold, 1926.

10 See J. Alexander, First Colloid Symposium Monograph, 1923, p. 297, and also
paper of H. A. Endres, "The Crystallization of Sulfur in Rubber," in Colloid Chem-
istry, Vol. I, pp. 808-13, Reinhold Publishing Corp., 1926. Both papers have several
illustrations of these phenomena. By ultramicroscopic examination, J. Alexander
found that the sulfur-Canada balsam crystals showed ultramicrons at their surface,
apparently representing pai tides unable to find placement in the crystal lattice.
Vogelsang expressed the view, also shared by G. Quincke, that globulites are
preliminary stages in the formation of crystals. Sir J. S. Flett more recently drew
attention to these forms.

11 Trans. Faraday Soc, 1933, 29, 990.

12 For further information in this interesting field, see a paper by G. Friedel on
"The Mesomorphic States of Matter," in "Colloid Chemistry," J. Alexander, Vol. I,
pp. 102-125 (Reinhold Publishing Corp.), which gives references to other work.

13 Robert Boyle, "Origin of Forms and Qualities," Oxford, 1666, and Rome de
l'lsle, "Crystallographie," I, p. 379, Paris, 1783.

14 See the papers of Stephane Leduc (Nantes) and of A. L. Herrera (Mexico) in
"Colloid Chemistry," Vol. II, pp. 59-79, and pp. 81-91, Reinhold Publishing Corp.,
1928.

15 Science, 1925,61, 184.

16 "On the Influence of Colloids upon Crystalline Form and Cohesion, with Ob-
servations on the Structure and Mode of Formation of Urinary and other Calculi,"
London, 1879.

17 Ord, Chapter II, "Containing a Discussion of the Causes of Molecular Coales-

62

LIFE: ITS NATURE AND ORIGIN

cence, and an Application of the Principles Established to Some Structural Phe-
nomena of Living Bodies" (p. 15 et seq).

18 D. L. and C. T. Morris [/. Phys. Chem. (1939), 43, 623] observed that many
biological substances show characteristic crystallization forms with cupric chloride.

19 A revised edition (the Pen T'sao Kang Mu) was published by Li Shih-chen,
1552-1578.

20 "Customs and Manners of the Ancient Egyptians," many editions.

21 See "Colloids and the Ultramicroscope," Eng. trans, by J. Alexander, p. 43,
J. Wiley & Son, New York, 1909.

22 Phil. Trans. Roy. Soc, 1861.
™phil. Trans. (1857), p. 145.
2*Zeit. phys. Chem. (1904), 48, 385.

25 See "Colloid Chemistry," by J. Alexander, 4th ed., p. 203, New York, D. Van
Nostrand Co., 1937.

™Zeit. phys. Chem. (1905), 51, 142.

27 Paper read before a Joint Symposium of the American Chemical Society, New
York, April 25th, 1935 (finally published in Journal of the Society of Chemical In-
dustry, London, March 13th, 1936.)

28 See paper on "Recent Advances in Starch Chemistry," by R. M. Hixon and R. E.
Rundle, in "Colloid Chemistry," Vol. V., pp. 667-683. Reinhold Publishing Corp.,
1944.

29 See her paper on "Plant Cell Membranes" in "Colloid Chemistry," Vol. V,
pp. 610-667, Reinhold Publishing Corp., 1944.

30 The research director of a large food producer, speaking of the use of the elec-
tron microscope in improving the taste, texture and appearance of familiar food
products, stated: "Food research scientists have known that the 'feel' of a candy bar
as it melts in the mouth has a lot to do with the flavor. A rough grainy texture will
suggest a poor flavor. All this is related to the size and shape of the tiny particles
which are visible for the first time through the electron microscope." (N. Y.
Times, Dec. 23rd, 1946.)

For time out of mind practical cooks, as well as ice-cream makers, had been
familiar with the use of such colloids as gelatin, gums, eggs, starch, etc., in keeping
their products smooth and pleasant-tasting on the tongue, even though they may
have been unaware of the scientific principles underlying what their experience
had taught them.

31 See my papers in Jour. Am. Med. Assn. (1910), Journal of the Society of Chem-
ical Industry (1909), and in Kolloid Zeitschrift (1909, 1910).

32 The subjoined table gives the data for the two kinds of milk, and also for
asses' milk.

Kind of

Casein

Lactalbumin

Protective

Behavior with acid

Milk

%

%

Ratio

Fat

and rennin

Cow

3.02

0.53

0.14

3.64

Readily forms large curds

Woman

1.03

1.26

1.13

3.78

Not readily curded;
curds small

Ass

0.67

1.55

2.31

1.64

33 "The Intestinal Diseases of Infancy and Early Childhood," New York, 1889.
3* See "Some Novel Aspects of Colloidal Protection," by J. Alexander, "Colloid
Chemistry," Vol. I, pp. 619-627, Reinhold Pub. Corp., 1926.
85 Rec. trav. chim. Pays-Bas, 1900.
«6J. Alexander, Science, (1922), 56, 323-6.
37 Compt. rend. (1903) 137, 129.

HOW MOLECULES MAKE MASSES 63

«8 Koll. Zeit. (1929), 50, 39.
**Koll. Zeit. (1911), 8, 198, 238.

40 See "Colloid Chemistry," Vol. Ill, pp. 542-6, Reinhold Pub. Corp., 1931.

41 "Cold Spring Harbor Symposium" (1940), 8, 216.

42 Kenneth B. Raper, Third Growth Symposium, 1941, pp. 41-76.

« "Colloid Chemistry," Vol. V, pp. 1162-73, Reinhold Pub. Corp., 1944.

44 The phenomenon of specific clumping has been described by W. W. C. Topley,
J. Wilson and J. T. Duncan, Brit. J. Exptl. Path. (1935), 16, 116.

45 Reference should be made to an extensive paper by Professor Leo Loeb (Wash-
ington Univ.) in "Colloid Chemistry," Vol. II (1928), pp. 487-514, in which tissue
formation is discussed. He concludes that the basic factors leading to the formation
of the most primitive tissues and of agglutination thrombi are the same. Both
processes find their prototype in the amoebocyte tissue, and gradually undergo
various developments and complications in the more complex classes of organisms.
"The primary changes underlying these conditions are localized alterations in the
colloidal state of certain constituents of the cells, which are probably protein in
nature." The differences in colony form shown by the "rough" and the "smooth"
dissociants of pneumonococci appear to be consequent upon the nature of their
polysaccharide coats or capsules, as shown by Professor Michael Heidelberger
(Columbia University), Dr. O. T. Avery (Rockefeller Inst.) and others.

Chapter 4

The Importance of "Impurities" and Trace Substances

The first question generally asked of a practicing professional
chemist is "What will it cost to analyze this sample?" The sample
may be anything from a patent medicine to a bit of composition
or plastic. The first question the chemist should ask is, "To
what use do you expect to put this analysis?" As a rule, the
answer will be, "I want to make the same thing." The chemist
must then explain that while a routine analysis may be one step
toward this objective, it seldom gives the answer; for a final
product rarely reveals directly the original raw materials which
were used to make it, or the details of the process. Thus, an
analysis of a loaf of bread, showing fat, carbohydrate, protein and
salt, would hardly tell anyone how to produce a loaf just like it.
Part of the original carbohydrate has been fermented away by the
yeast, which, in turn, has added somewhat to the protein; and in
baking, much of the water used to make the dough and practically
all the alcohol formed by the yeast have been driven off. A large
Swedish bakery runs most of its delivery automobiles with alcohol
condensed from its ovens; and I have heard of a small baker who
used to go on an occasional spree with the alcoholic liquid he
condensed from oven vapors, on the underside of a large metal
sheet cooled by spring water.

Consider an actual case. A client, with an air of great mystery,
presented a chemist with a sample of a red paste and asked the
cost of an analysis — "that's all." The client admitted that he
expected the analysis would show him how to make the product,
and on being told that this was most improbable, expressed sur-
prise. At first he refused to say what the material was, where it
came from, or for what purpose it was intended; and he was told
to find a chemist he could trust. Thereupon, he decided to take
the chemist into his confidence, and revealed that he was using
the red paste in a special cosmetic, and that it cost him five dollars
a pound. This high price made it impossible for him to operate

64

THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 65

at a profit, and he hoped to reduce his cost by duplicating the red
paste himself. Asked whether it was ideal for the purpose, he
admitted it had many deficiencies, but it was the best thing he
had found. He was then asked to write out the properties which
an ideal color paste should have for his purposes, and was told
that instead of trying to duplicate an inferior product, it would
be wiser to try to evolve a product as near the ideal as possible.
Actually, a superior color material was produced at a raw material
cost of nine cents a pound, and this was adapted for use on auto-
matic machinery which could be hired to turn out a completed
cosmetic. The cost of the final product, with very small invest-
ment, was less than 10 per cent of the original cost.

The actual analytical work in this case contributed but little to
its successful conclusion. But in many, if not most cases involving
biological questions, very delicate and ingenious analysis lies at
the very foundation of the solution of a problem. The presence
of small traces of substances may make or mar a product, process,
or organism, and exact means must be found for determining
them. When students are criticized for not finding, say, one half
of one per cent of some element present in an "unknown," they
are prone to consider their instructors very exacting and "mean."
Even students with a 90 per cent average must be brought to
realize that in business or professional life they are expected to be
100 per cent right, every day. Severe penalties await the food
manufacturer whose product contains more than the permissible
few parts per million of lead, arsenic, copper, etc.; and the lives of
patients often depend on proper and correct reports from the
laboratory.

The necessity of determining minute percentages has led to
ever-increasing refinements in analysis, and physical means are
being increasingly called upon to reinforce or to replace gravi-
metric and volumetric analytical methods.

Nephthelometry, which depends on measuring, often with the
"electric eye" or photoelectric cell, the amount of cloudiness produced
in a solution by appropriate reagents, can determine, e.g., one part of
phosphorus in 333 million parts of water.1 The quartz spectrograph
is used to determine trace impurities which may ruin a metal for cer-
tain purposes. Thus Colin J. Smithells states:2 "The solubility of
bismuth in copper is less than 0.002 per cent, and any excess forms
brittle films between the copper grains. For most purposes 0.005 per
cent of bismuth is the maximum permissible, and where the metal is

66 LIFE: ITS NATURE AND ORIGIN

to undergo severe cold work this element should be excluded. Anti-
mony exerts a similar influence in copper and its alloys, and brass is
practically unworkable if it contains 0.005 per cent of this element."
As little as 0.001 per cent of boron in steel necessitates a change in its
heat treatment. The crystallization of primary silicon in alumi-
num/silicon alloys (12 per cent Si) is inhibited by 0.002 to 0.01 per
cent of metallic sodium. Such facts indicate the great importance of
segregating the different kinds of metal scrap.

The polarograph, electron diffraction, infrared spectrography, the
mass spectrometer, and chromatography are all useful in analysis. The
last depends upon the differential diffusion of substances down a
column of a selected adsorbent, under the influence of a stream of a
selected "solvent."

With many biological substances, micro-analysis is resorted to, the
total amount of a sample often being less than a milligram, and the
substance sought being present only in gammas (1 gamma is 1/1,000,000
milligram). But still more minute traces can be determined by tests
with living organisms, e.g., by immunological reactions, or by the
effects shown on the growth of yeasts or plant seedlings. Yeast tests
show that biotin has a detectable effect in a dilution of one part in
400 billion. Dr. Joseph Needham of Cambridge describes3 an ingeni-
ous application of the Cartesian diver4 ultramicromanometer (origi-
nally designed by K. Linderstr0m-Lang) to measure the minute range
of gas exchange in the developing gastrula. Needham estimates the
approximate sensitivity of the unit as 0.00015 to 0.001 microliter
of gas.

The chemical properties of the recently synthesized element pluto-
nium were determined at first on an ultramicrochemical scale. Pro-
fessor Henry D. Smyth states5 that "one microgram (1/1,000 mg) is
considered sufficient to carry out weighing experiments, titrations,
solubility studies, etc. . . . Successful microchemical preparation of
some plutonium salts and a study of their properties led to the general
conclusion that it was possible to separate plutonium from the other
materials in the pile."

The Effects of Trace Substances

In some cases, small amounts of certain substances exert a bene-
ficial effect; the following will serve by way of illustration:

Helpful Traces

Gasoline: 0.06 per cent of tetraethyl lead inhibits "knock."
Rubber: Nitrogenous substances in crude Para facilitate the
"cure." Purer plantation rubber demands accelerators.

THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES G7

Condenser Tubes: Traces of arsenic in copper facilitate rolling
and greatly reduce corrosion.

Electro-plating: Tiny amounts of "addition agents" in the bath
may greatly improve the nature of the deposited metal.

Baking: "Arkady" flour (named after Professor Robert Kennedy
Duncan) was mainly calcium sulfate, to aid yeast growth.
Sodium bromate, a "yeast food", enables bakers to start with
much less yeast, the total savings running into millions of
dollars annually.

Lead: Tellurium (about 0.05 per cent) increases corrosion resist-
ance and establishes "work-hardening." Barium (0.08 per
cent) makes lead ring like a bell. Calcium (0.03 per cent)
increases tensile strength, valuable in sheathing cables.

Brewing: Traces of proteolytic enzymes prevent "cold-cloud" in
beer. Water may be "Burtonized" (like that of the River
Trent") by traces of lime salts.

Copper: Traces of copper (e.g., from preserving kettles) inhibit
the growth of molds in preserves; also the undesirable growth
of algae, etc., in reservoirs.

Cast Iron: Tellurium is a powerful carbide stabilizer; 0.0005 per
cent is added in making chilled car-wheels.
Technical DDT, the insecticide, contains some substance or

substances effective in inhibiting the catalytic release of hydro-
chloric acid by some insoluble impurity, possibly iron oxide.6
On the other hand, here are some cases where traces are

harmful:

Troublesome Traces

Foods: Less than one part of copper per million in coffee can be

tasted.
Breiuing: Minute traces of iron make "ink" with the tannin of the

hops, and in high dilution this gives some beers a sickly

greenish hue.
Soap: Coconut oil containing one part per million of sulfur gives

a soap prone to rancidity.
Lead-burning: Traces of arsenic in an oxy-hydrogen flame prevent

good welds. Traces of platinum in lead storage batteries

cause self-discharge.
White lead: Traces of silver produce a pinkish discoloration;

traces of copper, a greenish tone. Over 0.0015 per cent is

objectionable.

68 LIFE: ITS NATURE AND ORIGIN

Hydro genation: According to Sabatier, traces of bromine adsorbed

from the air of the laboratory, prevent the hydrogenation of

phenol; and thiophene in benzene prevents its hydrogenation

to cyclohexane.

Dry Batteries: Iron in the pyrolusite ((Mn02) and copper in the sal

ammoniac, both hurt "battery life."

Since we are here most interested in the biological effects of

"trace" substances, a few instances of the importance of mineral

elements must be mentioned. Iodine is an essential constituent

of thyroxine (4 atoms per molecule), an oxidation-accelerating

hormone of the thyroid gland. Copper facilitates the formation

of hemoglobin, and is a constituent of many oxidase enzymes

(e.g., ascorbic acid oxidase, polyphenol oxidase, tyrosinase, laccase).

Zinc is essential in carbonic anhydrase, which influences the

equilibrium between the H3CO3 and C02 being carried by the

blood. Cobalt is a vital element for sheep and cattle (seemingly

not for rats). When some New Zealand sheep suffering from

"bush sickness" were cured by administration of iron, it was at

first thought that the illness was due to iron deficiency; but later

investigation proved that a tiny amount of cobalt present in the

iron as an impurity was responsible for the cure.

Fluorine in minute amounts seems essential for proper tooth
structure, though in humans a slight excess causes trouble, such
as black and misshapen teeth. Vanadium is an important con-
stituent of the blood pigment of the ascidian Phallusia mammilata,
and F. Bernheim7 found that vanadium stimulates oxidation of
phospholipids in the liver. Molybdenum is being recognized as
of biological significance; and some molds will not grow in the
absence of traces of gallium. Female rats fed on a manganese-
deficient diet gave birth to young but lacked maternal instinct;
and 97 per cent were unable to suckle their young, which were
also neglected by foster mothers, indicating that the latter detected
some deficiency. In fowls, manganese is essential to normal devel-
opment and is the inorganic factor preventing perosis ("slipped
tendon"). Professor E. V. McCollum of Johns Hopkins Univer-
sity and his collaborators have done noteworthy work on trace
elements in nutrition.8

Vitamins and Hormones

These are considered together because they both represent sub-
stances essential in minute amounts for the normal development

THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 69

and functioning of plants and animals, including most micro-
organisms. Vitamins are as a rule found in foods, while hormones
— often called "endocrines" — are produced by the organism, com-
monly by "glands of internal secretion" whose potent products
enter the blood. For many years the criteria of food value were
fat, carbohydrate, and protein. Calcium and iron, and later
iodine, were regarded as essential minerals. Then it was found
that protein foods must contain a certain number of essential
amino acids. Since most proteins are deficient in some of these,
a variety of proteins in the diet is necessary. Though gelatin is
a valuable and readily assimilated protein food, it lacks trypto-
phane.9

In Java, C. Eijkman (Nobel prize, 1929) carried out the pioneer
work (1890-97) on polished rice as the cause of beriberi. Professors
E. H. Starling and William M. Bayliss of the University of London
coined the word "hormone" in 1902; but not until 1911 did Dr.
Casimir Funk suggest the word "vitamine" for the vital amine
found in unpolished rice. The term vitamin quickly came to
stand for unknown essential trace substances in foods. The isola-
tion, identification, synthesis and biological understanding of
vitamins and hormones are brilliant examples of scientific prog-
ress, and have led to great advances in nutrition and medicine.10

Dr. Wm. J. Robbins, Director, New York Botanical Garden, has
kindly prepared the following resume of some of his work.

It is now generally recognized that plants require vitamins and
similar growth substances. Most plants synthesize the vitamins they
need from simpler and more elementary substances. Only the minority
— and these chiefly the lower plants — suffer from vitamin deficiencies;
that is, they cannot develop unless the material upon which or in
which they grow contains some of the vitamins they require, but are
unable to make. Some bacteria, yeasts and filamentous fungi must be
supplied with vitamins; others are autotrophic for these substances.
All the higher plants, with the possible exception of the saprophytic
or parasitic forms, are autotrophic for vitamins, though the isolated
roots of some of them have been found to require an extra cellular
supply of thiamine, nicotinic acid or pyridoxine for growth.

Schopfer demonstrated in 1934 that Phycomyces blakesleeanus did
not grow without the presence of thiamine in the culture medium.
Robbins and others found that many fungi have one or more vitamin
deficiencies. The deficiency may be complete (the fungus does not
grow in the absence of the vitamin from the medium) or partial (the
fungus grows slowly in the absence of the vitamin, but more rapidly

70 LIFE: ITS NATURE AND ORIGIN

if some is present). Both complete and partial deficiencies may be
single (for one vitamin) or multiple (for more than one vitamin). The
deficiency may be either absolute or conditioned. An absolute
deficiency is one in which no known environmental conditions enable
the organism to synthesize the vitamin from simple foods and nutri-
ents; a conditioned deficiency means that under some conditions the
organism can synthesize the vitamin and under others it cannot.

The synthetic ability of a fungus for a particular vitamin may be
complete, incomplete or zero. For example, Aspergillus niger has
complete synthetic power for thiamine; it can make this substance if
supplied with sugar and mineral salts. On the other hand, Phytoph-
thora cinnamomi or Ceratostomella from the London plane tree must
be supplied with thiamine as such. Between these two extremes of no
synthetic power and complete synthetic ability there exist many types
of incomplete synthetic power. For example, Mucor Ramannianus
can make the pyrimidine half of the thiamine molecule but not the
thiazole portion; Ceratostomella pini can make the thiazole but not
the pyramidine part, and Ceratostomella montium can combine the
two intermediates into thiamine but is incapable of making either.

Among the filamentous fungi deficiencies for thiamine are common,
biotin deficiencies are numerous, pyridoxine deficiencies are infre-
quent, inositol is a growth substance for some and oleic acid for one.
Beadle and his associates have developed numerous mutants of
Neurospora deficient for a variety of vitamins and for specific amino
acids.

The potency of many biological trace substances appears from
the following: One part of adrenaline in a thousand million can
produce a visible effect on the isolated gut of the rabbit. Pro-
fessor Reid Hunt11 expressed the results of his experiments with
acetylcholine thus: one grain (originally the weight of a single
grain of wheat) is capable of lowering the blood pressure of a
thousand million cats, but this dosage might not kill a single cat.
Professor A. J. Clark12 observes that the spindle-shaped heart cell
of the frog measures about 130 by 10 microns (volume about 3400
cubic microns), and the acetylcholine molecule measures about
1.5 millimicrons. Professor Otto Loewi (Nobel prize 1936) showed
that the nerves of the vagus (pneumogastric) reduce heart action
by liberating acetylcholine around the heart cells, and Clark esti-
mates that a few thousand of these molecules are sufficient to
depress a single cell. "The relation in size is similar to that
between a large whale (100 tons) and a midge ($ mg)."

The tables of vitamins and hormones presented at the end of

f

THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 71

this chapter give the various vitamins and hormones at present
known, with some information as to their nature and action, but
with no suggestion of finality in this continually advancing field.
Professor David E. Green of Columbia University, in a recent ad-
dress13 on physiological function from the standpoint of enzyme
chemistry, stated:

"Vitamins B^ B2, B0, and the P-P [pellagra-preventive] factor, have
all been shown to be the prosthetic groups of certain enzyme systems.
When these vitamins are not available in the diet, the active enzymes
cannot be formed in the cell. In consequence of the failure of these
enzyme systems to function properly, an abnormal physiological situ-
ation develops, which, if uncorrected, will lead to death. Which
organ first registers the effect of a particular deficiency is determined
by the amount of the reserves of enzymes containing the vitamin and
by the relative importance of this set of enzymes in the economy of the
organ. Thus, in Bx deficiency in the pigeon, the brain is the first
organ to register disturbed function, presumably because there are no
reserves of this vitamin in the brain and because the enzyme formed
by the vitamin plays a key role in the metabolism of the brain. One
may well raise the point that if, as in avitaminosis, the causal link
between the physiological disturbance and the effect on enzyme sys-
tems is unquestioned, then surely there is a good case for assuming the
same link between normal physiology and enzyme systems."

"The study of endocrines has always been one of the most active
fields of physiological investigation, and it is of interest to inquire
to what extent hormones can be related to enzyme phenomena.
Until quite recently, hormones were held up as notable excep-
tions to the rule that substances which act at high dilutions must
be enzymes or parts of enzymes, or must specifically affect some
enzyme system. Recent research, however, fails to confirm the
hormones as exceptions to the enzyme-trace substance thesis — the
epoch-making discovery of Cori and his group14 that one of the
hormones of the anterior pitituary inhibits the action of hexo-
kinase, and that this inhibition, in turn, is released by insulin.
We have here a clear blueprint for the way in which hormone
antagonism can be effected. A key enzyme system which controls
some metabolic process can be regulated by a set of hormones,
one of which inhibits, while the other releases the inhibition.
All students of endocrinology have long been aware that hor-
mones regulate metabolic processes, and it is not surprising to find
in one instance, at any rate, that the regulation operates at the

72

LIFE: ITS NATURE AND ORIGIN

level of enzyme systems. Houssay and his colleagues in the Argen-
tine have presented cogent evidence that renin, a kidney hormone,
is a type of proteolytic enzyme which hydrolyzes one of the plasma
proteins to form a pressor substance. In this substance, the hor-
mone regulates metabolic processes by actually assuming an
enzymatic role."

INTERRELATIONS OF THE ENDOCRINE GLANDS AND SECRETIONS

(GENERAL METABOLISM AND REPRODUCTION)

ACTIVE NATURALLY OCCURRING HORMONES

EXCRETION PRODUCTS

I INACTIVATED HORMONES!

PROTEIN FAT CARBOHYDRATE

METABOLISM METABOLISM METABOLISM

(GROWTH)

thyroxin
(general metabol

[PARATHYROK

i

PARATHORMONE
(CA, METABOLISM)

POTASSIUM ESTRONE SULPHATE

SODIUM ESTRIOl GLUCURONIDE

(ESTRONE ESTRADIOL. SSTRiOl)

PANCREATIC
ISLETS

ESTRADIOL
ESTRONE
(UTERUS '
VAGINA
ETC)

LIVER
KIDNEYS

SODIUM PRIGNaNIDIOL
GIUCURONiOI

INSULIN
IIEDUCES BLOOD
SUGAR LtVEl

P»(GNAN[CtX

LIVER
KIDNEYS

CORTin

(membrane pliwc a3iiitt.

sugar. salt. water and

protein metabolism,

mOSPHOSTLATION^

ADRENALIN
(GIYCCHHNOLYSIS)

ANDROSTERONE

(DEMTDIOANDROSTIRONE I

1

iKIDNEYSl

Figure 5. The position of the pituitary in relation to the hormonal configura-
tion. (Courtesy Dennis T. Mayer, Missouri Agr. Exp. Sta. From "Bioenergetics and
Growth" by Brody, Reinhold Publishing Corp., N. Y.)

The profound and diverse influences of the pituitary hormones
indicated in Figure 5 led Sir Walter Langdon-Brown15 to call this
gland "the leader of the endocrine orchestra." But in a recent
address,16 he is reported as saying that it later transpired that the
hypothalamus holds the still more important rank of "conductor
of the endocrine orchestra." The mechanism of hormone action
is discussed at length by Oliver Kamm and D. K. Kitchen.17

Vitamin research continues to reveal new trace substances
important to the welfare of living things, and it may be that some
of these are a bit more complicated than at first thought. C. D.
Robeson and J. G. Baxter18 report a naturally occurring isomer
of vitamin A (termed by them Neovitamin A) isolated from fish-
liver oil where it constitutes about one-third of the total "vita-
min A." In rats both isomers have the same biological potency,
for rats can transform Neovitamin A into vitamin A. Catalytic
interconversion of the anthraquinone carboxylate esters of the
two vitamins was accomplished in vitro by a trace of iodine in
benzene solution. Since iodine catalysts (among many others) are

THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 73

active in many living things, we must envisage the possibility that
vitamins and hormones may, directly or indirectly, affect one
another.

An interesting example of hormonal interrelationships appears from
recent research on the thyroid gland and the iodine catalysts of the
body, which are continually being assembled and released, and when
broken down are salvaged and reconstituted for re-use, as follows:

(1) Within the gland a catalyst mechanism sets free or secretes a
mass of large, non-diffusible particles of thyroglobulin, forming visible
masses known as "colloid."

(2) The colloid specifically adsorbs and stores iodine in the form of
iodide, diiodotyrosine, and thyroxine, and gradually releases these
catalysts into the circulation for service in such cells as may take
them up.

(3) The thyroid-stimulating hormone of the anterior pituitary (TSP)
stimulates colloid formation, conversion of diiodotyrosine into thyroxin,
and release of the latter into the circulation. TSP is of protein nature.

(4) Iodine-containing material restored to the circulation from the
cells is recaptured by the colloid and returned to the iodine cycle, apart
from small amounts excreted in bile, urine, etc. The actual amount of
iodine in circulation at any time is normally very small.

(5) Thiouracil and similar goiter-forming substances inhibit absorp-
tion of iodine and its conversion into diiodotyrosine and thyroxin.
The latter process appears to occur in two steps: (a) oxidative libera-
tion of iodine to combine with tyrosyl radicles; (b) coupling of two
diiodotyrosyl groups to form thyroxin residues.

In addition to serving either directly as catalysts, or as carriers
or prosthetic groups in enzymes, trace substances may affect the
permeability of membranes (septa), through which the raw mate-
rials and reaction products of the catalysts must diffuse, and thus
influence reaction velocities. Working through the endocrine,
nervous, or circulatory systems, such stimuli, though physically
small, may trigger off vitally important reactions.

74

LIFE: ITS NATURE AND ORIGIN

%
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THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 75

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LIFE: ITS NATURE AND ORIGIN

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THE IMPORTANCE OF "IMPURITIES" AND TRACE SUBSTANCES 77

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78 LIFE: ITS NATURE AND ORIGIN

REFERENCES

1 Kober and Eggerer, /. Am. Chem. Soc. (1915), 37, 2375.

2 "Impurities in Metals," J. Wiley & Sons, New York, 1928, p. 94.

3 "Biochemistry and Morphogenesis," pp. 194-6.

4 Needham points out in a footnote that the Cartesian diver, often sold as a toy
under the name of "Cartesian devil," was first described in 1648 in a booklet on
the compressibility of water by Raffaele Magiotti, a pupil of Galileo; the book
has a diagram of the "diver," which, until this application, had remained a
philosophical toy. Descartes did not invent it, but the term "Cartesian" was some-
times applied to ingenious scientific or mechanical apparatus.

5 Atomic Energy for Military Purposes, 1945, p. 101-2.

6 Fleck and Haller, /. Am. Chem. Soc. (1946), 68, 142; A. L. Flenner, ibid., 68,
2399.

7 J. Biol. Chem. (1939), 127, 353.

8 See A. T. Shohl, "Mineral Metabolism," Chapter 11, Reinhold Pub. Corp., 1939.

9 Professor William C. Rose (Univ. of Illinois) and collaborators [Science (1937),
86, 298, and "Nutrition Foundation Symposium," Nov. 13th, 1946] give the fol-
lowing data:

Final Classification of the Amino Acids with Respect to
their Growth Effects in the Rat

Essential Non-Essential

Lysine Glycine

Tryptophane Alanine

Histidine Serine

Phenylalanine Aspartic acid

Leucine Glutamic acid

Isoleucine Proline

Threonine Hydroxyproline

Methionine Tyrosine

Valine Cystine

Arginine* Citrulline

* Arginine can be synthesized by the organism of the rat, but not at a sufficiently
rapid rate to meet the demands of maximum growth.

10 The following Nobel prizes were awarded for work in these fields: A. Windaus
(1928), A. Harden (1929), O. Warburg (1931), Paul Karrer (1937), Albert von Szent-
Gyorgyi (1937), Richard Kuhn (1938), A. Butenandt (1939), L. Ruzicka (1939),
Edward A. Doisy (1943), Hendrik Dam (1943), Arturi Wirtanen (1945).

11 Science (1930), 72, 528.

12 Chemistry and Industry (1930), 49, 533.

is Ann. N. Y. Acad, of Sci., Dec. 15th (1946) 47, 515-9.

14 W. H. Price, Carl F. Cori and Sidney P. Colowick, /. Biol. Chem., (1945), 160,
633.

15 Practitioner (1931), 127, 614.

"Abstract in /. Am. Med. Assn. (1946), 131, 1238.

17 Reference given in accompanying tables.

18 J. Am. Chem. Soc. (1947), 69, 136-141.

Chapter 5

What Are Living Units?

Many authorities maintain that it is not possible to draw a line
of cleavage between living and non-living entities. The task is
complicated by the fact that nature is so rich in examples and so
gradual in most changes, that it is hard to fit all the data into the
rigid frame of any definition. Nevertheless, we must first try to
define what Ave mean by "living" units or entities.

In its broadest sense a living unit or entity is one that can direct
chemical changes by catalysis,* and at the same time reproduce
itself by autocatalysis, that is, by directing the formation of units
like itself from other, and usually simpler chemical substances.
Among the simplest known living units are genes, and some of the
bacteriophages and ultrafiltrable viruses, which in size approxi-
mate molecular dimensions. The electron microscope indicates
that some bacteriophages ("the bacteria of bacteria") and some
viruses {e.g., that of psittacosis, or "parrot fever") are tiny organ-
isms.

Figure 7, prepared by Dr. W. M. Stanley (Nobel Prize, 1946)
shows that some viruses and bacteriophages approach molecular
dimensions. See also Figure 8, an electron micrograph of tobacco
mosaic virus.

Organisms are known which can synthesize their own organic com-
pounds from inorganic substances. These are called autotrophs. The
best known of this group are chlorophyll-containing plants, including
algae, which by photosynthesis form organic compounds from carbon
dioxide. The autotrophic bacteria may live in the absence of light,
are generally microscopic, and are not distinguishable morphologically
from other bacteria; but they derive their energy from the oxidation
of inorganic substances and utilize it to reduce carbon dioxide to
organic compounds. Intermediate between the autotrophic bacteria

* Catalysis is discussed in the next chapter. In brief, it is the process whereby a
specific particulate unit or surface (the catalyst) continuously brings about chemical
union, breakdown, or structural change in other units as a result of very close
contact or approach, under suitable conditions.

79

80

LIFE: ITS NATURE AND ORIGIN

a

^ik
^p^

v

y

/

Figure 6. Election micrograph of E. coli in the presence of bacteriophage parti-
cles. (Courtesy RCA Laboratories, Princeton, N. J.)

and chlorophyll-containing plants are the purple bacteria, which re-
quire both hydrogen sulfide and light for their development.1 Robert
L. Starkey classes known autotrophic bacteria as follows:

A. Bacteria which oxidize compounds of nitrogen

(a) ammonia to nitrate (Nitrosomonas, Nitrosococcus)

(b) nitrite to nitrate (Nitrobacter)

B. Bacteria which oxidize sulfur and compounds of sulfur
(a) Simple bacteria (genus Thiobacillus)

(1) Strictly autotrophic
a) Aerobic

WHAT ARE LIVING UNITS?

81

Diameter or

width X length

in mju

Red blood cells

750O

B. prodigiosus (Serratia marcescens)

750

Rickettsia

475--"

Psittacosis

450

Canary pox

260 x 310

Myxoma

230 x 290

Vaccinia

210 x 260

Pleuropneumonia organism

150

Pseudo rabies

150

Herpes simplex

150

Rabies fixe

125

Influenza

115

Newcastle disease

115

Vesicular stomatitis

100

Staphylococcus bacteriophage

100

Fowl Plague

90

T2 coli bacteriophage

60x80

Chicken tumor 1

70

Equine encephalomyelitis

50

T3 coli bacteriophage

45

Rabbit papilloma (Shope)

44

Pneumonia virus of mice

40

Tobacco mosaic and strains

15x280

Latent mosaic of potato

10 x 525

Qene (Midler's est. of max. size)

20 x 125

Southern bean mosaic

31

Rift valley fever

30

Tomato bushy stunt

26

Poliomyelitis (Lansing)

25

Hemocyanin molecule (Busycon)

22

Yellow fever

22

Hemocyanin molecule (Octopus)

20

Louping ill

19

Tobacco ring spot

19

Japanese B encephalitis

18

Alfalfa mosaic

17

Tobacco necrosis

16

Foot-and-mouth disease

10

Silkworm jaundice

10

Hemoglobin molecule (Horse)

3 * 15

Egg albumin molecule

2.5 x 10

Figure 7. Approximate sizes of viruses and reference materials. (Courtesy W. M.
Stanley, Chemical and Engineering News, 1947)

82 LIFE: ITS NATURE AND ORIGIN

1) Develop at reactions close to neutrality (species Th.

thioparus, Beijerinck)

2) Develop under very acid conditions (species Th. thio-

oxidans, Waksman and Joffe)
b) Anaerobic (species Th. denitrificans, Beijerinck)
(2) Facultative autotrophic

a) Facultative anaerobic (species of Trautwein)
(b) Higher bacteria (complex in morphology)

(1) Colorless (includes genera Beggiatoa, Thiothrix, Thioploca,

Achromatium, Thiophysa, Thiovulum, and Thio-
spira)

(2) Pigmented red or purple bacteria (over 16 genera)

C. Bacteria which oxidize ferrous or manganeous compounds

(a) Simple bacteria

(1) Long excretion filaments (genus Gallionella)

(2) Coccoid or oval shapes in masses (Siderocapsa, Sideromonas)

(b) Filamentous bacteria (genera Leptothrix, Crenothrix)

D. Bacteria which oxidize hydrogen.

S. Winogradsky2 pioneered in this field; first studying certain higher
sulfur bacteria, later iron bacteria and nitrifying organisms. The
latter convert urine, etc. into nitrates from which was made saltpeter,
a vital ingredient of gunpowder.

All known living units appear to have the further power of un-
dergoing generally infrequent but marked deviations from their
usual composition, structure and function; and in some cases
these changes alter or modify their ability to direct catalytically
the formation and decomposition of various chemical substances,
and are, furthermore, passed on hereditarily when the living unit
reproduces itself by autocatalysis.

Many geneticists have held, and a few may still believe, that all
heritable changes are due to abrupt changes in genes ("muta-
tions"). This notion was apparently supported by the pioneer
work of Professor Herman J. Muller (Nobel prize, 1946) and his
followers on the effects produced by subjecting to controlled x-ray
treatment eggs, sperms, and seeds. Later it appeared that they
might be caused by chromosomal rearrangements rather than
changes in gene structure. These matters are considered further
in Chapter 8.

Increasing experimental evidence is being found for the view
that — apart from heritable changes in the genes and chromosomes,
admittedly the main carriers of heredity — the cytoplasm, that pool
of "protoplasm" with its numerous enzymic catalysts, mito-

WHAT ARE LIVING UNITS? 83

chondria, chloroplasts, and other particulate inclusions, may also
undergo changes which are sometimes heritably transmitted. In
nature, mutations generally appear in a random, haphazard man-
ner, giving what nurserymen term "sports." The orderly and
regular development of individual organisms from seeds or fertil-
ized eggs indicates a more positive and dependable mechanism
for the differentiation of the original germ cell (zygote) into var-
ious types of cells, tissues and organs. In fact, differentiated cells
(heart, leucocytes, or cancer) in tissue culture may continue to
reproduce themselves true to their differentiated type, though de-
differentiation or reversion to some other type (e.g., "embryonic"
type) may occur.

The essential characteristic of true life units is their ability to
increase the number of their kind by direction of chemical
changes, whereby non-living and generally simpler atoms, mole-
cules and masses are transformed into the catalytic and reproduc-
tive structure of the living entities. Incidentally, besides the
catalyzed molecules incorporated into the living unit or into its
autocatalyzed "descendants," many other molecules may be dis-
charged into the surrounding medium or milieu,* and this mole-
cular waste is useful and often essential to other living things.
Thus many thousands of tons of urea are being excreted daily into
the world's chemical economy, besides large amounts of many
other substances. Non-living entities, such as molecules of ben-
zene or sulfuric acid, do not increase in number through the
direct catalytic action of pre-existing or "parent" molecules of
benzene or sulfuric acid, which are typical non-living entities.

Functional Life: Living vs. Dead

In a more restricted sense of the term, we may designate as
"living" any cell, tissue, or organ from a living unit while it is
carrying on the processes it ordinarily did during the functional
life of that unit. Thus a frog's heart may be kept "alive" and
beating after removal, though the frog is functionally dead. The
death of the organism as a whole (somatic death) is more slowly
followed by cellular death, as the blood ceases to circulate and the
cells perish in the products of their own metabolism. By quick
and careful work, living tissues from dead persons have been
successfully transplanted onto the living. Utilizing and improv-

* We have no English equivalent for this French term, and it has been adopted
into English by scientists.

84

LIFE: ITS NATURE AND ORIGIN

ing upon tissue culture methods originated in the laboratory of
Professor Ross G. Harrison of Yale University. Dr. Alexis Carrel
(Nobel prize, 1912) and his collaborators at the Rockefeller Insti-
tute for Medical Research were able to keep alive a culture of
chicken heart cells in an embryonic juice medium for over a
third of a century. Professor Robert Chambers of New York
University made moving-picture films of a group of heart-muscle
cells beating rhythmically in tissue culture, while from the other
side of the culture chamber rapidly growing cancer cells invaded

Figure 8. Electron micrograph of tobacco mosaic virus (x 18,000). (Courtesy

University of Toronto)

the "heart" and interfered with its contraction as a unit (fibrilla-
tion).

Where large numbers of cells are associated in community life,
as in multicellular plants and animals, most of the cells become
so highly specialized or differentiated (as in tissues, organs, or
blood), that they are quite incapable of carrying on an inde-
pendent existence. Therefore, if one organ or even a small group
of cells fails, the whole organism may perish. The deadly prus-
sic or hydrocyanic acid produces speedy death by inactivating
certain cells in the medulla which control respiration and heart-
beat. It is not generally recognized that sulfuretted hydrogen has
an action similar to that of prussic acid; but in some respects it
is even more dangerous because its fixation is irreversible. The

WHAT ARE LIVING UNITS? 85

use of cylinders of pure sulfuretted hydrogen to reinforce the
feeble content of some "sulfur springs" may, in careless hands,
cause deaths involving serious legal responsibility.

Some important bodily failures or injuries may not be fatal,
providing the deficiencies are made good artificially. Thus
diabetics who would otherwise die may be kept alive by regular
injections of insulin. In a case recently reported, a pregnant
woman, who had for six months remained unconscious and prac-
tically helpless following a head injury, gave birth to a normal
healthy child.

In the more restricted sense of "living" mentioned above, sterile,
castrated or isolated males or females are said to be alive, though
incapable of reproduction. About ten years ago the heath-hen
vanished, like the dodo and the great auk, with the death of the
sole surviving specimen at Martha's Vineyard. The passenger
pigeon is also extinct, though early Americans saw flocks con-
taining enormous numbers. On the other hand, given the proper
chemical and physical environment, i.e., proper food, milieu, and
where necessary, proper mates, some living units may produce
with great rapidity. It has been estimated that the ocean would
soon be a solid mass of herring, if all the eggs produced developed
into mature fish. It is only disease and the constant competition
of various forms of life with one another, whereby unrestrained
reproduction is counterbalanced, that permit the great diversity
and evolutionary development of elementary living units.

These aspects of the interrelations of living things are con-
sidered by the comparatively recently science of ecology, which
originated in the study of plants, but has been extended to include
animals. The devious nature of these interrelations has been
illustrated by the correlation mentioned by Darwin between old
maids and red clover. Because of the nature of its flower, red
clover is pollinated mainly by bumble bees, which build their
nests in the ground. Marauding mice prey upon the nests; but
cats, which prey upon the mice, are commonly kept by old maids,
who thus unwittingly help the red clover. The curiously shaped
flower of the "Dutchman's pipe" (Aristolochia macrophylla) has
its pistil well above the stamens in a long corolla, whose narrow
mouth contains many stiff hairs pointing inward. A tiny insect
can enter, but is held prisoner until it has effected fertilization of
the flower; whereupon the hairs droop and the imprisoned insect

86 LIFE: ITS NATURE AND ORIGIN

can escape. I have often cut open these flowers and found a tiny
fly entrapped within them.

When fig trees were planted in California, they grew splendidly;
but the fruit did not mature until a small wasp, Plastophaga
psenes (Linn.), which fertilizes the flowers, was imported (1890)
from Smyrna, cultivated, and released to do this necessary work.

Functional Life: Active vs. Latent

In still another sense we may say that a unit is "alive" if, having
ceased to carry on active life processes (catalysis and autocatalysis),
it is able to resume them on the reestablishment of suitable con-
ditions. Many plants and animals, e.g., many bacterial spores and
protozoa, revive after prolonged desiccation leading to a more
or less complete stoppage of active life. The African lung fish has
been known to survive as long as four years in a cake of dried mud.
Admiral Byrd found in the Antarctic regions primitive plants
whose activities began again as the long winter began to yield to
the equally long summer; for though high temperatures are fatal
to all living things, many organisms revive even after long im-
mersion in liquid air. R. B. Harvey3 reported finding an alga
(Phormidium) growing in Beryl Spring (Yellowstone Park) at a
temperature of 89° C.

The common notion that all functionally living things must
show visible signs of life, such as breathing or motion, is based on
experience with humans and many animals. In the case of hiber-
nating animals like bears, hedgehogs, and woodchucks, visible
breathing ceases for long periods. Although the irritability of
the heart is increased, it beats only enough to maintain a sluggish
circulation, and the body temperature approaches that of the
surroundings. The animal lives at a much reduced rate on its
accumulated reserves of fat and protein, and its slight demand for
oxygen seems to be met in part by diffusion. Fakirs and magicians
endure temporary burial by a rigid suppression of many bodily
processes. Sudden panic, leading to violent muscular activity to
escape, would no doubt be quickly fatal. The condition assumed
by successful practitioners of this feat seems in some respects to
resemble an artificial hiberation.

The vitality of "germs" (microorganisms, spores, etc.) and even
of seeds is astonishing. Using rigorous precautions against con-
tamination, Professor Charles B. Lipman, Dean of Graduate
Studies, University of California, reported the presence of viable

WHAT ARE LIVING UNITS? 87

bacteria in the interior of adobe bricks from old Spanish Missions
and from Aztec and Inca ruins, as well as in coal samples taken
1,800 feet below the surface of the earth. He believed that the
peat-like coal-forming material of past geologic ages was extremely
rich in bacteria, and that some of their spores still survive. He
also isolated an autotrophic bacterium from petroleum coming
from a well 8,700 feet deep.4 Confirmation of this work will be
welcomed.

To test the viability of seeds, Dr. W. J. Beale of Michigan Agri-
cultural College in 1879 buried 20 different kinds of plant seeds,
and had samples taken every five years for test. After forty years'
burial, half of the species produced sprouts.5 In 1902 Dr. J. W.
T. Duvel of the U. S. Department of Agriculture buried seeds of
107 species, and found that 69 species grew after 10 years' burial,
and 20 species after 20 years' burial. Most hardy were the seeds
of wild plants and weeds. Cereal, legume, and cultivated plants
generally failed to grow; apparently they depend upon human
help to perpetuate themselves.6

Becquerel7 tested 550 species of seeds which had been stored
at the Jardin des Plantes in Paris for from 25 to 135 years.
Nothing older than 80 years germinated. I have been assured by
the late Dr. A. Lucas, chemist of the Cairo Museum, that the so-
called viable "mummy wheat," sometimes "found" by native
guides in Egyptian tombs, represents recent crop material placed
there presumably by the finders. The fraud has been often ex-
posed. R. Whymper and A. Bradley report8 that a sample of
English wheat stored under conditions of desiccation favorable to
longevity, showed 69 per cent germination after 32 years' storage.
Though exhaustion of the sample (1945) ended this series of tests,
the yearly record indicates that an estimated extreme limit of life
of 50 years is rather an understatement.

On visiting Palestine a few weeks after unusually heavy rains, I
saw a gorgeous, multicolored floral display on the normally bare
hills. And in 1930, after one of the rare rainfalls in the desert of
Death Valley, California, there was a luxuriant growth of plants,
arising from long-dormant seeds, many probably carried there by
the winds.

In 1943 a slightly spotted greenish cast was noticed on the gray-
ish limestone wall of the corridor opposite the elevator shaft in
the Carlsbad Caverns, New Mexico, about 750 feet below the
surface; it gradually spread and became grass-green. In 1941 there

88 LIFE: ITS NATURE AND ORIGIN

had been an unprecedented rainfall in May; and in September
21.25 inches of rain fell in nearby Dark Canyon, the local Ranger
Station reporting 17 inches as falling within a few hours. Appar-
ently enough water seeped through imperfections in some 500 to
800 feet of rock to moisten the exposed rock wall and perhaps carry
some spores of algae; or the spores may have been carried in by
visitors or by down-draft air currents. An electric lamp, burning
seven hours daily, supplied the needed light. Several other growths
of algae were also found.9

Particular mention must be made of the extremely resistant
spores of the anthrax bacillus, which produces a highly contagious
and usually fatal disease in men and animals. Whole fields have
become a source of infection because of the burial there of sheep
that died of this disease, which is supposed to be the "very grievous
murrain" referred to in Exodus — a view supported by the further
statement that when Moses sprinkled toward heaven in the sight
of Pharaoh handfuls of "ashes of the furnace," it became "small
dust over all the land of Egypt, and "it became a boil breaking
forth with blains (blisters) upon man and upon beast." This
description would fit dried infectious material, which in the hot
climate of Egypt could be readily cultured and dried. The bio-
logical warfare now being spoken of may have thus had a very
early prototype. Anthrax (the word also means carbuncle) is
known as splenic fever; in French it is charbon, a burning coal.
It was also known as "wool-sorter's disease" because it was often
carried to human beings by unsterilized wool and by animal hairs
used for shaving brushes, etc.

In conclusion, it seems evident that the essential criteria of life
are twofold: (1) the ability to direct chemical change by catalysis;
(2) the ability to reproduce by autocatalysis. The ability to
undergo heritable catalyst change is general, and is essential where
there is competition between different types of living things, as
has been the case in the evolution of plants and animals. Even
with a single living unit, heritable catalyst change would be es-
sential to permit survival in ever-changing vicissitudes of the
milieu, including climate, irradiation, and chemical substances
presented as foods or as poisons.

While we are most familiar with relatively complicated living
units — from mites to elephants, from molds to oaks — we are con-
fronted in genes, bacteriophages, mitochondria and viruses with
units approaching the dimensions of large molecules or small mole-

WHAT ARE LIVING UNITS?

89

Duplicate of "template
surface
~~ {illustrating autocatalysis)

Reverse of template
-1-1 surface

(Illustrating antibody
formation)

Template surface
(Illustrating gene or an-
tibody area)

Figure 8a. Diagrammatic section of a specific surface, showing the complementary
relation between reproductive catalysis (autocatalysis) and antibody formation. If
conditions permit the formation and elution of a mono- or polymolecular layer or
plaque of this nature, its subsequent activities depend upon maintenance of the
integrity of its surface specificities. It could serve as the carrier or the prosthetic
group for a biocatalyst (enzyme), or as a gene or antibody surface. In an editorial
aroused by the paper of Alexander in Protoplasma (1931), Dr. Stephen Miall
(Chemistry and Industry, London, Sept. 30th, 1932) first used the term template
(also spelled templet) in this connection; but many others have since adopted this
apt expression. (See page 4.)

cular groups. In some cases these might even be considered as
molecules, or to use a term suggested by J. Alexander and C. B.
Bridges10 for the simplest conceivable unit, as moleculobionts.
There is no evidence that anything below the level of the molecular
has ever catalytically directed the formation of its like. The
resting or latent forms of life seem to persist as long as the basic
biocatalysts are not changed to so great a degree that resumption of
active life has become impossible; and active life involves the
direction of chemical change by the basic catalytic units, together
with self-duplication (autocatalysis).

REFERENCES

1 Chapter XXIV in Jordan and Falk, "The Newer Knowledge of Bacteriology
and Immunology," Univ. of Chicago Press, 1928.
2Botan. Zeit. (1887), 45, 489-610.
3 Science (1924), 60, 481.

*/. Bact. (1931), 322, 183-198; Science (1932), 75, 79, 230.
'Am. J. Bot. (1922), 9, 266-9.

6 /. Agr. Sci. (1924), 29, 349.

7 Compt. rend. (1906), 26, 1549.

8 Cereal Chemistry (1947).

9W. B. Lang, Science (1946), 103, 175.

10 Colloid Chemistry, Vol. II, p. 10, 53, Reinhold Pub. Corp., 1928.

Chapter 6

Catalysis: The Guide of Life

Two outstanding and superficially irreconcilable facts con-
front us when we consider the extremely complex and varied
phenomena of life and of living units, or bionts. Most striking is
the tendency of bionts to breed true. Despite wide differences in
food and living conditions, the fundamental processes of life,
growth, development and reproduction appear, as a rule, to be
unerringly shepherded along definite paths in orderly sequences:
overriding the vagaries of wind, wave and current, the ship of life
tends to maintain a fixed course.

On the other hand, closer examination of the facts reveals that
the course of life, like that of true love, never does run smooth.
We have ample evidence of abnormalities in structure and func-
tion, some of which may be inherited. Sometimes these are help-
ful, but often they are harmful and lead to disease and death. No
matter how we may differ in our attempts to explain these devi-
ations from ideal normality, it is a fact that evolutionary changes
occurred over pre-human geological epochs, that from the earliest
times men have selected desirable spontaneous varieties of plants
and animals for propagation. In passing, it may be mentioned
that present scientific views as to the order of the appearance of
living things are substantially the same as that given in Genesis:
following the emergence of dry land came grass, herbs and trees;
then living creatures of the seas, and birds; then living creatures
of the earth, cattle and beasts; and finally, man.

In our attempt to explain the basic mechanism whereby life
exists, persists and proceeds, we have invoked the old but now well
known and extensively utilized principle of catalysis, which in-
volves the direction of definite chemical changes by surfaces of
definite structure under definite conditions. Naturally, many
other mechanisms, such as differential diffusion, selective adsorp-
tion, and fluid movement are also operative, especially in relatively
large and complex organisms, and at various structural levels. But

90

CATALYSIS: THE GUIDE OF LIFE 91

it is the highly specific surfaces found in such biocatalysts as genes,
enzymes and similar areas, which direct the formation of the
specific chemical molecules that underlie all larger structures and
functions. Changes in biocatalysts or additions to their number,
where they are persistent or heritable, result in changes in the
biochemical output even under the same conditions; but the
demonstrable consequences of these changes in what I may call
the chemism or chemical output, may be so obscure and various
that we are deceived as to their common basic origin.

It is believed that a wide range of biochemical and biological
phenomena are readily understandable on the basis of specific
catalysts, their formation and the changes which they undergo.
No other simple, basic and ubiquitous mechanism is equally con-
sonant with the extremely diverse experimental evidence over
such a far-flung range, which includes immunology, genetics,
embryology, medicine, evolution and paleontology.

What Is Catalysis?

A little over a century ago Jons Jakob Berzelius, the great Swed-
ish chemist and physician, coined the word "catalysis," and ac-
curately anticipated modern views of its nature. Since then, it
has been often erroneously taught that catalysts merely speed up
reactions that would naturally occur of themselves in the course
of "infinite time." Since time is of the essence of all biological
processes, such a view, even if true, would be purely academic.
Consider, therefore, the original statement of Berzelius.1

"It is then proved that several simple and compound bodies,
soluble and insoluble, have the property of exercising on other
bodies an action very different from chemical affinity. By means of
this action they produce in these bodies decomposition of these
elements and different recombinations of these same elements, to
which they themselves remain indifferent.

"This new force, which was hitherto unknown, is common to
organic and inorganic nature. I do not believe that it is a force
quite independent of the electrochemical affinities of matter; I be-
lieve, on the contrary, that it is only a new manifestation of them,
but since we cannot see their connection and mutual dependence,
it will be more convenient to designate the force by a separate
name. I will therefore call this force the catalytic force, and will
call catalysis the decomposition of bodies by this force, in the same

92 LIFE: ITS NATURE AND ORIGIN

way that one calls by the name analysis the decomposition of
bodies by chemical affinity."

It is interesting to read the reaction of contemporaries of Berzelius
to his views:2

"On Catalysis and Catalytic Force, by Berzelius. As is well known,
in the action of gold, etc., on hydrogen peroxide, of acids on sugar, of
sulfuric acid on alcohol, (according to Mitscherlich), of spongy plati-
num on hydrogen, etc., we have recently had examples, even though
they are not all of like cogency, of the existence of various influences
that substances exert on each other, which differ from heretofore
known types of chemical activity. That is, there evidently are sub-
stances which possess the power to decompose into their constituents
other materials with which they come into contact, without entering
into combination to any appreciable extent with the new compounds
formed. This type of chemical activity has been known as decompo-
sition by mere contact. Berzelius proposes to call this power of sub-
stances catalytic power, and the process due to it catalysis. He does
not mean to say that the force is a new one, but is convinced that we
are here dealing with a special form of expression of known forces.
Catalytic force seems to reside in the power of the substances in ques-
tion to arouse in other substances, by their mere presence, affinities
according to which the elements of the compound substance rearrange
themselves, so as to attain complete electrochemical neutralization.
This is analogous to the action of heat, and the question arises
whether, as in the case of heat, a different degree of catalytic force will
produce different catalyzed products from various substances, and
whether different catalyzers will not produce different catalytic results
with a given material. This cannot now be answered, for according
to present experience, every substance having catalytic power appears
to have it only as against certain other substances.3

Since many biological catalytic changes occur in the colloidal
zone, the following excerpts from earlier publications are given,
before considering some more recent aspects of catalysis. We
begin with a fundamental paper of Thomas Graham:4

"The property of volatility, possessed in various degrees by so
many substances, affords invaluable means of separation, as is seen in
the ever-recurring processes of evaporation and distillation. So
similar in character to volatility is the diffusive power possessed by all
liquid substances that we may fairly reckon upon a class of analogous
analytical resources to arise from it. The range also in diffusive
mobility exhibited by different substances appears to be as wide as the
scale of vapor tensions. Thus the hydrate of potash may be said to

CATALYSIS: THE GUIDE OF LIFE 93

possess double the velocity of diffusion of sulfate of potash, and sul-
fate of potash again double the velocity of sugar, alcohol, and sulfate
of magnesia. But the substances named, belong all, as regards dif-
fusion, to the more 'volatile' class. The comparatively 'fixed' class, as
regards diffusion, is represented by a different order of chemical sub-
stances, marked out by the absence of the power to crystallize, which
are slow in the extreme. Among the latter are hydrated silicic acid,
hydrated alumina, and other metallic peroxides of the aluminous
class, when they exist in the soluble form; with starch, dextrin, and
the gums, caramel, tannin, albumen, gelatin, vegetable, and animal
extractive matters.

"Low diffusibility is not the only property which the bodies last
enumerated possess in common. They are distinguished by the
gelatinous character of their hydrates. Although often largely soluble
in water, they are held in solution by a most feeble force. They
appear singularly inert in the capacity of acids and bases, and in all
the ordinary chemical reactions. But, on the other hand, their
peculiar physical aggregation with the chemical indifference referred
to, appears to be required in substances that can intervene in the
organic processes of life. The plastic elements of the animal body
are found in this class. As gelatin appears to be its type, it is pro-
posed to designate substances of the class as colloids, and to speak
of their peculiar form of aggregation as the colloidal condition of
matter. Opposed to the colloidal is the crystalline condition. Sub-
stances affecting the latter form will be classed as crystalloids. The
distinction is no doubt one of intimate molecular constitution."

While it is impossible here to attempt to follow historically the
development of colloid chemistry and of catalysis, the following
brief quotation from a paper by Professor Leonard Thompson
Troland of Harvard5 clearly shows his appreciation of the
problem:

"As a matter of fact, in the school of the physical chemists there
has been in preparation, since the days of Thomas Graham, a sys-
tem of knowledge which, even in its present unfinished form, has
a most important and distinct bearing upon mooted biological
problems. This is the science of the colloidal state. The difficult
abstractions and elaborate classificatory scheme, in terms of which
the theory is now stated, will tend to be cleared up as our study of
colloids comes definitely under the dominion of the general
electro-molecular theory of matter. Intimate contact with the
latter has already been established, indeed, through recent remark-
able contributions by Langmuir, dealing with the atomic consti-

94 LIFE: ITS NATURE AND ORIGIN

tutions of solids and liquids. It is to colloidal chemistry that we
must look for answers to the large majority of the fundamental
problems of vital activity. These answers will be slow in appear-
ing, however, if we refuse to look.

"In fairness, it must of course be admitted that may biologists
are keenly alive to the importance of the theory of matter, and
especially of the theory of colloids, for the advancement of their
science. However, because the majority of these men are special-
ists in biochemistry, there seems to be a lack of coherent applica-
tions of modern physico-chemical ideas to the problems of evolu-
tion and heredity, which make up the heart of the biological
mystery.

"It has for some years been my conviction that the conception
of enzyme action, or specific catalysis, provides a definite, general
solution for all of the fundamental biological enigmas: the mys-
teries of the origin of living matter, of the source of variations,
of the mechanism of heredity and ontogeny, and of general organic
regulation. In this conception I believe we can find a single,
synthetic answer to many, if not all, of the broad outstanding
problems of theoretical biology ... It is an answer, moreover,
which links these great biological phenomena directly with molec-
ular physics, and perfects the unity not alone of biology, but of the
whole system of physical science, by suggesting that what we call
life is fundamentally a product of catalytic laws acting in colloidal
systems of matter throughout long periods of geologic time. This
view implies no absurd attempt to reduce every element of vital
activity to enzyme action, but it does involve a reference of all
such activity to some enzyme action, however distantly removed
from present activity in time, or space, as a necessary first cause.
Catalysis is essentially a determinative relationship, and the
enzyme theory of life, as a general biological hypothesis, would
claim that all intra-vital or 'hereditary' determination is, in last
analysis, catalytic."6

In a paper by J. Alexander and C. B. Bridges7 the following was
stated: "Before considering the modern view of catalysis, let us first
review some consequences of the structure of matter which make
catalysis possible and specific. When electrons and protons combine
to form atoms, when atoms combine to form molecules and when
molecules combine to form larger groups, there are always left over
some outwardly directed, unsatisfied fields of force. The residual

CATALYSIS: THE GUIDE OF LIFE 95

forces of molecules exert powerful attractions or repulsions on particles
which come within the range of attraction.

"If we consider a single molecule, or a very small molecular group,
A, it is obvious that the residual electrostatic or electromagnetic sur-
face forces present to the milieu a mosaic which is highly specific
in various directions. In Fig. 9 the specific nature of the surface of A
is shown diagrammatically by the convention of specific jaggedness in
the outline. In consequence of its mosaic pattern, a particle may
exhibit several different kinds of specific actions separately or simul-
taneously, on different portions of its periphery.

"Let us now imagine a simple molecule, B, approaching A, and the
process of fixing itself at the surface. This will occur only if the
surface charges presented by the approaching molecule bear a lock-

A h At& AS G.

Ctjj 0 ©

Figure 9

and-key relation to those of the particle, and if the velocity of approach
lies within critical limits.

"As soon as the oppositely charged areas come within their critical
distance, fixation occurs, as is diagramed A+B. Instantaneously
thereafter occurs a mutual neutralization of forces and a complete
reshuffling of all the internal and surface fields. The compound
molecule, after the fixation, will present to the milieu a different
configuration from what it presented before fixation. This is dia-
gramed as AB. The former B portion might now be able to make
other attachments previously not possible to it. The attachment of
a second molecule, C, would once more cause a reshuffling of all the
fields involved, as is diagramed ABC. Now, if the resulting bond
between the two added molecules were stronger than the bond be-
tween the former A and B portions, then there might be released
to the milieu a new type of duplex molecule, BC, while the fixation
surface of A would be freed for renewed action.

"Suppose now that we have a catalyst particle composed of several
simple molecular subunits which we can diagram roughly as A in Fig.
10. Suppose that at some one of its faces the catalyst fixes or absorbs

96 LIFE: ITS NATURE AND ORIGIN

the several subunits of which it is composed; that, because of the
order of their fixation or because of the reshuffling of electronic fields
which follows each addition, these component subunits form a new
group identical with the fixation or catalyst group, and suppose, lastly,
that the duplicate particles now separate or are separated. Each
would be an exact duplicate of the other in catalytic and in self-
duplicating behavior. Our original particle could properly be called
an autocatalytic catalyst.

"As an example of a simple and well-known chemical process,
analogous in a rudimentary way to the autocatalytic synthesis postu-
lated above, one may mention the formation of crystals of the alums.
If to pure cold water is added the salt potassium sulfate and the salt
aluminium sulfate, a solution strongly supersaturated for the potential
double salt, alum, may be obtained. But, in the absence of a frag-
ment of a previously formed crystal of alum the supersaturated

©P <5P0 ®o

<&9>

,. ©j

Figure 10

solution remains practically indefinitely without giving rise to alum
crystals. However, if a tiny fragment of alum crystal is dropped in,
or was present in the materials used, at its surface occurs an adsorp-
tion of the two separate salts together with a definite number of
water units, the whole addition condensing into a very specific space
lattice with repetitions of the unitary alum complex. Mechanical, or
even thermal, agitation may break the bonds between the newly
formed alum complexes and the parental crytsal, so that a host of
descendants may grow and reproduce in the nutrient solution.

"We do not contend that an alum crystal constitutes simple life,
although there may be some who would do so. In vital units the
building stones of the finer structure are not potassium, aluminum
and sulfanion, but are carbon, nitrogen, phosphorus, etc., which are
united in a unit complex which is far more voluminous and involved
than alum is. Besides this difference in constituents, or more prob-
ably because of it, the units properly called vital are more flexible in
their bonding and more diversified in the activities carried on at the
catalytic surfaces.

"The simplest living units of which we have indisputable evidence
are the genes. The forces governing the reproduction of each gene
are known to be within the individual gene. In evidence of this we
need cite here only the well-known fact that in a heterozygote, each

CATALYSIS: THE GUIDE OF LIFE 97

gene of the allelomorphic pair picks out of the common milieu exactly
those constituents which lead to its own particular formation. Fur-
thermore, this specific formation occurs nowhere else in the cell
except precisely at the locus occupied by each particular allelomorph.
All these properties conform to our postulated autocatalytic repro-
duction.

"We would like to point out one more property of genes which has
its analogue in a rudimentary way in the alum crystal. The growth
rates of the genes of a given cell are remarkable in their uniformity.
This holds true not only for a given temperature but throughout the
great range of temperatures to which some organisms are adapted.
If a particular gene did not keep step with the others it would either
overreproduce or else fail to reproduce in time to be included in the
daughter cells with the other genes.

"Not simply this uniformity in temperature characteristics, but a
considerable number of other properties, for example, the universal
synthesis of the substance called chromatin, which envelops the genes
or the string of genes, and the remarkable similarity in chemical con-
stitution of nuclear materials as revealed by the exceedingly crude
methods of chemical analysis now available, all point to one striking
conclusion. This conclusion is that the genes may all be viewed as
simple variants of one fundamental structure. We may suppose that
their power of autocatalytic synthesis is the outcome of the possession
of a common pattern of structure, and that the different allelomorphs,
or indeed the different genes in a given cell or even the different genes
in apparently very widely separated forms, are the same except for
differences in the fringe of the gene, in its side chains and in localized
additions or substitutions.

"To return to our oversimplified analogy in the alum crystal: it is
remarkable that alum crystals retain their specific structure through
a host of substitutions of materials, or "mutations." Thus, rubidium,
cesium and even ammonium can be substituted for the potassium;
iron, manganese, etc., can be utilized instead of the aluminum;
selanion (Se04), etc., instead of the sulfanion. The most essential
characteristic of an alum crystal seems to be the particular strain set
up in the local ether when alum crystals originated. It is the structure,
the particular space-lattice present, that matters, and the points in
that lattice can be taken by any materials whose outwardly directed
fields of force are flexible enough to adapt themselves to the particular
'set' that is in the local ether."

The Industrial Importance of Catalysts

In past years, sulfuric acid, a basic material to chemical indus-
try, was made in dilute state in large lead-lined "chambers" and

98

LIFE: ITS NATURE AND ORIGIN

then concentrated, the oxidizing nitrous gases being recovered by
"scrubbing" in Gay-Lussac and Glover towers. The sulfur dioxide
was made largely from iron pyrites. This often contained arsenic
which, unless removed at considerable cost, contaminated the acid
and "poisoned" platinum catalysts, when these were used to oxi-
dize the S02 into S03 in the presence of air. Due in part to the
availability of cheap and pure sulfur brought up from our western
"salt domes" by the Frasch process, most sulfuric acid is now made
by passing a mixture of air and S02 over catalysts, and getting
concentrated acid directly. Vanadium pentoxide is largely used
as catalyst, since it is much cheaper than platinum to install, and
is not so readily "poisoned."

*-*<*
#

/Mt

^ ox

%

Figure 11. CATalysis. Design of a wooden medal for Kettering. Suggested to
Baekeland, who did not believe cyclohexane could be manufactured.

During World War I, C. F. Kettering and Thomas Midgley, Jr.,
of the Research Department of General Motors, in the course of
their collaboration with the U. S. Bureau of Mines to produce an
aviation gasoline as free from "knock" as possible, made exten-
sive engine tests with a variety of volatile organic liquids. The
comparatively rare hydrocarbon cyclohexane was found to be a
superior airplane engine fuel, and the suggestion was made that
its manufacture be attempted. Dr. Leo H. Baekeland, then a
member of the Naval Consulting Board, regarded the project as
impractical and advised against it. He even promised a wooden
medal to Kettering and his collaborators if they could make a
single pint of cyclohexane.

CATALYSIS: THE GUIDE OF LIFE

99

Nothing daunted, the investigators applied to this problem
their knowledge and skill in the preparation and use of catalysts
for the hydrogenation of benzene and in a comparatively short
time sent Dr. Baekeland a liter bottle of cyclohexane ensconsed
in a plush-lined mahogany casket. Baekeland kept this on his
desk for many years as a prized possession. And since the product
had been made by CATalysis, Dr. Baekeland was furnished with
a design for the wooden medal he had promised (Figure 11).

Today, catalysts and catalysis have achieved extensive publicity.
The average newspaper reader, even if he does not know what a

REGENERATOR

GAS TO
RECOVER* UNIT

UNSTABILlZEO
GASOLINE

© £T

=^21

Figure 12. Flow sheet of a "cat-cracker" using the fluid catalyst process. (Courtesy

M. W. Kellogg Co.)

catalyst is, does know that 100-octane gasoline, which gives our
aviators speed and ceiling, is produced with the aid of catalysts.
The more technically informed reader knows that the catalytic
production of sulfuric acid, ammonia, nitric acid, and wood
alcohol is an old story. In fact, Germany was able to start World
War I in 1914 only because she had just then become independent
of Chile as a source of nitrates, owing to German perfection of the
Haber process, whereby nitrogen and hydrogen can be catalyti-
cally combined to produce ammonia. This, in turn, can be cata-
lytically oxidized to nitric acid, the basis of most explosives as
well as a vital ingredient in fertilizers. Those connected with the
chemical industry or profession know that an ever-increasing num-

100

LIFE: ITS NATURE AND ORIGIN

ber of useful and valuable organic compounds are now being
catalytically produced, some in immense quantities. For example,
the 1944 catalytic output of phthalic anhydride, used in making
plastics, was over 62,000 tons. In 1936 about 250 tons of nickel
were sold in the United States for catalytic use, about two-thirds

Figure 13. Projection of Phthalocyanine along the b axis, which makes an angle
of 44.2 degrees with the molecular plane (/. M. Robertson). From paper in "Colloid
Chemistry," Vol. 5, by J. Alexander, Reinhold Publishing Corp., N. Y.)

having been used for hardening vegetable oils by catalytic hydro-
genation to produce a huge tonnage of the well-known edible fats,
which, like lard, are nonfluid at room temperature.

To illustrate the magnitude and importance of catalytic processes in
the petroleum industry, consider in outline the recently perfected
"fluid-catalyst" cracking process, devised by long and expensive co-
operative research undertaken by large petroleum refiners, and now
operating in about 30 plants (Fig. 12).

CATALYSIS: THE GUIDE OF LIFE

101

Scale
0 1 2 3 4 5

IhiiImiiIiiiiIiiiiIiiiiIii I il mil lllll II lillllllA,

Figure 14. Projection of nickel phthalocyanine along the b axis, which makes an
angle of 44.2° with the molecular plane (/. M. Robertson). Each contour line repre-
sents a density increment of one electron per A.2, except the nickel atom where the
increment is five electrons per A.2 for each line. The one-electron line is dotted.
(From paper in "Colloid Chemistry." Vol. 5, by J. Alexander, Reinhold Publishing
Corp., N. Y.)

From a standpipe about 200 feet high, a claylike powdered catalyst
cascades into a stream of vaporized oil at the rate of about 2 carloads
a minute, and the torrid, oily duststorm swirls like a gas into a reactor
vessel where, at the huge catalyst surface, there take place the complex
chemical transformations termed "cracking." The cracked reaction
products are separated from the now blackened, carbon-coated catalyst,
which then falls into a stream of incoming air and is carried to a

102 LIFE: ITS NATURE AND ORIGIN

regenerator where the carbon is burned off. The revivified catalyst
is returned to the standpipe for reuse at the rate of about 40 tons a
minute. About 73,000 tons of catalyst are consumed annually in this
process, which has been yielding daily (after certain additions) over
400,000 barrels of 100-octane gasoline. Incidentally, there are also
produced certain raw materials for synthetic rubber.

Germany developed the chemistry of coal and coal tar — because
she had coal. American chemists realize that besides coal we have
in our enormous supplies of natural gas and petroleum important
raw materials for a great and novel organic chemical industry, in
which catalysts are finding ever-increasing use.

Although our knowledge of specific catalysts and catalytic proc-
esses has been greatly extended by actual experiment, Professor
P. H. Emmett states8 that the selection of catalysts is still an art;
the time has not yet come when it is possible to predict in advance
with any degree of certainty the exact type of catalyst that will be
most effective for a hitherto untried reaction.9

To illustrate the view of Berzelius that catalysis is "a new mani-
festation of the electrochemical affinities of matter," consider the
electronic contour maps of phthalocyanine and of nickel phthalocya-
nine (Figures 13 and 14), as developed by Professor J. Monteath
Robertson from x-ray spectrographic studies at the Royal Institution
of London. Note how the introduction of a single nickel atom at
the center changes the electronic contour or "physiognomy" at that
point. The four benzene rings in the corners, as shown by the hexa-
gons in Figure 15, are too far from the center to be greatly affected.
The central core of phthalocyanine, represented by four pentagons
in Figure 15, consists of four pyrrol groups, arranged similarly to
those in porphyrin, a constituent of chlorophyll, cytochrome and
other biocatalysts or enzymes. While the specific activity of chloro-
phyll depends upon its central atom of magnesium, hemoglobin and
cytochrome have each an essential iron atom. A. H. Cook10 found
that of all the metallic derivatives of phthalocyanine tried, only the
iron compound showed marked catalase activity; that is, it can catalyze
the decomposition of hydrogen peroxide.

How Catalysts Function

Catalysts function by virtue of their outwardly directed specific
fields of force, which produce characteristic distortions or warp-
ings in the fields of susceptible particles (atoms, molecules, ions or
larger particles) with which they come into contact for a suffi-
ciently long time to permit a synthesis or a breakdown. The dis-

CATALYSIS: THE GUIDE OF LIFE

103

torted or "activated" particle may combine with other particles,
or it may be split into smaller fragments. Catalysts thus function
like a duly qualified judge, who may wed or divorce couples who
come within his jurisdiction and remain there long enough for
the operation of due process of law. Another analogy is that the
catalyst functions like a "key" of a zipper closure. Drawn in one

Figure 15. Dimensions of the nickel phthalocyanine molecule (/. M. Robertson).
(From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Reinhold Publishing
Corp., N. Y.)

direction, the "key" massages the opposing "hooks" so that they
link together; if drawn in the opposite direction, the "key"
releases the bonded hooks from each other, and the closure opens.
The key and the hooks must be adjusted to each other within
rather close limits of size and shape. An adhering bit of solder or
paint, or a mechanical deformation of key or hooks may prevent
normal functioning, but a single key may open or close an enor-
mous number of bonds.

104 LIFE: ITS NATURE AND ORIGIN

Similarly, a tiny quantity of a catalyst may determine the building
up or the breaking down of an enormous number of molecules; but
catalysts may be "poisoned" and rendered inoperative for certain
reactions by physical or chemical change, or by adsorbed impurities.

In developing what is known as the theory of active centers on
catalytic surfaces, Professor Hugh S. Taylor of Princeton, in a paper
sent to the Royal Society of London in 1925, discussed the phenomenon
of progressive poisoning. Thus the surface of a nickel catalyst can
be "progressively and successively poisoned for the hydrogenation of
benzene with thiophene as a poison, then for the hydrogenation of
ethylene which occurs on a surface whose activity for benzene hydro-
genation has been destroyed by the poison used. A surface poisoned
for both reactions could still serve for the reduction of nitrobenzene."11

It must be remembered that though the active catalyst areas
may be but a small fraction of the total area of any particle or
surface, what happens at this active area may have great and far-
reaching consequences, e.g., the production of a hormone, a vita-
min, or the carrier or the prosthetic group of other catalysts. A
tiny zipper key can open a very large bag. The importance of
local happenings is also illustrated when a grindstone is used to
sharpen steel tools. Without the use of water, oil or some similar
lubricant, the local temperature at the metallic edge being ground
may rise high enough to draw the temper of the steel. A dry
grindstone immediately throws off a shower of sparks from steel.
The frictional heat developed by a shoe brush melts the wax in
the shoe polish, locally and momentarily. Sir George Beilby12
showed that when metals are burnished or polished, molecular or
atomic flow occurs; crystalline surface structure is practically
fluidified and converted into an "amorphous" layer resembling a
highly viscous liquid. Conduction dissipates the local heat
developed.

It is common industrial practice to provide means for absorbing
and removing the large amounts of heat locally developed by catalysts.
For example, the vanadium pentoxide catalyst used to oxidize naphtha-
lene vapor to phthalic anhydride in the presence of a limited supply
of air, is kept at a safe operating temperature by insertion of iron
tubes containing mercury, which boils at 357° C and thus prevents
fusion of the catalyst or charring of the organic substances in process.13
The various impurities in the naphthalene also suffer chemical or
physical changes, but no investigation has been made to see if these
are due to local heat, to specific action of the catalyst, or to both. In
industry, the "waste heat" from the main reactor (where the main

CATALYSIS: THE GUIDE OF LIFE 105

reaction may be either endothermic or exothermic), is generally used
to preheat reactants, to help initiate other processes, or to raise steam
for general uses.

Temperature Control in Biocatalysis

Most living things die on exposure for varying times to the
temperature of boiling water, especially in the presence of mois-
ture. Some dry spores are more resistant. E. Zettnow reported14
that some organisms in lime paste from a sugar factory survived
heating for 30 minutes at 310-320° C. Subsequent tests reduced
the killing temperature to 199° C and 220° C. In nature only
those biological systems and structures survive which keep temper-
atures down to non-lethal levels, by protecting the delicate, heat-
susceptible catalysts upon which life depends, against too high and
too localized a liberation of heat. How is this accomplished in
the cell?

Three main factors seem to be at work. (1) The over-all reac-
tion is broken down into a series of successive chemical steps,
mediated by different catalysts or catalyst areas, so that the whole
reaction proceeds in what may be called a step-wise manner.
(2) The intermediate products must move from one catalyst area
to another (which takes time), and the total heat of the reaction
is gradually set free at distributed areas in what may be called a
spot-wise manner. (3) The biocatalysts are surrounded by aque-
ous cytoplasm; and water, with its high specific heat, helps to
absorb and distribute the heat energy liberated.

The net result is that biological reactions usually proceed at a
very gradual rate, without sudden and violent local temperature
increase; this would be fatal, although the normal body temper-
ature is maintained by the regulated liberation of heat. Many
other factors are operative in control of body temperature, apart
from orderly liberation of heat by the biocatalysts specific to the
particular kind of animal. In cold-blooded animals (poikilo-
therms), the body temperature is much influenced by that of the
surroundings. Migration or descent underground protects some
against freezing to death, while others seek shade to prevent death
from too long an exposure to the sun (e.g., rattlesnakes). The
temperature of warm-blooded animals (home other ms) tends to re-
main constant, despite variations in the temperature of their
surroundings; but it varies greatly with the position of the animal
in the taxonomic scale.15

106 LIFE: ITS NATURE AND ORIGIN

For protection against cold, warm-blooded animals have hair,
fur, feathers, or layers of fat (whale). When we get "blue with the
cold," our blood has stagnated to reduce heat loss; and shivering,
probably initiated by the hypothalamus, represents involuntary
"exercise." As protection against heat, animals seek shade, but
rely mainly upon radiation of heat to the air, which may be aided
by perspiration, since water has a high latent heat of vaporization.
Dogs, which have no sweat glands, loll out their tongues, and I
have seen sparrows near Merced, Cal., in the meager shade of
fence posts, "panting" to endure a temperature which registered
over 110° F in the shade above ground level.

Efficiency in Biocatalysis

The ideal heat-engine of Carnot (1824) has a theoretical effi-
ciency of about 50 per cent. For steam engines, it is about 20 per
cent, for gas engines about 25 per cent, for diesel engines about
40 per cent; but actual results may go considerably below these
figures. A standard cadmium storage "battery" or cell, slowly
charged and discharged, may approach 100 per cent efficiency; and
it is to be expected that animals, operating likewise by chemical
energy rather than by differences of temperature, will show high
efficiency — and they do. But the situation is greatly complicated
by the fact that animals utilize much of the energy of their food
in mere maintenance and in growth and reproduction, which
involve synthetic processes which require heat. The efficiency of
some of these synthetic processes may be low, but the "waste" heat
may be utilized in speeding up or initiating other chemical
changes, as well as in keeping up the body temperature when dis-
tributed by the blood.

The efficiency of autotrophic bacteria in producing ammonia from
atmospheric nitrogen approximates 3 per cent,16 while that Nitro-
bacter, using the energy derived from oxidation of nitrite to nitrate,
to assimilate carbon from carbon dioxide, is reported as about 6 per
cent.17 O. Rahn18 estimates that one Calorie value in food produces
the following heat liberation (in Calories) in various animals: pig,
0.2-0.4; trout, 0.18-0.31; cockroach, 0.34-0.35; mold, 0.58-0.70; colon
bacillus, 0.13-0.24; pseudomonades, 0.21-0.22. Agriculturists estimate
efficiency in terms of useful or marketable products produced — wool,
meat, hide or skin, fat, eggs, milk, manure, etc.

By directing the course of chemical reactions with restricted
heat emission, at localized areas and at regulated velocities, cata-

CATALYSIS: THE GUIDE OF LIFE 107

lysts may become sources of "quanta" of kinetic energy. Despite
the influence of surrounding aqueous material, they may thus
increase the intraparticulate activity or resonance of some mole-
cules, or give them momentarily an increase in kinetic motion,
corresponding in effect to what a relatively high temperature
might do. A molecule so activated and accelerated could become
highly reactive. In some cases, activation might be imparted to a
specific portion of a large molecule or complex. These physico-
chemical aspects of the chemical changes which take place enable
us to form some reasonable picture as to how the "driving" energy
is distributed and utilized in what biological chemists term
"coupled reactions."

In considering the significance of coupled reactions for the enzymic
hydrolysis and synthesis of proteins, Drs. Max Bergmann and Joseph
S. Fruton19 point out that thermodynamic data alone tell us only the
approximate amount of energy needed to make the system operative.
"We must therefore look for the specific physical or chemical mech-
anisms which make possible the synthesis of peptide bonds." In
certain reactions they discuss, sparingly soluble compounds formed
crystallize out, and equilibrium conditions lead to further synthesis.
"In these peptide syntheses, therefore, the energy required for peptide
synthesis comes from the process of crystallization whereby the syn-
thetic product is removed from the equilibrium." In these cases
Bergmann and Fruton intimate that the kinetic energy (heat) set
free by the aggregation (crystallization) of the synthesized product,
is the mechanism whereby the energy is bandied about. The work
of Prof. Rudolf Schoenheimer20 "led him to the view that in the
dynamic equilibrium between proteins and amino acids in the tis-
sues, peptide bonds are constantly being broken and reformed under
the catalytic influence of the tissue enzymes."

In the ordinary microscope, fat globules in highly diluted milk
show an uneasy oscillation about a mean position. The ultra-
microscope reveals the violent Brownian motion of the colloidal
casein particles, whose swarming crowd can be seen jostling the
fat globules this way and that. But the more rapid kinetic motion
of the still smaller molecules of water and solutes is invisible,
though it underlies what we see and is also responsible for bring-
ing some molecules to a reactive state. Similarly, in the cell, the
unseen molecular activity greatly exceeds the intense activity of
particles made visible in the ultramicroscope.

Professor F. G. Donnan of the University of London concisely

108 LIFE: ITS NATURE AND ORIGIN

summarized the work of A. V. Hill, W. Hartree, O. Meyerhof
and others as follows:21 "When the muscle tissue contracts and
does work it derives the necessary free energy, not from oxidation,
which is not quick enough, but from the rapid exothermic con-
version of the carbohydrate glycogen into lactic acid. When the
fatigued muscle recovers, it recharges its store of free energy; that
is to say, by oxidizing or burning some of the carbohydrate, it
reconverts the lactic acid into glycogen. Thus in the recovery
stage we have the coupled reactions of exothermic oxidation and
the endothermic conversion of lactic acid into glycogen."

In a fuller discussion, including more recent work, Professor Otto
Meyerhof22 observes: "Three different anaerobic reactions were found
to be related to activity and also to be linked to one another: (1)
splitting of carbohydrate, preformed in the muscle as glycogen and
hexose-6-monophosphate, into lactic acid via phosphorylated inter-
mediaries and pyruvic acid; (2) splitting of phosphocreatine into
creatine and phosphate; (3) splitting of adenosine triphosphate to
adenylic acid plus 2-phosphate via adenosine-diphosphate plus 1-
phosphate." The lactic acid formation restores the phosphocreatine,
broken down in the earlier stages of activity, while the breakdown of
phosphocreatine is able to restore the adenosine triphosphate, and
the oxidation of carbohydrate can reverse every cleavage reaction of
(1), (2), and (3), whose respective energy stores are given as 1.2 Cals,
0.23 Cal, and 0.09 Cal respectively, whereas carbohydrate oxidation
into COo + H20 is listed as 30 — 60 Cals, and is, therefore, the main
energy source. For many other important details and references,
Meyerhof's paper must be consulted.

Summing up current views, Brody23 points out that phosphate
occupies a key position in biological oxidation. Pasteur observed
its importance in 1860, Young and Harden confirmed it in 1905,
and it is at present being extensively investigated by the Cori,
Lipmann, and Meyerhof schools, among others.24 Brody states:
"... some phosphate esters serve as temporary biologic energy
reservoirs, analogous to charged batteries. Thus, according to
Cori, the synthesis of 6 molecules of glucose phosphate is coupled,
or associated, with the oxidation of one molecule of glucose. A
mol of glucose phosphate, therefore, has a labile energy increment
which, depending on the energetic efficiency of the process, may
be as high as 115 Cal ($ of about 700 Cal, the free energy of glu-
cose). This is, presumably, what Lipmann refers to as phosphate-

CATALYSIS: THE GUIDE OF LIFE 109

ester bond energy, the main form or source of anaerobic energy as
illustrated by the reaction:

Glycerophosphate + H20±^Glycerol + phosphate -f energy

. . . The phosphate group also catalyzes the oxidation and trans-
port of fats. Other inorganic elements may participate in the
oxidation of fat and perhaps its transformation into carbohydrate.
Most electron donors (metabolites) must be phosphorylated as the
preliminary step; for phosphorylation and oxidation are indeed
coupled reactions."

Broadly, then, a "coupled" reaction is one so closely associated
with another reaction as to determine the latter by providing the
necessary energy. While it is conceivable that in some cases the
total energy may be transferred without loss from one molecular
grouping to another, it seems reasonable to believe that the kinetic
aspects above outlined must generally be taken into account.

Furthermore, living things do not depend upon any one type of
chemical change, the oxidation of glucose, though this is most im-
portant in so many plants and animals, including humans. The
autotrophic bacteria utilize the energy available in some common
exothermic reactions.25 The "steaming" of manure piles and com-
post heaps is well known, and farmers sometimes use fresh manure as
an "anti-freeze," as well as in hotbeds. Prof. J. M. Nelson of Columbia
University informs me that in the early days in the Middle West,
farmers often kept their sod-houses warm by a thick layer of fresh
manure at the ground level.

Quite a number of biological reactions can take place in the dark;
but in the synthesis of glucose by plants, solar energy is absorbed,
with a local decrease in entropy. Animals are directly or indirectly
dependent upon the glucose and other products synthesized by plants;
in fact, most living things depend upon the catalyzed chemical output
of others, and we are only beginning to understand these often curious
and multiple relationships.

The Time Factor in Catalysis

The catalysts used in industry are sometimes aggregated col-
loids (e.g., platinum sponge, nickel used in hydrogenation); but
generally they are extended on carriers. This not only exposes a
large active surface, but it also permits the finely divided catalyst
to remain in place when gases or liquids are passed over it, and
to be filtered off if it has been mixed into a batch.

Some biocatalysts are fixed, like genes in the chromosomes; but

110

LIFE: ITS NATURE AND ORIGIN

most of the enzymes, which, with the genes, mainly direct the
course of chemical change in bionts, are free particulate units of
colloidal dimensions. The establishment of colloidal dimensions
may come about in several ways. Some molecules are born col-
loids; some achieve colloidality by molecular growth or aggrega-
tion; and some have colloidality thrust upon them by adsorption
or chemical fixation on a colloidal carrier or an extended surface.
Whatever the underlying cause, increase in particle size causes

SPECIFIC
SURFACE

.KINETIC
MOTION

SOLIDS

SUSPENSIONS

CURVE SHOWING RISE AND FALL
OF COLLOIDAL CHARACTERISTICS

INCREASING PARTICLE SIZE

Figure 16. Degree of colloidality related to particle size, specific surface and
kinetic activity. (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Rein-
hold Publishing Corp., N. Y.)

a reduction in kinetic motion, as may be readily seen in an ultra-
microscope. Particles at the lower ranges of microscopic resolu-
tion (about 0.25 micron) show only the feeble Brownian move-
ment. On the other hand the kinetic motion of small molecules
is so rapid that if a hydrogen molecule were large enough for the
eye to resolve, it would still be invisible, just as in the case of a
rifle bullet in flight. Between these two extremes lie all degrees
of the kinetic motion of particles, which increases at an accelerated
rate as molecular dimensions are approached.

CATALYSIS: THE GUIDE OF LIFE 111

But decrease in particle size is also accompanied by great in-
crease in the area of surface exposed per unit weight. The degree
of dispersion where this surface area exerts its most effective
influence before rapidly increasing kinetic activity dominates has
been termed the zone of maximum or optimum colloidality.26
Figure 16 is a diagrammatic sketch of these relationships, based on
the assumption that the particles are spheres, which, of course, is
seldom the case. Particles have various, and even varying con-
tours (threads, rods, plates, aggregates); the diagram simply illus-
trates the principle.

When a particle approaches an active catalyst area, two factors
are of outstanding importance:

(1) the momentary electronic contours of the surfaces in apposi-
tion, for this determines the possibility of particulate union
or influence;

(2) the kinetic velocities of translation and rotation of moveable
areas, which determine whether the possibility may become
a reality.

The importance of this kinetic factor came to the fore in the
course of a lecture experiment made by Sir Ernest Rutherford
at the Toronto meeting of the British Association for the Advance-
ment of Science (1924). It was designed to illustrate how a posi-
tively charged atomic nucleus will repel an alpha particle emitted
by radium. An electromagnet, with its positive pole up, was
fastened to a table so that another electromagnet, swinging from
the ceiling with its positive pole down, could just pass over it.
The mutual repulsion of like magnetic poles caused the swinging
magnet to take a parabolic path in any off-center approach. To
illustrate the relatively rare recoil which occurs when an alpha
particle makes a direct approach to an atomic nucleus, Sir Ernest
took careful aim — but the swinging magnet passed completely
over and beyond the fixed one, probably giving a slight unseen
"jump" as it did so. Quickly retrieving the swinging magnet, he
swung it again from a lesser distance and got the expected recoil.

From this it is evident that if a certain relative critical velocity
is exceeded, particles or surfaces having the power to cohere, will
not do so. In catalysis, a certain period of time is necessary for
the electronic fields of the reactants to become fitted to each other,
so that apart from the effects of rotation of the particles, internal
kinetics, and mode of presentation, the kinetic velocity of trans-
lation is an important factor.

112 LIFE: ITS NATURE AND ORIGIN

Increase in thermal agitation increases the total number of en-
counters per unit of time between reactant catalyst and substrate
areas, and this works in favor of increasing the number of fruitful
encounters. As the temperature increases, however, a point is
reached where so many particles have so high a relative velocity
that the number of unfruitful encounters increases to such an
extent that the catalyst efficiency per unit of time tends to fall off.

Many other intercurrent factors may influence the thermal optimum
in catalysis besides the kinetic factors; e.g., the catalyst, reactants, or
end products may undergo decomposition; adsorbed substances may
"lame" the catalyst; specific substances or ions may affect the degree
of dispersion or electronic integrity of catalyst or reactants. Thus
Svedberg found that many proteins are dispersed into smaller sub-
units by change in pH, some of them being reconstituted from the
fragments when the pH is shifted to the stability zone; and many sub-
stances will "dissolve" or disperse glue at room temperature, e.g.,
calcium chloride, sodium nitrate, sodium naphthalene sulfonate.

Pepsin is "activated" by hydrochloric acid. What this means ki-
netically may in part be followed ultramicroscopically. A dilute solu-
tion of egg white heated nearly to boiling gave an opalescent dis-
persion full of bright, rapidly moving ultra-microns. On allowing a
droplet of pepsin solution (Fairchild's containing 15 per cent alcohol)
to diffuse under the cover glass of the slide, the albumin ultramicrons
immediately coagulated into large, motionless masses. When a drop-
let of O.IN hydrochloric acid was introduced under the cover glass
the coagulated masses burst into small groups and isolated ultra-
microns, which resumed their active kinetic dance. But almost im-
mediately the albumin particles began to grow fainter and to dis-
appear, the field meanwhile becoming brighter as smaller ultramicrons
or amicrons were formed. The addition of pepsin to the opalescent
albumin solution caused it to clear gradually at room temperature.

The kinetic motion of diastase particles may likewise be followed
ultramicroscopically, as they gather about and actively rub or "gnaw"
holes or cavities in starch granules. The chemical changes occurring
are, of course, far below the level of visibility.

Haurowitz and Schwerin27 found that the catalytic auto-oxidation
of linoleic acid by hemin in heterogeneous emulsions ceases when the
system is made homogeneous by addition of acetic acid, dioxane,
pyridine, alkali or bile, but recommences when homogeneity is
abolished by addition of water or stronger acid. These authors
believe that this reversal demonstrates that the catalysis takes place
only in the interfacial film between the water and oil phases, and
attribute the observed diminution of the velocity of oxidation by

CATALYSIS: THE GUIDE OF LIFE 113

excess of hemin to displacement of linoleic acid molecules from the
interfacial film. They conclude that orientation of substrate and
hemin molecules in the interfacial film is of decisive importance for
the establishment of the catalysis. This is, of course, true, and it
involves the electronic contour factor (1) mentioned above; but the
kinetic factor (2) is also to be reckoned with.

How Catalysts are Modified

The technological and patent literature has long reflected the
fact that the introduction of new atoms or molecules into the
active surface of a catalyst may stimulate, inhibit, or alter the
nature and/or rate of the catalyzed reaction.28 If a desired result
is accelerated, the added substance is termed a promotor; if it is
inhibited, the added substance is called an inhibitor or poison.
In cases where a catalyst can direct the formation of several sub-
stances and an inhibitor is found which depresses undesired reac-
tions, we speak of "beneficial poisoning." In a general sense any
substance which changes the behavior of a catalyst may be called
a modifier, a term free from implication as to the result of the
change. The importance of catalyst modification in biology will
be referred to later on.

One factor in the efficiency of a catalyst is the amount of free
active surface it exposes to the reactants. It is common commer-
cial practice to distribute the catalyst substance on carriers, or
supports, such as asbestos, charcoal, alumina, diatomaceous earth
(kieselguhr), etc., which are supposed to act merely mechanically.
It has been found, however, that the carrier often exercises a
marked effect, either by contributing small amounts of impurities
to the catalyst surface (which may thus be either promoted or
poisoned), or else by forming with the catalyst molecules some
new composite surface of different activity.29

According to recently released information30 a substantial
amount of the synthetic rubber produced during the recent war
was made from ethyl alcohol by the Lebedev process. An effi-
ciency of about 65 per cent in butadiene synthesis was obtained
with a silica gel catalyst promoted by tantalum oxide, and nearly
as good results were had with the more plentiful zirconium oxide
as promotor.

The potent effect of catalyst poisons is brought out by the remarks
of H. Bernthsen at the Eighth International Congress of Applied Chem-

114 LIFE: ITS NATURE AND ORIGIN

istry (1912) relative to the iron catalyst used in the first step of the
Haber process:

"Extremely minute quantities of these bodies (impurities), which are
almost always present even in the purest commercial products or in
so-called pure gases, suffice to render the catalysts absolutely inactive
or at least to diminish their activity very seriously. Thus iron, for
example, prepared from ordinary iron oxide with a content of one per
thousand of sodium sulphate is, as a rule, inactive. Iron containing
0.1 per cent sulphur is generally quite useless, and even with 0.01 per
cent is of very little use, although in appearance and when examined
with the ordinary physical and chemical methods no difference at all
can be detected as compared with pure iron.

"The recognition of these facts gave rise to two problems: (A) The
preparation of contact masses free from poisons or the removal of
poisons from them; and (B) freeing the gases to be acted upon
catalytically from all contact poisons. A trace of sulphur, one part per
million, in the gas mixture, can under certain conditions be injurious,
so that electrolytically prepared hydrogen must generally be further
specially purified."

Since a small amount of a catalyst may, if given sufficient time, direct
an enormous amount of chemical change, we can understand how
minute may be the quantity of promotor or modifier needed to pro-
duce a great change in the final output.

Experimenting with the catalytic production of methanol from
carbon monoxide and hydrogen, Sir G. T. Morgan31 observed that
while catalysts made by calcining equimolecular mixtures of manganese
and chromium nitrates gave methanol containing only traces of higher
alcohols, catalysts prepared by precipitating a mixed solution of oxides
of manganese and chromium in caustic potash gave a product con-
taining appreciable percentages of higher alcohols. This led him to try
the effect of regulated additions of alkali metals to the catalyst. To
quote one outstanding case, when the catalyst contained 15 per cent of
rubidium hydroxide, the carbon in the gases passing over the catalyst
was distributed as follows: (with equimolecular proportions of the
pure Mn and Cr oxides the yield of methanol was 80.5 per cent).

Methanol 41.5%

Ethanol 1.6

Higher alcohols 36.7

Aldehydes, acetals, ketones 15.5

Methane 2.0

Carbon dioxide 2.0

The higher alcohols in this case consisted chiefly of isobutanol, but
contained besides normal propanol, 2-methylbutanol, 2-methyl-
pentanol, and 2, 4-dimethylpentanol.

CATALYSIS: THE GUIDE OF LIFE

115

Morgan found that the addition of cobalt to the catalyst gave mainly
straight-chain alcohols, rather than the branching-chain alcohols
formed by alkalized catalysts. This is shown by the following table
which gives in parts per thousand, the alcoholic content of the liquid
formed by passing the same mixture of carbon monoxide and hydrogen
over different catalysts, under like conditions of temperature and
pressure.

Catalyst Used

Alcohols Formed

Rb-Cr-Mn

Co-Mn-Zn-K

Co-Cu-Mn

Methyl

420 —

12 —

43 —

69

— 8

— 6.5

89

198
86
17

— 11
4 —

— 1.5
1

1.5

220

Ethyl

200

n-Propyl

50

uo-Butyl

— 3

n-Butyl

16

/3-Methylbutyl

— 2

n-Amyl

6

/3-Methylamyl

n-Hexyl

2 —

w-Heptyl

Unidentified

1 —

In concluding his address before the Societe Chimique de Belgique32
Morgan said:

"All these experiments are of special significance, for they permit
us to see the enormous variety of organic compounds which can be
synthesized by secondary reactions following primary condensation of
carbon monoxide and hydrogen, a gaseous mixture well known under
the name of 'water gas,' made on a large scale from coal and steam.

"Up to the present time these condensations have been studied at
temperatures higher than the decomposition of many organic com-
pounds. With higher pressures and more efficient catalysts, we may
some day expect to lower the reaction temperature very materially.
When we shall have reached this point, the synthesis of organic com-
pounds of great complexity should be possible and among these
products we will find organic substances which up to now can be
formed only by the chemical activity of living beings."

Biocatalysts; Prosthetic Groups; Symplexes

The course of chemical change in organisms is directed by
catalyst units of colloidal dimensions — enzymes and genes, and
perhaps also by units in some symbionts, and units fixed at or on
various surfaces. Whereas with primal bionts gene-like units were
probably the sole directors of life chemistry, in higher forms we
find thread-like aggregations of genes (chromosomes) and a great

116 LIFE: ITS NATURE AND ORIGIN

variety of secondary but highly specific catalysts (enzymes), whose
production is in some way interwoven with the activities of the
truly living, self-reproducing catalysts. The experimental evidence
indicates that large numbers of biocatalyst units are destroyed or
inactivated in the course of their functioning, so that there must
be a continual replenishment of the supply.

How do biocatalysts arise? The broadest, and therefore the
most indefinite answer to this question would be: by the assem-
blage of smaller units (atoms, molecules, colloidal particles) so as
to constitute an exposed surface which has a suitable electronic
structure and contour. Genes in the chromosome string thus form
duplicates of themselves (autocatalysis), and must therefore be
considered as living. On the other hand, an active catalyst area
may be formed by being built into or upon a larger fixed surface,
e.g., a cell wall; or else there may be formed by adsorption and/or
chemical combination, colloidally dispersed units — the multitu-
dinous enzymes — which can flow and kinetically "swim" about in
cytoplasm, sap, or body fluids, and may even diffuse slowly. Texts
often give the erroneous impression that colloids will not diffuse;
but Thomas Graham33 clearly pointed out that they may diffuse,
though they "are slow in the extreme."

The catalytic effect of the walls of the containers in which chem-
ical reactions are carried out is not, as a rule, sufficiently appreci-
ated, and traces of substances existing in, forming on, or intro-
duced into these surfaces may powerfully influence results. Thus
a food product processed in aluminum vessels was deleteriously
affected by tiny fragments of iron left in the aluminum surfaces
when these were scoured with steel wool. G. Bredig34 found that
by fixing amino groups to cellulose, wool, or silk fibers, organic
catalysts were produced which split off carbon dioxide from brom-
camphocarbonic acid. Although inorganic catalysts may appear
to be simple, e.g., platinum black, those having first-hand experi-
ence with commercial catalysis know how potent is the influence
of structure, carriers, and impurities on their functioning.

Biocatalysts are composed mainly of complex organic molecules,
assembled into a delicate but specific structure. When a certain
molecular group enters a biocatalyst to form and characterize the
active catalyst area, it is termed a prosthetic group. The word
"prosthetic" is derived from a Greek root meaning to add to, or
to insert. Thus prosthetic dentistry deals with the insertion of
missing teeth. The prosthetic group, so to say, puts "teeth" into

CATALYSIS: THE GUIDE OF LIFE 117

the biocatalyst. Often the prosthetic group demands for its func-
tioning the presence of a single atom, e.g., magnesium with
chlorophyll, copper in the polyphenol oxidase of mushrooms and
in tyrosinase, iron in catalase, cytochrome, etc. Where "homeo-
pathic" doses are effective, their action may often be understood
along these lines.

Richard Willstatter35 proposed the term symplex for compounds
where high-molecular substances are bound by residual valencies,
e.g., a prosthetic group and a colloidal carrier. Symplexes are
distinguished from mere mechanical mixtures by one or more of
the following characteristics: (1) alteration or enhancement of
specific reactivity of one component; (2) change in solubility or
dispersion of one component; (3) change in optical properties;
(4) change in stability; (5) change in toxicity; (6) change in reac-
tions, e.g., color reactions.

True chemical combination is not necessary to make separate
units acquire new properties when combined. Neither an arrow-
head, an arrow shaft, nor a goose feather is an arrow; but the
three, when properly fitted together, will make an arrow and will
function as one.36

Structures of the "symplex" type are very loosely bound together.
E. L. Smith37 found that solutions of phyllochlorins (chlorophyll-
protein compounds extracted from spinach leaves) may be split into
free chlorophyll and protein by the detergents sodium desoxycholate,
bile salts (mainly sodium glycocholate) and digitonin. In the presence
of sodium dodecyl sulfate (SDS), the prosthetic group remains at-
tached to the protein, but the compound is split into smaller units, the
protein properties and absorption spectrum being modified. Tobacco
mosaic virus is also split by SDS into smaller fragments, nucleic acid
being simultaneously separated from the protein.38 In the presence of
SDS chlorophyll loses magnesium and becomes phaephytin; and this
substance, or the chlorophyll (depending on pH), remains attached to
the protein, since the prosthetic group is not separated by ultra-filtra-
tion, dialysis, or fractional precipitation. Smith believes that much
previous work on chlorophyll dealt only with the prosthetic groups of
extremely complex specific catalysts. Emerson and Arnold39 con-
cluded from photochemical studies that 2,500 chlorophyll molecules
form one functional unit in photosynthesis.

The importance of the carrier in the biological field is indicated by
the following two examples. Keilin and Mann40 report that per-
oxidase, which shows great resemblance to methemoglobin, can be
considered as a compound of protohematin with a native protein.

118 LIFE: ITS NATURE AND ORIGIN

Peroxidase forms two highly unstable compounds with H202, whose
decomposition is much accelerated by the acceptor present in plant
extract or by the addition of other acceptors, e.g., ascorbic acid,
hydroquinone, or pyrogallol. "The same hematin nucleus combined
with three different native proteins forms three distinct compounds:
methemoglobin, catalase, and peroxidase, which have many properties
in common but show, however, striking differences in the nature and
magnitude of their catalytic activities." Warburg and Christian41
report that the old "yellow enzyme" may really be an artifact resulting
from the loss of adenylic acid during its preparation. They describe
five different yellow enzymes, some with similar proteins but different
prosthetic groups, others with the same prosthetic group but different
proteins. The protein/prosthetic group combination is reversible,
and it is estimated that one molecule of alloxine dinucleotide can
transfer 1440 molecules of oxygen per minute. Vegetables and fruits
are "blanched" by steam before being dehydrated, to inactivate
enzymes which cause undesirable changes.

This gives us some insight as to the potency and flexibility of the
enzymic catalyst systems of living cells, and effectively answers the
antiquated gibe of orthodox organic chemists that whenever a biolog-
ical reaction is to be explained, a new enzyme is invented.

The formation of chlorophyll seems to demand the presence of iron,
just as the formation of erythrocytes in man demands the presence of
copper. The mode of formation of prosthetic groups is generally
obscure,42 but it has recently been shown that thiamin (vitamin Bx) is
combined with pyrophosphoric acid,43 and D. E. Green states:42
"There is ample evidence of the existence in animal tissues and micro-
organisms of enzymes which catalyze the phosphorylation of thiamin
as well as the dephosphorylation of diphosphothiamin." Some ani-
mals (man) must eat vitamin C; others (rats) can synthesize it, or in
any event do without it in their food.

Nature, with infinite time and opportunity for experiment, accom-
plishes results in manifold and devious ways. Thus the ascidian
Phallusia mamillata has an acid blood (3 per cent H2S04) which con-
tains as chromogen a non-dialysable organo-vanadium compound.
On plasmolysis this gives a brown solution, which yields, on drying, a
dark-blue powder showing over 10 per cent vanadium (two analyses
gave 10.36 and 15.4 per cent, but the latter figure is doubtful). Mus-
sels have a manganese-containing catalyst, pinnaglobin. Most crus-
taceans, including Limulus (the horse-shoe or king crab, of antediluvian
ancestry) are literally blue-blooded because of copper-containing
hemocyanin. A group of African birds known as the Touracous or
Plantain-eaters have in their pinion feathers red or crimson patches
or portions from which weak alkali or soap solutions will extract a
pigment, which, after precipitation by acid, dries to a rich crimson

CATALYSIS: THE GUIDE OF LIFE 119

solid44 called turacin. This has been recently proven to be a copper
porphyrin compound.45 Over sixty years ago Professor James F. W.
Johnston (University of Durham, England) made the following com-
ment:46

"The existence of an animal pigment so rich in copper as turacin
(about 8 per cent), offers many interesting problems for study. Traces
of this metal seem generally diffused in most vegetables and many
animals; but here are more than traces — weighable and visible quanti-
ties. It is true that these plantain-eaters have been seen to pick up in
their native countries grains of malachite, the green mineral carbonate
of copper; but we must rather look to the vegetable food they con-
sume as the true source of this metal. And when the copper is
ingested, how does it find its way, in the complex pigment of which
it is an essential part, precisely to those feathers, and to those barbs of
feathers, and to those parts of such barbs, which are red, and not to
the black portions? For if one of these feathers is burnt in a Bunsen
gas-burner, not till the red part of the feather is reached will the green
flash of the copper tinge the flame. However, in the crest of the violet
plantain-eater (Musaphaga violacea) and perhaps traces in blood of all
these birds, turacin, and therefore copper, does occur. Still the whole
mystery of this strange pigment is far from being understood."

It has recently been reported that certain molds will not grow in the
absence of traces of gallium; and Aguilhon and Sazerac47 found that
the addition of 0.0001 per cent of uranium acetate to a fermentation
mixture of Acetobacter suboxidans and sorbitol increased the yield of
sorbose by 76 per cent.

In an article on the biochemistry of microorganisms C. B. Van Niel48
refers to many other cases where trace substances are vital: e.g.,
molybdenum for the nitrogen-fixing organism Azobacter; copper for
common molds as well as for higher plants; boron, apparently needed
to form borocitrin, related to the flavin pigments and found in micro-
organisms by Kuhn. Van Niel also tabulates the recent work of vari-
ous investigators showing the diverse ways in which different organ-
isms split acetate and normal butyrate.

E. C. Auchter,49 Chief of the Bureau of Plant Industry, U. S. Dept.
of Agriculture, in discussing the interrelation of soils and plant, ani-
mal and human nutrition, lists some of the "physiological troubles"
of plants which can be cured by supplying the necessary small amounts
of certain missing but essential elements. It must, of course, be re-
membered that larger amounts than the tiny optima may be very
harmful, as is the case, e.g., with boron. Magnesium cures sand drown
of tobacco in the soils of the coastal plain; manganese cures chlorosis
of tomatoes on some calcareous Florida soils, and permits such soils to
give improved yields of potatoes, snapbeans, cabbage, lettuce, peppers,
carrots, beets, citrus and corn; zinc cures pecan rosette in the South,

120 LIFE: ITS NATURE AND ORIGIN

citrus leaf mottle in California, South Africa, and Florida, little leaf
of apples and other deciduous fruits in the West and Northwest, and
white bud of corn on the Norfolk and Hernando fine sands of Florida;
boron cures internal browning of cauliflower and dry rot of sugar beets
in Michigan, crown rot of sugar beets in Ireland, die-back of citrus in
Africa, internal cork and drought spot of apples in British Columbia,
West Virginia and elsewhere, and cracked stem of celery in Florida;
copper, added to muck soils in Holland and parts of western New
York and to organic soils of Florida, improves the growth of several
crops; sulfur corrects yellows of tea in Nyasaland (Africa), and im-
proves the growth of field crops in Oregon and other areas.

Since animals depend upon plants, "the soil is the mother of all
living things." Deficiency of cobalt50 in certain New Zealand soils
causes "bush sickness" in sheep, which seems identical with the "pine"
of sheep in Scotland. Iodine deficiency leads to goiter in man and
beast and caused an annual loss of thousands of pigs in Montana until
iodine feeding was practiced. Selenium, taken from the soil by
plants, causes disease and malformations in animals eating the plants.51
Marco Polo, on his journey to Tartary, observed hoof deformations of
this type, which may have had the same kind of origin. According to
A. L. Moxon traces of arsenic compounds, fed in water or in salt, tend
to protect animals against the toxic action of selenium, while bromo-
benzene aids in its excretion.

The eighth scientific meeting of the Nutrition Society held in Lon-
don, England, Oct. 17th, 1942, was devoted to "Trace Elements in
Relation to Health." Among the rarer deficiency diseases mentioned
were: enzootic ataxia (swayback of lambs), which may be prevented
by feeding traces of copper during pregnancy; molybdenosis (called
teart of Somerset), which affects ruminants, due to molybdenum taken
up by plants where the soil content of molybdenum was about 100
ppm, and helped by traces of copper sulfate; fluorosis, which may
cause osteosclerosis, though teeth with mottled enamel due to fluorine
are relatively immune to decay.

It must not be supposed that trace substances always operate in one
way, for the complications in any case may be great. Thus sulphur
may be oxidized by soil bacteria and affect the local pH — from which
a chain of other consequences may follow. However, much of the
evidence points to the conclusion that the inclusion of trace substances
in catalyst surfaces is a frequent factor that must always be considered;
for visible results develop from the products of catalysis.

Chemical Activators

A great mass of evidence has accumulated to indicate that many
important biological changes are directed, or powerfully influ-

CATALYSIS: THE GUIDE OF LIFE 121

enced, by exceedingly minute proportions of highly specific sub-
stances, even though the actual number of molecules (or other
particulate units) involved may be enormous. Some activators
come from outside the organism, e.g., vitamins from food, trace
substances from the soil; others are formed within the organism,
e.g., auxins in plants, hormones and neurohumors in animals.

Electric phenomena are associated with the functioning of ner-
vous and muscular tissue. Electrocardiograms from the heart
muscle and electroencephalograms from the brain are routine pre-
cedures in many hospitals. Sir Edgar A. Adrian (Nobel prize,
1932) and his collaborators measured the tiny electric impulses
passing along nerves.52 Herbert S. Gasser and Joseph Erlanger
(Nobel prize jointly, 1944) applied the oscillograph to demonstrate
the details of these impulses. Based on interpretations of experi-
mental work of Elliot, Howells, Dixon, Otto Loewi (Nobel prize,
1936), W. A. Cannon and Sir H. H. Dale (Nobel prize, 1936), it
has for many years been thought that nerves act upon effector
organs (e.g., muscles and other nerve cells) by releasing at the
nerve endings chemical substances (e.g., acetylcholine, sympathin,
adrenaline) which exert a stimulating or an inhibiting effect at
their place of liberation. These views were based on experiments
showing the pharmacological effects of acetylcholine, and a demon-
stration of its presence, under certain conditions, in the perfusion
fluid after stimulation.

The new concept is based on studies of the enzymic catalysts
which form and break down acetylcholine, and on the correlation
of these reactions with the physical happenings in the living cell.
Quite a variety of recent experimental data indicate that the
propagating agent along nerves and muscle fibers, as well as across
nerve synapses and neuromuscular junctions, is a flow of current
— the action potential. However, acetylcholine plays an essential
role in the alteration of the surface membrane (the "progressive
disturbance" of Keith Lucas), permitting the flow of current. The
following abstract was kindly prepared for me by Professor David
Nachmansohn of Columbia University, who has done so much to
establish the new view.

"The enzyme which inactivates acetylcholine by splitting the active
ester into its inactive compounds, choline and acetate, is cho-
linesterase. One of the most essential features resulting from studies
of this enzyme is the high speed with which acetylcholine may be in-
activated. This speed parallels that of the electrical manifestations,

122 LIFE: ITS NATURE AND ORIGIN

a prerequisite for any theory correlating chemical reactions with con-
duction. Significant amounts of the ester can be metabolized in a
millisecond or a fraction thereof. One square millimeter of neuronal
surface of the giant axon of Squid, e.g., can split one billion molecules
of acetylcholine in one millisecond. The turnover number of the
purified enzyme seems to be close to 20 million per minute, which
means that one molecule of enzyme can split one molecule of substrate
in a few millionths of a second. The enzyme is localized exclusively
in the suface where the bioelectrical phenomena occur. It is present
in all conducting mechanisms throughout the whole animal kingdom,
being found in the lowest animal form possessing neuromuscular tissue
(Tubularia, a hydrozoan coelenterate). The enzyme is distinctly
different from all esterases present in non-conductive tissues like liver,
kidney, pancreas, etc.53

"The activity of this enzyme can be correlated in different ways
with the electrical manifestations of nerve activity. A close parallelism
between voltage and cholinesterase activity has been established in
studies on electric tissue. The powerful discharge in these organs is
basically identical with the electric potentials produced in nerve and
muscle, the only distinction being the arrangement of the units in
series. Great variations of the voltage per centimeter are found in the
electric organ of Electro phorus electricus, the South American electric
eel, whether the organ of a single specimen or that of specimens of
different sizes are used. In experiments in which the voltage ranging
from 0.5 to 22 per centimeter was plotted against cholinesterase
activity, a direct proportionality was found between the physical and
the chemical event, the line correlating the two processes passing
through zero. These findings indicate the interdependence of the two
events. No other chemical reaction offers a comparable behavior.54

"Another line of observation was based on thermodynamic con-
siderations. If the primary alterations of the surface membrane are
connected with the release and removal of acetylcholine, then the
primary source of energy during recovery should be used for the resyn-
thesis of the ester. In experiments on the electric fish, it can be
demonstrated that energy-rich phosphate bonds are adequate to
account for the electric energy released during the discharge. If the
breakdown of adenosine triphosphate, as suggested in these experi-
ments, is the primary energy source in recovery, adenosine triphosphate
should yield the energy for acetylation of choline. In agreement with
this assumption, a new enzyme, choline acetylase, can be extracted
from brain, which in cell-free solution under strictly anaerobic con-
ditions, forms acetylcholine in the presence of adenosine triphos-
phate.55"58

"A third line of investigation in which the interdependence of

CATALYSIS: THE GUIDE OF LIFE 123

cholinesterase activity and conduction can be demonstrated is based
on the effect of cholinesterase inhibitors. If the breakdown of the
membrane during the passage of the impulse is connected with the
release of acetylcholine and the restoration of the resting condition
requires the immediate removal of the active ester, then inhibition of
cholinesterase should abolish conduction. It can be shown on a great
variety of nerves, that eserine, a strong inhibitor of cholinesterase,
abolishes the action potential. The enzyme-inhibitor complex in this
case is easily reversible. In agreement with the reversibility of the
chemical process, the nerve and muscle action potentials reappear
when the eserine is washed out.

"Recently a new potent inhibitor of cholinesterase became known,
namely, di-isopropyl fluorophosphate (DFP). This compound, in con-
trast to eserine, destroys cholinesterase irreversibly. The rate of
irreversible destruction depends, however, on several factors like tem-
perature, concentration, etc. A most striking parallelism can be
demonstrated between the rate of destruction of cholinesterase and the
rate of abolition of the action potential. The close correlation
between the two events can be established as a function of time as well
as of temperature. The rate of irreversible inactivation of the enzyme
in vitro at a given temperature coincides with the rate of irreversible
inactivation of the enzyme and the irreversible abolition of the action
potential in nerves. The experiments have established conclusively
that the activity of the enzyme is inseparably associated with the con-
duction in nerve and muscle. 59> 60- 61

"Prostigmine, another cholinesterase inhibitor, which is in vitro
as strong as eserine, has no effect on nerve and muscle conduction. It
can be shown on the giant axon of Squid that prostigmine, in con-
trast to eserine and DFP, does not penetrate the lipoid membrane sur-
rounding all nerves (whether myelinated or unmyelinated).62 Prostig-
mine is, like acetylcholine and curare, a methylated quaternary am-
monium salt. Such compounds are not soluble in lipoids. This may
explain why these compounds act only on the nerve endings where no
lipoid membrane is found, but do not affect muscle or nerve fiber.
The peculiar ability of the synapse to react to certain compounds, as
first demonstrated for curare by Claude Bernard, was the basis for the
assumption of a special mechanism for the propagation of the impulse
across the synapse. In the light of recent biochemical and biophys-
ical findings, this peculiar ability may be attributed to a difference in
the anatomical structure rather than the underlying basic mechanism.
Recent observations of Arvanitaki, Bullock, Eccles and others, support
the assumption that the flow of current is the propagating agent
across synapses, as it is along the fibers. In the pre- and post-synaptic

124 LIFE: ITS NATURE AND ORIGIN

membrane, however, acetylcholine will most likely have the same role
as in the active surface membrane of the fibers."

The precise mechanism whereby the flow of current acts in the
effector organs is still uncertain. It might produce chemical
change locally, or transient differences in the charge or the orien-
tation of colloidal particles or macromolecules. As Volta long ago
showed, the contraction of a muscle follows its electrical stimula-
tion; but muscular relaxation follows cessation of the nerve
impulses: merely to stand upright requires the subconscious
innervation of many muscles. When unconsciousness supervenes
(as in narcosis or fainting), the nerve impulses cease, the muscles
relax, and the person falls limp. In the "rest cure" for tubercu-
losis, where it is desirable to keep exercise at the lowest possible
level, the patient reclines in a nearly prone condition. Actually,
the nerve impulses reach muscles at the rate of about 100 per
second, so that the contraction of the muscles involves great num-
bers of "twitches." When age or disease alters the tempo of the
twitches, tremor may become evident. Temporary nervous shock
often causes trembling.

Professor George H. Parker of Harvard University has investi-
gated the activity of various chemical activators, originally termed
neurohumors by Henri Fredericq, which "really act as hormones
over shorter or longer ranges." In discussing the nervous control
of color in fishes, Parker goes back to Pouchet (1876), who showed
that if the integumentary nerves of a turbot are cut, the melanin
granules in its melanophores undergo a dispersion, spreading out
the color and darkening the skin. Parker further observes that
there are two classes of neurohumors: hydrohumors, soluble in
water and therefore found in blood, lymph, etc., and lipohumors,
soluble in lipoids, fats, oils, fat solvents, etc. He finds63 that the
color changes of catfishes are controlled by three chief neuro-
humors: intermedin from the pituitary gland; acetylcholine; and
a concentrating neurohumor (probably adrenaline) from nerve
fibers controlling, respectively, concentration and dispersion.
Acetylcholine induces dispersion of melanophore pigment; adrena-
line causes the reverse. Both are lipoid-soluble, and acetylcholine,
in its fatty retreat, may thereby be protected from destruction by
cholinesterase; in fact, it accumulates to such an extent that its
effects may persist after nerve action has ceased, and it may be
extracted in measurable amounts from dark fish skins. "Thus the
fatty or lipoid substances in the animal body may serve as storage

CATALYSIS: THE GUIDE OF LIFE 125

reservoirs for agents that may be of first consequence in the animal
economy."

Francis B. Sumner64 has discussed the quantitative changes in
pigmentation resulting from visual stimuli in fishes and amphibia.
We thus get an idea of how and why flat-fishes, chameleons, etc.,
change color in response to their surroundings. This is related to
the seasonal color changes in the hair of some animals (e.g.,
ermines, hares, rabbits), brought about as Bisonette and others
have shown, by seasonal variations in the amount of sunlight,
acting through variations in the amounts of pituitary hormones
secreted. If the animals are kept in illuminated cages, they
develop summer coats even in winter.

Since the chemical units represent mainly consequences of
catalytic activity, it would appear that the differences described
probably stem back to the original cellular biocatalysts.

In quite another field, we find remarkable evidence of chemical
control in bees. In full season a queen bee may lay in excess of 2,000
eggs daily, more than her own weight. Unfertilized eggs give rise only
to drones (males), but the fertilized eggs may give rise to workers (sex-
ually immature females) or to queens: nutritional difference decides
the outcome. Townsend and Lucas state:65

"All female larvae are fed on royal jelly for the first 2-3 days after
hatching and during this period their anatomical development is
similar. Only the queen continues to receive this special diet. Any
larva from a fertile egg, if given royal jelly throughout its larval
period, develops sexually so that it becomes a perfect or true female
bee, or what is called a queen; otherwise, the larva develops into a
sexually immature worker. The queen is structurally much the same
as the workers but with these important differences: the pollen-gather-
ing apparatus remains undeveloped, the mouth parts and sting are
modified, while the spermotheca and ovaries are highly developed."

These authors separated royal jelly into four fractions and found
some evidence that the physiologically active material responsible for
the sexual development of the queen bee is in the ether-soluble frac-
tion. More recently Pearson and Burgin66 report that bee royal jelly
is the richest known source of pantothenic acid, its 35.8 per cent dry
substance containing from 378 to 618 (average, 511) mg of pantothenic
acid per gram.

In discussing ants, G. H. Carpenter stated:67

"One of the most interesting features of ant-societies is the
dimorphism or polymorphism that may often be seen among the
workers, the same species being represented by two or more forms.

126 LIFE: ITS NATURE AND ORIGIN

Thus the British 'wood-ant' (Formica rufa) has a smaller and a larger
race of workers ('minor' and 'major' forms), while in Ponera we find
a blind race of workers and another race provided with eyes, and in
Atta, Ecitron and other genera, four or five forms of workers are
produced, the largest of which, with huge heads and elongate trench-
ant mandibles, are known as the 'soldier' caste. The development of
such diversely formed insects as the offspring of the unmodified females
which show none of their peculiarities, raises many points of difficulty
for students of heredity. It is thought that the differences are, in part
at least, due to differences in the nature of the food supplied to larvae,
which are apparently all alike. But the ovaries of worker ants are in
some cases sufficiently developed for the production of eggs, which
may give rise parthenogenetically to male, queen or worker offspring."

Discussing the role of chemoreception in the ability of rattle-
snakes to recognize ophidian enemies, C. M. Bogert68 states that
although rattlesnakes when confronted by man or by domesticated
animals, normally assume a coiled defense attitude, with head
raised ready to strike, immediately after exposure to ophiphagous
king-snakes they react to contact and to visual stimuli only by
assuming a characteristic "king-snake defense posture": head and
tail flat on the ground, with the body arched to a high loop with
which to strike a defensive blow. Rattlesnakes assumed this char-
acteristic posture when placed in a receptable that had previously
held king-snakes, and also when a clean stick that had been rubbed
on the back of a king-snake was held near. The activating sub-
stance is apparently taken up by the tongue and conveyed to
Jacobson's organ, which contains olfactory cells; and the response
was evoked by visual or by contact stimuli as long as three hours
after receipt of the original olfactory stimulus. Apparently some
trace of a volatile substance powerfully conditions the behavior
of the rattlesnake.

H. S. Raper and collaborators have shown69 that the enzyme
tyrosinase catalyzes the conversion of tyrosine (an amino acid con-
stituent of some proteins) into 3, 4-dihydroxyphenylalanine, called
dopa for short. Dopa is then oxidized by the same enzyme to a
red indole derivative which spontaneously changes to melanin, a
pigment which gives hair and skin a dark brown or black color.
Factors affecting the activation of the precursor of tyrosinase have
been studied by J. H. Bodine and collaborators.70 The pro-
enzyme separates in the aqueous layer obtained by ultracentri-
fuging mashed grasshopper eggs, and is activated when added to

CATALYSIS: THE GUIDE OF LIFE 127

the oily or lipid layer. Since chloroform, urethane, urea, heat
and detergents (Duponol, Areosol) all produce the same final
effect (active tyrosinase), Bodine states:

"The enzyme, tyrosinase, is protein in nature and as such shows
all the characteristic properties of this chemical group of com-
pounds. It, therefore, would seem logical to expect that activation
may possibly be related to or dependent upon some physio-
chemical properties of this protein molecule and that the various
activators employed bring about just such changes. Without add-
ing unnecessary details in the way of experimental data, it may
be stated that the activation of the melanin-producing enzyme in
the present studies is thought to be brought about by the selective
adsorption and orientation of the pro-enzyme molecules by the
activating agents." Activation ceases to increase when the acti-
vator surface is occupied, either by pro-enzyme, or by another
adsorbed protein.

The black spots on a Dalmatian dog appear where the local cells
enable the melanin-producing process to occur, the remaining hairs
being white. L. Earle Arnow71 found that in the presence of oxygen,
tyrosine may be converted by ultraviolet light into dopa, which is
then changed into melanin by an oxidase. Sun-tan appears to be so
caused in some persons. A curious case of inhibition of skin pigment
formation appeared in a large tannery, where a considerable number of
workers (about 50 per cent, many of them Negroes) developed white
patches on their skins. Investigation showed that the rubber in some
new gloves used to protect the workers' hands from an acid solution,
had contained the monobenzyl ether of hydroquinone as an antioxi-
dant, and that this substance also inhibits melanin formation; so that
when the melanin originally present in the skin is absorbed or other-
wised removed, the skin turns white (leukoderma). When the cause
was removed the skin slowly returned to its normal shade, indicating
that the pigment-forming mechanism was merely inhibited by the anti-
oxidant, not destroyed. Normal skin color thus seems to represent
a balance between pigment formation and removal.

E. L. Tatum and G. W. Beadle state:72 "The development of eye
color in Drosophila is known to be controlled by specific diffusible
substances designated as v+ and cn+ hormones." By growing certain
bacteria on an agar medium containing dead yeast, sugar, and /-trypto-
phane, "this bacterially produced v+ hormone has now been obtained
in a pure crystalline state," with "an activity of approximately 20,000,-
000 v units per gram when a solution is injected into vermilion brown
test larvae."

128 LIFE: ITS NATURE AND ORIGIN

An indication of how chemical control by trace substances may domi-
nate fertility and thereby contribute an important factor to the course
of evolution, is found in the Golden Rose strain of Petunia, which is
completely self-sterile under natural conditions. Microscopic examina-
tion shows that its pollen tubes grow slowly, and that even before the
most rapidly growing tubes reach half way down to the ovary, an
abscission layer forms and blocks the way. Yasuda found that the
placenta in the ovary of Petunia violacea secrets a "special substance"
which diffuses into the style and completely inhibits pollen germination
and tube formation. W. H. Eyster73 found evidence that the ovarian
secretion of the Golden Rose Petunia "which renders the plant self-
sterile, can be transferred to other plants and renders them cross-
sterile with pollen from self-sterile plants." Golden Rose Petunia
can be self-fertilized by two methods: (1) "If flower buds which are
beginning to develop anthocyanin in the petals are opened and
pollenated with pollen from fully opened flowers from the same plant,
seed capsules containing viable seeds are produced"; similar results
were found by Yasuda74 who calls this homo-pollination; (2) by spray-
ing the flowering plants with a solution of ten parts of a-naphthalene
acetamide in one million parts of water.

"Flowers which are sprayed with this solution immediately before
or shortly after they have been self-pollinated produce seed capsules
filled with viable seeds in exactly the same way that normal self-fertile
plants of other strains produce seeds. Obviously a-naphthalene aceta-
mide neutralizes the effect of the ovarian secretion which diffuses into
the style and inhibits or greatly retards the growth of the pollen
tubes."

Dwarfism in certain plants (e.g., maize, pea) has been shown to be due
either to deficiency of auxin (growth hormone) or to its destruction by
oxidative enzymes. J. van Overbeek75 further found that "laziness"
in maize (a prostrate habit of growth) is consequent upon higher con-
centration of auxin in the upper part of the plant, whereas normally
the reverse is true. He concludes: "It is thus evident that the lazy
gene interferes with the auxin distribution in the stems which normally
takes place under the influence of gravity."

While it has for some time been known that over about 1.5 parts
per million of fluorine in drinking water generally produces a dis-
coloration of the teeth known as "mottled enamel" (endemic dental
fluorosis), Dr. H. Trendley Dean and collaborators76 have found that
fluoride levels of less than 1.0 ppm were accompanied by a correspond-
ing increase in dental caries. While the function of fluorine has not
yet been established, it seems possible that the liberation of fluorine
ions locally, by acid-producing bacteria would result in the inhibition
or death of the bacteria if the fluorine concentration became sufficient

CATALYSIS: THE GUIDE OF LIFE 129

before material attacks on the tooth had resulted. The fluorine proba-
bly also gives the tooth a denser and less readily attacked structure.
"Bone gives an x-ray diffraction pattern similar to that of the mineral
apatite, the unit structure of which contains Ca10(PO4)cF2. Various
substitutions, such as (OH)- for F- and Mg+2 for Ca+2, are known to
occur in the apatite lattice without producing significant changes in
the diffraction pattern."77

Wide use is made of ethylene gas (about 1 part per 1000 of air) to
"color up" fruits and vegetables which must be shipped more or less
"green" in order to stand handling and avoid spoilage. Bananas,
melons, pineapples, persimmons, tomatoes, oranges, apples, pears, etc.,
are so treated, the natural coloring processes being greatly accelerated.
Celery may be thus blanched, and the hulls loosened from "stick-tight"
walnuts. The diverse changes seem to be dependent upon initiating
or facilitating specific enzymic changes.

Spraying apple trees with soluble thiocyanates, though it causes
"spray burn" and a chlorotic condition of the leaves, tends to increase
the red color of the fruit (blush) and to turn the green ground color
toward yellow, both features desirable to consumers.78 The red color
is due to idaein, a glucoside which, on hydrolysis, yields cyanidin and
galactose. There is some evidence that spraying apples with naph-
thaleneacetic acid and related compounds tends, with some varieties,
to reduce the percentage of windfalls, apparently by firming the
stems.79

D. W. Wooley has shown80 that the mouse requires a new "vitamin"
for normal growth and maintenance of hair. The facts indicate "that
the mouse anti-alopecia factor is inositol or its derivatives. They sug-
gest that inositol exists in liver in alkali-labile combination with a
large molecule which renders the former non-dialyzable."

These scattering instances, which might be multiplied many times,
illustrate how devious, various, and potent may be the effects of small
amounts of substances, which, until comparatively recent times, were
generally considered "negligible" in reports of chemical analyses.
Their effects are often expressed through catalysts.

Biocatalyst Systems or Chains

It is we who are simple, not nature. The physico-chemical
happenings at various structural levels, which underlie the phe-
nomena we observe, are numerous, intricate, often obscure, some-
times unsuspected. The complications involved in the structure,
lability, and functioning of individual enzymes are magnified in
cells, tissues, and organisms, where groups of catalysts and cooper-
ative chemicals form chains or systems which have not yet been

130 LIFE: ITS NATURE AND ORIGIN

constructed for experiments in vitro. Isolated enzymes, supposed
to be pure, have sometimes proved to be mixtures, and it is always
a question as to how far experiments with pure enzymes may be
applied to an intact biological unit. Liver slices energetically
oxidize certain of the lower fatty acids, but when the liver is
minced this power immediately disappears.

As an illustrative instance, we may take the fermentation of glu-
cose by yeast,81 widely practiced and long studied. Present experi-
mental data justify the belief that underlying the extremely naive

equation

C6H12O6=2C02+2C2H5OH
the following catalyzed system is operative (end products shown in
rectangles):

Glycogen (within the yeast cell) Glucose

Glucopyranose 1 -phosphate (Cori ester)

i
Glucopyranose 6-phosphate (Robinson ester) < —

1
Fructofuranose 6-phosphate (Neuberg ester)

Fructofuranose 1 , 6-diphosphate (Young-Harden ester)

| Glyceraldehyde phosphate < 1

2 "Triose phosphate" Dihydroxyacetone phosphate — '

I (Oxidation)
2 Glyceric acid 3-phosphate \

* \

2 Glyceric acid 2-phosphate \

1 H20

2 enol- Pyruvic acid phosphate \

1 . .\

(Phosphate removal by adenylic acid) \

2 Pyruvic acid /

I /

2 Acetaldehyde /

(Reduction) y

1

2COo

2 Ethyl alcohol

The successive steps tabulated are catalyzed by specific enzymes,
and many of the changes have been shown to be reversible. Besides
the final products (ethyl alcohol and carbon dioxide), a small
amount of glycerin is also formed. Since the formation of Cori
ester from glycogen is inhibited by glucose, enzymic formation of
glycogen within the yeast cell may serve to restrict glucose concen-
tration as glucose diffuses into the yeast cell.

If sodium sulfite is added to a yeast fermentation, the formation
of alcohol practically ceases and the small percentage of glycerin
which occurs in normal fermentation increases so that it becomes
a main product, with acetaldehyde and carbon dioxide. The

CATALYSIS: THE GUIDE OF LIFE 131

acetaldehyde is fixed by the sulfite, the C02 is liberated, and the
glycerin remains; during World War I Germany produced glycerin
by fermentation processes. Bell82 states that the traces of glycerin
in normal fermentation are due to the "mutase" system in the
yeast cells. It seems that, normally, acetaldehyde acts as a hydro-
gen acceptor in the anaerobic oxidation of triose phosphate; but
when the acetaldehyde is removed by the sulfite present, another
molecule of triose phosphate can act instead. Since the former
reaction is the more rapid, little glycerin is formed when acetalde-
hyde is present.

By carrying out the fermentation at an alkaline pH, Neuberg
found that the breakdown of the glucose yielded glycerin, alcohol,
and acetic acid, according to the following scheme, which is not
yet understood in detail:

Glucose

1
Triose Phosphate

/ \

CO 2 + acetaldehyde

1/2 Alcohol
l/2 Acetic acid

Glycerin

Not only does the apparently simple yeast cell contain a con-
siderable number of specific enzymic catalysts and collaborating
molecules, but it can be "trained" to ferment galactose,83 by add-
ing small and continually increasing percentages of this sugar to
the fermentation mixture. Evidently yeast can "manufacture"
new enzymes to meet new situations; probably the new substances
add their own specificity to a system of molecules to make a new
prosthetic group.

Modification of Biocatalysts

The writer has taken the view that biocatalysts are subject to
modification, which involves the fixation, at an active catalyst area
of a gene or other catalyst unit, of some particle (electron, ion,
atom, molecule, or colloidal particle) which changes the nature
and/or the rate of the catalytic change occurring there. A limiting
case under this general principle would be the formation of a new
catalyst area by the fixation, e.g., at a protein surface, of a pros-
thetic group. In the case of genes a change in catalytic output
may arise from an intra particulate change in the gene itself
(known as a point mutation), or because of some chromosomal

132 LIFE: ITS NATURE AND ORIGIN

upset (e.g., inversion, translocation, crossing over) which places
the gene in different surroundings (position effect). If heritable
and non-lethal, both these types of change generally lead to new
mutant forms of plants or animals. The modification of enzymes
within a cell, or the formation or introduction of new enzymes
there, could lead to catalytic variations of chemical output which
might simulate the effects producible by a point or a chromosomal
mutation; but the result would be transient unless sufficient of
the modifiers and prosthetic groups to maintain it were supplied
or produced. Another possibility is that a specific area may serve
as a template or mold against which may be formed specific cata-
lytic molecular structures or plaques. Still another possibility is
the local establishment of ionic or trace-substance conditions
favorable to the formation of new enzymes, e.g., by adsorptive
fixation of a prosthetic group by a carrier. Viruses and bacteri-
ophages reproduce themselves in cells, thus (where they exert
catalytic action) behaving as if they were free-living genes. What
is said of genes may be applied with equal force to mitochondria;
for whether these are symbionts or cytoplasmic inclusions, they
apparently reproduce and are efficient in directing chemical
changes within the cell (either directly or through enzyme forma-
tion), and behave somewhat as if they are free-living genes or gene
groups.

The stability of genes and the efficiency of the protections sur-
rounding them are evidenced by the regular and orderly sequences
normal to life, which shows that gene mutations are relatively
quite rare, and abnormal gene or catalyst modifications unusual.
Since non-lethal gene mutations may be transmitted by heredity,
they are basic factors in evolution; for beneficial mutations tend
to survive and dominate, whereas harmful ones tend to die out.
If mutation makes a gene (or other catalyst) more susceptible to an
abnormal modification, that is one way in which the effect of a
mutation may become evident.

Bacterial Dissociation and Transformation84

The colonies of most bacteria that have been studied may
appear in a rough, corrugated form (R), or in a smooth, glistening,
drop-like form (S). The change of a culture from R to S, or vice
versa, is known as dissociation. The methods used to produce
dissociation involve, mainly, change in the usual growth medium:
(1) by the addition of sera, normal or immune; (2) by addition of

CATALYSIS: THE GUIDE OF LIFE 133

definite chemical agents (e.g., LiCl2, FeCh, sodium taurocholate);
(3) by change in pH; (4) by animal passage, a method much used,
involving considerable, though unknown, changes in the culture
medium. For example, Alexander-Jackson85 was able to change
two strains of human tubercle bacilli of R form over into S by
the addition of 0.0004 per cent of ferric chloride to Bordet-Gengou
medium. As a rule, the S form is relatively more virulent than
the R form of the same strain. At the laboratory of the New
York City Board of Health the virulence of test strains of pneumo-
cocci is maintained by daily passage through mice, to give an
example of the well-known effect of animal passage, which also
exerts changes in the virulence of viruses; e.g., the virulence of
smallpox to man is reduced by passage through cattle.

On the other hand Herald R. Cox86 found that the virulence of a
Dermacentor variabilis strain of Rocky Mountain spotted fever was
enhanced, as against guinea pigs, upon growth in the yolk sacs of
developing chick embryos. The virulence decreased after about 50
passages, and after about 100 passages the strain, while causing slight
or no reaction in the guinea pigs, made them "solidly immune to
massive doses of highly virulent strains." See, also, R. E. Green77
on the nature of virus adaptations.

Griffith,87 working with white mice, discovered the interesting fact
that S forms of pneumococci can be transformed from one specific type
into other specific types through the intermediate stage of the R form.
Since the specificity of the types involves the formation of specific sub-
stances, (especially, as Heidelberger88 has shown specific carbohy-
drates), it seems obvious that the catalysts of the pneumococci in
Griffith's experiments must have undergone a change; either old
catalysts were transformed, or new ones were formed.

Dawson and Sia,89 working in vitro, found that R forms of pneu-
mococci derived from S forms of one specific type (Type II), can be
transformed into the S forms of other specific types (Types I or III),
by growth of small inocula of the R form of Type II in media con-
taining vaccines prepared from heterologous S cultures. It seems
possible that in this case the R form contains an enzymic carrier which
has been deprived of its prosthetic group, but which takes up a dif-
ferent prosthetic group from the new vaccine-containing medium.
That these R forms are more labile is brought out by Sia and Daw-
son,90 who state: "R cultures possessing only slight degree of R stability
are most suitable for transformation purposes by in vitro procedures."

Drs. Oswald T. Avery, Maclyn McCarty and Colin MacLeod, of the
Rockefeller Inst, for Medical Research, found that the substance indue-

134 LIFE: ITS NATURE AND ORIGIN

ing the transformation of pneumococcal types isolated from Pneu-
mococcus Type III, is "in the form of a desoxyribonucleic acid frac-
tion. The data obtained by chemical, enzymatic, and serological
analysis, as well as by electrophoresis and ultracentrifugation of the
purified material, strongly suggest that the nucleic acid is itself respon-
sible for the biological activity." Minute amounts of this substance
can cause uncapsulated "rough" variants of Pneumococcus Type II to
acquire the capsular structure and type specificity of Pneumococcus
Type III. Ascorbic acid (and other autoxidable compounds, e.g.,
catechol, hydroquinone, p-phenylenediamine) inactivate the trans-
forming substance.

With ascorbic acid inactivation is catalyzed by traces of cupric ion;
this is prevented by the presence of sulfhydryl compounds, which can
restore activity under certain conditions. Activity is irreversibly
destroyed by highly purified preparations of the specific enzyme
desoxyribonuclease, capable of depolymerizing authentic samples of
desoxyribosenucleic acid of animal origin. The enzyme requires the
presence of a metallic activator (in nature magnesium, though man-
ganese in like molar concentration is equally effective). The specific
transforming substance isolated from pneumococci of types II and VI,
in addition to type III, consists of desoxyribonucleic acid as the bio-
logically active substance. "Although the individual desoxyribo-
nucleates of different types cannot yet be distinguished from one an-
other on chemical grounds, the selective specificity they exhibit in
inducing transformation is difficult to interpret save in terms of indi-
vidual differences in chemical structure and molecular configuration."91

As pointed out in Chapter 3, note 1, naturally occurring carote-
noids having seven double bonds may have 128 possible stereo-
isomers. With 12 stereochemically effective double bonds the
number of possible isomers rises to 2800 for symmetrical chains,
and 4096 for unsymmetrical chains. How stereoisomerism can
affect the properties of substances having the same ultimate
chemical analysis may be seen from the following excerpts from
the review of L. Zechmeister of the California Institute of Tech-
nology.92

"A long conjugated double-bond system offers many spatial
possibilities, but the synthetic as well as the natural polyenes are
usually a\\-trans compounds. . . . This configuration can be easily
altered by various thermal, photochemical, or catalytic treatments.
Upon such treatment the stereochemical uniformity of the mole-
cules disappears and a complicated mixture of cis-trans isomers is
formed, in which ordinarily the unchanged portion of the initial

CATALYSIS: THE GUIDE OF LIFE 135

all-trans pigment still predominates. Theoretically, each possible
stereoisomer must be present in such an equilibrium mixture if
only in minute quantity.

"The chemical characteristics of the stereoisomers of a given
carotenoid are very similar, but fortunately the adsorption affini-
ties are highly dependent on configuration, perhaps more so than
any other known physical property. Therefore, the Tswett method
of chromatographic adsorption is the only effective technique for
the separation and study of the stereoisomers.93"

It appears that many biologically important compounds may
have superimposed upon their basic chemical structure physical
or physicochemical impressions or distortions which can affect
their specificities in the catalytic field of activity. While every
substance has a chemical structure, this does not preclude the
simultaneous formation of a superstructure in the case of compli-
cated molecules or molecular groups.

In cultures of Hemophilus influenzae, Escherichia coli, and Strep-
tobacillus moniliformis, the germination of "large bodies" has been
observed, and the descendants of these "L type" colonies, instead of
resembling the parent organism, are similar in both morphology and
development to the pleuropneumonia group of organisms. Such "L
type" colonies come from strains which are rare in most species, but
they were also observed in cultures of a Flavobacterium, of Bacteroides
funduliformis, and of the gonococcus, and have been isolated in pure
cultures from the two former. L. Dienes94 believes that they represent
a variant type, in which case the variability of bacteria extends much
further than is commonly supposed. E. Kleinberger (references in
Dienes' paper) thought that they represented symbionts, a view that
Dienes opposes. The question is not finally decided.

Speaking of the enzymatic synthesis of polysaccharides, M. Stacey95
states: "There is good evidence for the theory, here advanced for the
first time, that the synthesizing enzyme remains in combination with
the polysaccharide it has synthesized, and there is progressively built
up a complex macromolecule in which comparatively short polyglucose
chains are 'cemented' together by a nucleoprotein. In the case of one
dextran from Betabacterium vermijorme (Ward-Meyer), the aggre-
gating process can go on until the macromolecule is so large that it
settles out of the solution in the form of granules. The separation of
granular synthetic starch takes place in precisely the same manner and
the product contains significant amounts of a nitrogenous constituent
which could only come from the phosphorylase preparation."

Evidence that bacterial catalysts direct the formation of specific

136 LIFE: ITS NATURE AND ORIGIN

polysaccharides appears in the statement of E. J. Hehre96 and J. Y.
Sugg that a serologically reactive polysaccharide of dextran nature was
produced from sucrose by sterile filtered extracts derived from sucrose
broth cultures of Leuconostoc rnesenteroides, a Gram-positive coccus
widely distributed on plants. "Rigorous controls were included to
prove that this reaction occurred in the absence of microorganisms."
The polysaccharide was recognized chemically and also by its ability
to react with the anti-serums of types 2 and 20 pneumococci, as well as
with the anti-serum of the homologous bacteria.

These and many other facts support the view that the specificity
of all species, both plant and animal, stem from, or least involve,
differences in the basic biocatalysts. The visible forms with which
taxonomy deals, and even the specific substances which biochem-
ists isolate and identify, are mainly an aftermath. The basis of
species specificity and even of evolution rests largely on bio-
catalysts and their changes.

REFERENCES

i Jahesberichte (1836), 15, 237.

2 Pharmaceutisches Centralblatt (later Chemisches Centralblatt), Feb. 6th, 1836,

p. 82.

3 "Further information on this subject may be had in the article by Berzelius in
Schumacher's Jahrbuch for 1836, pp. 88-97."

4 "Liquid Diffusion Applied to Analysis," read before the Royal Society (London)
June 13th, 1861 (Phil. Trans. Roy. Soc. (1861) 151, 183-224).

5 "Biological Enigmas and the Theory of Enzyme Action," The Am. Naturalist
(1917), 41, 326.

6 Further extracts from Troland's various papers are given by Alexander and
Bridges, in Vol. II of "Colloid Chemistry," pp. 19-21 (Reinhold Pub. Corp., 1928),
in a paper entitled "Some Physicochemical Aspects of Life, Mutation and Evolu-
tion."

7 Presented before the Genetics Section of the American Society of Zoologists and
the Botanical Society of America on Dec. 28th, 1928 (Science (1929) , 70, 508-510) .

8 "Catalysis and Its Industrial Applications," in "Colloid Chemistry," Vol. VI,
Reinhold Pub. Corp., 1946.

9 Berkman, Morrell and Egloff ("Catalysis — Inorganic and Organic," Reinhold
Pub. Corp., 1940) give an extensive list of catalysts for many different types of
chemical reactions, including hydrogenation and dehydrogenation, oxidation, hydra-
tion and dehydration, cyclization, halogenation and dehalogenation, hydrocarbon
cracking, polymerization, alkylation, and isomerization.

10 /. Chem. Soc. (1938, 1761-80, 1845-7).

11 H. S. Taylor, American Scientist (1946) 34, 59.

12 /. Soc. Chem. hid. (1903), 22, 1166-1177.

13 U. S. P. No. 1,604,739, Oct. 26th, 1926, to Charles R. Downs.

"Centralbl. f. Bakteriol. (1912), 66, 131, Abt. I.

15 Roughly, the following represent normal rectal temperatures:

36-38° C ( 96-101° F.)— man, monkey, mule, horse, elephant, rat, mouse.

CATAYLSIS: THE GUIDE OF LIFE 137

38-40° C (100-103° F.) — cattle, sheep, goat, dog, cat, rabbit, pig.

40-41° C (104-106° F.) — cluck, goose, turkey, owl, pelican, vulture.

42-43° C (107-109° F.) — fowl, pigeon, quail, sparrow, starling, bluejay.
The duckbill (Omithorhynchus paradoxus, a monotreme), and the Australian
anteater (Myrmecobius faciatus, a marsupial) represent forms intermediate between
the cold- and the warm-blooded animals, their body temperatures averaging only
25° C (77° F.), and changing by about 10° C with an environmental change of 30° C.
While the terrible consequences to the closely packed prisoners in the Black Hole
in Calcutta were originally ascribed to lack of oxygen, it seems likely that lack of
cooling in that stagnant atmosphere was a big factor. In hot weather we seek breeze
or electric fans to help us cool off by transpiration. On the other hand, sheep and
bees huddle together to keep warm, and I have seen "ladybugs" (actually, beetles)
gathered together in masses for hibernation. For details and references, see Brody,
"Bioenergetics and Growth," Chapter 11.

16 D. Burk, Internal. Cong. Soil Sci., 1930, 3, 67.

17 O. Meyerhof, Pfliiger's Archiv. (1916) 164, 353.
is Growth (1940) 4, 77.

™Ann. N. Y. Acad. Sci. (1944) 45, 409-423.

20 "Dynamic State of Body Constituents," 1942.

21 In an address before the British Association for the Advancement of Science
at Glasgow, 1928 (Smithsonian Report, 1929, pp. 309-321) .

22 "Colloid Chemistry," Vol. V, pp. 883-900, Reinhold Pub. Corp., 1945.

23 "Bioenergetics and Growth," p. 111.

24 F. Lipmann, Advances in Enzymology (1941) 1, 99; C. F. and G. T. Cori, Ann.
Rev. Biochem. (1941), 10, 151; J. C. Sowden and H. O. L. Fischer, ibid. (1942), 11,
203; O. Meyerhof, Cold Spring Harbor Symp. Quant. Biol. (1941), 3, 239; H. M.
Kalkar, Biol. Rev. (1942), 17, 28.

25C + 02=C02+94 Cal*
H2-£02=H20+68Cal
S+ lJ02+H20=:H2S04+142Cal

NH3+1^02r=HN02+H20 + 79 Cal (Nitromosas, nitrite producer)
HN02+i02=HN03+21 Cal (Nitrobacter, nitrate producer)
* The large Calorie (Cal or Real) is the amount of heat necessary to raise the
temperature of one kilogram of water 1° C. The small calorie (cal) is one thousandth
of a Cal.

26 Alexander, /. Am. Chem. Soc, 43, 434 (1920).

27 Enzymologica, 9, 193 (1941).
28Ipatieff, V. N., Science, 91, 605 (1940).

29 To illustrate the importance of the carrier, it may be mentioned that Adkins,
Richards and Davis found marked carrier effects in the catalytic dehydrogenation
of hydromatic compounds containing a completely or partially saturated benzene,
naphthalene or phenanthracene nucleus. In the case of decahydronaphthalene, the
yields of naphthalene varied not only with the catalyst but also with the carrier.

% yield of naphthalene
Catalyst from decahydronaphthalene

Pt. on charcoal 87

Ni on charcoal 34

Ni on chromium oxide 78

Ni on kieselguhr 62

Ni on Alumina I 0

Ni on Alumina II 11

Ni on Alumina III 0

Ni on Alumina IV 36

138 LIFE: ITS NATURE AND ORIGIN

Note: The charcoal was purified Norit. Alumina I was prepared through sodium
aluminate; alumina II, III, and IV, by hydrolyzing alumina isopropoxide by three
different procedures.

The authors remark that nickel on alumina and on kieselguhr are better catalysts
for the dehydrogenation of substituted cyclohexanols than is platinum, because
they show less tendency to induce condensations. Nickel on chromium was the most
active catalyst in the case of resistant saturated hydrocarbons. In all, 28 representa-
tive compounds, including hydrocarbon alcohols, ketones, and ethers, were heated
at 300° to 350° in the liquid phase under nitrogen, in the presence of the catalyst
and also of benzene, which serves as a hydrogen acceptor or oxidizing agent.
(J.A.C.S., 1941).

™Ind.Eng. Chern., (1947) 39, 121-125.

31 /. Soc. Chem. Ind., 52, I T. (1932).

32 Bull. Soc. Chim. Belg., 45, Apr. 19 (1936).

33 Proc. Roy. Soc. London, June 16, 1864.
Zi Biochem. Z., 250, 414 (1932).

35 Z. Physiol. Chem., 225, 103 (1934).

36 J. Alexander, Science, 80, 79 (1934); 81, 44 (1935); also H. Theorell, "Structure
and Function of Some Vitamins," A. A. A. S. Pub. No. 14, p. 136.

37 Science, 88, 170 (1938); 91, 199 (1940); Proc. Am. Physiol. Soc, 129, 466 (1940).

38 Screenivasaya and Pirie, Biochem. ]., 32, 1707 (1938).
39 /. Gen. Physiol, 16, 191 (1930).

40 Proc. Roy. Soc. London B, 122, 119 (1937).

41 Biochem. Z., 298, 150, 368; 301, 139, 221 (1938).

42 Green, D. H., "Mechanism of Biological Oxidations," 1940.
^Tauber, H., /. Am. Chem. Soc, 60, 2263 (1938).

44 Church, Trans. Roy. Soc, 627-636 (1869).

45 D. J. Bell, "Introduction to Carbohydrate Chemistry," London. 1940.

46 "The Chemistry of Common Life," p. 489, London, 1879.

47 Compt. rend., 155, 1187 (1912).

48 "Biochemistry of Microorganisms," A. A. A. S. Pub. No. 14, p. 106 (1940).

49 Science, 89, 421 (1938).

50Filmer, J. F., and Underwood, E. J., Australian Fit. J., 10, 83 (1934); 11, 89 (1935).

81 Moxon, A. L., So. Dakota Agr. Expt. Sta. Bull. 311, p. 1-91 (1937); S. F. Trelease,
Scientific Monthly, 54, 12 (1942).

82 "Electricity in Our Bodies," by Bryan H. C. Matthews, 1931.

53 Nachmansohn, D., and Rothenberg, B. A., /. Biol. Chem., 158, 653, 1945.

54 Bullock, T. H., Grundfest, H., Nachmansohn D., and Rothenberg, M. A., /.
Neurophysiol., 10, 11, 1947.

55 Nachmansohn, D., and Machado, A. L., /. Neurophysiol., 6, 397, 1943.

56 Nachmansohn, D., and John, H. M., /. Biol. Chem., 158, 157, 1945.

57 Nachmansohn, D., John, H. M., and Berman, M., /. Biol. Chem., 163, 475, 1946.

58 Nachmansohn, D., and Berman, M., /. Biol. Chem., 165, 551, 1946.

69 Bullock, T. H., Grundfest, H., Nachmansohn, D., Rothenberg, M. A., and Ster-
ling, K., /. Neurophysiol., 9, 253, 1946.

60 Bullock, T. H., Grundfest, H. Nachmansohn D. and Rothenberg M. A., /.
Neurophysiol., 10, 63, 1947.

61 Grundfest, H., Nachmansohn, D., and Rothenberg, M. A., /. Neurophysiol., in
press.

62 Bullock, T. H., Nachmansohn, D., and Rothenberg, M. A. /. Neurophysiol,
9, 9, 1946.

63 Science, 81, 279 (1935).
^Biol. Rev. 51, 351 (1940).

C AT AY LSI S: THE GUIDE OF LIFE 139

^Biochem. /., 34, 155 (1940).

™Proc. Soc. Exptl. Biol. Med., 48, 415 (1941).

67Encyclo. Britannica, Vol. 2, p. 86 (1916).

68 Am. N. Y. Acad. Sci., 41, 331 (1941).

69 Physiol. Rev., 8, 253 (1928).

™ /. Gen. Physiol., 24, 99, 423 (1941) ; Am Naturalist, 75, 97 (1941) .

™ Science, 86, 76 (1937).

"J. Gen. Physiol., 22, 239 (1938).

73 Science, 94, 144 (1941).

™Bot. Mag. (Tokyo), 46, (548) 510 (1932).

75 /. Heredity, 29, 339 (1938).

™ Public Health Reports, 57, 1155 (1942).

" Green, R. G., Science, 95, 602 (1942).

78 Dustman, R. B., and Duncan, I. J., Plant Physiol., 15, 343 (1940); Science, 90,
233 (1939).

79 Hitchcock, A. E., and Zimmerman, P. W., Proc. Am. Hort. Soc, 38, 104 (1940).
so/. Biol. Chem., 136, 113 (1940); Science, 92, 384 (1940).

81 Newberg, C, "Handbuch der Biochemie" and supplements, 1925-1933; Am.
Brewer, 75, 22 (1924). W. W. Umbreit ("Problems of Autotrophy," Bad. Rev., 11,
156-166, Sept. 1947) discusses energy-rich phosphate bonds.

82 "Introduction to Carbohydrate Chemistry," London, 1940.
83Deinert, F., Am. Inst. Pasteur, 14, 139 (1900).

84 Manwaring, W. H., Science, 79, 466 (1934) .

85 Rev. Tuberculosis, 33, 767 (1936) .

86 Science, 94, 399 (1941).

87 /. Hygiene, 27, 113 (1928).
88 /. Expt. Med., 38, 81 (1923) .
89 /. Expt. Med., 54, 681 (1931) .
so/. Expt. Med., 54, 101 (1931) .

91 /. Expt. Med. (1944), 79, 137; (1945), 81, 501; (1946), 83, 89, /. Gen. Physiol.
(1946) , 29, 123.

92 Chemical Review's (1943), 34, 267-344.

93 Chromatographic analysis is treated in a paper by Beverly L. Clarke, dealing
with selective adsorption and differential diffusion, in "Colloid Chemistry," Vol. V,
pp. 457-471, Reinhold Pub. Corp., 1944.

94 /. Bacter., 44, 37-72 (1942). See also Dienes' paper, published June, 1947, in
Cold Spring Harbor Symposia, 11, 51-59.

95 "Mucopolysaccharides and Related Substances," Chemistry and Industry, 62,
110-112 (1943).

96 Science, 93, 237 (1941); /. Expt. Med., 75, 339 (1942).

Chapter 7

Immunology and Self-Saving Catalysts

Immunity itself must have begun with the development of the
mechanism whereby organisms respond to the presence of infec-
tious organisms by forming antibodies. But the science of im-
munology, which studies the extent, nature and mechanism of
immunity, is of relatively recent development, and has been given
extensive study by specialized groups of physicians, bacteriologists
and chemists. As early as the 7th century A.D. person-to-person
inoculation was used in China to protect against smallpox — a
practice also known in Arabia. A full century before Jenner
introduced vaccination in England, the Chinese were using cow-
fleas, an insect carrier, to give a protective attack of cowpox.1 As
a practical method, immunology dates from Louis Pasteur, who
developed methods of protection against the dreaded anthrax and
rabies by the use of weakened or attenuated infective agents. I
reproduce here the signature of

^z-^

As a small boy, he was the first person saved by Pasteur from
rabies. This signature was obtained in 1926 at Institut Pasteur
in Paris, where Meister was concierge, a living monument to the
great chemist-bacteriologist-immunologist.

Since the precise chemical nature of the colloidal substances
involved in immunological reactions was unknown, they were
given names corresponding to their observable effects. The spe-
cial nomenclature which developed is here outlined.

Substances are termed antigens if they can stimulate or cause a
plant or animal to produce other substances, termed antibodies,
which are able to react specifically with the inciting antigen.
Time is required for the formation of the antibody, or immuniza-
tion, as it is called; and an organism may inherit immunity to
many antigens or may develop immunity to them, e.g., either by

140

IMMUNOLOGY AND SELF-SAVING CATALYSTS 141

their proper injection or by their introduction through invading
organisms or viruses in an attack of a disease. The U. S. Army
uses immunization to protect against cholera, smallpox, tetanus,
typhoid fever, typhus, and yellow fever, and sometimes against
diphtheria, influenza and some forms of pneumonia.

Chemically, antibodies are proteins present in blood serum,
whose physical properties class them primarily with the globulin
fraction of the serum; they are globulins according to electro-
phoretic studies by Arne Tiselius and E. A. Kabat;2 but their
peculiar specificities are not necessarily and exclusively due to
chemical differences, as so many assumed. The paper and metal
industries show how many lasting contours may be impressed on
sheets without involving chemical change. The ultracentrifugal
work of The Svedberg3 (Nobel prize, 1927) indicates the molecular
weights of some antibodies and other large molecules:

Serum globulin (horse) 68,000— 167,000

Serum albumin (horse) 70,000

Antipneumonococous globulin (horse) 910,000

Serum globulin (man) 176,000

Antipneumococcus (man) 195,000

Lactoglobulin 41,000

Pepsin 35,500

Insulin 46,000

Catalase 250,000

Urease 480,000

Hemocyanins (various sources) 400,000 — 8,700,000

But these "molecules" are not spheres. A. Neurath4 makes the
following estimates: Rabbit pneumococcus antibody, 37A x 338A;

horse pneumococcus antibody, 20-47A x 950A. J. R. Marrack
reports5 that on immunization there may be an increase in serum
protein, mainly in the globulin fraction.

Apart from these immune bodies developed from the introduc-
tion of the specific antigen, the blood serum may carry, as the
result of genie or humoral inheritance, a number of natural anti-
bodies to some antigens; and such inherited immunities may in
some cases be important factors in survival. Huge numbers of
various American, Mexican, and South American tribes suc-
cumbed to smallpox, and measles decimated the natives of Pacific
islands among whom natural immunity to this disease was rare if
not non-existent.

142 LIFE: ITS NATURE AND ORIGIN

The envelopes of erythrocytes have areas of what appear to be
specific polysaccharide substances which act as agglutinogens and can
react with corresponding agglutinins. K. Landsteiner's pioneer work
(1900-1) has been extended, and there are now recognized, in humans,
the following types: A, B, AB, O; subgroups of A and AB; the M. N,
and P agglutinogens of K. Landsteiner and P. Levine0; and the Rh
factor of K. Landsteiner and A. S. Wiener.7 These agglutinogens can
be distinguished by tests with suitable antisera prepared by immunizing
human beings or animals. Agglutination generally occurs, but in
some cases hemolysis of the red blood cells takes place. A. S. Wiener
states: "In place of the original, single Rh factor, transmitted by a
pair of allelic genes, Rh and rh, three Rh factors are known at the
present time, together with a so-called Hr factor, and these, in com-
bination, give rise to a large series of different varieties of Rh agglu-
tinogens, determined by a corresponding set of at least ten or more
allelic genes."8 In fact, all the different "blood groups" seem to be
distributed genetically, and the bloods of animals close together on the
phylogenetic scale, (for example, man and chimpanzee, rat and mouse)
are immunologically related. If a goat is immunized by injections of
red blood cells of man, rabbit, and pigeon, the blood cells of each of
these three animals will absorb from the goat's serum only its own
specific agglutinin.

The immunological consequences arising from differences in
blood groups have much to do with incompatibility of blood used
in making transfusions, so that a suitable blood donor must be
selected. In plasma transfusions, blood group differences can
usually be disregarded. Transplantations of tissues may also fail
because of such or similar incompatabilities. In some cases this
may cause the death of a child in utero, or shortly after birth
(Erythryblastosis fetalis), unless the blood of the infant which has
been damaged by the maternal antibodies, can be replaced soon
enough by compatible blood.

Embryonic and new-born animals usually have passive immu-
nity to certain antigens, acquired by diffusion of parental anti-
bodies through the placenta, or else by their deposition in the
egg. Embryos and young are able to form antibodies very
slightly, if at all; and before the new-born animal develops this
power and thus establishes its own active immunity, its passive
immunity begins to drop off. Hence the very young are generally
susceptible to many antigens, especially to the viruses and bacteria
of "children's diseases."9 Passive immunity is now commonly
given children by injections of antibodies, of antigen-antibodies,

IMMUNOLOGY AND SELF-SAVING CATALYSTS 143

or of modified antigens (e.g., diphtheria toxoid). Vaccination
(from vacca, a cow) infects one with the usually very mild cowpox,
and thereby establishes an active immunity against smallpox.

While most antigens are proteins with large colloidal molecules,
certain carbohydrate and lipo-carbohydrate substances have been
recently shown to act as antigens. Simpler proteins do not serve
as antigens, for example, protamines consisting mainly of com-
plexes of diamino acids, and gelatin lacking tryptophane which
contains a benzene ring.

Toxins are poisonous antigens. Many antigens, such as egg
albumin, casein, and animal sera, are not toxic in the small quanti-
ties needed for immunization. As Prof. J. J. Abel pointed out,
the Greek word toxikon originally meant "of or belonging to the
bow," a meaning that still survives in the word toxophilite, a lover
of the bow or archery. The word was carried over to the arrows
shot from the bow, and then to the poison into which the arrow
heads were usually dipped. Many substances like phenol, arsenic,
prussic acid and morphine which do not elicit the formation of
antibodies, should be called poisons, not toxins.

Many toxins are formed by pathogenic microorganisms. Endo-
toxins come from the bacterial body itself on breakdown
(typhoid bacillus), while exotoxins are substances formed by and
excreted by the bacteria (e.g., diphtheria). Snake venoms and
the highly poisonous toxalbumins, such as abrin (from the
jequirity bean) and ricin (from the castor bean) induce the forma-
tion of specific antibodies. Some toxins, when altered chemically
or physically, become non-toxic but still preserve the power to
form antibodies to the original toxin, for example, diphtheria
toxin treated with formaldehyde and alum. A modified toxin of
this sort is known as a toxoid, and its immunizing power may well
be due to the slow liberation of the toxin or a closely similar sub-
stance.

Synthetic Antigens

This interesting field was developed by Dr. Karl Landsteiner
(Nobel prize, 1930), who coupled organic substances of known
chemical constitution to proteins by a process known as diazotiza-
tion. For example, when metanilic acid (/?t-aminobenzene sulfonic
acid) is treated with nitrous acid, the amino group yields a highly
reactive diazo group, which chemically fastens the metanilic acid
molecule residue to the protein. This is a counterpart of the

144 LIFE: ITS NATURE AND ORIGIN

process long in commercial use for making certain dyes or colors;
thus para red is made by diazotizing p-nitraniline and adding
beta-naphthol.10

Landsteiner found that his newly synthesized protein addition
compounds could evoke the formation of specific antibodies, but
that the specificity depended largely upon the nature of the mole-
cule attached, which he termed the hapten. While haptens, of
themselves, are unable to cause antibody formation, when they are
attached to the protein they determine to a large extent the
specificity of the antibody formed.* The fact that haptens which
are very similar chemically, interact serologically ("cross-reac-
tions"), supports the view that the specificity of antibodies and of
antigens is determined by their outwardly directed electronic
fields, which naturally vary with change in chemical and physical
structure.

Reactions Between Antigens and Antibodies

Most immunological reactions fall into one of the following
groups:

(1) Toxin-antitoxin neutralization: If properly made, a mix-
ture of toxin and its specific antitoxin is innocuous. A toxin
formed in or introduced into an animal can be neutralized by its
specific antibody, if administered in time. Thus diphtheria anti-
toxin must be given before the diphtheria toxin, produced by
the invading bacteria, has been irreversibly fixed by certain nerve
cells in the medulla. Death from paralysis of the heart and the
respiratory system may follow injury to these cells, and even in
cases that recover, temporary paralysis of the limbs may occur.
Injections of toxoid or of toxin-antitoxin mixtures are now gen-
erally used to establish immunity to diphtheria. As far back as
1909, Dr. J. G. M. Bullowa and the writer followed in the ultra-
microscope the mutual coagulation of diphtheria toxin by diph-
theria antitoxin and of tetanus toxin by tetanus antitoxin. But
neither toxin formed a coagulum with the antitoxin specific to
the other one.11

(2) Precipitin reactions: When a suitable amount of a soluble
antisren is mixed with the blood serum of an animal immunized
by injections of this particular antigen, a precipitate appears, and
generally is visible. This is known as the Ramon test.12

(3) Agglutination reactions: When an antigen having visible

* This recalls the action of prosthetic groups in enzymic catalysts.

IMMUNOLOGY AND SELF-SAVING CATALYSTS 145

particles {e.g., bacteria, red blood cells) is mixed with a serum con-
taining the specific antibody elicited by injections, the particulate
antigen agglutinates, or forms floes which usually settle out. Motile
antigen cells, such as typhoid bacteria or sperms, lose their inde-
pendent motility on coherence, though some cells in a floe may
show some motion for a while. This is seen in the Widal test for
typhoid fever, for in the serum of a person who has, or has recently
recovered from the disease, live, motile typhoid bacilli agglutinate
and soon dissolve — the phenomenon termed lysis (solution).

(4) Lysis: Antibodies that can dissolve or disintegrate a par-
ticulate antigen are termed lysins. Special names indicate the kind
of antigen dissolved: bacteriolysis, for bacteria; cytolysis, for cells;
hemolysis, for blood corpuscles.

Complement or Alexin

After 15 minutes' heating at 55° C an immune serum capable of
causing lysis of cholera vibrios loses this power, but regains it on
the addition of some unheated non-immune serum. Obviously,
both immune and non-immune sera contain a factor essential to
the action of the lysin. Prof. Jules Bordet of the University of
Brussels (Nobel prize 1922) termed this factor alexin (from the
Greek meaning helper), while Prof. Paul Ehrlich of the University
of Berlin (Nobel prize 1908) called it complement. In the Wasser-
mann test a normal serum furnishes the proper amount of com-
plement, so that complete lysis occurs. With the serum of a person
having syphilis, the complement is altered, bound, or "deviated" to
a greater or less extent, so that lysis takes place only partially or not
at all. Absence of lysis is recorded on an arbitrary scale as 4 + .

Antibody Formation

Though antibodies are usually tested for in body fluids such as
blood serum and spinal fluid, it is believed that they are formed
within the cells. On bleeding an immunized animal, for example
a horse, to extract diphtheria antitoxin, a new supply is con-
tinuously forthcoming. Since a small amount of antigen can pro-
duce an indefinitely large amount of specific antibody, it is obvious
that the original antigen molecules cannot constitute the antibody,
even in part. This led me to the view that the antigen formed a
specific catalyst surface or template, against which a specific anti-
body of opposite contour could be molded. I have illustrated this
notion in frequent private discussions and public lectures, by

146 LIFE: ITS NATURE AND ORIGIN

pressing a sheet of tin foil against a coin and showing that the
coin produces a reverse impression on the foil on the near surface.
A duplicate of the coin contour is produced on the off surface,
and the significance of this will be referred to presently. Free dis-
cussion for several years having disclosed no opposing evidence or
reasonable alternative, a brief paper was offered for publication to
several American scientific journals; but publication was refused
on the advice of "referees." Realizing that the paper could not be
published here because of this opposition, it was sent to Proto-
plasma and was published by this journal in October, 1931, under
the title "Some Intracellular Aspects of Life and Disease." The
following quotations are from this paper.

"Immunological specificity, like all other kinds of chemical speci-
ficity, is consequent on the outwardly directed electronic fields of
the units involved in precipitation, agglutination, lysis, etc. The
minimum sensitizing dose of egg albumin approximates 0.000,05
milligram; and in general the minute quantities of antigen demon-
strable by immunological methods cannot be detected by any other
known method. How shall we account for the potent effects of
such incredibly minute quantities, and also for the fact that if an
animal be bled, the temporary drop in the titer of antibodies in the
remaining blood is retrieved or even surpassed? Furthermore, the
blood of a non-sensitized animal may be used to replace the blood
of a sensitized animal, without impairing the sensitivity of the
animal or of its isolated tissues.

"These facts point to the formation, within the cells themselves,
of neiv specific catalysts which are able to direct the formation of
antibodies. Three possibilities present themselves as the method
whereby specific antigens produce specific catalysts which in turn
determine specific antibody formation: (1) modification of a gene;
(2) modification of a non-genic catalyst; (3) fixation of the antigen
particle by a non-catalyst cytoplasmic particle in such a manner
that the combination functions as a specific catalyst. Nature may
utilize any or all of these methods, and perhaps others unthought
of at present.

"All three of these possibilities involve the idea that the antigen
becomes an essential part of the directive surface of a catalyst
particle, which would tend to determine the formation of particle
groups having essentially a reverse of the electrostatic charge pat-
tern of the active catalyst surface and therefore of the antigen, or
else of particle groups which can acquire essentially such a reverse

IMMUNOLOGY AND SELF-SAVING CATALYSTS 147

pattern when they are detached and removed to some other part of
the organism. Changes in hydrogen ion or other ion concentration
might readily account for such detachment and changes, which
would be in the nature of an electroversion. In its simplest form
this concept may be illustrated by the following diagrams,*
wherein positively charged areas are represented as depressions
below, and negatively charged areas as elevations above, the dotted
line representing neutrality. (See Figure 17).

"The applicability of Emil Fischer's well-known analogy of lock
and key, which he applied to the fitting of enzyme to substrate, is
at once manifest. That such an antibody particle would tend to
unite with particles of its specific antigen seems obvious; and the
neutral units would tend to flocculate if conditions would permit —
presence of precipitating ions and absence of colloidal pro-
tectors. . . .

Figure 17. (Left) Active "antigen area" in modified catalyst. (Right) Oppositely
changed area in antibody formed by modified catalyst. [Courtesy Protoplasma, Vol.
14, No. 2 (1931).]

"The effectiveness and lasting effect of minute quantities of
antigens becomes comprehensible on the basis of this view, for in
theory at least, one single molecule or colloidal particle would be
sufficient to convert a cell or an extracellular catalyst into a
potential producer of a specific antibody. Furthermore, there is
no reason why large numbers of different antigens may not simul-
taneously or successively affect the same cell with its many thou-
sands of genes and other catalyst particles — which corresponds with
the experimental facts. As long as the catalyst-antigen complex
continues to function to produce the specific antibody, so long will
the production of immune bodies continue, despite bleeding.
Variations in the duration of immunity would correspond to
variations in the persistence of the antigen-catalyst complex while
inability to establish immunity would indicate the non-formation
of such a complex (or destruction of the antibody). All these
phenomena appear in 'vaccinations,' a general term indicating in-
troduction of antigens with the hope that immunity will result."

* The actual fields of force extend in three dimensions.

148 LIFE: ITS NATURE AND ORIGIN

And in a more recent publication1211 I wrote: "The functioning of
the antigen 'mold' or 'template' may be crudely illustrated, at a much
higher structural level, by pressing a piece of tinfoil against the sur-
face of a coin.13 The surface of the foil next to the coin acquires an
impression which is the specific opposite or reverse intaglio of the
coin pattern, while the upper surface of the foil acquires a surface
pattern which duplicates the coin pattern. If something analogous
occurs when a molecular plaque is formed against an antigen mold,
the subsequent influence of the detached plaque would depend upon
which of the plaque surfaces remains exposed to the milieu, if the
plaque serves as adsorbent or is itself adsorbed. There could thus
be formed a new surface like the mold, or a surface with a reverse
contour, or modifications of either of these surfaces if the plaque is
distorted on adsorption or is subject to enzymic or other biochemical
attack.

"The separation of duplicated chromosomes during mitosis shows
that forces exist which separate the duplicated gene-strings from each
other. As N. K. Koltzoff14 and C. B. Bridges15 independently showed,
the huge salivary gland chromosomes in the small grub that develops
into Drosophila, which are enlarged or swollen to about 200 times
normal size, appear to consist of a number, possibly 16 or more, of
gene strings which, instead of separating, remain coherent and, when
stained, show specific bands and structures at the loci of specific genes.
On comparing the location of these bands with the gene maps
developed from the data of geneticists, their matching indicates that
we have before us what has been termed a 'genetic spectrum.'

"What forces normally separate each template gene from the new
gene formed against it, so that the new chromosome may separate
lengthwise from its originator? And what forces would determine
the separation of our hypothetical plaque from the surface against
which it was formed? While no simple or positive answer can be
given, it must be recalled that small changes in ionic concentration
(pH with protein units, CCa in the developing zygote) could be effec-
tive, as may also be the presence of small amounts of specific sub-
stances which act as "detergents," as Svedberg found with proteins
and as Smith found with natural chlorophyll. Another possibility
is suggested by the experiments of Goranson and Zisman16 who found
that when about 500 successive X-multilayers of calcium (or barium)
stearate were deposited upon an ebonite 'probe,' the polymolecular
layer spontaneously detaches itself.17 Possibly the cohesive surface
forces diminish as the layer becomes thicker, and are no longer effec-
tive when the deposit reaches a critical thickness. It is not unreason-
able to envisage the possibility that specific natural proteins, car-
bohydrates, etc., may be thus formed at the surface of specific catalysts
as templates, and float away to become effective units elsewhere. A

IMMUNOLOGY AND SELF-SAVING CATALYSTS 149

contrary effect seems to be produced by colchicine, which causes
chromosome doubling or polyploidy, apparently by interfering with
spindle formation during mitosis.

On the other hand C. C. Lindegren and C. B. Bridges18 advanced
the hypothesis that the surface of each chromosome (not necessarily
the gene surface), may stimulate the protoplasm to form specific anti-
bodies, which on being specifically adsorbed at the chromomere inter-
face, renders it capable of adhering specifically to its partner chromo-
mere in synapsis. Any two allelic chromomeres happening to touch
"would be cemented together by the antibody junctions specific to
themselves. The chromomeres which are on each side of the already
agglutinated ones would then be more likely to touch and fuse, so
that synapsis would proceed, zipper-like, from the first points of the
homologous contact throughout the entire length of the chromo-
somes.

In this connection, it is interesting to consider the concept of
"cohesive colloids." W. W. C. Topley, J. Wilson, and J. T. Duncan19
found that when a heterogeneous mixture of bacteria is agglutinated
by a heterogeneous mixture of specific antisera, each cluster of bacteria
is homogeneous. Apparently each kind of bacterium becomes coated
by a layer of its own specific antibody, and the bacteria are so
specifically conditioned that each kind forms a lattice or clump of
identical unions through the adsorbed antibodies. The submicro-
scopic particles containing glycogen isolated by fractional ultra-
centrifugation by A. Lazarow20 from finely dispersed liver, appear to
be aggregates of smaller glycogen particles held together by about
1 per cent of protein, a coacervating agent which "seems to parallel
the action of insulin, because insulin is known to lower blood sugar
and facilitate glycogen storage in the liver."

The Nature of Antigen-Antibody Reactions

"Out of the efforts to explain the diverse and often confusing
phenomena appearing in immunological reactions, there arose an
unfounded and totally unnecessary antagonism between those who
attempted to explain all of them on the basis of simplified con-
cepts of colloid chemistry and those who could see nothing in
them but applications of the stoichiometric laws of classical chem-
istry, which had been developed from observations on the be-
havior and reactions of relatively simple substances. Nature does
not order the interrelations of particulate units to meet the peda-
gogical necessities of propagandists of this or that school. The
simple phenomena have both chemical and physical aspects, and
part of the whole truth lies in each aspect."21

150 LIFE: ITS NATURE AND ORIGIN

J. R. Marrack22 gave an excellent review of both the chemical
and the physical aspects of immune reactions and pointed out the
fact that it is possible to distinguish two stages in immunity
reactions: (1) specific combination of "determinant" groups with
antibody, and (2) secondary reactions — precipitation, agglutina-
tion, etc. Many "determinative" groups lack chemically reactive
areas, and immunological equivalence may be shown by groups
chemically different, e.g.,

CH3

and
NH2 NH2

Marrack states: "Such a result can only be due to intermolecular
forces and the specific character must be ascribed to (1) an
appropriate distribution of polar fields on the determinant group
and on the antibody; and (2) to purely spatial considerations,
since the approach of a determinative group to a receptive site on
the antibody may be prevented by an inert substituent which gets
in the way (steric hindrance). These are the same factors as deter-
mine the specific selection of the molecules which are built into a
crystal."

It may here be noted that if adsorbed molecules are polar, which
is commonly the case, the pattern of the molecular "ends" ad-
sorbed on the oppositely charged areas of a complex surface
would tend to form a monolayer or plaque having the reverse
pattern of the surface on the near side and a duplicate pattern
of the surface on the off side.23 Over 20 years ago Nellensteyn
found that diamond will adsorb methylene blue but not succinic
acid; but the reverse is the case with graphite, which differs from
diamond only in the spacing of the carbon atoms. While the
formation of pure crystals of simple compounds with exclusion of
"foreign" molecules may take place by the selective and oriented
specific "adsorption" of new particles at the various growing
crystal surfaces, in the case of very large molecules or molecular
groups, like antigens and antibodies, a "spot welding" of molecules
at limited reactive areas may suffice to form aggregates strong
enough and large enough to settle out. Since time is a factor here,
the drop in kinetic activity which accompanies particle growth
will, up to the zone of optimum colloidality, favor the proper
adjustment of attractive areas to each other. Moderate agitation

IMMUNOLOGY AND SELF-SAVING CATALYSTS 151

may also be a help, as is the case in the Kahn test for syphilis.24
The simple physico-chemical principles involved in immunology
extend to many other fields, as might be expected. F. R. Lillie2"'
found that seawater in which sea-urchin eggs had stood for a while
("egg-water"), will agglutinate the spermatoza of the same species,
though the agglutinization is spontaneously reversible, seldom last-
ing over an hour. The phenomenon is observed in all echinoids,
in many molluscs, and in some annelids. The substance respon-
sible is called fertilizin, and A. Tyler found20 that it comprises
part or more probably the whole of the gelatinous superficial
coat of the egg, which swells and slowly disperses, but which can
be quickly dissolved in acidified seawater of pH 3.5 to 4.5. "Egg-
water" also activates sperms. As evidence of this fact Dr. E. E.
Just demonstrated to me at Wood's Hole (1925) that if a small
dish in which a female Nereis has been floating were rinsed out
several times with fresh seawater and then filled, a male Nereis
dropped in will immediately shed its sperm.

Fertilizin reacts with a substance termed anti-fertilizin which
can be extracted from the sperm surface by acidified seawater,
which is of interest in connection with the mode of development
of the sex glands. Curiously enough, the surface of the egg from
which the fertilizin has been removed also furnishes a substance
showing the same behavior and immunological specificity as anti-
fertilizin. Commenting on the fact that these substances react
with one another in the specific and complementary manner of
antigens and antibodies, Tyler suggests application of this notion
to explain the auto-agglutination of bacteria and the production of
bacterial antibodies.

"The finding of two mutually complementary substances leads to
the expectation that more may be found deeper within the cell. This
view may then be expanded into a general theory of cell structure;
namely, that a cell is a mosaic of substances that are mutually com-
plementary (i.e., capable of combining with one another in the manner
of antigen and antibody) substances which are actually in combination
with one another in regions where they adjoin. The compounds
would be represented by the various membranes, such as the cell
membrane, nuclear membrane, nucleolar membrane, vacuolar mem-
brane, etc., which in turn keep the complementary substances apart."

This view is consonant with the establishment of interfacial films,
which, as the work of Harkins, Langmuir, Adam, Freundlich and
others has shown, may be polymolecular and more complicated than

152 LIFE: ITS NATURE AND ORIGIN

is indicated by the simple union of two oppositely charged ends of
polar molecules. It also accords with the view of Alexander and
Bridges that the cell is a "box-within-box" structure.

It must be remembered that every free unit or surface having
unsatisfied residual electronic fields tends to draw to itself units of
opposite charge pattern or areas of opposite electronic contour,
even if several molecules are needed to complete the opposite
mosaic. Crystallization proceeds this way with the elimination of
stranger molecules; but it can also happen that there are "lacunae"
or adsorbed "impurities," so that the film or layer, especially if a
thick one, may not ideally perfect.

To go to one extreme, when atomic nuclei are deprived of one or
more electrons, they strive to replace them or at least to share
electrons with other nuclei, as in covalent compounds. At higher
structural levels the residual forces become more feeble and in-
definite, but nevertheless effective. Sir W. B. Hardy27 showed
how exceedingly difficult it is to secure a really clean surface, and
we can understand how nascent atoms, molecules, and areas may
be highly and specifically active, especially in the loci where they
are liberated or formed. Lord Rayleigh pointed out that a film
of "grease" adsorbed from the atmosphere exists on most exposed
surfaces, and to this film all kinds of small particles of "dirt"
may adhere. In South Africa when a slurry of diamond-bearing
clay flows down a trough lined with tallow, the grease selectively
fastens most of the diamonds. Microscopic examination of "house-
moss" (or 'cobwebs") — that fluffy horror of meticulous house-
keepers— shows it to consist mainly of tiny textile fibers (cotton,
wool, etc.) with adsorbed "grease" and mineral particles. By
twisting "house-moss" between the fingers, it can be "spun" into a
weak but coherent "thread." And millions of letters daily travel
in the mails with their postage stamps securely attached, though
not even a strict stoichiometrist among chemists would suggest that
the "compound" should be called stampate of envelope, or en-
velopate of stamp.

REFERENCES

1 Alexander, Science (1936), 83, 230.
2/. Exp. Med., 69, 119 (1939).
3 "Colloid Chemistry," Vol. V, pp. 564-6.
4/. Am. Chem. Soc, (1939).

5 "The Chemistry of Antigens and Antibodies," 2nd ed., Brit. Med. Res. Council,
London, 1939.

6 /. Exptl. Med (1928) 47, 757.

IMMUNOLOGY AND SELF-SAVING CATALYSTS 153

7 Proc. Soc. Exptl. Biol. Med. (1940), 43, 223.
*Ann. N. Y. Acad. Sci. (1946), 46, 969.

9 Review by E. Grasset, South African Inst. Med. Publ. (1929), 4, 171; also J.
Needham, "Chemical Embryology," pp. 1 444 ff.

10 For further details, see Landsteiner's book, "The Specificity of Immunological
Reactions," C. C. Thomas, 1936.

11 J. Alexander, "Selective Adsorption and Differential Diffusion," /. Am Cliem.
Soc. (1917), 39, p. 87.

12 Compt. rend. soc. biol. (1922), 86, 661, 711, 813; details may be found in standard

texts.
12a"Colloid Chemistry," Vol. V, p. 571, Reinhold Pub. Corp., 1944.

13 See J. Alexander, "Colloid Chemistry," 4th ed., p. 385, D. Van Nostrand Co.,
1937.

" Science, 80, Oct. 5 (1934).

15 /. Heredity, Feb., 1935.

i«/. Chem. Phys. (1939), 7, 492-505.

17 The authors say: "In plating X-multilayers it has been observed that after
about 500 layers have been deposited, and the electrostatic repulsive field of the
multilayer has thus reached a certain value, the upper portion of the submerged
probe has a silvery appearance which gradually moves down the probe with increas-
ing number of dips, and film does not adhere to the multilayer over this portion.
The electrostatic repulsive field thus sets a limit to the thickness of X-multilayers
on insulators." Dr. Goranson informs me (private communication) that "if plating
is made on a metal, more layers can be put on because of the oppositely induced
charge of the metal."

™ Science (1938), 87, 510.

™Brit. J. Exptl. Path. (1935), 16, 116.

20 Science (1942), 95, 49.

21 "Colloid Chemistry," 4th ed., p. 418, by J. Alexander, D. Van Nostrand Co.,
N. Y., 1937. Those interested in a historical account of the long conflict between
proponents of the various views and theories will find much summarized in "The
Chemical Aspects of Immunity" 2nd ed., 1929, by H. Gideon Wells, and in earlier
publications. More recent views are given by Wm. C. Boyd in "Fundamentals of
Immunology" (Interscience Pub., 1943) and in his paper on Immunology in
"Colloid Chemistry," Vol. V, pp. 957-979, Reinhold Publishing Corp., 1944. M. G.
Sevag in "Immuno-catalysis" (C. C. Thomas, 1945) has also adopted the catalytic
view.

22 lib. cit., reference 5.

23 A review of the question of adsorption and crystal modification by Wesley G.
France is given in "Colloid Chemistry," Vol. V, pp. 443-457, Reinhold Pub.
Corp., 1944.

24 R. H. Kahn, in Alexander, "Colloid Chemistry," Vol. II, 1928.

25 7. Exptl. Zool. (1913) 14, 515.

26 Albert Tyler, "Specific interacting substances of eggs and sperm," Western J.
Surgery, Obstetrics and Gynecology (1942) 50, 126-138.

27 "Colloid Chemistry," Vol. I, 1926.

Chapter 8

Genetics: The Heritable Transmission of Catalysts

The Nobel prize in medicine for 1935 was awarded to Thomas
Hunt Morgan, the outstanding geneticist, who with his able
collaborators, Calvin B. Bridges, A. H. Sturtevant and others,
did so much to establish experimentally the view that hereditary
characters are carried by particulate units called genes (or gens),*
arranged linearly in the chromosomes of the germ cells. This
award to Morgan called attention to the great importance of
developments in the science of genetics, a branch of biology deal-
ing with heredity and its mechanisms.

While breeders of cattle, horses, dogs, pigs, fowl and other do-
mestic animals, as well as farmers and seedsmen dealing with vege-
tables, wheat and other grains, had from time out of mind been
making selections of favored forms, it was Gregor Mendel, Abbot
of Briinn (Bohemia) who introduced atomism into genetics, as
J. B. S. Haldane puts it. In his cloister garden, Mendel assembled
the results of breeding experiments with the common garden pea
(Pisum sativum), which were published in 1865, only six years
after the appearance of Charles Darwin's "Origin of Species."
Mendel attributed the differences, which he found were distrib-
uted by heredity, to discrete representative factors or producers,
which in general pass unaltered through successive generations,
though their distribution may vary. It was not until 1900, eight-
een years after Mendel's death, that the importance of his work
was independently recognized by three distinguished botanists,
Hugo de Vries (Holland), C. Correns (Germany) and G. Tscher-
mak (Austria).

Mendel crossed a tall with a dwarf pea, and observed how these
characters were inherited. All members of the first family (Fx)
were tall; but this was not the case with the second family (F2)
developing from the seeds of the Fx hybrids.

* The Standard Dictionary of 1913 gives timidly the following definition of "gen":
"A minute hypothetical particle supposed to be the bearer of hereditary qualities."

154

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 155

Mendel's First Law: Segregation

The F2 families always gave an average ratio of three tails to
one dwarf. The F2 dwarfs always bred true to type, and so did
one-third of the tails. The other two-thirds of the tails behaved
just like the original Fx hybrids; that is, they gave, in F3, three
tails to one dwarf. Mendel termed tallness a dominant charac-
ter, and dwarfness a recessive character, since it reappeared in sub-
sequent generations raised from the hybrid seed. Several other
pairs of contrasting characters gave similar results, which are
shown in the following diagram, where R indicates plants with a
recessive character, D dominants which breed true, and D dom-
inants which carry the recessive particular producer or gene, as it
is now called:

Parents DXR

i
Family Fi D

1

Family F2 D D D R

1

1

D

D

1

i

, .A

Family F3 D DDDK DDDR R

Although each cell of the hybrid Fi evidently developed under
the joint influence of a dominant and a recessive gene, in both
the ova and the pollen grains these factors separate cleanly from
each other, or segregate, so that, according to the laws of chance,
each ovum or pollen grain would get a pure dominant gene, D, or
equally often a pure recessive gene, R. Thus with random or hap-
hazard fertilizations, we would get

Pollen D R

JVM

Ova D R

leading to an F2 family averaging D/D; 2DR; R — that is, three
dominants to one recessive.

Mendel tested this hypothesis by what is known as a backcross:
he fertilized dwarf flowers with pollen from Fx hybrids, and ob-
tained, as he expected, equal numbers of tall- and dwarf- producing
seeds. The following diagram indicates what happened:

Pollen of Fx hybrid (tall) D R

Ova of recessive dwarf R R

Progeny of backcross D/R, D/R ; R/R, R/R

2 tall 2 dwarf

156 LIFE: ITS NATURE AND ORIGIN

Mendel's Second Law: Independent Assortment

When peas having yellow and round seeds were crossed with peas
having green and wrinkled seeds, Mendel found that all the Fi
seeds were yellow and round, these characters being dominant over
the recessive alternates, green and wrinkled. But the plants from
these Fi seeds, when self-fertilized, gave seeds, and therefore
progeny, of jour types: yellow/round; green/wrinkled; green/
round; green/wrinkled, in the ratios 9:3:3:1. To explain these
results Mendel assumed that the segregation of the genes of the
yellow/green pair takes places independently of the segregation of
the round/wrinkled pair; so that there would be four equally
numerous kinds of ova and four equally numerous kinds of
pollen grains, which, uniting at random during fertilization,
would give sixteen different combinations that yielded (bearing in
mind the factor of dominance) visible types in the 9:3:3:1 ratio
actually found.

Linkage

Soon after the resurrection of Mendel's work, Sir William
Bateson and R. C. Punnett of Cambridge (England), in making
experiments with sweet peas, found that the factor pairs (red
vs purple flower) and (long vs round pollen grain) did not assort
at random. When (red) and (long) entered a cross together, they
tended to remain together in subsequent generations to a greater
extent than warranted by random assortment. This failure of
random assortment is understandable on the assumption that the
genes of the two pairs involved act as discrete units or gene blocks
in the chromosomes. Chromosomes are microscopically resolvable
bodies in the cell; they contain invisible genes arranged in linear
order. Chromosomes were well known to cytologists, but their
importance in genetics became evident in 1907 when Frances E.
Lutz, working with the evening primrose, Oenothera (the experi-
mental plant used by H. de Vries), found a great variation in the
the number of chromosomes in the various varieties, as follows:
O. lamarckiana, 14 (its variety gigas has 28); O. lata and O. albida
have each 15 chromosomes. Gates independently published some
of these results a few months later.

In 1901 Charles E. McClung of Princeton discovered unequal
chromosomes in the two sexes, a fact brought out in Figure 18,
indicating how the chromosomes behave in the formation of sperm

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 157

and ovum, and the union of these units as the initial step (concep-
tion) in the formation of an individual. Besides the single pair of
sex-chromosomes which determine the sex of the individual, there
are a number of autosomes ("ordinary chromosomes"), which in
man number 46 (23 pairs). In mammals, including man, female
cells have additionally two x-chromosomes (female determiners),
while male cells have additionally one x- and one y-chromosome.
In ordinary cell duplication, termed mitosis, the chromosomes

MALE FEMALE

Primary
Spermatocyte

X- Chromosome

(Tem»\e* . ^ ft
Sex- determiner; [£

Y- Chromosome
/ yMMe" . \
^sex-deterrtunev

Worn ajermina\ epithelium-
Double set ot chromosomes

Primary
Oocytg

.TV»re<i
X-Qvromosome^

Other chromosomes (23 pairs
inman)arerepresen\e<i here b«|
two pairs. These chroTnosomes
are «eulr&\ or o? secondary im-
portance w Se*-AeYemunat»on.

REDUCTION DIVISION

"Paired chromosomes sep-
arate, one jjoinci to each cetl

Number orchromosomes

TedaccA to '£ that 'in bod»*
C*\»S

EQUATIONS DIVISION

Chromosomes split lono;-
ItudinaUy. Number in
daughter ceUs unchained

X- bearing

SPERtiATOZOA

"POLAR eooits

(Degenerate)

MATURE OVUM

FERTILIZATION

Chromosome number restored
bj fusion or Sperm and ovum

Devetops mto

MALE

Develops »nto

FEMALE

Figure 18. The mechanism of sex-determination. [Courtesy Journal of Heredity,

Vol. XXXI, No. 12 (1940)]

158

LIFE: ITS NATURE AND ORIGIN

»V

J

in

•

i

i •

m

<j

v

k

k

m

Bl

SINGLE CROSSING-OVER

y*

Parental

Synapsis

chromosome

and

type

crossing-over

m

B i. B

DOUBLE CROSSING-OVER

Disjunction Crossing-over

of the gamete

chromosomes tyI)e

k

Figure 19. (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Rein-
hold Publishing Corp., N. Y.)

duplicate themselves and the side-by-side partners separate, one
set going to each of the two cells formed when the original cell
divides. However in meiosis, the process of formation of the sex
cells or gametes, the members of each chromosome pair separate,
and the chromosome number in the resulting daughter cells is
reduced to half the number in the somatic, or ordinary body cells.
In 1909, Janssens (a Jesuit) in investigating meiosis, discovered
what he called chiasmata (from the Greek letter X, chi) involving

:^

jy

Before
break

X

y

u

y

Broken Rejoining

INVERSION

a
b

10

y Uz

Broken section

transferred to

another chromosome

TRANSLOCATION

u

y

n

w

U

Broken section
entirely eliminated

DELETION

Figure 20. (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Rein-
hold Publishing Corp., N. Y.)

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 159

exchanges of substance between maternal-derived and paternal-de-
rived chromosomes, and thus establishing the cytological basis of
the phenomenon of linkage. The four gametes formed by the
extra (equational) division following upon reduction division, are
thus usually different.

Variations in Chromosomal Behavior

The commonest of these variations is crossing-over, illustrated
in Figure 19, which occurs when two chromosomes of a pair twist
around each other in some stage of germ cell formation (meiosis).
Less common forms are illustrated in Figure 20: inversion, when
a block of genes breaks loose from a chromosome and returns
to that same chromosome "upside down"; translocation, in which
a loose gene block joins another chromosome; deletion or defi-
ciency, in which the loose gene-block is lost. Heritable variations
produced by x-rays often involve chromosomal variations.

A great impetus was given genetics in 1910, when Professor T. H.
Morgan and his school began work with a tiny yeast-eating "fruit
fly," which matures in about 10 days and lives only about a month
(Drosophila melanogaster). About thirty or more prolific generations
can be cheaply raised in a year, in quart milk bottles in the laboratory,
quite independently of weather conditions. The breeding and cross-
ing of strains is readily controlled. There are many recognizable
variations, and a biologist can live long enough to make large numbers
of "Mendelian" experiments, not possible where the life cycle is long
or the progeny few. With elephants the gestation period is 22 months,
and elephants do not produce litters used to count Mendelian
averages.

From the strength of linkage between genes, it became possible to
construct a map of the chromosomes indicating the relative position
of many genes. Figure 21 is a "gene map" prepared by C. B. Bridges;
the practical meaning of a few of the characteristics identified in the
"shorthand" of geneticists, is shown in Figure 22.

A large variety of plants and animals, including microorganisms,
are now being used in genetic experiments, and besides the visible
characters or differences which so readily meet the experienced eye,
many latent or hidden chemical differences are being explored. Thus
by raising microorganisms in media with carefully controlled chemical
content, it has been possible to learn something of the synthesizing
properties of their genes, as shown in the work of Prof. George W.
Beadle and collaborators of Stanford University with the red bread
mold Neurospora crassa.

160

LIFE: ITS NATURE AND ORIGIN

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43.7 Clipped •• _|_

/'31-VM7\
V C.B.B. /

-17.1 lit*
'13.0 dumpy*

-lot Streak*

-T.'± Bristled •

46±
4U±
48. S
48 7
51 0

53 9

54 5
54.7
550-
55.0
55.1
SS.3
57.5
62±

Minute.e
padvb
black ••
jaunty
reduced*
hooked*
purple ••
Bnstie**
light ••
spindle-libei
rolled
thick

cmnajbar*
engrailed*

67.0 vestigial** 66Z

_7lt
-J 72 0
172±
-74 +
-75.5

-80 +
-83±

eitended-b
Lobe ••
chubby

gap
curved**

(ringed
lance

91+ humpy

-99.5 arc*

-100.5 pleius**

-104.5 brown ••

'106± purpieold

C--106.5+ lanceolate ••

106 8 morula*
107.0 speck ••

107 2 blistered*
107.5 balloon

rOO uughold-
l0 + tr.ansta

soindie-tiber
bent*
naked"
shaven.

/0 0±
.-£•0 2*

Ki0.3i

V)0 6± eyeless ••

0 61 Eyeless (dom.J

0.91 Cubitus Inc.*

0.91 Cubitus Int. *.

0 91 abdomen rot.*

0.9+ Winuie-.V

-18 +
-20 0

Crimper]
divergent*

- ?6 0 sepia ••
-264 hairy ••

^

35 +

36 5±
37±
40 1
40 2
40.4
42 2
«4.0
46 +
46.5 +
4/5
480

49 7

50 0
51.5
54.8
58 2
585
58 7
59.5
62.0
63.1

-69.3
-70.7

rose

ac.m III
routed abdomen
Minute ti
tilt

Dichaete ••
thread**
scarlet ••
warped
spindle- liber
Oelormed*
pink **
maroon*
curled ••
tettapter
suppressor Ha
Stubble ••
spineless ••
buhorai •
bithoraib
stripe ••
glass •

. Delta*

Hairless ••
ebony •'•

— 73.7 cardinal*
--76.2+ white-ocelli

-] 80± Minule-w

-91± taxi

-91.1 rough ••

-93+. crumplerj

"94.1 Pointed

-100.7
-101.0

claret ••
Minute

\ii

-*■ — 106.2 Mlnute-a*

Figure 21. Genie map of the four chromosomes of Drosophila melanogaster,
showing the linear order and distance apart of the genes (after Calvin B. Bridges).
(From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Reinhold Publishing

Corp., N. Y.)

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 161

The two mating types or sexes of this mold are morphologically
indistinguishable, but they may be cultured indefinitely by asexual
multiplication if kept separately, though when put together under
suitable conditions mating and sexual reproduction occur. Unlike
the higher plants and animals which are diploid (i.e., their chromo-
somes occur in pairs), Neurospora is a haploid organism (i.e., its seven
chromosomes are singletons), which simplifies matters genetically.

B.

A.

D.

E.

Figure 22. A. Normal wild-type female Drosophila, gray body color, red eyes,
long wings, absence of speck at base of wings. B. Male Drosophila having four
linked, recessive characters, viz., black body color, purple eyes, vestigial wings, and
speck at the base of the wings. C. Fly showing the mutant character "Curly." (The
wings curl up at the ends and are held somewhat apart.) D. Eye of female fly homo-
zygous for "Bar" (eye is bar-shaped). E. Fly showing the mutant character "Lobe."
(The eyes are small and protruding.) (Courtesy "The Theory of the Gene" by
Thomas Hunt Morgan, Nobel Laureate. Yale Univ. Press, 1926.) (From paper in
"Colloid Chemistry," Vol. 5, by J. Alexander, Reinhold Publishing Corp., N. Y.)

When a sexual diploid is formed by the fusion of two individuals of
opposite sexes, it does not multiply as such, but immediately forms
haploid spores which are the equivalent of gametes. As Beadle
states:1 ". . . all the products of the nuclear divisions which reduce the
chromosome number from the double number 14 to the single number
7 can be recovered in sexual spores and cultured. The result of this
is that the offspring of parents different by one gene will occur in a
mechanically fixed ratio of one-to-one. We can omit the phrase 'on
the average' which has to be applied to genetic ratios observed in an
organism like man."

162

LIFE: ITS NATURE AND ORIGIN

Considering its simpler needs, Neurospora's synthesizing catalysts
enable it to make its needed amino acids and vitamins from simpler
chemical compounds. By the use of standard bacteriological tech-
nique the mold can be kept uncontaminated on a "minimal" medium
containing water, certain inorganic salts, sugar or some other source
of carbon and energy, and a minute amount of biotin, a vitamin of
the B complex.

In 1927, H. J. Muller (Nobel prize, 1946) made an outstanding
advance by showing2 that heritable changes may be induced in animals
and plants by treating their sex cells with x-rays of selected nature;
and since then a huge literature has developed. This was at first
called the "artificial transmutation of the gene," but it is now known
that chromosomal breakage is often involved. Assuming that Neuro-
spora has genes which govern the production of the chemical sub-
stances needed for its life, Beadle bombarded sexual spores with ultra-
violet or x-ray photons, and then placed the treated spores on media
to which various growth factors had been added. If a treated strain
could grow on the special medium but not on the "minimal" medium,
it was obviously deficient in catalysts capable of making the substance
added to the fortified medium. Thus several dozen mutant strains
produced in Neurospora by irradiation are unable to synthesize the
amino acid arginine from the minimal medium, though normal
Neurospora can do so. These mutants thrive only when arginine is
supplied.3

In mammals, arginine is formed in the so-called ornithine cycle of
Krebs and Henseleit.4 Neurospora appears to make arginine in the
same way, for some mutant strains cannot convert citrulline into
arginine, and therefore require arginine; others cannot convert orni-
thine into citrulline, and therefore require citrulline or arginine; still
others cannot synthesize ornithine, and therefore fail to grow in the
absence of ornithine, citrulline or arginine. Beadle states: "The
interesting thing about this from the standpoint of gene action is that
we find just what would have been predicted from the hypothesis that
enzymes are dependent upon specific genes and that for each enzyme
there is a specific gene, and vice versa. In each instance of defective

NH;

OOH

\ /NH2

^

H2N\/0

N
/ 00H

\y

NHZ

H2Nv^NH

N
/ OOH

V

NH2

H2N\zNH2
0

NH2
/ OOH

J

NH2

Ornithine

Citrulline

Arginine Ornithine A- urea

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 163

arginine synthesis the genetic study shows a modification of one gene."
Tryptophane, an amino acid essential for humans, is made by
Neurospora by condensing serine with indole. The catalyst deficien-
cies of certain Neurospora mutants prevent them from making indole;
but if indole or tryptophane is supplied, they form in the medium
anthranilic acid, the precursor of indole. Still another mutant is
unable to synthesize anthranilic acid, but can convert it into indole.
"Each strain differs from the original wild-type Neurospora by a single
gene, and the two mutant genes concerned can be shown to lie in dif-
ferent positions in the chromosomes. ... In the future we may

Scale f-

-lo/x-

•£^V<>V*.>--4* ••'•'tfv-*!-'

Figure 23. Salivary gland chromosome from Drosophila melanogaster. (From
paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Reinhold Publishing Corp.,

N. Y.)

expect to see increasing use of genetics this way by biochemists."
Choline, a carrier of methyl groups to other molecules, and a com-
ponent of the important protoplasmic constituent lecithin, is made by
first synthesizing a precursor, monomethylethanolamine and then add-
ing two additional methyl groups.

The Salivary Gland Chromosomes

In 1935 Professor T. S. Painter of the University of Texas ex-
amined the cells in the salivary glands of the tiny grub repre-
senting the larval stage of Drosophila, and made the important
discovery that in these cells the chromosomes are swollen from
175 to 200 times their length in ordinary cells. In the extended
chromosomes there are great numbers of characteristic bands,
which vary with and correspond to the genetic constitution of the
individual grub, and therefore constitute a "genetic spectrum."

164

LIFE: ITS NATURE AND ORIGIN

, Chromocenter

H»

|P

^lg

(Spindle Fiber)

,~^ Diagram of right half of
Chromosome 3

Synapsed

W,£$^h\. Unsynapsed

%* Normal End 3->

'^S. Inversion Point-"*"

V53 Inverted End Chrom. 3"

Terminal Inversion "C3-l3a"
Heterozygote

Salivary Chromosome

h

-50 H

H 1 —

H

31 di (Revised 35a6)C.D.B.

(94E1)

Figure 24. (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Rein-
hold Publishing Corp., N. Y.)

Figure 23, on which the scale of magnification is indicated, shows
in the upper right-hand corner the four pairs of autosomes and
the one pair of sex chromosomes as usually seen in cells of
Drosophila. The main portion of the figure, at the same mag-
nification, shows large size and the wealth of details revealed in the
tiny sex chromosomes as found in a salivary gland cell. Figure

24 illustrates a case wherein a terminal inversion in chromosome
3 has prevented complete synapsis of the chromosomes. Figure

25 illustrates a portion of chromosome 2 where a deficiency (lack
of a gene block) has caused an outward looping of the normal
chromosome during conjugation. Figure 26 shows a portion of
salivary gland chromosome 2 in which the data of the gene maps

Non-terminal Deficiency
"Plexate" heterozygote

Section involved

End of Normal
Chromosome 2

Deficiency

m

h iom -j

i i i i i i i i i i i

34 d 4 (Revised 35 320) C.B.B.

Figure 25. (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander, Rein-
hold Publishing Corp., N. Y.)

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 165

mi pd mr In bs M

Figure 26. Section of the right end of second chromosome (salivary gland of
Drosophila melanogaster) with corresponding portion of the chromosome map (after
Calvin B. Bridges). (From paper in "Colloid Chemistry," Vol. 5, by J. Alexander,
Reinhold Publishing Corp., N. Y.)

finds visual confirmation in the "genetic spectrum" there revealed.
Many more complete concordances are shown in the elaborate
salivary chromosome maps recently published in the Journal of
Heredity. Figure 27 outlines the 48 human chromosomes (24
pairs).

Sex Determination

In contradistinction to the main number of autosomes are the
usually smaller "sex chromosomes," so called because their segrega-
tion determines the sex of each offspring. The basic sex chromo-
some, known as the X-chromosome, has no discovered mate in
some species (XX-XO types). Only comparatively recently (1901)
was the F-chromosome found in human sperm, placing man in a
major XX-XY group in which the fertilized ovum that develops

C< ft OO ȣ(!<*"

Figure 27. The 48 human chromosomes in outline (after H. M. Evans arid O.
Swezy, Mem. Univ. Cal., Vol. 9, No. 1929). (From paper in "Colloid Chemistry," Vol
5, by J. Alexander, Reinhold Publishing Corp., N. Y.)

166

LIFE: ITS NATURE AND ORIGIN

into a normal female has two X-chromosomes, whereas the normal
male has one X and one Y chromosome. In man during meiosis
(including reduction-division) each female gamete (ovum) is left
with one X-chromosome, while the sperms are equally divided
between X and Y; therefore the sex of the off-spring is determined
by which kind of sperm happens to fertilize the ovum. With an-
other group of animals, including birds and moths, it is the female
that has the differing sex chromosomes (WZ), the male cells (ZZ)
yielding only Z sperms. The following diagrams indicate how,
in these two groups, these microscopic gene-carrying units dom-
inate sex determination:

XX

WZ

X

4
(f) xx

T
x

XY

\

/

\

X

w

z

i

i

i

XY (m)

(f) WZ

ZZ (m)

T

T

T

Y

z

z

/

\

/

zz

In sex determination, as in all other cellular developments,
all the genes exert an influence. The net results which emerge
(only some, of which can be demonstrated) are dependent upon
the final results of all the very complex and interrelated cellular
catalysts and their physiological and morphogenic consequences, a
summation of all this being included in the expression genie
balance. The biont (plant or animal) may die or fail to reproduce
if genie balance is too greatly disturbed — in fact, most mutations
are lethal.

In certain abnormal cases chromosome pairs fail to separate
during reduction-division in meiosis, a phenomenon termed non-
disjunction. As a consequence abnormal numbers of chromo-
somes may enter into a gamete (germ cell) and hence into a zygote.
With Drosophila, some of the consequences are tabulated below, A
representing a single set of autosomes. Each parent contributes
one autosome set, under normal conditions.

AAXY (normal diploid fly)

AAXX (normal diploid fly)

AAXXY

AAXXX

AAXO

AAYO

AAAXXX (triploid fly)

Male (normal

Female (normal)

Female, giving abnormalities.

"Superfemale," abnormal

Male, sterile

Dies (sex?)

Female, producing abnormalities

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 167

AAAXX Intersex, sterile

AAAXXY Intersex, sterile

AAAXY "Supermale," sterile

It must not be supposed, however, that heredity is carried by
the genes alone, or even solely by the chromosomes in which x-ray
treatment may produce "position effects" having consequences
as marked as "point mutation." In Chapter 9, these matters are
discussed at length in connection with differentiation and morpho-
genesis. However, we may here refer to a few other non-genic
and non-chromosomal factors.

First are the so-called "maternal effects," observed for example in
the mode of coiling of the shell of the snail Limnaea peregra; the
direction of coiling (righthand or lefthand) depends in the Fx gener-
ation upon the genotype of the mother, not upon the genotype of the
individual (Sturtevant, 1923). The work of Toyama (1912) with silk-
worms (Bombyx mori) indicated that the appearance of an egg (shape,
color) depends not upon its own genetic constitution (maternal and
parental genes), but upon the genes of the mother in whose body the
egg developed.

Definite cytoplasmic inheritance is illustrated by the self-reproduc-
ing plastids, e.g., chloroplasts which largely dominate photosynthesis
in plant cells.5 Wanda K. Farr has shown6 that cellulose is formed
in a chloroplast or colorless plastid. Starch granules likewise develop
by deposition of material from the plasma of certain plastids around
small starch-forming centers.

In the case of variegated plants, the leaves show whitish spots or
stripes where the cells are devoid of chlorophyll generally because
viruses (infective agents approaching molecular dimensions) destroy
the chlorophyll or prevent its formation. These viruses, and there-
fore their effects, may be heritably transmitted; variegation apparently
does not harm the plant and is regarded as a desirable feature by
nurserymen. On the other hand, some viruses produce very undesir-
able effects, e.g., influenza, poliomyelitis, foot-and-mouth disease, yellow
fever, chicken sarcoma (Rous), rabbit papilloma (Shope), encephalitis.
But though these may be transmitted by some form of infection or
inoculation, and may lead to formation of specific antibodies, they
are not effectively transmitted by heredity. However, we do not know
to what an extent harmless or beneficial virus-like symbionts or
"diseases" may be carried by heredity, as is the latent potato mosaic
virus which shows its effects only in susceptible strains of potato.

But in many plants plastid color is gene-determined, and is trans-
mitted on a Mendelian basis.7 Most geneticists express the Scotch
verdict of "not proven" on experimental work supposed to demon-

168 LIFE: ITS NATURE AND ORIGIN

strate cytoplasmic inheritance, even though V. Jollos produced
"Dauermodifications" in which cytoplasmic effects persisted through
hundreds of generations, and V. von Wettstein was able to keep some
hybrid mosses for fifteen years without indication that their cytoplasm
had been gradually reconstructed by foreign genes. Wettstein
classified components of the germ plasm (cytoplasm plus all particulate
units) as follows: (1) the genome, i.e., all genes carried by the chro-
mosomes; (2) the plastidome, arising from the properties of the plastids
themselves; (3) the plasmon, genetically effective portions of the
cytoplasm.

Where prolonged and skillful experiments fail to secure a de-
sired result, the feeling grows that "it can't be done." Such a
despairing note is sounded by calling viruses "obligate parasites,"
when the truth simply is that we have as yet been unable to find
a non-living medium for them. However, some kinds of viruses
are now cultivated on chorio-allantoic membranes of developing
hen's eggs, on a commercial scale for use in immunization. The
viruses of poliomyelitis and of the foot-and-mouth disease do not
grow on these membranes.

Professor E. G. Conklin stated:8 "The classic argument of the
Weismannians was that we can conceive of no mechanism by
means of which somatic changes can be carried back into the
germ cells, and therefore there is no such mechanism. Now the
fallacy of this argument is obvious; even if we could conceive of
no suitable mechanism for this purpose, this does not preclude
the existence of such a mechanism." As the all-pervasive phe-
nomena of catalysis became more and more recognized and under-
stood, it became evident that in catalysis we have what still seems
to be the only basic mechanism whereby we can explain the under-
lying chemical changes which directly or indirectly govern life
and its physical manifestations. Catalysis discloses the required
mechanism, which is not revealed by valid views of what happens
at higher structural and organizational levels, so that the very
terms used in expressing these views imply results rather than
mechanism. As Thistleton Dyer remarked in his address to the
British Association for the Advancement of Science at Bath in
1888: "Science will always prefer a material modus operandi to
anything so vague as a tendency."

Everyone recognizes that the cytoplasm is a specialized milieu
in which and with which the genes and other inclusions function.
Chapter 9 considers the importance in differentiation of the mil-

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 169

lions of specific molecules included in the cytoplasms of sperm
and ovum. Many other kinds of specific atoms and molecules are
in most cases essential to full growth, development and reproduc-
tion, e.g., numerous vitamins and trace elements. These sub-
stances commonly serve as prosthetic or activating groups in essen-
tial biocatalysts which have a more or less limited functional
life and must therefore be continually renewed.

What happens if strange and unusal atoms or molecules find
their way into the cytoplasm? While no unequivocal answer can
be given, in most cases where the invading substance is not
destroyed or utilized, it would probably be lethal. Certain con-
stituents of venoms or toxalbumins like ricin, abrin, botulinus
toxin, seem to function directly or indirectly as catalysts* and to
produce extensive chemical breakdown entirely out of proportion
to their small mass. It is certainly reasonable to expect that in
some cases stranger molecules may produce effects which are bene-
ficial, either by modifying existing catalysts or by serving to create
new ones. From the standpoint of genetics the important ques-
tion is: Can these new catalysts be carried on by heredity? Ex-
perimental evidence is accumulating to show that they can, thus
establishing a physicochemical basis for a mitigated form of
Lamarckism, which has been taboo in biological texts and teach-
ings because of lack of experimental evidence.

Of particular interest here is the work on the ciliated protozoan
Paramecium aurelia by Professor T. M. Sonneborn of Indiana Uni-
versity, who was awarded the prize of the American Association for
the Advancement of Science on Jan. 1, 1947. One race of variety 4 of
this organism makes the fluid in which it lives poisonous for nearly
all other races of Paramecium, and is therefore known as a "killer";
but it is resistant to its own poison. The "killer" character is deter-
mined by a four-component system:

(1) a nuclear gene, K

(2) an active product of this gene

(3) a cytoplasmic unit, known as kappa

(4) a final poisonous product or substance, called paramecin
The paramecin produced by one "killer" race may kill animals of

another "killer" race; in one instance, two "killers" reciprocally killed
each other. At least one "non-killer" race was found resistant to the
paramecin produced by certain "killers"; but as a rule "non-killers"
are "sensitives" — that is, they are affected by the killer poison.

Though no gene or genes can alone initiate the production of

* Or catalyst inhibitors or "poisons".

170 LIFE: ITS NATURE AND ORIGIN

kappa, gene K mast be present if kappa is to be maintained and
multiplied in the cytoplasm, because if K is replaced by its allel k,
kappa disappears within a few cell divisions and the progeny become
permanently sensitive to paramecin. However, gene K cannot alone,
when introduced into a cell that has lost kappa, re-establish kappa
formation. But if a small amount of kappa is introduced into sensi-
tive KK stocks, then kappa is maintained and multiplied in all the
progeny. This Sonneborn terms "primer" action, and notes its
analogy to the finding of Cori in phosphorylase studies, that the pres-
ence of some glycogen is apparently necessary to the formation of
more glycogen. A reasonable but unproved explanation is that gene
K, modified by or under the influence of kappa, molds off or produces
something (molecule or molecular group) which serves as an enzyme,
or else that kappa forms a cytoplasmic catalyst, with some product of
K, the net result of the new catalyst area being the production of
paramecin and of kappa.

The macronucleus of P. aurelia is a compound nucleus containing
at least 60 K genes. Several experimental methods indicate that about
250 kappa particles exist in the cytoplasm of a "killer" cell; but there
appears to be much less paramecin than kappa. The paramecin is
released into the medium very slowly, at any stage of the five-hour
fission life cycle.

The rate of kappa multiplication varies in different stocks, and is
affected by conditions, temperature being important. When the
concentration of kappa is somewhat reduced experimentally, para-
mecin is no longer formed, but the cells remain resistant to its action.
Further reduction of kappa lowers resistance to paramecin; but as
long as a single particle of kappa remains in a cell containing gene K,
the concentration of kappa can be increased by appropriate conditions.
As kappa concentration increases, the sequence of phenotypic types
is reversed, sensitivity to paramecin disappears, and the cells become
resistant. With further increase in kappa concentration, production
of paramecin begins again.

On cell division, kappa is unequally divided, and the studies of
J. R. Preer show that this inequality corresponds precisely to chance
or random distribution of kappa at the time of fission. Referring to
the differences found in the Dionne quintuplets by J. W. MacArthur,9
J. Alexander stated:10 "The slight differences found in monozygotic
twins do not seem to be due to the precisely duplicated genes, but
rather to inequalities in the apportionment of the zygote cytoplasm
upon mitosis, involving unequal distribution of catalyst modifiers
between the cells, which later develop into separate individuals."
Sonneborn points out that the concentration of kappa is of the order
of magnitude of one particle per 1,000 ^3, which suggests that the
chemical laws of mass action, predicated upon probability calcula-

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 171

tions, may here be replaced by the laws of the action of single particu-
late units. And the formation of a new catalyst area can change the
whole course of chemical events.

The experimental facts indicate that gene K and kappa cooperate
in forming catalyst areas capable of synthesizing both kappa and
paramecin, and that this heritable result is not exclusively genie.

Results of experiments on the chemical production of mutations,
begun in 1940 at the University of Edinburgh, have recently been
released.11 Mustard gas, the diethyldichlor sulfide used in World
War I, produces heritable changes in Drosopliila and Tradescantia by
causing chromosome breaks and rearrangements, and genie changes,
in some respects like those produced by x-rays.12

Treatment with mustard gas produces a much larger percentage
of sex-linked lethals than does x-ray treatment, and also a much
larger percentage of "mosaics" among the mutated individuals. In
one striking case "a son of a mustard-gas-treated male was, both in
the gonads and in the soma, a mosaic for two different mutations of
the same gene, although it must be assumed that in the treated
spermatozoon each treated gene was present only once. An explana-
tion which seems particularly satisfactory in accounting for all these
observations is that the gene affected does not always mutate at once,
but may acquire a tendency to mutate which remains latent until a
later cell division. Support for this hypothesis was obtained when it
was found in several cases that the offspring of gonadic mosaics for a
mutation again were gonadic mosaics for the same mutation. In
these cases an induced specific instability seems to have been trans-
mitted from one generation to the next before giving rise to a stable
change. No parallel observations have been reported in literature
on radiation genics; but it seems worth noting that so-called unstable
genes, i.e., genes which tend to mutate repeatedly in the same direc-
tion, have been found several times in untreated material. Says
D. E. Lea,13 ". . . it is tempting to consider the possibility that one of
the means by which evolution adapts mutability to environmental
requirement is the achievement of a balance between the production
of mutagens and sensitivity to them."

While this experimental evidence of cytoplasmic inheritance
does not mean that any and all nongenic changes are necessarily
heritable, it demonstrates the principle and compels us to regard it
— to use a legal analogy — as permissive, though not mandatory
in function.

In his book "Hormones and Heredity" (London, 1921) J. A.
Cunningham suggested that the mechanism whereby "modifica-
tions produced in the soma by external stimuli could affect the

172 LIFE: ITS NATURE AND ORIGIN

determinants in the gametes in such a way that the modifications
would be inherited," involved the action of hormones; the latter
were defined as special chemical compounds which take the place
of the imaginary gemmules in Darwin's theory of pangenesis and
of the "constitutional units" of Herbert Spencer. In stressing the
view that the theory of the hereditary transfer of somatic modifica-
tions is not in conflict with the theory of genie mutations, Cun-
ningham wrote: ". . . there are two kinds of variation in evolution,
one somatic and due to external stimuli, acting either directly on
passive tissue or indirectly through function, and the other
gameto-genic and due to changes in the chromosomes of the
gametes which are spontaneous and not in any way due to modi-
fications of the soma. Adaptations are due to somatogenic modi-
fications, non-adaptive diagnostic characters to gametogenic
mutations. It is a mistake to attempt to explain all the results of
evolution by a single principle."

Professor W. H. Manwaring of Stanford University14 stated:
"These studies suggest a Lamarckian rather than a Darwinian
world, or at least a world in which both Lamarckian and Darwin-
ian evolutionary mechanics are operative." (This refers to his
review).

Henry Fairfield Osborn stated15 in the third of a series of
addresses on the origin of species, that the theories of Buffon
(direct action of environment), Lamarck and Darwin, usually
regarded as contradictory, are really complementary, for they all
turn on the question of inheritance or transmission of individual
adaptation, which may furnish the key to evolution. "On the
affirmative side paleontology proves in the long run of geologic or
secular time that both Buffon and Lamarck, as well as Darwin,
were right in their main conceptions: organs starved by unfriendly
environment finally disappear; organs which do not pay their way
or are starved by disuse slowly drop out of the germ-plasm; vitally
essential organs are either absolutely stable or progressive. Why
not therefore concede the truth of the great conceptions of Buffon
and Lamarck, even if immediate inheritance by the germ is dis-
proved in the great majority of cases? Why not concede the still
greater conception of Darwin, misled as he was to time by the
marvelously rapid evolution of the germ-plasm witnessed in
artificial selections?"

Professor Herbert S. Jennings16 in speaking of the interaction of
cytoplasm and chromosomes in genetics and in development, points

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 173

out that these two cellular divisions "are not separate in fact and in
substance, though they are often kept isolated in concept — to the
great detriment of sound understanding. There is a continual cycle
of interchange between them, a transformation of material from one
into the other . . . The cytoplasm is not merely passive; it actively deter-
mines what shall happen in the chromosomes . . . Every cell retains
all the chromosomal materials, but which of these materials comes into
action in each cell depends upon what cytoplasm is there present, as
well as upon the conditions under which the reactions occur . . ."

In the case of the killifish (Fundalus), A. Richards17 observed that
the condensed chromosomes become vesicular by taking in cytoplasmic
material and forming a vesicle hundreds of times the size of the orig-
inal chromosome. These swollen chromosomes touch, press together,
and form the nucleus. Then the vesicles discharge their content into
the cytoplasm, including great numbers of chromatin particles detect-
able by cytological methods. The condensed chromosomes for the
next cell division are formed from minute reserve parts of the large
vesicles. Jennings states: "The pictures that we see of the condensed
stages of chromosomes, at the time when they are undergoing division,
are most misleading if they are assumed to show the distinctive char-
acteristics of chromosomes. The chromosomes are active and change-
able; they continually operate on the remainder of the cell (which we
lump together as cytoplasm), visibly interchanging material with the
cytoplasm, altering it, differentiating it . . ." Professor E. G. Conklin18
summarized his similar observations on the common slipper-limpet
Crepidula thus: "One might speak of these changes in the nucleus as
systole and diastole, by means of which an exchange of nuclear and
cytoplasmic material is brought about." But it must be remembered
that the material discharged by the vesicles has been subjected to the
influence of the local catalysts, including the genes and the enzymes
arising from them.

Jennings then lists three classes of heritable modifications in pro-
tozoa: (1) degenerate changes induced by unfavorable conditions
acting for many generations; (2) acclimatization to high or low tem-
peratures or to injurious concentrations of chemicals (As, Sb, quinine,
methylene blue and various organic substances); and (3) alterations in
form and structure not involved in (1) and (2), which may be re-
tained for hundreds of generations. Referring to the work of G. F.
De Garis19 on Paramecium caudata through a long series of asexual
generations, Jennings remarks: "At every succeeding fission the orig-
inal cytoplasm is diluted to one-half, so that after ten generations it is
diluted to less than 1/1000 part, the remainder being new cytoplasm
produced by growth. Yet after ten generations the original cytoplasm
still has a marked effect on size. The original cytoplasm seemingly
must therefore have to some extent the power of reproducing itself

174 LIFE: ITS NATURE AND ORIGIN

in its distinctive nature, at the time that growth occurs. In this respect
it partakes of the character of a gene or genetic material, in that it
affects the character of the individuals and reproduces itself in some
degree true to type. But in time it is made over by the nucleus."

When a race of Paramecium averaging 198 microns in length was
mated with another true-breeding race averaging 73 microns, the in-
fluence of the cytoplasm was evident in one experiment for 36 gen-
erations, for only then did the descendants reach about the same size,
even though they all had the same chromosomal content. Referring to
experiments of V. Jollos,20 which indicate that such environmental
modifications as acclimatization may be inherited for as much as 800
generations, Jennings says: "If they are merely modifications of the
cytoplasm one might anticipate that long before so many generations
had passed the cytoplasm would have been made over by the nucleus,
and its modifications would have disappeared. Yet we do not know
that the time required for the nucleus to dominate the cytoplasm
would be subject to the same limits in all cases. The question whether
inherited environmental modifications are exclusively cytoplasmic, or
whether they affect the nucleus, the chromosomes, must be left open
for the present."

It is fortunate that heritable nuclear, genie, symbionic, and cyto-
plasmic changes are the exception rather than the rule, for other-
wise nature would present a confused Babel of bionts. Before
any change can be passed on by heredity, the catalysts or other
precursor units involved must themselves be able to run the
catalytic and chemical gantlet of the organism and not only sur-
vive but also be duplicated. Furthermore, the consequences to
the organism, stemming from these heritable changes must be
advantageous (and thus possible steps in evolution), or else harm-
less or not too detrimental.

As a counterbalance to the slight probability of the emergence
of a markedly advantageous heritable change, we must remember
that nature is continually conducting vast multitudes of experi-
ments of this kind, over endless eons, and under an enormous
range of ever-shifting conditions. But even where a newly devel-
oped individual is of a type capable of persisting and of dominat-
ing under conditions existing at the time of its emergence, it
would still have to face the possibility of being overwhelmed by
established forms and predators.

However, each new form of biont which becomes established
tends to add to the amount and especially to the variety of chem-
ical substances available to other bionts, either through the prod-

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 175

ucts of its metabolism or through its own body, living or dead.
In general, each higher form of life depends upon simpler forms
to supply it with essential molecules, either for the main mass of
its food (fats, carbohydrates, proteins), or for many trace sub-
stances (e.g., vitamins, minerals), largely needed to make up the
catalytic machinery of the body, whereby the food molecules are
molded into its own species-specificity through the analytic and
synthetic action of its own catalysts. All this shows the truth of
the French aphorism: "Rien n'est la proie de la mort; tout est la
proie de la vie." (Nothing is the prey of death; everything is the
prey of life.)

Apart from the obvious fact that the chemical nature of "food"
has thus an important evolutionary aspect,21 we may refer to
symbiosis and parasitism, in which bionts live in very close asso-
ciation. Many parasites (e.g., tapeworms) pass part of their life
cycles in intermediate hosts. The wood-eating termite would
starve to death on this diet, were it not for the fact that it harbors
an intestinal messmate (an endameba) whose catalysts can convert
the wood into substances which the termite can utilize as food.
Cleveland found that slight increase in oxygen pressure kills the
endameba without harming the termite, but the termite then
starves to death on a diet of wood.

Only recently (since about 1870) symbiosis was first discovered
in lichens, which consist of an association of a higher fungus with
a unicellular or filamentous alga. The fungus supplies water,
salts, nitrogenous substances and "lichen acids" which slowly at-
tack rocks, while the alga synthesizes carbohydrate; so that the
partnership can succeed where either member would fail. Not
only have lichens been "synthesized" from suitable fungus and
alga, but small lichen-thalli have been grown on nutritive solu-
tions in the absence of their algal constituent. The culture of
orchids from seed became possible only after it was found that in
nature a certain symbiotic fungus surrounds the seeds with special
moisture and other conditions. Similar is the case of trailing
arbutus, that delicate gem of the woodland in earliest spring.

Since there seems to be an ever-increasing amount of experi-
mental evidence that some non-genic heritable changes actually
are transmitted, we are justified in asking this question: How can
heritable factors, apart from genie and chromosomal changes,
enter into and affect the germ cells (gametes) through which
heredity is transmitted?

176 LIFE: ITS NATURE AND ORIGIN

A great variety of specific molecules and other particulate units
are carried throughout every biont by diffusion, convection and
circulation. In the course of time each cell, including the
gametes, will receive whatever of this molecular flotsam and jetsam
can enter into and endure in its cytoplasm, or else establish there
specific catalyst surfaces, so that among these entering molecular
or near-molecular units would be those that determine, or assist
in determining, differentiation. Apart from other evidence, the
fact that some differentiated cells have been found to breed true
in tissue cultures warrants the belief that specific tissues or organs
contribute to the molecular melee in the organism units capable
of determining the formation of their own specific type of cell.
On the other hand, de-differentiation may occur: heart cells tend
to breed true as heart cells, cancer cells as cancer cells, etc.

Since excessive use of a part or of an organ commonly leads to
its hypertrophy, this would tend to increase the total quantity of
hypothetical modifier substances emanating from such part or
organ, and would increase its equilibrium amount in the gametes.
This is a hypothetical physicochemical mechanism which might
in some cases lead to the inheritance of acquired characteristics
based on the use or disuse of parts.

Without suggesting a mechanism for their action, J. T. Cunning-
ham22 advanced a Lamarckian view involving hormones as active
factors in heredity. He pointed out that special glands are not essen-
tial for the production of these internal secretions; for his colleagues
at the University of London, W. M. Bayliss and E. H. Starling, had
shown in 1902 that the wall of the intestine produces the hormone
secretin which, carried by the blood, activates the pancreas to secrete.
Cunningham stated: "There is nothing improbable in supposing that
a tissue stimulated to excessive growth by external irritation would
give off special substances to the blood. We know that living tissues
give off waste products, and that these are not merely pure C02
and H20, but complicated compounds. The theory proposed by me
in 1908 was that we have within the gonads numerous gametocytes
whose chromosomes contain factors corresponding to different parts
of the soma, and that these factors or determinants might be stimulated
by waste products circulating in the blood and derived from the parts
of the soma corresponding to them. There is no reason to suppose
that an exotosis formed on the frontal bone as a result of repeated
mechanical stimulation due to the butting of stags would give off a
special hormone which was never formed in the body before, but it
would probably in its increased growth give off an increased quantity

GENETICS: THE HERITABLE TRANSMISSION OF CATALYSTS 177

of intermediate waste products of the same kind as the tissues from
which it arose gave off before. These products would act as a hormone
on the gametocytes, stimulating the factors which in the next genera-
tion would control the development of frontal bone and adjacent
tissues. ... If the factors in the gametes were thus stimulated they
would, when they developed in a new individual, produce a slightly
increased development of the part which was hypertrophied in the
parent soma. No matter how slight the degree of heredity effect, if
the stimulation was repeated in every generation . . . the heredity
effect would constantly increase until it was far greater than the direct
effect of stimulation."

Starling formed the word "hormone" from a Greek root mean-
ing "to stir up, or excite," and Cunningham uses the term in its
original meaning, which is lost sight of in speaking of "endo-
crines" produced by "glands of internal secretion." Certain sub-
stances, ordinarily regarded as waste products of cellular metab-
olism, are known to affect the activities of organs, and have been
called parahormones. Thus carbon dioxide activates the respiratory
center of the medulla and is administered with oxygen to avoid
respiratory collapse; and the normal heart-beat of some lower
vertebrates (e.g., sharks) seems to depend upon a certain concen-
tration of urea.

While much is known as to the effects produced by hormones,
little is known about the mechanism whereby these effects are
produced. It appears that a probable explanation in many cases
may be based on catalyst modification, including inhibitions and
the formation of new catalysts. Alteration in membrane perme-
ability is another factor, and from this many catalyst possibilities
might later emerge.

REFERENCES

1 Chem. Eng. News (1946) 24, 1369, Westinghouse Forum address.

2 Science, 66, 84-87.

3 See also Chapter 4 for the work of Dr. William J. Robbins (N. Y. Botanical
Garden) on the demands of molds for vitamins and similar trace substances.

*Zeit. physiol. Chem. (1932), 210, 33.

5 See P. Rothmund, "Photosynthesis," in Alexander's "Colloid Chemistry," Vol.
V, pp. 600-610.

eIbid., pp. 610-667.

7 See C. Correns, "Nicht mendelnde Vererbung," in Handbuch Vererbungswiss.,
Berlin, 1937.

8 "Heredity and Environment," 1919.

9 /. Heredity (1938), 29, 323-329.

10 "Colloid Chemistry," Vol. V, p. 573.

178 LIFE: ITS NATURE AND ORIGIN

11 C. Auerbach, J. M. Robson, and J. G. Carr, Science (1947), 105, 243-247.

12 The following also act as chemical mutagens; (CH2.CH2.S.CH2.CH2C1)20;
(CH2.CH2C1)3N; CHS.N(CH2.CH2C1)2. The last two compounds are known as
"nitrogen mustards," and represent a class of compounds being used in cancer
research.

13 "Action of Radiations on Living Cells," Cambridge University Press, 1946.

14 "Environmental Transformation of Bacteria," Science (1934), 79, 466-470.

15 Scientific Monthly (1926), 22, 185-192.

16 "The Cell and Protoplasm," Pub. No. 14, Am. Assn. Adv. Science, 1940, pp. 44-55.

17 Biol. Bull. (1915), 32, 249.

18 /. Acad. Nat. Sci. Phila. (1902), 12, 1.
19 /. Exptl. Zool. (1935), 71, 209.

20 Arch. Protozool. (1921) 43, 1; (1934), 83, 134.

21 See J. Alexander, Scientia, October, 1933.

22 "Hormones and Heredity," 1920.

Chapter 9

The Catalyst Entelechy in Differentiation and Morphogenesis

Facts may be recognized and expressed in language, without
being understood and explained by having their underlying
mechanisms made clear in terms of matter. The ever-wonderful
development of a human being from the then unknown fertilized
ovum is thus expressed in the 139th Psalm, entitled "God's
omnipresence and omniscience":

14. / will praise Thee; for I am fearfully and wonderfully
made; marvelous are Thy works; and that my soul knoweth right
well.

15. My substance was not hid from Thee, when I was made in
secret, and curiously wrought in the lowest parts of the earth.

16. Thy eyes did see my substance, yet being unperfect; and in
Thy book all my members were written, which in continuance
were fashioned, when as yet there was none of them.

Even after men had freed themselves from kingly and priestly
taboos, and began to use their God-given powers of reason and
ingenuity, it took centuries of patient study and experimentation
by many thousands of devoted seekers after truth to acquire and
to learn how to extend our present knowledge of the mechanism
whereby we are "made in secret and curiously wrought." Besides
the microscope, we now have many instruments such as the ultra-
microscope, the electron microscope, spectrographs and spectro-
meters, with whose aid we can peer into "the lowest depths of the
earth" to try to learn what goes on there. And from chemical
behavior we deduce the activities of unseen atoms and molecules.

The establishment of important facts, such as the isolation,
identification, and often the synthesis of individual chemical sub-
stances, as well as the demonstration of the effects they produce,
has been the result of much work that fills us with wonder and
admiration. But all will end in verbiage unless we carry through
and explain how "organizers" organize, how "evocators" evoke,
and how "inductors" induct.

179

180 LIFE: ITS NATURE AND ORIGIN

The notion that many happenings in morphology and dif-
ferentiation are understandable on the basis of the direction of
chemical change by specific catalysts existing initially in the fer-
tilized egg, or formed or modified in the developing embryo,
seems consonant with the experimental data. The formation of
various structures — catalysts, cells, organs, tissues — of specific
nature and at definite times and places in the developing or-
ganism depends upon the formation and assembly of a wide
variety of specific chemical molecules at suitable rates, in suitable
ratios, and at suitable times and places. Apart from formation
in situ, the assembly and distribution of small material units is
controlled by such factors as Brownian motion, convection, cir-
culatory systems and especially by selective adsorption and dif-
ferential diffusive mobility. But catalysis is the basic mechanism
whereby are produced the particular chemical units which under-
lie metabolism, development and growth. Catalysis makes these
descriptive terms mechanistically and materially intelligible.
Without a mechanism they are symbols for unknowns.

When we consider the numerous catalysts and chemical changes
dominating what was supposed to be the comparatively simple
breakdown of glucose by yeast into alcohol and carbon dioxide,
and recall that catalysts may synthesize as well as decompose mole-
cules, we may well stand aghast at the catalyst-based chemical and
physico-chemical complexities emerging in a single cell. Further-
more, when we remember that most of the happenings observed
and recorded by biologists lie at or above microscopically visible
structural levels, it is astonishing to see the wealth of information
that has been deduced from critical experiments, which often
reach far below what is seen. For example, the presence and
location of sulphydryl groups ( — SH), which among many other
potencies affect the activity of many proteases (catalysts directing
protein formation, alteration or destruction), may be made evi-
dent by the nitroprusside test. Glutathione, important in growth
and containing the — SH group, is thus revealed to be present in
the blastoderm* of the chick, but not in the yolk or the white of
the unincubated egg.

Since we are here maintaining the view that embryological
development and differentiation, in common with other life proc-
esses, are directed by what may be called a material entelechy

* Blastoderm: The flat sheet formed by the embryo's cell-layers when cleavage is
discoidal (Needham).

THE CATALYST ENTELECHY IN DIFFERENTIATION 181

working largely through the direction of chemical change by
catalysis, we must consider what material equipment the fertilized
ovum carries with it from its parents. In referring below to what
is ordinarily found, we must not forget that in nature curious
and unusual things may develop, if they are physically and chem-
ically possible.

This material entelechy is something utterly different from the
metaphysical entelechy of Driesch, referred to by Professor Ed-
mund W. Sinnott of Yale University.1 After pointing out that
"we have been confusing analysis with solution," and that "it
is not an understanding of units we now seek, but of unity," he
states that some biologists "have needed little encouragement to
run after the strange gods of mysticism and metaphysics and have
set up in their midst the golden calf of entelechy. Even those
who remain in the ranks of the orthodox speak the unfamiliar
language of holism, organicism, metabolic gradients, allometry,
organizers, morphogenetic fields, gestalten and other words out-
landish in the ear of analytical biology and which for the most
part are merely the terminology of enlightened ignorance." Like
views are reiterated in his Presidential address before the Amer-
ican Society of Naturalists,2 in which he states: "Organic form is
the external manifestation of this underlying biological organiza-
tion . . . This integrated and organized behavior, this unity in
the midst of diversity, is the most distinctive feature of life in
general. What the mechanisms are which underlie it and what
is the physicochemical basis by which it is established and persists
are deep problems which long have vexed students of develop-
ment." He concludes: "Let us try, in these days of intense spe-
cialization, to cultivate more of the catholicity of the earlier
practioners of our science, and especially to implant in our stu-
dents an interest in and respect for all the branches of biology.
From somewhere in this wide field — perhaps from where we
least expect it now — may come the next new unifying idea which
will show how system relates to substance and how life depends
on both."

In the unfertilized ovum, the maternal chromosomes with their
genes and aura of adhering substances, are generally afloat in a
relatively large pool of maternal cytoplasm. The sperm which
enters and fertilizes the ovum brings with it the paternal chro-
mosomes with their genes and adherent material, and a much
smaller volume of apparently condensed paternal cytoplasm which

182 LIFE: ITS NATURE AND ORIGIN

nevertheless is of great importance when the fertilized ovum or
zygote develops into an individual — a process dubbed ontogeny.

The actual fertilized ovum in the hen's egg, with which we are
most familiar, is also very small, the main mass of the egg (its
yolk and white) consisting of water and nutrient material suffi-
cient to enable the germ to develop into an individual when the
egg is cast off or "laid" by the hen. Such a self-contained egg is
termed cleidoic (closed box), for it has within its shell everything
it needs, except some atmospheric oxygen which can diffuse in,
to supplement the air bubble supplied to the egg by the hen.
But in some of the lower animals (e.g., sea-urchin, squid, dogfish)
the developing embryo absorbs much of what it needs of water,
salts, and probably trace elements, from seawater. Mammalian
embryos develop a sucker-like attachment (the placenta), and live
and grow practically as parasites on the wall of the mother's
uterus.

The first mammalian egg observed was that of a dog, by K. E.
von Baer in 1827.3 Mammalian eggs are almost microscopic, rang-
ing from about 70 to 85 microns in rodents (rats, mice, guinea
pigs) to about 140 microns in horses, dogs, sheep, goats, pigs,
monkeys, apes, man, and whales. Yet this tiny spherical unit, say
one-tenth of a millimeter in diameter, contains determinants
which enable it regularly to develop, under suitable conditions,
into its predestined individual. How is this miracle so regularly
accomplished?

As an approach to this problem, let us first estimate what the tiny
zygote means in terms of molecules, figuring molecular dimensions
to be 0.2 to 5.0 millimicrons, and the zygote as a sphere whose diameter
is 100,000 millimicrons. The volume of this sphere (v = ^Trrs) is
approximately 262 xlO9 m/x3, that is, 262 million million cubic milli-
microns. Since a considerable percentage of the molecules are small
ones (water, salts) there is ample room, in addition to the chromosomes,
enzymes and other inclusions, for many million million highly specific
organic molecules supplied by the mother and the father through the
ovum and the sperm. Therefore there is plenty of space in the zygote
for an enormous number and variety of catalysts, and of specific mole-
cules to serve as modifiers, prosthetic groups and carriers to form, as
cell duplication proceeds and as new substances are produced, new
catalysts with new chemical ambits.

To envisage what we desire to explain by the catalytic direction
of chemical change, consider as one example the following dia-

THE CATALYST ENTELECHY IN DIFFERENTIATION

183

s:

184

LIFE: ITS NATURE AND ORIGIN

grams showing in part what is seen when a zygote develops into
an individual. "Everyone has been impressed by the miraculous
transformation of the sticky white and yellow mass of hen's egg
into a fully dressed, befeathered, respectable chick, all in 21 days.

ALLANTOIS

AMNION

/

ALBUMEN — — YOLK SAC

5 DAYS

ALLANTOIS

AMNION

ALBUMEN YOLK SAC

10 DAYS

BLASTODERM
I

AIR-CELL

SHELL MEMBRANE

Figure 29. Domestic fowl's egg and its development. Beginning of alimentary
tract, 18 hours; vertebral column, 20 hours; nervous system, 21 hours; head, 22 hours;
blood island-vitellin circulation, 23 hours; eye, 24 hours; ear, 25 hours; heart beat,
42 hours; amnion, 50 hours; legs and wings, 63 hours; allantois, 70 hours; reproduc-
tive organs, 5th day; feathers, 8th day; beak turns toward air cells, 17th day; yolk sac
begins to enter body cavity, 19th day; yolk sac completely drawn into body cavity,
20th day; hatching of chick, 21st day. (Courtesy A. L. Romanoff, Cornell Exp. Bull.
205, 1931 and 1936). (From Brody's "Bioenergetics and Growth.")

The original egg cell must have travelled at a dizzy pace to build
up so complex a mechanism — probably exceeding in complexity*
the astronomical wonders with their galaxies and supergalaxies."4
The following epitome of the development of a mammalian egg
is more detailed.

* This, of course, applies to structure levels where stars may be considered as units.
On this relatively tiny satellite (the earth) of a medium size star (the sun), untold
numbers of similar miraculous transformations proceed daily. J. A.

THE CATALYST ENTELECIIY IN DIFFERENTIATION 185

Though the first few cleavages of the zygote do not greatly
increase the size of the cell group, differentiation is already mani-
fest at the 16-cell stage, distinction being evident between the
part which later implants the egg on the maternal tissue, and the
trophoblasts, the cells later to form the fetal membrane, which
divide more rapidly and therefore are smaller than the other cells.
Next is seen the formation of the blastocyst, a vesicle which cups
into a hollow sphere that distends with fluids possibly secreted by
the trophoblasts; and now the cell mass visibly enlarges.

The outstanding feature of blastocyst development is the ab-
sorption of tremendous quantities of water. C. B. Davenport5
estimated that after six weeks the human egg weighs about a
gram, nearly 500,000 times its initial weight; and 98 per cent of
the weight increase is water. The blastocyst develops the embry-
onic envelope and the placenta, the latter really special tissue
formed where the circulatory systems of embryo and mother come
into contact. The development of the placenta in mammals has
been shown by Pincus to be controlled by progesterone, the corpus
luteum hormone.6

Following attachment of the egg to the placenta, formation of
the embryo continues by segmentation and differentiation of the
inner cells; and the amnion and yolk-sac vesicles develop and
flatten together to form, with an intervening layer of cells (meso-
blast), the triple-layered germ disc which comprises the embryo.
In man this occurs about the third week, and by the end of the
second month the embryo (in the case of man) is recognizable as
human. Eyes, mouth region, and limb buds may be seen by the
fourth month and the organs are formed the month before. The
"ground plan," as Brody puts it, "is laid very early in life and
rounded out later through enlargement and remodeling of the
parts. Age changes in shape are due to differences in growth
rates of the constituent parts. There is an orderly sequence or
gradient1 in organ formation. The head has precedence in de-
velopment over the tail end, and so on in cephalochordal sequence
for the other organs. The sequences may be associated with
organizer and hormone action."

How is all this orderly development to be explained? The
view suggested by W. Roux in 1883 that mitotic division of the
zygote establishes development by a qualitative distribution of
the nuclear germ plasm was a great advance beyond the medieval
notion that a homoculus or "little man" existed initially in the

186 LIFE: ITS NATURE AND ORIGIN

egg and simply grew larger. Experimental confirmation of Roux'
view seemed evident when, in 1888, he reported that if one of the
first two blastomeres in the developing frog's egg was killed by a
hot needle, the remaining cell developed only a half-embryo.

But in 1891 H. Driesch separated the first two blastomeres of a
sea-urchin's egg and was astonished to find that each cell formed
a normal though smaller gastrula and larva. The next year he
found that even in the four-cell stage, the single cells could pro-
duce complete individuals, as could also two eggs fused into each
other. It thus became evident that, initially, what was to happen
to any part of the egg was undetermined, even though if undis-
turbed it had a "prospective significance" (prospektive Bedeu-
tung). The fact that any part of the egg could be made to de-
velop quite differently from its normal expectation was due to
its multiple potency (pluripotency), and the term "prospective
potency" (prospektive Potenz) covered the total possibilities of
the part, irrespective of what might happen to it in any particular
experiment.

Driesch was so impressed on finding in the egg this mysterious
ability to carry on, for which no material explanation seemed pos-
sible, that he invoked a metaphysical vital force or entelechy, to
account for it, and actually abandoned experimental science to
follow philosophical speculation. Notwithstanding this, we be-
lieve that the directing vital force is real enough, and that it is
explainable on the basis of comparatively simple physicoehemical
principles, chief of which is catalysis.

Comparative Experimental Embryology

Comparative experimental embryology, as contrasted with ob-
servations of naturally developing morphology, received a great
stimulus about 1897 when Gustav Born observed the remarkable
healing powers of amphibian embryos, and devised experimental
techniques which his early death prevented him from utilizing.
Fortunately, H. Spemann (Nobel Prize, 1935) made brilliant ex-
tensions of this work. With newts it was found that the develop-
mental fates of most embryonic regions are not irrevocably
determined until after a certain stage of gastrulation. Thus if a
bit of presumptive tube material from one embryo was trans-
planted to the presumptive gill region of another embryo, it
developed into gills, not neural tube. Presumptive skin, if trans-
planted into another embryo at a suitable region in what would

THE CATALYST ENTELECHY IN DIFFERENTIATION 187

become nerve tube, would develop into brain or spinal chord.
That is, up to this stage in gastrulation, the regions are undeter-
mined and develop in step with their new actual surroundings
(ortgemdss), and not according to what their natural undisturbed
position would have made of them.

Gastrulation, however, ends this plasticity and irrevocably de-
termines the fate of each part, which can then undergo only its
own special type of development, even if grafted on to another
embryo. That is, the bit of transplanted tissue now develops ac-
cording to its self-contained possibilities and its place of origin
(herkunftsgemass), and not according to its new place of growth.
Thus an eye region will develop an eye, even though the eye may
point inward. As Needham puts it,* the invisible process of
determination has ushered in a new period of self-differentiation,
in which the embryo has become a mosaic of irreplaceable regions,
similar to the development of certain eggs ("mosaic eggs"), which
never manifest a period of plasticity or pluripotency.

But one particular region in the amphibian embryo is much
less plastic than others — the dorsal lip of the blastopore which
has arisen from the grey crescent and will eventually form the
mesoderm, notochord, somites, etc. A piece of this region, when
grafted into another embryo in the blastula or early gastrula stage,
will cause, direct, or induce the nearby host tissues to form a
secondary embryo, including nerve tube, brain, eyes, ears, somites,
notochord, etc., irrespective of what might have developed if no
transplantation had been made. So Spemann called this fate-
determining portion of the blastopore the organizer (in German
organisator).

Later it was found that local developments in already deter-
mined regions, e.g., the induction of a lens from the ectoderm
by the eye-cup, were dominated by local inductors. Spemann
therefore (1924) termed these secondary organizers. Thus, in the
case of the eye, if the dorsal ectoderm had not first been stimu-
lated by the "grey crescent" region, no neural tube and therefore
no eye-cup would have been formed. So the bit of living tissue
which heads what Needham terms "the heirachy of organizers in
animal development," was called by Spemann the primary organ-
izer, while organizers acting at later successive stages are secon-
dary, tertiary, etc. (see Figure 30).

* Needham suggests the following English equivalents: neighborxvise for orts-
gemass; selfwise for herkunftsgemass.

188

LIFE: ITS NATURE AND ORIGIN

Then it was found that a dead tissue, a chemical fraction or
a substance of known constitution could serve as an inductor;
and J. Holtfreter8 found that certain tissues which when alive did
not induce, acquired this power after being boiled. The term
inductor is therefore much broader than organizer, which is
limited to living tissue. The chemical substance emitted by an
organizer and responsible for all or part of its morphogenetic
stimulus was termed by Needham an evocator; its action is evo-
cation.

Gastrula invagination

Organisation centre
/v

SZ

r.

Head-organiser"

' Tail-" or " Trunk -organiser '

Head endodenm

Head mesoderm

r

Notochord

Somites

Fore-brain Mid-brain Hind-brain

Gills Mouth Teeth
opening

r

Side-plate
mesoderm

"N

Gut lumen / Neural tube

Eye-cup Ear-vesicle Balancer Spinal ganglia

and mesenchyme

Frontal Nasal
glands grooves

Lens Ear-capsule Placodes Dorsal fin

Cornea Tympanic
membrane

Ectodermal
mesenchyme

Skin Limb buds

Figure 30. The succession of inductors of second and lower grades. (From Need-
ham's "Biochemistry and Morphogenesis," Cambridge University Press, Cambridge,
England, 1942.)

But it has been found that stimuli of this kind will be ineffective
unless the tissues on which they act are properly receptive. This
state of reactivity is known as competence? Competence and organizer
activity are not retained indefinitely, but may arise and fade away at
different times; however the latter appears to begin sooner and to
persist longer. Needham states9a that no tissue is known which
possesses competence but no evocator.

While the terms "competence," "organizer activity," "morphological
stimulus" express the facts, they fail to give any inkling of the opera-
tive mechanism, which we believe is more nearly approached by the
several catalyst mechanisms mentioned below. Thus a tissue may be
"competent" to supply a carrier for the prosthetic group of an
organizer, or vice versa; and these two units may form a specific and
active catalyst or enzyme, providing that all conditions (e.g., pH,
absence of inhibitors) are favorable. If competence involves, for
example, the presence of a labile but powerfully adsorbent protein

THE CATALYST ENTELECHY IN DIFFERENTIATION 189

carrier, slight change in local conditions may incapacitate the carrier;
or adsorption of some diffusate may block it. Then even a steady
supply of prosthetic group molecules, from the more stable catalytically
functioning organizer, would fail to form the enzyme normally ex-
pected. Experimentally, competence would disappear.

By implanting the embryonic dorsal lips of a toad (Bombinator)
into the blastococle cavity of a newt (Triton), Geinitz10 obtained
inductions, thus proving that the primary evocator is not species-
specific. Subsequently many other mixed implantations led to success-
ful inductions, e.g., chick in newt, (Triton), chick in rabbit, rabbit in
chick, zebra fish (Danio rerio) in newt (Triturus torosus), lamprey in
newt (Molge). Then Holtfreter11 made the surprising discovery that
the evocator exists not only in the developing embryo, but is also
present in all adult tissues of all family groups (phyla). Tests included
tissues from two worms, two molluscs, three insects, a crustacean, two
fishes, three amphibia, a reptile, two birds, two mammals, and man.
Some of these adult tissues manifested inductive capacity without
special treatment (e.g., boiling, protein denaturents). Even pieces of
the coelenterate Hydra viridis, which develops no neural axis, showed a
feeble but positive inductive effect on amphibian blastoceles. It has
also been reported12 that implantation of blastomeres from the four-
cell stage will induce a neural tube in a competent (or receptive)
ectodermal ball.*

Needham believes that the evocator exists in masked or inactivated
form in all parts of the embryo except in the organizer region. Mask-
ing and inactivation are terms which express results, not mechanisms;
but they may be the consequences of the adsorption, or the aggregation,
of specific substances which would thereby become incapable of diffu-
sion, until they were eluted, or deflocculated as explained below.
Such specific substances might then exhibit electronic fields having
catalytic power, or they could then serve as units needed to complete
such fields. Adsorption or chemical fixation of specific units may also
result in inhibition, masking or inactivation of the adsorbent or the
fixing units.

O. Mangold and H. Spemann13 found that in the course of the
determination and histological differentiation of the neural tube,
it develops the power of inducing another neural plate when
implanted into the blastocele cavity of another embryo (termed
homoiogenetic induction). As Needham9a states: "Its cells acquire
induction power, and in later development the evocator appears

* A dispersion of 7-day chick embryo extract in Tyrode solution produces induc-
tions most nearly approaching those of a living amphibian organizer. To Dr. Lillian
Baker of Carrel's laboratory fell the main task of keeping alive the bit of chicken
heart in a continually renewed chicken embryo juice medium.

190 LIFE: ITS NATURE AND ORIGIN

free in all tissues." This is readily understandable on the basis
of the catalyst mechanisms discussed below. Needham also points
out many resemblances in behavior between the primary organ-
izer and the plant hormones, auxin and "bios," which also can
exist in "bound" condition, show no species-specificity, and are
"unmasked" subtly. He also remarks that the retort of Prof. W.
Lash Miller to critics of Miller's and other early work on "bios",
"is not without moral for embryologists." Miller said: "All those
who say, 'No doubt some chemical in the wort makes all the dif-
ference, but it need not be Bios', have qualified to join the Last
Ditch Bacon Club, which holds that Shakespeare's plays were
written, not by Shakespeare, but by some other person bearing
the same name."

The Chemical Nature of the Primary Organizer

By use of various solvents and precipitants, fractions acting as
organizers have been prepared; but as their inductive capacities
vary with the treatments, it may be that the organizer consists of
more than one substance or else becomes altered or broken down
in the separation process. It seems to be of steroid nature, a view
supported by the work of Waddington, Needham and co-work-
ers.14

L. G. Barth15 obtained excellent inductions of brain tissue by
implantation of cephalin prepared from mammalian brain. Then
Fischer and collaborators16 obtained inductions of neural tubes
by implantation of thymonucleic acid and of adenylic acid derived
from muscle. Later they found both purified and synthetic oleic
acids to be effective, as well as linolenic and octadecenic acids
and nucleo-protein from calf thymus; so they believed that acid
stimulation is responsible, a concept which the buffer action of
cell groups (tissues) renders most indefinite.

Methylene blue in high dilution causes induction.17 Thus a
piece of ventral ectoderm isolated from the gastrula and cultured
two days in M 10 5 methylene blue nutrient induced a large brain
in a host, and being competent, became neuralized itself. A simi-
lar isolate became neuralized by longer cultivation in methylene
blue medium. Histochemical tests revealed in the gastrula ecto-
derm (the presumptive mesoderm and presumptive neural plate)
a substance termed "plasmogen," later found to be a phosphatide
in which aldehydes of higher fatty acids are combined with glyce-
rol, phosphoric acid and amino-ethylalcohol; it is related to the

THE CATALYST ENTELECHY IN DIFFERENTIATION 191

important cytoplasmic nucleotides and shows the Feulgen reac-
tion.

Woerdeman18 observed a sharp disappearance of glycogen from
the dorsal lip during invagination. Now it had been shown by
Willstatter and Rhodewald19 that two forms of glycogen exist in
the cell, one readily soluble (lyoglycogen) the other comparatively
insoluble (desmoglycogen); and it was found that both of these
could induce neural tubes, because they contain, in adsorbed
state, some ether-soluble material in amounts so small that after
50 hours' extraction in a Soxhlet apparatus the solution, on
evaporation, left a scarcely visible residue. Yet this trace material
was a potent inductor.

The view here being maintained is that the mechanism whereby
an undifferentiated (neighborwise) group of cells becomes con-
verted, irreversibly as a rule, into a differentiated (self-wise) group,
is a transmissible, i.e., cellularly heritable, change in biocatalysts.
This leads to a change in chemical output having physiological
and morphological consequences. Similar, but progressively more
specific and limited catalyst changes determine or are associated
with the formation, activity and location of secondary, tertiary
and subsequent organizers, until the various structural fields ex-
haust the existing possibilities and enter the adult stage of equi-
librium. That the equilibrium is a dynamic one, at least in some
respects, is shown, e.g., by the growth of skin, hair and nails, the
healing of wounds, and the development of abnormalities such
as tumors and acromegaly.

How do there arise in a cell new or changed catalysts which
are transmissible to a daughter cell upon cell division?

Nature will, no doubt, utilize somewhere every possible effec-
tive mechanism, and no limitations on nature are suggested in
the following discussion of what appear to be the principal mech-
anisms:

(1) Gene mutation

(2) Gene modification

(3) New catalyst formation

(4) Deflocculation and elution

Before considering these possibilities further, it should be
pointed out that cellularly heritable change seems to be a basic
factor in the following:

(A) The "Anlagen." An Anlage is a cell group which develops
into a certain organ, e.g., liver, heart. Though not always dis-

192 LIFE: ITS NATURE AND ORIGIN

tinguishable in early stages, these cells tend to breed true in tissue
culture.

(B) Morphogenetic fields or gradients. The field is an ordered
pattern of instabilities set in a cellular matrix.20 The field effect
results from an equilibrium position, and the term gradient
stresses the increase or decrease of field potency from one point or
pole to another.

(C) Individuation, the field forces which render asymmetrical
the neural axis (arising from the chemical stimulation of the evo-
cator) by differentiating head end and tail end.

Needham9a says that "individuation is one of the most difficult
problems confronting embryology today . . . the possibility is
by no means excluded that other chemical substances may be at
work in the formation of the normal neural axis besides the pri-
mary evocator. The existence of second grade inductor sub-
stances is, of course, beyond doubt. . . . But we may also find it
worth while to distinguish between substances which stimulate
tissues to form an organ (inductors) and substances which modify
in various ways the shape of organs so induced. If such sub-
stances exist, it is at any rate clear that the position in which they
are normally liberated is so exactly controlled by the individua-
tion field of the inducing tissues that the regional correspondence
of inducer and induced is secured. Waddington21 has discussed
the possible existence of these substances or Eidogens in a short
review. The important thing which head-organizer does as op-
posed to tail-organizer is to modify the cross section of the neural
tube to form a brain rather than spinal chord. Inductors and
eidogens would thus be the mechanism by which the individua-
tion field of the inducer controls that of the induced."

This last statement follows the very common but erroneous notion
that the demonstration of chemical compounds, and even their isola-
tion, complete analysis and synthesis (though all this is of primary and
vital importance) make clear the mechanism by which they act. For
example, the "bios" problem was under attack for many years before
Professor F. Kogl (Utrecht) in 1936 isolated biotin, which noticeably
affects the growth of yeast in dilutions of one part in 400 billion. Its
structure was unravelled by K. Folkers and V. du Vigneaud,22 and
biotin itself was successfully synthesized in the laboratories of Merck &
Co.23 But this admirable work of itself does not demonstrate the
mechanism by which biotin acts. It seems, however, that individua-

THE CATALYST ENTELECHY IN DIFFERENTIATION 193

tion and other Gordian knots of embryology may be cut by the versatile
sword of a physico-chemically dominated catalyst entelechy.

We now consider the four classes of transmissible catalyst
changes before mentioned.

(1) Gene Mutation

Professor Richard Goldschmidt devotes a large portion of his
book "Physiological Genetics" to "The Mutated Gene and the
Potentialities of Development." At the outset he states:

"One of the basic facts of genetics is, then, that the action of the gene
in controlling the development of hereditary traits cannot be studied
directly but may only be extrapolated from the knowledge of the action
of a mutant gene: the existence of the normal or +-gene is only inferred
from the existence of a mutant allelomorph showing Mendelian be-
havior. The action of the mutant gene is a different one from the
assumed action of the +-gene; i.e., the mutant gene must control or
produce a deviation in a series of developmental processes leading to
the visible character. Development ... is ... a process of extraor-
dinary precision . . . the possibilities of changing the details of
developmental processes without injuring the proper cooperation of
those processes are rather limited. . . . But certain processes may be
changed without deleterious consequences; and if this is done by a
genetic change, we call it a mutation."

Professor Theodosius Dobzhansky24 states: "For the time being the
term mutation subsumes a variety of phenomena. In a wide sense,
any change in the genotype which is not due to recombination of
Mendelian factors is called a mutation. In the narrower sense, it is
a presumed change in a single gene, a Mendelian variant which is not
known to represent a chromosomal aberration."

From our point of view a gene mutation is an intraparticulate
change (chemical or physical) which results in outwardly directed
changes in the gene's electronic fields of force, sufficient to alter
its catalytic activities. Conceivably, this could be brought about
by intramolecular change, by a change in molecular orientation,
or by electroversion.25 Where a genie unit (molecule, macro-
molecule, or aggregate) changes its contacts, as in cases of chromo-
somal translocations, inversion, deletion, or crossing-over, a new
catalytically effective surface may be formed at the new zone of
contact with other genes or with the milieu, as the case may be.
The so-called "position effect" in genetics can be thus accounted

194 LIFE: ITS NATURE AND ORIGIN

for. It is a question of language as to whether this is to be called
a mutation — in physical effect it may be.69

As far back as 1903, H. Devaux26 found that, when a lens of molten
fatty acid (stearic) was allowed to chill on a water surface and was
then carefully dried, the top surface of the lens which had set in con-
tact with air was water-repellant (hydrophobe) because of the out-
wardly directed hydrocarbon groups; whereas the bottom of the lens
could be wet, because there the water-loving (hydrophile) COOH
groups were outwardly directed. Work on surface phenomena by Sir
W. B. Hardy, W. D. Harkins, I. Langmuir, N. K. Adam, The Svedberg
and many others indicates how potent may be slight changes in pH,
trace substances, etc., in affecting the nature of a surface, even though
nothing or the merest trace be added directly to it.

The publication (1927) by H. J. Muller27 of work showing that
both gene mutations and chromosomal changes can be brought
about by x-ray and other short-wave irradiation* exerted a pro-
found effect on genetics and particularly on ideas regarding mu-
tation. While mutations produced by x-rays appear to be like
those which occur spontaneously, the mutation rate is greatly
increased — about 200 times in some cases. Many species of plants
(from fungi to flowering plants) and animals (from protozoans to
mammals) have been heritably changed, and recently a filterable
virus. Cosmic, solar, and telluric (via uranium or thorium) ra-
diations are possible factors demanding further investigation.

In a recent review,28 Muller states: (1) "As to the mechanism of
production of those radiation mutations which affect individual
genes or narrowly circumscribed chromosome regions, the most
important fact that has come to light is the dependence of a given
mutation upon a change that was initiated in a single individual
atom, by its ionization or other excitation." (2) Structural changes
occur in the chromosomes because of breaks in the chromatin and
a two-by-two fusion of the ends derived from different breaks.

Genes at the new junctions or new free ends of chromosomes
often show "position effects" probably due, as stated above, to
the formation of new or modified catalyst fields.

In his argument that the individual genes as separate units do
not exist, R. Goldschmidt29 states that "many effects that originally
were regarded as due to gene mutation have turned out to be
position effects of rearrangements." Assuming "that the whole
chromosome is a large chain molecule of complex arrangement,"

* Professor Muller (Indiana Univ., Bloomington) received the Nobel prize in 1946.

THE CATALYST ENTELECHY IN DIFFERENTIATION 195

he states: "All points taken together suggest strongly that the
chromosome is the actual heredity unit controlling the develop-
ment of the Wild type, that purely steric changes30 at the indi-
vidual points of its length produce deviations from the Wild
type which may be described as mutations, even as point muta-
tions, though no actual Wild-type allelomorph and therefore no
gene exists." "If the chain is intact, and each residue is in its
proper steric position, the catalytic processes dependent upon
this chain molecule occur in a way that leads to what is called the
Wild type. Any change in the chain, however, of whatever type,
may disturb the interplay of the catalyzed reactions, and a devia-
tion occurs which is called a mutation." The final words of his
book are: "It remains for the physico-chemist to decide whether
or not the new model could also take care of the independent
catalytic actions of what was considered to be a gene."

The structural and mechanically operative nature of the
chromosome is not made clear, nor is it fairly expressed by the
words "a large chain molecule of complex arrangement." Work
with the various textile fibers31 indicates that in them there are
many structural levels above the macromolecular chains, and that
these chains form bundles which in turn are bound into still larger
micells, probably in part by the cohesive action of adhering sub-
stances and by interpenetrating fibrils. Whatever the structure
of the chromosome, it seems to be more complex than a simple
protein chain molecule of the nature described by M. Bergmann,
even though many such molecules may be in the chromosome.
Goldschmidt's abandonment of the gene is rather verbal than
factual, for even if considered as a side-chain in a macromolecule,
it is still there as a specific atomic complex. His views have been
adequately critized by Dobzhansky.32

It is, however, encouraging to see that so eminent a biologist
as Goldschmidt appreciates the biological importance of catalysis,
even though his language seems to limit it to the gene. In deal-
ing with embryological questions he fails to invoke catalysis. His
quandary regarding the position effect of rearrangements is readily
clarified by the fact that the genes, as well as many other biological
units such as the enzymes, exert their specific catalytic effects be-
cause of their outwardly directed electronic fields, and the ques-
tion of importance is the nature and directive power of these
fields rather than the terms we use to describe the units which
establish the fields. Thus three units CAT would exhibit dif-

196 LIFE: ITS NATURE AND ORIGIN

ferent electronic fields if rearranged into ACT; and this would be
true whether the letters represented atoms, radicals, molecules,
macromolecules, or even larger units.

(2) Gene Modification

If a gene group adsorbs a particulate unit, such as an atom, ion,
or molecule, and the gene is able to duplicate itself so as to main-
tain the new specific catalyst surface consequent upon the adsorp-
tion, we have the same effect as a gene mutation. Something
allied to this occurs when a carcinogen like 3:4-benzpyrene acts
to make cells heritably cancerous, for the carcinogen itself is not
reproduced, though the cell culture continues cancerous.

Even if a gene that has been modified by adsorption were to
duplicate itself in unchanged form, the new catalyst area could
be maintained in the cell clone* providing:

(a) the new catalyst surface could direct the formation of par-
ticles of such specificity that, when adsorbed by the unmodified
gene surfaces appearing on gene duplication, the modified gene
surface (with the modified electronic field) would be formed.

(b) the food, milieu, or the activities of other catalysts furnished
a continuous supply of the specific modifying particles.

The ability to adsorb specific particles previously not adsorb-
able might be one of the consequences of a gene mutation; the
specific effect would not be produced in the absence of the specific
adsorbable particle.

(3) New Catalyst Formation

The attachment of a prosthetic group to a suitable carrier may
form a specific catalyst surface, which may serve as a mold or
template from which are produced more areas of like electronic
contour, to serve in turn as prosthetic groups for additional
catalyst areas having a specificity like that of the first-formed
catalyst unit.

We pointed out in the chapter on immunology what happens
when a piece of tin-foil is pressed against a newly-minted coin:
the surface of the foil which lies next to the coin acquires the
reverse impression of the coin surface, but the top surface of the
foil forms a duplicate impression of the coin surface. In like
manner the thin molecular "plaque" formed against a new catalyst

* A clone (also spelled clon) is a group of cells having a common ancestor, which
they generally resemble. The term is derived from the Gaelic klonn, a twig, and is
allied to the Scotch word clan.

THE CATALYST ENTELECHY IN DIFFERENTIATION 197

area has essentially the reverse electronic impression on its near
side, but a duplicate impression on its off side. If on leaving the
molding surface the plaque is adsorbed by some other surface
(which may be a particulate carrier) in such manner that its off
side faces the milieu, we may have a workable duplication of the
original catalyst area. (Adsorption the other way round may
lead to antibody formation).

This notion of new self-duplicating catalysts does not gainsay
the dominating importance of the chromosomes and genes, but
it does indicate how even one single molecule could serve to estab-
lish the catalytic formation of new substances in a cell clone. In
fact it has been reported33 that one crocin molecule is able to in-
duce a sexual change in an alga. The position of the gene is
sufficiently secure to permit even the most devoted followers of
T. H. Morgan to admit the existence of non-genic heredity of
the catalyst type; or they may prefer to consider a new auto-
catalytic catalyst as a symbiont or an extrachromosomal gene.

Let us now consider some of the experimental evidence indi-
cating that cells are able to form new and heritable catalysts.

Apart from the many specific catalysts known to exist in yeasts, it has
long been known that yeast can be "trained" to ferment certain sugars.
Nearly half a century ago F. Dienert34 found that a yeast which was
unable to ferment galactose acquired this power when small but con-
tinually increasing percentages of this sugar were added to the fer-
mentation mixture.

Karstrom35 divided the enzymes of microorganisms into two groups:

(1) constitutive enzymes, whose formation is common to all media;

(2) adaptive enzymes, which are formed only if the cell is "stimulated
by the presence of a specific chemical substance in the milieu," a pro-
cedure which recalls the formation of antibodies in animals as a
response to an antigen. On experimenting with nine strains of yeast
(Saccharomyces), H. E. Rhoades36 found that each strain could ferment
glucose, mannose, sucrose and raffinose regardless of the carbon source
in which the cells had grown; that is, these sugars were fermented by
constituent enzymes. On the other hand, maltose, trehalose, alpha-
methylglucoside and galactose* were fermented only if the organism
had been "trained" by growth in the presence of the specific substrate
or a closely related substance, that is, after the formation of adaptive
enzymes.

Evidently, yeast can "manufacture" new enzymes to meet new

* One strain (S. cerevisiae Hansen) possessed the inherent ability to ferment
galactose.

198 LIFE: ITS NATURE AND ORIGIN

situations, and it appears that the new substances which the yeast
"learns" to ferment add their own specificity to a system of molecules
to make a new prosthetic group. (See also the work of T. M. Sonne-
born in Chapter 8.)

(4) Deflocculation and Elution

These may liberate carriers and/or prosthetic groups, which can
then become effective as gene modifiers or as catalyst formers; or
pre-formed enzymes may be freed from inhibitors or from an
inactivating adsorption.

The Svedberg (Nobel prize, 1927)37 and his collaborators
found that the molecules of the respiratory protein hemocyanin
from the snail Helix pomatia shows, when slightly acid (pH 6-8),
a molecular weight of 6,740,000; but when made slightly alkaline
(pH 8-0) the protein splits into three components whose molec-
ular weights are 6,740,000, 3,370,000, and 842,000 respectively.
Restoration of the pH to 6-8 causes the fragments to reunite.
Dissociation of proteins may follow high dilution, or the addition
of an amino acid or another protein. As little as 0.001 per cent
of thyroxin causes an appreciable dissociation of thyroglobulin.
The action of a dissociating compound on a protein is more or
less specific. Thus in the presence of ammonium chloride, argi-
nine dissociates serum albumin but not Helix hemocyanin, while
lysine plus ammonium chloride splits the latter protein but not
the former. Guadinine chloride affects Helix hemocyanin very
strongly, but serum albumin only slightly. Clupein splits both
proteins, but arginine, in the absence of ammonium chloride,
affects neither.

Epitomizing the work on the important respiratory proteins,
which are interesting from a taxonomic as well as a physico-chem-
ical point of view, Svedberg distinguishes two groups:

(1) Respiratory proteins active in cells: e.g., Keilin's cytochrome-C,
Warburg's "yellow enzyme" (now known to be of complex nature),
and myoglobin ("muscle hemoglobin") which takes up and gives off
oxygen along a dissociation curve, and seems to serve as an oxygen
reservoir for the organism. The first two take part in cellular oxida-
tion-reduction reactions.

(2) Respiratory blood proteins, falling into the following classes:

(a) red pigments (erythrocruorins, hemoglobins)

(b) green pigments (chlorocruorins)

(c) blue pigments (hemocyanins)

(d) reddish-brown (hemerythrins)

THE CATALYST ENTELECHY IN DIFFERENTIATION 199

Classes (a) and (b) have similar iron-containing prosthetic groups,
and can take up one molecule of oxygen for each iron atom. In class
(c) the prosthetic group contains copper, and these proteins can take
up one molecule of oxygen to two atoms of copper. In class (d) the
prosthetic group also contains iron, but the oxygen-binding capacity is
one oxygen molecule to three atoms of iron. The cellular respiratory
proteins cytochrome-C and myoglobin both have iron in their pros-
thetic group and have about the same molecular weight (17,000) one-
fourth that of hemoglobin (68,000) which has four iron atoms per
molecule, and is found in the blood of all vertebrates except the lowest
class, the Cyclostomata. Mammalian hemoglobin dissociates reversibly
upon addition of certain amino compounds, e.g., urea, acetamide,
formamide.

"The hemocyanins form an interesting class with a number of inner
connections. The molecular weights of the hemocyanin molecules
found in the blood of certain species are always simple multiples of
the lowest well defined component. Thus, for the Malacostraca the
relationship is 1:2 and for the Gastropoda 2:8:16:24. Moreover, the
weights of all the well-defined hemocyanin molecules seem to be simple
multiples of the lowest among them. In most cases the hemocyanin
components of certain species are interconnected by reversible pH-
influenced dissociation-aggregation reactions. At certain pH values
a profound change in the number and percentage of the components
takes place. The shift in pH necessary to bring about reaction is not
more than a few tenths of a unit. Consequently, the forces holding
dissociable parts of the molecule together must be very feeble.

"Not only the molecular weights of the hemocyanins but also the
mass of most protein molecules — even those belonging to chemically
different substances — show a similar relationship. This remarkable
regularity points to a common plan for building up protein molecules.
Certain amino acids may be exchanged for others, and this may cause
slight deviations from the rule of simple multiples; but on the whole,
only a very limited number of masses seems to be possible. Probably
the protein molecule is built up by successive aggregations of definite
units, but only a few aggregates are stable. The higher the molecular
weight the fewer are the possibilities of stable aggregation. The steps
between the existing molecules, therefore, become larger and larger
as the weight increases."

All this indicates how delicate is the physico-chemical mech-
anism controlling the particle size of proteins, which may affect
catalyst formation, and thereby determine the pH and the forma-
tion or deflocculative liberation of specific substances that may
exert profound effects on protein structure and function, e.g., as

200 LIFE: ITS NATURE AND ORIGIN

carriers and prosthetic groups for still other catalysts. Changes
in aggregation and particle size will also greatly influence kinetic
activity, diffusibility, passage through septa, adsorbability, and
the nature and extent of the outwardly directed electronic mosaic.
With the biologically important colloid proteins, as indeed with
most other substances, we must, at a certain stage of organization,
envisage the possibility of particulate unions and dissociations
which are not comprehensible in terms of simple stoichiometry,
even though they are due to residues of the same subatomic
potencies which are responsible for chemical attraction. There
comes a zone in the successive levels of increasing complexity of
material structure, where the externally directed electronic mo-
saics of the particulate units may be somewhat variable and af-
fected by adsorbed "impurities," and yet the attraction (or
repulsion) of the units may be biologically important (e.g., con-
sider mitosis and "crossing over"), although not as powerful or as
precise as with true chemical combinations between smaller and
less organized particulate units.

As to elation, we need only recall the masterly work of Richard
Willstatter,38 who concentrated enzymes several thousand fold by
adsorbing them on suitable adsorbents, filtering off the exhausted
fluid, and then stripping off or eluting the adsorbed enzyme from
the adsorbent by slight changes in the pH or the chemical nature
of the dispersion medium. Besides being important in many
analytical procedures (e.g., chromatography), this process of selec-
tive adsorption and differential elution has extensive industrial
applications; for example, the important drug penicillin was
concentrated from highly dilute dispersions by adsorption on
activated carbon, and was eluted from the carbon by a suitable
solvent.39

An eluate may, in turn, serve as an elutor of other substances
from the adsorbed state; or it may act as a prosthetic group, a
carrier, a complete enzyme, or as an inhibitor of enzymes.

It must also be considered that the formation and release, at
catalyst surfaces, of substances of low diffusive mobility may
establish local concentrations of these substances far higher than
their average distribution as shown by an overall chemical deter-
mination. In fact, a number of geneticists have applied this
notion of accumulation to explain the "position effect."40 In-
creased length of the diffusion path tends to limit the distribution
of the output of a catalyst surface, and this, in turn, may affect

THE CATALYST ENTELECHY IN DIFFERENTIATION

201

the "raw material" supply and therefore the output of other cata-
lysts.

Selective adsorption, followed by elution, could also establish
local concentrations sufficiently large to permit a substance to
function in any of the just-mentioned capacities of prosthetic
group, carrier, catalyst, elutor, or inhibitor. The work of Sved-
berg and his school, above mentioned, adumbrates how profound
may be the consequences for catalyst formation or modification.
On the other hand substances locally formed may be carried else-
where to exert specific effects — the hormones, for example.

The interplay of these numerous possibilities indicates that in
these simple mechanisms the cell has ample scope for the most
diverse activities. The potency of local accumulations of trace
substances might well be called "trigger action."* The formation
of new carriers and prosthetic groups makes possible new enzymic
catalysts, which, in turn may direct the formation of still other
chemical outputs and structures as the material entelechy devel-
ops.

Sex Determination

Very slight chemical differences may lead to enormous physio-
logical and morphological differences at higher structural levels.
Consider the close resemblance of the chief mammalian male and
female sex hormones which exert such potent but characteristically
different influences. For example, when twin calf embryos are

0=

Testosterone
(male sex hormone)

CM!

Estrone (o? Theelin)
(female sex hormone)

genetically of different sex and the union of the fetal membranes
establishes continuous circulation, the sex hormone of the de-
veloping bull calf causes the female calf to develop into a free-
martin, a sterile intersex with testes and male ducts.41 Following

* Iodide therapy may precipitate an attack of acute lead poisoning, by converting
lead phosphate stored in the bones into soluble lead iodide.

202 LIFE: ITS NATURE AND ORIGIN

injections of female hormones, roosters become "broody" and will
hatch out and care for chicks; while under the influence of male
hormones., hens become combative and will "tread" other hens.
Injections of male hormones make non-singing female canaries
assume male courtship behavior and sing like males. Chick em-
bryos of both sexes develop combs and spurs, but those of the
female soon degenerate. If the left (functional) ovary is removed
from a very young female fowl, the bird assumes male character-
istics, its right ovary becoming functionally a testicle; and it is
reported that a normal fertile hen has been changed to a "normal"
fertile rooster.42

Although Prof. C. E. McClung43 discovered the sex chromo-
somes about half a century ago, it is only recently that their
operative mechanism has been made evident. The expression
"genie balance" applies to sex characteristics and indicates that
many genes play a role.

The action of sex-controlling genes, presumably through sex
substances formed by their activities, may be glimpsed from the
following resume of the development of the sexual system in
amphibians, based mainly on Needham's description.

What are to become the germ cells arise from the dorsal wall of
the gut endoderm. They become embedded in the wall of the
splanchic mesoderm as it moves in to form a median dorsal mesentary
plate. This plate splits lengthwise into two bundles which move
outwards. Next, chains of cells from the blastema of the mesonephros
migrate into the gonad and form a medulla or central core. The
endodermal germ-cells are thus connected with two sorts of mesoderm:
a cortex having female potentialities, and a medulla having male
potentialities; and no other mesoderm has like competence. It had
been shown by M. Laulanie44 that in the case of a genetic female, the
cortex develops at the expense of the medulla and induces the for-
mation of eggs; whereas in a genetic male, the medulla develops at the
expense of the cortex, and induces the formation of sperms. Though
egg cells and spermocytes both have the unique power of reduction
division which halves the chromosome number,* the two haploid
sperms survive, one with an x chromosome, the other with a y chromo-
some; but only one of the haploid egg cells (with an x chromosome)
survives, the other being aborted and cast out as a "polar body." This
recalls, though at much different structural levels, the freemartin
effect above mentioned, and also the instinct which leads a queen
bee to sting to death all other queens in her domain.

* The subsequent longitudinal splitting of the chromosomes in "equatorial divi-
sion" does not affect the haploid number.

THE CATALYST ENTELECHY IN DIFFERENTIATION 203

Considering now the amphibian sex duct systems, the Wolffian
duct, with male potentialities, arises as the pronephric or segmental
duct on each side of the body. The Mullerian duct, with female
potentialities, generally originates independently from the epithelium
of the coelom. These two form all the later ducts, and both of them
appear in every organism; but the particular sex hormone poured into
the blood stream determines which of the two systems will persist
and develop. The non-developing system normally degenerates into
a vestigial structure; but we can understand how in abnormal cases
there may develop intersexes or hermaphrodites. The various second-
ary sex characters (external genitalia, accessory sex glands; wattles,
spurs and combs of fowl) are all controlled by the sex hormones.

Sex reversal is known to occur spontaneously (Pflugerian herma-
phroditism), and as before noted can be artificially induced. Oysters
are usually male when young, but become female as they grow older.
The Florida silver palm also changes sex.45 With the sex substances
there seems to be a balance, controlled in part by temperature and
differential diffusibility. If two frog larvae of opposite sexes are
grafted side by side and develop toward maturity, the male medulla
will suppress the cortex of only the nearer ovary. But if the larvae
are grafted in tandem, no effect is noticed, the diffusion path being too
long. With urodeles (newts) side-by-side grafting suppresses both
ovaries of the female partner. The effect may be quantitative; for if
the female of a large species is grafted to the male of a small species,
the ovaries suppress the testes. High temperature and over-ripeness
of eggs favor maleness, e.g., the medulla over the cortex. By grafting
an ovary into a cool spot (ear or scrotum), involuted sex organs of
castrated mice have been restored to normal, apparently by the small
amount of androgen supplied by the ovary; but grafting onto the
warmer abdomen was without effect.40

By injections of oil solutions of estrone into the allantoic cavity
of birds' eggs on the fourth day of incubation, V. Danschakova and
J. Massavicius47 completely feminized the embryos of genetic male
birds. But the introduction of testosterone proprionate to effect
masculinization was lethal in birds, though with guinea-pigs the free-
martin effect was produced, the male hormone suppressing feminiza-
tion.

The case of the gephyrean worm Bonellia is fantastic. From the
body of the female, about the size of a walnut, there projects a yard-
long probosis which serves to collect the nutrient-containing mud.
The tiny male, less than 3 millimeters in length, lives as a commensal
in the female's intestine and uterus. Less than one percent of the
larvae spontaneously develop into males. Ninety-nine percent of the
free-swimming larvae will become females unless they happen to

204 LIFE: ITS NATURE AND ORIGIN

become fastened by a sticky secretion of certain larval glands, to the
probosis of some female worm, where their gradual development into
males can be followed. Those who have experimented with this
rather rare worm, speak of the number of "probosis hours" in the life
of such a male.

Artificial Parthenogenesis

Recent research in artificial parthenogenesis has developed
facts of great interest here. E. B. Harvey48 obtained by ultra-
centrifugation nuclei-free fragments of sea-urchin eggs which,
when activated by hypertonic seawater49 in many cases gave rise
to a single cy taster (and frequently to several cy tasters). The
cytaster was followed by an amphiaster and division of the cell
between the two asters. Afterward, when cell division does not
carry through, the cytasters multiply within the unsegmented
fragment. Sometimes the merogens develop as far as the 500-cell
stage and form free-swimming blastulae, before development
ceases. The egg cytoplasm evidently carries sufficient directive
agents for the early stages of development, but chromatin or
nuclear material appears necessary for gastrulation and further
differentiation. J. Needham comments that the failure of these
parthogenetic merogens to show the Feulgen reaction (used to
identify nuclear material) is inconclusive, for though there must
be much of this ribo-nucleotide type nuclear material in the
cytoplasm anyway, it cannot bring about gastrulation; neither
has the external addition of nucleotides, vitamins or hormones.

Waiving the question as to the possible presence of dispersed
nuclear material in the non-nucleated merogen, A. Tyler50 be-
lieves that in normal mitoses asters arise in connection with, and
are probably due to, the activity of a self-perpetuating central
body, even though Harvey51 did not describe definite central
bodies in the cytasters. For as far back as 1901 E. B. Wilson,52
figured them quite clearly in his cytological observations on ac-
tivated non-nucleated fragments; and more recently Fry53 showed
that differences in cytological technique may greatly affect the
appearance of the central body. Therefore Tyler believes "it
is reasonable to assume that the appropriate method would dem-
onstrate distinct central bodies in Harvey's material too. It ap-
pears then that the production of a cytaster involves in effect the
de novo formation of a self-multiplicative, genetically continuous
body."

THE CATALYST ENTELECHY IN DIFFERENTIATION 205

Some Instances of Inductor Action

The importance of nuclear inductors in determining developmental
form or morphology is brought out by the striking work of J. Ham-
merling54 with the umbrella alga, Acetabularia, whose huge single
cell may grow to 2 or 3 cm. high, the rhizoid or root-like base having
a long stem terminating in an "umbrella" 0.6 cm. in diameter. The
umbrella is preceded by a series of wreaths of hairs, and consists of
a number of radial chambers which later contain the sex cells
(gametes). The single nucleus is in the rhizoid end, away from the
umbrella, but from this nucleus there diffuse substances which can
specifically direct regeneration of either end of the plant. Thus if
the plant is cut in two, the nucleated rhizoid end will reproduce an
umbrella. The other end, having no nucleus, may live quite a while,
but before eventually perishing it may regenerate an umbrella or a
rhizoid. The regeneration of the umbrella takes place more readily
the nearer the cut is to the "umbrella" end, while the opposite is the
case with the regeneration of the rhizoid. But in the absence of the
nucleus the amount of regeneration is sharply limited.

Hammerling concluded that the nucleus produces two directive
substances which diffuse differentially so that more of the umbrella-
forming stuff accumulates toward the umbrella end, and more of the
rhizoid-forming stuff remains nearer the supplying nucleus. When
a nucleated piece was allowed to begin regeneration and the nucleus
was then removed, regeneration proceeded even if the cut exposed
part of the stem which would not ordinarily form an umbrella; for
the nucleus had supplied the necessary form-directing materials.
Their stability is indicated by the fact that if the umbrella is cut off
two months after removal of the nucleus, a new umbrella is re-
generated. If the stem is cut near the root, an umbrella will develop
at this unusual place; but if the nucleus is removed before completion,
regeneration will cease after the exhaustion of the umbrella-producing
substance.

Are genes within the nucleus involved in the formation of these
directive substances? An affirmative answer was given by further
experiments with two species of the alga whose umbrellas showed dif-
ferences in color, in number and shape of their chambers, etc., namely
Acetabularia mediterranea and A. wettsteinii. On grafting anucleate
fragments of one species onto nucleated fragments of the other, in both
directions, it was found that the nature of the nucleus determined what
kind of umbrella would develop. Thus a mediterranea stem grafted
onto a nucleated wettsteinii rhizoid, gave a typical wettsteinii umbrella.
Goldschmidt remarks: "This shows that actually the genes within the
nucleus control the production of a specific formative stuff (not

206 LIFE: ITS NATURE AND ORIGIN

unspecific, as in the hormonic type) which diffuses through the cyto-
plasm to the place of its form-controlling action." Owing to the
complex nature of the resulting umbrella, the formative material may
consist of several substances; or a substance with several catalytic
potencies; or else it must initiate in the cytoplasm of both species the
same "entelechy" of catalyst formation and chemical change.

After describing Hammerling's work, Needham states: "From
all that has been said in the preceding sections, it will have become
clear that the genes act in development by producing, inhibiting
the production of, or masking and unmasking, hormones, cata-
lysts or inhibitors in more or less diffusible states. Hence their
undoubted effects upon rates of reaction in the embryo. It might
even be said that the main difference between genetics and embry-
ology is that in the former study only those inductors are described
which are unable to pass through the cell-membranes of the cells
in ivhich they are formed, while in the latter, only inductors of a
more diffusible nature are described. But this would leave out
the whole question of competence, which is likely to remain
mysterious long after our present knowledge of genes and in-
ductors has quadrupled its present state."

It is strange that Needham should see such mystery in compe-
tence, which he defines as "the state of reactivity of a part of an
embryo, enabling it to react to a given morphogenetic stimulus
by determination and differentiation in a given direction." As
pointed out above, the formation or activation of specific cata-
lysts will commonly call upon local tissues to bear some part of
the burden, e.g., by supplying carriers, prosthetic groups, elutors,
or suitable pH; and if the prosthetic group should find the es-
sential carrier already preempted by some other group, the pros-
pective catalyst may not be formed. By blocking one reaction in
a catalytic chain, the absence of a single catalyst may alter the
local chemical output, and therefore the formation of substances
and structures which are criteria of physiology as well as of de-
termination and differentiation.

Some Abormalities

Let us now consider some of the consequences which may fol-
low if the usual course of catalytically directed chemical change
is upset. The normal catalyst entelechy is all askew.

First come the naturally occurring abnormalities termed teratomata,
defined as a group of histologically differentiated tissues (often

THE CATALYST ENTELECHY IN DIFFERENTIATION

207

malignant) embedded in an otherwise normally developed organism,
and showing various degrees of morphological differentiation. Despite
the chaotic assembly of various tissues and organs (in one case dozens
of tiny "tonsils" in separate little patches of "pharynx"), the specific
glands may function and the muscle be capable of contraction. By in-
jection of 5 per cent zinc chloride into the testis of a fowl, H. J. Bagg55
found in many the development of "teratomata" sometimes big enough

lil" '" ,

]fi ', I r,-|l . • UJ''

Figure 31. Grades of otocephaly. Semi-diagrammatic ventral views of the head
and throat of the 12 grades in comparison with the normal (o). [Courtesy Journal
of Agricultural Research, Vol. XXVI, No. 4 (1923)].

to fill most of the visceral cavity, and containing cartilage, bone, fat,
muscle, skin, feather follicles, glands, and also nerve, connective and
cancerous tissue. Since zinc chloride is a powerful disperser of some
proteins (it will fluidify glue or gelatin), it might well be that a variety
of specific proteins (prosthetic groups or carriers) in the fowl's gonads
or sperms are dispersed and set free to act with the carriers or pros-
thetic groups normally present in adult tissue, but functionless unless
converted into active catalysts by appropriate combination.

Other groups of abnormalities, mainly involving malforma-
tions, where the animal or plant departs greatly in form or struc-
ture from what is usual for the species, are termed monsters.

208 LIFE: ITS NATURE AND ORIGIN

They may, for example, lack certain organs or parts or have too
many limbs. I have seen a bull with two heads, one quite small
and imperfect. A well-known instance is the heritable abnormal-
ity otocephaly (loss of head) in guinea-pigs found by Sewall
Wright,56 which probably results from inbreeding. While the rest
of the body is normal, the following graded degrees of interference
with head formation are found, which F. E. Lehmann57 believes
to be due to a defect in the head organizer: in Figure 31 (1) lower
jaw is reduced; (2) no mandible palpable externally; (3) ears con-
nected under throat by bare skin; (4) single median ear opening
on throat; (5) mouth and upper incisors lost; (6) nostrils fuse;
(7) eyes are in contact below a narrow nasal probosis or are more
or less fused; (8) eye fusion complete; (9) probosis lost; (10) eye
lost; (11) ear opening lost; (12) body rounds off in front of
shoulders, with no sign of a head except a small single median
external ear.58

Goldschmidt states that the various defects which combine to
make otocephaly are traceable to a small number of centers of ab-
normality: ventral mandibular arch, olfactory placodes, cerebral
vesicles, median optic rudiment and some others.

Embryological investigation of the heritable x-ray induced
mutations produced in mice by C. C. Little and H. J. Bagg59 made
by K. Bonnevie60 and G. M. Plagens61 showed that while the
abnormalities may be much diversified, e.g., lack of eye (anoph-
thalmia), extra digits (polydactyly), club foot, etc., they follow
as a consequence of an overflow of medullary fluid in the neck of
the embryos when they are 7 or 8 milimeters in length. The blebs
or blisters thus produced move about uncertainly as embryonal
growth continues, and interfere with normal development. What
the recessive mutant gene does is simply to establish the conditions
leading to the release of the medullary fluid; and since this hap-
pens at an early stage, quite a variety of final effects may follow.

Similarly, it is uncertain what may be the consequences of an
embolism in the circulatory system of a human being. It might
kill by obstructing the circulation in the heart, the brain, the
lungs, etc. Hence the wisdom of absolute rest in phlebitis, so
that no dangerous blood-clot is set free while redispersion of the
large local clot is proceeding.

We now mention a few of the many cases where developmental
abnormalities have been experimentally produced by the presence
or the lack of definite chemical substances.

THE CATALYST ENTELECHY IN DIFFERENTIATION 209

F. E. Lehmann62 found that trichlorbutyl alcohol, a narcotic which
does not inhibit the primary evocator in the dorsal lip of the amphi-
bian blastophore,63 can inhibit the secondary evocators which direct
the formation of a lens by an eye-cup. The degree of inhibition, up
to complete absence of lens, depends upon the temperature (less at 10°
than at 22°), on the narcotic concentration, and also on the stage of
development when the narcotic is applied. After the lens-forming
ectodermal thickening had appeared, lens formation proceeded despite
the narcotic, which seems incapable of interfering with the catalyst
system, once this is established. Before this, the narcotic may possibly
block off some carrier or prosthetic group.

Needham points out that "These facts raise the question of the
naturally-occurring blindness in cave-dwelling animals. There can
be little doubt that it involves a series of effects due to interference
with the inductor chain brain— ^eye-cup— >lens-»cornea at various dif-
ferent points."

An eye-cup brought experimentally into contact with undeter-
mined ectoderm for 24 hours induces lens formation; and ectoderm,
transplanted from a distant region to a place over the eye-cup, devel-
oped a lens. But Spemann found that in many amphibia, lens forma-
tion can take place without eye-cup assistance; in fact, in the frog
Ra?ia fusca and the newt Triton vittatus lens-forming competence is
distributed all over the ectoderm. In the toad Bombinator, any part
of the head ectoderm will form a lens, but trunk ectoderm will not.
In the frog Rana esculenta, only the presumptive lens district showed
competence (ability to form a lens following stimulation by the
evocator).

These facts show the danger of framing a theory on the basis
of too limited a group of experiments, even within a very re-
stricted field. An acceptable theory of life processes must be
broad and versatile enough to be consistent with all experiments
in any field, no matter how remote from the field in focus. The
catalyst theory of life seems to meet this criterion, despite our
present inability to unravel the enormous intricacies in a single
cell.

Returning now to the cave-dwelling animals, they and prob-
ably also their foods, are protected from direct solar radiation,
though possibly more exposed to such telluric radioactive radia-
tions as might exist in their habitat. Apart from any effects
which might be produced by abnormal or mutant genes, it is well
known that eye-cup and other suppressions such as loss of hind
limbs may be produced in pigs by restricting the mother's dietary

210 LIFE: ITS NATURE AND ORIGIN

vitamin A, a substance related chemically to carotene and other
lipochromes (retinene, astacin) which are functional in the eye
region. Thus the Texas State Agricultural Experimental Station
reported in 1932 that a Duroc-Jersey gilt on a vitamin A-deficient
diet farrowed eleven pigs all without eye-balls. F. Hale repeated
the experiment,04 and one pig was born without any eye-cup at all.

It is interesting to note that vitamin A (carotene) serves as a
prosthetic group in the conjugated protein system serving vision
in the higher animals. The equilibrium visual purple (rhodopsin)
^± visual yellow (retinene) ^± visual white concerns the retinal
rods, while the visual violet (iodopsin) is involved in the retinal
cones useful in night vision and especially important to nocturnal
animals, e.g., owls. To prevent "night blindness" aviators wear
special red glasses before flying at night, in order to protect their
visual cones and render their night vision acute.

Among cave-dwellers some of the eye deficiencies reported are
the following:

In the salamander Proteus anguineus cornea induction is in-
hibited by a thick wad of connective-tissue mesoderm which
develops between the eye-cup and the epidermis. In the blind
cave-fish Anoptichthys jordani lens induction spontaneously fails.
The lizards Amphisbaena and Rhineura lack lens and cornea.

The blind fishes and blind amphibia form series showing
various graded degrees of eye abnormalities, from degeneration
of the retina following normal development, to absence of lens,
of cornea and of eye-cup differentiation. The caves also have
many blind invertebrates, e.g., the shrimp-like crustacean Niph-
argus. Reference should here be made to the work of Prof.
George H. Parker on neurohumors, and of Prof. Francis B.
Sumner on the effects of visual stimuli on the colors of fishes and
amphibia.

These facts raise the question as to what extent deficiencies in
foods and in solar radiation (due e.g., to long periods of intense
volcanic activity, as in the upper Cretaceous), may result in
abnormalities under natural conditions. Thus J. Alexander
stated:65 "The riddles presented by the disappearance of various
animal species and human tribes are, of course, open to many
possible interpretations — change of climate, pestilence, extermina-
tion or submergence by other animals or tribes. A more subtle
but equally potent possibility is food failure — not necessarily
actual famine, but a deficiency in the supply of certain foods

THE CATALYST ENTELECHY IN DIFFERENTIATION 211

which furnish small quantities of essential substances, or the
failure of the plants or animals furnishing such substances to
produce them in sufficient quantity."

V. L. Colucci66 and G. Wolff'37 independently reported that, on
removal of the lens from a larval or an adult amphibian, a new
lens develops from the upper margin of the iris. Recent ex-
periments with this "Wolffian regeneration" showed that if small
bits of iris are snipped off and pushed into the eye-chamber
(corpus vitreum), lenses develop there; but bits of ectoderm acted
likewise. With Rana esculenta Wolffian regeneration fails in the
presence of a normal lens, but if the lens is removed, lenses form
on implantation into the eye of neural plate tissue, ectoderm,
eye-cup, somite mesoderm and ear vesicle. Tissue cultures of chick
iris are reported to have produced lenses. It might well be that
the eye-chamber can supply specific prosthetic material, while the
other diverse tissues supply the specific carrier material, or vice
versa.

The secondary organizers responsible for lens formation are
stable enough to stand boiling, and like primary organizer they
seem to be present in all tissues. But the amount is limited
locally, for on repeated extirpation and regeneration the third
lens in the series was poorly developed, and no fourth lens ap-
peared. Prolonged rest restored the regenerative power; either
the active substance had been reformed locally, or else the widely
distributed organizer had diffused in. If the latter possibility is
true, it would be evidence in favor of the view advanced by J.
Alexander68 as to how the gametes (ovum and sperm) receive the
enormous number and variety of particulate units which are
needed to form, or to serve as templates for forming the specific
catalysts, prosthetic groups or carriers needed to carry out the
material catalyst entelechy. Alexander stated: "How can heritable
factors, apart from genie or chromosomal changes, enter into and
affect the cells which carry heredity?

"It is reasonable to believe that the cytoplasm of germ cells,
like that of other cells, tends to receive an average supply of the
molecular flotsam and jetsam, that is, of all particulate units
which are carried throughout the body by circulation and diffu-
sion, and that among these molecular or near molecular units
are those that determine or aid in determining, differentiation.
Apart from other evidence, the fact that some differentiated cells
can breed true in tissue culture warrants the belief that specific

212 LIFE: ITS NATURE AND ORIGIN

tissues or organs contribute to the molecular melee in the organ-
ism units capable of determining their own specific type of cell."
The simple processes of circulation and diffusion may thus
help to lift from the genes and the chromosomes some of the tre-
mendous responsibilities placed upon them by considering them
as the sole carriers of heredity. The great numbers and varieties
of specific molecules trailing along in the gamete cytoplasms, and
especially numerous in the ovum, act through the catalyst
entelechy as cooperators with and supplementors of the genes.

REFERENCES

1 Presidential address before the Botanical Society of America (Science (1939)
89, 41-46), on "The Cell and the Problem of Organization."

2 Am. Naturalist (1946) 80, 497-505.

3 "Uber Entwicklungsgeschichte der Tiere," 1828.

4 Brody, "Bioenergetics and Growth," p. 484, Reinhold Pub. Corp., 1944.

5 "How we came by our bodies," New York, 1936.

6 G. Pincus, Cold Spring Harbor Symposia on Quantitative Biology (1937) 5, 44.
The rabbit passes half (18 days) of its development before the fetus outweighs the
placenta.

7 Cf. C. M. Child, "Individuality in organisms," University of Chicago Press, 1915.
In recent experiments, Child has demonstrated oxidation-reduction gradients in
developing embryos, by the use of suitable dyes, e.g., indophenol blue, Janus green,
in high nontoxic dilutions. The colors developed correspond to the local degree of
activity of an intracellular oxidizing enzyme, now believed to be cytochrome oxidase
(Proc. Nat. Acad. Sci. (1941) 27, 523-528; /. Exptl. Tool. (1945) 100, 577-589).

8 Arch. Entw. Mech. (1933) 128, 584; (1934) 132, 225.

9C H. Waddington, Nature (1930) 125, 924; Phil. Trans. Roy. Soc. B. (London)
(1932) 221, 179.
9a "Biochemistry and Morphogenesis," Cambridge Univ. Press, 1942.
10 Arch. Entw. Mech. (1925) 106, 357.
^Naturwiss. (1933) 21, 766; Arch. Entw. Mech. (1934) 132, 307.

12 B. Mayer, Naturwiss. (1939) 27, 277.

13 Arch. Entw. Mech. (1927) 111, 341.

14 They obtained inductions with the following polyhydrocarbons and steroids
(structural formulas given by Needham, lib. cit., pp. 245-6):

Estrogens: l:9-dimethylphenanthracene

9:10-dihydroxy-9:10-di-n-butyl-9:10-dihydro-l:2:5:6-dibenzanthracene

estrone (female sex hormone)

4:4'-dihydroxy-diphenyl

1:2 dihydroxy-l:2-di-a-naphthyl-acetnaphthene

5:6-cyc/o-penteno-l :2 benzanthracene
Carcinogens: 3:4-benzpyrene

methylcholanthrene

styryl blue

sodium l:2:5:6-dibenzanthracene-endo-a -^-succinate*
• Optimum dosage (yielding 40 per cent inductions where implant was retained)
was 0.0125 7 per embryo. (S. C. Shen, /. Exp. Biol. (1939) 16, 143).
i° Biol. Bull. (1934) 67, 244.

THE CATALYST ENTELECHY IN DIFFERENTIATION 213

16 F. G. Fischer, E. Wehmeier, and L. Jiihling, Nachr. Gesell. Wiss. zu Gottingen
(1934) (IV), 9, 394.

" C. H. Waddington, J. Needham and J. Brachet, Proc. Roy. Soc, B (1936) 120,
173.

18 Proc. Kon. Akad. Wetenskap. Amsterdam (1933) 36, 423.

wZeit. physiol. Chem. (1934) 225, 103.

20 C. H. Waddington, Science Progress (1934) 29, 336.

21 C. H. Waddington, "Morphogenetic Substances in Early Development," Trans.
du Congres du Palais de la Decouverte, Hermann, Paris, 1938.

22 Science (1942) 96, 455.

23 S. A. Harris el al., J. Am. Chem. Soc. (1944) 66, 1756.

24 "Genetics and the Origin of Species," Columbia Univ. Press, 1941, p. 22.

25 See J. Alexander & C. B. Bridges, "Colloid Chemistry," Vol. II, p. 13, Reinhold
Pub. Corp., 1928.

26 See Ann. Rept. Smithsonian Inst. (1913) 261-73; Soc. franc, phys. (1914) 55, 3;
57,3.

27 Science, 66, 84-87; (1928) 67, 82.

28 Cold Spring Harbor Symp. (1941) 9, 151-65; 290-308.

29 lib. cit., p. 309ff.

30 According to L. Zechmeister [Chemical Reviews (1944) 34, 278] the calculated
number of stereoisomers for naturally occurring carotenoids are, for example, as
follows: a-carotene, 32; /3-carotene 20; 7-carotene 64; lycopene, 72; crocetin, 20;
vitamin A, 4. (J. A.)

31 See, e.g., J. Alexander, hid. Eng. Chem. (1939) 31, 630-642.

32 lib. cit., p. 110.

33 R. Kuhn, F. Moebus, and D. Jerchel, Berichte (1938) 71, 1541.
SiAnn. Inst. Pasteur (1900) 14, 139-189.

35 Helsingfors Univ., Thesis, 1930, "Ueber Enzymbildung in Bacterien"; "Enzyma-
tische Adaptation bei Microorganismen," Ergeb. Enzymjorsch. (1938) 7, 350-376.

36 H. E. Rhoades, /. Bad. (1941) 42, 99-115.

37 See Alexander, "Colloid Chemistry," Vol. V., p., 562-8, Reinhold Pub. Corp.,
1944.

38 Alexander, "Colloid Chemistry," Vol. II, (1928) pp. 361-6.

39 W. A. Helbig, in Alexander, "Colloid Chemistry," Vol. VI (1946), pp. 814-39.

40 See R. Goldschmidt, lib. cit., p. 309.

41 F. R. Lillie, Science (1916) 43, 611; /. Exptl. Zool. (1917) 23, 371.

42 F. A. E. Crewe, Proc. Roy. Soc. (1923) 95 B, 256; O. Riddle, Am. Nat. (1924) 58,
167; M. M. Zowandowsky, Trans. Lab. Exp. Zool. (Moscow) (1928) 4, 9.

43 Biol. Bull. (1902) 9, 75.

44 Compt. rend. soc. biol. (1886) 38, 87.

45 J. T. Presley, /. Heredity (1934) 45, 485.

46 R. T. Hill, Endocrinology (1937) 21, 495, 633.

47 Bull. Biol. Fr. Belg., (1936) 70, 241.

48 "Parthenogenetic merogony or cleavage without nuclei in Arbacia punctulata,"
Biol. Bull. Wood's Hole (1936) 71, 101.

49 The eminent Jacques Loeb, who described this activation about forty years ago,
used to tell, with amusement, that he was privately consulted by two nervous maiden
ladies to find out whether sea-bathing would be perfectly safe for them.

In 1907 J. H. McClendon [Biol. Bull. (1907) 12, 142; Arch. Entw. mech. (Roux)
(1908) 26, 662] had sucked out the nucleus from an echinoderm egg and fertilized
parthogenetically the non-nucleated cell, or "merogen," that remained.

50 Biol. Rev. (1941) 16,301.

214 LIFE: ITS NATURE AND ORIGIN

51 "A comparison of the development of nucleate and non-nucleate eggs of
Arbacia punctulata," Biol. Bull. Wood's Hole (1940) 79, 166.

52 "Cytological study of artificial parthenogenesis in sea-urchin eggs," Arch. Entiv.
Mech. Org. (1901) 12, 529.

53 H. J. Fry, Biol. Bull. Wood's Hole (1933) 65, 207; (1937) 73, 565.

5iBiol. Centralbl. (1931) 51, 633; (1932) 52, 42; Arch. Enwt. Mech. (1934) 131, 1.

55 Am. J. Cancer (1936) 26, 69.

56 "On the genetics of subnormal development in the head [otocephaly] in the
guinea-pig," Genetics (1934) 19, 471-505.

57 Rev. Suisse Zool. (1936) 43.

58 Fig. 27 and these descriptions are taken from the original paper by Sewall
Wright and Orson N. Eaton, /. Agr. Research (1923) 26, 161-181. H. B. Adelmann
[/. Exptl. Zool. (1929) 54, 249, 291, and subsequent volumes to 1937; Quart. Rev.
Biol. (1936) 11, 161, 284] found that in normal development the two eye-districts
overlap, but the intermediate section does not develop into eyes because the
prechordal plate inhibits it. If this inhibition is obstructed, either mechanically or
by the action of specific substances, e.g., lithium, a single eye (cyclopia) results.
C. R. Stockard (1913) produced cyclopia in a sea urchin (Fundulus) by treatment of
the early embryonic stages with magnesium salts. In the heritable eye-abnormality
termed coloboma, there is incomplete coalescence of the eye bulb. By feeding tur-
pentine to a pregnant rabbit a similar malformation (non-heritable) has been
produced in the young. The hatteria (Sphenodon punctata), a lizard-like reptile
survival of ancient times found only in islands near New Zealand, has a pineal or
median "eye," corresponding to vestiges found in snakes. This eye seems to have no
visual function, though it was more fully developed in various extinct groups of
reptiles and Stegocephali (H. F. Gadow, Cambridge). Possibly it is sensitive to
slight differences in temperature.

59 /. Exptl. Zool. (1929) 41.

60 J. Exptl. Zool. (1931) 67, 433, and earlier (1930-31) Norwegian publications.

61 /. Morph. (1933) 55, 151-178.

62 Arch. Entiv. Mech. (1934) 131, 333.

63 A. Marx, Arch. Entiv. Mech. (1931) 123, 333.
« J. Heredity (1933) 24, 105.

65 "Some Physicochemical Aspects of Life, Food and Evolution," Scieritia, October,
1933.

66 Mem. d. R. Accad. dell'Inst. di Bologna, 1891.

67 Arch. Entiv. Mech. (1894) 1, 380.

68 "Colloid Chemistry," Vol. V, p. 596, Reinhold Publishing Corp.. 1944.

60 J. W. Mellor (Vol. V, p. 720, [1924]), quotes Lucretius (60 B.C.) as follows: "It
matters much with what others and in what positions, the same atoms are held
together. . . . When the configuration of the atoms is changed, the properties of the
body which is formed from them must also change."

See also the fourth line in the quotation from Lowell on page 248.

Chapter 10

Some Catalytic Aspects of Disease and Drugs

Disease is defined as "any departure from, failure in, or per-
version of normal physiological action in the material constitu-
tion or functional integrity of the living organism." This
indicates that an understanding of diseases must be based on a
consideration of what happens to the biocatalysts, whose activities
are responsible for material structure and physiological action.
Biocatalysts determine what substances will be formed in the
organism, where and at what rates they appear, how they will be
chemically combined or altered, and whether they will persist un-
changed. Abnormalities in the biocatalysts or their activities often
are the basic causes of disease; but every abnormality does not
necessarily result in disease. For the most part diseases have been
classified on the basis of clinical "syndromes" (concurrent aggre-
gate of symptoms) having constant pathologic conditions, and for
convenience have been grouped according to the part of the body
most affected — heart, lungs, brain, stomach, eyes, nose and throat.
Progress in scientific medicine has been largely due to our ability
to trace disease processes to lower and lower structural levels and
to discover Iioav happenings at these lower levels affect the clinical
picture which confronts the practising physician.

Knowledge that many diseases follow infection by microorgan-
isms is so widespread that it is difficult for us to hark back to the
days when Anton von Leewenhoek (1632-1723) first saw "little
animals" with his home-made microscopes and astonished the
Royal Society with his findings; when Francesco Redi (1626-1695)
and Lazaro Spallanzani (1729-1799) disproved "spontaneous gen-
eration"; and when Louis Pasteur (1822-1895) read his epoch-mak-
ing papers "Lactic Acid Fermentation" and "Alcoholic Fermenta-
tion" (1857). But we are all familiar with pasteurization of milk,
beer and other foods, with the Pasteur preventive treatment against
rabies, and with the happy results so generally gained from antisep-
tic surgery and treatment of wounds introduced by John Lister

215

216 LIFE: ITS NATURE AND ORIGIN

(1827-1912), which paved the way to modern aseptic surgery. Yet in
1863 Pasteur told the Emperor of France that it was his ambition
"to arrive at the knowledge of the causes of putrid and contagious
diseases." This recalls the remarkable statement of Robert Boyle
(1627-1691) that whoever could discover the nature of ferments
and fermentation would be more capable than any other of ex-
plaining the nature of certain diseases.

In 1876 Robert Koch (1843-1910), who later discovered the
bacteria of tuberculosis, cholera, and other diseases, confirmed the
earlier observation (1863) of Devaine that minute rods (bacteridia)
exist in the blood of animals dead of anthrax, and are the cause of
the disease. Pasteur confirmed Koch's work and convinced those
who opposed it. Finally in the spring of 1881 in the farmyard of
Pouilly le Fort at Melun (France) came dramatic evidence of the
value of immunization: twenty-five sheep protected against
anthrax by Pasteur's vaccine survived massive inoculation with
these virulent germs, while every one of a like number of unpro-
tected sheep died of anthrax. Protection of human beings and of
animals against infectious diseases of many kinds is now exten-
sively practised, and we have developed an ever-increasing number
of substances which will kill or inactivate pathogenic microor-
ganisms without too much harm to the patient.

The struggle to understand the basic causes of diseases has led,
in many cases, from the infecting organisms themselves to the in-
jurious substances which they produce (exotoxins, e.g., diphtheria)
and/or of which they consist (endotoxins, e.g., tuberculosis). Our
knowledge of the mechanism whereby definite chemical sub-
stances produce definite clinical syndromes is only slowly emerg-
ing; but we are here aiming to demonstrate that the lowest effi-
cient structural level where the damage becomes determinative of
disease is that of biocatalyst structure and activity. "Poisons" may
act (1) by massive chemical attack (strong acids or alkalies), which
crudely destroy both the catalysts and their protecting milieu;
(2) by disintegration of catalyst structures, e.g., by separating
carriers and prosthetic groups, or by "lysis" of essential catalyst
structures (snake venoms); (3) by coagulation of biocatalysts or of
their milieu; (4) by inhibiting the activities of essential biocatalysts
(cyanides); and (5) by establishment of new or modified self-repro-
ducing biocatalysts under whose influence damage is done to the
organism, as in cancer, to be considered below.

It must be stressed, however, that such catalyst formations or

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 217

changes do not necessarily produce disease; their effects may be
unimportant or even beneficial. They may be basic in evolution,
for example, by leading to the production or modification of
structures, odors, etc. more attractive to the opposite sex, by giving
superior resistance to predators or microorganisms — in short by
establishing an effective superiority over competitors. Further-
more, every new self-duplicating catalyst may not be persistent.
It may be inactivated or destroyed by the immunological mechan-
ism of the cell; indeed, recovery from disease is often effected in
this manner.

In final analysis, cellular death comes when the stoppage of the
circulation of the blood deprives the cellular biocatalysts of their
necessary sources of supply and elimination, and they are soon
disintegrated or irreversibly coagulated by the changed milieu
conditions. Brain cells are particularly sensitive to lack of oxygen
(anoxemia), which can quickly produce irreversible damage to
them. The cellular chromosomes speedily clump after somatic
death (the death of the organism as a whole): Professor H. A. Evans
(University of California) and his collaborators had to work with
great speed to demonstrate the 48 separate chromosomes in human
somatic cell.1

Nature and Classification of Diseases

Some years ago2 the writer attempted to outline a classification
of diseases dependent rather upon physicochemical principles
than upon the part of the body most noticeably affected, and often
carrying the name of the discoverer (Bright's disease, Paget' s
disease). A revised form of this large table is herewith presented,
for it offers a "bird's-eye" view of what goes on in the human body,
and stresses the necessity of having breadth as well as depth of
mental focus in considering so highly complicated an organism.
Naturally there is no attempt at completeness in a diagram of this
kind, but it will serve to outline many of the main interrelations
between structure, function, health, ageing, disease, and death.
Certain details for which there is no space in the diagram are
represented there by numbers which refer to accompanying notes
where some details are given.

Discoveries in various sciences have enabled medicine to peer
more and more profoundly into happenings at progressively lower
structural levels of the organism, and thus gain a deeper knowl-
edge of the basic causes of various diseases. As the science of

218

LIFE: ITS NATURE AND ORIGIN

DISEASES

Structural and Functional

Infectious

Hormonal — Diabetes mellitis
Acromegaly
Exopthalmic goiter

Enzymic — Apepsia

Traumatic — Acute and occult

Emboli — Cassion disease (bends)

Psychic — Nervous and mental

Allergies — Hay fevei

Some asthmas

Ageing — Senility

Poisoning — Gases (CO, H2S)
Pb, As, Se, etc.
Alkaloids, etc.
Ptomaines

Excesses — Alcohol, drugs

Dietary — Avitaminoses

Inanition
Lack of trace substances'

Immunological — Inability to produce anti-
bodies

Neo-catalytic — temporary or transmissible
changes in biocatalysts
(cancer)

Ultrafilterable Viruses

Rabies, Influenza, Smallpox
Poliomyelitis, Yellow fever

Bacteria

Endotoxins — (typhoid, tuberculosis)
Exotoxins — (diphtheria, tetanus)
Mechanical block — (anthrax?)

Protozoa

Syphilis, malaria,
Amebic dysentery

Fungi

Actinomycosis
Athlete's foot, ringworm

Vermes

Tape, pin, hook worms
Liver-fluke

Insects

Bott or warble fly

medicine thus increasingly added to the clinical picture, it went
far beyond Galen's recognition of the following "temperaments":
(1) sanguine; (2) phlegmatic; (3) bilious or choleric; (4) melan-
cholic. Later, medical men spoke of diathesis, a predisposition
to certain forms of disease. For example, hemorrhagic diathesis
was defined as "a morbid condition marked by lessened coagula-
bility of the blood and an abnormal liability to bleed at slight
wounds"; and the Greek term hemophilia did not add to knowl-
edge of the cause, even though the condition was observed to "run
in families", e.g., the Spanish royal family.

Individuals differ widely in their ability to form and maintain
antibodies capable of protecting them against common infections
and antigens. The rather unusual disease termed noma, a gan-
grenous condition of the mouth and some other orifices, seems to
be due to inability of the individual to form the usual protective
antibodies. Hutt states3 that resistance to disease usually depends
on more than one gene. But in one recorded case a simple re-
cessive mutation was responsible for the loss of an entire strain of
animals; this happened in guinea pigs that were unable to form
blood complement.4

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS

219

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222 LIFE: ITS NATURE AND ORIGIN

One good feature of these older clinical aspects is that they
stressed the fact that patients differ widely in potentialities, and
that it is not alone a stereotyped "disease" which must be treated,
but also the variable reactions of patients having the disease, or
exposed to conditions which produce it. These mainly genetic
differences in individuals in colonies of animals kept for experi-
mental purposes, and even in litter mates, were discussed at a
Conference on Animal Colony Maintenance,5 and constitute a
criterion in judging the results reported on animal experiments.
In his introductory remarks Dr. Edmond J. Farris (Wistar Insti-
tute) stated that in his undergraduate days "type" experiments in
mammalian physiology "hardly ever agreed with the textbook
picture. This was common classroom experience."

Dr. F. B. Hutt of Cornell University points out that the physi-
ologist, the pathologist, and particularly the nutritionist want a
steady supply of animals showing minimum variability. "The
geneticist, on the other hand, thrives on variability. It is his stock
in trade. The recalcitrant rat that lingers on long after its or-
thodox litter-mates have terminated their abbreviated careers on
the diet lacking vitamin Q is merely a statistical nuisance to the
nutritionist, but to the geneticist it is the potential progenitor of
a race able to manage nicely with much less vitamin Q than mil-
lions of other rats that are less fortunate in the matter of genes . . .
Because some biologists still think that genes cause only such
'sports' as freaks of hair color, of hair form, of eye-color, or other
inconsequential mutations, but have little or no effect on funda-
mental physiology, these examples are chosen to refute that view."

In yellow mice the gene Ay (one of a series of allels affecting hair
color in the common house mouse) is lethal to the homozygote, which
dies in utero. The mice born alive show a ratio of 1 non-yellow to
2 yellow heterozygotes, which latter are characterized by (1) adiposity;
(2) a subnormal metabolism; (3) slightly greater body size, apart from
their excessive fat; (4) lower susceptibility to spontaneous mammary
carcinoma than their black or brown litter mates.6 In fowl a dominant
autosomal gene produces the condition "frizzle," the feather curling
back toward the head. When "frizzles" are mated, the progeny show
three types: so extremely frizzled as to appear woolly; standard frizzled
type; not frizzled. The ratio is 1:2:1. The extremely frizzled birds
become more or less bare as their feathers break off; and these
homozygous birds differ from normal fowl in (l)viability; (2) rate
of growth; (3) age of sex maturity; (4) metabolism; (5) rate of heart

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 223

beat and size of heart; (6) size of endocrine glands, etc.7 A type of
dwarfism in the house mouse is caused by a simple recessive mutation
which, while not affecting secretion of the gonadotropic hormone by
the anterior pituitary, interferes with secretion of its growth-promoting
hormone. H. Griineberg8 lists the following effects of this mutation:
(1) endocrine malfunction; (2) adult weight about one-quarter of nor-
mal; (3) complete sterility in both sexes; (4) histological abnormalities
in interior lobe of the pituitary; (5) small, abnormal thyroids; (6) sub-
normal metabolism; (7) infantile structure of thymus, adrenals and
gonads; (8) subnormal viability.

Enough has been said to show that there is much yet to be
learned about the real underlying causes of predisposition to dis-
ease (diathesis). Uric acid diathesis was defined as "a condition of
the system in which uric acid is deposited in the joints." In Sir
William Osier's great book9 the following appears in the discus-
sion of gout:

"Uric acid, in the body almost completely in the form of urates,
is the end-product of purine metabolism in man, just as urea is
the end-product of nitrogenous substances of amino-acid and py-
rimidine origin. In man the end product of purine breakdown
is excreted as urate, there being no enzyme in man to break it
down further to allantoin, as occurs in most mammals." Curi-
ously enough, Dalmatian coach dogs differ from most other dogs
in their inability to convert uric acid to allantoin, and excrete
over four times as much uric acid daily per unit of body weight
as do other dogs. H. C. Trimble and C. E. Keeler10 showed that
this characteristic is determined by a recessive mutation not linked
with the spotting characteristic of the Dalmatian breed.

For the most part, the great numbers of diseases described
in Osier's book classify the data as follows: etiology; pathology
(where known); symptoms; prognosis; diagnosis; treatment. For
some diseases prophylaxis and epidemology are given, and only
rarely pathological physiology, although from the latter the clini-
cal syndrome emerges at higher structural levels. A classification
of diseases based on physiological abnormalities traced to biocata-
lyst lack or deviation might be helpful not only in understanding
and treating diseases, but also in understanding the mode of ac-
tion of drugs which in many cases affect biocatalysts directly.
Apparently no such classification of diseases exists, and the fol-
lowing resume is given of a few instances where existing knowl-

224 LIFE: ITS NATURE AND ORIGIN

edge is sufficient to permit us to refer a disease or symptoms of an
ailment to abnormal catalyst conditions.

To illustrate how extensive may be the varieties of chemical
and enzymic attack on an organism following infection by a single
agent, Dr. John E. Blair, of the Hospital for Joint Diseases, kindly
prepared for me an outline regarding the toxins and enzymes or
enzyme-like substances (catalysts) generally liberated by Staphylo-
cocci, the common cause of boils, carbuncles and similar troubles.
The following is based on this outline.

Toxins and other products of Staphylococci

Toxins

(1) Exotoxin. This soluble, filtrable, thermolabile product can
produce demonecrosis, hemolysis, and death, and may be a mixture
of "lethal toxin," necrotoxin, and hemolysins, mentioned below.11

(2) Necrotoxin. Produces intense necrosis on intradermal injection,
liberating leucotaxine which initiates blocking off of the infected
area.12

(3) Lethal Toxin. Venous injection quickly kills mice and rabbits.
Mice killed in 2 to 4 minutes by 0.05 ml.13

(4) Enterotoxin. Soluble, filterable, thermostable; responsible for
food poisoning due to staphylococci.14

(5) Leucocidin. Destructive for leucocytes, often causing their com-
plete disintegration. Produced in varying amounts by most path-
ogenic staphylococci, especially those responsible for furuncles and
severe infections.15

Enzymes

(1) Alpha-hemolysin. 0.002 ml often hemolyses 1 per cent rabbit
erythrocytes in 1 hour at 37° C. Little or no action on human red
cells and apparently not harmful to humans, though produced by
many Staphylococci harmful to man. Useful in estimating the
potency of exotoxin, whose titer it closely parallels.16

(2) Beta-hemolysin. Hydrolyzes sheep and human cells, but not
rabbit cells. Found in animal, and occasionally in human strains.
No apparent relation to pathogenicity.17

(3) Gamma-hemolysin. Affects rabbit cells; no evident pathogen-
icity.18

(4) Spreading Factor. Increases permeability of connective tissue,
until negatived by leucotaxine action.19

(5) Coagulase. Induces clotting of glood plasma and fibrinogen
solutions. Found only in pathogenic staphylococci, and useful in
their laboratory identification.20

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 225

(6) Fibrinolysin. Can cause lysis of fibrin clots. Found only in
pathogenic strains; but action is much slower than fibrolysin found
in hemolytic streptococci.21

Inflammation. Professor Valy Menkin of Temple University finds
that inflammation is characterized by the formation of various com-
mon denominators, which are liberated from cells previously injured
by an irritant. The following substances have thus far been identified
in inflammatory exudates:

(1) Leucotaxine. Seems to be a peptide, possibly with attached
prosthetic group. It increases capillary permeability and leucocyte
migration.

(2) Leucocytosis-promoting Factor. Protein in character, or associ-
ated with proteins. It induces discharge of immature leucocytes
from the bone marrow, where it also causes marked hyperplasia of
granulocytes and megakaryocytes.

(3) Necrosin. A toxic material in the euglobulin fraction of the
exudate. It enters the general circulation and can damage essential
structures. Possibly it is a proteolytic enzyme.

(4) Pyrexin. Apparently a hydrolytic product formed by necrosin
or associated enzymes. Separable from the euglobulin fraction. It
produces fever, probably via the hypothalmic heat-regulating nerve
centers.22

(5) Leukopenic Factor. May be only a separate factor in pyrexin,
but seems to be a polypeptide when separated from pyrexin or
otherwise recovered. Apparently it leads to rapid trapping of leuco-
cytes in the alveolar walls of the lungs, in the sinusoids of the liver,
and in the spleen.

(6) Dextrose. Formed on protein breakdown. In diabetics, this
may enhance the diabetes, when there is a superimposed infection.
The emergence and the extent of these various factors in the syn-
drome of inflammation varies with the nature of the irritant and its
amount, and with the animal involved. The degree of injury done to
the cells varies, even in individuals of the same species. The view
here maintained is that these specific substances owe their origin to
interference with normal cellular catalysis. While some catalyst
changes may be reversible or recoverable, others may be irreversible
or irreplaceable, and may lead to the death of the cell and the chem-
ical breakdown of its constituents. Pus contains many dead leucocytes
in addition to necrotic material, as well as living and dead bacteria.

It must not be supposed, however, that the catalytic or enzymic
aspects of diseases represent isolated entities that can be dissected
out from the other related facts. For example, interference with
the blood supply to cells, whether brought about by mechanical

226 LIFE: ITS NATURE AND ORIGIN

constriction (strangulation) or by reduction of the lumen of ar-
terioles (by arteriosclerosis) or capillaries (by drugs or by hor-
monal or nervous imbalance), can result in diminished oxygen
supply and delayed removal of metabolic products. The normal
oxidative breakdown of glucose may thereupon veer toward an-
aerobic fermentation whereby lactic acid is released. The con-
sequences in the various cells and organs will no doubt differ
considerably, as will also the secondary consequences throughout
the body; but in general, lack of oxygen will upset the normal
function of the cellular enzyme systems, even if it does not lead
to enzyme inhibition or even to cellular death. During violent
exertion, for example, in a 100-yard dash, some of the muscular
energy comes from anaerobic breakdown of glucose. The "oxy-
gen debt" of the tissues is gradually restored by accelerated breath-
ing or panting.

As above mentioned, many diseases have a genetic basis, and
involve inherited enzyme abnormalities, or are established by
structural abnormalities consequent upon abnormal embryologi-
cal development. In his recent book (1941) on "Medical Ge-
netics" Prof. Laurence H. Snyder of Ohio State University points
out that the familiar 3:1 ratio of Mendel no longer covers the
major portion of the field of heredity, for geneticists have demon-
strated varied types of heredity transmission — dominant, recessive
and blending — as well as varied relationships and behaviors of
genes, e.g., autosomal, sex-linked, sex-influenced, lethal, epistatic
and combined genes as seen in multiple allels and multiple factors.
Epistasis, in Mendelian inheritance, means "the expression of one
character to the exclusion of another not of the same allelomor-
phic pair." Thus in rabbits and mice the factor for gray, if pres-
ent, prevents the development of the factors for black and choco-
late. This recalls the fact that some plants lie prone ("lazy" corn)
or develop chlorophyll-free areas ("variegated"), probably because
of the development by them of catalysts whose activities lead
to these results. Many traits are transmitted by heredity, even
though we have thus far been unable to unravel the precise mech-
anism. Thus strains of Dalmatians ("coach dogs") have been se-
lected and bred which take definite positions — some close to the
horse, some beneath the wagon, and some behind it.23 Identical
twins generally develop like heritable diseases and show like re-
actions on exposure to other diseases.

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 227

The following are mentioned by Snyder as among the many
diseases transmitted by heredity:

Eye and Ear: albinism (the eyes are pink, since lack of pigments
permits the blood color to come through); color blindness; deaf-
mutism.

Skin: icthyosis; absence of sweat glands; beaded hair (which
breaks off, leaving bristle-like pieces); Von Recklinghausen's dis-
ease (due to a dominant gene), a neurofibromatosis affecting skin
and nerves; Mongolian spot.

Skeleton and Muscles: polydactyly (extra digits); syndactyly
(digits joined or "webbed"); "crab-claw" and like imperfections;
club-foot; myotonia congenita (Thomsen's disease); myopathy
(progressive muscular dystrophy).

Blood: hemophilia; anemia; troubles due to blood groups, in-
cluding Rh factor.

Nerves: a variety of nervous conditions, including insanities
and Huntington's chorea. The violent involuntary movements
in this disease generally appear only in adult life, and follow de-
generative changes of ganglion cells of the frontal cortex and of
the cordate nucleus and putamen.

C. B. Davenport states24 that traits known to have a chemical
basis have the cleanest-cut genetics, e.g., blood groups, cretinism
(thyroid deficiency), amurotic family idiocy (a recessive associated
with the storage of phosphatides). "The relation between the
somatic expression of a trait and its chemical basis may be remote.
Thus hardness of hearing seems to depend on a defect in calcium
metabolism such as causes abnormal bone formation in the oval
window of the inner ear and simultaneously in other parts of the
temporal bone. In the latter case there is reason for concluding
that the result depends on a dominant factor in an autosome
which modifies the reaction of the mesenchyme and a sex-linked
gene which perhaps affects calcium metabolism. Indeed it seems
probable that in time chemical errors in the body may throw light
upon the chemical processes of development."

A rather rare kind of recessively heritable metabolic error is
alkaptonuria, first described by von Boedecker,24a and recently ob-
served in an American Negro family.25 In these cases the urine
contains homogentisic acid, shown by M. Wolkow and E. Bau-
mann26 to be 2,5-dihydroxyphenyl acetic acid, which is labile and
oxidizes, turning the urine black. Apart from occasional blacken-
ing of cartilage (ochronosis) no other symptom is evident. Homo-

228 LIFE: ITS NATURE AND ORIGIN

gentisic acid apparently appears because of the blocking, at this
stage, of the normal oxidation of tyrosine and phenylalanine,
which are normal constituents of many proteins. Normal persons
completely oxidize the acid, and perfusion through normal liver
converts it into acetoacetic acid. It was shown by H. D. Dakin27
that alkaptonuria patients can fully catabolize p-methylphenyla-
lanine and p-methoxyalanine, which cannot form quinoid deriva-
tives; he believes that inability to catabolize homogentisic acid is
associated with increased formation of the quinoid intermediate
from which it is derived.

Detoxication, the route whereby organisms rid themselves of
certain poisonous substances, also varies with the changing cata-
lytic and chemical nature of the animal. Thus fowls eliminate
phenylacetic acid and its homolog, benzoic acid, by combining
them with ornithine, while all mammals combine benzoic acid
with glycine (amino-acetic acid) and eliminate it as hippuric acid.
However, Sherwin and Thierfelder,28 found that though the lower
mammals, including monkeys, combine phenylacetic acid with
glycine and eliminate it as phenaceturic acid, man couples phenyl-
acetic acid with glutamine and eliminates it as phenylacetylgluta-
mine. But experiments on the chimpanzee by Prof. Francis W.
Power of Fordham University showed that this "man-ape" elimi-
nates phenylacetic acid in the same manner as does man. Here
too, as in the biochemistry of muscle, there is a definite relation-
ship between chemical mechanisms and the position of the animal
in the evolutionary or taxonomic scale.

In some cases disease may follow photosensitization after intro-
duction of stranger molecules. As far back as 1897 O. Raab ob-
served that small amounts of acridine exerted a lethal action on
paramecia in the presence of light, though the same doses had no
effect in the dark. Later, similar effects were seen with eosine,
chlorophyll, etc., H. F. Blum describes29 a number of diseases
which develop in grazing animals (sheep, horses, cattle) when they
eat certain plants. Among these are fagopyrism due to buckwheat
(Polygonum fagopyrum); hypericism, due to St. Johnswort (genus
Hypericum); and geeldikkop ("yellow thick head") caused by a
South African plant Tribulus, popularly called "devil's weed."
In geeldikkop the active material seems to cause liver injury and
occlusion of bile, accompanied by retention of phylloerythrin, a
chlorophyll derivative. This substance, accumulating in the skin,
makes the animal light-sensitive and leads to edema of the head

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 229

and other places exposed to light. Blum believes that the only
way to account for all the evidence is to assume that when a quan-
tum of light strikes a dye unit in a substrate-dye combination, the
dye portion is activated and thereupon transfers its activation to
the substrate, which then reacts with oxygen and injures cell struc-
ture. The reaction is evidently of catalytic nature, for it continues
steadily without continuous addition of dye.

Cancer*

From a clinical point of view cancer is a progressive growth of
somatic cells which are abnormal, which invade and injure healthy
tissue, and form abnormal structures that often become infected
and break down. Cancer cells, breaking away from the main mass,
may wander elsewhere in the body, and there establish new
cancerous growths (metatases). Furthermore, many cancer cells
duplicate themselves in tissue culture. It is therefore obvious that
in cancer we are confronted with a heritable change in the somatic
cell affected. The medical terms are in general descriptive, indi-
cating the tissue involved; e.g., glioma (nerve); carcinoma (epi-
thelium); sarcoma (connective tissue); nephroma (kidney), etc.

A much clearer understanding of the basic cause of this protean
group of diseases emerges if we descend to the catalytic level of
biological happenings. For catalysts (genes, enzymes, symbionts)
dominate the chemical and physico-chemical changes which are
responsible for morphology and physiological function. Mere
heritable change in a cell is not alone enough to make it cancer-
ous, for, as has been pointed out, differentiation and evolution
both involve heritable catalyst changes in cells. It is the peculiar
and harmful consequences of the heritable catalyst change that
leads the clinician to make his diagnosis of cancer.

It has long been known that the development of cancers in man
and animals is associated with exposure to certain influences, and,
more recently, to certain definite chemical substances. Thus the
natives of Kashmir, who often suffer from burns from a charcoal
brazier (kangri) which they carry about their waist, are prone to
develop kangri cancer. The British surgeon Sir Percival Pott ob-
served that chimney-sweeps frequently developed scrotal cancers;
and later it was noted that cotton spinners exposed to oils and
workers in tar and aniline factories show a high incidence of can-

* See review by Professor Leo Loeb (Washington Univ.) in Vol. V, "Colloid
Chemistry," 1944.

230 LIFE: ITS NATURE AND ORIGIN

cer. The compounds dimethylaminoazobenzene (butter yellow)
and o-aminoazotoluene can produce liver and bladder cancers in
rats if given orally or subcutaneously, and 3,4,5,6-dibenzcar-
bazole (made by hydrogenating and condensing two molecules of
beta-naphthylamine) causes proliferation of the gall ducts in mice.
Seamen exposed to tar and to insolation, as well as sufferers from
x-ray and radium "burns" are apt to develop cancer, though care-
fully regulated x-rays of certain wave length and intensity are now
used in attacking cancers.

When butter yellow is fed to rats, biotin favors tumor forma-
tion, whereas riboflavin and allied vitamins oppose the carcino-
genic effects of this azo dyestuff.30 These findings are understand-
able on the view that biotin favors or contributes to the formation
of a new, reproducible catalyst area in what becomes a cancerous
cell, whereas selective adsorption of the vitamin material blocks
this development. A somewhat analogous case exists in the antag-
onism between the sulfa drugs and p-aminobenzoic acid (PABA),
later referred to in this chapter. The relations between PABA,
inositol and pantothenic acid, in affecting the graying of the hair
of black rats, are curious and devious. According to G. J. Martin31
the absolute amount of PABA is not the important factor in this
syndrome, but its ratio to pantothenic acid, which dominates the
vitamin-synthesizing powers of the gastrointestinal flora in the
rats.32

In 1915 Yamagawa and Ichikawa33 produced cancers in the ears
of rabbits by continued application of certain tars. In the valua-
ble book34 by Prof. Louis F. Fieser of Harvard University there
is reviewed the fascinating story of the team-work of chemists,
physicists, physiologists and others, which led to the isolation,
from carcinogenic tar, of a previously unknown but potently ac-
tive hydrocarbon, 3,4-benzpyrene, although it was present only
to the extent of about 0.003 per cent. Synthetic 3,4-benzpyrene,
prepared after its structure was clarified, is identical in its action
with that obtained from tar. A few details of this important de-
velopment may be mentioned. High-boiling tar fractions proved
to be non-carcinogenic; but I. Hieger35 observed that active tars
and oils gave a characteristic fluorescence spectrum, with bands
at 4,000, 4,180, and 4,400 A. Since 1,2-benzanthracene was found
to give similiar bands, J. W. Cook prepared a large number of al-
lied compounds, among which 1,2,5,6-dibenzanthracene proved
to be actively carcinogenic — the first pure substance of known

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 231

structure thus characterized. Finally, J. W. Cook, C. L. Hewett
and I. Hieger36 extracted from about two tons of active tar a tiny
percentage of 3,4-benzpyrene; it produces epitheliomas in mice
after about 5.7 months application of dilute benzene solutions,
whereas 1,2,5,6-dibenzanthracene takes about 8 months to produce
a like effect. Later it was found that methylcholanthrene, closely
related to certain sex hormones and first synthesized by degrading
desoxycholic acid (a bile constituent), is still more potent, giving
cancers in about 5 months. These carcinogenic agents may cause
cancers to develop in various tissues, e.g., epitheliomas when ap-
plied to the skin, sarcomas when injected subcutaneously. Prof.
Fieser stated:

"While proof is entirely lacking, it appears possible that many
forms of cancer may originate in the metabolic production of
methylcholanthrene or related substances from the bile acids, or
perhaps from sterols or sex hormones, of the body. . . . Entirely
unknown is the mechanism whereby certain hydrocarbons start
normal cells on a career of malignancy. If chemical reaction is in-
volved, the nature of the change is entirely obscure. . . . Possibly
the molecular dimensions and the surface activity of the substances
are as important as their chemical characteristics."

The view here being maintained is that the effects of carcinogens
are due to their ability to produce heritable changes in biocatalysts,
either by inhibiting or modifying existing catalysts, or by entering
into the creation of new ones.

In some cases viruses are known to produce cancer (e.g., Rous
chicken sarcoma), but it is not yet clear whether the self-repro-
ducing (autocatalytic) virus acts as a catalyst of itself, whether it
induces changes in other biocatalysts, or whether both of these
events simultaneously occur. In any event, the virus, whether
catalyst or catalyst inhibitor or modifier, is continually supplied
by its own autocatalysis. It can catalyze the formation of specific
antibodies in the host fowl, and it may compete for, utilize or
destroy substances essential to the normal catalysts or metabolism
of the cell.

Since there is not even a suspicion of evidence that the trivial
quantities of chemical carcinogens reproduce themselves, it ap-
pears that their specificities of chemical structure, reflected in
their active surfaces, enter into the formation of new self-dupli-
cating catalyst areas. This is the mechanism whereby the cell
starts off on a career of malignancy. Where cancer cells reproduce

232 LIFE: ITS NATURE AND ORIGIN

themselves in tissue culture, no steady supply of the original
carcinogen itself need be furnished; but in some instances a steady
supply of activating substance may be important or essential.
Thus Dr. Charles Huggins of the Dept. of Surgery, Univ. of
Chicago, stated36* that "it is possible by reducing the amount or
the activity of circulating androgens to control, more or less but
often extensively, far-advanced prostatic cancer in large numbers
of patients. In this special case, androgen control seriously dis-
turbs the enzyme mosaic of the cancer cells at least with respect to
the important energy producing protein-catalysts, the phosphatases.
As a contribution to the problem of cancer treatment, it is well
to emphasize that any interference with an important enzyme
system of a cell, normal or malignant, will cause in that cell a
decrease in size and function." Apart from castration, the ad-
ministration of female sex hormone (estrone), or of the chemically
quite different diethylstilbestrol, could cut down the circulating
androsterone; and I am informed that this type of treatment is
being successfully used in prostatic cancer.

It may be noted that the tendency toward cancer development
in older people may be related to chemical alteration of sex hor-
mones or their precursors, resulting in formation of carcinogenic
substances.

In this connection it is interesting to refer to another case where a
steady supply of an activating substance has led to cancer-like develop-
ments. Dr. Peyton Rous,37 of the Rockefeller Institute for Medical
Research, whose discovery of the Rous chicken sarcoma virus exposed
a new type of cancer-producing agent, states*:

"Yet one discovery there was, made almost 40 years back,38 which
justified the inference — though this has only lately been drawn — that
an actuating cause for neoplastic change need not necessarily originate
within the cell. A certain few substances, notably the fat-soluble dyes
Sudan III and Scharlach R, when dissolved in olive oil and injected
just beneath the covering epithelium of the skin, will cause its cells to
proliferate vigorously and invade the underlying tissue like those of
a carcinoma. They may even penetrate into the blood and lymph
vessels, though no secondary growths result. To all appearance an
active epidermal cancer has come into being, but this state of affairs
continues only so long as the stimulating influence of the dye permits.
Within a few weeks, as the latter is carried away, the cells leave off
aggression and differentiate like healthy epidermal elements, and soon

* Reprinted by permission from "Science in Progress," Series V (Yale University
Press) and American Scientist.

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 233

all that remains is some scattered oil-containing cysts lined with ordi-
nary epidermis. No real conversion into the neoplastic state has taken
place, though a second injection of dye at the same spot causes malig-
nancy to be simulated for a longer time. If the Scharlach R were not
lost, if it went along with the multiplying cells, increased as they did,
and because of this continued to urge them on, surely a growth run-
ning the course of a true neoplasm would result. Agents which do
precisely these things have been discovered. They are the tumor-
producing viruses."

There is evidence showing that the viruses may often persist in cells
as harmless symbionts, ready to bring about disease when favorable
conditions permit. An example of these so-called "latent" viruses
occurs in the King Edward potato, where it causes no evident disease;
but it can kill other varieties upon inoculation. And a virus infec-
tion superimposed upon a "pre-cancerous" irritation may cause rapid
cancer development. Thus when the virus from the naturally occur-
ring papilliomas of wild cottontail rabbits is injected into the blood
stream of domestic rabbits already having papilliomas induced by tar,
"it localizes in these growths, which are benign and usually indolent,
with the result that some of them start growing with unprecedented
speed, while others change equal swiftness to carcinomas, often very
malignant, an alteration which tar papilliomas undergo only occa-
sionally and after a long while if let alone. It is plain that the virus
acts in concert with the unknown cause for tar tumors, with result in
cancers which otherwise would not occur."37 It must here be pointed
out that the action of both the tar and the virus are explicable in
terms of persistent and heritable changes in biocatalysts; the virus
and/or its products may upset existing catalyst structures.

In certain strains of mice most of the old females develop breast
cancers. If fathered by a male of a relatively "cancer-free" strain,
the young of a "cancer strain" mother develop cancers. But the
young of a "cancer-free" mother by a "cancer strain" father seldom
develop cancers. It was found by workers at the Roscoe B. Jackson
Memorial Laboratory at Bar Harbor, Maine, that in these cases
this "maternal influence" is not genetic, but is transmitted to the
sucklings by way of the milk. "So effective is the 'milk factor'
that a single nursing during the first days after birth is enough to
confer the liability to mammary tumors not only on the young
but on their descendants. Whatever it is that the milk contains
must get into the blood or lymph through the gut wall — which is
especially permeable to large molecules during the first days of
life — and be conveyed to the rudimentary mammary glands.
Here it persists and increases in quantity as the glands develop.

234 LIFE: ITS NATURE AND ORIGIN

At times it is demonstrable in the blood and in certain other
tissues, but it causes no visible changes anywhere and has no
untoward effect until the mouse begins to age. Then one or
more cancerous growths appear. This happens earlier, and the
tumors are more often multiple, in mice which have had many
litters of young and in those injected with the sex hormones
which stimulate mammary proliferation. From the cancers noth-
ing can be secured which will cause tumors on direct inoculation,
though they yield the 'milk factor' in quantity. The many phys-
ical and chemical studies made of this factor all go to show that it
has the attributes of a virus, and it exhibits the narrow specificity
of those which give rise to tumors, its presence ultimately resulting
in growths of a single organ and of but a single sort, the kind of
mammary cancer common in mice. Furthermore, antibodies
capable of neutralizing it are formed by the body, as in the case
of the tumor-producing viruses. Yet with all this it fails to cause
growth when injected into mammary tissue."37

However, many specific molecules are known to lead to the
development of cancers, e.g., l:2-benzanthracene and quite a
number of its derivatives, besides other organic substances pre-
viously mentioned. While these carcinogens are not themselves
duplicated in the cell or the organism, they give rise to auto-
catalysts which are duplicated, even in tissue cultures of the cells
whose cancerous potencies they determine. It seems more rea-
sonable to consider the few cases where viruses are known to
produce cancers as special examples under the broader view of
heritable cellular catalyst change, rather than to stretch the term
"virus" far beyond its generally accepted meaning. Nor is it neces-
sary to assume that "latent" viruses lurk in all plants and animal
cells awaiting merely for a preliminary excitation before launch-
ing their cancerous onslaught. The experiments of Peyton Rous
and W. E. Smith39 are illuminating. Realizing that the period of
gestation is too short for experimental production of mouse
cancers in utero, they applied a mixture of the potent carcinogen
methylcholanthrene and Scharlach R to embryo mouse epidermis
inplanted in the thigh muscles of mice. The majority of the
tumors that appeared were progressively enlarging, invasive carci-
nomas. By similar technique cancerous growths were produced
in wide variety in lung, stomach, biliary tract, intestine, kidney,
ureter, urinary bladder, ovary, testis, and nerve tissue. Consid-

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 235

ering these experiments, Rous states in the American Scientist
(1946):

"To account for these multifarious neoplasms by the localiza-
tion in the embryo tissues, before and after implantation, of tumor
viruses like those already known, each capable of producing neo-
plasms of but a single sort, one would have to suppose that a great
swarm of such agents circulate constantly in the blood of the
mother mice or those to which the tissue had been transferred,
and that they regularly lodge, each in the embryo cells suited to
harbor it. Nature is profuse and often does things in what seems
to be the hard way, yet the existence of such a state of affairs seems
beyond belief. So, too, with the possibility that a single source
virus reaches cells of every sort early in gestation, from then on
sojourning with them and becoming peculiar to them, and that
variants arise after awhile — if conditions are right — which mani-
fest the narrow specificity and limited scope of the viruses with
which we are acquainted. The milk factor can hardly be cited in
support of this conception of a widely disseminated and pluri-
potential source virus, since its localization and its effects are both
restricted to mammary tissue, while furthermore it is responsible
for but a single kind of tumor out of the number to which the
mouse mamma is liable. One is forced to conclude that the cells
of the embryo have an inherent capacity to undergo neoplastic
change."

Every cell, embryonic or not, has enormous numbers of specific
molecules in extensive variety, and most kinds of cells may develop
neoplasms. Besides carrying the specific molecules responsible for
differentiation, the gametes or the egg may also carry particles (in
some cases even viruses) responsible for neoplastic developments
if suitable conditions permit the formation of cancer-determining
catalysts.

There is reason to believe that the structures determining the
specificities of some biocatalysts are, in part at least, held together
by forces much weaker than those of primary chemical valency —
by van der Waals forces, adsorption, or hydrogen bonds. That
these forces are strengthened by desiccation and weakened by
hydration is well known to all users of aqueous adhesives. Em-
bryonic tissues are much more highly hydrated than adult tissue,
and this might be a factor in their susceptibility to catalyst change.
In the presence of suitable specific particles, new self-duplicating
catalyst areas might form and lead to cancer. The phenomenon

236 LIFE: ITS NATURE AND ORIGIN

of "crossing over" in the chromosomes bespeaks their soft, quasi-
gelatinous nature, which permits them to break apart and re-
cement themselves in new arrangements. Whatever truth there
may be in the popular belief that a blow, on the tender and
hydrous tissues of the breast, for example, may sometimes lead to
a cancer, might become understandable on this basis of traumatic
fracture of a harmless or useful catalyst area followed (fortunately
rarely) by the formation of a harmful one. Experiments with
localized and not too violent ultrasonic vibrations represent an
experimental approach to such questions.

There is evidence that a virus, entering the body as an infective
agent, may persist there and be transmitted to progeny, possibly
forming a persistent addition to the self-duplicating units of the
cytoplasm of body cells, or of the body fluids. Mice experimentally
inoculated with a non-fatal dose of choriomeningitis virus develop
an immunity in 5 to 7 days and rapidly become free of demon-
strable virus. Pregnant mice when inoculated seem to pass the
virus on to their offspring, which develop after birth almost as
normal mice, but continue to carry the virus and pass it on to
their progeny.40 Dr. Charles Armstrong reported41 that a strain
of choriomeningitis virus had been passed "in an unbroken series
from an infected mother through 1 1 generations of her offspring
with no apparent tendency of the virus to weaken or disappear.
It has also been observed by Haas42 that these congenitally infected
mice are far more efficient transmitters of the disease to normal
cage mates than are mice inoculated after birth." Probably mice
develop antibodies against the virus antigen. Furthermore, we
have here evidence for a non-genic inheritance mechanism.

Plant Galls and "Plant Cancers"

Inoculation of a host plant with the bacterium Phytomonas
tumorjaciens produces "crown gall." In the case of sunflower
plants, true secondary tumors developed several internodes away
from the primary tumor.43 On confirming this work recently,
P. R. White and A. C. Braun found that the secondary tumors
were generally sterile, and their tissues could breed true in vitro
in a medium which remained bacteria-free, even though capable
of supporting a profuse growth of the gall-initiating Phytomonas
tumorjaciens. These authors conclude that the affected tissues
have undergone a drastic change, indicated (1) by the abnormal
capacity to produce galls, and (2) by their abnormal growth habits

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 237

in vitro. "That this change was originally brought about by some
stimulus from the crown gall organism seems clear. That its
maintenance is not dependent on the continued presence of the
bacterium is equally clear."44

These results are understandable on the basis of transmissible
change in biocatalysts or catalyst systems, either through the
modification of, or the creation of, self-duplicating catalysts, or
through inhibitions of individual catalysts. Conceivably, these
heritable changes may be carried by the genes or by the cytoplasm;
but the original stimulus must form some new autocatalytic (self-
duplicating) specific area or template.

45

Fasciation

The commonest example of fasciation is the cockscomb (Celosia
cristata), which came from Asia where the wild normal form (C.
argentea) is widely distributed. Professor Orland E. White of the
University of Virginia says46 that "the term fasciation, like the
term cancer, has been used to describe a series of phenomena, the
most striking of which is regions of uncontrolled or unregulated
and disordered tissue growth, resulting in an increase in weight
and volume of plant tissue . . . When fasciation occurs in a specific
structure, such as a branch, a stem, an inflorescence, an androecium
or a root, it may remain localized in these structures, or it may
occur as a general phenomenon fundamentally and simultaneously
affecting the whole plant . . . Fasciation bears an analogy to cancer
from the standpoint that apparently the same character is produced
in a given organism by many different causes some of which are
primarily and fundamentally environmental, while others are
heredity mutations."

A species of tropical mistletoe (Phorodendron) seems to exist
only in fasciated form. Fasciation is widely distributed geograph-
ically, climatically, ecologically and taxonomically, and is recorded
from over 102 of Engler's vascular plant families. Though its
effects in the growing point are most striking, it may occur in
practically any part of the plant.

It is evident that quite a number of different kinds of chemical
and physical initiators, some heritable, some environmental, may
lead to the dreadful syndrome found in the clinical cancers.
Science, through sanitation, engineering, chemistry, medicine, etc.,
is saving many lives; but as the average span of life grows longer,

238 LIFE: ITS NATURE AND ORIGIN

the greater is the chance that one of the cancer-producing mechan-
isms may become effective. The view that cancers, basically, in-
volve heritable changes in biocatalysts, has been fruitful in the
case of prostatic cancer, and it may be helpful in finding preventive
means for certain types. However, the problem is as wide as
biological science and is progressing toward solution by work in
many scientific fields, which should be encouraged. Help, and
even cures for some cases, may come from unexpected sources.
Meanwhile, surgery and other competent medical treatment are
doinsr much. The far-sighted directors of research funds realize
the importance of flank attacks on the cancer problem, and it is to
be hoped that any legislative funds will not be limited to a direct
frontal attack. Research is to be judged by results, rather than by
the amounts of money given or spent; but it often takes time
before the facts developed by research can be understood and
applied.

Drugs

The Chinese Emperor Shen Nung (2838-2798 B.C.) is credited
with having written the first Pen T'sao (Native Herbs), the three
volumes describing 365 drugs. Modern editions of the Chinese
pharmacopeia are much more extensive. In the reign of Djoser
(Zoser), first Pharaoh of the Third Dynasty of the old Kingdom,
who ruled from 2780 to 2760 B.C., the great architect and engineer
Imhotep did much to advance the healing art. In fact, the ver-
satile Imhotep, the Leonardo da Vinci of his time, became a
legendary figure and was deified as the God of Medicine, a posi-
tion later given by the Greeks to Aesculapius. Faith in the
physician no doubt was an important factor, and it still is; but
real knowledge regarding drugs grew then as it does now — by
observing and recording results. Our more intensive, intelligent,
and coordinated experimentation is termed research. However,
even the most primitive peoples have contributed to the modern
pharmacopeia: South America contributed quinine; North
America, cascara sagrada; ancient China, stramonium, chaul-
moogra oil, and ephedrine (ma huang). The African pygmies
are said to pursue a huge elephant for days, peppering his hide
with tiny arrows dipped in strophanthus, until this potent heart-
poison brings him crashing to earth.

In more modern times, active chemical substances have been
isolated from many natural drugs, such as, morphine, atropine,

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 239

and strychnine, and their actions appraised. Then experiments
were made with chemically modified drugs. For example, in 1868
Drs. A. Crum Brown and T. R. Fraser found that by introducing
a methyl group into strychnine, theobaine, or brucine, their
tetanizing action was changed into a paralyzing one (Sir T. C.
Allbutt). Then synthetic organic drugs appeared: antipyrine
(1883), phenacetin (1887), acetylsalicylic acid or aspirin (1899),
and salvarsan (1912). This last was known as "606," because that
was its identification number among the many compounds being
tested out by Professor Paul Ehrlich (1854-1915, Nobel prize,
1908), founder of modern chemotherapy, in his search for "magic
bullets" which would kill pathogenic organisms but spare the
patient. Strangely enough, Sir William Henry Perkin, whose
chance discovery of the aniline dye Mauve opened up the synthetic
dye industry, was actually trying to synthesize quinine. We still
await its synthesis; but chemotherapy has meanwhile produced
quinacrine (Atebrine), plasmoquin (Pamaquine), and plaudrine.
The sulfa drugs are recent valuable synthetics, though sulfon-
amide was known about half a century before its pharmacological
potency was revealed by G. Domagh (Nobel prize, 1939). In
penicillin and streptomysin we have again relied on biological
synthesis, though formidable technological problems had to be
solved to produce the final drugs.

Many if not all drugs which are effective in small amounts
operate on specific enzyme systems. Since much depends on
purity of the drug, the dosage, the kind of animal tested, and
many other conditions, it is not surprising that the literature is
at times a bit confusing. Results of experiments made on isolated
enzymes in vitro may not parallel what happens in vivo, where
conditions are much more complicated. Much recent work has
been summed up by Professor Frederick Bernheim of Duke Uni-
versity47 and by A. J. Clark.48

The luminescence of various bacteria, fish, and insects (glow-
worm, fire-fly) is due to the reversible oxidation of luciferin (an
organic compound) by an enzymic catalyst, luciferase.49 Other
conditions being normal (e.g., state of culture, supply of oxygen
and glucose, temperature, pressure), a growth of suitable bacteria
tends to maintain a constant level of luminosity, which is affected
by various drugs. Professors Frank H. Johnson and Henry Eyring
of Princeton University found that sulfanilamide inhibits lumi-
nescence, acting as if the drug combined with a prosthetic group

240 LIFE: ITS NATURE AND ORIGIN

of the enzyme. Drugs like urethane, alcohol, ether, and similar
"lipoid solubles" seem to combine with bonds of the protein
carrier, when reversible denaturization by heat or pressure renders
these bonds available.50

Professor Clifford S. Leonard of the University of Vermont, in
discussing the problem of the role of sulfhydryl enzymes in the
mechanism of the action of certain chemotherapeutic agents51
suggests that the action of mercurials and arsenicals is on protein
enzymes containing SH groups. To be useful, the drug must
adversely affect the catalysts of the invading organism, without
too much harm to the host; so research now includes work on the
biocatalysts of malarial plasmodia, trypanosomes, etc. According
to von Brand et a/.52 90 per cent of the respiration of the South
American Trypanosoma crazii, in cultures, is stopped by inhibitors
of oxidases and dehydrogenases, and only 10 per cent by inhibitors
of SH enzymes. The respiratory mechanism of this organism is
therefore quite different from that of the African trypanosomes,
and Chagras disease, which it causes, does not respond to drugs
successfully used in the African type infections.

Referring to the work of Professor E. A. G. Barron of the University
of Chicago and P. Singer,52a which aimed to determine "which of the
enzymes are 'SH' enzymes and which enzymes are not dependent on
the presence of free SH groups for their activity," Professor Leonard
states:

"We can perhaps review Barron and Singer's work to advantage
from a viewpoint which they did not discuss, namely the mechanism
of action of arsenicals and mercurials on parasites, and on the host's
tissues. For the concept that the essential attack of these agents is on
an essential enzyme system which is dependent on SH groups for its
function, or on multiple such systems, seems far more illuminating
than the general attack on proteins or on glutathione. RSH becomes
ESH, where E is the residual part of an enzyme. It would seem that
far lower concentrations than those needed for such general attack
would suffice to stop the intermediary metabolism of cells by means of
this inhibition of enzymes. What processes would thus be stopped?
Barron and Singer show that there are many SH enzymes.

"Thus in the first phase of metabolism of carbohydrate, SH enzymes
include: muscle phosphorylase, phosphoglucomutase, hexokinases, and
phosphoglycaraldehyde oxidase. In the stages: pyruvate to lactate, or
to acetaldehyde and C02, carboxylase is an SH enzyme, lactic oxidase
is not. In the oxidative phase of carbohydrate metabolism among
the SH enzymes are: hexosemonophosphate oxidase, pyruvic oxidase

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 241

(and this is very sensitive to reagents), alphaglutarate oxidase, malate
oxidase, succinoxidase, and the phosphorylases, myosin (adenosine tri-
phosphatase) and myokinase.

"Not affected, and hence not SH enzymes, are: lactate oxidase, iso-
citrate oxidase, acid phosphatase, carbonic anhydrase, polyphenol oxi-
dase and catalase, although they may have SH groups in their protein.
SH enzymes of fat metabolism are: liver stearate oxidase, E. coli
stearate oxidase, betahydroxybutyric dehydrogenase, acetate oxidase,
pancreatic lipase; while among the enzymes concerned in protein
metabolism, SH enzymes include: d-amino acid oxidase, transaminase,
/-glutamic dehydrogenase and monamine oxidase, but not diamine
oxidase, pepsin or trypsin.

"Barron and Singer concluded that the role of glutathione is to
produce reactivation of SH enzymes where they have been rendered
ineffective by oxidation or mercaptide formation. After all the years
of controversy about the role of glutathione, this is a rather interesting
postulate.

"Thus we see that there is such a multiplicity of enzymes which the
arsenicals can attack, that we can scarcely put our finger on any one
point of attack where we could say: this will damage the parasite
before it will damage the host. One of the most sensitive enzymes was
pyruvate oxidase. Should we consider that arsenical attack upon this
enzyme is crucial for the parasites?

"Reiner and Smythe53 showed in 1934 that Trypanosoma equi-
perdum splits glucose to two moles of pyruvic acid. Perhaps the
amount of pyruvate oxidase which this parasite can form is limited,
for late in trypanosomiasis in the rat there is a pyruvic acid acidosis
in the host."

In a note Dr. Leonard points out that this pyruvic acid formation
by Tr. equiperdum may account for its virulence in hosts, since
L. Reiner and co-workers found that Tr. Lewisi, which many common
gray rats may harbor in their blood as a low grade avirulent infection,
splits glucose to succinic acid (4 C chain) and acetic acid (2 C chain),
and both of these acids are readily handled by host tissues in processes
which do not require the aid of the limited essential dietary factor,
thiamine.

Immunological experience shows that antigens closely alike
chemically may react with both their respective antibodies (cross
reactions). Similarly, enzymes may in some cases attack chemically
similar substrates (metabolites), and enzyme poisons or inhibitors
may be anticipated or fended off by chemically similar substances
which do not inhibit. The fact that para-aminobenzoic acid
(PABA) commonly nullifies the antibacterial activity of sulfa

242 LIFE: ITS NATURE AND ORIGIN

drugs,54 led D. D. Woods55 to the widely accepted view that the two
substances compete for a bacterial enzyme system which uses PABA
as an essential metabolite. But R. J. Henry56 believes that
PABA excludes the sulfa drug from some enzyme, probably the
dehydrogenases or the protein co-enzymase systems.

The well-known ability of many pathogenic organisms to develop
resistance to sulfa drugs, streptomycin, etc., indicates that they can
form specific antibodies, or else develop catalysts which can destroy
the drugs, or can become incapable of combining with the drugs,
either by physicochemical change or by the formation of a pro-
tective layer.57

One of the most feared "poison gases" of World War I was lewisite
(CI — CH=CHAsCl2), which poisons various catalysts. Peters, Stocken
and Thompson58 reported that dimercaptopropanol

OH SH SH

1 I J,

C — C — C

I I I

H2 H H2

known as BAL (British anti-lewisite) serves as an antidote. Among
other things, it stops the toxic action of lewisite on the pyruvate oxi-
dase system of the brain; and its selective affinity for arsenic and
heavy metals enables it to reverse or detoxify the inhibition of SH
enzymes by other metals. It has been used successfully against arsenic
poisoning after intensive arsenical therapy for syphilis, and also in
corrosive sublimate poisoning (HgCl2), and in brass founders' fever
(Zn). "BAL in oil for intramuscular injection should be stocked in
every hospital pharmacy" (Leonard).

In World War II, a much feared but unused "gas" was di-isopropyl
fluorophosphate (DFP), which irreversibly inhibits cholinesterase, the
enzyme (or rather, group of like enzymes) that plays an essential role
in muscular contraction and in the transmission of nerve impulses.
There is evidence that rabbit and human plasma, blood cells, and
tissues contain an enzyme capable of hydrolyzing the fluorophosphate,
and much of this enzyme is contained in the liver. It may be seen
that the degree of physiological symptoms or the death of the animal
is a resultant of the two processes. The present data do not permit
a quantitative evaluation of the role of each of these processes.59

Fluoroacetate of sodium, recently introduced as a rodenticide, kills
many mammals, the results varying with the species; most commonly
ventricular fibrillation or excessive stimulation of the central nervous
system causes death.60 The plant Dichapetalum cymosum, known to
South African farmers as "Gifblaar" is reported by J. S. C. Marais to
contain monofluoroacetic acid, and 1.0 to 1.5 grams per kilo of the
dried plant is lethal for rabbits.61 The "nitrogen mustards'* (bis and

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 243

tris betachloroethyl amines) are nitrogen analogs of sulfur mustard
(bis-betachloroethyl sulfide). Several enzymes, including hexokinase,
are highly sensitive to nitrogen mustards. "However, the fact that
there has been little correlation between the susceptibility of enzyme
systems in vitro and in vivo has delayed the acceptance of the enzyme
inactivation theory of nitrogen mustard intoxication."

Enough has been said to show the extensive and basic importance
of the catalytic aspect in disease, in disease-producing agents, and
in drugs helpful in curing disease. While an understanding of
the underlying physicochemical basis of disease is not in itself a
remedy, it should be helpful in efforts to avoid, ameliorate, and
cure diseases, and it may light the way for research. However,
we should always be ready to recognize and accept the unexpected
and the unsuspected actualities.

When a drug irreversibly damages some essential catalyst of an
invading organism, the organism dies. If the damage is reversible,
the activities of the organism may be only temporarily inhibited.
Where the catalysts affected are not vital ones, the organism may
carry on what, for it, may be considered an abnormal life, and its
usual forms may be modified. In this connection the facts re-
garding Mycobacterium tuberculosis and the closely allied M.
leprae are of interest; their classical forms are the acid-fast rods
which stain red in the Ziehl-Neelson technique (carbolfuchsin
followed by acid-alcohol). Dr. Eleanor Alexander-Jackson of
Cornell University62 developed a differential triple stain for
demonstrating and studying non-acid-fast forms of the tubercle
bacillus in sputum, tissue and body fluids. The non-acid-fast
forms, including hitherto undemonstrated zoogleal and globoid
forms, are clearly brought out by this triple staining method,
which can be summarized as follows:

The Ziehl-Neelson technique is first followed, including flooding of
the slide with Loeffler's methylene blue counterstain; but the power
of this blue stain is increased by mixing in, on the slide, 8 small drops
of normal NaOH, and allowing this to remain not over one minute.
The entire slide, apart from the acid-fast forms (if present) is stained
deep blue. The washed slide is then flooded with a freshly made
solution of sodium hydrosulfite (250 mg in 50 cc water), which removes
the blue from all but the non-acid-fast tubercle forms. The slide is
quickly washed and then counterstained with an acid green, and
against the green background acid-fast red and non-acid-fast blue
forms stand out clearly.63

244 LIFE: ITS NATURE AND ORIGIN

Dr. Alexander Jackson has observed in cases of tuberculosis treated
with streptomycin, and of leprosy treated with promin and chaul-
moogra oil, that the rod form seems to be suppressed, while zoogleal
and globoid forms predominate.

REFERENCES

1 H. A. Evans and O. Swezy, Mem. Univ. Cal. (1929) 9, No. 1.

2 "Life As a Biochemical Mechanism," contributed to the Symposium on Physical
Education and Health held at New York University, Feb. 27-March 1, 1930 (N. Y.
Univ. Press, Jay B. Nash, Ed., 1930).

3 F. B. Hutt, /. Genetics (1930) 23, 109.

4F. A. Rich, Vermont Agr. Expt. Sta. Bull. (1923) 230.

5 Ann. N. Y. Acad. Sci. (1945) 46, 1-126.

e C. C. Little, /. Exptl. Med. (1934) 59, 229-250.

7 W. Landauer and L. C. Dunn, /. Hered. (1930) 21, 290-305; F. B. Hutt, /. Genetics
(1930) 23, 109-127; W. Landauer Biol. Symposia (1942) 6, 127-166.

8 "Genetics of the Mouse," Cambridge Univ. Press, 1943.

9 "The Principles and Practice of Medicine," 15th ed., 1944.
"> /. Hered. (1938) 29, 280-289.

11 F. M. Burnet, /. Path, and Bad. (1929-1932).

12 J. T. Parker, /. Exptl. Med. (Dec, 1924); V. Menkin, 1940.

13 J. E. Blair, Bact. Rev. (1939); B. Kleiger and J. E. Blair, Arch. Surg. (Oct., 1942;
Apr., 1943).

14 G. M. Dack, "Food Poisoning," Univ. of Chicago Press, 1943; C. E. Dolman,
Can. J. Pub. Health (May, 1943).

15 P. M. Panton and F. C. O. Valentine, Lancet (Mar. 5th, 1932); Valentine, ibid.
(March 7th 1936); J. Wright, ibid. (May 2nd, 1936).

16 F. Burnet, loc. cit.; J. E. Blair, Bact. Rev. (June, 1939).

17 L. M. Bryce and P. M. Rountree, /. Path, and Bact. (July, 1936); M. Llewellyn
Smith and S. A. Price, ibid. (Nov. 1938).

18 Smith and Price, loc. cit.

19 F. Duran-Reynalds, Bact. Rev. (Dec, 1942).

20 A. M. Fisher, Bull. Johns Hopkins Hosp. (Dec, 1936); R. W. Fairbrother,
/. Path, and Bact. (Jan., 1940); W. Smith and J. H. Hale, Brit. J. Exptl. Path. (June,
1944).

21 A. M. Fisher, loc. cit.; R. R. Madison, Proc. Soc. Exptl. Biol. Med. (Nov., 1935);
R. Christie and H. Wilson, Austral. J. Exptl. Biol. Med. (1941).

22 S. W. Ranson, C. Fisher and W. R. Ingram, Arch. Neurol. Psychiatry (Sept.,
1937) re hypothalamus.

23 Keeler and Trimble, /. Heredity, 51 (Feb. 1940).
2* Science (1942) 95,99.

^Annalen (1861) 117, 98. •

25 Abbott and D. E. Lynn, Jr., Science (1941) 94, 365.

26 Z. physiol. Chem. (1891) 15, 228.

27 J. Biol. Chem. (1914) 9, 151.
^Berichte (1914) 47, 2630.

29 "Photodynamic Action and Diseases Caused by Light" (Reinhold Publishing
Corp., 1941).

30 V. du Vigneaud et al., Science (1942) 95, 147; see also /. Am. Med. Assn. (1942)
118, 982.

SOME CATALYTIC ASPECTS OF DISEASE AND DRUGS 245

31 Am. J. Physiol. (1942) 136, 124.

32 See also Brody, "Bioenergetics and Growth," p. 127, Reinhold Pub. Corp., 1945.
88 Mitteil. med. Fakultdt Kaiser Univ. Tokyo, 15, 295.

34 "The Chemistry of Natural Products Related to Phenanthrene," Reinhold
Publishing Corp., 1936, Supplement, 1940.

35 Biochem. J. (1930) 24, 505.
36 /. Chem. Soc. (1933), p. 395.
868 Science (1943) 97, 541-4.

37 American Scientist (1946) 34, 329-358.

38 B. Fischer, MiXnchen. med. Wochenschr. (1906) 53, 2041.
39 /• Exptl. Med. (1945) 81, 579.

40 E. Taub, J. Exptl. Med. (1938) 68, 229.

41 Kober Lecture, Military Surgeon (1942) 91, 129-146.

42 V. H. Haas, Pub. Health Rep. (1941) 56, 285.

43 E. F. Smith, N. A. Brown and U. S. McCulloch, U. S. Dept. Agri. Bull. 255 (1912).

44 Science (1941) 94, 239; Cancer Research (1942) 2, 597-617. See also J. P. Martin,
Science (1942) 96, 39; and P. R. White, Fourth Groiuth Symposium (1942) 6, 55-71.

45 For further discussion on plant galls, with references, see "Biochemistry and
Morphogenesis," by Dr. Joseph Needham (Cambridge Univ. Press, 1942, pp. 106-110.

46 /. Hered. (1945) 36, 11-22.

47 "The Interaction of Drugs and Cell Catalysts."

48 "The Mode of Action of Drugs on Cells," Williams and Wilkins Co., 1933; also
Heffter's "Handbuch der Exptl. Pharm.," 1937.

49 See review by Professor E. Newton Harvey, Princeton Univ., in "Colloid Chem-
istry," Vol. II, pp. 395-402, Reinhold Pub. Corp., 1928.

s0 Conference on Bioluminescence, N. Y. Acad, of Sciences, Nov. 8th, 1946.

51 Bull. Natl. Formulary Committee (1946) 14, 139-149.

52 /. Gen. Physiol. (1946) 30, 163.

B2a/- Biol. Chem. (1945) 157, 221, 241; Singer, Brewer's Digest (1945) 20, 85, 104.

53 Proc. Soc. Exptl. Biol. Med., 31, 1086.

54 P. Fildes, Lancet (1940) 238, 955.

55 Brit. J. Exptl. Path. (1940) 75, 383.
™Bact. Rev. (1943) 7, 175.

57 Recent work in these very active fields of research is abstracted in two excellent
and extensive reviews: "Metabolite Antagonists," by Dr. Richard O. Roblin, Jr.,
[Chemical Reviews (1946) 38, 255-337, 471 references], and "Interference with
Biological Processes Through the Use of Analogs of Essential Metabolites" by
Professor Arnold D. Welch (Western Reserve Univ.), Physiological Reviews (1945)
25, 687-715 (94 references).

58 Nature (1945) 156, 616.

59 A. Mazur, /. Biol. Chem. (1946) 164, 271-289.

60 M. B. Chenoweth and Alfred Gilman, /. Pharmacol. Exptl. Therapeutics (1946)
87, 90-103.

61 Onderstepoort J. Vet. Sci. and Animal Ind., (1944) 20, 67-73.

62 Science (1944) 99, 307.

<* Ann. N. Y. Acad. Sci. (1945) 46, 127-152.

Chapter 11

Catalysis as the Efficient Cause of Evolution

The basic notion of evolution goes back at least as far as the
Greek philosopher Empedocles (450 B.C.). A little later Aristotle
(384-322 B.C.) anticipated the theory of descent. The ancient
Greeks, who acquired so much in art and practical skills from the
earlier civilizations of Egypt and Crete, were no mere copyists,
but transmitted to the modern world superlatively improved
phonetic writing as well as great literary and artistic creations.
But while Greek philosophy produced many ingenious intel-
lectual explanations of physical happenings, these were seldom
submitted to the touchstone of experiment. Archimedes
(287P-212 B.C.), who devised experimental means for determining
specific gravity, was the exception rather than the rule.

Henry F. Osborn ("From the Greeks to Darwin") gives the fol-
lowing resume of Greek notions of causation: "The Greeks left
the later world face to face with the problem of Causation in
three forms: First, whether Intelligent Design is constantly oper-
ating in Nature; second, whether Nature is under the operation of
natural causes originally implanted by Intelligent Design; and
third, whether Nature is under the operation of natural causes
due from the beginning to laws of chance, and containing no
evidence of design, even in their origin."

In this epitome Osborn evidently confines his remarks to the
first of the Aristotlian causes, which are:

(1) Formal Cause: the conception or idea of what is to be real-
ized, whether this idea exists in the mind or in the nature of
things.

(2) Material Cause: what is to be acted upon by (1).

(3) Efficient Cause: the force or agent that does the work.

(4) Final Cause: the object or end to be reached by the process.
We are here concerned largely with (3), the mechanism whereby
the material substance of living things is so directed that there
emerges the echelle des etres, indicative of gradual evolution.1

246

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 247

Since what Osborn terms "natural causes" commonly operate
under the laws of chance, there seems no experimental method of
differentiating between the second and the third of the three
causation forms he mentions, though many feel compelled by the
wonders of natural phenomena as revealed by science, to believe
in and admit the existence of something beyond human under-
standing. Apart from such metaphysical considerations, modern
science tries to explain the causes of phenomena on the basis of the
behavior of material units at various stages of structure or organ-
ization. This is real dialectic materialism, and is in itself most
wonderful and interesting.

The materialistic political expansion of Rome left little room
for scientific advance. According to Gibbon, the Roman Em-
peror Tiberius, on being shown a specimen of "unbreakable"
glass, sent the inventor to immediate execution because the im-
perial coffers received taxes on glass.2 The fall of Rome and the
establishment of the Church as a factor dominating medieval
thought reduced science largely to ecclesiastical quibbling under
the fiat that the divine mind guided every detail in nature, a
concept allied to the Mohammedan view: "It is the will of Allah."

The development of the Renaissance began to liberate science.
Roger Bacon (c. 12 14-1 294), the clear-thinking Franciscan who
studied Arabic lore and dabbled with gunpowder, was imprisoned
for 14 years. The protean Leonardo da Vinci (1452-1519), known
to most for the great artist that he was, prided himself most on
being an engineer, studied the flight of birds and sketched a flying
machine. He also made keen anatomical and physiological ob-
servations and experiments, and pointed to the fossil shells found
on mountains as evidence that those areas were once covered by
the sea. His remarkable records, kept in "mirror writing," have
only recently been published in part. Giordano Bruno (1549-
1600) was burned at the stake as a heretic. But the world con-
tinued to move.

With the classification ("Systema Naturae") of plants and ani-
mals by the Swedish professor Carl von Linne (1707-1778), com-
monly known as Linnaeus, we begin to approach modern times.
Georges Cuvier (1769-1832), who founded the sciences of paleon-
tology and comparative anatomy, believed with Linnaeus that
species were fixed by special divine creation, and so great was
Cuvier's influence supported by that of Buffon (1707-1788), that
when Jean Lamarck (1744-1829) advanced the view that there is a

248 LIFE: ITS NATURE AND ORIGIN

progressive and imperceptible transformation of one species into
another, the notion was rejected. Speaking of Cuvier, Prof. R. C.
Punnett said: "Had it not been for him and his influence it is pos-
sible that Lamarck's views would have attracted more support,
and that contemporary copies of 'Philosophic Zoologique' would
not be among the rarefies of zoological literature."

Unfortunately, Lamarck coupled his valid concept that animals
become adapted to modes of life different from their ancestors,
with what seemed a naive theory of causation. Without attempt-
ing to explain the mechanism whereby the employment of the
head in butting could lead to outgrowths of bone and epidermal
horn in stags and bulls, he attributed the formation of these pro-
jections to "an interior sentiment in their fits of anger, which
directs the fluid more strongly toward that part of their head."3

It was this vulnerable aspect of Lamarckism that led James
Russell Lowell to include in the "Remarks of Increase D.
O'Phace"4 the following amusing lines:

Some flossifiers think thet a fakkilty's granted
The minnit it's proved to he thoroughly wanted,
Thet a change o' demand makes a change o' condition,
An' thet everything nothin' except by position;
Ez, fer instance, thet rubber-trees fust begun bearin'
Wen p'litikle conshunces came into wearin', —
That the fears of a monkey, whose holt chanced to fail,
Drawed the vertibry out to a prehensile tail

But the spirit of inquiry was in the air. The great Scotch-
German philosopher, Immanuel Kant (1724-1804) in his "An-
thropology," a book assembled in 1798 from lectures he had deliv-
ered during his long life, actually raised the question of man's
origin from animals. Pointing out that when early man was
surrounded by hostile wild animals, human infants, if they cried
as loudly as they now do, would have been found and devoured
by beasts, and that, therefore man must have been different then
from what he now is, Kant wrote: "How nature brought about
such a development, and by what causes it was aided, we know
not. This remark carries a long way. It suggests the thought
whether the present period of history, on occasion of some great
physical revolution, may not be followed by a third, when an
orang-outang or a chimpanzee would develop the organs for
walking, touching, speaking, with a central organ for the use of

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 249

understanding, and gradually advance under the training of social
institutions."

The great poet Johann Wolfgang von Goethe (1749-1832) was
much interested in science, and observed, among other things,
that the flower consists of metamorphosed leaves. In fact the term
morphology was introduced by Goethe in 1817, and this branch
of science has had much to do with the development of evolu-
tionary theory.5

The foundations of comparative embryology were laid by
Karl E. von Baer (1792-1876), who discovered the human ovum.
His Biogenetic Law may be summarized (following Singer) as
follows:

(1) In development, general characters appear before special
ones.

(2) Less general characters developed from more general ones;
then follow the special characters.

(3) As development proceeds, animals of one species diverge
continuously from animals of another species.

(4) In the course of development, a higher animal passes
through stages which resemble stages in development of
lower animals.

His law of "corresponding stages," in the development of ver-
tebrate embryos is exemplified by the story told of him that, when
he had forgotten to label some jars containing specimens preserved
in alcohol, he said: "I am quite unable to say to what class they
belong. They may be lizards, or small birds, or very young mam-
malia, so complete is the similarity in mode of the formation of the
head and trunk in these animals. The extremities are still absent,
but even if they had existed in the earliest stage of development
we should learn nothing, because all arise from the same funda-
mental form." Von Baer asked:6 "Are not all animals in the
beginning of their development essentially alike, and is there not
a primary form common to all?"

Developments in the newer sciences of morphology, embryology
and paleontology were steadily undermining the notion, acceptable
to ecclesiastics and accepted by authoritative scientists, that species
are fixed. Robert Chambers, a Scotch publisher, wrote (1843-
1846) what became a very popular book entitled "Vestiges of the
Natural History of Creation," which was published anonymously
because he did not want to bring on his publishing firm the
opprobrious charge of heterodoxy. In the course of his exposi-

250 LIFE: ITS NATURE AND ORIGIN

tion, Chambers remarked that the existence of various domes-
ticated races of animals indicates that at best certain species could
become heritably modified. He also thought that the existence
of rudimentary organs militated against the hypothesis of special
creation, i.e., small teeth in the fetus of the whalebone whale, tiny
imperfect extra toes on the splintbones of horses, traces of hind
limbs in certain snakes. As Punnett observes, the great popularity
of "Vestiges" indicated that educated people were not averse to
the notion of the mutability of species; but apart from scientific
imperfections, the book gave no reasonable suggestion as to the
process whereby a heritable succession of forms could be estab-
lished.

Natural selection was the mechanism proposed by Charles
Robert Darwin (1809-1882) and Alfred Russell Wallace (1823-
1913) to account for this heritable succession, and they reached
this conclusion independently — Darwin as a result of twenty years
of study, Wallace during an attack of intermittent fever at Ternate
in the Moluccas, in February, 1858, when thinking of Malthus's
"Essay on Population" which he had read a few years before.
This essay had also stimulated Darwin. When the idea of the
survival of the fittest emerged, Wallace said that in a couple of
hours he had thought out the whole theory. In three evenings
he finished his paper, which he sent to Darwin for an opinion, and
thus precipitated the publication of Darwin's work, first in a joint
paper read to the Linnean Society on July 1st, 1858, and next
year in "The Origin of the Species." P. C. Mitchell, Secretary of
the Zoological Society of London, points out that the theory of
natural selection, or survival of the fittest, had been suggested by
William Charles Wells in 1813, and further elaborated by Patrick
Matthew in 1831; but their pregnant suggestions remained prac-
tically unnoticed or forgotten.

It is interesting to note that Constantine Samuel Rafinesque wrote
in 1832: "There is a tendency to deviations and mutations through
plants and animals by gradual steps at remote irregular periods. This
is a part of the great universal law of perpetual mutability in ever-
thing." Born in Constantinople (Istanbul) in 1783, Rafinesque spent
ten years in Sicily, and lost his extensive herbal and sea-shell collec-
tions together with all his papers when shipwrecked on his way to
America in 1815. Within the next 20 years he accumulated an herb-
arium of 40,000 specimens. He visited Audubon, taught foreign
languages at Transylvania University (Lexington, Kentucky), and in

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 251

spite of his protean activities as scientist, poet, philosopher, author,
etc., he died in dire poverty in 1840 in Philadelphia.7

Another early American evolutionist was James Lawrence Cabell,
Professor of Comparative Anatomy and Physiology in the University
of Virginia, to whose book8 Professor Charles M. Blackford has called
attention.9 It contained much in common with the views of Darwin
which appeared a few months later.

The powerful support given Darwin's carefully documented
views by Sir Charles Lyell, Sir William J. Hooker and Thomas
Huxley led to their speedy acceptance by scientists. But ecclesi-
astical opposition, focused on a defense of dogma, was immediate,
violent and persistent, and its repercussions appeared some years
ago in the Stopes case,10 involving a law passed by the State of
Tennessee to prohibit the teaching of "evolution" in state-sup-
ported institutions. For centuries orthodox chronology was based
on the "Annales" (1650-1654) of the English Archbishop John
Ussher, who calculated from biblical data that the Creation began
on Sunday, Oct. 23rd, 4004 B.C., and ended at sundown six days
later, after the creation of animals and of man. But archeology
has found that the ancient Egyptians had a well-developed civiliza-
tion about 6000 B.C., and science has credible evidence that the
earth is about two billion years old. The Proterozoic era is esti-
mated at 500 million years, the Mesozoic at 125 million years, and
the Cenozoic at 60 million years. Evidences of man appear in
the early Quaternary, and may go back to the Pliocene epoch
of the Cenozoic.

Today, however much scientifically informed people may differ
as to the relative value of the various factors influencing evolution,
they are unanimous in accepting evolution as a fact. It will be
noted that natural selection and the survival of the fittest operate
at what may be termed macro-levels of organization, involving not
only competition between various groups of plants and animals,
but also their adaptability to changing climates and other natural
conditions. On the other hand, unless heredity could be de-
pended upon to carry on the genetic and other changes which
occur at micro-levels of organization or structure, natural selection
would have nothing upon which to operate. Therefore, while
fully recognizing the existence and operation of many aspects and
factors governing the evolution of populations over the long past,
we must confine ourselves here to the more basic micro-level, or
ultramicro-level of catalysis, from which emerge all the heritable

252 LIFE: ITS NATURE AND ORIGIN

structural and physiological changes that underlie the happenings
at macro-levels. How complex these happenings may be, can be
seen, for example, from the papers of Professor Sewall Wright,11
from T. Dobzhansky's book "Genetics and the Origin of Species"
(1941) and from G. G. Simpson's book "Tempo and* Mode in
Evolution" (1944).

We have no space here to enter these interesting fields of
ecology and paleontology which deal with a very real phenomenon
— natural selection. But as Sir Wm. Bateson remarked, its func-
tion is to select, preserving beneficial and destroying harmful
changes, and remaining indifferent to neutral ones. Bateson also
stated:12 We cannot see how the differentiation into species came
about. Variation of many kinds, often considerable, we daily
witness, but no origin of species. But that particular and essential
bit of the theory which is concerned with the origin and nature of
species remains utterly mysterious. The claims of natural selec-
tion as the chief factor in the determination of species have con-
sequently been discredited. Our doubts are not as to the reality
or truth of evolution, but as to the origin of species, a technical,
almost domestic problem."13 Bateson became a geneticist "in the
conviction that there at least must evolutionary wisdom be found."
Actually, the basic problem may be put thus: By what material
mechanism are heritable changes in bionts produced and trans-
mitted?"

Our answer to this question is simply expressed: The primal
cause of evolution is a heritable change in existing and potential*
biocatalysts, leading to heritable changes in form, function and
behavior, and therefore to heritable changes in reaction to and
interaction with the surrounding conditions of life. Some of these
conditions affect the living unit as an individual, for example,
ability to secure and survive on existing food, and to accomplish
successful mating. Other conditions affect principally groups or
populations, e.g., the existence of adequate food and group com-
petition for it, geographical factors involving isolation, and
ecological factors involving attrition between groups (red squirrels
vs. grey squirrels, carnivores vs. herbivores). Another set of condi-
tions upon which living things depend involves the presence in air,
water or soil of many essential substances and the absence of

* This refers to the transmission of new, or increased amounts of, specific mole-
cules which may in later development modify existing catalysts or help form new
catalysts.

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 253

detrimental substances. Since most living things depend upon
molecules which must reach them through the living or dead
bodies of other bionts or through biological wastes or excreta, it
is obvious that, from the chemical standpoint, few existing indi-
viduals or groups can live alone. But underlying all these and
other complexities is the basic fact that evolution depends upon
heritable changes in biocatalysts, the successful ones tending to
survive, the unsuccessful ones to die out.

The record of the rocks, imperfect as it is, represents what
actually has happened over millions of years with many widely
scattered populations of plants and animals, only some (probably
few) of which have left discovered fossil remains. It is impossible
to obtain an exact picture of the ever-varying conditions in
geologic times, though we have evidence of great movements in
the earth's crust, of glacial periods, of the probable existence of
an atmosphere containing more carbon dioxide than ours. Point-
ing out that the great defect of paleontology is that it cannot
directly determine any of the cryptogenetic facors instrumental in
the evolution of populations, because we cannot experiment with
fossil animals, G. G. Simpson states:14

"On the other hand, experimental biology in general, and genetics
in particular, have the grave defect that they cannot reproduce the
vast and complex horizontal extent of the natural environment and,
particularly, the immense span of time in which population changes
really occur. They may reveal what happens to a hundred rats in the
course of ten years under fixed and simple conditions, but not what
happened to a billion rats in the course of ten million years under
the fluctuating conditions of earth history. Obviously, the latter
problem is much more important. The work of geneticists on pheno-
genetics and still more on population genetics is almost meaningless
unless it does have a bearing on this broader scene. Some students,
not particularly paleontologists, conclude that it does not, that the
phenomena revealed by experimental studies are relatively insignifi-
cant in evolution as a whole, that major problems cannot now be
studied at all in the laboratory, and that macro-evolution differs
qualitatively as well as quantitatively from the micro-evolution of
the experimentalist. Here the geneticist must turn to the paleontolo-
gist, for only the paleontologist can hope to learn whether the prin-
ciples determined in the laboratory are indeed valid in the larger field,
whether additional principles must be invoked, and if so, what they
are."

254 LIFE: ITS NATURE AND ORIGIN

The difficulties here expressed are rather of a semantic nature.
The word "evolution" subsumes a great number of physical hap-
penings at a variety of structural and organizational levels, ex-
tending from the atomic and molecular, to plant and animal
groups having continental and even world-wide distribution. It
is seldom possible to think of and reason with phenomena emerg-
ing at any one level, in terms of the structural or organizational
units of some other level, especially if it be a remote one. Thus
the farmer understands crops in terms of choice of seed, planting,
cultivation, weeding, fertilizers, water and weather conditions,
etc., without even knowing anything about the chemistry or
genetics involved, though these underlie his success or failure.
Similarly, chemistry and genetic factors underlie the various
evolutionary phenomena emerging at higher levels. Since these
factors operate through heritable changes in biocatalysts, we may
justly consider such biocatalyst changes as the basic or primal
cause of evolution.

What catalysts undergo heritable changes or additions? Not so
long ago geneticists would have answered: Heritable change is
due to gene mutations. Later, because of the "position effect,"
the word "mutation" was extended to include certain heritable
chromosomal abnormalities affecting gene action. Dobzhansky
states15 "In a wide sense, any change in the genotype which is not
due to recombination of Mendelian factors is called mutation.
In the narrower sense, it is a presumed change in a single gene, a
Mendelian variant which is not known to represent a chromosomal
aberration."

The inheritance of non-chromosomal and non-genic catalysts is
still under investigation, and the importance of cytoplasmic in-
clusions has been already mentioned. It is generally admitted
that the particulate units known as plastids, found in plant cells,
are independent constituents of the cell in regard to heredity.
Viruses are also known to live in the cytoplasm of some cells, and
to be transmitted from one generation of cells to another. The
cytoplasm of the gametes must also contain specific particulate
units which govern differentiation. Physical or chemical changes
in any of these cytoplasmic inclusions may persist and may be
carried by heredity; and so also may the results of addition of new
or stranger molecules, as is the case in cells treated with cancer-
producing substances (e.g., 3:4-benzpyrene), or with yeasts which
become "trained" to ferment new sugars.

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 255

What heritable catalyst changes are effective in evolution?
The answer here must be, Only those which persist and give a
biont (plant or animal) some heritable advantage over com-
petitors in the struggle for life, under the conditions existing at
the time and place at which the particular heritable catalyst
change occurs. Many catalyst changes are lethal, or else produce
sterility or low rate of reproduction; others are of no evolutionary
importance. Many bionts possessing promising heritable catalyst
changes may succumb to the perils of surrounding conditions, and
only the survivors among these advantageous changes live and
establish clones or families, which may then become factors in
evolution at higher organizational levels where the struggle for
existence is visibly waged.

The case of ascorbic acid (vitamin C) is in point. Many animals
(dogs, cats, rats, fowls, rabbits) can synthesize this antiscorbutic,
factor, and do not develop scurvy if it is missing in their diet; and
they can survive the long winter when natural greens are scarce
or lacking. But monkeys and guinea pigs readily develop scurvy
if deprived of ascorbic acid, and A. Szent Gyorgyi (Nobel prize,
1937) comments16 that these two experimental animals "come
from the ever-green tropical surroundings where there is green
food (which contains ascorbic acid) all year round. One of the
basic laws of Nature is laziness; Nature will not do unnecessary
things, and if a species has no need to make ascorbic acid, it will
not make it; it will forget, or never learn to make it. The rabbit
cannot permit itself to do this, for it would die during the long
winter in our moderate climate." Obviously if an animal's
catalysts cannot synthesize ascorbic acid and this is essential to its
life, the animal in nature is limited to areas where adequate
vitamin C is found in foods naturally available. The habitat of
such an animal could be greatly extended if it became independent
of dietary ascorbic acid. This could happen in a variety of ways;
by a gene mutation; by acquisition of a messmate or symbiont
which can produce it (as is the case with many ruminants*); or by
developing catalysts that can synthesize it.

The notion that all heritable change must be genie may sterilize
thought, but will not affect nature. Dr. Francis B. Sumner17
states: "It seems obvious that any one who sponsors a theory of
evolution by large steps must provide an agency through which
functionally related parts are brought to vary together in such a

* Cf. the case of the termite and of the lichen (see Index).

256 LIFE: ITS NATURE AND ORIGIN

way as to insure the harmonious co-operation of the parts affected.
That neither genetic linkage nor the manifold effects of single
genes affords a mechanism for such correlation, to more than a
very limited extent, will probably be readily granted. It is prob-
able that such an agency, if it exists, must be sought in the field
of developmental physiology rather than that of genetics." In
physiology catalyst formation and/or modification is a most potent
factor, even though not the sole factor.

We must also remember that what Sumner terms "large steps"
have usually taken very long times under unknown conditions,
and that our general experimental inability to induce corre-
sponding changes by "accelerated" tests done within a few genera-
tions, cannot controvert the existing paleontological data. Henry
Fairfield Osborn,18 in summing up the results of over fifty years
of study, states: "The evolution of the Titanotheres has little to
say about physical or chemical adaptations, but it gives us the most
thorough and profound insight we have ever gained into mechan-
ical adaptations." Osborn then lists twelve "principles" of adap-
tations at the visual or mechanical level of structure, and con-
cludes:

"Whatever may be true as to fortuitous mutation and as to
chance or random variation in chemical and physical adaptations,
the mechanical evolution of the Titanotheres, a unique record of
ten million years in the development of the Titanothere germ-
plasm, shows absolute continuity in every single organ examined.
There is not the slightest trace of discontinuity or of random
origin. There is a firm undeviating orthogenic* order in the entire
animal mechanism. There is a phytogenetic continuity of ger-
minal adaptation and reaction in response to secular changes of
habit and of environment."

To a book entitled "Creation by Evolution,"19 twenty-six out-
standing scientists contributed papers covering many aspects of
evolution. The Editor states that the book does not attempt to
explain the origin of life, or to determine the causes that lie
behind the changes in living things from age to age. It attempts
to show that there are changes and to describe how they come
about. Though the various authors are unanimous in their dem-
onstrations that evolution is a fact, not a single one of them sug-

* Orthogenesis is denned as "the doctrine that the phylogenetic evolution of
organisms takes place systematically in a few definite directions and not accidentally
in many directions; determinate variation; a theory of evolution propounded by the
German naturalists W. Haacke and T. Eimer" (Standard Dictionary).

CATALYSIS AS THE EFFICIENT CAUSE OF EVOLUTION 257

gests any casual mechanism at the physico-chemical level. The
index has one entry under "Evolution, causes of," which refers to
a section of Prof. E. G. Conklin's paper "Embryology and Evolu-
tion," entitled "The Causes of Development and Evolution,"
where Conklin states:

"The causes of the development of an individual or of the
evolution of a species are twofold, internal and external. The
internal causes are represented by the organization of the germ
cell, the external by surrounding conditions; the internal causes
may be called heredity, the external causes environment. . . .

"The character of development depends primarily upon the
nature (that is, the heredity organization) of the egg concerned,
and secondarily upon the environmental stimuli. The former
determines all the possibilities of development and its main
course; the latter determines which of these possibilities are
realized and modifies more or less the course of development.

"Entirely similar causes are at work in the evolution of races
or species. With true insight Charles Darwin wrote many years
ago: 'Although every variation is either directly or indirectly
caused by some change in the surrounding conditions, we must
never forget that the nature of the organization which is acted on
essentially governs the result.' Whether these variations are first
wrought in mature organisms and then transferred in some un-
known way to the germ cells, as Lamarckians assert, or whether
they first appear in the germ cells, as Weismann and his followers
maintain, is a secondary, although important, consideration, into
which we will not enter here. In conclusion it may be confidently
asserted that the causes or factors of the evolution of the species
and of the development of an individual are fundamentally the
same."

The view here maintained is that catalysis is the basis of both
individual development and evolution. However, all this deals
with our origin, not with our destination, which is considered in
the last chapter.

REFERENCES

1 Incidentally, it may be mentioned that Aristotle was a surprisingly keen observer,
even though he did record many erroneous notions of his time. In Historia Ani-
malium (Book 4 Part I, Thompson's translation) Aristotle stated: "The octopus, by
the way, uses his feelers either as feet or hands; with the two which stand over his
mouth he draws in food, and the last of his feelers he employs in the act of copula-
tion. . . ." Only recently has this observation been confirmed. J. T. Cunning-

258 LIFE: ITS NATURE AND ORIGIN

ham states (Encycl. Brit., 11th ed. (1913) Vol. 19, p. 993): "One arm is always con-
siderably modified in structure and employed in copulation, but it is only in three
genera, one of which is Argonauta, that the arm spontaneously separates. The
detached arm is found still alive and moving in the mantle cavity of the female, and
when first discovered in these circumstances was naturally regarded by the older
naturalists as a parasite. . . . Whether detached or not, the modified arm possesses
a cavity into which the spermatophores are passed and the arm serves to convey
them to the mantle cavity of the female."

2 Pliny states (Historia Naturalis, Liber XXXVI, Par. 195) that under the reign
of Tiberius the inventor's workshop was destroyed, but that even this story is not
fully authenticated.

3 Lamarck wrote "Phil. Zool." (1873) reprint, p. 254: "Dans leurs acces de colere
qui sont frequents surtout entre les males, leur sentiment interieurs par ses efforts
dirige plus fortement les fluides vers cette partie de leur tete, et il s'y fait une
secretion de matiere cornee dans les unes (Bovidae) et de matiere osseuse melangee
de matiere cornee dans les autres (Cervidae), qui donne lieu a des protuberances
solides: de la l'origine des comes, et des bois, dont la plupart de ces animaux ont la
tete arm£e."

4"Biglow Papers," First Series, No. 4, lines 31 et seq., 1846.

5 Goethe's "Naturwissenschaftliche Werke" occupy 12 volumes in the great
Weimar edition of 126 volumes, including "Letters" (45 vols.) and "Diary" (13 vols.).
6*'History of the Evolution of Animals," Vol. I, Leipzig, 1828.

7 See his biography, by Richard E. Call.

8 "The Testimony of Modern Science to the Unity of Mankind," copyrighted in
1858 and published in 1859 by Robt. Carter & Brothers, New York.

9 "Popular Science Monthly," 187-8, Vol. 52, pp. 224-228.

10 See "Let Freedom Ring," by Arthur G. Hays (H. Liveright, N. Y., 1928).

11 "The genetical theory of natural selection, Journal of Heredity, 1930, 21,
349-356.

12 In an address entitled "Evolutionary Faith and Modern Doubts," Science (1922)
55, 55-61.

13 When two groups of plants or of animals become incapable of cross-fertilization,
they would no doubt be recognized as separate species. Despite enormous differ-
ences in color, size, features, mentality, etc., the diverse races of Homo sapiens are
cross-fertile.

14 "Tempo and Mode in Evolution." (1944).

15 "Genetics and the Origin of Species." (1941).

10 Publication No. 14, Am. Assoc. Adv. Sci. (1940) p. 163.

17 Am. Naturalist (1942) 76, 433-44.

18 "Paleontology Versus Genetics," Science (1930) 62, 1-3.

19 Edited by Frances Mason, Macmillan, N. Y., 1928.

Chapter 12

Philosophy, the Guide of Mental Life

The intimate relation between philosophy and science is evident
from the fact that until comparatively recent times scientists were
known as natural philosophers. Etymologically, philosophy means
the love of wisdom. In its broadest sense, philosophy includes
the physical and mathematical sciences, as well as mental and
moral philosophy, now often called mental and moral science.
Metaphysics (literally after physics) is a branch of philosophy
which studies the first principles of being and of knowledge; and
though it makes full use of scientific facts, it is often loosely spoken
of as "speculative philosophy." Students of social phenomena
want to be called "social scientists," for science to-day is a word
to conjure with; but they are really social philosophers because
they seek not only knowledge but also wisdom in social matters.

The social, moral, and political turmoil caused by the impact
on mankind of numerous and basic discoveries of facts by experi-
mental scientists brings into sharp focus the great difference be-
tween scientific knowledge and philosophical wisdom. Wisdom
involves making proper and desirable use of what science reveals.
The Duke of Wellington, addressing an officer whose report was
replete with undigested details, blurted out: "Sir, your informa-
tion is too great for your understanding." Stung into action by
failure of statesmen and politicians to make wise use of the power
scientific discoveries placed in their hands, many scientists are
adding philosophy, politics, and statesmanship to their endeavors.
Benjamin Franklin, an outstanding natural philosopher, was also
a wise and capable statesman.

The main part of this book having been devoted to purely
material matters, this last chapter considers some of the philosoph-
ical aspects and conclusions which a personal review of the im-
personal facts of science seems to warrant. Since mathematics is
largely used to develop new knowledge from experimental ob-

259

260 LIFE: ITS NATURE AND ORIGIN

servations, it is necessary to stress the difference between pure and
applied mathematics.

Pure mathematics is comprised of arithmetic, algebra, geometry,
trigonometry, calculus, etc., while applied mathematics includes
mechanics, astronomy, navigation, and physics (including molec-
ular physics). Pure mathematics develops logical consequences
from assumed facts — indeed it has been said that a pure mathema-
tician is never so happy as when he does not know what he is
talking about. But when we come to apply mathematics to any
particular problem, we must be careful to start with proper facts
and to apply suitable mathematical forms or formulas.

Scientific Facts and Mathematical Deductions

An essential preliminary to the application of mathematics to
any problem is a statement of the facts and the assumptions in-
volved. The facts are determined by such careful observations as
we are able to make; the assumptions, either by our inability to
determine the facts, or by the compulsions of mathematical ex-
pediency. The resulting deductions are frequently given the hall-
mark of "rigid or rigorous mathematical analysis," notwithstanding
the assumptions or uncertainties on which they depend.

Take, for example, Stokes' formula or "law," which is widely used
for calculating the fall of a sphere in a homogeneous fluid. While
weighing the electron on extremely small oil droplets, Millikan found
that Stokes' law failed, because to such tiny ultramicroscopic particles
air was no longer a homogeneous fluid, and the drops fell more
rapidly than the law indicated, through the voids between the mole-
cules of the gases comprising air.

The often fruitful practice of mathematicians, physicists, and biolo-
gists of dealing with "fields" is a deliberately chosen form of escape
mechanism, which enables scientists to deduce and explain the beha-
vior of material units when complications of numbers, structures, and
interactions become too great for the human mind to follow. The
comparatively simple "three body problem," in general, is conceded
to be insoluble; but mathematicians deal safely with four, five, and
polydimensional space and with V — 1, an imaginary quantity.

While throwing these sops to the mathematical Cerberus, we
attempt, as far as our mentality permits, to envisage the physical
mechanisms underlying phenomena. Energy may be correctly
expressed by a formula, but we visualize it as due to material
units in motion. When matter is "converted" into energy, as in

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 261

nuclear disintegration, neither matter nor energy is destroyed.
The atomic nucleus apparently breaks up into smaller material
units, most of which have high velocities and some of which have
"negligible" masses. We continue to grope our way toward the
demonstration of ever smaller material units.

Our senses operate by and through particulate units, and we are
fortunate that certain threshold values of excitation must be
reached before an effect is registered on our consciousness. It is a
great protection to our nervous system that we cannot hear every
sound, no matter how faint; but we can use microphones to am-
plify these sounds when we wish. The rushing circulation of the
blood is not noticed by normal persons, but when the nerves are
supersensitive it may be felt as a "thrilling" or "tingling."

Physical measurements are made by our senses, often assisted
or fortified by some kind of apparatus. Most apparatus is so
constructed as to outline a result on some visible graph or scale,
whereon height, inflections, cusps, rate of change, etc., become
visible and recordable. We thus avoid grave difficulties which
are likely to appear if we rely solely upon the unaided senses of
sight, taste, touch, smell or hearing. Thus among the 70 per cent
to whom phenyl thiocarbamide has any taste at all, some will find
it sour, others bitter, others sweet — and these idiosyncrasies are
heritable as Mendelian recessives. There is a real basis for the
old Latin maxim de gustibus non est disputandum. Most human
ears are deaf to sound vibrations in excess of about 20,000 per
second; but mice can hear supersonics far beyond the human
range. Bats ("bald mice" in French, and "flying mice" in German)
guide themselves in dark caves by sensing the reflections from the
walls of the supersonic squeaks they emit during flight.

The thimble-rigger,* the three-card monte man,* the pick-
pocket, and the magician, all know that the hand is quicker than
the eye; and the many optical illusions known to psychologists
show how careful we must be before assuming that seeing is be-

* The following definitions (Standard Dictionary) are for the benefit of guileless
mathematicians, who are not always the calculating persons some might imagine:

Thimble-rig: A gambling game in which three thimble-shaped cups are placed
upside down on a board with a pea or ball under one of them, and shifted about
by sleight-of-hand, the aim being to induce bystanders to bet under which cup the
pea or ball is; frequently played at race-tracks, fairs, etc., in a swindling manner.

Three-card monte: A sleight-of-hand game or trick played with three cards, one
of which is usually a court-card, in such a manner as to deceive the eye of the
onlooker, who is induced to bet that he can pick out the court-card. Called in
England three-card trick.

262 LIFE: ITS NATURE AND ORIGIN

lieving. Tests indicate that insects have a visual wave-length
range different from ours; and human beings too have a relativity
in sensitiveness to light, for example, color blindness or Daltonism,
so called after the great chemist, who discovered it in himself.
Buildings are erected on the sufficiently close assumption that
plumb-lines are parallel, although we know that plumb-lines in
Istanbul are about at right angles to those in New York.

There has been much controversy and probably also much
fraud in connection with "dowsing," the art of locating under-
ground streams of water with a "divining rod"; but so eminent a
scientist as Sir J. J. Thomson reports in his autobiography,
"Recollections and Reflections" (1938), that there is no doubt
about the reality of the phenomenon, even though at present we
have no explanation for it. Possibly it might be associated with
the ability of some persons to respond to radioactive, electric, or
other influences developed by flowing water (streaming potential).
Electroencephalograms and electrocardiographs recording elec-
trical impulses developed in our bodies, are matters of routine
determination in many hospitals. Homing pigeons have been ex-
tensively used for years, but we have no idea as to how they manage
to reach their home lofts from great distances.

The results which the physicist deduces by mathematical logic
can never rise above the level of the accuracy of his data or assump-
tions— and there are limits to the accuracy of practical measure-
ments. The plea of Portia for Shylock's death "if the scale do
turn but in the estimation of a hair," is good drama, but bad
law; for the law in an analogous case would allow a reasonable
tolerance in weight. Engineers, however, generally insist that
"reasonable tolerance" be expressed in specifications, which may,
for example, call for rods having a length of five inches "plus or
minus one thousandth." With ball-bearings, turbines, etc., closer
tolerances are called for; and photo-cell devices and diamond-
tipped calipers are used to avoid errors that might follow wear
on less durable material.

Heisenberg's Principle of Indeterminism1

When we attempt to measure such basic things as the velocity of
an electron and its location, we find that our very means of
measurement influence the result. This has led physicists to accept
Heisenberg's principle of indeterminism or uncertainty. In
common language this principle states that there is a limit to

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 263

observational experiments, which is reached when the observa-
tional or determining factors begin to interfere with the normal
happenings in the experiment under observation.

The uncertainty principle having demonstrated the impossi-
bility of making critically accurate measurements at subatomic
levels, modern physicists, as mentioned above, transferred their
attention to "fields," which permitted them, in the words of Pro-
fessor Charles Galton Darwin,2 "to carry through a formal mathe-
matical analogy without ever asking what it all meant in terms of
observable things . . . There grew up a great cult of doubting
the reality of unobserved things, and then a curious thing was
found; the charm did not work again . . . The work of the new
quantum theory has in fact run most surprisingly in the opposite
direction. The technique is largely concerned with wave func-
tions, which are much more abstract than anything in classical
mechanics. There is certainly nothing observable, or even pictur-
able, about waves propagating themselves in many-dimensional
space with absolutely unknowable phase, and with intensity con-
trolled by the curious extraneous rule of normalization. Largely
by use of these wave functions the whole of atomic physics has been
reduced to order, and so has molecular physics, except that it yields
problems in which so many electrons are interacting that a full dis-
cussion is not feasible.% So the doctrine of theorizing only about
observables was really not a useful doctrine; it merely provided a
geminating idea. In fact, we may well ask what an observable is,
and if we go at all beyond direct sensations, which as physicists
we certainly intend to do, the answer becomes perfectly indefinite.
This opinion I heard admirably expressed by the late Professor
Ehrenfest. It was in a physics meeting in Copenhagen and some
one was proposing a way out of certain difficulties which involved,
as he maintained, a reversion to the cult of the observable. Pro-
fessor Ehrenfest said: 'To believe that one can make physical
theories without metaphysics and without unobservable quanti-
ties, that is one of the diseases of childhood (das ist eine Kinder-
krankheit).' "

Probability

Chemical and physical kinetics recognize the impossibility of
predicting the behavior of single atoms or molecules, and base
their calculations on the laws of chance and probability, just as
do life insurance actuaries, who can never foretell just when anv

264 LIFE: ITS NATURE AND ORIGIN

one policy holder will die. With the Gaussian laws of chance, as
with the Boltzmann entropy probability theorem, the more units
we deal with, the more accurate our calculations; but they cannot
be applied to a single unit. Since the behavior of individuals de-
pends on myriads of non-calculable physical and physico-chemical
contingencies, it is obvious that mathematical calculations regard-
ing the behavior of any individual (if indeed such calculations
could be made at all) would be tainted with elements of uncer-
tainty.

The saying that marriage is a lottery has a physico-chemical
basis. The potencies of inheritance, sex, hormones, vitamins,
drugs, alcohol, dyspepsia, nervousness, suggestion, autosuggestion,
etc., being what they are, social scientists, military leaders, and
business men base their calculations on what may be expected of
the average person. Business proceeds on the basis that most men
are honest, but allows for shop-lifting, locks its doors at night,
employs watchmen, and insures against theft. The Devil can al-
ways quote Scripture to his purpose; but over-stern judges should
read Robert Burns' "Address to the Unco' Guid, or the Rigidly
Righteous."

The Time Factor

Bertrand Russell wrote:3 "If you put a kettle on a nice hot fire,
will the water freeze? 'Certainly not,' says common sense, indig-
nantly. 'Probably not', says physics, hesitatingly. According to
physics, if every member of the human race put a kettle on the
fire every day for the next million million years (during which,
according to Jeans, the world is to remain habitable), it is not
unlikely that sooner or later the water in one these kettles would
freeze instead of boil."

But Russell failed to state that among the ever-changing con-
catenations of molecular agitation, the extremely rare situation
that would permit freezing would last for so short a time that it
is unreasonable to believe that any freezing could take place —
certainly no demonstrable freezing. Similarly, a probability cal-
culation would show that if we only wait long enough, a brick
might float in air, because at a certain instant all or nearly all of
the impinging air molecules would strike the brick on the under
side, thus giving it an upward lift (at sea level) approximating
fifteen pounds to the square inch. But this calculation should
also indicate that this condition would be so fleeting that no one

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 265

would notice it. It would be succeeded by other equally fleeting
instants where molecular bombardment would actually add to the
fall of the brick.4

It will be observed that the principle of indeterminism as well
as the deductions from probability calculations are generally ap-
plicable to the "same time" or a "given instant." However, an
instant — mathematically, a point of time — has no more practical
existence for us than a point in space. What we term the "pres-
ent" is in reality the immediate past and the immediate future.
The "present" has become the "past" before our sensory and in-
tellectual apparatus can inform us what was then occurring, even
when aided by clever mechanical devices.

Free Will

Theology long ago advanced the metaphysical notion of pre-
destination or pre determinism, according to which an omniscient
and omnipotent God has decided, for all eternity, exactly what
will happen; and if everything was thus "foreordained," there is
really no such thing as free will. The philosophical and scientific
analog of predestination is the doctrine of determinism, according
to which physical events, whether on the outside or in the brain,
strictly necessitate the character of all human volition. If we ac-
cept this materialistic fatalism, probability and the physical prin-
ciple of indeterminism (Heisenberg) make man a mechanical auto-
maton, a helpless plaything of chance. On the other hand, the
doctrine of predeterminism makes man a helpless tool in the hands
of God or Fate (Kismet).

Rebellion against this impasse appears in the quatrains of Omar
Khayyam:

We are no other than a moving row

Of Magic Shadoiu-shapes that come and go

Round with the Sun-illumined Lantern held
In Midnight by the Master of the Show.

But helpless Pieces of the Game He plays
Upon this chequer-board of Nights and Days;

Hither and thither moves, and checks, and slays,
And one by one back in the closet lays.

If man, like the billiard shark condemned in Gilbert's "Mi-
kado," must play extravagant matches, with fitless finger-stalls,

266 LIFE: ITS NATURE AND ORIGIN

on a cloth untrue, with a twisted cue and elliptical billiard balls,
what becomes of free will?

Freedom of ivill is mental, not physical. What we call freedom
of the will is essentially the self-imagined ability if a person to
select, at a certain time and under certain conditions, a certain
alternative of thousrht or action. The selection involves no infal-
lible assumption or guarantee as to what the immediate or remote
consequences will be in every case, and absolute uniformity of
results is seldom achieved or expected. The ethical and moral
criteria of the situation are met, and free will is exercised, when
a choice is made or, to throw a sop to the pure mechanists who
claim a material force majeure, when the chooser thinks he makes
a choice. Descartes' dictum, Cogito ergo sum, indicates how basic
are the unseen springs of our consciousness and reason, from
which emerge conscience and the power to make choices.

The law has long recognized this situation. Criminal choice
or intent (moral turpitude) is generally alleged in felonies. A
common allegation in indictments is that the act was committed
"wilfully, wickedly and maliciously, with malice prepense and
aforethought." In some of the old English court records it was
applied even against animal offenders. In order to obviate the
difficulty of proving the putative state of mind of the law-breaker,
laws often rehearse or assume that certain acts are in themselves
presumptive evidence of criminal intent. It must be stressed, how-
ever, that the laws existing at any particular time represent merely
what is put into effect by the dominant powers of the state; that
these laws will differ widely from time to time and from place to
place; and that, owing to legal and legislative time-lag, they often
do not represent the current popular mores.

Thousands of years of human experience have established cer-
tain actions and inhibitions as desirable in human society. Thus
the injunctions laid down in the Ten Commandments are gener-
ally accepted by civilized mankind. They seem, in part, to repre-
sent a condensation and extension of the forty-two items of the
chapter, in the Egyptian "Book of the Dead," known as "The
Negative Confession." Seven of these negative statements to the
underworld Judges (e.g., "I have not robbed with violence; I have
not made light the bushel") represent forms of stealing which are
condensed into the Eighth Commandment, "Thou shalt not steal."
The statement, "I have not defiled the wife of a man," corresponds
to the Seventh Commandment, "Thou shalt not commit adul-

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 267

tery." It is to be noted that many of the Ten Commandments
are also in the negative form. In any event, moral and ethical
codes reflect states of human and social development, which
change from time to time and vary from group to group.5

In final analysis, a human being can actually carry out only two
types of activity: he can think, and he can change the position of
some material things. The phenomena which then follow are
usually the resultants of the natural mental or physical forces
which are thus set in motion; for the effects may be on the minds
of other human beings, as well as upon mechanisms actuated by
push-buttons or levers.

The immediate or the remote consequences of what an indi-
vidual chooses (or thinks he chooses) to think or to do may not
always be rigidly certain; but they are, as a rule, sufficiently cer-
tain to serve as guides for human behavior in the future, as they
have been during the long past. Sciences of all kinds teach us to
see more and more clearly what we may reasonably expect to be
the consequences of our thoughts and choices of action. Both
material and ethical progress lie along such lines. It may be re-
called that when Jesus of Nazareth was being crucified, He said:
"Father, forgive them, for they know not what they do."

Now it may very well be that certain configurations of physical
units possessing the power of thought and of action would, if pre-
cisely duplicated and placed in precisely the same conditions, al-
ways respond with precisely the same thoughts and choices. But
the law of probability indicates how vanishingly small are the
chances for precise duplication of any complicated set of structural
and milieu conditions. The particulate nature of all matter, in-
cluding our scientific apparatus, our sense organs, nerves and
brain, as well as the electrical and other forms of energy whereby
sense impressions are received, transmitted, and integrated into
concepts, leads to the conclusion that neither human senses nor
mentality can secure accurate premises whereon to base any logical
conclusions as to causality. "The principle of logic remains true
that from given premises there always follows a unique conclusion,
but it does not apply where there are no premises or not suffi-
ciently accurate premises."6

Genetics teaches us, on the other hand, how powerful are the
effects on thought and action of inherited physical structure.
Identical twins, arising from the same fertilized ovum, are sur-
prisingly alike in structure, action, and thought. Their finger-

268 LIFE: ITS NATURE AND ORIGIN

print patterns and electroencephalograms are often difficult to
distinguish.7

The similarities of physical structure and behavior just referred
to are evident to other individuals, that is, to outside observers;
but the thoughts controlling the actions of the individual himself
involve what we term his conscience, and are directly known only
to himself. Acts of individuals which are in accord with mores
are regarded by others as ethical and moral. If consonant with
existing law, they are legal. But thoughts, the secret springs of
action, are dominant factors in the scope of choice we call free
will. No matter how a person may be limited by his physical in-
heritance, and his social environment, he is ethical and moral
(even if not legal), when he honestly follows his own "inner light."
Education has important ethical and moral responsibilities. Wis-
dom should guide those who learn to think independently; but
many are guided solely by what they are taught or by the example
set by teachers, parents, or associates.

The essential difference between the material and the mental,
ethical, spiritual or moral aspects of an action is illustrated by the
story of the Scot who attempted to retrieve a half-crown he had
dropped into the plate at church, thinking it was a penny, but was
frustrated by the Verger, who quickly covered the plate with his
hand and remarked: "Nay, nay, mon — in for ance, in for aye!"
"Weel", said the Scot, "I'll get credit for it in Heaven." "Nay,
mon," returned the Verger, "in Heaven ye'll get credit only for
the penny ye intended to put in." (John Brown: "Rab and His
Friends").

Ethics and morality are not inherent in molecules, atoms, or
subatomic particles. They are, rather, emergent relations which
come into being only with the development of complicated ma-
terial structures capable of thinking and choosing. These powers
we believe to be most highly developed in man, but they are fore-
shadowed in the lower animals. It is interesting to note how
the poet's eye in glancing "from heaven to earth, from earth to
heaven," has envisaged these relationships between the physical
and the metaphysical. Thus in his poem "Caliban upon Setebos,"
Robert Browning pictures the self-centered reaction to natural
phenomena of that low form of human mentality, "a freckled
whelp, hag-born — not honour'd with a human shape":

'Thinketh, such shows no right or wrong in Him,
Nor kind, nor cruel: He is strong and Lord.
'Am strong myself compared to yonder crabs

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 269

That march now from the mountain to the sea;
'Let twenty pass, and stone the twenty-first,
Loving not, hating not, just choosing so.
'Say the first straggler that bofists purple spots
Shall join the file, one pincer twisted off;
'Say, this bruised fellow shall receive a xoorm,
And two worms he whose nippers end in red;
As it likes me each time, I do: so He.

The introspective mind of Rabbi Ben Ezra responds on a much
higher spiritual level:

He fixed thee mid this dance

Of plastic circumstance,

This Present, thou, forsooth, xvouldst fain arrest;

Machinery just meant

To give thy soul its bent,

Try thee and turn thee forth, sufficiently impressed.

In "Saul," Browning sees evidence of perfection everywhere in
nature:

Do I ask any faculty highest, to image success?
I but open my eyes, — and perfection, no more and no less,
In the kind I imagined, full-fronts me, and God is seen God,
In the star, in the stone, in the flesh, in the soul, and the clod.

Resentment at the inability of humanity, despite choice, to con-
trol the inexorable powers of nature, blazes forth again and again
in Omar's lines:

And this inverted bowl we call the sky,
Whereunder, crawling, cooped, we live and die —

Lift not thy hands to it for help for it
As impotently moves as thou and I.

Ah, love! Could thou and I with Fate conspire
To grasp this sorry scheme of things entire,

Would we not shatter it to bits and then
Remold it nearer to the heart's desire?

But in William Henley's "Invictus" we find a defiant trumpet-
call of humanity to material limitations:

It matters not how straight the gate,
How charged with punishments the scroll;
I am the master of my fate,
I am the captain of my soul.

270 LIFE: ITS NATURE AND ORIGIN

Not only are we limited in our efforts to make physical measure-
ments and to understand the vast complexities of nature, but the
very ultimates of both mind and matter continue to elude us. As
Herbert Spencer said, they are unthinkable.

Science and Religion

Science and religion originated together as a duplex reaction
of the developing human mind to the physical universe, and to the
needs and yearnings of the individual and of family and social life.
Contact with physical nature led to primitive sciences (skills,
manufacture, agriculture, and the household arts), while at the
same time fear, love, wonder and introspection gave rise to primi-
tive philosophies and religions. Primitive man looked with awe,
love, or fear upon the gigantic forces of nature, and the early
"medicine man" was both scientist and priest, striving to under-
stand nature and to propitiate the many potent man-like gods to
whom a naive animism attributed control of rain and crops, light-
nings and storms, and the mysteries of life, illness, and death.

Science and religion have undergone and are undergoing par-
allel evolutions, and we must not scorn "the base degrees by which
we did ascend." There is a wealth of wisdom concealed among
the many errors of folk-lore.

A few examples may be mentioned. In No. 11 of a series of
books on "Tales from the Outposts," there is a chapter on "The
Savage as Scientist," from which the following is quoted:

"Kinga, who was one of the most famous chiefs and rain-doctors in
East Africa, refused to be moved from his kraal at Mandi on the Daua
Plateau down to Sekenke in the Wambare Plains, as medicine-man
Mgendu urged: and Mgendu came to ask advice of the writer, who was
then administrative officer in charge of the Iramba tribe. (Kinga was
suffering from general paralysis.)

"Said Mgendu: 'The vidudu of paralysis must fight with the pilintu
of malaria so that the pilintu may be devoured; then must Kinga eat
of the nzizi chungu (bitter roots), and he will be strengthened' . . .
Vidudu are mysterious insect-like things; a pilintu is a strange un-
known wormlike thing . . . that half-naked savage doctor was prescrib-
ing the most up-to-date medical treatment for paralysis based on the
most recent discoveries of medical science . . . Sekenke is one of the
worst malarial districts in all Africa.

"Many tribes, not only the Masai and Nandi of Kenya, knew the
cause of malaria. The Somalis knew, for a British traveller in their
country was told by Somali tribesmen thirteen years before Ross's

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 271

discovery that the kan'ad or mosquito was a bad insect, biting a man
and making his blood boil with fever. Chief Kitandu of the Iramba
tribe knew four centuries ago, for his minstrels sang to the twang of
the lusembi, a primitive calabash guitar, 'Ni aza kusengila pana nu
imbu; nu imbu mbii masaka kasenkilal' (Do not build huts where
mosquitoes live; for mosquitoes are evil, and make your blood hotl)
And that song, with others full of savage wisdom, is to be heard to
this day in the kraals of Tanganyika."

In 1927 Dr. J. Wagner-Jauregg received the Nobel prize in medicine
for his discovery that malarial infection may be used to produce high
fever, with which certain nervous consequences of syphilis may in
many cases be successfully combatted.

Only a dozen years ago8 the mistaken notion was advanced that the
biochemical aspects of scientific medicine began in 1894 "when the
use of thyroid gland in the treatment of myxodema was discovered."
Professor Edward H. Hume, then at the College of Medicine at
Changsha (Yale-in-China) stated:9 "Organotherapy is described as
early as the 6th century A.D., when sheep's thyroids were used for
cretinism. The practice is familiar to housewives throughout the
land."

The use of "ashes of sponges" as a remedy for goiter was common
from the latter part of the 13th century, and was probably based on
earlier folk lore. The disease was, of course, known in ancient times
and is mentioned by Pliny. In 1812 Courtois discovered iodine, and
seven years later Dr. Coindret, a well known physician of Geneva,
walked into Le Royer's pharmacy there and asked the chemist J. B. A.
Dumas (then only 19 years of age) to determine for him whether
sponge, especially burned sponge, contains iodine. When Dumas
reported that he found iodine, "Dr. Coindret no longer hesitated to
consider iodine as a specific against goiter."10 In 1833 Bouissingault
suggested the addition of iodine to cooking salt, since he observed in
South America that goiter was prevalent where iodine was lacking.
Today iodized salt is widely used; but an excess of iodine must be
avoided, as this, too, can cause trouble.

Through all the non-essential beliefs and rituals of early reli-
gions, there runs the basic attempt of the introspective mind and
developing soul to reconcile the hard facts of experience with hu-
man life and love. Care for the dead is one of the lines of cleavage
between men and brutes, and with it came thoughts of a hereafter.
The embalmers of Egypt were of the priestly clan, which included
the scientists also. Moses, educated in Egypt, outdid his teachers,
who had followed him as far as bringing up frogs upon the land
of Egypt; for it is stated in Exodus VIII, 18: "And the magicians

272 LIFE: ITS NATURE AND ORIGIN

did so with their enchantments to bring forth lice, but they could
not."

It is unfortunate that in the past most organized religions have
magnified their differences, thus tending to obscure their basic
unity in God. Much blood has been shed over unimportant dif-
ferences of opinion or ritual, to the exclusion of the common
belief that God is the Father of us all. But religions are slowly
changing. Thus Jonathan Edwards saw hell paved with the vic-
tims of the Calvinistic doctrine of infant damnation; but the
somewhat more humane Michael Wigglesworth (1631-1705) in
his poem on the Last Judgment ("The Day of Doom"11), had God
grant as a boon to unbaptized infants "the easiest room in Hell."
Not until 1902 was this doctrine of infant damnation removed by
vote from the creed of one of our prominent churches, whereupon
a modernist member of the convocation moved that the vote be
made retroactive!

Though much has been written and said about the supposed
conflict between religion and science, such a conflict never really
existed. The eternal verities of both religion and science tower
unconcerned above the storms of creed and dogma, glowing in the
light of ever-advancing scientific knowledge and true religious
understanding. For many years scientific development was ob-
structed by the fear that demonstrable facts would render unten-
able the dicta of theologians, as witness the treatment accorded to
Galileo, for example. Astrology, the ancient art of divining the
future by observations of the heavenly bodies, goes back to the
earliest Babylonian history (about 3,000 B.C.); but this pseudo-
science of the early priests and magi did not begin to slough away
from real astronomy until about the time of Isadore of Seville
(died, 636 A.D.), and it was utterly discredited by the scientific
revelations of the great natural philosophers, Copernicus and
Newton.

Science, too, has had to struggle for its advances. Thus Prout's
hypothesis as to the basic origin of the elements from hydrogen,
was supposed to have been completely disproved by the meticulous
atomic weight determinations of Stas; but discoveries in this cen-
tury by Curie, Rutherford, and others show that Prout was quite
near the truth.

Mind and Matter

Although philosophy, which coordinates and appraises all
knowledge, indicates that both material and psychic ultimates

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 273

are beyond the range of human conception, the daily life of every
person demonstrates belief in and guidance by the actual realities
of matter and of mind. Without attempting to explain them, the
law deals with both matter and mentality. Ralph Waldo Emerson
in his first publication (1836) entitled "Nature," said: "Philo-
sophically considered, the universe is composed of Nature and the
Soul. Strictly speaking, therefore, all that is separate from us, all
which Philosophy distinguishes as the NOT ME, that is, both
nature and art, all other men and my own body, must be ranked
under this name, NATURE."

What Emerson considers as the ME, the mental and spiritual
personality, is not a fixture. Our personalities like our bodies,
grow from infancy to maturity, and may in some cases return again
to an infantile senility. Oliver Wendell Holmes said in "The
Chambered Nautilus,"

Build thee more stately mansions, O my soul.

And there is no doubt but that most human beings show great de-
velopment, both mental and spiritual.* Coincidentally, the atoms
and molecules comprising our bodies are undergoing continual
change, and even the basic patterns of our physical frame are by
no means constant. Gradually, we feel our age — and look it. The
mental and spiritual possibilities in the brains of most of us are
sometimes pitifully limited by physical, chemical, and environ-
mental conditions. Though all service ranks the same with God,
as Browning put it, mankind is often slow in recognizing, much
less in emulating, even outstanding example and superlative serv-
ice in individuals. Contemporaries are often poor judges of
values. It takes courage to follow the judgment of one's own
conscience. Jesus of Nazareth, whose teachings pilloried the bru-
tal materialism of imperial Rome, suffered crucifiction, a Roman
form of punishment,12 by Roman soldiers, under a Roman Pro-
curator. But the Golden Rule based on the Law and the Prophets
and emphasized by Jesus, remains the ideal of great numbers of
human beings.

Science recognizes that matter is real and indestructible, even
though its ultimates are unknown; and similarly we are led to the

* In a paper entitled "Natural Selection and the Mental Capacities of Mankind"
(Science, 1947, 105, 587-90) Th. Dobzhansky and M. E. Ashley Montagu state: "The
genetically controlled plasticity of mental traits is, biologically speaking, the most
typical and uniquely human characteristic." Man is extremely adaptable, whereas
"the behavior of an individual among social insects is remarkable precisely because
of the rigidity of its genetic fixation."

274 LIFE: ITS NATURE AND ORIGIN

view that mind, or spirit, or soul (the exact word is unimportant)
is also real and indestructible, even though we cannot define it,
plumb its depths, or understand the basis of its obvious interrela-
tions with matter.

Sir Edwin A. Adrian (Nobel prize, 1932) has stated: "The nervous
system is a mass of living cells which has the extraordinary property
of appearing to influence, and to be influenced, by the mind ... It is
a material system somehow responsible for such non-material things
as emotions and thoughts. These are in a category outside the range
of mechanical explanation, and for this reason the working of the
nervous system will never be fully explainable in terms of physics and
chemistry." This parallels the view of Lord Balfour that "No man
can either perceive or imagine the mode in which physiological
changes give birth to psychical experiences." But the fact remains
that they do.

The idealistic philosophy of George Berkeley, Bishop of Cloyne
(1684-1753), was based on the psychological principle that, for all
sensible things, being in reality is identical with being perceived
(the esse of things is percipi). Though all material existences have
their reality only in some concious mind, human souls have been
endowed by God with a substantive existence. To save his system
from being entirely subjective, Berkeley added the view that the
material universe has a permanent being in the Divine mind.
There is a story that one day Bishop Berkeley found the following
limerick pinned on a tree in the University quadrangle:

A young Oxford man remarked: "God
Must think it exceedingly odd

That this sycamore tree

Continues to be
When there's no one about in the Quad."

On the following morning, the philosopher's reply was found
pinned below:

Dear Sir: Your bewilderment's odd:
I'm always about in the Quad;

So this sycamore tree

Will continue to be
Since observed by, Yours faithfully, God.

Somewhat different versions are given in "The Oxford Book of
Light Verse," and in the "Peter Pauper Book of Limericks."

PHILOSOPHY, THE GUIDE OF MENTAL LIFE 275

Spinoza's attempt to escape from this dilemma by regarding
matter and spirit as aspects of unity still leaves us in ignorance of
this all-embracing unitary ultimate. Robert G. Ingersoll, the
great agnostic, wrote: "Our ignorance is God; what we know is
Science." But the separation of knowledge from ignorance de-
mands successful mental effort, and assumes a mind capable of this.
Furthermore, as we enlarge the frontiers of our knowledge, we
correspondingly enlarge the frontiers of our ignorance, thus com-
ing more and more into contact with the unknowns and unknow-
ables which Ingersoll termed God.

EVENSONG

However vast our strength or frame,
Or great our power, our wealth or name,
Lord, You are Father of us all,
And we are but Your children small.

Like curious children, we explore
And open many a wond'rous door —
To other doors, but not our goal,
The master-mystery of soul.

With child-like faith, without a care,
At eve we quietly prepare
Ourselves in dreamless sleep to lay,
Until You waken us next day.

REFERENCES

1 Hackh's "Chemical Dictionary" defines it thus:

"Within the atom it is meaningless to define both the position and the velocity
of the electron, because ^x, the error of specifying the velocity of x, multiplied
by £±P> tne error in specifying the position p, is always of the order of magnitude
of Planck's constant, h; that is xxp~h. Hence, assuming a definite velocity, only
approximate position is possible; likewise, assuming a definite position, only ap-
proximate velocity can be calculated."

2 Charles Galton Darwin, Presidential Address before the Section on Mathematical
and Physical Science, British Association for the Advancement of Science, Science
(1938) 88, 155-160.

3Bertrand Russell, Atlantic Monthly, August, 1930.

4 On this question there is an interesting paper by Professor Edward Kasner
(Columbia University) in Scripta Mathematica (January, 1938) entitled "New Names
in Mathematics." Kasner defines a googol as 10 to the 100th power, and a googolplex
as 10 to a power represented by a googol. This latter number is so great that we
could go out to the farthest star and then make a tour of the nebulae, writing down
zeros all the way in an attempt to express it. (What a few mathematical signs can

276 LIFE: ITS NATURE AND ORIGIN

do!) Professor Kasner thinks that a suspended book might move upward toward
the hand holding it within a googolplex of years, or within some other larger finite
number of years. Owing to the inertia-time factor, I still remain a "doubting
Thomas."

5 See, e.g., "The Dawn of Conscience," by Professor James H. Breasted (1932),
and "Moses and Monotheism," by Dr. Sigmund Freud (1939).

6 Dr. Paul Epstein, Scientific Monthly, July, 1937.

7 What differences identical twins do show are probably attributable to differences
in cytoplasmic inheritance; for though gene duplication is normally precise, there
is, even in identical twins, probably some difference in the apportionment of the
cytoplasm of the zygote during the first (and subsequent) mitotic divisions, and this
involves particulate inclusions in the cytoplasm.

8 F. C. Carr, Chemistry and Industry (1934) 53, 123.

9 Science, April 18th, 1924, p. 349 (The Contributions of China to the Science and
Art of Medicine).

10 A. W. von Hofmann, Berichte (1884) 17, 637, referate.

11 The British Museum has a unique copy, published in London, 1666; but from
memoranda left by Wigglesworth, it is possible that undated copies owned by
several American historical societies may represent an earlier American edition
about 1662.

12 Cicero said in an oration against Verres: "Facinus est cruciare civum Romanum;
scelus verbere; prope parricidum necare; quid dicam in crucem tollere?" (It is a
wrong to harm a Roman citizen; a crime to beat him; practically parricide to kill
him; but to crucify him, what shall I call it?).

Author's Note

My interest in minerals, plants, and animals goes back to my early boyhood.
When I entered the College of the City of New York in 1891, it was my good fortune
to be introduced to physics and chemistry by Professor Robert Ogden Doremus,
and to botany, zoology, geology and paleontology by Professors Ivan Sickels and Wil-
liam Stratford. My thanks are due to these teachers and their assistants, who made
science so interesting that my initial leanings toward it were quickened and ex-
tended. The fact that my college courses were very broad rather than specialized
gave me a wider point of view than I might otherwise have acquired; so that when
I graduated in 1896 and took up technological work instead of being able to realize
an ambition to become a physician, I was able to continue my scientific studies
alone.

In the spring of 1899 I submitted for my degree of Master of Science a thesis*
entitled "The Importance and Trend of Recent Work on the Chemistry of Life and
the Products of Life," which indicates my early interest in the matters dealt with
in this volume — an interest excited largely by the then recent (1895) isolation of
zymase from yeast by Buchner. The opening paragraph of this thesis, with a few
others, are given below. These views were advanced fifty years ago, on the basis of
some of the comparatively slim evidence then available.

"Recent work on the chemistry of life, and its products, has thrown much light
upon vital or physiologic phenomena, and has given us no uncertain insight into the
nature of life itself. I intend to review briefly part of this work, taking up first
ferments and enzymes, and the nature of their action. The discussion of these cell-
products leads the way to the second topic — cells and microorganisms, and the
nature of their life. . . .

"Buchner's discovery (of zymase) is strong and almost conclusive evidence in favor
of the view of Berthelot and Hoppe-Seyler [that organisms produce chemical sub-
stances which cause fermentation], and is of the utmost importance because it helps
to break down a false barrier which had been erected between physiology and
chemistry. Physiological laws are chemical laws, however great their complexity;
and matter is bound by these same laws, be it organic or inorganic, living or dead.
As a vital function fermentation must always be mysterious and inscrutable, while
as a chemical process it is susceptible of explanation.

"It appears then that all fermentations are purely chemical changes brought
about by substances which usually are highly complex and highly nitrogenous,
as analysis shows. To confirm this assumption more fully, work should be done
along the lines laid down by Buchner, and the active enzymes should be isolated
from all fermentative microorganisms. In the meanwhile we may examine into
the nature of the chemical action that takes place.

"There are numerous reactions which go by the name of continuous processes.

The decomposition of the diazo-compounds by cuprous salts (Sandmyer's reaction)

is a case in point. It proceeds according to the equation

CflH5N :N :R+Cu2R2=C8HBR+N2+Cu2R2

so that the process is theoretically continuous. The cuprous salt acts the part of a

carrier or "go-between," just as do iodine, ferric chloride, aluminum chloride and

* A short excerpt from this unpublished thesis appears in a paper written jointly with Dr.
Calvin B. Bridges, entitled "Some Physico-Chemical Aspects of Life, Mutation, and Evolution,"
published in Vol. II, of series "Colloid Chemistry, Theoretical and Applied," edited by Jerome
Alexander, Reinhold Publishing Corp., N. Y., 1928.

277

278 LIFE: ITS NATURE AND ORIGIN

many other substances under different circumstances. The catalytic decompositions
of hydrogen peroxide and hypochlorous acid . . . are apparently continuous proc-
esses, although the intermediate compounds have not been determined.

"Not alone can a small quantity of one substance decompose a large quantity of
another, but the same substance yields varied products depending on the nature of
the go-between. Ethyl acetoacetate, when hydrolyzed with dilute boiling acids,
yields ketones; while if strong alcoholic potash be employed, acids are produced.
This latter is not a continuous process because the potash is eliminated by com-
bining with the acid produced; but it illustrates the point.

"Now I believe that the actions of diastase, and in fact of all other enzymes, are
in the nature of continuous processes. I base this, as yet, almost entirely upon
analogy, but can indicate the line of experimentation necessary to confirm the
theory:

(1) Active enzymes must be isolated, and their chemical constitution and struc-
ture investigated.

(2) The composition of the substances to be decomposed must be understood, and
also the nature of the compounds they can form with the structurally deter-
mined enzymes. . . .

"The enzymes and enzyme-like toxins we have just been considering occur only
in, or as the products of, living cells. What is their relation to the life of the cells?
Do they throw any light upon the actual nature of life itself? After carefully con-
sidering the question, it appears to me that life is an enzyme-like continuous
chemical process, or rather a series of such processes. Among the facts that led to
this conclusion, a few may be discussed: attenuation, immunity, antisepsis and soil
nitrification. . . .

"Enzymic and cell-metabolic processes are so completely dependent upon chemical
conditions that they are without doubt purely continuous chemical processes. True,
the changes which take place are of great, almost appalling complexity; but they
need not overcome us. The sugars, once regarded as of almost unknowable com-
plexity, are now known as a series of hydroxy derivatives of normal hexane. . . ."

The scientific literature shows an ever-increasing realization of the importance of
catalysis in life processes. It must be remembered that enzymes are biocatalysts,
and that antibody formation occurs catalytically, as indicated in my Protoplasma
paper (1931) and in the section on "Immunology and Serology" in the fourth
edition (1937) of my book "Colloid Chemistry" (D. Van Nostrand Co.). In 1936
Dr. Karl Landsteiner was kind enough to review with me the manuscript of this
section, as indicated on p. 413.

Dr. Alwin Mittasch, well known for his work in industrial catalysis, has recently
published the following books (J. Springer, Berlin): "Ueber katalytische Verur-
sachung im biologischen Geschehen" (1935), "Katalyse und Determinismus" (1938).
and "Kurtze Geschichte der Katalyse in Praxis und Theorie" (1939). A still later
book is now on press, entitled "Lebensproblem und Katalyse" (J. Ebener-Nerlag,
Ulm/Donau).

Author Index

Abbott, c. G., 24

Abbott, 244

Abel, J. J., 143

Acheson, E. G., 52, 53

Adam, N. K., 151, 185

Adams, Leason H., 29

Adkins, H., 137

Adrian, Sir E. A., 121, 274

Aesculapius, 238

Aguilhon, 119

d'Albe, Fournier, 38

Albutt, Sir T. C, 239

Alexander, Jerome, 8, 54, 61, 62

94, 110, 136, 138, 144, 148, 152,

160, 163, 178, 210, 211, 213,

277
Alexander-Jackson, Eleanor G.,

243, 244
Anderson, C. D., 20, 34
Andrews, W. S., 39
Ansbacher, S., 77
Archimedes, 246
Aristotle, 9, 246, 257
Armstrong, Chas., 236
Arnold, 117
Arnow, L. Earle, 127
Arvanitaki, 123
Aston, F. W., 16
Auchter, E. C., 119
Auerbach, C, 178
Avery, O. T., 63, 133

Bacon, Sir Francis, vii, 8

Bacon, Roger, 247

Baekelund, L. H., 98, 99

von Baer, K. E., 182, 249

Bagg, H. J., 207, 208

Baker, Lillian, 189

Balfour, Lord, 274

Barnes, H. T., 44

Barrow, E. A. G., 240

Barth, L. G., 190

Bateson, Sir Wm., 156, 252

Baumann, E., 227

Baxter, J. G., 72

Bayliss, Sir Wm. M., 176

Beadle, G. W., 70, 127, 159, 162

Beale, W. J., 87

Bechhold, H., 54

Becquerel, 87

Becquerel, H. A., 11

Beijerinck, 82

Beilby, Sir Geo., 104

Bell, D. J., 131, 138

Bentley, Wilson A., 47

Bergmann, Max, 107, 195

Berkeley, Bishop George, 274

Berkman, 136

Berman, M., 138

Bernal, J. D., 44

Bernard, Claude, 123
, 89, Bernheim, F., 239
158, Bernthsen, H., 113
275, Berthelot, 277

Berzelius, J. J., 91, 92, 102
133, Bethe, H. A., 25

Bisonette, 125

Blackett, P. M. S., 20

Blackford, C. M., 251

Blair, John E., 224, 244

Blum, H. F., 228

Bodine, J. H., 126, 127

Bogert, C. M., 126

Bohr, Niels, 18, 22

Boltwood, 14

Boltzmann, 264

Bonnevie, K., 208

Bordet, Jules, 133, 145

Born, Gustav, 186

Boyle, Robt., 10, 61

Boyd, Wm. C, 153

Brachet, J., 213

Bradley, A., 87

Bragg, Sir Lawrence, 17

Bragg, Sir Wm. H., 17, 48

von Brand, 240

Braun, A. C, 236

Breasted, Jas. H., 276

Bredig, G., 116

Bridges, Calvin B., 8, 89, 94, 136, 148,
149, 152, 154, 159, 160, 163, 165,
213, 277

Brody, S., 72, 74, 108, 183, 184, 185,
212

Brown, A. Crum, 239

Brown, John, 268

Brown, N. A., 245

Browning, Robt., 268, 269

279

280

Bruno, G., 247
de Bruyn, Lobry, 57
Bryce, L. M., 244
Buchner, 277
Buffon, 247
Bullock, 123
Bullock, T. H., 138
Bullowa, J. G. M., 144
Burgin, 125
Burk, D., 137
Burnet, F. M., 244
Burns, Robt., 264
Butenandt, A., 78
Byrd, Richard, 86

Cabell, Jas., L., 251

Call, Richard E., 258

Cannon, W. A., 121

Carnot, 106

Carpenter, G. H., 125

Carr, F. C, 276

Carrel, Alexis, 84, 189

Cavendish, H., 13

Chadwick, Sir Jas., 17, 20, 21, 34

Chamberlin, T. C, 25, 27

Chambers, Robt. (1846), 249

Chambers, Robt. (N. Y. U.), 84

Chaucer, 9

Chenoweth, M. B., 245

Christie, R., 244

Church, 138

Cicero, 276

Clark, A. J., 70, 239

Clarke, Beverly L., 139

Cleveland, 175

Cockcroft, J. D., 23

Coindret, 271

Colowick, S. P., 78

Colucci, V. L., 211

Combes, Frank C, 43

Conklin, E. G., 168, 173, 257

Cook, J. W., 230, 231

Copernicus, 10, 272

Cori, 71, 130, 170

Cori, C. F., 78

Cori, G. T., 137

Correns, C, 154, 177

Cox, Herald R., 133

Crommelin, A. C, 26

Crewe, F. A. E., 213

Crookes, Sir Wm., 10

Cunningham, E., 39

Cunningham, J. A., 171

Cunningham, J. T., 176, 177, 257, 258

Curie, 272

Curie, Eve, 12

Curie, Marie S., 1 1

Curie, Pierre, 12

AUTHOR INDEX

Curie-Joliot, Irene, 20
Cuvier, Georges, 247, 248

Dack, G. M., 244

De Garis, G. F., 173

Dakin, H. D., 228

Dale, Sir H. H., 121

Dam, H., 78

Dampier, Sir Wm. C, 38

Danschavoka, V., 203

Darwin, Chas. Galton, 263, 275

Darwin, Chas. Robt., 154, 172, 250,

257
Davenport, C. B., 185, 227
Davis, 137
Dawson, 133
Deinert, F., 139, 197
Democritus, 9
Descartes, 78, 266
Devaine, 216
Devaux, H., 194
Dienes, L., 135, 139
Dirac, P. A. M., 20
Dixon, 121

Dobzhansky, T„ 193, 195, 252, 273
Dolman, C. E., 244
Domagh, G., 239
Donnan, F. G., 107
Doremus, Robt. Ogden, 11, 277
Dorsey, Edward A., 78
Dorsey, N. E., 44
Downs, Chas. R., 136
Driesch, H., 181, 186
Dubois-Reymond, E., 37
Duncan, I. J., 139
Duncan, J. T., 149
Dunn, L. C, 244
Duran-Reynolds, F., 244
Dustman, R. B., 139
Duvel, J. W. T., 87
Dyer, Thistleton, 168

Eaton, Orson N., 214
Eccles, 123

Edwards, Jonathan, 272
Eggerer, 78
Egloff, G., 136
Ehrlich, Paul, 145, 239
Ehrenfest, 263
Eijkman, C, 69
Einer, T., 256
Einstein, A., 22
Elliott, 121
Elvehjem, C. A., 76
Emerson, 117
Emerson, R. W., 273
Emmett, P. H., 102
Empedocles, 246
Endres, H. A., 61

AUTHOR INDEX

281

Epicurus, 9

Erlanger, J., 121

Evans, H. M., 165, 217, 244

Evans, Robley D., 40

Eyring, Henry, 239

Eyster, W. H., 128

Fairbrother, R. W., 244
Fajans, K., 14
Falk, 89

Faraday, M., 53
Farr, Wanda K., 55, 167
Farris, E. J., 222
Fermi, E., 21
Fernbach, A., 57
Fieser, L. F., 230, 231
Fildes, P., 245
Filmer, J. F., 138
Fischer, B., 245
Fischer, Emil, 147
Fischer, F. G., 213
Fischer, H. O. L., 137
Fisher, A. M., 244
Fisher, C, 244
Fleck, 78
Flett, Sir J. S., 61
Flint, 40
Folkers, K., 192
Foster, Sir M., 37
Fouquier-Tinville, 12
Fowler, R. H., 44
France, Wesley C, 153
Franklin, Benj., 259
Fraser, T. R., 239
Freud, Sigmund, 276
Freundlich, H., 16, 151
Friedburg, L. H., 11
Friedel, G., 61
Frisch, O. R., 22
Fruton, J. S., 107
Fry, H. J., 214
Funk, C, 69

Gadow, H. F., 214

Galen, 218

Griineberg, H., 223

Galileo, 10, 272

Gasser, H. S., 121

Gauss, 264

Geiger, E., 15

Geinitz, 189

Gengow, 133

Gilbert, W. S., 265

Gilman, A., 245

von Goethe, J. W., 249, 258

Goldschmidt, R., 193, 194, 195, 208,

213
Goldstein, 10
Goodman, Clark, 40

Goranson, 148

Graham, Thos., 17, 31, 45, 46, 47, 50,

53, 92, 116
Grasset, E., 153
Green, David E., 71, 118, 138
Green, R. E., 133
Green, R. G., 139
Green, Robt. H., 3
Greenwich Observatory, 26
Griffith, 133
Grundfest, H., 138
Guthrie, 50

Haacke, W., 256

Haas, V. H., 236, 245

Hackh, 275

Hahn, O., 22

Haldane, J. B. S., 154

Hale, J. H., 244

Hall, 59

Hallock, A. P., 13

Hammerling, J., 205, 206

Hansen, 197

Harden, A., 78, 108, 130

Hardy, Sir Wm. B., 152, 185

Harkins, Wm. D., 15, 19, 27, 151, 185

Harris, S. A., 213

Harrison, Ross G., 84

Hartree, W., 108

Hartung, 48, 51

Harvey, E. B., 204

Harvey, E. Newton, 245

Harvey, R. B., 86

Haurowitz, 112

Hays, Arthur G., 258

Heffter, 245

Hehre, H. J., 136

Heidelberger, M., 63, 133

Heisenberg, W., 262, 265

Helbig, W. A., 213

Helmholtz, 24

Henley, Wm., 269

Henseleit, 162

Herbst, C, 55

Herrera, A. L., 61

Hertz, H., 15

Hieger, I., 230, 231

Hill, Sir A. V., 108

Hill, R. T., 213

Hillebrand, W. F., 13

Hitchcock, A. E., 139

Hittorf, 10

Hixon, R. M., 62

von Hoffmann, A. W., 276

Holmes, D. W., 273

Holtfreter, 189

Hooker, Sir Wm. J., 251

Hoppe-Seyler, 277

Houssay, 72

282

AUTHOR INDEX

Howells, 121
Hubble, E., 33
Huggins, Chas., 232
Huggins, M. L., 44
Hume, E. H., 271
Hunt, Reid, 70
Hutt, F. B., 218, 222, 244
Huxley, Thos., 251

Ichikawa, 230
Imhotep, 238
Ingersoll, Robt. G., 275
Ingram, W. R., 244
Ipatieff, V. N., 137

Jacobi, A., 56

Jakus, 59

Jassens, 158

Jeans, Sir J. H., 3, 26

Jennings, H. S., 61, 172, 173

Jerchel, D., 213

Joffe, 82

John, H. M., 138

Johnson, F. H., 239

Joliot, J. F., 20

Jollos, V., 168, 174

de Jong, H. G. Bungenburg, 58

Jordan, 89

Juhling, L., 213

Just, E. E., 151

Kabat, E. A., 141
Kahn, R. H., 151, 153
Kalkar, H. M., 137
Kamm, Oliver, 72, 75, 77
Kant, Immanuel, 248
Karrer, P., 76, 78
Karstrom, 197
Kasner, Edw., 275
Keeler, C. E., 223, 244
Keilin, 117, 198
Kellogg Co., M. W., 99
Kelvin, Lord, 25, 52
Kettering, C. F., 98
Kitchen, D. K., 72, 75, 77
Kleiger, B., 244
Kleinberger, E., 135
Knopf, S., 40
Kober, 78
Koch, Robt., 216
Kogl, H., 76, 192
Koltzoff, N. K., 148
Krebs, 162
Kruyt, H., 58
Kuhn, R., 78, 119, 213

Lamarck, Jean, 176, 247, 248, 258

Landauer, W., 244

Landsteiner, K., 52, 142, 143, 144, 278

Lang, W. B., 89

Langdon-Brown, Sir W., 72

Langmuir, Irving, 15, 93, 151, 185

Laulanie, M., 202

Lavoisier, 12

Lawrence, Ernest O., 20

Lazarow, A., 149

Lea, D. E., 171

Lea, M. Carey, 57

Lebedev, 113

Leduc, S., 61

von Leewenhoek, Anton, 215

Lehmann, O., 48

Lehmann, F. E., 208, 209

T pimTfi P It

Leonard, Clifford S., 240, 241, 242

Levine P., 142

Lewis, G. N., 15

Lichtwitz, L., 51

Lillie, F. R., 151, 213

Lindegren, C. C, 149

Lindestr0m-Lang, K., 66

Linnaeus, 247

von Linne\ Carl, 247

Lipman, Chas. B., 86

Lipmann, F., 108, 137

Lippmann, G., 57

Li Shih-chen, 62

Lister, Sir John, 215

Little, C. C, 208

Lockyer, Sir J. N., 13

Loeb, Jacques, 213

Loeb, Leo, 63, 229

Loewi, O., 70, 121

Longwell, 40

Lorentz, H. A., 22

Lowell, J. R., 248

Lucas, 125

Lucas, A., 87

Lucas, Keith, 121

Lucretius, 9, 214

Lutz, Frances E., 156

Lyell, Sir Chas., 251

Lynn, D. E., Jr., 244

MacArthur, J. W., 170
Machado, A. L., 138
MacLeod, C, 133
Madison, R. R., 244
McCarty, Maclyn, 133
McClendon, J. H., 213
McCollum, E. V., 68
McClung, Chas. E., 156, 202
McCulloch, V. S., 245
Magiotti, R., 78
Mangold, O., 189
Mann, 117

Manwaring, W. H., 139, 172
Mason, Frances, 258

AUTHOR INDEX

283

Massavi£ius, J., 203

Matthews, B. H. C, 138

Marco Polo, 120

Marrack, J. R., 150

Marsden, E., 15

Martin, G. J., 230

Marx, A., 214

Maxwell, J. Clerk, 1

Mayer, Dennis T., 72

Mazur, A., 245

Meister, Joseph, 140

Meitner, Liese, 22

Mellor, J. W., 214

Mendel, Gregor, 154

Mendele^f, 14

Menkin, Valey, 224

Merck & Co., 192

Meyerhof, O., 108, 137

Miall, Stephen, 89

Midgley, Thos., Jr., 98

Miller, W. Lash, 190

Millikan, Robt. A., 10

Mittasch, Alwin, 278

Moebus, F., 213

Montagu, M. E. Ashley, 273

Morgan, Sir G. T., 114, 115

Morgan, T. H., 154, 159, 161, 197

Morrell, J., 136

Morris, C. T., 62

Morris, D. L., 62

Moseley, H. G., 17

Moses, 271, 272

Moulton, F. R., 27

Moxon, A. L., 120

Muller, H. J., 82, 162, 185

Midler, J., 37

Nachmansohn, David, 121, 138

Neddermeyer, S, 34

Needham, Joseph, 66, 78, 153, 180,

187, 188, 190, 192, 202, 204, 206,

209 212, 245
Nellensteyn, 150
Nelson, J. M., 109
Nelson, W. A., 28
Neuberg, Carl, 130, 131, 139
Neurath, A., 141
Newlands, 14
Newton, 272
du Noiiy, P. Lecomte, 3

Omar Khayyam, 6, 265, 269
Ord, Wm. M., 48, 51, 57, 61
Osborn, H. F., 172, 246, 256
Osier, Sir Wm., 223
van Overbeek, J., 128

Painter, T. S., 163
Panton, P. M., 244

Parker, Geo. H., 124, 210

Parker, T. J., 244

Pasteur, Louis, 41, 108, 140, 215, 216

Pearson, 125

Pegraus, G. B., 13

Perkin, Sir W. H., 239

Pfliiger, E., 1

Pincus, G., 185, 212

Pirie, 138

Plagens, G. M., 208

Plato 9

Pliny', 44, 258, 271

Poe, E. A., 6

Pott, Sir Percival, 229

Pouchet, 124

Power, F. W., 228

Preer, J. R., 170

Presley, J. T., 213

Price, S. A., 244

Price, W. H., 78

Prout, 38, 49, 272

Punnett, R. C, 156

Pupin, M. I., 3

Quincke, G., 61

Rafinesque, C. S., 250, 251
Rahn, O., 106
Rainey, Geo., 48, 51
Ramon, 144

Ramsey, Sir Wm., 10, 13
Ransom, S. W., 244
Raper, H. S., 126
Raper, K. B., 63
Rayleigh, Lord, 152
RCA Laboratories, 80
Redi, Francesco, 215
Reiner, L., 241
Remsen, Ira, 41
Rhoades, H. E., 197, 213
Rhodewald, 191
Richards, 137
Richards, A., 173
Richards, T. W., 14
Riddle, O., 213
Robbins, Wm. J., 69, 117
Robertson, J. M., 100, 101
Robeson, C. D., 72
Robinson, 130
Roblin, Richard O., 245
Robson, J. M., 178
Roentgen. W. K., 10
Romanoff, A. L., 184
Rose, H., 46
Rose, Wm. C, 78
Rosetti, D. G., 6
Rothenberg, B. A., 138
Rothmund, P., 177
Rountree, P. M., 244

284

AUTHOR INDEX

Rous, Peyton, 167, 232, 234
Roux, W., 185
Russell, A. S., 14
Russell, Bertrand, 264, 275
Russell, Sir E., Jr., 55
Ruzicka, L., 78

Rutherford, Sir Ernest (Lord), vi, 12,
15, 18, 19, 20, 34, 111, 272

Sampson, R. A., 24

Sazerac, 119

Schmitt, F. O., 59

Schoenheimer, R., 107

Schopfer, 69

Schwerin, 112

Screenivasaya, 138

Seaborg, Glenn T., 21

Sevag, M. G., 153

Sheean, Victor, 38

Shen, S. C, 212

Sherwin, 228

Shohl, A. T., 78

Shope, 167

Slichter, L. B., 27

Sia, 133

Sickels, Ivan, 277

Silverman, A., 46

Simpson, G. G., 252, 253

Singer, P., 240

Sinnott, E. W., 181

Snyder, L. H., 226

Smekal, 48

Smith, E. F., 245

Smith, E. L., 117

Smith, M. Llewellyn, 244

Smith, W., 244

Smith, W. E., 234

Smithells, C. J., 65

Smyth, H. D., 22, 23, 66

Smythe, 241

Soddy, F., 14, 38, 39

Sonneborn, T. M.. 169, 170, 198

Sowden, J. C, 137

Spallanzani, Lazaro, 215

Spencer, Herbert, 7, 10, 172, 270

von Spemann, H., 186, 187, 209

Spitzer, Lyman, Jr., 27

Stacey, M., 135

Stanley, W. M., 79, 81

Starkey, Robt. L., 80

Starling, E. H., 176

Stas, J. S., 38, 272

Stewart, G. W., 48

Stockard, C. R., 214

Stoney, G. J., 10, 34

Strassman, F., 22

Stratford, Wm., 277

Sturtevant, A. H., 154, 167

Sugg, J. Y., 136

Sumner, F. B., 125, 209, 255
Svedberg, The, 112, 141, 185, 198, 201
Swezy, O., 165, 244
Szent-Gyorgyi, A., 76, 77, 78, 255

Tatum, E. L., 127

Tauber, H., 138

Taylor, Hugh S., 104, 136

Theorell, H., 138

Thierfelder, 228

Thomson, Sir J. J., 10, 15, 16, 34, 262

Tiberius, 247

Tiebackx, F. W., 58

Tiselius, Arne, 141

Topley, W. W. C, 149

Townsend, 125

Toyama, 167

Traub, E., 245

Trautwein, 82

Trimble, H. C, 223, 244

Troland, Leonard T., 93, 94

Tschermak, G., 154

Tswett, 135

Turner, W. E. S., 61

Tyler, A., 151, 153, 204

Tyndall, 6

Umbreit, W. W., 139
University of Toronto, 84
Urey, H. C, 17
Ussher, John, 251

Valentine, F. C. O., 244

Van Niel, C. B., 119

Varley, 10

du Vigneaud, V., 76, 192, 230

da Vinci, Leonardo, 10, 247

Virgil, 6

Vogelsang, 61

de Vries, H., 154, 156

Waddington, C. H., 190, 192, 212, 213

Wagner- Jauregg, J., 271

Waksman, S., 82

Wallace, Alfred R., 250

Walton, E. T. S., 23

Warburg, O., 78, 198

Ward-Meyer, 135

Wehmeier, E., 213

von Weimarn, P. P., 46

von Weizsaker, C. S., 39

Welch, Arnold D., 245

Wellington, 259

Wells, H. Gideon, 153

von Wettstein, V., 168

White, H. E., 18

White, Orland E., 237

White, P. R., 236, 245

Whymper, R., 87

AUTHOR INDEX

285

Wiener, A. S., 142
Wiggelsworth, Michael, 272, 276
Wilkenson, Sir J. G., 52
Wiley, H. W., 55
Williams, R. J., 76
Williams, R. R., 76
Willstatter, R., 117, 191, 200
Wilson, Edmund B., 204
Wilson, H., 244
Wilson, J., 149
Windaus, A., 78
Winogradsky, S., 82
Wirtanen, A., 78
Woerdeman, 191
Wolf, J., 57
Wolff, G., 211
Wolkow, M., 227

Woods, D. D., 242

Wooley, D. W., 77, 129

Wassermann, 145

Wright, J., 244

Wright, Sewall, 207, 208, 214, 252

/amagawa, 230
Yasuda, 128
Young, 108, 130

Zechmeister, L., 41, 61, 134, 213
Zimmerman, P. W., 139
Zisman, 148
Zsigmondy, R., 29, 53
Zowandowsky, M. M., 213
Zweifach, B. W., 58
Zwicky, 48

Subject Index

Abnormalities in development,

207
Abrin, 143

Acetabularia, 205, 206
Acetylcholine, action of, 121, 122
Adaptive enzymes, 197
Adrenaline, potency of, 70
Age, of earth, 27
Agglutinations, 144, 145
Alexin, 145
Alkaptonuria, 227
Alum, as deodorant, 44
Americum, 21
Amino acids, essential, 78
Analyses, use of, 64, 65
Analysis, refined, 66
Anlagen, 191
Annihilation energy, of one

unit, 26
Ant-eater prominence, 26
Anthrax spores, life of, 87
Antibodies, 61, 140, 144
Antibody formation, 145, 146
Antigen-antibody reactions, 149
Antigens, 140, 144
Ants, 125, 126
Arbutus, 175

Artificial parthenogenesis, 204
Ascorbic acid, 255
Athlete's foot, 44
Atom, 9

Atomic bomb, 30
Atomic nuclei, density of, 19
Atomic theory, history of, 9
Atomic transmutation, 18
Atoms, emptiness in, 15
Autocatalysis, 96
Autosomes, 157, 166
Autotrophs, 79, 109, 139

Dackcross, 155
Bacteria, 80, 82
Bacterial dissociation, 132
Bacterial products, 224
Bacteriophages, 79, 80, 81
BAL, 242
Bees, 125

3,4-benzpyrene, 230
Biocatalysis, and heat, 105

206, Biocatalysis, efficiency in, 106

Biocatalyst chains, 129, 130

Biocatalysts, 115

Biogenetic law of von Baer, 249
, 124 Bionts, structures in, 58

Biotin, 192

Black Hole (Calcutta), 137

Blastocyst, 185

Blastoderm, 180

Blindness, in cave animals, 209

Blood clots, 208

Blood groups, 142

Body heat, 105

Bonellia, 203

Book of the Dead (Egypt), 266

British anti-lewsite, 242

Bush sickness, 68
mass Butter yellow, 230

Calcium, role of, 55

Cancer, 229, 230

Cancer, basic cause of, 231, 232

Caramel, 53

Carcinogens, 212, 229, 230

Carotene, 41, 42

Carotenoids, 41, 134

Carrier effect, in catalysts, 137

Cartesian diver, 66, 78

Catalysis, 90, 91

Catalysis and reproduction, 96

Catalysis, in industry, 97, 98

Catalysis, time factor in, 109

Catalyst entelechy, 179, 180

Catalyst modification, 113, 131

Catalyst modification, modes of, 191

Catalysts, mode of action, 102

Catalysts, new, 196

Catalytic heat, 104, 105

Cat-cracker, 99

Cathode rays, 10

Causation, 246

Cave animals, blind, 209

Cellular death, 83

Chagras disease, 240

Chemical activators, 119, 120

Chiasmata, 158

Chicken sarcoma, 167

Chinese drugs, 238

Chlorophyll groups, 117

286

SUBJECT INDEX

287

Choline, 163

Cholin acetylase, 122

Cholinesterase, inhibitors of, 123

Chromatography, 135

Chromosomal behavior, 159

Chromosomes, in Drosophila, 148

Chronology, orthodox, 251

Cleveite, 13

Clone, 196

Coagulase, 57

Coal, formation of, 53

Cohesive colloids, 54, 55, 60, 149

Collagen, structure of, 59

Colloidal protection, 52

Colloidality, zone of maximum, 110

Colloids and crystallization, 48

Colloids and crystals, 43

Colloids, defined, 93

Color change, in animals, 124, 125

Coloring fruits, 129

Competence, 188

Complement, 145

Conscience, 266

Constitutive enzymes, 197

Coupled reactions, 107, 108, 109

Cow fleas, as carriers, 140

Creation, date of, 251

Creation, vestiges of, 249

Criminal choice, 266

Critical mass, 33

Crossing over, 159

Cross-reactions, 144

Crown gall, 236

Crystal, origin of term, 45

Crystallization and reproduction, 96

Crystallization, course of, 47

Crystallization, effect of collioids on,

48
Crystallization, slow, 46
Crystals and colloids, 43
Crystals, purification of, 60
Cumulative protection, 57
Curium, 21
Cybotactic groups, 48
Cyclohexane, 98
Cyclotron, 20
Cytoplasm, 82

Dalmatian dogs, 127, 223, 226
Dangerous radiations, 32
Determinisms, 265
Dauermodifications, 168
Death, somatic vs cellular, 83
Deficiency, 159, 163
Deflocculation, 198
Deletion, 159

Dental caries and fluorine, 128
Detoxication mechanisms, 228
Diastase, action of, 112

Dictyostelium, 60

Diethylstilbestrol, 75

Differentiation, 179

Diffusion, 31, 92, 93

Di-isopropyl fluorophosphate, 123, 242

Dionne quintuplets, 170

Displacement law, 14

Disease, 215

Disease, basis of, 216, 217

Diseases, classification of, 217, 218

Diseases, hereditary, 226, 227

Dissociation, bacterial, 132

Dominants, 155

Dopa, 126, 127

Dopplerite, 53

Double colloidal protection, 48, 57

Dowsing, 262

Drosophila, types of, 161

Drosophila, eye color of, 127

Drugs, 215, 238

Dutchman's pipe, 85

Earth, age of, 27

Efficiency in biocatalysis, 106

Egg, molecules in, 182

Einstein equation, 22, 23

Einsteinian universe, 35

Electric eel, 122

Electric phenomena, in nerves, 121

Electron, 10, 34

Electron, weighing of, 10

Electroversion, 193

Elementary particles, 34

Elements, in living things, 37

Elution, 198, 200

Embryology, comparative experimen-
tal, 186

Emptiness, in atoms, 15

Endocrine relations, 72

Endotoxins, 143

Energy, from phosphate bonds, 108,
109, 122, 139

Energy-mass relation, 22

Entelechy, 179, 180, 181, 186

Enzyme theory of life, 94

Epistasis, 226

Equivalence of mass and energy, 23

Erythryblastosis fetalis, 142

Estrogens, 212

Ethics, 268

Ethylene gas, for ripening fruits, 129

Evocation, 188

Evocators, 188

Evolution, basis of, 246

Exotoxins, 143

Eyes, replacement of, 211

Faith, necessity of, 6
Fasciation, 237

288

SUBJECT INDEX

Fermentation, 130, 131

Fertilizin, 151

Fuelgen reaction, 204

Fields, as escape mechanisms, 260, 263

Figs, fertilization of, 86

Fission, nuclear, 21

Flour, protection in, 57

Fluid-catalyst process, 100

Fluorosis, 128

Folic acid, 77

Folk-lore, wisdom in, 270

Food, deficiencies in, 210

Foreordination, 265

Frazil, 44

Free will, 265, 266

Frizzle, in fowl, 222

Gametes, 158, 166

Gene, 2

Gene map, 160

Gene modification, 196

Gene mutation, 193

Genel, 2

Genie balance, 202

Genetic spectrum, 163

Genetics, 154

Glass, crystallization of, 46

Globulins, 141

Glucose, fermentation of, 130, 131

Glycogen, 191

Gogo bark, 53

Googol, 275

Googolplex, 275

Gout, 223

Graviton, 34

Grey crescent, 187

Guinea pigs, defective, 207, 208

Haber process, 114

Haptens, 144

Hatteria, 214

Heat, in catalysis, 104, 105

Heat, of sun, 24

Helium, 13

Helmholtz theory, 25

Helpful traces, 66

Hemophilia, 218

Hen's egg, development of, 183, 184

Heritable modifications, 171

Hexokinase, 71

Hibernation, 86

Hormone, origin of term, 176

Hormomers, 75

Hormones, 68, 70, 74

Homing pigeons, 262

Homogentisic acid, 227

House-moss, 152

Human body, systems in, 220

Hydrohumors, 124

Hydrogen sulfide, a dangerous gas, 84

"Hypon," 39

Ice, 44, 45, 47

Ice cream, 55, 56

Identical twins, 276

Immunization, 140, 144

Immunization demonstrated, 216

Immunology, 140

Impurities 64

Impurities, in catalysts, 113, 114

Independent assortment, 156

Indeterminism, 262, 263

Individuation, 192

Induced radioactivity, 20

Inductors, 188

Infant damnation, 272

Infant feeding, 56

Inflammation, 225

Inhibitors of cholinesterase, 123

Iodine metabolism, 73

Iodine therapy, 271

Iodine therapy, one danger of, 201

Insects, fertilization by, 85

Isotopes, 14, 16

Isotopes of tin, 38

Inversion, 159

Kahn test, 151
Kangri cancers, 229
Kappa, 169, 170
Killifish, 173
King-snake, 126
Knowledge vs. wisdom, 259
Krakatoa, 28

Lamarckism, 248
Lange test, 52, 54
Law and intent, 266
Lazy gene, 128
Lead poisoning, 201
Lebedev process, 1 1 3
Leprosy, 243
Leucotaxine, 225
Leukoderma, 127
Levels of structure, 33
Lewisite, 242
Lichens, 175
Life, active vs. latent, 86
Life, criteria of, 88
Life, origin of, 1
Linkage, 156
Liquid crystals, 48
Living units, 79
Living vs. dead, 83
Lorentz' equation, 39
Luminescence, to gauge drug effects,
239

SUBJECT INDEX

289

Lung fish, 86
Lysins, 145
Lysis, 145

Macromolecules, 35

Malaria, 270, 271

Mammalian egg, 182

Mammalian egg, development of,

184, 185
Man and chimpanzee, in detoxica-

tion, 228
Masking, 189
Mass-energy relation, 22
Mass-space-time, 36
Masses, from molecules, 41
Maternal effects, 167
Mathematics, pure vs. applied, 260
Matter and mind, 272, 273
Matter-energy change, 260, 261
Matter, structure levels of, 33
Measurements, units of, 36
Meiosis, 158
Melanin, 126, 127
Mendel's First Law, 155
Mendel's Second Law, 156
Merogens, 213
Mesons, 34

Metals, as prosthetic groups, 118
Metals, trace impurities in, 66
Methanol synthesis, 114, 115
Methylene blue, 190
Micells, 35

Milks, composition of, 62
Milk factor, in cancer, 233
Milk, protective colloids in, 56
Mind and matter, 272, 273
Mitosis, 157

Mixtures vs. pure substances, 58
Modification of catalysts, 113, 131
Molecular aggregates, 35
Molecular association, 44
Molecules, 35

Molecules, aggregation of, 41
Monsters, 207, 208
Morphogenesis, 179
Morphogenetic fields, 192
Morphology, origin of term, 249
Mosaic eggs, 187
Mother-of-coal, 53
Mottled enamel, 128
Mt. Pel£, eruption of, 29
Multilayers, 148
Mummy wheat, fraud in, 87
Mumpsimus, defined, 30
Murexide crystals, 49
Mustard gas, mutations caused by, 171
Mutagens, 178
Mutations, 132
Myoglobin, 198

Nascent state, 49

Native drugs, 238

Natural selection, 250

Nebulas, 33

Necrosin, 225

Negative confession, chapter of the,

266
Negative meson, 34
Nematic state, 48
Neovitamin A, 72
Neptunium, 21, 31
Nerve conduction, 123
Neurohumors, 124
Neurospora, 159, 162, 163
Neutron, 34
Neutrino, 34

Nickel phthalocyanine, 101, 103
Nitrogen mustards, 178
Noma, 218
Non-disjunction, 166
Nuclear energy and volcanism, 28
Nuclear fission, 21
Nuclear fission bomb, 30

Obligate parasites, 168
Ochronosis, 227
Oenothera, 156
Orchids, 175
Organizers, 187
Organotherapy, 271
Ornithine cycle, 162
Orthogenesis, 256
Otocephaly, 207, 208
Oxygen debt, 226

PABA, 242

Pair production, 20

Paleontology, 253

Pantothenic acid, in royal jelly, 125

Para-aminobenzoic acid, 241, 242

Parahormones, 177

Paramecium, 169

Parasites, 175

Paricutin, 28

Parsec, 35

Peas, Mendel's experiments with, 151,

155
Peiping throat, 55
Pen T'sao, 238
Pepsin, action of, 112
Periodic table, 14
Petunias, 128
Pile, 31
pH, 43

Phallusia, 44, 68, 118
Philosophy, the guide of mental life,

259
Phosphate-ester bond energy, 108, 109,

122, 139

290

SUBJECT INDEX

Photon, 34

Photosensitization, 228
Phthalic anhydride, 104
Phthalocyanine, 100
Physicochemical basis of evolution,

251, 252
Planetesimal theory, 27
Plant cancers, 236
Plant galls, 236
Plaques, elution of, 148
Plasmogen, 190
Plural protection, 57
Pluripotency, 186, 187
Plutonium, 21, 31
Pneumococci, 133, 134
Polonium, 12
Polyelectrons, 35
Polysaccharide formation, 136
Position effect, 132, 193, 200
Positive meson, 34
Positron, 20, 34
Pouvoir hydrogene, 43
Preciptin reactions, 144
Predestination, 265
Predeterminism, 265
Probability, 263
Probability calculations, 3
Prominences, solar, 25, 26
Prospective potency, 186, 187
Prostatic cancer, 232
Prosthetic groups, 115, 116
Prostigmine, 123
Protection, colloidal, 52
Protection, nature of, 54
Proteins, changes in, 198
Proton, 34
Protoplasm, 1

Pure substances vs. mixtures, 58
Pyrexin, 225

Quanta of interaction, 34

Rabbit papilloma, 167

Radiations, dangerous, 32

Radioactivity, 1 1

Radioactivity, induced, 20

Radio-sodium, 21

Radium, 11, 12

Rh factors, 142

Ramon test, 144

Rare gases, 13

Rattlesnake, 126

Recessives, 155

Rectal temperatures, 136, 137

Referees, obstruction by, 146

Religion and science, 270

Renin, 72

Reproductive catalysis, 96

Resonance region, 32

Respiratory proteins, 198, 199

Responsibility, 267

Ricin, 143

Roentgen rays, 10

Rous chicken sarcoma, 232

Royal jelly, 125

Salivary gland chromosomes, 163

Science and philosophy, 259

Science and religion, 270

Segregation, 155

Senses, deception of, 261

Sex determination, 157, 165, 201

Sex hormones, 201

Sex reversal, 203

Sex transformation, 202

Shortening, action of, 58

Skin, acid mantle of, 43

Slime molds, 60

Smectic state, 48

Snake venoms, 143

Sodium fluoroacetate, 242

Solar system, origin of, 27

Somatic death, 83

Space-mass-time, 36

Specific catalysis, 94

Sphenodon, 214

Staphalococci, 224

Starch, 54

Stegocephali, 214

Stokes' law, 260

Stereoisomers, 41, 42

Structure and taste, 62

Structure levels, 33

Structures in bionts, 58

Sulfur, crystallization of, 61

Sumpsimus, defined, 30

Sun, energy of, 24

Symbiosis, 175

Symplexes, 115, 117

Tar cancers, 230

Taste and structure, 62

Temperaments, 218

Temperature gradient, in earth's

crust, 29
Template formation, 89, 145, 148
Ten commandments, 266
Teratomata, 206, 207
Termite, 175, 255
Thiouracil, 73
Thyroid interrelation, 73
Time factor, 264
Time factor, in catalysis, 109
Time-space-mass, 35
Tin, isotopes of, 38
Tinea, 44

SUBJECT INDEX

291

Tin-foil impressions, 196, 197

Tissue formation, 63

Toxalbumen, 143

Toxin-antitoxin reactions, 144, 145

Toxins, 143

Trace substances, 64

Trace substances and health, 120

Trace substances, in biology, 68

Trace substances, in plants, 119, 120

Transformation, bacterial, 132

Translocation, 159

Transmutation, of atoms, 18

Travertine, 46

Trichlorbutyl alcohol, 209

Trigger action, 201

Triple stain, Alexander-Jackson, 243

Trophoblasts, 185

Troublesome traces, 67

Trypanosome infections, 240

Tryptophane, 163

Tubercle bacillus, 133

Tuberculosis, 243

Turacin, 119

Units of measurement, 36
Universe, observable, 33
Uric acid, 223
Ussher's chronology, 251

Vaccination, 140

Variations in experimental animals,

222
Vestiges of creation, 249
Virus, transmission of, 236
Viruses, 79, 81, 84
Vitamers, 77

Vitamin A and blindness, 210
Vitamins, 68, 69, 76
Vitality, of bacteria, seeds, etc., 86, 87
Vitriol, origin of word, 45
Volcanism, basis of, 28

Wassermann test, 145
Water, structures of, 44
Wheat seed, life of, 87
Wisdom vs. Knowledge, 259
Wolffian regeneration, 211

X-ray spectra, 17
X-rays, 10

/east fermentation, 129, 130
Yeasts, training of, 197
Yellow enzyme, 198
Yellow mice, 222

Ziehl-Neelson stain, 243
Zygote, molecules in, 182