THE LIBRARY

OF

THE UNIVERSITY
OF CALIFORNIA

LOS ANGELES

THE PROTEOMORPHIC THEORY AND
THE NEW MEDICINE

ABBREVIATED CHRONOLOGICAL LIST OF THE

MORE IMPORTANT SCIENTIFIC AND HISTORICAL

WRITINGS OF HENRY SMITH WILLIAMS

Field Notes of a Naturalist (with over two hundred original draw-
ings), 1877-1880; Nesting Habits of the Ruffed Grouse, 1881; Prairie
Life and Prairie Seasons, 1881; A Plea for the Better Observance
of Medical Ethics, 1884; Modern Philosophy, 1885; Idealism, 1886;
Check List of Iowa Birds, 1887; On a Case of Shock, with Observations
in the Vaso-Motor System, 1889; The Encephalic Circulation and Its
Relation to the Mind, 1889; The Treatment of Haematoma Auris,
1889; Some Psycho-Somatic Base Lines, 1890; Molecular Dynamics of
the Encephalon, 1890; The Dream State and its Psychic Correlatives,
1891; A Modern Form of Insanity, 1892; General Paresis, 1892; The
Philosophy of Bird Life (2 vols.), 1892; The Prairie Hen and Its
Enemies (illustrations by the Author), 1892; A Modern Angelo, 1892;
The Lesson of Heredity, 1892; Can the Criminal be Reclaimed? 1893;
Shall We Look Forward or Backward in Dealing with the Criminal? 1894;
The New World of the Microscope, 1895; A New Form of Radiation
(Roentgen Rays), 1896; Science at the Close of the Eighteenth Cen-
tury, 1897; The Progress of Chemistry in the Nineteenth Century, 1898;
The Progress of Physiology in the Nineteenth Century, 1898; The Prog-
ress of Medicine in the Nineteenth Century, 1899; The Story of Nine-
teenth-Century Science, 1900; The Literature of Science, 1901; The
Marine Biological Laboratory at Naples, 1901; Ernst Haeckel and the
New Zoology, 1902; Low-Temperature Researches, 1902; The History
of the Art of Writing (4 vols.), 1903; The Royal Society, 1903; The
Influence of Modern Archaeological Research on the Scope of World
History, 1903; The Historians' History of the World (25 vols., edited
with the cooperation of many specialists), 1900-1905; Prehistoric
Science, 1904; Galileo and the New Physics, 1904; A History of Science
(5 vols.), 1904; The Conquest of Nature, 1905; The Conquest of Time
and Space, 1905; Tribute from the Vegetable World, 1906; Tribute
from the Animal World, 1906; The Science of Happiness, 1907; Alcohol
and the Individual, 1908; Alcohol and the Community, 1909; The
Scientific Solution of the Alcohol Problem, 1909; Every-Day Science:
The story of man's application of organized knowledge to the needs of
practical life (n vols.), 1909; How the Body Fights Disease, 1910;
Civilization (article in "Encyclopaedia Britannica"), 1910; The Wonder-
Working Electron, 191 1 ; To- Day's Science in Europe, 191 1 ; The Wonders
of Science in Modern Life (10 vols.), 1912; Miracles of Science, 1913;
Metchnikoff and the Search for the Philosopher's Stone, 1913; Mastering
the Microbe, 1913; Adding Years to Your Life, 1914; The Life and Work
of Luther Burbank (12 vols.), 1914; Painless Childbirth, 1914; The
Mechanism of Immunization, 1914; Better Brains for the Race, 1914;
Race Breeding, 1914; Mental Obliquities, 1914; The Protein Treatment
of Cancer in the Light of the Proteomorphic Theory, 1915; Detective
Work in the Blood Stream, 1915; Modern Warfare, 1915; The Proteal
Treatment of Cancer: A New Therapeutic Method as Interpreted in the
Light of the Proteomorphic Theory, 1916; Medicine as a Machine
Process, 1916; The Proteal Treatment of Rheumatism, 1917; Science
and Progress, 1917; Why Die Before Your Time? 1917; The Proteomor-
phic Theory and the New Medicine, 1918.

THE

PROTEOMORPHIC THEORY
AND THE NEW MEDICINE

AN INTRODUCTION TO PROTEAL
THERAPY

BY

HENRY SMITH WILLIAMS, B.Sc., M.D., LL.D.

Member of the National Committee for Mental Hygiene, and of the Hygiene Refer-
ence Board of the Life Extension Institute; successively Pathologist to the
Iowa State Hospital at Independence; Assistant Physician to the
Blackwell's Island and Bloomingdale Asylums, and Medical
Superintendent of the New York Infant Asylum and
the Randall's Island Hospitals, New York City.

NEW YORK
THE GOODHUE COMPANY

1918

COPYRIGHT, 1918,
THE GOODHUE COMPANY

QVC/

5-70

35ooh

The Chart of a Blazed Trail in a Virgin Territory

•ffs Beofcateo to

ORRILLA WEBSTER WILLIAMS,

Latter-day exemplar of the traditional spirit of the Roman
matron and the Spartan mother, from whom in a large mea-
sure the present explorer acquired by inheritance and through
childhood training the mental, moral, and physical equipment
that made possible the conception and the successful prose-
cution of a pioneer journey not lacking in obstacles.

Q
\M

I

CONTENTS

PAGE

F.OREWORD 9-24

General Analysis of Discoveries Involved, 9 — The Ter-
minology of the New Science, 13 — How the Proteals are Pre-
pared, 14 — The Practical Administration of the Proteals, 15
— Development of the Proteal Method, 20 — Other Non-
Specific Proteins, 21 — Scientific Medicine Versus Empiri-
cism, 22.

CHAPTER I
THE MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION — 25-79

General Statement of the Proteomorphic Theory, 25 —
Facts and Theories of Immunity, 3O-?-Protein Metabolism, 33
— Proteolytic Activities of the Leucocyte, 43 — The Leucocyte
and Bacterial Proteins, 47 — Transplanting Organs, 47 —
Tracing Blood Relationship, 48 — How the Test Fluids are
Developed, 50 — Man's Remote Relatives, 51 — The Source
of Specific Antibodies, 52 — The Primordial Leucocyte, 56 —
The Leucocyte as a Microcosm, 61 — Antitoxins and New
Chemical Problems, 64 — New Experimental Evidence, 69 —
The Red Corpuscle as Master Immunizer, 70 — Specific
Affinities and Antagonisms, 72 — Loss and Gain Through the
Division of Labor, 76 — The Coalition Between Red Corpuscles
and White, 77.

CHAPTER II
THE PROTEOLYTIC MECHANISM IN OPERATION. 80-106

The Blood Corpuscles and Parenteral Digestion of Proteins,
80— The Phenomena of Anaphylaxis, 83— The Synthesis of
Protein, 88 — The Leucocyte Balance, 93 — Hormones and the
Corpuscle-Balance, 97 — General Therapeutic Applications
of the Proteomorphic Therapy, 98 — Serums, Vaccines, and
Direct Cyto-Therapy, 103.

CHAPTER III
THE DISCOVERY OF THE PROTEIN PRINCIPLE IN THERAPEUTICS. . . 107-126

Influence of Radium on Neopolastic Cells, 107 — Cor-
relating Data from Many Fields of Science, 108 — The Formu-
lation of the Proteomorphic Theory, 108 — The Ideal of
Chemo-Therapy, 109 — A Bizarre Shot-Gun Formula, m —
Observed Reactions Interpreted in the Light of the Proteo-
morphic Theory, 1 13 — New Clinical and Laboratory Investiga-
tions, 115 — The Protein Principle Demonstrated, 118 —
Theory Tested by Prophecy, 119 — Proteals and the Malig-
nant Neoplasm, 120 — Other Remedial Uses of the Proteals,
122 — Wide Acceptance in Recent Months of the Principle of
the Protein Response in Therapeutics, 125.
vii

Vtii CONTENTS

CHAPTER IV

PAGE

THE SCIENCE AND ART OF PROTEAL THERAPY 127-220

Essentials of the Protein Response, 127 — Modification of the
Leucocyte Count, 135 — Blood Changes in Tuberculosis, 139
— Tuberculosis and Protein Poisoning, 141 — An Interpreta-
tion of Corpuscular Action, 144 — Age and the Blood Count,
151 — Further Hints as to Differential Functions, 153 — Rel-
ative Non-Toxicity of the Proteals, 158— The Preparation
of the Proteals, 162 — Specific Properties of Non-Specific
Proteins, 165 — The Administration of the Proteals, 167 —
Proteal Treatment of Cancer, 169 — Wider Applications of
Proteal Therapy: Rheumatoid Conditions, Asthma, and
Psoriasis, 174 — Dietetic Anomalies Explained, 177 — Proteals
in the Hands of the Practitioner, 179 — How Theory Explains
Practise, 1 86— Proteal Therapy and Tuberculosis, 188—
Intestinal Toxaemias and the Anaemias and Leukaemias
under Proteal Treatment, 196 — Blood Changes Tentatively
Explained, 199 — A Case of Leukaemia, 206 — Studying the
Blood Smear, 211 — Intestinal Toxaemias and the Corpus-
cular Balance, 214 — By Way of Summary, 217.

PART II

CANCER: INTERPRETED IN THE LIGHT OF THE PROTEOMORPHIC

THEORY AND THE PROTEIN RESPONSE 223-304

The Nature of Cancer, 223 — The Origin of Cancer, 225 —
The Local and Surgical Treatment of Malignant Neoplasms,
229 — Biological Measures in the Treatment of Cancer, 233
—The Evolution of the Protein Principle, 239— The Protein
Response Interpreted, 247 — Vegetable Proteins in Cancer
Treatment, 251 — The Blood in Cancer Subjects, 259 — Cancer
and the Lymphoid System, 271 — Animal Experimentation
and Proteal Therapy, 276 — The Prevention and Cure of
Cancer, 296.

FOREWORD

This book is essentially a Monograph detailing the author's
personal discoveries, original theories, and practical experiences
in a new domain of therapeutics.

It presents a series of new observations and certain novel
theories of which it may unqualifiedly be affirmed that they are
important if valid.

As a matter of course, not all these series of new observations
and theories are on the same plane, either of importance, of orig-
inality, or of verisimilitude. It will be "well, therefore, to give
a preliminary outline of both theories and practical discoveries,
with suggestions as to their relative importance in the estimate
of the author. Such an outline will be of value to the reader,
both in his preliminary appraisal of the matter presented and
in orienting his detailed study of the evidence as given in the text.

First of all, as constituting the most general analysis, I would
point out that three fundamental new discoveries are conceived
to be represented. These are :

(1) A physiological discovery, to the effect that (a) the
mononuclear leucocytes are the agents vitally concerned in begin-
ning hydrolysis, and (b) the red corpuscles the agents concerned
with the completion of decompounding of foreign proteins in the
parenteral system. This is the essence of the Proteomorphic
theory.

(2) The therapeutic discovery that foreign proteins and pro-
tein by-products introduced hypodermically into the parenteral
system constitute antigens that stimulate responsive activities of
the organism of such character as to aid tremendously in the fight
of the organism against the evil effect of other foreign proteins
of whatever character, introduced by pathological processes, in-
cluding (a) the proteins associated with the bodies of pathogenic
bacteria, (b) heterologous protein products associated with de-
fective digestion and assimilation, and (c) autologous proteins
associated with the hyperplasia of various organs, including the
so-called malignant neoplasms. This conception, in itself an
application of the Proteomorphic principle, furnishes the founda-
tion for Non-specific Protein Therapy in general and Proteal
Therapy in particular.

(3) The discovery that a single protein or combination of pro-
teins used therapeutically cannot usually produce optimum re-
sults, because the system becomes sated or immunized and no

9

10 FOREWORD

longer gives a maximum response. This principle, combined
with the others, furnishes the basis for Proteal Therapy as at
present developed.

The first of these discoveries was announced by the writer in
American Medicine of October and November, 1914 ; the second
had first detailed announcement in the writer's article in the New
York Medical Journal of October 2, 1915. The two discoveries
are interlinked and associated, but not necessarily interdependent.
Either one of them might be proved fallacious without necessarily
affecting the status of the other. But if both should be shown
to be true, it will appear that corollaries of practical importance
are associated with each that give mutual support to one another.
The third discovery was first publicly announced in a Monograph
issued December 1, 1916, under title of The Proteal Treatment
of Cancer and Allied Conditions.

The above statement of principles may be considered as a
fundamental analysis or summary of the most novel contents of
this book. Let me now make an analysis of a slightly more
detailed character, outlining the observed facts that appear to
give support to one or the other of these principles, and the
various collateral theories associated therewith.

The series of new facts, then, cited sequentially somewhat in
the order of their discovery, comprise the following :

(1) Certain substances administered hypodermically have been
observed to have a definite influence on the clinical progress of
persons suffering from inoperable cancer of many types. These
substances include extracts of plant products and animal products
of many kinds ; but they have this point in common — all of them
contain protein or the products of partial protein hydrolysis.

(2) The observed modifications in cancer subjects through
administration of these substances include: Alleviation of pain,
modification of discharge, modification in the tumor itself, and
modification in the general health and mental attitude of the
patient.

(3) The same protein substances, administered hypodermically,
have been observed to benefit markedly cases of (a) rheumatoid
arthritis, (1>) pulmonary tuberculosis, (c) pernicious anaemia,
(d) intestinal toxaemia, (e) leukaemia, (f) Graves' disease, (g)
psoriasis, (h) asthma, (i) arteriosclerosis, (j) neurasthenia, (k)
primary and secondary anaemias.

(4) The clinical betterment of these cases has been observed to
be associated with blood modifications of a definite and pre-
dictable character, namely: increase of haemoglobin, increase in
number of red corpuscles, increase of large mononuclear leuco-
cytes, increase of eosinophiles, and modification of numbers of
polunuclears and small lymphocytes in the direction of the nor-

FOREWORD 11

mal; also with conspicuous qualitative changes in the direction
of the normal.

(5) Physiological changes, including rises of temperature,
quickened pulse, and a chill are not infrequently associated with
the administration of the remedies in question, suggesting an
anaphylactic reaction, not known to be produced by anything
but protein or its products. This reaction appears not to be
evoked in the same degree by partially hydrolyzed proteins.

(6) It has been observed that a condition of immunization
appears to be attained sooner or later, after which the patient
no longer responds in the same way to a particular protein;
but that change to another protein may bring about a new re-
sponse, with possibilities of cumulative beneficial effects.

The theories on which these observed facts are explained by
the present writer are the following:

(1) The essential point of contact between the different sub-
stances administered hypodermically is their protein content
(either the full molecule or products of partial hydrolysis).

(2) Any foreign protein injected into the parenteral system
serves as an antigen and stimulates the defensive mechanism of
the body to the production of antibodies capable of hydrolyzing
foreign proteins of various types.

(3) Such antibodies are enzymic in character, and both specific
and general in nature — that is to say, they hydrolyze the par-
ticular protein injected, but also other foreign proteins if present.

(4) The proteins of cancer are in a sense foreign proteins and
fall within the scope of action of the enzymes called forth by
the medical protein antigens. The degenerative diseases of
middle life and old age are usually associated with disturbances
of metabolism involving the parenteral invasion of foreign pro-
teins or the undue retention or incomplete catabolism of protein
end products. Tuberculosis falls within the same category be-
cause of associated secondary infections and the accumulation of
localized foci of autologous and bacterial proteins subject to
hydrolysis by the corpuscular enzymes.

(5) The mechanism particularly involved in the production of
the protein-hydrolyzing enzymes is the blood-forming mechanism
and its products, the white and red corpuscles.

(6) The general province of the white corpuscles is to deal
with the full-sized protein molecule or its early cleavage prod-
ucts, and the province of the red corpuscles is to deal with the
end products of polypeptid order, including bodies of the hypo-
zanthin-zanthin-uric acid-urea series.

(7) The condition of the abnormal hyperplasia of the cells
of various organs of the body, including the blood-forming or-
gans, the coats of the arteries, and the cells of epithelial, endo-

12 FOREWORD

thelial, and connective tissues, may be spoken of as a condition
of hyperproteomorphism or the cancerous condition. All such
conditions are more or less subject to clinical and physiological
benefits from the administration of protein antigens — the effect
being indirect, and conditioned on changes in corpuscular num-
bers or enzymic activities.

(8) Autolyzed cancer cells themselves serve as antigens, stim-
ulating the blood-forming mechanism, but ultimately, in unfavor-
able cases, leading to the exhaustion and overpowering of this
mechanism through over-stimulation and to the excessive destruc-
tion of corpuscles. Similar stimulation and possible exhaustion
result from the parenteral presence of other foreign proteins,
heterologous or autologous.

(9) Protein antigens as a whole may conveniently be spoken
of as Proteantigens. Considering the observed action of these
proteins in stimulating the increase of the ranks of large mono-
cytes, the word Monocytosins may be used as a synonym for
proteantigens. A more general and perhaps more appropriate
word would be Cytogens. It is convenient to refer to the non-
bacterial vegetable proteins, now for the first time used as thera-
peutic proteantigens or cytogens, under the name of Proteals.
Animal substances such as white of egg and milk albumen, sim-
ilarly used, may be spoken of as Proteils.

It goes without saying that the essential facts as to the action
of the proteantigens are matters of chief importance. Theories
are necessarily subordinate, and questions of terminology need
give us no concern whatever. The latter are suggested here
merely as matters of convenience.

There is a considerable body of evidence in support of all the
observations and all the theories above cited ; but naturally much
more evidence for some than others. Beyond saying that the
evidence is based on a first-hand study of a large number of
cases, and on a fairly extensive series of microscopical observa-
tions, together with reports from a large group of associated
physicians in various parts of the United States, I shall not
attempt to summarize it here. The object of this book is to
present the evidence somewhat in detail; yet even here the
presentation is explicative rather than argumentative. I have
not thought it expedient to cumber the text with long lists of
repetitive cases, as I might readily have done. I have not dupli-
cated the tabular records of my Monograph of 1916 (of which a
new edition will appear presently). I have endeavored, rather,
to summarize the salient facts and theories in the most condensed
form consistent with clear exposition.

In view of the importance of the subject, I venture to hope that
the candid reader will reserve judgment as to an estimate of

FOREWORD 13

both facts and theories until he has attentively considered the
evidence. It can scarcely be doubted, I think, that the principles
of action of the white and red corpuscles and of bodily response
to proteantigens are matters of fundamental importance, and I
think also that the evidence in favor of the validity of these prin-
ciples is of so cogent a character that it cannot be dismissed
without a full and candid hearing.

When I first put forward the Proteomorphic Theory, I sug-
gested that it opened up entirely new fields of cyto-therapy ; and
in the first exposition of the protein-antigen hypothesis, I sug-
gested that the new method must stand on a par with serum
therapy and vaccine therapy, if indeed it did not ultimately largely
supplant these methods. Since these estimates were made, in
October, 1914, and October, 1915, respectively, a great mass of
new evidence has been collected, all seemingly in the same scale
of the balance.

Confidence in the validity of the predictions just noted has
grown with the accumulation of new evidence.

Possibly it may not be an exaggeration — should the above facts
and theories be demonstrated to have validity — to speak of the
protein response as constituting the most comprehensive thera-
peutic action known to modern medicine.

THE TERMINOLOGY OF THE NEW SCIENCE

In the Monograph of December 1, 1916, I cited the need of a
new terminology for convenience in referring to the new thera-
peutics. I suggested the comprehensive term Proteantigen as a
family name for all types of proteins used as antigens in thera-
peutics. As an alternate name, I suggested the word Macrocy-
tosin (perhaps Monocytosin would be better), made appropriate
by the observed increase of large monocytes that constitutes an
important feature of the protein response.

I further introduced the word Proteal as a generic term for
vegetable Proteantigens ; on a par with the familiar words Serum
(proteantigens derived from the blood of animals) and Vaccine
(proteantigens of bacterial origin). A little later (April, 1917)
in medical addresses I suggested the word Proteil as an addi-
tional member of the group, applied to proteantigens of animal
origin other than serums — for example, protein extracts of animal
organs, like the "autolysates" of Klinger and the "X-Substance"
of Gwyer ; preparations of milk protein, egg protein, and the like.

It was in the Monograph of December 1, 1916, also, that I
first publicly enunciated the principle (backed at that time by a
half-year of experimental observation) 'that it is necessary to
change the type of proteantigen from time to time, in order to

14 FOREWORD

get cumulative and optimum therapeutic effects — a principle of
great theoretical interest in the light of the Proteomorphic
Theory, and of fundamental importance in the practical admin-
istration of non-specific protein therapy.

In the succeeding pages the proteantigens chiefly referred to
are Proteals of various types. These non-toxic vegetable pro-
teins, as prepared in my private laboratory, are the agents with
which the wide therapeutic possibilities of non-specific protein
therapy and the essentials of the physiological response on which
these possibilities are conditioned have been demonstrated in
my hands and in the hands of associated physicians in various
parts of the world. Full details as to the perfected methods of
preparation of the Proteals hitherto used in my laboratory are
given in the concluding chapter of the present book.

How THE PROTEALS ARE PREPARED

It is desirable to call attention here to the fact that two dif-
ferent types of protein extracts have been used, one containing
the unbroken protein molecule, the other proteins partially hydro-
lyzed. The former were used almost exclusively until late in the
year 1916. It will be well to recall that the results attained up
to that time (and in particular the blood observations recorded)
are ascribable to the unbroken protein molecule.

The essential procedure consists of the extraction of the pro-
tein from the ground seed or other vegetable substance with a
salt solution ; precipitation of the protein from this solution with
hydrochloric or acetic acid ; washing with distilled water ; and
the redissolving of the relatively pure protein with sodium hy-
droxide. The final solution is standardized by testing for nitro-
gen, so that as ultimately used it contains two per cent, protein,
this percentage, however, being modified in various experimental
tests. The solution, being kept slightly alkaline, can be sterilized
by heat after sealing the ampules in which it is placed for safe
and convenient subsequent handling.

The proteins thus preserved will, of course, be quite inert if
given by the mouth. Administered hypodermically in doses of
from ten to sixty minims the effects are striking and charac-
teristic. They include a certain amount of local erythema at
the point of injection ; a feeling of giddiness ; nausea, malaise,
rise of temperature, and a more or less pronounced chill.

These familiar anaphylactic symptoms vary in their intensity
with different patients, and are not produced in the same degree
by different proteins. The protein of rape seed, for example,
produces a much less severe general reaction than the protein of
alfalfa seed.

FOREWORD 15

After the above-described method of preparing the protein
extracts had been employed for several months in my laboratory,
a more expeditious method was devised, the essential features
of which consist of boiling the powdered plant products for from
two to four hours in a very dilute solution of hydrochloric acid
(20 to 80 cubic centimeters of 10 per cent, hydrochloric acid to
the liter of water, incorporating 50 to 100 grams of the plant
powder) ; filtering; neutralizing with sodium hydroxide; refilter-
ing; standardizing by the Kjeldahl nitrogen test; sealing in the
ampules, and sterilizing for three days discontinuously.

This extract contains more extraneous matter (starch, glucose,
lipoids, salts) than the other, but if properly prepared it is a
perfectly transparent fluid, varying in color from amber to claret
according to the specific protein content. The partially hydro-
lyzed protein (alkali albumen, proteose, peptone) does not coag-
ulate on heating, but is partly precipitated by alcohol. Nitric acid
precipitates it in part ; the precipitate being dissolved on boiling,
to reprecipitate on cooling (the familiar test for proteoses).

Proteals thus prepared are pleasant to administer, and as a
rule produce little or no reaction, and, in ordinary dosage, no con-
spicuous systemic reaction. No case of anaphylactic shock from
their use has been observed by me, or reported, although many
thousand ampules of Proteals of this character have been sent
from my laboratory to physicians in all parts of the western
hemisphere, and administered to a large aggregate number of
patients suffering from disturbances of protein metabolism asso-
ciated with anaemias, intestinal toxaemias, neurasthenia, rheuma-
toid conditions, arteriosclerosis, cancer, psoriasis, asthma, and
tuberculosis.

THE PRACTICAL ADMINISTRATION OF THE PROTEALS

A few words about the practical administration of the Pro-
teals above described will perhaps be of service to the physi-
cian who may consult this book without having time or inclina-
tion to read the more elaborate presentation of the subject which
makes up the chief content of later chapters.

As above explained, Proteals are non-toxic vegetable proteins
in sterile saline solution, standardized by a nitrogen test. They
give opportunity for the application of non-specific protein ther-
apy to a wide range of maladies associated with disturbed protein
metabolism, with or without bacterial infection.

The name Proteal originated with me, and has not been applied,
so far as I know, to any product made elsewhere than in my pri-
vate laboratory. There is no restriction, however, on the use
of the word or on the preparation of the products themselves.
I hope presently to see the Proteals made in Board-of-Health

16 FOREWORD

laboratories everywhere, as certain serums and vaccines are now
made, for free distribution to the profession for treatment of the
poor. Meantime, to the full extent of my personal resources, I
shall see that no one is denied the benefactions of the Proteal
treatment for want of money.

The Proteals hitherto used most extensively, as supplied from
my laboratory to several hundred physicians in various parts of
the world, are chiefly those made from Alfalfa seed, Alfalfa
meal, Mustard seed, Rape seed, Hemp seed, and Millet seed.
Numerous other vegetable materials and some animal materials
have been tested experimentally, and some of these give promise
of therapeutical usefulness as suppliers of proteins. Meantime,
the available Proteals (which have passed entirely beyond the
experimental stage, having been used for minimum periods of
eighteen months, and administered to hundreds of patients in
the aggregate) are sufficiently varied to meet a wide range of
therapeutic needs.

The Proteals now available, as prepared in my laboratory, are
distinguished merely by numbers — No. 29 contains the protein of
Alfalfa meal ; No. 36, Mustard seed protein ; No. 38, Millet seed
protein ; No. 39, Alfalfa seed protein ; No. 42, Rape seed protein.
No. 37 is a mixture of the proteins of Mustard and Alfalfa ; No.
40, a mixture of Mustard and Rape proteins ; No. 45, a mixture
of proteins of Alfalfa seed, Alfalfa meal, and Millet seed ; No.
60, a mixture of proteins of Alfalfa seed and Alfalfa meal ; No.
65, a mixture of the seed proteins of Alfalfa, Mustard, Millet,
and Rape, and the protein of Alfalfa meal.

A newer series includes proteins of Oats, No. 50 ; Potato, No.
61 ; Wheat, No. 62 ; Carrot, No. 63 ; Flax, No. 64 ; Cotton, No.
66 ; Red Clover, No. 67 ; White Clover, No. 68 ; Spinach, No. 70.

A new combination, designated No. 75, includes the seed pro-
teins of Red Clover, Cotton, Hemp, Flax, and Carrot. A mix-
ture of this combination, in equal parts with the combination
above designated as No. 65, gives ten types of protein and is
designated Proteal No. 100.

All these Proteals are standardized on the basis of a two-
per cent, protein solution, as above detailed ; and the dosage and
method of administration are substantially the same for all.

Administration of the Proteals is always hypodermic, prefer-
ably subcutaneous (not intramuscular or intravenous). The in-
jection may advantageously be given into the back of the upper
arm, about midway between elbow and shoulder. Some physi-
cians prefer the gluteal region. If properly administered in suit-
able doses, the injection should cause very little local irritation,
and practically no reaction, local or general. Patients differ con-
siderably, however, in their sensitiveness.

FOREWORD 17

The technique of administration is simple. It is well to steri-
lize the patient's skin by touching the point of injection with
Tincture of Iodine and then with Alcohol. Touch the neck of
the ampule with a file, and it may readily be broken. Insert a
sterile hypodermic needle and withdraw the amount of the in-
tended dose. A partially used ampule may be resealed by touch-
ing the neck immediately to a drop of melted sealing wax. If
contaminated, the extract becomes an excellent culture medium
and must, of course, be discarded.

The initial dose of any Proteal is from three to five minims.
Repeat this daily or on alternate days until three or four doses
have been given. Thereafter, if there has been no severe reac-
tion, increase the dose by one or two minims with each adminis-
tration until a satisfactory dosage is established for the particular
case in hand.

The maximum dose varies with individual cases and with dif-
ferent maladies.

In anaemias, intestinal toxaemias, asthma, and tuberculosis,
optimum results have been attained with a maximum dose of five
to ten minims, administered on alternate days for a more or less
protracted period. Obstinate cases of psoriasis have yielded to a
similar dosage.

With rheumatic conditions, and especially rheumatoid arthritis,
on the other hand, it is usually desirable to advance to a dosage
of fifteen or twenty minims at least; sometimes to twenty-five
or thirty minims, administered on alternate days or even daily.

Maximum doses and frequent administration are usually de-
sirable, also, to get optimum and cumulative results, in cases of
cancer, particularly where the neoplasm is large.

The blood count furnishes the best guide to dosage in admin-
istering the Proteals. The Proteal response is essentially a
blood reaction. The ideal is to bring the haemoglobin to approxi-
mately normal ; the red corpuscle count to normal or supernor-
mal; and the average leucocyte count to seven or eight thou-
sand, with the differential count showing polynuclears relatively
low, and large mononuclears advancing to high supernormal — ten,
fifteen, or twenty per cent, of the total.

Where the blood count is not available, clinical symptoms
must, of course, furnish a guide to dosage. It goes without
saying that the administration of the Proteals gives opportunity
for the exercise of skill and judgment on the part of the prac-
titioner. The response and the needs of each individual patient
should be carefully studied, as in the administration of any other
line of scientific treatment.

A change of Proteals from time to time is essential in the
treatment of most protracted cases, in order to secure cumulative

18 FOREWORD

and optimum results. A measure of immunization to any par-
ticular type of protein appears to be developed in most cases,
after periods varying from a few weeks to several months.
A change of Proteals is then indicated. Each protein appears to
produce an individual response, so the new Proteal should be
given in minimum doses at first, advancing gradually to a max-
imum as with the first extract.

The possibility that a change of Proteals is indicated should
always be considered when a patient, after a term of favorable
progress, appears to reach a static period short of the desired
optimum of improvement.

The wide range of therapeutic applicability of the Proteals
is due to the fact that their response is a non-specific protein
response, directly evoking modifications of the blood — as re-
gards both its corpuscular elements and their enzymic activities —
that are beneficial to the entire organism. This explains the ob-
served anomaly that the same Proteal may be administered with
benefit in conditions so widely removed, pathologically, as the
anaemias, intestinal and other toxaemias, arteriosclerosis, rheuma-
toid conditions, asthma, tuberculosis, psoriasis, and cancer.

There are, indeed, few, if any, conditions involving disturbed
protein metabolism in which the Proteals may not be appealed
to with a large measure of confidence. The degree of improve-
ment to be hoped for depends, of course, on the conditions of
the individual case.

The particular Proteal to be selected for initial use in any
individual case is to some extent a matter of experiment. I have
pointed out that the Proteal response is largely non-specific. Ob-
servation shows that to a large extent the different Proteals are
therapeutically interchangeable. Often it seems a matter of in-
difference as to which one is selected. Yet there are specific
differences among the vegetable proteins, as a matter of course ;
and some of them evoke a much more active response than
others.

I have suggested, as a general principle, that the proteins sup-
plied by food products will, as a rule, evoke a less active response
than the proteins of vegetables that have not been used as food
by our race. Experience seems to justify this theory ; for I have
observed that proteins of the food cereals (also the proteins
of milk and egg) and the proteins of mustard and rape seed are
less active in therapeutic response than the proteins of millet
seed and alfalfa.

In the treatment of individual cases, guided by this principle,
I am likely to administer Mustard seed protein (Proteal No.
36) or Rape seed protein (Proteal No. 42) or their combination
(Proteal No. 40) in the initial treatment of mild anaemias, with

FOREWORD 19

the attendant conditions of "general debility," neurasthenia, etc.,
where a general tonic effect is desired. For treatment of severe
rheumatoid conditions, of tuberculosis, and of cancer, I turn at
once to a Proteal containing Alfalfa protein (Proteals No. 29,
No. 39, or No. 60), or to the combination of proteins of Alfalfa
seed, Alfalfa meal, and Millet, as represented by Proteal No. 45.
Not infrequently I shift from one Proteal to another, experi-
mentally, after a few doses; and sometimes I have found that
an individual patient responds far better to one type of protein
than to another, regardless of the type of malady.

In my office recently a case of tuberculosis, for example,
showed slight modification of symptoms under Rape seed protein
(No. 42), but responded promptly when a shift was made to
Alfalfa protein (No. 60). Such individual idiosyncrasies are to
be expected, in the light of our knowledge of varying suscepti-
bility to the proteins of therapeutic serums, and should always
be looked for when a case fails to respond to initial Proteal treat-
ment. No conclusion should be drawn, however, until after the
administration of at least eight or ten doses.

It should be borne in mind, also, that gradual and cumulative
improvement, rather than sudden and spectacular changes, may
be expected in the treatment of such chronic and intractable con-
ditions as psoriasis and rheumatoid arthritis, even in the most
favorable cases.

The Proteal response is totally different from the specific re-
sponse of the therapeutic serums and vaccines. Proteals are not
Serums or Vaccines. Each of these words is a generic term,
having a restricted meaning, and the words cannot properly be
used interchangeably. By definition, a Proteal is a solution of
non-specific vegetable proteins. Serums are specific agents with
an animal blood serum for the excipient. Vaccines, in the mod-
ern interpretation, are specific bacterial cultures containing the
dead bodies of bacteria and their toxins.

Serums and vaccines necessarily contain proteins, and no doubt
they have a non-specific action along with the desired specific
action. To a limited extent they have been used non-specifically
(typhoid vaccine, for example, in the treatment of arthritis), but
such use seems to me unwarranted unless it shall appear that,
when thus used, they have therapeutic advantages over the non-
specific and non-toxic vegetable proteins (Proteals), which lack
their toxicity.

The vaccines in particular, whatever their value in this con-
nection, cannot be expected to duplicate the Proteal response, be-
cause their type of protein (bacterial) is different from that of
the higher vegetables. As illustrating a typical difference in re-
sponse, the vaccines invoke a polynucleosis, whereas a typical

20 FOREWORD

feature of the Proteal response is a mononucleosis, and in par-
ticular a large monocytosis.

A pronounced anaphylactic reaction has not been observed in
the use of the Proteals prepared by the newer method. The rea-
son may be that the proteins in the Proteals as now prepared
are partially hydrolyzed, appearing as proteoses, and perhaps in
small part as peptones. The earlier Proteals, comprising saline
and alcoholic extracts, contained the unbroken protein molecule,
and their use in repeated and maximum dosage was attended
with more or less marked anaphylactic reactions. Indeed, it was
my custom to force the dosage until a marked systemic reaction
was produced. The absence of this reaction makes the newer
Proteals far pleasanter to administer, and far more acceptable to
the patient, but leaves us without a clinical guide to maximum
dosage in intractable cases.

It may fairly be said that no one at present knows what is the
maximum permissible dose with any Proteal. Even with the
old form of Proteal, containing the unbroken protein molecule,
the dose was sometimes advanced (gradually) to forty, fifty,
sixty, and even to ninety minims; and, although a severe sys-
temic reaction was expected and even desired, no untoward result
was ever observed. I have repeatedly given to guinea pigs day
after day doses of proteins that, weight for weight, were equiva-
lent to fifty or one hundred times the maximum dose adminis-
tered therapeutically ; and the animals thrive under the experi-
ment.

Notwithstanding the relative non-toxicity of the Proteals, I
regard it as desirable to administer the smallest doses that will
produce results. If a dosage of six or eight minims will keep
the blood conditions as I like to see them, with corresponding
clinical improvement, I hold to such dosage. If it is necessary
to go to a dosage of fifteen or twenty minims, there should be
no hesitancy in doing so, but beyond this it is usually better to
shorten the interval between administrations rather than to give
inordinate single doses. These are matters, however, regarding
which individual cases differ, as do also the preferences of dif-
ferent physicians. The experienced practitioner, guided by per-
sonal observations, will develop his own technique in the use
of the Proteals as with other lines of treatment.

DEVELOPMENT OF THE PROTEAL METHOD

The theory of action of Proteals and other non-specific pro-
teins, which originated .with the present writer (so far as I am
aware, no other has been suggested), is based on my inter-
pretation of the mechanism of immunization as first published

FOREWORD 21

in American Medicine for October and November, 1914, under
title of the Proteomorphic Theory. I made the first specific ther-
apeutic application of the theory in detail to the treatment of a
particular malady, with the explicit suggestion that the non-
specific proteins would be applicable in combating all types of
protein toxaemias, including bacterial diseases, in the New York
Medical Journal of October 2, 1915. A more elaborate explica-
tion was given, with detailed study of the blood modifications
attending the use of the Proteals, in a Monograph of 126 pages
bearing the title The Proteal Treatment of Cancer and Allied
Conditions, issued December 1, 1916. The name Proteal was
first introduced (together with the name Proteantigen as a fam-
ily name for all proteins used as antigens, including Serums and
Vaccines as well as Proteals), and the principle that a single
protein or combination of proteins must not be depended on to
secure optimum results in the majority of cases was first pub-
licly enunciated, in this Monograph, which bore the sub-title A
Practical Study of a New Therapeutic Principle as Interpreted
in the Light of the Proteomorphic Theory.

The practical results of Proteal therapy in my own hands
and in the hands of several hundred associated physicians have
been of a character calculated to arouse enthusiasm. I made a
statistical analysis of 766 cases, treated by 152 physicians, in a
preliminary report published in the New York Medical Journal
of November 13, 1915. A considerable body of new evidence
was available when my Monograph above cited was published a
little over a year later, but this work was largely devoted to the
theory of Proteal action, with especial reference to the modi-
fication of blood conditions, to which I had devoted assiduous
attention, believing that to be the crux of the entire matter.

During the summer of 1917, in the course of a long lecture
tour in the West, I delivered about one hundred addresses on
Proteal Therapy before gatherings of medical men, including sev-
eral County Medical Societies. The interest aroused is evidenced
in the subsequent use of the Proteals by a large number of phy-
sicians who heard these addresses. The co-operation of these
practitioners has been a valuable asset in further tending to es-
tablish the applications of the Proteals in a variety of maladies
with which previous experience had been limited — including
asthma and tuberculosis. The joint experience of this group of
physicians and of others previously interested has served to for-
tify and extend my personal observations.

OTHER NON-SPECIFIC PROTEINS

It should be clearly understood, however, that, whereas I make
constant specific reference to the Proteals, and tell of the defi-

22 FOREWORD

nite therapeutic advantages attained with their aid, there is no
contention, explicit or implied, that the particular proteins thus
used have any specific advantages over other types of proteins,
of animal or vegetable origin, that may ultimately be introduced.
New types of proteins, and new methods of extraction, are con-
stantly being sought in my laboratory, and will presently be
sought in numberless other laboratories, if I mistake not, as a
result of the publication of the present book. It is easily within
the possibilities that proteins far more desirable than any hith-
erto used may presently be made available. But that is a mat-
ter of mere detail. The thing of importance is that the principle
of protein response has been — so I believe — conclusively demon-
strated, and that simple extracts of the proteins of alfalfa seed,
millet seed, rape seed, hemp seed, clover seed, cotton seed, and
the like furnish the therapeutist with new and effective weapons
in combating many prevalent maladies associated with disturb-
ances of metabolism and the invasion of foreign proteins — mal-
adies that, in the aggregate, take toll of hundreds of thousands
of lives in the United States alone each year, and mar the health
of uncounted millions.

SCIENTIFIC MEDICINE VERSUS EMPIRICISM

The physician who would handle these new therapeutic agents
effectively must have a clear understanding of the principles that
underlie their therapeutic action. To that end it is essential
to gain a full knowledge of the important bearings of the Pro-
teomorphic Theory. I would urge the professional reader who
wishes to gain a really comprehensive grasp of the foundations
of Non-specific Protein Therapy in general and of Proteal Ther-
apy in particular to follow the chapters of this book sequentially,
even though he should find some of them repellent because of
their technicality.

When he has done so, it will be clear to him that Proteal
Therapy differs from routine medical practice in that it may with
propriety be said to be an applied science. Within the wide
bounds of the application of the Non-specific Protein method,
medicine ceases to be a merely empirical art. No man knows
how or why morphine or strychnine or atropine or digitaline pro-
duce their perennially observed and perfectly recognized effects.
With the Proteals, the case is different. We know how and why
they operate. The physiological response that they evoke may
be observed and demonstrated under the microscope. The dosage
may be gauged in the same way. In administering them, we are
no longer groping in the dark, along an empirical pathway. We
are practising scientific medicine.

FOREWORD 23

To be sure, our knowledge of this new science of Non-specific
Protein Therapy is only in its rudiments. Prior to the appear-
ance of my paper of October, 1914, the principles upon which
it is based had not been explicitly formulated. Prior to October
2, 1915, no comprehensive statement of the therapeutic possibili-
ties of the method had been published. Prior to July, 1916, no
conclusive demonstration of the Protein principle, as such, had
been made. And the first elaborate formulation of the micro-
scopical evidence in support of the earlier inferences was pub-
lished as recently as December 1, 1916. Meantime a collocation
of the entire evidence available up to date, reproducing in full
the original formulation of the Proteomorphic Theory itself,
with sundry amplifications, and detailing the applications of the
method throughout the wide domain of disturbed protein meta-
bolism, is given for the first time in the present work, in com-
bination with the second edition of the Monograph on The Pro-
teal Treatment of Cancer and Allied Conditions, announced for
issue early in April, 1918.

Notwithstanding the newness of the subject, however, Proteal
therapy has passed far beyond the experimental stage. Much
remains to be learned, of course, but much that is definite and
tangible is already precisely known. I have personally adminis-
tered many hundreds of doses of the various Proteals to patients
suffering from a wide range of maladies, from simple asthenias
and anaemias to pernicious anaemia, intestinal toxaemia, lymphatic
leukaemia, arteriosclerosis, rheumatoid arthritis, goitre, cancer,
and tuberculosis. My direct, personal office and bedside observa-
tion of patients under Proteal treatment comprises not far from
five hundred cases. I have been professionally consulted by
fellow-physicians and have advised with reference to the Pro-
teal treatment of about two thousand additional cases. My office
files contain more than six thousand letters dealing directly with
the subject, received (and I may add, without exception, promptly
answered) within the past two and a half years. My original
blood-examination records number not far from twelve hundred.

Meantime more than fourteen thousand ampules of the various
Proteals have been sent out from my private laboratory to co-
operating members of the profession within the past year, and
reports from these physicians give invaluable clues to the appli-
cations and limitations of the method.

The deductions from this substantial experience, including a
full elaboration of my hematological discoveries, constituting the
first comprehensive study of the Theory and Practice of Proteal
Therapy, appear in the present book.

Here, and in the Monograph so frequently cited, I have at-
tempted to justify by evidence my belief that the non-specific

24 FOREWORD

protein response constitutes one of the most comprehensive prin-
ciples known to scientific therapeutics, and that the Proteals fur-
nish the practitioner with new weapons of genuine value in
combating a long list of intractable maladies of middle life and
old age, including anaemias, leukaemias, toxaemias, rheumatoid
conditions, goitre, arteriosclerosis, asthma, tuberculosis, psoriasis,
and cancer. The candid physician who has not had personal
experience in the use of the Proteals may advantageously reserve
judgment regarding the possibilities of the method until he has
reviewed the evidence as presented in these books.

With a method so new there is necessarily much still to be
tested. Some of the open problems will be discussed in the
succeeding pages. But in the main the record here presented
deals with the definite achievements already in hand. The work
is by no means finished, but I repeat that it has passed far beyond
the experimental stage. Proteal therapy is to-day a verity. In
the hands of hundreds of practitioners it has proved its utility.
When the newly discovered physiological laws on which it is
based are generally known and recognized, the use of the method
will become universal.

Such, at least, is the confident belief in which this book —
the first attempt at comprehensive presentation of the Theory
and Practice of Proteal Therapy in its wider relations — is offered
to the medical profession.

THE PROTEOMORPHIC THEORY
AND THE NEW MEDICINE

CHAPTER I

THE MECHANISM OF PROTEIN HYDROLYSIS AND
IMMUNIZATION

The main theses of the Proteomorphic Theory are these : That
the mechanism which gives the human organism partial or com-
plete immunity against bacterial disease comprises what may be
called the cytogenic or haematopoietic system — including lym-
phatics, bone marrow, and spleen — with its daughter cells the
white and red blood corpuscles as its active agents, and with the
liver as the excretory organ of the waste products incidental
to the immunizing process; and that the same mechanism deals
with all foreign proteins in the parenteral system; the case of
the bacteria being only a special case within the general law of
protein hydrolysis..

The white corpuscles are believed to begin hydrolysis of foreign
protein, and the red corpuscles to complete the decompounding
from the polypeptid stage, liberating amino-acids, and dealing also
with residual end products of the zanthin-uric acid-urea series.
Sundry antibodies of the general character of enzymes are coin-
cidentally developed, their individual qualities being determined
in response to the specific nature of the invading protein, bac-
terial or non-bacterial.

The theory assumes that the entire cellular system of the
organism — viscera, muscles, brain — may be considered as a sec-
ondary apparatus, standing as it were in the background, ready
to supplement the work of the chief immunizing agents. So
general an implication as the latter may seem to savor of the
nature of a truism ; but it will appear that the theory ascribes a
specific and definite part in the immunizing process to the body-
cells in general and in particular, attempting to trace the precise
rationale of their activity. Equally specific is the interpretation
of the activities of the leucocytes and the red blood corpuscles,
which are posited as the chief and controling mechanism in the
process of protein hydrolysis in general and immunization in
particular.

It will be well here at the outset to present a summary of the
chief tenets of the theory, by way of orienting the mind of the

25

26 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

reader, and preparing him better to follow the detailed argu-
ment to which the ensuing hundred pages or so are devoted.
The essentials of the theory, then, are the following:

1. The chief immunizing mechanism of the body is the cyto-
genic mechanism, of which the recognized members are the bone
marrow, the spleen, and the lymphatic system. The active agents
through which the process of immunization is carried out are the
leucocytes and red blood corpuscles generated in the various
organs of this system.

2. The prime function of the leucocyte, after it becomes a
freely moving cell, is to facilitate and complete protein cleavage
or digestion, preparing for assimilation (to the limit of its ca-
pacity) all foreign proteins that enter the blood stream. In pur-
suance of this function, it is provided with digestive enzymes,
and with a mechanism for the production of special types of pro-
teolytes to cleave an endless variety of protein molecules, and
to counteract toxic proteins or enzymes due to bacterial activities.

It is believed that, generally speaking, the eosinophiles and
large monocytes deal with the protein molecule unbroken or at
an early stage of hydrolysis ; the small lymphocytes and polynu-
clears with intermediate and later stages of hydrolysis; their
functions, however, more or less overlapping, and their aggregate
activities carrying the invading protein to the polypeptid stage
of decompounding.

3. The red blood corpuscle completes the hydrolysis of poly-
peptid and allied protein products that find their way into the
blood stream. It absorbs or counteracts the toxic residual mole-
cules that are not completely hydrolyzed ; and it antagonizes the
products of bacterial activity, producing antitoxins. When ulti-
mately autolyzed or destroyed, chiefly in the liver, it gives its
protein and enzymes to the blood stream, and its waste products
are discharged from the body through the bile duct and (in the
form of uric acid, urea, and creatinine) through the kidneys.
The functions of the red corpuscles in thus dealing with the end
products of protein hydrolysis (reducing polypeptids to ammo-
acids and residual products) is conceived to be of fundamental
importance, as indispensable as the function of carrying oxygen.
An important specific feature includes the oxidizing of the purin
bases to form uric acid, and the more or less complete transfor-
mation of the uric acid into urea.

4. The chief work of synthesizing protein out of amino-acids
in the organism resides with the mother cells of the cytogenic
apparatus — notably the bone marrow and the spleen. But the
cells of each specialized tissue — muscles, brain, glands — can on
occasion synthesize each its own special type of protein, utilizing
the amino-acid building materials. Each tissue can also, on occa-

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 27

sion, hydrolyze nitrogenous molecules of the polypeptid order,
and give out antitoxic ferments in response to specific toxins.
But as a rule the tissues are shielded by the red blood corpuscles
from the necessity of performing these functions.

5. The vast multitudes of red blood corpuscles, with an aggre-
gate bulk of about four pounds in the ordinary human body,
their substance having been synthesized by the mother cells out
of amino-acids, constitute the chief source of the specific pro-
teins in the blood stream, which proteins on being decompounded
(possibly with the aid of the lymphocytes and polynuclears) are
the prominent sources of bodily energy.

6. Every cell that can unite with a foreign proteid product
can produce an "antibody" calculated to antagonize that prod-
uct. The leucocytes and red blood corpuscles are the particular
cells that come most in contact with such foreign bodies, and
they are therefore the chief source of specific proteolytes and
antibodies directed against the invaders. The presence in the
blood stream of these specific proteolytes and antibodies, se-
creted by the leucocyte and red cells, and to a certain extent by
the body-cells (backed up by the presence of an adequate army
of leucocytes and red cells themselves, capable of producing more
of the antibodies under stimulus of invasion), constitutes the
condition of immunity.

7. Immunization to bacterial disease is merely a special case
of protein assimilation. It has in the past been as necessary
to acquire immunization against the dietetic proteins — oyster,
fish, egg, fowl, milk, mutton, pork, beef — and against "benign"
bacteria as against the most virulent bacteria.

8. So-called harmless or benign bacteria are those that have
been long with us, and which, therefore, the leucocytic and ery-
throcytic mechanisms have learned adequately to combat and con-
trol. Virulent bacteria are the relatively rare ones or those that
have visited us infrequently. A relatively benign bacterium may
become malignant, however, through changed conditions leading
it to ingest unwonted types of protein ; or through developing
exceptional vigor; or through invading the system in excessive
numbers.

9. Protein anaphylaxis of any type (including "serum disease")
is merely a special case of protein intoxication, strictly homolo-
gous with protein poisoning from the toxins of virulent bacteria.
It results when a general proteolytic (leucocytic) enzyme is pres-
ent in sufficient quantity to hydrolyze the foreign protein partly,
while the red-cell mechanism is temporarily exhausted, so that
cleavage cannot be completed, and the tissue cells — in particular
the brain cells — are attacked. Protein anaphylaxis is strictly
homologous with protein immunization. They are different as-

28 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

pects of the same subject corresponding respectively to the "pas-
sive phase" and the "active phase" of Wright's "opsonic index."

10. The activities of the cytogenic system, leading to an in-
crease in the number of blood corpuscles and a stimulus to the
activities of the individual corpuscles ; and through these to com-
pleted protein assimilation and immunization, are governed in
part by hormonic stimuli ; the internal secretions actively engaged
including those of the adreno-thyroid system and secretin from
the duodenum.

11. The cytogenic system (including the bone marrow, the
spleen, and the lymphatic glands) is a highly important member
of the endocrinous system ; the detached blood corpuscles are
to be regarded as still a part of that system; and the study of
the system as a whole offers a fruitful field for discovery of
new methods in immunization and the treatment of infectious
diseases.

The hypothesis of immunization thus summarized, being based
on the activities of the cells, might appropriately enough be termed
the Cytoclastic theory, were it not that the term seems too
general and not sufficiently explicative. It might be termed the
Corpuscular theory, in token of the role ascribed to both types
of blood corpuscles, were it not that physical science has already
usurped that term. To call it the Leucocytic theory would be
quite inadequate, as it would credit only one member of the!
triumvirate, and would, moreover, signalize the least original por-
tion of the theory itself. The term Erythrocytic theory would
have somewhat greater propriety, as pointing out what is con-
ceived to be the most important single agent in the immunizing
process, and also as signalizing the most novel feature of the
theory. But this term also is condemned by its obvious inade-
quacy.

On the whole, the term Proteomorphic theory is the most com-
prehensive and explicative one that suggests itself; inasmuch
as the theory at all stages, and in its widest implications, has to
do with the metamorphoses (mainly hydrolytic) of protein
compounds.

It was through study of proteoclasis, mainly — in connection of
course with the fairly wide survey of a good many allied fields —
that the theory itself was elaborated. But for the data supplied
by study of proteolytic activities, in connection with the meta-
bolic processes of normal and abnormal digestion and assimila-
tion, the theory could not have been conceived. So the word
proteomorphic may be used to designate it with peculiar propriety.

It will appear in the course of the following exposition that
a good many other laboratory and clinical observations, hitherto

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 29

utterly obscure or but vaguely interpreted, find clear and tangible
explanation when viewed in the light of the proteomorphic theory.

It will be shown that the precise role of the leucocyte on one
hand and the side-chain mechanism on the other are inter-
preted from a new point of view ; that the red blood corpuscle
is conceived to enter into the scheme of immunization as a mas-
terful and dominating force, with all-important activities never
hitherto ascribed to it; and that, as a whole, the scheme of
immunization here presented has — if its tenets be accepted — a
measure of comprehensiveness in the interpretation of the find-
ings of physiologist, bacteriologist, and clinical pathologist that
could not well be claimed for any theory of immunization here-
tofore submitted. More than that, the theory has pointed the
way to a new field of therapeutics, already demonstrated to be
large and important, the full limitations of which will not be
determined for a long time to come — the field of Nonspecific
Protein Therapy.

Before going on to the practical therapeutic developments of
the idea, it is desirable to present the evidence for the Proteo-
morphic theory itself, drawn from various fields of biology and
pathology.

In collating the evidence it will be necessary to summarize the
results of experiments and observations gleaned from many dif-
ferent sources, some of which must necessarily be familiar to
all medical readers, and all of which will perhaps be familiar
to a few. This is unavoidable if the evidence in its totality is
to be made generally comprehensible.

It will appear as we proceed that much of this evidence is
indirect or circumstantial ; yet in the aggregate, I believe, it
establishes a strong presumption in favor of the validity of the
theory advanced. And if the theory is accepted, certain very
definite and rather important inferences as to practical thera-
peutic applications follow as matters of course. The study of
the blood corpuscles assumes new interest and importance for
the practical therapeutist. The genesis of anaemias of various
types, including pernicious anaemia, is more clearly explained
than ever before, on the assumption that the destruction of red
corpuscles is due to excessive demands put upon them by the
surcharging of the blood with protein end products. The differ-
ential count of the leucocytes other than the polynuclears becomes
for the first time intelligible and susceptible of interpretation.

Specifically, it would appear that a monocytosis is as char-
acteristic and as pathognomonic an evidence of protein intoxi-
cation as a polynucleosis is of bacterial infection; and that the
artificial stimulation of a large monocytosis (as by hypodermic
introduction of foreign proteins) is a therapeutic expedient sus-

30 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

ceptible of application in dealing with a wide range of maladies
associated with disturbances of protein metabolism.

All this will be taken up in detail as we proceed. Our first
concern, however, is with the previously established facts as to
the systemic response to the invasions of proteins chiefly of the
bacterial order.

FACTS AND THEORIES OF IMMUNITY

For generations physicians have been aware that an attack
of a contagious disease tends to give the subject immunity against
further attacks of that disease. The discovery of Jenner gave
an inkling of the possibilities of preventing disease by inocula-
tion, but this purely empirical procedure did not lead directly
to any extension of the method. It was only after the bac-
teriologist had discovered the tangible cause of disease that a
way was found to produce artificial immunization.

In 1887 Pasteur startled the world by demonstrating that a
virulent bacillus could be attentuated as to its virulence by cul-
tivation in an artificial medium, and that an animal inoculated
with the virus thus produced was given immunity from the dis-
ease, even though subsequently inoculated with virulent germs.
In 1890 Behring discovered that the blood of an animal thus
immunized has power to transmit the immunizing principle, what-
ever it might be, to another animal if the blood serum of the
immune animal is injected hypodermatically or intravenously.
The diphtheria antitoxin thus developed by Behring, and a tet-
anus antitoxin discovered by Behring and Kitasato, were soon
added to the armamentarium of the physician.

At about the same time, Ehrlich conducted his classical series
of experiments with vegetable poisons, notably ricin and abrin
(the toxic principles, respectively, of the castor-oil bean and the
seed of jequirity). He found that an animal inoculated with
either of these proteid substances developed an immunizing prin-
ciple which, when mixed with the poison itself in vitro neutralized
the poison. It was necessary to make the admixture in certain
proportions, thus showing the chemical nature of the reaction.
Ehrlich thought of the phenomenon in chemical terms ; yet, for
the purpose of bringing the matter vividly to the attention of the
profession, he devised a mechanical scheme in explanation of the
phenomenon of immunity which soon found almost universal
acceptance, and which is often incorrectly thought of as suggest-
ing something quite different from chemical combinations.

Ehrlich's tangible diagrams showing his "receptors" of the first,
second, and third order ; his haptophores and toxophores ; his
zymorphous and complementophile groups of the complex — all

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 31

depicted as tangible structures, some of them resembling hungry
polywogs biting eagerly at inviting bits of protruding protoplasm
of just the right size to make a mouthful — proved altogether
alluring. A glance at such a diagram enables one to form a clear
mental picture of the relations of receptive cells and complement
and immune bodies in happy disregard of all possible chemical
complexities.

In due course numerous workers proved the universality of
application of the principles of the formation of the antibodies
through the introduction of toxic agents into the organism. We
learned of antitoxins, anti ferments, cytotoxins, agglutinins, pre-
cipitins, and opsonins in the normal blood serum or developed spe-
cifically in response to the invasion of toxins ; then it appeared
that there may be anticytotoxins, anti ferments, etc.; in bewilder-
ing profusion. And it was at least suggested that were our
means of investigations sufficiently delicate we should find anti-
antibodies in unending series, each new antidote becoming in
turn a toxin and requiring an antidote ; and the orgainc labora-
tory proving quite capable of developing series of such responsive
mechanism ad infinitum.

To add to the confusion, different workers gave different names
to the substances revealed in the course of their investigations ;
and in many cases they were talking of the same thing in terms
of a different nomenclature. Thus the ferment that Ehrlich calls
addiment was named by others alexine, by still others cytase
and yet again complement — the last name being the one ulti-
mately adopted by most authorities.

In the same way the immune bodies came to be known as
amboceptor, copula, desmon, hilfskorper, zwischenkorper, fixa-
teur substance, sensibilisatrice, etc. And it became a matter
for dispute as to whether agglutinins, precipitins, and opsonins
are identical one with another, and also as to the relations that
these substances — recognized only by their effects — bear to the
various hemolysins, bactericides, and bacteriolysins.

Out of the confusion, however, emerged pretty clearly the
conception that there are two types of so-called bodies or chem-
icals involved in the immunizing process. One of these is a
ferment-like substance which is thermolabile, its action being
prevented by heating to a temperature of about sixty degrees
centigrade ; this substance being conveniently referred to as the
complement. Joined with the complement in the immunizing
process is a thermostable substance which may be comprehen-
sively termed the immune body which apparently includes agglu-
tinins, opsonins, and bacteriolysins (whether or not these are
identical). The thermolabile complement is non-specific, in the
sense that the same complement may unite with many types of

32 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

immune bodies. But the thermostable immune body is specific,
in the sense that it is evoked in response to a specific protein or
toxin (called an antigen), and is antidotal to the particular antigen
that evokes it alone. A bacteriolysin, for example, evoked in
response to the typhoid bacillus will not destroy the tetanus
bacillus.

The validity of the conceptions associated with these terms is
not to be questioned. Multitudes of experiments have shown
that the terms "complement" and "immune body," and the ideas
associated with them, are compatible with observable phenomena
of the bacteriological world. The assumption that active comple-
ment must be present in order that immune body may be linked
with the toxic agent to neutralize it, finds support in such prac-
tical work as Widal's agglutinizing test for typhoid fever and
Wasserman's fixation-of-the-complement test for the diagnosis of
syphilis. The conception that the toxic molecule has a "hapto-
phore" group and a "toxophore" group and that the cell has
receptors of a typical mechanical structure on which the hapto-
phores adjust themselves is so tangible that it makes immediate
and strange appeal to the imagination, or, better stated, it makes
it unnecessary to call the imagination into play at all, the dia-
grams supplying its place.

I chanced to be living in London in 1900, and I had the pleas-
ure of hearing Ehrlich deliver his Croonion Lecture before The
Royal Society, expositing his epoch-making theory. Subse-
quently I visited Ehrlich at the famous Institute at Frankfort,
and talked with him about newer aspects of the great problem
of immunization, with particular reference to the possibilities of
specific therapy, which were then holding his attention in con-
nection with the development of salversan and the attempted
selenium cancer specific. My own original investigations have
led to developments rather along the line of extension of an-
other field in which Ehrlich was a pioneer, namely the study of
the tangible activities of the corpuscles; but like all workers in
allied fields I have found aid and stimulation in the graphic de-
signs with which Ehrlich attempted to make his conceptions
intelligible.

Unquestionably these diagrams have proved very useful, and
the entire mechanical conception has done much to promul-
gate widely a more or less comprehensible conception of the
mechanism of immunity. But it is at least an open question as
to whether these diagrams have not now served their purpose,
and whether it may not be well to revert to a somewhat differ-
ent point of view, and, ultimately, to adopt a terminology more
in keeping with the expression of chemical ideas in general. For
of course it would be absurd to imagine that the mechanical dia-

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 33

grams have any representation in the world of fact. They are
figments of the imagination, and may serve some such useful
purpose as picture blocks serve in teaching a child the alphabet.
But as the time comes when the child puts aside the blocks and
takes in hand the pen, so pathologists must ultimately lay aside
the crude mechanism of haptophores and amboceptors and learn
to deal with the phenomena of immunity in terms of the protein
molecule and the chemical atom.

PROTEIN METABOLISM

To be sure the chemistry of the protein molecule is by no
means as clearly understood as might be desired, even by spe-
cialists in biochemistry. But the researches of many workers
in recent years have resulted in tearing the molecule apart in
the laboratory, and in revealing the major part of its primary
constituents. We are now gaining an inkling as to what really
happens when proteid foods are taken into the digestive tracts
and subjected to the digestive ferments. And we are beginning
to realize that the subject has supreme importance from the
standpoint of the student of infectious diseases, for the simple
but all-sufficient reason that the microbic agents that cause these
diseases are themselves protoplasmic bodies — that is to say, com-
pounds of protein. I shall argue presently that the bacterial
proteins are of a relatively unevolved type, comparable perhaps
in complexity to peptones rather than to full-sized molecules of
the proteins of higher plants and of animals; but in any event
the difference is one of degree only. The bacterial substance,
within its lipoid membrane, is a nitrogenous or proteid body.

When we reflect that there are always myriads of these pro-
teid bodies in the digestive tract; and that legions of them on
occasion find their way into the vascular system, and are there
digested, the pertinence of the topic, in relation to protein meta-
bolism, becomes evident.

And from the present standpoint the chief interest centers
on the fact that there is in the human body one set of cells and
one only that has been demonstrated to be able to digest and
metamorphose the bacterial proteins when once they have invaded
the blood stream — namely the leucocytes. What the ferments
of the digestive tract accomplish in the case of the food pro-
teins, is accomplished by ferments of the leucocyte in the case
of the bacterial proteins with which it comes in contact.

I shall suggest that the function of the leucocyte in this capac-
ity is far more general, having to do with the metamorphosis
of many types of protein in addition to those that come with the
bacteria; but for the moment it suffices to call attention to the

34 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE .

fact that the leucocyte is demonstrated to be able to deal with
complex proteins, inasmuch as it is observed to engulf and assim-
ilate protein-bearing bacteria in toto.

That the leucocyte actually performs this feat, was first dem-
onstrated by MetchnikofT, and has been re-demonstrated thou-
sands of times over in recent years, notably by the students of
vaccine therapy. But the significance of this phenomenon, in
its broader aspects, although at least partially conceived by
Metchnikoff himself, was largely overlooked by his successors.

It must not be understood, however, that the capacities of the
leucocyte as a proteoclastic agent have been altogether ignored
by recent workers. On the contrary, it is probable that some
of the physiological chemists have ascribed to the leucocyte in
this connection a larger measure of activity than it actually exer-
cises. Thus Hofmeister, stimulated no doubt by the discoveries
of MetchnikofT, was led to ascribe to the leucocyte the all-
important function of taking up the peptone believed (errone-
ously) to be absorbed through the intestinal wall, and converting
it into protein either directly or with the aid of the adenoid
tissues, thus making it available for assimilation by the body cells
in general.

The peptone molecule, it will be recalled, is a cleavage product
developed from the original protein molecule of a food protein
hydrolyzed through the agency of the digestive ferments of stom-
ach, upper intestine, and pancreas. The molecule of peptone has
a molecular weight of only about four hundred, being therefore
about one-fortieth the size of its parental protein molecule. To
conceive that the leucocyte habitually takes this relatively small
molecule as its building stone and elaborates the complex pro-
tein molecule the molecular weight of which runs high into the
thousands — and does this in case of all the protein that the
body utilizes — is to make an assumption that at the least seems
amazing.

Yet Hofmeister thought that he found justification for this
assumption in the fact that there is a marked postprandial leuco-
cytosis. If the leucocyte does not perform the function of com-
pleting digestion of the food and facilitating assimilation, he
argued, why should the number of leucocytes be habitually in-
creased after a meal?

His reasoning seemed so valid that he has a good many fol-
lowers. Cramer and Pringle, for example, and Noel Paton be-
lieve that the leucocyte plays a very important part in the assim-
ilation of the protein food-products; and Pavy elaborated the
hypothesis, arguing that the entire conversion of the food pep-
tones into body protein is brought about by the leucocytes.

The particular type of leucocyte believed to be chiefly involved

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 35

is the lymphocyte, it having been shown by Paton, Goodal, and
Gulland that the most marked postprandial increase in leucocytes
occurs among the lymphocytes, although there is also increase
among the polymiclears. My own researches, as will appear
presently, show that the large monocyte is importantly involved,
particularly when the parenteral protein to be dealt with includes
the full-sized molecule, as frequently happens.

It is interesting to add that the leucocytic recruits come, ac-
cording to Paton and Goodal, not from the intestinal lymphatic
tissue, but from the marrow of the bones. Their development
is stimulated, we must assume, either (1) directly by food prod-
ucts in the blood, or indirectly (2) through the agency of the
sympathetic nervous system, or (3) in response to a hormone
sent out from the intestine. It is conceivable that the hormone
that produces this effect is the secretin of the duodenum, which
is known to have a similar stimulating effect on the secretions
of the pancreas.

Pavy developed the hypothesis, which Noel Paton has also
advanced, that the leucocytes, after synthesizing the proteins,
undergo autolysis, thus discharging their proteins into the blood,
to furnish material for the tissue cells.

It seems probable that there is a measure of truth in the lat-
ter part of this hypothesis, referring to the autolysis of the leu-
cocyte. In fact, the assumption that autolysis occurs seems
unavoidable, in view of the observed rapid fluctuations in the
leucocytic population even in health. But it is highly improb-
able that the leucocyte (in its mature state) synthesizes pro-
tein ; or that the main function of handling protein-products of
the intestine is dependent upon the leucocyte. As to this, Halli-
burton's suggestion, to the effect that the number of leucocytes
in the blood stream is inadequate to perform this function in its
entirety, seems fairly conclusive. Halliburton argues that the
total blood stream contains only about one gram of lymphocytes ;
and even if this amount were doubled during digestion, "it is
difficult to see how two grams of lymphocytes can tackle the
enormous burden which every meal must put upon them." It
should be observed, however, that the quantity of foreign protein
in the blood at any one time is small. But the aggregate quantity
of serum protein is, of course, relatively enormous, and in the
last analysis it is clear that this is the product of the synthesis
of food proteins.

According to the present view, the leucocytes are not called
upon to "tackle" this problem, which is handled effectively by
the mother cells that generate leucocytes and red corpuscles,
notably the latter. These mother cells (in bone marrow, spleen,
and in case of certain leucocytes lymphatics) synthesize protein

36 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

from its ammo-acid elements in great quantity, as evidenced in
the bodies of the corpuscles themselves. But the province of the
mature corpuscles is to deal with proteins in a quite different
way.

Their task is not that of synthesis but of proteolysis, and it
is exercised, not only (1) in connection with the regular supply
of food proteids, but (2) with bacterial proteins and (3) with
exceptional increments of unbroken or only partially cleaved pro-
teins that find their way by inadvertence into the vascular
mechanism.

In view of the relatively small bulk of the cells making up
the normal leucocyte population, it should be recalled that the
amount of foreign protein in the blood serum at one time has
been variously estimated between a minimum of .005 per cent,
and a maximum of 0.12 to 0.19 per cent. — say from three to
twelve grams in a person of average size.

In my original statement of the Proteomorphic theory, it was
suggested that the polynuclear leucocyte deals with the unbroken
proteins (bacterial or dietetic) ; the red corpuscle with partially
cleaved molecules of the polypeptid order ; and that the lympho-
cyte inaugurates the decompounding of the normal serum pro-
teins, to supply energy for the activities of the digestive organs,
the muscles, and the tissues in general. It now seems to me
improbable, however, that the leucocytes are called upon to deal
with the normal serum proteins. I shall revert to this aspect of
the matter a little later.

I did not originally attempt a more detailed analysis of the
relative share of the different types of white corpuscles in the
work of proteolysis. My subsequent studies, however,, which in-
volved observation of the modified differential count in several
hundred human subjects under influence of foreign proteins in-
troduced parenterally, enabled me to elaborate the thesis, and
to develop at least a provisional hypothesis as to the system of
division of labor among the various groups of the leucocyte
population.

These experimental observations and conclusions will be fully
presented in later chapters of the present work. By way of
anticipation, I may say here that they give the strongest possible
support to the general thesis of the Proteomorphic theory as re-
gards the essential proteolytic activities of the corpuscles. They
also furnish suggestive clues to the solution of sundry problems
as to the differential distribution of the various types of leuco-
cytes, in health and disease, at different ages in the human sub-
ject, and among different orders of animals, that have hitherto
gone quite unsolved.

In point of fact, very little is definitely known as to the pre-

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 37

cise mutual relations of the different types of leucocytes. There
is a general impression that these fall into two groups, one of
myelytic origin and the other of lymphatic origin. In the former
group are the basophiles, the eosinophiles, the large mononuclears,
and the neutrophiles. In the latter group are the lymphocytes.
Whether or not the lymphocytes should be divided into small
and large, as two different classes, is a matter regarding which
the authorities are not agreed. Also the question of the precise
origin and functions of the large monocytes is by no means
settled. Ehrlich regarded them as the forms which, developing
through a transitional stage, became transmuted to polynuclears.
But it does not appear that there is any positive evidence in sub-
stantiation of this view.

Furthermore, it has been disputed as to whether the large
lymphocytes are the parent forms of which the small lympho-
cytes are the daughter cells; or whether, on the other hand, the
small lymphocyte grows and develops into a large lymphocyte.

Meantime, it does not appear that any one has given close
study to the question as to the precise material out of which
the bodies of the various leucocytes are developed, nor as to the
specific distribution of their protein bodies after disintegration.
It has been observed that there may be deviation of two thousand
or three thousand leucocytes to the cubic millimeter under nor-
mal conditions in the course of a day. Reinart, for example, gives
the average number of leucocytes at six o'clock in the morning as
5,125; and the average at 4 P.M. as 8,262. If we may accept
such a variation as this as typical, it becomes obvious that the
growth and disintegration of three thousand leucocytes to the
cubic millimeter as a normal process during a period of twenty-
four hours involves a cycle of protein metabolism that is highly
significant. A very interesting question — and a question of great
importance — arises as to whether the transmutation of raw mate-
rials, so to speak (with amino-acids for the ultimate building
stones), through which the bodies of the leucocytes are built up
takes place only in the mother organs of bone marrow and lymph
nodes, or whether the free leucocytes in the blood stream con-
tinue to grow and develop, taking to themselves food pabulum,
and passing through stages of individual development that may
be properly spoken of as juvinility, maturity, and old age.

The well-known fact that the larger types of leucocytes exer-
cise a phagocytic function, seeming to feed on the bodies of
bacteria, gives strong support to the supposition that these cells
are capable of ingesting protein pabulum and converting it into
material for the increment of their own particular protein sub-
stance. It is believed by some observers that the granular struc-
ture of the leucocytes commonly spoken of as myelocytic (that

38 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

is to say, of bone-marrow origin) represents something compar-
able to a glandular substance, constituting a secreting mechanism.
The secretions in question are supposed to be enzymic in char-
acter, representing the various antibodies, in particular the so-
called complement.

According to one view, the granular leucocytes are all of bone-
marrow origin, and constitute a class apart. But this view is
obviously inconsistent with Ehrlich's claim that the large non-
granular mononuclear leucocytes develop individually into neu-
trophiles.

Evidence in the matter is by no means as conclusive as could
be desired, yet it is universally admitted that different organs of
the body may on occasion take on the function of leucocyte-
production; and it may very well be questioned whether there
is any such distinct and fundamental difference between the blood-
forming cells of the bone marrow and the similar cells of the
lymphatic system as has sometimes been suggested. It may fairly
be assumed, however, on embryological grounds that the lym-
phatic system constitutes a somewhat more primordial structure
than the bone marrow, inasmuch as the latter is a relatively late
development in the fcetus. But, on the other hand, many ob-
servers are disposed to trace the origin of the primitive forms of
cells that appear in the blood under certain abnormal conditions
(notably the leukaemias) to the bone marrow rather than to the
lymphatic system.

It is more than likely that, when the systemic disturbance is
sufficiently profound, both sets of organs may revert to a some-
what primordial manner of functioning, and put out cells of a
more embryonic type than the ones usually sent into circulation.

By way of anticipation, I may say that in a later chapter of
this book I shall suggest an hypothesis of the specific functions
of the different types of leucocytes according to which the eosino-
philes deal with the unbroken protein molecule, the large mono-
cytes with full protein molecules and proteoses, the small lym-
phocytes with proteoses and peptones, the polynuclears with
peptones and polypeptids, and the red corpuscles with polypep-
tids and amino-acids. It is further suggested that the polynu-
clears have to do with the digestion of lipoids and fats.

Details as these elaborations of the Proteomorphic theory can
more appropriately be given after the general preliminary state-
ment of them, to which the present chapter is chiefly devoted,
has been made. Meantime, however, I venture again to depart
from chronological sequence to the extent of citing two series
of laboratory investigation by independent workers that have
been carried out since the original publication of the Proteomor-
phic theory, and which in themselves furnish strong presumptive

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 39

evidence of the validity of (1) the general thesis that the cor-
puscles deal with foreign proteins, and (2) the important feature
of the theory which ascribes to the red corpuscles the work of
ultimate proteolysis and oxidation of the split molecules of the
order of polypeptids.

The experiments that (if I correctly interpret them) throw
corroborative light on the first-mentioned aspect of the Proteo-
morphic theory were made by Drs. M. W. Man waring and Yoshio
Kusama, of the Department of Bacteriology and Immunity of
Leland Stanford, Jr., University, as recorded in the Proceedings
of the Society for Experimental Biology and Medicine, of May
24, 1916. These experiments go to show that the blood corpuscles
of a rabbit actively absorb goat serum proteins, whether the goat
serum is mixed with the (defibrinated) rabbit's blood in a recep-
tacle outside the body or whether it is injected into the system of
the living rabbit.

This observation, obviously, gives the strongest support to the
assumption of the Proteomorphic theory that the blood corpuscles
are the agents chiefly concerned in dealing with foreign proteins ;
the assumption that forms the chief basis for the explanation of
the therapeutic action of the proteal remedies with which the
present monograph is concerned.

It should be added that, in the experiments just cited, it is
further recorded that about 25 per cent, of the goat protein may
remain in the rabbit's blood serum. "If the serum and cor-
puscle fractions (of the blood), are allowed to undergo inde-
pendent autolysis (10 hrs., 37° C.) a distinct restoration of the
goat protein is observed in each fraction. The restoration of
the protein in the corpuscle fraction, however, is usually much
more pronounced than that in the serum fraction, and may amount
to as much as 50 per cent, of the total protein originally added to
the blood."

From this it would appear that something like 25 per cent,
of the goat serum originally injected is unrecovered, presumably
having been hydrolyzed to a stage of decomposition at which
it is no longer recognized as goat protein.

It would appear to be a logical inference that such hydrolysis
of the goat serum proteins has been effected by enzymes gen-
erated in the bodies of the corpuscles which, according to the
observations of the experimenters, constituted the chief medium
for absorption of the foreign proteins. As far as they go, these
experiments afford direct collaboration of one of the principal
theses of the proteomorphic theory.

Possibly it may seem surprising that so large a proportion of
the goat serum proteins remained unhydrolyzed after 10 hours'
maceration. It must be obvious, however, that corpuscles under-

40 THE PROTEOM'ORPH c THEORY AND THE NEW MEDICINE

going autolysis outside the body may have far less enzymic
activity than they would exhibit under normal conditions. But
in addition to this it should be observed that the amount of goat
serum introduced in these experiments was enormously large as
contrasted with any doses of foreign protein administered thera-
peutically to the human subject, amounting, in fact, to one per
cent, of the rabbit's blood. Assuming that the goat serum com-
prises at least 20 per cent, of proteins, the amount of foreign
protein thus introduced would constitute one-fifth of one per
cent, of the total bulk of the rabbit's blood.

That the corpuscles of the rabbit's blood were able to absorb
at least 50 per cent, of this shows remarkable capacity on the
part of the corpuscles for handling foreign proteins that invade
the medium in which they lie.

As a still further anticipation of matter to be discussed in
detail later, it may be noted that the normal proteals under
consideration in this book contain only 3 mgm. of nitrogen to
the cubic centimeter, or the equivalent of less than 2 per cent,
of vegetable proteins. Meantime the amount of this 2 per cent,
solution of proteins used in a hypodermic dose is only one or
two cubic centimeters, as a rule ; and almost never more than 3
or 4 cubic centimeters. Such a dose, introduced into the large
quantity of blood in the human body, obviously constitutes an
infinitesimal protein intrusion in comparison with the one per
cent, of goat serum mixed with the rabbit blood in the experi-
ments of Manwaring and Kusama.

Since these experiments now give us an inkling of the capac-
ity of the blood corpuscle, the thought not unnaturally suggests
itself that possibly we have hitherto used proteals in much smaller
doses than might be permissible or advantageous. Here, ob-
viously, is an interesting field for future experimentation, in
connection with cases that have proved intractable to the pro-
teal medication as hitherto administered. It must be recalled,
however, that it has been customary to carry the dosage to the
point of producing an anaphylactic response, and that with most
patients this is likely to occur with a dose of thirty minims or
less of a two per cent, protein solution. On the other hand, in
some early tests that antedated the beginning of proteal therapy,
an experimenter administered doses of one hundred cubic cen-
timeters of sheep-blood serum into the peritoneal cavity of a
cancer patient, with seemingly beneficial results. It is noteworthy
that the severity of the deferred anaphylactic reaction (including
chill) is by no means determined exclusively by the quantity of
protein administered. It has already been noted that proteins
to which the system has not been habituated, such as those of
alfalfa, produce relatively strong reactions.

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 41

The second laboratory investigation, to which reference was
just made, concerns the presence of uric acid in the red cor-
puscles. In the Journal of Biological Chemistry, August 20,
1915, Benedict shows that uric acid exists in the blood in two
forms, in a "free" and in a "combined." Ox-blood, which, when
tested by the method of Folin, hitherto considered reliable,
showed a content of 0.2 mgm. of uric acid per 100 c.mm., was
found as a rule to contain in reality about 7 mgm. of total
uric acid per 100 c.c. of blood, practically all of this being con-
tained in the red blood cells. "If the ox blood were allowed to
stand at room temperature and protected from bacterial con-
tamination, there was found to take place a gradual transition
from the combination to the free form of uric acid, apparently
due to the action of some ferment. . . . Benedict suggests that
possibly the free uric acid is that which is ready for excretion as
such, while the combined is capable of further catabolism."
(Summary appearing in Medical Record.}

It must be obvious that this finding of large quantities of uric
acid in the red cells gives strong support to that part of the pro-
teomorphic theory which postulates the red cells as the seat of
the enzymic activities which accomplish the ultimate decompound-
ing of the protein by-products. Uric acid is one of the most im-
portant of these by-products. It chances to be one that can ulti-
mately be eliminated by way of the kidneys ; but whether the red
cells excrete it into the blood for that purpose, or whether it
merely is left in the blood stream when the red cell is disin-
tegrated in the liver, is still conjectural. Meantime Benedict's
experiments give additional evidence that the red cells have pre-
cisely such enzymic functions in connection with the later stages
of decompounding of the protein molecule as the proteomorphic
theory postulates.

Possibly a few words of further exposition and interpretation
may be desirable, illustrating a little more in detail the chemical
aspects of the observed facts in connection with the suggested
explanation along the lines of the proteomorphic theory.

Note, then, that the chemical formula of uric acid is C5H4N4O3.
Obviously we have here a substance not distantly related to some
of the amino-acids, but proportionally richer in nitrogen than
any one of these, the only one approaching it in this regard
being arginine (C6H14N4O2). Another significant distinction be-
tween uric acid and amino-acids is the fact that it contains three
atoms of oxygen and only four atoms of hydrogen. There is
no amino-acid with less than five atoms of hydrogen; and all
but three of them have either two or four atoms of oxygen, each
of the three exceptional ones having only a single atom of
nitrogen.

42 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

We have, then, in uric acid a compound relatively rich in
nitrogen and oxygen, but poor in hydrogen. To modify it by
adding a molecule of water would probably (in view of the
four atoms of oxygen) give it extreme instability; and to take
a molecule of water away from it would deplete its hydrogen
supply, which is already below the minimum amino-acid stand-
ard. Uric acid, therefore, appears to represent an end product
of the split protein molecule of such structure that it does not
afford available material for the making of amino-acids — the only
form of nitrogenous building material that the system can utilize
in its synthetic operation. This applies, at any rate, to the por-
tion of uric acid which finally appears in the blood plasma. The
red blood corpuscle does, apparently, modify a part of the orig-
inal uric acid supply, since only a fraction of it appears in the
plasma.

Similar reasoning applies, seemingly, to those other waste-
products of protein metabolism, urea (CH4N2O) and bilurubin
(C16H18N2O3) ; each with an odd number of oxygen atoms; one
hopelessly deficient in carbon atoms, the other with an excess of
them. The origin of bilurubin as a product of the destruction
of red corpuscles in the liver has long been known; and as a
matter of course, it received consideration in the development of
one important aspect of the Proteomorphic theory. That the
observations linking uric acid with the red corpuscles were made
subsequently to the putting forth of the Proteomorphic theory,
and quite independently, gives them added value as corrobora-
tive of the truth of the theory itself.

Meantime, as throwing light from another angle, we may recall
experiments made thirty years ago by Horbaczewski, which
showed that uric acid was formed during the digestion of spleen
pulp with blood in the presence of oxygen, but that in the absence
of blood only the purin bodies hypozanthin and zanthin were
formed ; the so-called zanthin oxydase requisite to complete the
transformation into uric acid being apparently lacking. It seems
a plausible inference that the corpuscles supply this oxydase, since
the presence of blood was the determining factor in bringing
about the final oxidation through which zanthin, C5H4N4O2, is
transformed into uric acid, C5H4N4O3.

This observation, linked with the new revelations of Benedict,
above cited, makes plausible the further assumption that the red
corpuscles (found thus, apparently, to have an essential share
in the genesis of uric acid from purin bases, and demonstrated
as the chief locus of uric acid after it is formed), are the source
also of the uricase that transforms uric acid (by removal of a
molecule of the carbonyl group, CO, and the substitution of a
molecule of H2O) into allantoin, C4H0N4O3; and in due course

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 43

effects the hydrolysis or oxidation of each molecule of allantoin
(by removal of two molecules of CO2 and substitution of a
molecule of H2O) into two molecules of urea, CH4N2O, the
ultimate waste product of purin-bearing proteins.

If this assumption is valid, a still clearer view is gained of the
modus operandi of non-specific proteins as therapeutic agents in
dealing with rheumatoid conditions (commonly believed to be
associated with the inadequate catabolism of purin bodies and
their oxidation product, uric acid), and with malignant neoplasms,
the structure of which is largely made up of purin-bearing pro-
teins. An agent which stimulates production of red corpuscles
and enhances their enzymic activities, as the non-specific pro-
teins have been amply demonstrated to do in my hands and
those of my associates, should theoretically be effective in pre-
cisely those conditions in which the proteals have been observed
to have clinical value.

Further consideration of this aspect of the subject must be
deferred, however, until we have dealt with the more general
fundamental properties concerned. Taking up the sequence of
the original presentation of the Proteomorphic theory, we may
advantageously make inquiry as to the extent to which foreign
proteins are present in the parenteral system under usual
conditions.

PROTEOLYTIC ACTIVITIES OF THE LEUCOCYTE

It has been shown by various experimenters (Voit and Bauer,
Haidenhain, Friedlander, Waymouth Reid, Ascoli and Vigano)
that, under certain conditions, unmodified food proteins may find
their way through the intestinal walls and enter the general cir-
culation. It is against these, according to the present view, that
the digestive functions of the various types of leucocyte are exer-
cised; the work of the leucocyte with these, as with the bacterial
proteins, being a work of proteolysis strictly comparable to that
performed by the digestive ferments in case of proteids in the
digestive tract — with certain variations to be noted.

This view finds strong support in the fact that one at least
of the enzymes found in the body of the leucocyte is closely com-
parable to, if not identical with, the trypsin of the digestive
canal. It is possible, according to some experimenters, that syn-
thetic activities also lie within the capacities of these enzymes
(all catalytic phenomena are conceivably reversible). But, as-
suredly, their habitual province is to break down or cleave this
protein molecule, not to synthesize it.

It is known that the unbroken food protein, and even so small
a cleavage product as peptone, do not exist normally in the

44 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

blood stream. The peptones of the digestive canal are believed
to be further hydrolized, with the production of amino-acids,
in their passage through the intestinal wall. The leucocyte accom-
plishes the same cleavage (or at all events the early parts of this
cleavage) in the case of foreign proteins that come to it. And
the quantity of these is sufficient to give full scope for the leuco-
cytic activities; for experiments show that the intrusion of the
unbroken protein molecule must be an extremely common inci-
dent, even if it cannot be considered a strictly normal one. More-
over, there are complications involved in the task of disposing
of these unwelcome visitors.

The first of these complications is contingent on the fact that
the leucocyte is thus called upon to deal with large protein mole-
cules of many types, and that it can scarcely be supposed to be
able to do so without producing toxic cleavage molecules at some
stage of the process that may escape from its substance — say
through dissolution of the body of the leucocyte itself — and con-
taminate the blood plasma. Even though the original protein
was in the form of a wholesome foodstuff, say protein of beef
or of egg or of milk, there is always possibility that in its de-
compounding there may arise combinations of molecules that
are poisonous to the tissues of the organism.

As Vaughan phrases it, there is a poisonous group in every
protein molecule.

Possibly it would be correct to say that there are many poison
groups ; but Vaughan finds that their physiological effects are
essentially the same in all proteins. He has attempted to isolate
this group of molecules which, in its free state, becomes a poison
(so he believes) on account of the avidity with which it disrupts
other protein molecules. In the purest form in which he has
been able to isolate this group (and this is probably, he conceives,
far from chemical purity), it kills guinea pigs of from two hun-
dred to three hundred grams weight, when injected intracar-
diacally in doses of half a milligram. In the original protein
molecule, it is held, the poisonous group is physiologically inert,
because it is combined with secondary groups called side-chains.
But these secondary groups are detached or decompounded in the
proteolysis of the molecule ; and there is conceivable danger that
during this process the poisonous group may become detached
and, diffusing in the blood stream, exert a toxic effect on the
central nervous system. There are no observed phenomena asso-
ciated with the therapeutic parenteral introduction of the pro-
teins that suggest this, however, unless the anaphylactic reaction
occasionally induced be so interpreted.

The danger of such a result when proteins are digested in the
alimentary tract is small, because the poisonous group is prob-

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 45

ably not readily absorbed through the intestinal wall. But the
leucocyte itself is suspended in the blood stream, and it must on
no account permit the formation of a poisonous group, or if such
is formed it must be retained within the substance of the leuco-
cyte until it is further transformed and rendered innocuous, or
is otherwise guarded (for example by the red corpuscles) or
extruded from the blood stream.

Something as to what this implies may be conceived from an
attempt to visualize the protein molecule, even in the vaguest
way. A typical protein, for example, is globin, the basis of
hemoglobin. Plimmer gives this formula for globin : C72fl, H1174,
N194S3O214. In the process of digestion, this enormously large
and complex molecule undergoes hydrolytic cleavage again and
again. A single molecule of protein thus cleaved (always in such
a way that each new molecule contains a modicum of nitrogen
along with the other elements) makes up successively molecules
of proteoses and of peptones and polypeptids, and ultimately, if
the cleavage is carried far enough, the disintegrated fragments
constitute the relatively simple amino-acids, which form the
building stones of all proteins, and of which almost a score of
different types are now known, a few of which have become rea-
sonably familiar in recent medical literature under the names of
glycine, alanine, valine, leucine, tyrosine, etc. The simplest of
these, glycine, has the formula C2H5NO2 ; but the others are not
much more complex ; leucine, for example, being fairly typical,
with the formula C6H13NO2.

It will be seen that something like two hundred molecules of
the amino-acids — each with its single atom of nitrogen — would
result from the final cleavage of a single ordinary protein mole-
cule. So the digestion or proteolysis of even a small group of
protein molecules is like the 'tearing to pieces of a building com-
posed of many thousands of individual bricks, stones, and timbers.
It is obvious that the task thrust upon the leucocytes by the in-
truding protein molecule is by no means a simple one. Yet
there is abundant experimental evidence that such proteolysis
of an invading protein does take place parenterally ; and to the
present writer, at any rate, it seems highly probable that it is
the blood corpuscles, rather than any of the more specialized
tissues, that perform this function.

The fact that only small quantities of foreign proteins, if ex-
perimentally introduced into the blood stream, are transformed
(the major part being excreted by the kidneys unchanged), is
obviously consonant with the relatively small bulk of the leu-
cocytes in their totality, as above referred to.

To be sure, there do remain residual molecules, after final

46 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

cleavage is effected, that are actually toxic — though not in the
same degree as the artificially produced product of Vaughan.
These are the familiar end products uric acid, urea, and creati-
nine — substances with which the body has learned to cope by
bringing about their early elimination. Save for this small residual
portion, the protein molecule will have been transformed into
amino-acid foodstuffs which, we may suppose, do not differ
in any essential particular from those supplied in far larger
bulk from the usual digestive-tract proteolysis of the proteins,
including the stages of dismemberment effected in the walls of
the intestine itself during absorption.

So much has been said about the toxic molecule elaborated
in the course of protein hydrolysis in Vaughan's laboratory ex-
periments that it is desirable to call attention to the fact that
this is an artificial product devised by special manipulation. The
possibility that similar toxic molecules are developed in normal
proteolysis of the protein molecule has been considered above.
But experience shows that if such toxic molecules are indeed
developed, short of the familiar end products (of which there
is no evidence), they are handled in such a way as to shield
the system against untoward consequences. The entire thera-
peutic procedure under discussion in the latter part of this vol-
ume (namely, Proteal therapy) is based on the hypodermic in-
jections of foreign proteins. Toxic results (aside from a tem-
porary anaphylactic reaction) have not been observed.

Moreover, in experimentally testing the Proteals I have admin-
istered vegetable proteins of many types hypodermically to small
(400 to 800 gram) guinea pigs day after day in doses of 20 to
30 milligrams, with no harmful effects whatever. The animals
thrive under the treatment, proving conclusively that there are
no toxic molecules developed in the natural hydrolysis of these
vegetable proteins with which their corpuscles (or other tissues)
cannot adequately cope.

It should be recalled, however, that the proteins with which
these therapeutic tests and animal experiments are made all
have their origin in vegetables not far removed, botanically, from
food plants, and hence are relatively non-toxic. This, however,
does not greatly change the argument, since (as above stated)
Vaughan liberates his toxic molecule from various types of pro-
tein indifferently. From the standpoint of practical therapeutics,
so far as present evidence carries us, this toxic molecule is a
negligible quantity in non-specific protein therapy. The admin-
istration of the Proteals day after day, for a term of months,
to patients who improve steadily in blood conditions and in gen-
eral health, sufficiently establishes that important point.

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 47

THE LEUCOCYTE AND BACTERIAL PROTEINS

But the task of the corpuscles in shielding the tissues against
the intrusion of unwelcome proteins in non-assimilable form
becomes enormously complicated when the proteins in question
are of unfamiliar types and are encased in protective cell walls
— in other words, when they make up or enter into the bodies
of bacterial invaders. As already pointed out, however, the
capacity of the leucocyte to engulf these bodies and to digest
them and make them part of its own substance is not at all a
matter of theory, but a matter of observation under the micro-
scope.

According to the present view, there is no fundamental differ-
ence between the digestion of the bacterial proteins and of any
other type of protein — say a morsel of muscle. There are prac-
tical difficulties to be solved, such as getting through the cell
wall of the bacterium, but the transformation of its protein,
through cleavage, into amino-acids is a process of the same gen-
eral type as any other proteolysis.

As qualifying this statement somewhat, however, it should be
borne in mind that no two proteins from different sources — from
the bodies of different species of animals for example — are iden-
tical as to all their groupings of molecules. Dr. Nuttall's remark-
able precipitin experiments show how marvelously the specificity
of proteins holds throughout the animal kingdom. The highly
interesting demonstration in the transplantation of organs from
one animal to another made by Dr. Alexis Carrel evidence the
same thing from a quite different angle. This aspect of the sub-
ject is so important, and its bearing in the ultimate problems of
protein therapy is so significant, that it will be well to present here
a brief review of the two groups of experiments in question,

TRANSPLANTING ORGANS

Dr. Carrel has shown that the lost members of a higher animal
may be replaced by the substitution of a new member through
a surgical procedure. He has amputated the leg of a dog, for
example, and replaced the member with a closely similar one
taken from another dog; and has seen the new member grow
into place and become a part of the body of its new host.

Dr. Carrel has similarly transplanted various internal organs,
including the kidneys, from one animal to another, and caused
them to take root, as it were, and perform their normal func-
tions. The success of his experiments is due largely to his
introduction of a new method of uniting arteries and veins,
whereby they are so cleverly sutured together that scarcely a
trace of the point of union remains when the wound has healed.

48 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

From the present standpoint, the thing of chief interest is
that Dr. Carrel's observations show that there is a specific quality
about the tissues of an animal that is profound and individual.
The kidney of a cat seems to perform identically the same func-
tion as the kidney of a dog. But one cannot be substituted for
the other in these experiments in transplanting members. The
kidney of a dog may be transferred to another dog; the kidney
of a cat to another cat ; but the two must not be interchanged.

Even where the organ experimented with is so simple as the
tube of an artery, it is with difficulty that an exchange between
animals of different species may be effected. To all casual obser-
vation, and even to close observation with the microscope, the
artery of a cat seems identical with that of a dog; but there is
a deep-seated chemical difference which makes itself felt if, for
example, a section of cat's artery is made to replace an exsected
portion of the artery of a dog.

It was a foregone conclusion, therefore, that the attempt re-
cently made by a Berlin surgeon to replace a diseased human
kidney with the kidney of a monkey would be a failure. The
surgeon of the future will doubtless replace diseased kidneys
and other vital organs with normal ones, but the substituted
organs will be taken from human subjects — say from the vic-
tims of accidents, or from executed criminals.

TRACING BLOOD RELATIONSHIP

The specific quality which thus pervades every tissue of an
organism — so that the remotest cell of a cat, for example, has
some quality of felineness that distinguishes it from a cell of
any other species of animal — extends its mysterious influence so
comprehensively that it includes not merely every fiber of the
organism, but every drop of blood in an animal's body.

The proof of this has been given by Professor G. H. F. Nut-
tall, the American biologist, now of the University of Cam-
bridge, in the series of experiments just referred to.

Professor Nuttall has developed a system of blood testing of
such delicacy as quite to transcend the bounds of microscopic
examination or of any chemical methods hitherto known; and in
so doing has found a method of testing the relationships of dif-
ferent tribes of animals that seems little less than magical.

The tests show, for example, that man is more closely related
to the old-world monkeys than to the monkeys of the new world ;
our closest relatives being the chimpanzee, the gorilla, and the
orang in the order named. Similarly the relationships between
different members of the dog family, the cat family, and the
like, are traced. Thus the hyena appears to be to some extent

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 49

intermediate between dog and cat tribes, but, contrary to what
might be expected, it is much more closely related to the cat
than to the dog. The seal and sea lion, on the other hand, are
closer to the dog family than to the cats. Moreover, the seals
are somewhat more closely related to the weazel tribe than to
the felines.

The porpoise, which might be supposed to be allied to the
seal, is found instead to show close affinities with the ox tribe,
and in particular with the pigs. Indeed the porpoise may be
regarded as a pig that has taken to the water and perforce be-
come carnivorous in diet. It is necessary also to record the
rather unflattering observation that the blood of the porpoise
shows more pronounced affinities with human blood than with
that of most other animals.

The family groupings among reptiles show close blood rela-
tionship between lizards and serpents, and a slightly less close
relationship between turtles and crocodiles. The reptiles are
more closely related to birds than to mammals. The relation-
ship appears to be particularly close between birds and turtles;
less close between birds and crocodiles ; the avian relationship
with lizards and serpents being still more remote.

These tests singularly confirm the conclusions of the zoologist,
based on study of the anatomical structures of the different tribes
of animals ; but the testimony is absolutely independent, the tests
being made, as already pointed out, by means of blood alone.

Indeed the maker of the test may never have seen a specimen
of the species whose rank in the organic scale he is determining.
The specimens of blood that Professor Nuttall used in his classi-
cal series of experiments were collected from a multitude of
sources; no fewer than seventy different persons sending speci-
mens from different parts of the globe.

Many of the collectors were hunters, who merely dipped a
piece of filter paper in the blood of a quarry and transmitted
it to the Cambridge Laboratory. There the discolored piece of
paper was soaked in water to produce a clear solution of blood
serum. A portion of this solution was placed in a test-tube, and
this test-tube put in a rack along with scores of other specimens,
each bearing only a number.

Into each test-tube a small drop of a certain liquid was placed.
If the solution in the test-tube became cloudy, the experimenter
was able to pronounce definitely that the blood was that of an
animal of a certain tribe. It might, for example, be the blood
of a tiger or a leopard or a panther or a cheetah; but it could
not be the blood of a hyena or a wolf or a dog.

Again the test might be applied to a blood stain on a hand-
kerchief or knife, or on a fragment of wood from a floor or

50 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

window sill, or scraped from the surface of a boot or a coin. In
this case the question as to whether the stain was caused by
human blood or by that of some animal might be the deciding
testimony in a murder trial.

Here the method of procedure would be the same as before.
A solution being made from the blood stain and placed in a
test-tube, the trial fluid would determine whether the stain was
due to human blood. If the test proved negative, other tests
might determine what particular animal supplied the blood. In
a case reported by Professor Uhlenroth, for example, a blood
spot in the road, suspected to be of human origin, was found to
be from the blood of a pig. In another case blood stains on a
garment were reported as being partly human and partly due
to the blood of the sheep. In this case it was subsequently proved
in court that the wearer of the garment had committed a mur-
der, but that he had slaughtered sheep two weeks before the
murder.

How THE TEST FLUIDS ARE DEVELOPED

A word now as to the production of the magical fluid with
which such tests are operated. The fluid consists of a portion
of blood serum drawn from the veins of a rabbit. The peculiar
properties of the serum have been developed by repeated injec-
tions into the system of the serum of human blood or that of
some other member of the animal kingdom, according to the
particular type of test that is to be made.

A rabbit inoculated with human blood develops a so-called
anti-human serum. Another rabbit inoculated with the blood
serum of a cat, will develop an anti- feline serum; and so for
all other tribes of animals — including not merely mammals, but
birds, reptiles, and even crustaceans, such as the lobster and its
allies.

The explanation of the development in the body of the rabbit
of the peculiar quality of blood that gives the anti-serum its
value in such tests as those outlined, is found in the fact that
the blood of almost any animal has a certain quality of toxicity
when injected into the veins of an animal of different species.
In some cases this action may be very virulent.

For example, fifteen drops of the blood of an eel injected into
the veins of a dog weighing about thirty pounds may produce
death in seven or eight minutes.

In another experiment ten drops of the blood serum of an eel
killed a rabbit of ordinary size in two-and-a-half minutes. The
foreign blood serum appears to attack the blood corpuscles, ren-
dering them functionless and presently dissolving them.

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 51

Curiously enough the blood corpuscles of new-born rabbits
are much more resistant to foreign blood than are those of the
adult rabbit. But a certain degree of resistance obtains in all
animals, and this may be accentuated by introducing a very small
quantity of foreign blood serum, and from time to time repeat-
ing and increasing the dose. In this way the system of the
animal becomes to some extent immune to the poisonous effect
of the foreign blood, through development of what for want of
a better term is called an anti-serum.

The blood of a rabbit that has attained this condition may
then be used in testing for the presence of the particular type
of blood that was used in developing the anti-serum. For ex-
ample, if human blood was the kind injected into the system
of the rabbit, the rabbit's blood will now serve as a test for
human blood.

MAN'S REMOTE RELATIVES

It appears, however, that the anti-serum thus developed, while
its most pronounced reactions will be given with solutions of
human blood, will also react in a less marked degree with the
blood of other animals.

If successive drops of the anti-serum are introduced into one
test-tube after another, as in Dr. Nuttall's experiments, it will
be observed that in some tubes there is an immediate reaction,
resulting in a white precipitate. In other tubes the reaction
will set in only after some minutes; in yet others after hours;
and the remaining test-tubes will remain permanently clear. It
is these graded results that enable the experimenter to test the
blood relationships of the different animals.

It is found, for example, that when a test is made with human
anti-serum, an immediate reaction is observed only in test-tubes
containing human blood. Less prompt and less marked reaction
occurs in the tubes containing the blood of the man-apes; still
milder reaction in the case of baboons, monkeys, and marmosets
in succession ; and a long delayed or altogether negative result
in all other cases. It is obvious how similar tests with other
types of anti-sera enable the experimenter to follow out the
relationships of different tribes of animals.

Professor Nuttall's experiments comprised sixteen thousand
individual tests, with a total of at least 586 species — mammals,
birds, reptiles, batrachian, fishes, crustaceans — coming from all
parts of the globe. These experiments are in themselves highly
interesting; in their implications they are nothing less than as-
tounding.

Doubtless some hundreds of thousands of years have elapsed

52 THE PROTEOMORPHIC THEORY A*TD THE NEW MEDICINE

since the direct ancestors of men branched from a common stem
with the direct ancestors of the gorilla. There has been no blend-
ing of blood in the intervening centuries. Cats have been cats
and dogs dogs from geological epochs so remote that we hesi-
tate to guess their span in terms of years. So the intimate chem-
ical qualities that denote man or ape or cat or dog, each in con-
tradistinction to all the others, must have been transmitted
unmodified through countless thousands of generations.

It taxes credulity to believe that such intangible properties
could be transmitted unmodified through the blood streams of
such myriads of individuals ; but the evidence of the test-tubes
proves that this has been done.

What makes the marvel greater is the fact that the bodies
of the animals have meantime been so modified as to develop
utterly divergent species — for example, the lion, the tiger, the
puma, the leopard, and the house cat; different types of dogs,
wolves, foxes, and their allies. But in each case some intangible
quality of the blood remains unchanged to prove the common
origin. Blood is indeed thicker than water.

THE SOURCE OF SPECIFIC ANTIBODIES

In making the above presentation of the experiments showing
the specificity of proteins, I have drawn on the text of one of
my popular books, Miracles of Science, which appeared not
long before the original publication of the Proteomorphic theory.
I have thought it well to present this detailed account of the
precipitin experiments, because they bear so fundamentally on
the essential problem of the protein response in therapeutics, the
elucidation of which is the chief purpose of the present book.

These experiments make it clear that the phrase "non-specific
proteins," notwithstanding its convenience, is in the final anal-
ysis a misnomer. Proteins may be used non-specifically, but no
two are precisely alike. Making present application of this prin-
ciple, and recalling that the single enzyme trypsin is observed
to begin the digestion of many types of protein, it must be sup-
posed that the exact steps of the successive metamorphoses are
somewhat different in each case. It is even possible that there
are various types of the enzymes that now go by the name
trypsin, each one adapted to deal with a different protein. But
this is only conjectural, as the chemistry of the enzymes is still
very obscure.

Be that as it may, however, it is certain that each type of
protein undergoing parenteral digestion and assimilation evokes
from the digestive mechanism a unique response, which finds
expression in the secretion into the blood stream of specific types

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 53

of antibodies. These specific antibodies are no mere by-products
of the cleavage of the foreign proteins, as was once supposed.
They are chemical compounds put forth by the defensive mechan-
ism and having such specific properties as will enable them to
antagonize the particular protein that evoked them. This is
equally true of proteins of every type — of the molecules that
make up the most wholesome foodstuff, no less than of those
that make up the most virulent bacillus.

The chemicals in question are known as bactericides, bacterio-
lysins, hemolysins, agglutinins, precipitins, and opsonins. Some
of these names may be duplications, but the existence of a cer-
tain number of what may conveniently be termed "antibodies,"
developed through response of the organism to the intrusion of
the foreign proteins, is a chemical fact supported by unassailable
evidence, quite apart from any theory whatever as to the pre-
cise bodily mechanism through which they are produced. We
have just seen this illustrated in detail in the case of Dr. Nut-
tail's precipitins.

But when we attempt to localize this mechanism, we find our-
selves at once involved in difficulties. To be sure, the line of
reasoning just presented seems to point rather clearly to the leu-
cocyte as the developer of the antibodies; inasmuch as that cell
is known to be the digester of the offending protein itself. But
if we seek direct proof, we find the evidence not altogether
convincing. Nevertheless a number of observations have been
recorded, as to the result of direct experiments, that are at least
highly suggestive.

Thus, for example, Ruffier and Crendiropoulo, as cited by Nut-
tall, found evidence that agglutinins may exist in the leucocytes
of rabbits and guinea pigs, inasmuch as an extract of leucocytes
from an immune animal had greater agglutinating power than
did the same animal's serum. The observations of Metchnikoff
convinced him that the output of "fixatives" varies directly with
the degree of phagocytosis. Gengou, following up Metchnikoff's
conception at the Pasteur Institute, "concluded that the hemo-
lysins are derived from leucocytes, for the reason that plasma
separated from fresh blood, when cooled throughout, by cen-
trifugalization, was less hemolytic than serum." The experiments
on which this last conclusion were based were repeated, however,
by Ascoli, with opposite results, and Pfeiffer and Marx found
antibodies less abundant in the ground bodies of leucocytes of
immunized animals than in the plasma.

Again, according to a recent analysis of Gay and Rusk, "the
work of Deutsch, Castellani, Rath, Weil and Braun, and Kraus
and Schiffmann all shows that the agglutinins appear in the
blood serum before they are present in the extract of any organ."

54 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

But "although Gruber originally suggested that the polymor-
phonuclears form the agglutinins no experimental evidence goes
to prove this, and the experiments of Achard and Bensaud, Widal
and Sicard, of Paetsch, and of Kraus and Schiffmann all seem
to disprove leucocytic or local origin."

"Sweet found that he could increase the complement-content
by the injection of substances having a positive characteristic
action on leucocytes." (Nuttall.)

As to precipitins there are experiments by several observers
(including Cantacuzene and Swerew, Hiss and Zinsser, and Sten-
strom) seeming to point to the leucocytes as a definite source ;
and Kraus and Schiffmann "emphatically regard the blood as the
source of precipitins." Here again there is contradictory evi-
dence; but, on the whole, it may be said that a strong case is
made out for the leucocyte as the source of precipitins and agglu-
tinins, and a somewhat less convincing case for bacteriolysins
and hemolysins. I shall have occasion presently to refer more
at length to some recent experiments of J. W. Vaughan, in which
antibodies evoked by cancerous tissues were definitely located in
the large mononuclear leucocytes.

Meantime it is to be noted that a considerable number of the
workers who failed to localize the immune bodies in the leuco-
cytes found evidence for their localization in one or another of
the leucocyte- forming tissues — the spleen, the lymphatics, and the
bone marrow. Thus, according to Nuttall, "Shibayamia found
hemolysin for dog corpuscles in the spleen and lymphatic glands
of normal guinea pigs, not elsewhere."

Again Gay and Rusk interpret the work of Pfeiffer and Marx
as seeming "to indicate very clearly that the protective antibodies
directed against the cholera spirillum are elaborated in the leuco-
poietic organs, particularly in the spleen, but to a less extent
in the bone marrow, inasmuch as extracts of these organs pro-
tect guinea pigs from infection before the blood serum does.
Deutsch essentially corroborated these findings with B. typhosus
and Castellani with B. dysenteriac. . . . These authors agree
that the spleen is not essential, as its removal at best but slightly
inhibits antibody formation; the bone marrow and lymph nodes
are secondarily concerned."

As to hemolysins, we find this comment: "Among the fixed
tissues, the liver and spleen seem to have shared the honors as
the possible sites of hemolysin formation. Leuckhardt and Becht,
following the work of Hektoen and Carlson, found that the
spleen alone of the organs of a dog that has received goat or
rat corpuscles 24 hours previously has the property of immuniz-
ing new animals." But this experiment is not considered con-

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 55

elusive. "Carrel and Ingebrister have produced hemolysins in
the growing embryonic spleen." As to agglutinins, it is noted
that "there is some evidence of agglutinin formation in the spleen
offered by V. Emden, Jatta, and Girgoleff." •

All this is interesting; but there are contradictory experiments
all along the line, and Gay and Rusk do not regard the evi-
dence on the whole as conclusive. They say, however, "there
seems greatest agreement on the point that antibodies are formed
either by the leucocytes or the leucocyte- forming organs. And
yet a good deal of recent work points with increasing emphasis
to the liver, an organ which, in view of its other functions, might
logically likewise serve to produce antibodies.

It will appear that the conflicting testimony is largely har-
monized so soon as we take account of the red corpuscles along
with the leucocytes and cytogenic system. For the moment, how-
ever, it suffices to point out that all the different experimenters
are at one in designating either (1) the leucocyte- forming organs,
or (2) the leucocytes themselves, or (3) the liver, as the prob-
able sources of the origin of antibodies. As to the liver, I now
call attention to the fact that this organ is the seat of destruc-
tion of great numbers of red blood corpuscles ; and that its fluids
are very freely supplied with leucocytes, some of which come to
it directly through the portal vein after their apparent origin
in the spleen. It has even been suggested (by Sajous) that the
eosinophiles may be formed in the liver.

All in all, it may fairly be said that the experimental evi-
dence raises at least a strong presumption in favor of the belief
that the lymphoid tissues that develop the leucocytes, and the leu-
cocytes themselves, are closely associated * with the processes
through which certain types of antibodies are developed. The
antibodies in question, according to the Proteomorphic theory,
are the "complement" and sundry bactericides, bacteriolysins,
agglutinins, opsonins, and precipitins — in a word, the antibodies
evoked by antigens composed of unbroken proteins, including,
of course, the bodies of living and dead bacteria.

If the direct evidence for this part of the theory is not abso-
lutely demonstrative, at least it may be said that there are no
experiments that clearly contradict it. Meantime, it is worth
while to inquire whether the general relations of the leucocyte
and its parent cells, viewed in the evolutionary scale, are such
as to justify the assumption that they perform the particular
functions here ascribed to them. Such a discussion could, of
course, have no force were it contradicted by direct experimental
evidence; but it may have confirmatory value when its findings
seem to accord with those of the experimenters.

56 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

THE PRIMORDIAL LEUCOCYTE

In such a view, it would appear that the leucocyte is a rela-
tively unspecialized cell, the least-modified present-day repre-
sentative of the prototypal single-celled ameboid organism from
which the entire body has developed. It is consistent with this
view that the leucocyte should have retained the primitive func-
tions of digestion and assimilation of proteid bodies as its essen-
tial task in the developed body.

It is not unlikely, then, that in reviewing the conditions which
determine the relations of the protozoan to its environment we
may gain an insight for the better interpretation of some of the
activities of the leucocyte, its lineal descendant.

If, then, we go back to the evolutionary beginning, and review
in imagination the conditions of the time when the only living
organisms were single-celled ones, we must think of our primor-
dial ancestor as a protoplasmic cell endowed with a curious ca-
pacity to absorb certain materials from the environment, and
through assimilating them to grow ; endowed, also, in the pur-
suance of this mission, with capacity to respond to impressions
received from the environment.

The protoplasm making up the body of this primitive organism
was a compound of carbon, hydrogen, oxygen, and nitrogen, with
minute quantities of a few other chemicals, notably sulphur;
which was liquid in character, but differed in its essential qual-
ities from the inorganic substances about it, chiefly, we may
suppose, because of the exceedingly intricate character of the
relations of the very large number of atoms that entered into
each molecule. The physical principles that determined the rela-
tions of this protoplasmic solution with other solutions in which
it might be immersed were determined in accordance with the
laws of capillary absorption and of osmosis.

The essential functions of the protoplasm, in virtue of which
it might be spoken of as a living organism, were probably con-
tingent on the fact that each molecule contained a large num-
ber of atoms of carbon, an element having four chemical valences ;
and a considerable number of atoms of nitrogen, an element
that may have either three or five valences, and which is signally
characterized by its unwillingness to enter into combination, and,
contrariwise, its exceeding desire for liberty when once it has
been combined, resulting in the instability of all nitrogen com-
pounds. Nearly all explosive compounds, it may be noted, con-
tain a nitrogen element. Indeed, the analogy as to composition,
between protoplasm and dynamite and other high explosives, is
striking and highly suggestive. There is one important differ-
ence, however — artificial explosives contain enough oxygen to

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 57

burn their other constituents; whereas the protein molecule, in
order that it may not be too unstable, is provided with a com-
paratively small supply of oxygen.

Recall now the principles of osmosis, as revealed by the studies
of Van't HofT. It appears that osmosis, or the passage of liquid
through a membrane from one solution to another, is due, not
to any suction principle, but to the pressure on the membrane
exerted by the molecules of the denser liquid; that is to say, the
liquid which has the larger number of free molecules in a given
volume.

A single liberated atom or ion of oxygen or any other element
is the osmotic equivalent of the most gigantic protein molecule.

This is the curious fact discovered by Van't Hoff, and substan-
tiated through the researches of Arrhenius and Ostwald. It is
of fundamental importance in its application to the relations of
the living cell.

Suppose, for example, that a full-sized protein molecule in the
protoplasm of a living cell were suddenly to be disrupted into
molecules of its component substances, the amino-acids. Imme-
diately the osmotic pressure exerted by the molecule would be
increased a hundred fold. The pressure might disrupt the cell-
Short of that, it would result in pressing the cell wall outward
against the surrounding fluid, with the result that a certain
amount of that fluid would pass through the cell wall and be-
come a part of the cell content. Suppose, then, just as equi-
librium of pressure between the cell and its surroundings is re-
established, there is a recombination of the dissociated elements
to produce full-sized protein molecules. A hundred or so amino-
acid molecules becoming a single protein molecule, the osmotic
pressure in the cell would be correspondingly reduced, with the
result that the cell would contract under stress of outside pres-
sure and exude a portion of its content.

It is not unlikely that this process may explain the enigmatic
action even of such highly developed cells as the muscle cell in
the animal body, the contraction of which has never been clearly
understood.

I am not unaware that some physicists have denied that the
laws of osmosis apply to colloidal substances. But, aside from
the apriori improbability that these liquids defy the operation of
so fundamental a law, the balance of evidence seems corrobora-
tive. And, as regards the particular application in hand, there
is, I believe, no alternative hypothesis that explains muscular
action so satisfactorily. A decompounded molecule of muscle-
cell protein becomes, let us say, one hundred molecule of amino-
acids; and the osmotic pressure within the cell is increased a
hundred fold. The swelling and hardening of the muscle, with

58 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

associated contraction due to the arrangement of the cells in the
muscle-fiber sheath, is the tangible aggregate result. When the
ammo-acid molecules are recompounded into larger protein
molecules, their number and consequently their osmotic pressure
are correspondingly reduced, and the muscle relaxes.

Whatever the force of this parenthetical suggestion, however,
it is certain that osmotic action explains many of the funda-
mental processes of assimilation. It should be added, however,
that in a comprehensive view, the character of the cell wall itself
must not be overlooked. The permeability of this is an impor-
tant consideration ; and it has been found that the nature of the
medium in which it lies, notably with reference to mineral salts,
may greatly modify this permeability. At the moment, however,
this aspect of the subject need not be examined in detail.

It is obvious that our primitive bit of protoplasm, under the
shifting conditions of osmosis, expanding and contracting as por-
tions of its protein content are dissociated and re-formed, may
have acquired, by virtue of this principle alone, a certain function
of primitive motion. Granted a group of unstable carbon-nitro-
gen compounds encased in a cell wall, we have a primitive organ-
ism which may manifest the fundamental conditions of assimila-
tion and excretion.

The precise chemical composition of the cell-content making up
the body of this living organism, in connection with its funda-
mental proteins, will depend upon the chemical composition of
the medium in which it lives, and from which it absorbs matter,
and into which it excretes residual matter. And in any case
in which the mechanism of absorption and excretion of a given
cell-laboratory has reached a status of equilibrium, the intrusion
of any new chemical substance into the medium must serve as a
disturbing element.

Suppose that this disturbing element takes the form of another
organism, which has been accustomed to a different medium, and
hence which has developed a somewhat different chemical com-
position, to the extent at least of modifying the side-chains of its
protein molecule. Then, in the nature of the case, there must
be a certain antagonism between the two organisms. Each,
through its excretions, modifies somewhat the character of the
medium, and makes it in a sense an abnormal medium for the
other. Unless both organisms are able to modify somewhat their
previous mode of existence, finding a way either to assimilate
or to neutralize the abnormal elements now introduced into the
medium, they cannot survive.

If either of them does survive, that fact is proof positive
that the organism in question has found a way to adapt itself
to the new conditions. It has so adjusted and modified the

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 59

regular routine of its internal chemical processes, that the excre-
tions of the other organisms are no longer noxious to it. If we
choose, we may say that the organism has developed autobodies
or antitoxins against the offending neighbor organism. Thus it
would appear that the production of such antibodies must be
one of the most fundamental and primordial of life processes.
It is a function that is retained throughout the history of all
descendants of the protozoan, even to the remotest cell of the
highest organism.

The reason for this is not far to seek; for it is a familiar
axiom of the evolutionist that all life is a struggle; and it is
obvious that the developing organism must come constantly in
contact with other organisms. With each new one, the old
struggle must be renewed with slightly new aspects, and new
methods must be found to equalize the adverse conditions
introduced.

As the organism evolves to a multi-cellular condition, and de-
velops the various members and organs that mark the higher
animals, it will pass constantly to new environments and come
in contact with new enemies. Every time it encounters a new
type of food, be it vegetable or animal, it will present a new
problem to its chemical laboratory of the digestive and the
assimilative system. And unless this chemical laboratory proves
adequate to the new task put upon it, the organism will die.

It follows that every existing organism has been able to run
this gauntlet and to find a solution of the new problems pre-
sented to it.

In other words, every existing organism has learned to digest
and assimilate a great variety of proteins ; developing mechanisms
for neutralizing their poisons, until foods that were toxic have
now become wholesome.

In this view, it will be observed, there is no suggestion that
one kind of protein rather than another is poisonous. It is simply
that each specific type of protein is somewhat antagonistic to
organisms composed of any other type of protein. It is only a
cannibalistic protein diet that can be said to be intrinsically harm-
less. But cannibalism involves the penalty of probable race
extinction ; and so in the nature of things evolutionary all living
organisms have learned to feed on the protein of other races
of organisms, adapting their own metabolic processes until they
are able to deal effectively with the offending side-chains in the
foreign molecule. Such a process of adaptation requires time,
and we may take it for granted that foreign proteins are "whole-
some" to any given organism somewhat in proportion to the
length of time during which the ancestors of that organism have
been accustomed to ingest it. That any given protein food is

60 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

observed to be non-toxic is in itself proof positive that the organ-
ism is equipped with an immunizing mechanism adapted to deal
with the specific minor combinations of atoms that make up the
side-chain components of its protein molecules.

Nor does this apply exclusively to the proteins that we com-
monly think of as foods. It has equal application to the micro-
scopic proteid organisms. Thus bacteria are relatively harmless
if they are so abundant that the organisms of our ancestors have
dealt with them generation after generation ; contrariwise, they
are classed as toxic if they are comparatively rare, so that the
race has not developed a defensive mechanism against them.
Note, by way of illustration, that measles is a mild disease in
Europe and America, but becomes a very virulent one in Japan.
The presumption is that the germ of measles did not come in
contact with the ancestors of our race until a period subsequent
to that in which the Japanese stock had branched from the
western stock.

There is abundant evidence to show that any inherent habit
of action once fixed on a living organism is a perpetual endow-
ment, to be transmitted from one generation to another in per-
petuity (subject, in case of recently acquired characters, to elim-
ination in a certain proportion of the progeny through Mundelian
inheritance). So we may safely assume that when an organism
has learned to deal with any given protein in such a way as to
render it innocuous, the descendants of that organism will retain
the capacity to repeat the process indefinitely. It follows that
every higher organism can deal effectively — under proper condi-
tions and in restricted quantities — with all the different types of
proteins that have come in regular contact with its ancestors to
the remotest generations.

Thus is explained the familiar fact that each higher organism
can find nourishment in a great variety of foods ; coupled with
the fact that the blood plasma of the organism normally con-
tains the antidotes for a considerable number of bacterial poisons.

Of course this higher organism has become a very complex
mechanism, with many members, each specialized to perform a
particular function. As regards this function of combating the
noxious forces of the environment, the digestive system is pre-
eminent. But this system, in the broad view, is not so much
an inherent part of the organism, as an outer wall of defense so
placed as to make sure that in general no unmodified proteins shall
find their way through the mucous membrane fortifications. But
the organism cannot depend absolutely on this defensive mech-
anism, as we have just seen ; so it is necessary to have other
defenders on guard inside the walls. And it seems on its face
a plausible suggestion that the cell which retains most of the

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 61

character of the primitive primordial protozoal ancestor, and
which, so far as we can see, is not specialized to perform any
other function, is the one which has retained pre-eminently this
primordial capacity of harmonizing the organism with the living,
or, once living, elements of its environment.

Such a primitive cell is found in the leucocyte. No other cell
in the body retains so fully the primitive characteristics of the
protozoal ancestor. And, patroling everywhere the blood stream
which carries particles ingested from the outer world, the leuco-
cyte is most favorably situated to come immediately into contact
with intruding substances, and to take up with the least pos-
sible loss of time the work of so modifying them that they meet
the needs of the organism.

The leucocyte looks like an ameba, and it is seen to ingest
solid particles of food just as an ameba does. Can we doubt that
its chemical processes of digestion are closely comparable to those
of its prototype?

THE LEUCOCYTE AS A MICROCOSM

At the first thought, it might seem to strain probabilities to
the breaking point to suggest that a cell of such proportions as
the leucocyte could conceivably be the habitat of a series of chem-
ical substances so complex and varied as is here implied. But
a very brief consideration of the facts as to the size of mole-
cules and atoms, as placed at our disposal by the modern physicist,
dispels any such doubts.

It is known that the smallest particle visible under the micro-
scope is about one fifty-thousandth of a centimeter in diameter.
Cubing this number, we find that a cubic centimeter will contain
one hundred and twenty-five thousand billions of such particles.
But the researches of Rutherford, who has somewhat accurately
determined the size of the atom, show that a cubic centimeter
of space may contain twenty billion times that number of helium
atoms.

In other words, the smallest particle visible under the micro-
scope is large enough to contain many times twenty billion atoms ;
inasmuch as the atoms computed by Rutherford were in the gas-
eous condition, and hence very much more widely separated than
those in the solid particle under the microscope.

It appears, then, that if we were to assume that there are one
thousand different antibodies developed in the organism — each
one antagonistic to some specific type of protein — there is ample
opportunity for such a collection of antibodies in the smallest
particle of matter visible under the microscope, even if we assume
that each one of these antibodies is made up of at least twenty

62 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

million atoms. So even if the leucocyte were far smaller than
it is (for, of course, it is by no means at the limit of microscopic
visibility), its nucleus might be a very intricate structure indeed,
chemically considered — a chemical laboratory quite elaborate
enough to generate all the different types of antibody that the
system could conceivably require.

Each of these nascent antibodies, as lodged in the leucocyte,
may be supposed to represent a specific protein, capable of taking
to itself the right combination of atoms to increase in size and,
under proper conditions, to multiply indefinitely, to meet the
needs imposed by the intrusion of a particular type of toxic pro-
tein. In the ordinary course of events, doubtless, only a compara-
tively small number of the different types of antibodies in the
equipment of the leucocyte laboratory would be called upon to
come into action at a given time. It might even happen that
for long periods of time, even for generations, a particular type
of nascent antibody that has been developed in the cell might
not be called upon to meet and antagonize its specific antigen.

But what we know of the germ-cell, and of the possible qui-
escence of hereditary factors for successive generations, teaches
us that it may readily be possible for the cell to carry forward
during an indefinite period such unused increments of nascent
antidotes ; and yet to call them into action when the proper stim-
ulus comes, even though such stimulus has not hitherto been
applied for many human generations.

In this view, then, we may think of the cells that generate the
leucocyte as a storehouse in which minute quantities of large
numbers of different types of proteins are arranged, in what
may be called the nascent state, all of them with potentialities of
development, and a certain number of them constantly called
upon to meet the stimulus of external conditions in the form of
different types of protoplasms or proteids that, but for their aid,
would be poisonous to the organism in the blood stream of which
their daughter cells, the leucocyte, are liberated.

It is, of course, the mother cells, in bone marrow and spleen
and lymph node, that must be thought of as the permanent source
of supply of these nascent antibodies. For, of course, the devel-
oped leucocyte, once it has gone out from the parental abode, is
in a sense an independent organism, lying beyond the bounds of
the cellular system of the complex organism in the blood stream
of which it operates. The force of this view is very well illus-
trated in the familiar fact that when toxic bacteria are ingested
by a phagocytic leucocyte, these toxic bacteria are no longer able
to exert a malignant influence on the organism. For a time they
retain their normal form and appearance ; but the leucocyte, by

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 63

engulfing the intruder, has given entire protection to its human
host.

Let it be further recalled that this probably would not be true
of any cells other than the leucocytes in the entire organism.

This fact, taken by itself, gives strong corroboration to the
thought that the leucocyte is primarily and fundamentally a de-
tached organism, acting in close alliance with the animal body, but
being in a broad sense independent.

Of course, the same line of reasoning applies in considerable
measure to the red corpuscles as well. And, in both instances,
the general idea under consideration finds strong support in the
fact that the blood corpuscles of different mammals are histo-
logically so similar as to appear practically identical under the
microscope. Place a drop of guinea-pig's blood, for example,
and a drop of human blood, under the microscope, and not even
the trained hematologist can distinguish one set of corpuscles
from the other. Even as regards the numerical count, there is
striking similarity in case of the red corpuscles ; and the modi-
fications in leucocyte count, aggregate and differential, are such
as may readily be accounted for by long-established minor differ-
ence of dietetic habits — modifications, moreover, that may be
brought into strict conformity by fluctuations in the human leuco-
cyte count under conditions of slight abnormality.

Obviously, such conformity of corpuscular population in the
blood of mammals widely separated in the evolutionary scale,
suggests functions of very general and fundamental character,
responsive to environmental conditions universally distributed —
for example, foodstuffs substantially the same, and bacterial in-
vaders absolutely identical.

In this comprehensive view, then, we shall do well to get
away from the notion of virulent bacteria, and to think of all
the stages of assimilation and immunization as closely allied,
and as applying to proteins in general. In practice we must
recognize the virulence of certain types of bacteria; but we
shall do well to understand this virulence as conditioned merely
on the fact that the organism has come somewhat rarely in con-
tact with these particular microbes. There are myriads of bac-
teria always in the organism and these for the most part are
as innocuous as flecks of albumin, for the simple reason that
they have been so long with us that they have become domesti-
cated— that is to say, the body-tissues have become immunized
against them.

According to the Proteomorphic theory, as we have seen, such
immunization has resulted in part from the activities of the
leucocyte, through which the blood plasma has come to be con-
stantly permeated with antidotal chemicals.

64 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

ANTITOXINS AND NEW CHEMICAL PROBLEMS

There are certain types of these antidotal chemicals, however,
to which we have hitherto given scant attention. These are the
so-called antitoxins which are developed in the blood not neces-
sarily because of the presence of proteid bodies, but in response
to toxins that are themselves the product of protoplasmic activ-
ity. No organism can grow and develop without giving out waste
products that are poisonous to living protoplasm ; and the bac-
terium is no exception to the rule. So when it finds access to
the human system, it necessarily vitiates that system with its
waste products.

We ordinarily think of these as toxic properties that are put
out by the bacteria with the express design of injuring the human
body. But such a view is altogether anthropomorphic and mis-
taken. The so-called toxins are merely either (1) waste prod-
ucts, or (2) enzymes put forth by the bacteria to aid its own
digestive processes. But they may serve as virulent poisons to
the tissues of their host nevertheless — which is highly unfor-
tunate for the bacteria themselves, since death of their host will
in many cases mean death for them also.

Of course, the bacteria that are being digested by the leuco-
cyte give out such toxic principles, and it is necessary in over-
coming them to neutralize these toxins as well as to proteolize
the body of the bacterium itself. In this case, we may suppose,
the leucocyte adds antitoxins to its list of responsive enzymes,
along with the antibodies directly aimed against the proteid bodies
of the enemy. It is possible that opsonin is such an antitoxin.

But there are also cases in which the bacteria only lodge on
some surface of the body — say the throat — and use the vascular
channels as a sort of sewer into which to discharge their waste
products. The local injury may be very slight, the entire danger
to the organism resulting from the presence of the excretory
toxins, not to protein itself of any type. The colonization of the
diphtheria bacillus furnishes a typical illustration in point.

In such a case, as is well known, the body may be able to
produce chemicals that neutralize the toxins, thus saving the life
of the human organism. Moreover, these chemicals may be pro-
duced in such excess that the blood becomes more or less satu-
rated with them, giving the organism immunity to similar attacks
in the future, at least for a time. These neutralizing chemicals
are known as antitoxins. They are not necessarily poisonous
to the bacteria the toxin of which led to their development. The
diphtheria bacillus, for example, will grow and thrive in a me-
dium containing large quantities of diphtheria antitoxin.

Here, then, is a type of antibody that has not been developed

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 65

directly through the parenteral presence of a protoplasmic body.
And the question at once arises as to the source of this anti-
toxin. Is the leucocyte here as before the agent that guards
the body from the insidious attack?

The attempt to answer this question has proved more puzzling,
if possible, than the attempt to localize the mechanisms that an-
tagonize and give immunity to the bodies of the bacteria them-
selves. Most workers in the field leave the question quite unan-
swered. It suffices for them that the antitoxin is produced some-
where in the body, and that it ultimately permeates the serum
of the blood. But it is obvious that a satisfactory theory of
immunity must give us a far more definite answer.

In the opinion of the present writer, there are data at hand
that enable one to answer the question with a fair degree of
definiteness. It must be admitted, however, that these data do
not include unequivocal and demonstrative experiments, such
for example as the discovery of the antitoxin in some specific
tissues before it appeared in the blood serum. We must be
content with indirect evidence. This, however, is to say the
least highly suggestive, and its findings are full of interest. In
my opinion, they justify the belief that the chief agents in the
formation of antitoxins are the red blood corpuscles ; their efforts
being supplemented, however, on occasion, by the work of the
leucocytes on one hand and by the various body tissues on the
other.

The evidence is based very largely on experiments undertaken
for a quite different purpose and having to do with the hydrolysis
and synthesis of proteids. In particular the work of Emil Fischer
and his pupils has given the clue, although, so far as I am aware,
no one had attempted to interpret or follow it up until this was
done in my original presentation of the Proteomorphic theory in
American Medicine of October and November, 1914.

To gain an inkling of the import of this work, in the present
connection, we must very briefly summarize some of its impor-
tant findings as to proteolysis. The most significant of these ex-
periments, from the present standpoint, are those in which Abder-
halden has tested the capacity of enzymes excerpted from differ-
ent bodily tissues to hydrolyze various synthetic polypeptids. The
polypeptids were so named by Fischer to indicate their relation-
ship with peptones. It is believed that the peptones (as hydro-
lyzed from protein through the medium of proteoses) consist
of a chemical aggregation of various polypeptids. Stated other-
wise, polypeptids would result from the cleavage of peptones;
although in point of fact those experimented with were syn-
thesized in the laboratory by the combination of various amino-
acids.

66 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

The simplest polypeptids (di-peptids) result from the union
of two amino-acids; more complex ones from the combination
of three or four or five amino-acids. The molecule of a poly-
peptid is, therefore, complex as compared with the molecule of
an amino-acid ; but, on the other hand, it is relatively simple as
compared with the molecule of peptone. In other words, a mole-
cule of peptone could be cleaved, perhaps by successive stages,
to form a goodly number of molecules of the most complex poly-
peptids yet synthesized.

It is important to get clearly in mind this position of the poly-
peptids as nitrogenous compounds, which are considerably more
complex than amino-acids, and yet very simple indeed as com-
pared even with peptones, which in turn have but a fraction of
the complexity of the original protein from which they are hydro-
lyzed. There are some thousands of atoms in a molecule of pro-
tein ; some hundreds in a molecule of peptone ; some scores in a
molecule of the more complex polypeptids ; and, as we have
seen, less than two dozen in the molecule of an average amino-
acid.

It is familiarly known that the giant protein molecule which
comes into the stomach as the chief constituent of proteid foods
is hydrolyzed and disintegrated to the peptone stage (via pro-
teoses) by the enzymes of the digestive tract. Just what happens
to the peptone after it is absorbed into the intestinal wall has
been a matter of dispute. There is no question that it is further
metamorphosed, for it does not appear as peptone under normal
conditions in the blood stream. The balance of authority lends
strong support to the belief that the peptone is further hydro-
lyzed in the intestinal wall, until its molecules reach or approx-
imate a degree of smallness that makes them available for the
use of the various body-cells to which they will presently be
carried by the blood stream. It seems highly probable that they
enter the blood as amino-acids, of various types, and are thus
carried to the tissues as dispensers of building materials, among
which each individual type of cell may select in accordance with
its needs — for the different body proteins are made up of dif-
ferent combinations of amino-acids.

But we have seen in our earlier discussions that it happens on
occasion that portions of the proteins taken into the stomach
find their way through the intestinal wall unmodified, or not
greatly modified, by the digestive ferments, and introduce a com-
plication in the problem of assimilation ; a complication which,
according to our thesis, is met by the activities of the leucocyte.
If the gigantic molecule of protein thus finds its way on occa-
sion through the intestinal wall, it seems plausible to suppose
that the comparatively small molecules of the polypeptid order

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 67

must make similar entrance into the blood stream even more
frequently. But if such is the case, we may fairly assume that
means will be found there to effect further hydrolyses in the
fluids of the body. And, in point of fact, experiments have
shown that when certain polypeptids are artificially introduced
into the blood stream of animals, they may fail to appear in
the excretions, proving that they have been metamorphosed in
the body. Abderhalden found that a considerable number of the
polypeptids might thus be utilized by the organism of a dog.

Obviously, then, there may be developed within the body tis-
sues or in the blood stream enzymes capable of hydrolyzing the
polypeptid molecule — a molecule, be it understood, which the
combined juices of the stomach and pancreas and duodenum,
under ordinary circumstances, are unable completely to cleave
or break down.

The interesting question arises as to what particular tissue or
tissues of the body accomplish this remarkable feat.

Abderhalden set himself the task of experimentally answering
this question. In conjunction with Pernuchi, Hunter, and Rona,
he prepared extracts and juices of various organs, using Buch-
ner's method of grinding up with sand and expressing the juices
under a pressure of one hundred to three hundred atmospheres,
by which method the cell enzymes are obtained. The tissues
thus treated included the liver, the kidney, and the muscles of
rabbits and dogs ; lenses from the eyes of pigs ; the brain of the
calf; blood serum of ox, rabbit, and dog; and blood corpuscles
of various types. Different types of polypeptids were used, to
test the selective affinities of the various enzymes.

It was found that the juices of each and all of the tissues
just named (as also juices of germinating wheat, germinating
lupine, the mushroom, and various moulds) contain enzymes that
hydrolyze one or another of the polypeptids; each juice, as a
rule, acting on several different types of polypeptids. Juices of
liver, kidney, and muscle hydrolyzed the simpler polypeptids. The
plasma and serum of the blood both hydrolyzed complex types of
polypeptids, which are known not to be attacked by trypsin,
proving that the blood fluids did not receive their enzymes by
absorption from the intestinal tract.

But, in any event, it was needless to look far afield for the
origin of the enzymes in the blood fluids, inasmuch as the juices
expressed from the red blood corpuscles proved capable of hydro-
lyzing the most complex polypeptids.

The leucocytes of a horse, on the other hand, failed to hydro-
lyze a polypeptid which the red blood corpuscles of the horse,
and also the blood platelets, hydrolyzed actively. -Blood plate-

68 THE PROTEOMORPHlC THEORY AND THE NEW MEDICINE

lets, there is reason to believe, are only extruded contents of red
corpuscles.

It may fairly be concluded, then, that the hydrolyzing of poly-
peptids that find their way into the blood stream may be accom-
plished by enzymes secreted by various organs and tissues, includ-
ing the muscles; that the red blood corpuscles are very active
agents in this capacity, notably, perhaps, with regard to the
most complex polypeptids ; and that it does not fall within the
range of the activities of the leucocyte to deal with these com-
paratively simple nitrogen compounds. The leucocyte, like the
organs that produce the digestive ferment of the intestine, acts
on the full-sized protein molecule, and begins its cleavage. But
in the light of the new evidence, it may somewhat be doubted
whether the leucocyte is able to carry on this cleavage to its
final conclusion. It is at least possible that the protein molecules,
multiplied by cleavage, acquired an osmotic pressure that causes
the disruption of the leucocyte when the polypeptid stage of hy-
drolysis has been reached. If such is the case, the autolyzed
leucocyte would discharge its contents in the midst of myriads
of red blood corpuscles capable of taking up the work of hydro-
lysis where the leucocyte left it, and completing the cleavage of
polypeptids into amino-acids.

According to the hypothesis already expounded, it would be
only comparatively small quantities of foreign protein that would
thus come under the auspices of the leucocyte ; but it is not un-
likely that considerable quantities of polypeptids may find their
way habitually into the blood stream ; and it is to be recalled
that the red corpuscles, marshaled in numbers not far from a
thousand times as great as the number of leucocytes, should be
able to deal with the polypeptids in almost any quantity.

It is even conceivable that all the protein foodstuffs are ab-
sorbed in this state (since the evidence for their change into
amino-acids in the intestinal wall is not quite conclusive), and
normally undergo their final stages of hydrolysis under influence
of the erythrocytic enzymes ; the tissues of the liver and brain
and muscle standing guard meantime in the background, as it
were, ready to attack (each within the limits of its capacity)
any portions of polypeptids that escape the militant army of red
corpuscles. The numbers and aggregate bulk of the red cor-
puscles suggest their possible capacity to accomplish such a task.

These experiments, then, enable us to form a more complete
and more satisfying mental picture of the processes of digestion
and assimilation than has ever hitherto been possible. We shall
be able to fill out certain gaps in the picture as we proceed, ulti-
mately presenting at least a suggestive scheme of the entire cycle
of protein metabolism in the body.

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 69

NEW EXPERIMENTAL EVIDENCE

The above exposition of the theory of proteolytic activities
of the red corpuscles is reproduced precisely as it was presented
in the original exposition of the Proteomorphic Theory in Amer-
ican Medicine of October, 1914. It will be obvious that the
hitherto unsuspected function thus ascribed to the red corpuscles
matches in importance, if its validity is demonstrated, the function
of carrying oxygen to the tissues — each being absolutely essen-
tial to the life of the individual. The subject having such funda-
mental importance, then, it will be of interest to cite here a
series of experiments made about two years later, which give
strong support to the theory of erythrocytic polypeptid digestion.

The experiments in question have to do with the distribution
of the residual nitrogen between the blood cells and the plasms,
originally published in the Biochemische Zeitschrift, as reported
in Physiological Abstracts (published by the Physiological Society
of Great Britain and Ireland with the co-operation of the Amer-
ican Physiological Society) in the tissue of October, 1916. The
experimenter was Dr. Ivar Bang. The abstract is as follows:

"The residual and urea nitrogen in the blood and plasma were
determined in well-nourished rabbits before and after a seven-
day fast during which no water was given. The amino-acid frac-
tion was represented by the difference between the residual and
urea nitrogen. In accordance with the findings of earlier experi-
ments, an increase in residual nitrogen occurred after the fast
which concerned the urea fraction only. Before the fast urea
was equally distributed between the cells and the plasma, while
the cells were richer than the plasma in amino-acid; these rela-
tions persisted after the fast.

"After the introduction of a solution containing two to three
grams of glycine into the bowel, there was an increase in the
residual nitrogen of the blood, which affected the amino-acid frac-
tion almost exclusively. The increase was confined to the plasma,
and hence the amino-acid content of the blood cells is probably
formed in the cells themselves."

It will be observed that "blood cells" as a whole are here
referred to, with no specific reference to the red cells. But the
fact that the latter are about one thousand times as numerous as
the leucocytes, constituting the main bulk of the formed matter
of blood, makes it highly probable that the amino-acids in ques-
tion were contained very largely at any rate in the eryphrocytes.

Such experimental proof of the completion of protein hydroly-
sis in the corpuscles is interesting from a theoretical standpoint,

70 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

but doubly so from the practical standpoint of the physician ad-
ministering proteins therapeutically. There remains little doubt
that the red corpuscles are an essential part of the mechanism
through which intruding proteins are ultimately reduced to innoc-
uous amino-acids.

It becomes necessary, then, to watch the red corpuscles no less
than the white ones as an aid to the interpretation of the patient's
progress. Not merely their numbers, but their qualitative condi-
tions should be considered— the presence of normoblasts, megalo-
blasts, poikailocytes, crenated and friable cells, and the like should
be closely observed, as giving clues to the regulation of dosage,
a change of frequency of administration, or a modification of the
type of proteal employed.

The fact that the proteals produce rapid and significant modi-
fications in the number and character of the red cells has been
too frequently observed to be matter of doubt.

The subject has obvious importance, from the standpoint of
the practical physician, as will appear when we take up the ques-
tion of the therapeutic protein response in later chapters.

THE RED CORPUSCLE AS MASTER IMMUNIZER

But where, it will naturally be asked, is the point of contact
between this scheme of polypeptid digestion and the develop-
ment of antitoxins?

The answer is this: The bacterial toxins that evoke the re-
sponsive antitoxins are products of protoplasmic activities ; and
they are known to be comparatively simple in chemical composi-
tion, their molecules being in all probability of the same order of
complexity as the molecules of polypeptids. It is a fair presump-
tion that the bodily enzymes proved to act on the polypeptids
are the ones that act also on these allied bacterial toxins.

If the inference is justified, the sources of the antitoxins are
clearly revealed : They are the cells of the entire body, each type
having a selective action of its own; and, in all probability, the
red blood corpuscles being the ones that have the most general
and the most comprehensive activities in this connection.

Now it is obvious that so bold an assumption as this requires
all the support that can be found for it in analogical reasoning.
Fortunately there are several lines of such reasoning that supply
confirmatory evidence.

Thus, bearing in mind the nitrogenous character of the waste
products of protoplasmic action in the animal organism (for
example urea, with the formula CH4N2), we are justified in
assuming that the toxic principles given out by the virulent bac-
teria are not altogether dissimilar nitrogenous compounds. This

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 71

assumption is strongly supported by the observed similarity of
action of these toxins and sundry narcotic drugs of the familiar
alkaloids. And these alkaloids have known chemical formulae
that at once reveal their chemical relationship with the poly-
peptids.

Morphine, for example, is C17H19NO3 ; strychnine is
C21H22N2O2 ; and glycyl-glycine, the simplest of the polypeptids
has the formula C8H16N4O6. If we knew how to combine the
amino-acid called valine (C^uNC^) with the amino-acid called
leucine (C6H13NO2), we should have a molecule with the compo-
sition C11H24N2O4, in still closer simulation of the strychnine
molecule. The combination of two molecules of the amino-acid,
glycine with one of leucine, which has been effected, gives the
formula C17H33N3O7.

Of course, we can by no means assume that because the com-
binations of atoms in a given pair of molecules are similar the
gross physiological effects of these molecules on the organism will
be identical or even comparable. To disprove any such hypoth-
esis, nothing more would be necessary than to consider the chem-
ical composition of certain other alkaloids, for example quinine,
which, with its formula C20H24N2O2 seems to have close touch
with strychnine ; yet which, as every tyro in medicine knows, is
very fundamentally different in its physiological action.

It should be understood, however, that in the modern view a
drug acts on only those tissues with which it can enter into
chemical union ; and that the markedly different physiological
actions of drugs depends upon the affinity for them shown by this
or that type of cell in the tissues of the body. Quinine and strych-
nine appear to us radically different drugs, because their effects
on the human system are so conspicuously diverse ; yet their
chemical composition proves their close similarity; and a rea-
sonable explanation of the difference in their effect is given if
we assume that the precise combination of "side-chains" in the
strychnine molecule chances to fit in with the scheme of the
molecules making up the substance of the central tissue of the
brain; whereas the side-chains of the quinine will link it with
other tissues that are in themselves no less profoundly affected
than are the brain tissues by strychnine ; but which are not so
vitally and intimately associated with the life-processes of the
organism as a whole.

It is in the fact that most alkaloids, in common with toxins,
find their affinities in the cells of brain and spinal cord that the
seeming toxicity of these substances lies. Many a "harmless"
compound may affect muscle cells, let us say, far more pro-
foundly than the brain cells are affected by morphine or strych-
nine, yet have no "toxic" effect, because the muscles do not

72 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

contain the centers of cardiac and respiratory control, as do the
nervous centers.

Considered in this broad way, there is ample justification for
the belief that the physiological activities of all drugs are inti-
mately linked with their chemical composition ; and that, in the
sense just interpreted, drugs of closely similar chemical compo-
sition have strictly analogous effects.

But everything depends upon the particular tissue cell which
chances to have affinity for any given drug ; and the experiments
of Abderhalden as already cited, showing the elective affinities
of different tissues for polypeptids, may be considered as labora-
tory interpretations of familiar facts of clinical medicine. The
fact that many alkaloids and such poisons as that of B. tetanus,
and, indeed most of the, bacterial toxins, give evidence of affecting
the brain, dove-tails, at least presumptively, with the highly inter-
esting experiments that show that two of the most complex of
the polypeptids were hydrolyzed by the juices expressed from
the brain cells of a calf.

It may be added that in the case of two less complex types of
polypeptids, the juices of the calf-brain failed to act; and con-
ceivably it is not stretching analogies too far if we observe that
the alkaloids which are known to have a pronounced cerebral effect
are considerably more complex, particularly as regards their car-
bon and hydrogen atoms, than the simpler (di-amino) polypep-
tids; and if we associate relative complexity of molecular struc-
ture in a drug with affinity for the cerebral tissue, in itself
presumably the most complex of organic bodies.
. Such a conception must be held with great reserve, however,
in view of the extraordinary toxicity of the simple combinations
CS2, carbon bisulphide, and HNC, prussic acid, and of the con-
flicting evidence elicited by observation that, whereas nitriles of
the fatty series, from acetonitrile to isovaleronitrile, increase in
toxicity with growing molecular weight, substances of an allied
series, starting with cyanacetic methyl ester, C4HBHO2, become
less toxic (according to Berthe and Ferre) with increased com-
plexity, losing toxicity altogether when two groups of C2H5O2 are
inserted. A clue will perhaps be found in the study of the
valencies of the nitrogen atom, which, as is familiarly known,
is either trivalent or quinquevalent.

SPECIFIC AFFINITIES AND ANTAGONISMS

Closely in keeping with these rather abstruse theoretical con-
siderations are the familiar and very practical experiments of
Pasteur through which the anti-rabic virus was developed. Here,
as is well known, the material used for making the protective

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 73

inoculation is found in the spinal cord of a rabbit that has been
successively inoculated with the virus of rabies.

Equally suggestive in their way were the experiments of Was-
sermann, who mixed tetanus toxin with the brain substance of
a susceptible guinea pig and found that the mixture was no longer
toxic for other guinea pigs. This seemed to show a special
affinity between the brain substance and the toxin, inasmuch as
emulsions of other organs of the guinea pig when brought in
contact with the tetanus toxin exerted no such effect. "It would
appear from this experiment," says Nuttall, "that a toxin may
have a special affinity for special tissue cells, and this appears
to explain the neuro-toxic character of the symptoms which are
observed in tetanus."

It would be better, perhaps, to say that certain cells have an
elective affinity for the toxin, rather than to make the converse
statement; best of all to think of the attractions as mutual. In
chemical terminology some cells have side-chain groups of mole-
cules for which the molecules of the toxin can readily be sub-
stituted ; or with which they may be combined through a new
arrangement of the atoms. What determines these affinities we
shall not know until we are better informed as to the ultimate
nature of chemical valences in general ; but for the present pur-
poses it suffices to note the seeming demonstration that such
elective affinities exist, and that they are exercised by various
tissue cells of the body in connection with an endless variety
of nitrogen compounds.

Another very striking illustration of such elective affinities,
in this case involving the muscle cells of the unstriped muscles,
is furnished by the amino-acid-like product, known as adrenalin.

The origin of this product in the supra-renal glands, and its
extraordinary effect in constricting arterioles, are familiar to the
profession. But it may not be so generally known that adren-
alin differs by only two hydrogen atoms in chemical composi-
tion from one of the familiar amino-acids named tyrosine. Such,
however, is the fact, the formula of tyrosine being CgN^NOg,
and that of adrenalin C9H13NO3. That adrenalin exercises its
contractile function by directly influencing the muscle fibers of
the arterioles is shown by the continuance of its characteristic
action when applied locally after severance of the nerves leading
to the tissue under treatment. Let it be observed, too, that it is
the cells of the unstriped muscles alone that seize on the adren-
alin molecule; the cells of other muscles seeming to let it pass
unnoticed.

When we add that adrenalin exists normally in the blood only
in the proportion of one part in a million, yet that its presence

74 THE PROTEOMORFHIC THEORY AND THE NEW MEDICINE

in this infinitesimal quantity seems necessary to the very life of
the organism, light is thrown from yet another direction on the
intricate co-ordinations of the animal machine as effected with
the aid of the nitrogen-bearing molecule.

Here is a substance which, were we able to remove but two
of its hydrogen atoms, would become merely a commonplace
member of the group of amino-acids, ready to be taken up by
this, that, or the other tissues of the body, as a component part
of its protein ; and yet, in virtue of the presence of those two
supernumerary hydrogen atoms, it gains special affinity for cells
of a particular type, and causes those cells, in recombining their
structural materials, to undergo a destructive metabolism of
an almost explosive type which finds 'tangible expression in a
muscular contraction.

Could we look into the structure of the muscle cells during
this time of its explosive activity, with vision more ultra-micro-
scopic than is afforded by any instrument yet devised, we should
see that the cell, in readjusting its molecules, has some left-over
materials, like the shavings and sawdust of a carpenter, that
are not needed in the new combinations; and that these left-
over products are excreted into the surrounding fluid medium.
And what is true of the muscle cell under these circumstances
is equally true of every other muscle cell whenever it contracts
from whatever cause, and of the cells of every other bodily tissue
when they undergo characteristic activities. Changes in the molec-
ular structure of the cell — incident to or underlying all activity —
are affected only at the expense of potential energy, and with
actual gain or lo'ss of physical material. Destructive metamor-
phoses, which attend the active functioning of all tissues, are
attended by a loss of substance. And it is almost axiomatic to
say that the precise character of the substance given out as a
waste product or a by-product must be dependent on the char-
acter of the substance available to replace it. On occasion there
comes to hand, let us say, a group of atoms that is admirably
suited to fit into the structure of the molecule of the cell, pro-
vided that another group similar in character, but, on the whole,
somewhat less satisfactory is excluded. So the substitution is
made, and the discarded group of atoms flows away in the blood
stream.

It is obvious that groups of atoms that can thus be substituted
one for the other may bear to each other a certain complementary
relation. It is one way of expressing this relation to say that
the intruding molecule is an antigen, and that the extruded one
is an antibody. In view of the mutual relations of these struc-
tures, it does not seem strange that members of the two clans,
when they chance to meet in the blood stream, can enter into

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 75

mutual combinations. Two groups of atoms' each of which can
unite with a third group may very well unite with each other.
But when the antigen has thus combined with an antibody, it
no longer has free valences, and so it cannot combine with the
cell that it formerly would have entered. In the event that the
particular antigen in question was the kind of plotoplasmic prod-
uct that we call a toxin, we may well enough call the antibody
an antitoxin ; and we may speak of the union of the two as
neutralizing the poison and rendering it harmless. But this, of
course, applies only to exceptional instances in which the antigen
had properties that made its presence objectionable in the cell
with which it has affinity. Most antigens that would ordinarily
be found in the body have not such harmful properties, and their
antibodies, although acting in the same way, would not serve
the same purpose.

But at the moment, of course, I have specifically in mind the
antigens that are toxic ; and their specific antibodies are the anti-
toxins. And the purport of the present phase of the discus-
sion is, it will be recalled, to make it seem plausible, on various
analogical grounds, that each and every living cell of the body
must on occasion take to itself what we may call antigens, and
give out what we may call antibodies ; and that the particular
tissues that can produce antibodies in response to any given
toxins are precisely those tissues that are receptive to the inva-
sion of that toxin.

If the toxin be one for which the brain tissues have pre-
eminent affinity, the antitoxin produced will come from the brain
cells. If the toxin be one attacking the liver, the liver cells
will furnish the antitoxin.

However specialized any cell may be to perform pre-eminently
a particular function through division of labor in the entire body
every cell must retain the primitive capacity to take in nourish-
ment and give out excrementitious products, else it obviously
could not maintain existence. And it is conceived that the pro-
duction of an antitoxin in response to a toxin that the cell can
absorb is merely a special manifestation of this primal and funda-
mental function.

The bacterial toxins are, according to the present hypothesis,
relatively simple nitrogen compounds of a type suitable for com-
bination with various of the body cells — not distantly related to
the amino-acids ; the production of complementary bodies or anti-
toxins by these body cells, under these conditions, may be said
to be a commonplace of physiological activity — though sharing,
of course, in the inscrutability that attaches to all chemical
processes.

76 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

Loss AND GAIN THROUGH THE DIVISION OF LABOR

But the reader who would clearly apprehend the bearings of
the theory of immunity thus exposited must on no account fail
to note the exact terms of this definition just given. The anti-
toxins, in this view, are produced by various and sundry of
the body-cells, because these antibodies are evoked in response
to the coming of toxins that are relatively simple nitrogenous
compounds. When, however, the antigen that comes is not a
by-product of protoplasmic activity, but the protoplasm itself
as evidenced in the body of a bacterium or in molecules of un-
broken protein in any form, the case is quite altered, because the
body-cells in general are not adapted to absorb such materials.
Their location in the body, shielded by encompassing walls of
skin and mucous membrane, puts them out of contact with such
crude raw materials, the transformation of which has been turned
over to an especially adapted apparatus known as the digestive
system.

Each cell must retain the capacity to take food ; but it may
have lost the capacity to imbibe this food in a crude or undi-
gested form.

Such is indeed the condition of the specialized cells of the brain
and muscles and of the parenteral organs in general. The pen-
alty of their specialization is that each of them, while gaining in
one feature, has lost in various others. The single speck of
protoplasm that constituted the entire structure of the primor-
dial protozoal ancestor was at once stomach and muscular sys-
tem and circulatory apparatus and brain. But in the developed
organism each individual cell retains only the faint reminiscence
of each type of function except the one for which it has been
especially developed ; and this one it can carry out in exaggerated
fashion. The particular cells that have made themselves mas-
ters of that department of the work which has to do with the
ingestion of food and the splitting up of proteins is called the
digestive apparatus ; and its work is supplemented, we have found
reason to believe, by the leucocytes and erythrocytes.

But when, as occasionally happens through inadvertence, a
considerable quantity of protein in the unbroken form makes its
way into the circulation and comes thus (unmodified) in contact
with the body-cells in general, it is as useless to these cells as
if it were composed of utterly unassimilable materials.

The proof of this is that proteins thus introduced in quantity
are excreted unchanged through the kidneys. The leucocytes and
erythrocytes, to be sure, deal with part of this foreign protein;
but their capacity is limited, and beyond that nothing remains but
to eliminate the foreign substance as rapidly as possible. In

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 77

case this cannot be accomplished, the protein which might, under
other conditions, be invaluable as food for the tissues becomes a
menace through a mechanical clogging of the spaces about the
cells, and perhaps through the accumulation of partially meta-
morphosed product as the result of the activity of the leucocyte.
Antibodies quite different from antitoxins will be developed by
the leucocytes; but, of course, these can avail only if the foreign
proteins come in relatively limited quantity.

Making an anticipatory therapeutic application, it is clear that
the ideal to be aimed at when proteins are introduced hypodermi-
cally (as in Proteal therapy), is to give the dose that will evoke
a maximum corpuscular response with a minimum introduction of
foreign proteins that must themselves be proteolyzed. Whether
this may best be accomplished by using a single foreign protein
or by combining a number of such proteins is an important prac-
tical question that will be discussed later in this volume.

So much by way of recapitulation, and to make clear the dis-
tinction that I conceive to exist between the sources and the
character of the antibodies as evoked by antigens that on one
hand are protein bodies and on the other are the metamorphosed
products of protoplasmic activity — so-called toxins.

THE COALITION BETWEEN RED CORPUSCLES AND WHITE

Reverting now to the latter, in continuance of the theme, it
remains only to point out that, whereas it is conceived that all
the cells of all the tissues of the body have capacity for the
production of antitoxins in response to small moleculed toxins,
it would appear that there is one type of cell that is pre-eminently
adapted, by virtue of its location in the organism, to absorb these
toxins and render them innocuous ; at the same time, of course,
giving out the residual products which we term antitoxins. The
cells in question are the red corpuscles of the blood.

A very prominent function of these cells, according to the pres-
ent thesis, is thus to shield the body-cells in general against the
attacks of the numerous toxins that necessarily, under existing
conditions, find their way more or less continuously into the blood
stream. In particular, to shield the brain cells, because they take
(in Abderhalden's experiments) the same type of complex nitro-
gen compounds that have affinity for the cerebral tissues. Ordi-
narily the red corpuscles come in contact with them first, and
thus the brain is protected.

As justification for the conclusion, we have the entire line of
analogical reasoning just presented, supported specifically by the
experiments of Abderhalden, which showed, it will be recalled,
that the red blood corpuscles manifested exceptional activity in

78 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

the proteolysis of those polypeptids which I have all along likened
to the toxins.

Of course, the specific antitoxins developed by the red blood
corpuscles would, in the nature of things, be liberated into the
blood plasma. But there would doubtless be a good many com-
pounds formed that could not advantageously be thus disposed
of; and possibly it is to meet the complications thus introduced
that the body has developed the custom of destroying vast quan-
tities of the red blood corpuscles constantly in the liver, where
the refuse matter they contain may be promptly eliminated in the
form of bile. It may be doubted whether any other hypothesis
hitherto presented more plausibly accounts for the constant de-
struction of red blood corpuscles (estimated to represent about
three per cent, of the entire corpuscular supply daily), which,
at first blush, seems to set at defiance the usual bodily custom
of conserving materials.

In this view, then, the red blood corpuscles have an immuniz-
ing function strictly complementary to that of the white blood
corpuscles, and no less important. One legion of cells co-operates
with the other, each having its own special field. The white
corpuscle deals with all formed bodies and full-sized protein
molecules of foreign type that make their way into the blood
.stream. The red blood corpuscle deals with the later cleavage
products of protoplasmic activity. In carrying out their respec-
tive tasks, the leucocyte supplements the work of the ferments
of the digestive tract; the red corpuscle supplements the work
of the leucocyte and relieves the ultimate tissues in considerable
measure of the task of protecting themselves against small-
moleculed nitrogenous end products that might prove harmful.

Interpreting the work in the words of the bacteriologist and
pathologist, we may say that the leucocyte, in the pursuance of
its general scavengering function, produces "complement" that is
a digestive ferment somewhat of the order of trypsin; and
"antibodies" of the types known as bactericides, bacteriolysins,
opsonins, and precipitins; also antitoxins to neutralize the of-
fensive or defensive toxins put forth by the living bacterium.
Meantime the red blood corpuscles, aided and supported on occa-
sion by various and sundry of the specialized tissues — liver, kid-
ney, muscle, brain — produce complements of a different order
from those produced by the leucocyte, capable of dealing only
with partially hydrolyzed protein products ; and produce also
specific antitoxins that chemically neutralize bacterial toxins and
in particular the final by-products of bacterial decompounding,
but do not attack the bacteria themselves. It is not unlikely
that hemolysis also falls within the scope of the erythrocytic
activities.

MECHANISM OF PROTEIN HYDROLYSIS AND IMMUNIZATION 79

If the implications of the theory are clearly grasped, it will
be obvious that, according to the present view, there is no funda-
mental distinction between the various "complements" and "anti-
bodies" thus defined. The word "complement" as commonly
used merely serves to define such members of an endless series
of ferments as are relatively susceptible to the influence of high
temperatures. The line of demarcation thus established has ob-
vious practical value ; but we should not be led thereby to imag-
ine a duality of action which in all probability does not exist in
fact.

What we term "complement" in any given case is the ferment
or combination of ferments regularly developed in quantity by
the cell in question to meet the more or less habitual needs inci-
dent to the ingestion of proteins of its environment. What we
term an "antibody" in any given case is one of a series of fer-
ments developed in response to a specific impulse given by an
individual type of protein or protein product. The trypsin of
the leucocyte would stand at one end of that scale; the anti-
toxins of the red corpuscle at the other; but there would be
intermediate forms to cover all the field between the two, each
enzyme doubtless overlapping more or less with its neighbors.

That the general ferments or complements should be themola-
bile and the antibodies relatively thermostable may conceivably
be due to the greater complexity of the former, consistent with
their more generalized function. But that there is any radical
and fundamental distinction in "the nature of the two types of
structures seems theoretically improbable.

The demonstration or refutation of the validity of this assump-
tion, however, is a matter for the chemistry of the future, with
its extended knowledge of the nature of enzymes in general.

CHAPTER II
THE PROTEOLYTIC MECHANISM IN OPERATION.

Such, then, is the immunizing mechanism of the body as I
conceive it: (1) a system of lymphoid tissues, comprising lym-
phatics, bone marrow, and spleen, and sending into the field
legions of leucocytes and still greater legions of red corpuscles
to support them; (2) body-cells of many types standing in the
background, each equipped only for individual defense; and (3)
the liver and kidneys as the chief excretory organs of the by-
products of the conflict. This is the system which guards the
body from within, as skin and mucous membrane guard it from
without, against the intrusion of foreign proteins of every type,
and against the products of proteid activity.

Some further details as to manner of working of this impor-
tant mechanism may perhaps be presented to best advantage if we
make inquiry as to precisely what takes place on the various
occasions when the efficacy of the defensive mechanism is put
to an exceptional and decisive test.

Let us assume a case in which a few molecules of unbroken
protoplasm have found their way through the intestinal wall —
evading the pepsin and trypsin and erepsin of the digestive tract
— and enter the blood stream. This is not a strictly normal oc-
currence, to be sure, but it must be a very common one, under
slightly maladjusted conditions of digestion, as the experiments
already cited show. In these experiments the proteins proved
thus to enter the circulation unbroken, including those of egg
albumen, blood serum, and milk. So we may fairly assume that
any of the ordinary food proteins may on rather frequent occa-
sions find their way in small quantities into the blood stream.
We have now to inquire what happens to them there.

The inquiry has practical interest for the clinicism no less than
for the physiologist, because it is obvious that it applies equally
to the bodily activities responsive to the therapeutic introduc-
tion of a foreign protein, through the hypodermic injection of a
serum or vaccine or proteal. There are very important quanti-
tative differences, however, evidenced in the varying degrees of
toxicity, as interpreted by the clinicism.

Let us first consider the case in which the introducing protein

comes through the intestinal wall, through partial failure of the

normal digestive enzymes. Then, according to assumption, the

protein is a mere fragment of a normal food stuff; but it is a

80

THE PROTEOLYTIC MECHANISM IN OPERATION 81

disturbing element in its present location. According to the
theory here presented, what happens to it is this : the leucocytes
having had to deal with this particular type of protoplasm many
times before have already secreted into the blood serum an
enzyme (allied to trypsin) that is capable of attacking the pro-
tein and accomplishing the early stages of its proteolysis. This
process will be facilitated if the molecules of foreign protoplasm
chances to be engulfed in the body of a leucocyte. But in any
event the leucocytic enzymes will hydrolyze the protein to the
peptone stage; conceivably to the stage of polypeptids.

At this stage the partially hydrolyzed foreign protein is turned
over to the red blood corpuscles. To them these particular
polypeptids are familiar materials, since they have dealt with
their like often enough before, and the particular department of
their enzymes-making apparatus that will deal with these specific
polypeptids is in good working order; indeed, the enzymic prod-
ucts are already in the blood stream. So the further hydrolysis of
the intruding matter is rapidly carried forward ; with the result
that presently the main bulk of the material has been transformed
into amino-acids — thus supplying normal material for the uses
of the cells that are to build up the specific body proteins.

We must suppose, however, that there is a small residual mat-
ter, of doubtful constitution, which has not been thus hydrolyzed ;
for the complete hydrolyzation of a protein through the agency
of enzymes has not been accomplished in the laboratory, and we
have no reason to suppose that it is accomplished in the body.
It requires from two to five hours of digestion in strong hydro-
chloric acid to hydrolyze protein completely in vitro; the organ-
ism has no enzymes of corresponding power.

But, according to hypothesis, the residual molecules, whatever
their exact nature (uric acid, urea, bilurubin), have been largely
or perhaps exclusively developed in the bodies of the red cor-
puscles ; with the result that the corpuscles themselves are more
or less damaged. The residual molecules, that is to say, are
poisonous to protoplasm. The red corpuscle in retaining or ab-
sorbing them is thus injuring itself, but protecting the body-cells
that would otherwise absorb the poison.

But whereas such an injury to the body-cells would be highly
detrimental to the entire organism, the injury to the red blood
corpuscle is not necessarily a matter oj consequence. The cor-
puscle bearing its poison is whirled on in the blood stream until
it comes to the liver, and there destroyed, its noxious molecules
being discharged, with countless others of similar origin, into
the bile duct.

It would be interesting to inquire as to just what is the char-

82 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

acter of the physiological action that leads to the destruction
of the red corpuscle, but this would carry us too far afield.

Conceivably osmotic pressure alone may suffice ; the substance
of the hemoglobin being in part decompounded by the imbibed
foreign enzymes, and its osmotic pressure thus enhanced. Rup-
ture would then be likely to take place in the liver, because that
organ serves as a great lagoon in which blood from the portal
vein becomes relatively static, and reduced in pressure. Some-
what similar conditions in this regard obtain, it may be added,
in the spleen ; and it is perhaps significant that many physiologists
believe that this organ also is the seat of erythrocytolysis.

In any event, through osmotic or chemical action disruption
does occur, and the unassimilable remnant of the foreign proteid
is thus extruded into the intestine, whence it originally came;
the general protein content of the red corpuscle (transformed
now through partial disruption into globulin and albumin) being
liberated to contribute to the regular protein contents of the blood
serum.

It requires but the most casual study of corpuscles in the Tois-
son solution in the counting chamber to suggest the widely differ-
ing conditions of osmotic pressure among the corpuscles of a
drop of blood, and the diversified conditions that obtain in asso-
ciation with various toxaemias. In freshly drawn supposedly
normal blood all the erythrocytes will appear smooth in contour,
the cell-membrane seemingly taut. But in the course of half
an hour or so the appearance of most of the corpuscles may be
utterly changed. They become shriveled, and assume the appear-
ance of diminutive sea urchins. Modifications of size and con-
tour continue, presumably, until the contents of the cell become
isotonic with the saline medium.

It is my belief that valuable inferences may be drawn as to the
physiological and pathological activities of the corpuscles, in
individual cases, from study of the variable time and character
of modification undergone by the corpuscles in thus reaching a
state of osmotic equilibrium.

For example, cells that shrivel in a medium of moderate hyper-
tonicity may be assumed to have a large-moleculed content. And
this gives presumptive evidence that the functions of completing
hydrolysis of absorbed peptones or polypeptids is being per-
formed sluggishly or inadequately. In such a case compensation
may for a time be effected by increase of red corpuscles, and we
are confronted with the clinical paradox of a virtual ansemia in
which the number of erythrocytes is perhaps five and a half or -
six million.

If in such a case the white corpuscles appear fairly normal in
number, quality, and differential count, it may be inferred that

THE PROTEOLYTIC MECHANISM IN OPERATION 83

the patient suffers from protein end product absorption — a com-
mon and characteristic form of intestinal toxaemia.

In a typical case of this description recently under my obser-
vation, the patient is a youth of eighteen, with no pronounced
clinical symptoms other than habitual constipation and suscepti-
bility to infection ("catches cold" readily; has occasional crops
of boils). Pulse 68; blood pressure, 120-80; haemoglobin, 85-90.
The white corpuscles numbered 6,400, and on the smear ap-
peared normal purple and showed no tendency to clump. Red
corpuscles, 5,608,000, largely checkered and vacuolated when
fresh in (diluted) Toisson solution; platelets fairly numerous.
After three hours ninety per cent, shriveled, spiny, more or less
distorted (a condition I am accustomed to refer to in my labora-
tory notes as the "sea urchin" effect) ; so small as to show pro-
nounced Brownian movement.

Closely similar blood conditions are often found in patients
suffering from chronic arthritis. This is not the place, how-
ever, to discuss in further detail the pathological and clinical
bearings of the implied disturbances of the erythrocytic func-
tion of ultimate protein hydrolysis. That observation of the
corpuscles in this connection have practical bearing on problems
of disturbed digestion and assimilation clinically spoken of as
autointoxication and intestinal toxaemia, will be obvious. Full
discussion of the phenomena in question, with particular refer-
ence to acidosis and the rheumatoid condition, will be given in a
subsequent chapter.

THE PHENOMENA OF ANAPHYLAXIS

But suppose now that the protein that enters the blood stream,
instead of being the product of a familiar foodstuff is a protein
of an unusual type — that is to say, one that the organism does
not habitually ingest. Or suppose that the protein, although of
a familiar type, is introduced in rather large quantities. In either
case complications arise; and these complications are precisely
similar in character in the two cases, being due in each case to
the inadequacy of the protective equipment, as will appear in a
moment.

Illustrative cases in point are the laboratory experiments in
which a foreign protein is injected into the system of a rabbit
or guinea pig; and, in case of a human subject, those instances
in which proteids are ingested in great quantity and fail of nor-
mal complete digestion.

In either case the phenomena may result that have become
more or less familiar under the name of anaphylaxis. It is a
condition of toxicity in which the symptoms clearly indicate in-

84 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

volvement of the brain — or, at all events, of the central nervous
system.

In the laboratory experiments this condition of so-called ana-
phylactic shock may occur after a single inoculation with a large
dose of a foreign proteid ; but in that case it is somewhat delayed.

The condition is usually induced by following a small initial
dose of protein (which has no apparent effect) with a larger
one at an interval of a week or ten days. A strictly comparable
condition is sometimes produced in the human subject through
the use of antitoxic serums, anaphylaxis being due not to the
antitoxin itself, but to the foreign blood serums (usually that of
the horse) in which it is suspended. In the case of the animal
in the laboratory, the condition is often fatal, sometimes very
rapidly so. In the case of the human subject, it may constitute
a serious "serum disease."

My personal observation of the phenomena of anaphylaxis in
the human subject has been chiefly associated with the thera-
peutic administration of sheep serum (antithyroid) and various
vegetable proteins (proteals). A mild anaphy lactic reaction may
manifest itself locally, a few hours after the hypodermic injec-
tion is given, by a condition of erythema at the point of injec-
tion, involving only a small locus, or in some cases extending to
the entire arm. There may be marked ecchymosis of the tissues,
with attendant swelling lasting for twenty-four or forty-eight
hours.

Whether or not there is pronounced local reaction, there may
be a general reaction two or three hours after the protein is
injected, manifested by rise in temperature, accelerated pulse,
feeling of malaise, and a more or less pronounced chill. These
symptoms disappear presently, without calling for treatment.

Very different are the manifestations of acute anaphylactic
shock that may occur when a patient who for some time has been
under protein treatment receives by accident a full dose of the
protein into a vein. The anaphylactic reaction supervenes in the
course of fifteen or twenty seconds. The patient's face flushes
violently, more or less severe pains are located in the head and
back, and the pronounced dyspnoea simulates an acute attack
of asthma. In extreme cases the patient may lose conscious-
ness. The violent symptoms usually subside rather quickly, al-
though the backache may persist for fifteen or twenty minutes.
Aromatic spirits of ammonia may be administered, and the back-
ache may be controlled by a few whiffs of chloroform. Caffeine
may be given to stimulate the heart. But all these measures
are more or less of the nature of placeboid palliatives. The pa-
tient rallies quickly even without treatment, and, except perhaps
for the persistence of a frontal headache, soon feels as well as

THE PROTEOLYTIC MECHANISM IN OPERATION 85

ever. The experience, nevertheless, is an unpleasant one for
both patient and physician.

But fortunately an anaphylactic shock of this character from
the administration of a protein in therapeutic doses is exceed-
ingly rare. I have personally witnessed it only a few times in
the course of an experience covering the administration of thou-
sands of doses of proteins. Moreover, it would appear that
the vegetable proteins, when partially hydrolyzed, as in the prep-
arations of the Proteals now made in my laboratory, do not
produce anaphylactic reactions of this character. A possible
explanation of this gratifying modification will be attempted in
another connection. For the moment we are concerned with
the general theory of the anaphylactic response.

The current interpretation of this condition is that the first
injection of the foreign protein has "sensitized" the tissues, so
that when the second injection occurs there is a sudden and mor-
bid reaction. Vaughan explains the condition far more plaus-
ibly as not due to an increased sensitiveness of the tissues, but
to the presence of enzymes of the antibody order induced by
the first inoculation. He suggests that this ferment is put forth
in sufficient quantities not merely to neutralize the protein that
called it forth, but to saturate the blood more or less ; so that
when the second dose of protein appears its molecules are imme-
diately broken up in such a way that the poison group is released
and enabled to act upon the tissues toxically.

But this suggestion involves an obvious and fundamental diffi-
culty ; it assumes that the antibody put forth in response to a
foreign protein will become a menace instead of protection —
which precisely reverses the prevalent and seemingly correct in-
terpretation of the character of antibodies.

According to the view of the present writer, the rationale of
anaphylaxis is something quite different from this. In my view,
there is no question of "sensitizing" the tissues to a foreign pro-
tein ; inasmuch as they are inherently sensitive to all proteins,
foreign or otherwise, at the proper stage of disintegration. Nor
can I conceive that the system has developed the incongruous
habit of putting forth, in response to a protein invasion, anti-
bodies that will necessarily menace the system itself in the event
that the invasion is repeated. Such a phenomenon would seem-
ingly be an exact contradiction of the established customs of the
organism.

Yet how are we to explain the anomalous fact that the organ-
ism was seemingly unaffected by the first dose, and yet was
severely poisoned by the second one, administered after an inter-
val of several days?

In my original exposition of the subject, I suggested that the

86 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

Proteomorphic theory supplies a clear and definite answer, con-
ditioned on the activities of the white and red blood corpuscles
in the regular processes of assimilation, as already outlined. It
assumes that the white blood corpuscle began the proteolysis of
the first dose of foreign protein, and that the red blood corpuscle
completed it, quite as before ; but that the specific enzymes of
the red corpuscle adapted for dealing with that particular protein
were present in very limited quantities in the blood, and suscep-
tible of being reformed but slowly by the corpuscle, precisely be-
cause the organism was little subject to that particular invasion.
Meantime, however, the more generalized enzymes of the leuco-
cyte, known to be largely non-specific in action, were able to
begin hydrolysis of the second dose of foreign protein when it
appeared, reducing it to the polypeptid stage at which the red
corpuscle should take it in hand. But these corpuscles, ex-
hausted at the moment of the specific ferment (from dealing
with the first dose) are, for the time being, helpless. They will
gradually replace the lost enzymes, of course; but as yet they
have not had time to do so, at least in adequate quantity, so the
foreign polypeptids pass on to the tissues, and some of them are
seized on by the brain cells with disastrous results.

The difficulty arises, it will appear, from the fact that the
enzyme of the white corpuscle, which begins hydrolysis, is able
to attack a great variety of proteins; whereas the enzymes to
complete the hydrolysis of the 'resulting polypeptids must be
made, in the case of any specific protein, in a particular depart-
ment of the red corpuscles' laboratory.

To meet this necessity, the red corpuscle has developed a very
elaborate type of protein, each molecule of its hemoglobin being
composed of several thousand atoms; and under ordinary cir-
cumstances it is able to manage all the diverse materials that
are turned over to it by the leucocyte.

But the circumstances under which anaphylaxis occurs are
not ordinary. It is only a protein of unusual type, or a protein
that comes in large quantities repeatedly, that can induce the
condition, through disarranging the harmonious working of the
proteolytic apparatus; except, indeed, that a single large dose of
a foreign protein may, under exceptional conditions, be retained
in the system for a considerable period (instead of being excreted
rather promptly through the kidneys as is usual), in which case,
obviously, there may be opportunity for the white corpuscle to
begin proteolysis of larger quantities than the red corpuscles can
handle.

In the case of the human subject, as just suggested, anaphylaxis
may be due to the faulty digestion of the ordinary food pro-
teids, under conditions that lead to the absorption of an excep-

THE PROTEOLYTIC MECHANISM IN OPERATION 87

tional quantity of unbroken protein. It may also result from
the ingestion of an unusual type of protein, notably, of course
of a type difficult of digestion. In general, we might expect
that anaphylaxis from food proteids would result with a fre-
quency in direct ratio to the rarity with which different proteids
are digested. It is confirmatory that anaphylaxis from eating
shell-fish, lobster, and various fishes seems to be somewhat more
usual than that resulting from the proteins of beef, mutton, or
fowl. A severe case of anaphylaxis from eating flesh of the
snapping-turtle has come within the observation of the writer.
Yet for most people the flesh of the snapping-turtle is entirely
wholesome — as wel) as exceedingly palatable.

It should be observed that there are doubtless idiosyncrasies
of individual organisms with regard to parenteral proteolysis,
just as there are with regard to digestion ; and this accords with
the familiar laboratory observation that not all animals of a
species suffer to the same extent from anaphylaxis under the
same conditions.

In the consultation room, also, marked differences are to be
observed among different patients. Some patients are pecu-
ilarly sensitive to any protein; others are peculiarly resistant
to all proteins. Yet others appear to be sensitive to one protein,
but resistant to another. Such idiosyncrasies are, of course, quite
to be expected. It does not appear, however, that inherent sus-
ceptibility to a particular pr6tein is necessarily associated with
susceptibility to severe anaphylactic shock from the . sudden in-
troduction of a large dose of protein into the system previously
"sensitized." Such "sensitization," in the view here represented,
consists in surcharging the blood with corpuscular enzymes
capable of affecting rapid proteolysis of the proteins in question.

The anaphylactic shock is probably to be interpreted as a vaso-
motor phenomenon. The almost instantaneous onset leaves it
scarcely open to question that the primary action is exercised
upon the vaso-motor and cardiac centers in the brain.

The reason, presumably, why shock takes place when the pro-
tein is injected directly into the vein, and not when the injec-
tion is merely subcataneous or intramuscular, is that in the for-
mer case a relatively large amount of protein is brought instantly
in contact with the brain centers ; whereas in the latter case
absorption is slow and there is ample opportunity for the red
corpuscles to perform their regular functions of shielding the
brain cells by themselves absorbing the partially hydrolyzed pro-
tein molecules.

The observed fact that the therapeutic administration of the
proteoses does not tend to produce the same anaphylactic shock
that is produced by the full-sized molecule of the same type (for

88 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

example, alfalfa seed protein) is difficult of explanation. The
thought naturally suggests itself that the anaphylactic shock may
be due to the action of the full-sized protein molecule on the
brain cells, which is not entirely consistent with the explanations
of anaphylaxis above suggested. It should be understood, how-
ever, that this explanation is at best only tentative. The phe-
nomena of anaphylaxis are exceedingly puzzling and by no means
fully understood. I wish frankly to state that no other hypothe-
sis in connection with the general thesis of the Proteomorphic
theory is presented with greater diffidence or should be held
with greater reserve than that connected with anaphylaxis. The
full and satisfactory explanation of the subject awaits a much
more comprehensive and penetrating knowledge of the general
relations of foreign proteins in the blood stream to the central
nervous system than is at present available.

Nevertheless, it appears to me that, in view of what we have
already seen of the relations of the red corpuscles to the process
of ultimate protein hydrolysis, the further investigation of the
phenomena of anaphylaxis should be conducted always with the
newly discovered functions of the red corpuscles clearly in mind.

As corroborating the view just presented, according to which
protein-product intoxication is due to the incapacitating of the
red corpuscle; and at the same time in corroboration of the
general view that the red corpuscle is the agent called upon to
deal with the toxic products of protein generation, we may recall
the clinical fact that when a tapeworm dies in the intestinal
tract, and decomposes there, the absorption of its toxic products
may induce the condition known as bothriocephalus anemia, a
characteristic symptom of which is the very great and persistent
reduction in the numbers of the red blood corpuscles.

The red cells absorb the toxin, and effect its removal through
the liver ; but, owing to the persistence of the supply, such num-
bers of the corpuscles are involved that their ranks are presently
depleted, the cytogenic apparatus being unable to manufacture
them at so abnormal a rate. The general symptoms of pernicious
anemia, due to reduction of the oxygen- and food-carriers, fol-
low as a matter of course ; but all the symptoms clear up rapidly
so soon as the dead worm is expelled from the bowel.

THE SYNTHESIS OF PROTEIN

Incidentally, it may be urged that the profound systemic dis-
turbances that accompany a reduction in the number of red blood
corpuscles in this case would never result were the chief func-
tion of these cells merely to carry oxygen, as is commonly con-
ceived. Under ordinary conditions the systemic cells require but

THE PROTEOLYTIC MECHANISM IN OPERATION 89

a fraction of the oxygen that the red corpuscles can carry, as
proved by the fact that protein metabolism is unchanged when
the corpuscles are artificially reduced in number by thirty per
cent.

The new physiological studies which suggest that air may be
breathed over and over without detriment — that, in short, the
"fresh air" fetich is founded on a misconception of the needs of
the organism — is of peculiar interest in this connection.

In any event, it would not seem to have been necessary to
build a cell of an intricate type of protein merely to carry oxygen.
Nor is it clear why the substance of the red corpuscle should
contain nucleo-protein were it merely an oxygen-carrier.

But there was need of a cell carrying a molecule of intricate
structure, in which might be stored the potentialities of an in-
finite number of atomic recombinations having their tangible rep-
resentation in the output of endless series of enzymes calculated
to carry the hydrolysis of proteins to its ultimate stages ; as also
to prove antidotal to an unending series of toxic by-products of
protein metabolism in the living or dead tissues of the number-
less species of animals and plants and micro-organisms with
which the environment teems.

In the evolutionary history of the race, these needs have in-
creased pari passu with the increasing activities of the individual
organism, and the correspondingly varied character of the en-
vironment contact. And so we find, as we come up the animal
scale, that the red blood corpuscles constantly increase in rela-
tive number in the blood stream. In fishes the red corpuscles
form about twenty per cent, of the total volume of the blood ;
in frogs about twenty-five per cent.; with mammals it rises to
from forty to fifty per cent., and the proportion of red cor-
puscles to leucocytes rises in something like the same proportion.

The primitive and generalized leucocyte retains from first to
last the same appearance and, as I believe, fulfills the same prim-
itive functions. It is a wandering phagocyte in the vascular
system of the sponge ; it remains a wandering phagocyte in the
vascular system of man.

In the primordial state the red cell was relatively large and
nucleated as it still is in the embryonic state, and in certain
reversional diseased conditions.

But in the developed condition the reproduction of the cor-
puscles devolves upon the mother cells in the red bone marrow
so the corpuscle itself needs no nucleus — or perhaps we should
rather say that it is all nucleus, since it contains nucleic acids.
It is decreased in size, giving it relative increase of surface,
that it may more effectively patrol its environment ; and it is sent
forth from the mother cells in such galaxies that, under normal

90 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

conditions, there are five million individuals in each cubic mil-
limeter of the blood-plasm.

In some of the lower mammals the number is far larger — in
the goat, for example, upward of ten million; in the sheep, up-
ward of fourteen million. Goat and sheep are not inordinately
active creatures. Their oxygen needs can scarcely be so great
as those of birds, which are said to have only from one million
to four million red corpuscles to the cubic millimeter. But the
herbivorous animals ingest large quantities of protein-bearing
foods, and it is probable that the proteolytic demands made upon
their corpuscles are far greater than in case of animals whose
diet includes a large proportion of carbonaceous and fatty foods.

But, regardless of relative numbers, the red corpuscles lead
a precarious life. Millions on millions of these cells are anni-
hilated every hour in the juggernaut of the liver. It has been
estimated that the destruction amounts to three per cent, of the
total number each day — say, 150,000 corpuscles to each cubic mil-
limeter of blood, or an aggregate bulk of perhaps sixty grams
in the entire body. To gain a clear conception of what this means,
recall that, according to Atwater's estimate, a man of average
size requires only 92 grams of protein daily to maintain the
nitrogen balance. Chittenden makes the amount far less. Yet
the ranks of the corpuscles thus perpetually depleted are no less
perpetually replenished. To build the new cells requires a con-
stant supply of materials capable of being elaborated into an
intricate type of protein. To build each molecule of this proto-
plasm requires some thousands, in the aggregate, of atoms of
carbon and hydrogen and oxygen and the elusive nitrogen ; some
hundreds of molecules of amino-acids, the materials directly
utilized.

The total energy required in the building up of these intricate
molecules in the bodies of uncountable myriads of red corpuscles
hour after hour and year after year, throughout the life of the
individual organisms, is colossal. Each red corpuscle is a pro-
teid body, its substance composed in part of hemoglobin, the
formula for which has been computed as C758H1203N195O218S3.
To suppose that the organism exhausts this material and wastes
the energy essential to its compounding merely to produce a trans-
porter of unmodified oxygen would require a reversal of all our
conceptions of economy of management in the cellular body poli-
tic. Yet such is the current conception of physiologists in general.

But there has been experimental evidence at hand for many
years that, if properly interpreted, would dispel this miscon-
ception. As long ago as 1872 Bauer, in Voit's laboratory, stud-
ied the results of bloodletting in the dog, and found that when
from eighteen to twenty-seven per cent, of the total blood in the

THE PROTEOLYTIC MECHANISM IN OPERATION 91

dog's body was removed, there was increased proteid metabolism,
but no change in the carbon dioxide elimination. Some years
later Finkler, in Pfliiger's laboratory, withdrew one-third of the
total blood from a dog, thereby reducing the rapidity of blood-
flow in the femoral artery by one-half, without producing any
change in the quantity of oxygen absorbed or of carbon dioxide
exhaled. More recently Hawk and Gies have confirmed the
early experiments to the extent of showing that there is a higher
proteid metabolism after bloodletting.

Such experiments are utterly disconcerting so long as we con-
sider the red blood corpuscle only as a carrier of oxygen. Note
the conditions : the blood is reduced in quantity even by a third,
the corpuscles being, of course, reduced proportionately. Yet
the absorption of oxygen and the giving out of carbon dioxide
are unmodified ; and, even more strange to relate — according to
accepted physiological teaching — the rate of proteid metabolism
is increased.

There is nothing in the least anomalous about these phenomena,
however, if interpreted in the light of the Proteomorphic theory.
In this view, the mother cells that produce the red corpuscles,
together with those that produce the leucocytes, constitute the
great protein-synthesizing mechanism of the body. Out of the
amino-acids in the blood stream and lymph stream, according
to my belief, the mother cells of bone marrow and spleen and
lymph nodes build up protein of the specific types characteristic
of the particular organism, storing it hour by hour in the bodies
of unending series of offspring which we call leucocytes and red
blood corpuscles. The protein of their bodies will be ultimately
discharged into the blood stream, to make up the proteins (globu-
lin and albumin) of the serum, the great common food supply
for all the tissues, and an important source of energy for the
bodily activities.

What, then, could be more natural than that when there is
5uch depletion of the ranks of the corpuscles through hemor-
rhage, the cytogenic mechanism should take on exceptional activ-
ity, in the effort to make amends for the loss? But, of course,
the bodies of the corpuscles, being themselves proteins, cannot be
built up without requisitioning a supply of protein-building mate-
rial and giving out a certain amount of left-over material as
nitrogenous waste.

Hence the observed increase in the protein metabolism, after
severe hemorrhage — which might, in the light of this theory,
have been predicted in advance of the experiment. As to the
lack of increase in oxygen intake and carbon dioxide outgo, that
only furnishes another piece of incidental evidence that no such
number of red blood corpuscles is necessary as that normally

92 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

found in the body merely to carry on the work of oxygen con-
veying. The necessity for an unfailing oxygen supply is so
great that provision is made for a supply far in excess of the
average needs of the organism, as the bloodletting experiments
show.

Without minimizing the value of the services of the red blood
corpuscles as a carrier of oxygen, then, we may safely assume
that its service as a provider of body protein is at least as great.
A realizing sense of the significance of this function comes to us
when we reflect that the intricate bodies of the red corpuscles are
built up in such numbers, that, massed together, they make up a
bulk of about four pounds in the body of a man weighing one
hundred and sixty pounds.

So this erythrocytic body surpasses in size every other organ
in the body with the single exception of its collaborating organ,
the liver. The fact that the individual cells of this great organ
are scattered should not have blinded physiologists to the neces-
sity for the assumption that so massive a structure must have
vastly important functions in addition to the simple task of car-
rying oxygen. In point of fact, if the analysis just presented
be accepted, it is clear that this anomalous viscus is an organ
of the assimilative system having a share in protein metabolism
subordinate to no other. The function of dealing with bacterial
poisons may, after all, in the widest view, be considered — even
as the function of carrying oxygen must be considered — but an
incident in the career of the red blood corpuscle.

Its supreme functions are to supply fuel in the form of pro-
tein for the bodily activities, and to complete the proteolysis of
foreign and native proteins in the blood stream.

Yet the incidental function of aiding the leucocyte to deal
with bacterial toxins cannot be considered an insignificant one,
inasmuch as the safety of the organism as a whole may at any
time depend upon it. Measured in terms of the health of the
human individual, and even in human life, this function of the
red corpuscle has paramount importance. It would be rash to
assert that its defensive and immunizing functions are less con-
stantly called into action or less important in their results than
the allied functions of the leucocyte. Both are essential to the
life of the organism.

I have suggested, indeed, that the immunizing functions of
the two types of corpuscles must be regarded as complementary,
rather than as in any sense competitive. It has been suggested
also that, to a certain extent, the functions overlap, so that an
enzyme secreted by one might facilitate the work of the other.
It was tentatively suggested that perhaps opsonin, which so con-
spicuously aids the leucocyte in its phagocytic functions, may be

THE PROTEOLYTIC MECHANISM IN OPERATION 93

produced, partly at least, by the red corpuscles in response to
bacterial toxins. But in general it is probably the leucocyte,
with its less specialized organization, that aids the red corpuscles,
rather than the converse.

As a typical instance, we may note that whenever the red
corpuscles are decreased in number — say from vigorous blood-
letting— the army of leucocytes at once receives notable acces-
sions, being fully replenished within a few hours. A far longer
time will be required to replace the vast coteries of red cor-
puscles; meanwhile it is the part of wisdom to strengthen the
leucocytic outposts. In some cases the numbers of leucocytes
may become so great that their bodies must have a really sig-
nificant share in replenishing the proteins of the blood stream,
thus making partial amends in this direction also for the paucity
of red corpuscles.

THE LEUCOCYTIC BALANCE

The consideration of such fluctuations in the ranks of the cor-
puscles naturally raises a question as to how the leucocytic bal-
ance is maintained.

We know that under average conditions of normal health the
number of leucocytes in the blood stream averages about six
thousand to the cubic millimeter, rising to about eight thousand
three or four hours after a hearty meal ; and that the number
of red corpuscles averages about five million to the cubic mil-
limeter and is less subject to wide variations in times of health.

These facts are so familiar that we scarcely think of them
as requiring explanation. Yet a moment's consideration makes
it clear that the maintenance of the corpuscular balance is a
very puzzling phenomenon.

How are the mother cells in the bone marrow and spleen, for
example, to know that protein foods have been taken into the
stomach, and that therefore an additional supply of leucocytes is
needed? How are these mother cells to know that there has
been a great destruction of red corpuscles in the liver; or that
a wound in some remote part of the body has resulted in a
severe hemorrhage? How are they to know that a colony of
pneumococci has found lodgment in the lungs, and that fresh
bands of phagocytes are required to fight them? How are they
even to know that the body is undergoing vigorous muscular exer-
cise; or that a cold bath has been applied to the skin?

These surely are interesting questions. Under all the condi-
tions just noted, the cytogenic cells do, in point of fact, take on
exceptional activity, and produce leucocytes in particular in un-
wonted numbers.

94 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

But where is the census-taker of blood corpuscles who has sig-
naled to them that these exceptional recruits are needed?

The more one considers that problem the more puzzling it
seems ; particularly in view of the fact that the bone marrow is
but doubtfully connected with the nervous mechanism. There
are sympathetic nerves in connection with the blood-vessels, to
be sure, and these might serve to modify the blood supply; but
we can scarcely suppose that this by itself can control the activ-
ities of the cytogenic cells, particularly if we recall that the blood-
pressure may be increased indefinitely without necessarily caus-
ing leucocytosis ; whereas, on the other hand, active generation
of leucocytes may occur after a hemorrhage that has reduced
blood-pressure to the minimum.

It does not necessarily follow from this that the sympathetic
nervous system may not have a share in determining the activ-
ities of the cytogenic cells. The nervous mechanism may well
be supposed to take part in the co-ordinating of the activities
of the various mother cells, located in bone marrow and spleen
and widely scattered lymph nodes. But there is another and
quite different stimulating and co-ordinating mechanism which
recent studies have brought into the foreground, namely the
endocrinous system, with its various internal secretions and
hormones.

The messengers of this system travel in the blood stream itself,
as also doubtless in the lymph stream, and there is a good deal
of evidence pointing to these agents as the stimulators and reg-
ulators of cytogenic activity.

I have had verbal report from a colleague of cases of dia-
betes and Graves' disease, in which the therapeutic exhibition
of the duodenal hormone, secretin, is reported to have led to a
rapid and extraordinary rise in the blood count, including both
leucocytes and erythrocytes. It is interesting to note, as strongly
supporting the Proteomorphic theory, that this corpuscular in-
crease is said to have coincided with very marked amelioration
or total disappearance of the symptoms of protein poisoning
that characterize the disease. But at the moment our attention
is directed to the probably direct connection between the exhi-
bition of secretin and the increased activities of the cytogenic
cells.

It has been clearly demonstrated that secretin, as produced in
the duodenum, enters the blood, and being carried to the pan-
creas, stimulates that organ to the production of its charac-
teristic tryptic enzymes. What more natural than that the same
hormone should carry similar messages to the bone marrow to
stimulate the production of the leucocytes that are known to
secrete an enzyme closely allied to trypsin, and to subserve,

THE PROTEOLYTIC MECHANISM IN OPERATION 95

within the vascular mechanism, a function of proteid digestion
comparable in a small way to that of the pancreas itself?

In the activities of the hormone secretin, then, if these infer-
ences are justified we find a solution of one aspect of the prob-
lem of maintenance of the corpuscular balance. This duodenal
hormone being available as a messenger, the fact that the tissues
of the bone marrow take on fresh activities in response to the
taking of food into the stomach seems no longer mysterious,
or at least no more mysterious than, for example, the increase
in the activities of the pancreas brought about through the same
agency.

There are other conditions, however, in which there is increase
in the blood count, where the agents through which the cytogenic
mechanisms are stimulated may not be so readily traced. How,
for example, shall we explain the leucocytosis that takes place
in the course of violent muscular exercise?

Here the explanation offered must be regarded as altogether
theoretical and provisional, although assuredly not lacking in
plausibility. The suggestion I would make is that the increase
of leucocytes here is due, in part at least, to the increased flow
of lymph resulting from muscular contraction. It is known that
lymph scarcely flows at all in the lymphatics of the limbs during
quiescence, but is stimulated by active or even by passive move-
ment. It is known also that lymph flowing through a lymphatic
gland is observed to emerge with an increased increment of
leucocytes, and the inference seems unavoidable that the leuco-
cytes in question were developed in the lymph node. It is a fair
inference that their rate of development depends on the rate
of flow of the lymph which must bring the food albumen to
their mother cells, and if this be admitted the increase in such
of the leucocytes as are developed in the lymphatic system as
a result of muscular exercise is accounted for.

The function of the lymphocytes thus brought forth would be,
perhaps, to assist in the catabolism of products of protein de-
compounding associated with muscular activities (e.g., creati-
nine) or of materials (proteins or fats) for supplying foods
or fuels to these cells. In the original presentation of the Pro-
teomorphic theory it was suggested that this lymphocyte assists
in the decompounding of the normal serum proteins. I am now
disposed to question the validity of this assumption, but there
were certain collateral suggestions that perhaps warrant repro-
duction of the paragraphs in question here :

"A word should be said about the precise service which the
lymphocytes thus called forth in response to muscular action
render to the muscles that have indirectly engendered them. This
lymphocyte is not a phagocyte, but it may have to do with the

96 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

decompounding of the normal proteins of the blood serum
(globulins and albumins). These are decompounding to make
fuel (including a large proportion of glycogen) to supply energy
to the body-cells, and notably (1) to the digestive apparatus, or
(2) to those most important dispensers of energy, the muscle
cells.

*"I have suggested that the activity of the muscle cell is con-
ditioned on an increase of osmotic pressure due to a decom-
pounding of the protein within the cell. This is necessarily
accompanied by loss of energy, expended as mechanical energy
and as heat. The physical contents of the cell are for the most
part not wasted, but they cannot be recompounded into proteins
except through the agency of energy supplied from without.
The molecules of serum protein, suspended in blood stream and
tissue fluids, are decompounded to supply this energy. And,
according to the present view, the lymphocyte is the agent (or at
least one of the agents) supplying the enzymes that inaugurate
this process of decompounding.

"Hence the urgent necessity for an increased supply of these
leucocytes in times when the muscles are called upon to undergo
excessive contraction for prolonged periods.

"Hence, also, the necessity for an increase of lymphocytes
after the ingestion of food, to aid in the decompounding of serum
proteins to supply fuel for the activities of the glands of stom-
ach and pancreas and upper intestines. It is to meet this need
that the lymphocytes are observed (as we have seen) to be sent
out in greatly increased numbers during digestion. The supply
of digestive ferments cannot be made out of nothing. The cells
of the digestive apparatus cannot keep up their activities un-
less they are supplied with energy from without. It is the
province of the serum proteins to supply this energy, in part
at least, here as in the case of the muscles and other tissues ;
and the lymphocytes, according to the present view, have a
share in bringing about the decompounding of the serum pro-
teins, through which their energy is liberated and made available.

"Should the numbers of the lymphocytes seem inadequate for
such a task, it may be pointed out that their work is the rela-
tively simple one of tearing to pieces an unstable molecule. Pos-
sibly nothing more is required than to seize on a single group
containing the protein molecule's three sulphur atoms to send
the entire structure, with its thousands of carbon hydrogen, oxy-
gen, and nitrogen atoms, tumbling.

"Incidentally, attention may be called to the curious interest
that attaches to the observation of the cyclic co-ordination of
parts evident in the observed fact that the lymphocytes which
(in this view) aid indirectly in the production of the digestive

THE PROTEOLYTIC MECHANISM IN OPERATION 97

ferments, are themselves called into being through a stimulus
to their mother cells sent out as a hormone messenger from the
digestive apparatus itself.

"Similar cycles of co-ordination, however, are not unusual
in the organism. Indeed, the case just cited of the lymphocytes
developed in the lymph nodes through the action of the muscles,
and in turn serving presently to aid the muscles that indirectly
engendered them, furnishes us another and no less striking illus-
tration of such an harmonious dual alliance,"

HORMONES AND THE CORPUSCLE-BALANCE

I shall not here discuss in detail the rationale of operation of
the remaining causes that are observed to promote leucocytosis.
which include cold baths on one hand and fevers of microbic
origin on the other ; contenting myself with the suggestion that
the cold bath stimulates the vasomotor apparatus of the sympa-
thetic system ; and that the bacterial toxins, when present in the
body fluids, doubtless stimulate the cytogenic apparatus directly,
while the bodies of the bacteria serve as a food pabulum for
the leucocytes that may lead to the proliferation of the latter
through cell division.

The normal leucocytosis of pregnancy may also be dismissed
with the remark that it furnishes, in view of the known inva-
sion of the blood by foreign (placental) protein, strong cor-
roborative evidence for one phase of the Proteomorphic theory.

It seems desirable, however, to speak a little more in detail
(though still very briefly) of the part in maintaining the cor-
puscular balance, and in determining the activities of the leuco-
cytes, that appears to be played by the endocrinous organs; in
particular by the adrenal bodies, the thyroid apparatus, and the
glands of the duodenum.

To establish a strong a priori probability that some at least
of the internal secretions directly stimulate the activities of the
corpuscles, it is only necessary to appreciate the fact that the
corpuscles themselves must be classed among the important mem-
bers of the endocrinous system ; and to recall that the products
of the various ductless glands are observed to interact in mutual
stimulation and inhibition of the organs that produce them.

When, therefore, to cite a specific instance, it is observed (as
in Cannon's experiments) that a sudden increase in the adrenal
secretions, induced by an emotional state of fear or anger, results
in an immediate increase of glycogen in the blood, in prepara-
tion for active muscular exertion, we may justifiably infer that
the increase has been brought about, in part at least, by stimulus
to the enzyme forming functions of the lymphocyte, induced by

98 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

the presence of unusual quantities of adrenalin in the medium
in which the lymphocyte is suspended.

Again, the observed fact that persons suffering from hypo-
thyroidism are unduly susceptible to the attacks of bacterial dis-
eases, finds suggestive explanation in the theory that a normal
supply of thyroidin is essential to the normal functioning of the
cytogenic apparatus. Moreover, there is a certain amount of
direct evidence for the claim that the exhibition of thyroid
extract promotes cytogenesis.

An increase of proteid metabolism has been observed in cases
of exophthalmic goiter; and the experiments of Anderson and
Bergman show a similar increase from the giving of large doses
of thyroid extract. If the role of the corpuscles in proteolysis
here presented be accepted as valid, these observations would
form another bit of presumptive evidence linking the thyroid
apparatus with the cytogenic mechanism.

GENERAL THERAPEUTIC APPLICATIONS OF THE PROTEOMORPHIC
THEORY

To the clinician it perhaps does not so greatly matter as to
what theoretical explanations are given of the relations of hor-
mones or other agent to the stimulation of the cytogenic sys-
tem. It suffices to know that there are certain available agencies
through which the production of corpuscles may be stimulated ;
and through which, therefore, according to the present theory,
the processes of normal protein metabolism and incidentally, but
most importantly, the immunization of the patient against bac-
terial diseases, and the cure of these diseases themselves, may
be facilitated. What these agencies are has been suggested in
the course of the preceding discussion.

It remains now to make a few practical suggestions as to the
utilization of these agencies ; and, in general, as to the benefits
that may accrue to the patient through recognition, on the part
of the physician, of the principle that the blood corpuscles, white
and red, are the all-important agents in the fight against bac-
terial diseases.

Let us take as a typical illustration — because the most com-
mon and familiar — the case of a patient suffering from tubercu-
losis.

The tubercle germ invades practically every human organism.
But so well defended is the average system against its attacks
that ninety per cent, of all the individuals of a given genera-
tion are able to throw off the invader, and attain full individual
immunity to its attacks. Such immunity, conditioned on the

THE PROTEOLYTIC MECHANISM IN OPERATION 99

hereditary status of the germ-plasm, is passed on to the offspring
of the individual.

But ten per cent, of the individuals of each generation are not
able thus to ward off the attacks ; on the contrary, they suc-
cumb to it, and after all their tissues are devitalized to an extraor-
dinary degree, they ultimately die. Their failure to fight off the
germs is, of course, due to an inherent lack in the make-up of
their defensive mechanism. The mechanism in their leucocytic
and erythrocytic apparatus that should produce anti-ferments
against the tubercle germ is either altogether absent or is de-
vitalized and minimized in efficiency. The result is that their
tissues are in a condition comparable to that which the student
of anaphylaxis speaks of as "sensitization," and which I have
suggested, should be considered merely as lack of defence. Re-
gardless of the precise terms of the explanation, they are sus-
ceptible to the attacks of the germs, and this inherent sus-
ceptibility may be passed on to their offspring.

It is of important, even if of incidental, interest to recall that,
according to the recent studies of heredity, this susceptibility
appears to act as a Mendelian recessive.

That is to say, a susceptible person, mated with a normal or
resistant person, will have offspring that are normally resistant,
but who contain in their germ-plasm, as a recessive tract, the
factors of susceptibility or lack of immunity. If such personally
resistant, but potentially susceptible, individuals are mated, one
of their offspring in four, on the average, will be susceptible.
This is of great importance from the standpoint of the eugenist,
but need not be considered further in the present connection.

Suffice it, for the present, that even the susceptible person is
susceptible only in a relative sense, and is by no means alto-
gether without a defensive mechanism. His chief danger may lie
in the fact that his cells are partially habituated to the presence
of this toxin, and therefore will not respond to it actively.

If we inquire what can be done to stimulate the defensive
response, we are at once reminded of the methods that lead to
an increase of the numbers of the leucocytes in the blood. The
ingestion of hearty food, notably protein, leads to such increase.
Active exercise leads to such increase. Cold baths stimulate such
increase. Nourishing food in the largest quantities that can be
assimilated ; exercise of a fairly vigorous type, and hydrotherapy
would seem to be theoretically indicated. Also fatty foods to
conserve the protein, and iron to facilitate production of hemo-
globin. No practical physician needs be told that these measures
have been shown empirically to be of the greatest value in the
treatment of tuberculosis.

Recent experiments have shown that air at very low tempera-

100 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

ture has a stimulative influence similar to that of the cold bath.
This observation seems to explain the familiar clinical fact that
tuberculosis may be treated advantageously in very cold climates.
The results of sleeping in the open air in an almost arctic tem-
perature are familiar to clinicians. The cold temperature is
probably as directly beneficial as the fresh air itself.

As to exercise, practised before the patient reaches a stage of
asthenia that makes it dangerous, the beneficial results are equally
little in doubt. Mountain climbing, with attendant fatigue falling
just short of extreme exhaustion, is a recognized therapeutic
measure of the utmost importance. In all probability, the climb-
ing rather than the mountain air produces the benefit.

Incidentally we may note, in confirmation of the view of ery-
throcytic activities here presented, that the blood is thicker at
high altitudes, so that the red corpuscles are relatively more
abundant and hence patrol the blood better ; but that the total
amount of hemoglobin is not correspondingly increased (Viault,
Abderhalden).

The value of the cold bath has long been recognized by a few
astute clinicians, who have found it difficult to gain headway for
their views partly, perhaps, because the rationale of the benefits
to be expected has hitherto been obscure. The knowledge that
the cold bath directly stimulates the production of an additional
army of leucocytes; coupled with the belief that the leucocyte
is the pre-eminent agent of immunization against the direct inva-
sion of bacilli, furnishes the all-sufficient answer. The cold bath
may have other beneficial effects, but this one alone justifies its
use in all bacterial diseases in which there is an inherent tendency
to defective leucocytosis.

A striking illustration of the value of the cold bath is fur-
nished in the reports of the Munich military hospital, in which
records of more than eight thousand cases show that since the
cold bath was used habitually in the treatment of typhoid fever
the mortality of that disease was reduced from forty-two per
cent, to three per cent.

As to the matter of a liberal diet, there would be no difference
of opinion in the case of the consumptive, but opinions might
differ, and undoubtedly would differ, when acute fevers are in
question. Indeed, the old familiar rule to "starve a fever" has
been an axiom upon which the average physician has acted some-
what persistently. But it has recently been suggested by Cole-
man that this rule is perhaps as fallacious as the other rule, now
fortunately abandoned, that the fever patient should be deprived
of water as well as of food. Coleman reports gratifying results
in typhoid fever cases in which a liberal diet was provided. "Not

THE PROTEOLYTIC MECHANISM IN OPERATION 101

only is the course of the disease favorably influenced," he says,
"but the condition of the patient is vastly improved."

And these recent observations are, after all, only confirmatory
of experiments conducted by Von Hosslin more than thirty years
ago, which showed the value of a liberal diet in ordinary fevers.

If we ask why a liberal diet, including proteins, is essential
in the treatment of fever, the answer is not far to seek. Accord-
ing to theory, the leucocytes and red corpuscles fight the invad-
ing proteins and enzymes by constantly putting out chemical com-
pounds that antagonize them by cleaving their complex molecules
on one hand and by combining them into new and harmless asso-
ciations on the other. But this constructive work on the part
of the corpuscle implies the expenditure not merely of energy,
but of matter. And material for this expenditure must in some
way be found to make up for the constant depletion.

The corpuscles can no more be expected to perform their
work without being supplied with fuel than can any other
machine.

Nor can new corpuscles be developed to fill the constantly
decimated ranks without drawing on an unfailing supply of
proteins. And unless this material is supplied in the pabulum
that comes from the outside world, usually through the medium
of the intestinal canal, it must be found elsewhere. And ob-
viously the only other source is the body tissues themselves. So
if the defending hosts are not supplied with food pabulum from
without, they must draw on the tissues of the body, with a
weakening effect. Hence the rapidly emaciating effect of fevers,
with attendant weakness; an effect largely avoided through use
of a liberal diet.

It will be understood, of course, that the catabolic activities of
the leucocyte and red corpuscles, in which complex protein mole-
cules are constantly cleaved to smaller molecules and arranged
in new combinations, must be attended by a constant liberation
of heat. So the fever itself is in part an evidence of the activ-
ities of the corpuscles. And liberal feeding, provided the food
is assimilated, may unquestionably tend to enhance the fever.

But the modern clinician does not regard fever as in itself
necessarily disadvantageous to the patient. On the contrary,
he associates it with the immunizing and curative processes in
the body. So he does not regard a rise in temperature as neces-
sarily an evil. He knows that the phagocytic activities of the
leucocytes are greatly accelerated when the temperature is high;
the leucocytes have been observed at increased temperatures to
"dart about like bees around a hive." It may reasonably be
inferred that the chemical activities of all the immunizing agents
are correspondingly accelerated.

102 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

Nevertheless there are dangers in excessive temperature, if
for no other reason because tissues that it is essential to con-
serve are also stimulated thereby to unwonted activity. So it is
highly desirable from time to time to accelerate the removal
from the body of the excessive heat due to the chemical activ-
ities. And, of course, the best practical means of accomplishing
this is the cold bath.

The idea of giving a fever patient liberal potations of water,
feeding him freely with nourishing foods, and from time to
time plunging him into cold baths or swathing him in cold packs
would have come very near to giving an apoplectic shock to the
best clinicians of a century ago. But nowadays such procedures
have the fullest experimental or clinical warrant, and find expla-
nation in the data of physiological chemistry.

It is probable, however, that comparatively few clinicians
among these who use the cold bath habitually in fever cases,
and recognize its value in the direct reduction of temperature,
take cognizance also of its significance in stimulating the cyto-
genic organs to the production of new hosts of germ destroyers.
Yet it is probable that the latter is by no. means the least of the
services performed by the cold bath.

It is a little difficult to accustom one's self to the idea that
there is no necessary connection between the degree of fever
and the virulence of intoxication. But the truth of this propo-
sition is suggested by the familiar observation that infants often
show a high temperature when their maladies are comparatively
mild. And it receives experimental demonstration through the
observations of Vaughan and others to the effect that small doses
of a protein poison may cause a rise of temperature in animals
where far larger doses of the same toxin produce no fever, but
may even cause a fall in temperature.

Vaughan very justly refers to this as a puzzling and not clearly
explicable fact. A conceivable explanation might be that small
doses stimulate the defensive leucocytic mechanism, while large
doses act with such suddenness and violence as to paralyze them ;
just as they sometimes seem to be helpless when they have in-
gested a large number of toxic bacteria. It should be recalled
that the introduction of these large doses of foreign proteins
directly into the vascular system is a phenomenon that would be
of exceeding rare occurrence outside the laboratory. The fang
of a serpent is about the only mechanism in the natural world
that would be capable of introducing a foreign protein in quan-
tity into the animal system. So the defensive mechanism has
not often been called on to reckon with this contingency, and
it cannot deal effectively with excessive doses of toxic proteids.

But, however explained, these laboratory experiments are of

THE PROTEOLYTIC MECHANISM IN OPERATION 103

great value in teaching the clinician that he must not depend
too fully on his clinical thermometer as a guide to the virulence
of disease.

As to pharmaceutical agents calculated to stimulate the activ-
ities of the cytogenic system, mention was made in the original
presentation of the Proteomorphic thesis, of secretin, of thyroid
extract, of powdered spleen, and of bone marrow. Doubtless
these agents have a measure of utility, but in the light of recent
experience they assume an altogether subordinate role. The
parenteral injection of non-toxic proteins has been shown to
offer therapeutic possibilities scarcely more than adumbrated by
any stimuli to the cytogenic apparatus hitherto known. These
possibilities are forecast in the general treatment of the theory
of antigenic response in the original presentation of the Pro-
teomorphic theory.

The details of their application, through the development of
Proteal therapy, will form the subject matter of most of the
succeeding chapters of this book.

SERUMS, VACCINES, AND DIRECT CYTO-THERAPY

Of specific serum and vaccine therapy in general I shall speak
only in the most general way, although reference to the non-
specific elements always necessarily involved will be made in
another connection. By way of anticipation, however, there
are one or two aspects of the subject that may advantageously
be given brief consideration here, from the standpoint of the
Proteomorphic theory.

Consider, for example, the observation of Dr. W. H. Park, to
the effect that when a horse having a strongly antitoxic blood is
injected intravenously with a definite amount of toxin, very
little production of antitoxin takes place, because the toxin is
neutralized by the antitoxin in the blood, whereas the same
amount injected in scattered spots subcutaneously will produce a
large amount of antitoxin. Dr. Park argues, logically enough,
that such portions of the subcutaneously injected toxin as come
into the blood stream will meet the same fate as that injected
intravenously. He concluded, therefore, that some or all of the
cells in the area in the subcutaneous tissues that the toxin reaches
must take part in producing antitoxin.

This conclusion is obviously in harmony with the Proteomor-
phic theory, which postulates that body-cells of many types may
on occasion respond to the invasion of toxins of the polypeptid
order of chemical complexity. It should be recalled, however,
that white and red corpuscles are everywhere within reach, in
more or less static capillaries and tissue fluids, and that their

104 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

services may have been available, even though the injection was
not made directly into the blood stream.

Again in Sir Almroth Wright's application of vaccine therapy
to localized infections already in being, such as boils, and even
to general infections, including typhoid fever, the injection is
usually subcutaneous or intramuscular, not intravenous, but it
is obvious that the leucocytes residing at the moment in the
static tissue fluids and lymph spaces are brought directly into
contact with the invading bacteria (in this case dead, but laden
with their foreign proteid). They are seen to accumulate and
to attack the dead bacilli actively, and we can hardly doubt that
they are directly stimulated to send out antidotes — complement,
opsonin, bacteriolysin — that presently percolate into the general
blood stream and are carried to the special tissues where the
invasion of living germs is taking place.

In this case the locally injected germs are unquestionably at-
tacked and largely engulfed by the local garrisons of leucocytes,
and it is difficult to conceive what other agent can be responsible
for the secretion of the antibodies with which the blood presently
becomes infused.

Although it seems almost unavoidable to conclude, in such a
case as this, that the white blood corpuscle is the agent of anti-
body production, where protein poisons are in question, yet the
conclusion, after all, is inferential only. Some remarkable ex-
periments have recently been made by J. W. Vaughan, however,
in which the genesis of specific enzymes in the body of the leuco-
cytes in response to protein poisoning, is demonstrated.

In these experiments, as recorded by Victor C. Vaughan, the
inoculation of sheep or rabbits with finely ground cancer tissue
led to the rapid increase of large mononuclear leucocytes in the
blood, until they reached twenty-five per cent, or more of the
entire leucocytic population. The animal is then bled, the blood
is laked with acetic acid, and the leucocytes are collected in a
centrifuge. They are rubbed with sterile sand in salt solution
and passed through a Berkefeld filter.

It is found then that the filtrate contains the specific proteolytic
ferment which splits up cancer cells.

"This is shown by incubating it with cancer cells, when the
poisonous portion of the protein molecule is freed, as is shown
by the fact that when injected in the fresh rabbit it causes sud-
den death. Incubated with other proteins, the leucocytic extract
liberates no poison. This leucocyte extract when injected in
certain amount directly into cancer tissue produces anaphylac-
tic shock."

The experiment led the elder Vaughan to conclude that "this
work seems to indicate that the specific enzyme for cancer cells

THE PROTEOLYTIC MECHANISM IN OPERATION 105

is furnished by the large mononuclear leucocyte." Another in-
terpretation is possible, as I shall show presently, but the experi-
ment justifies the conclusion "that in work of this kind lies a
promise of at least partially insulating the anaphylactic enzymes
and studying their effects."

"Anaphylactic enzymes," it will be understood, is the term
used by Vaughan to describe the so-called antibodies put out in
response to foreign proteins, about which we have all along
been speaking.

This experiment certainly shows that in some cases the leu-
cocyte may be the agent of origin, or at least of transfer, of
the antibodies directed against poisons. It should be added, how-
ever, that the elder Vaughan does not ascribe this function ex-
clusively to the leucocytes, for he expressly states in another
connection that it is possible that the protective enzymes are
formed by different cells according to the "sensitizer" (i.e., the
proteid toxin) used — a view obviously in harmony with the pro-
teomorphic theory, though far too general to be cited as spe-
cifically supporting the theory.

In the original presentation of the Proteomorphic theory it
was noted, in pursuance of this aspect of the subject, that
Vaughan was then testing his extract of mononuclear leucocytes
in the treatment of cancer, and the following comment was
made, which has peculiar interest in the light of more recent
developments : "Whatever the immediate results of this par-
ticular test, there is every reason to hope that the method in-
augurated, in which the leucocytes are directly looked to for the
production of immunizing enzymes, will be generalized and given
an important place in therapeutic procedure in the near future.
It is a short step from the clear conception that the leucocytes
are the chief agents in the producing of immunizing ferments
to the direct utilization of the leucocytes themselves in thera-
peutic procedure.

"That an antidote thus prepared may have marked advantages
over an antitoxic serum is clearly suggested in the work of
Vaughan just referred to. For he found it impossible to use
the serum of a 'sensitized' animal, because, in the first place,
repeated injections of the serum caused albuminuria ; and, in
the second place, they 'sensitized* to the proteins of the serum.
The leucocytic extract also 'sensitizes' to the blood serum, until
it is passed through a Berkefeld filter, after which it is innocu-
ous. All of which may readily be interpreted in terms of the
Proteomorphic theory.

"Here, then, is at least a strong suggestion of the possibility
of producing antibodies directly from the filtered bodies of the
leucocytes, and avoiding the danger of serum disease which is

106 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

well recognized as attendant on the present method of serum
therapy and which sometimes has such alarming results."

I wrote these words in September, 1914. Following them I
presented a recapitulatory summary of the essentials of the
Proteomorphic theory, concluding with these words:

"The general theory of the action of the cytogenic system
above outlined finds support in clinical observations of disease
and in empirical therapy; and the theory itself gives important
clues to the scientific application of old and new therapeutic
measures, including an extension of serum-therapy and vaccine-
therapy and the development of a new cyto-therapy.

"Such, then, are some of the salient aspects of the Proteo-
morphic theory of immunization ; a theory which postulates the
cytogenic system as the chief immunizing mechanism, and its
daughter cells, the leucocytes and red corpuscles, as the active
direct agents in carrying out the beneficent functions of that
mechanism.

"It is not claimed that a complete demonstration of the truth
of this theory in all its aspects has been presented, nor that
such demonstration is possible with data at present available.
Nor can it be supposed that all parts of so novel a theory have
been correctly conceived. Yet, even as presented, it would appear
that the theory throws light into a good many dark places of
the realms of physiology and pathology.

"In any event, I feel that the fundamental concept of the
theory has been made sufficiently plausible to justify, and in-
deed to demand, a far larger share of attention for the leucocyte
and the red corpuscle on the part of bacteriologist, pathologist,
and practicing physician than has hitherto been accorded these
small but highly important bodies."

The story of the development of the "new cyto-therapy" thus
adumbrated, under guidance of the Proteomorphic theory, has
been told in part on earlier pages of this volume, and will be
further elaborated in succeeding chapters.

CHAPTER III

THE DISCOVERY OF THE PROTEIN PRINCIPLE IN
THERAPEUTICS

Shortly after the first publication of the Proteomorphic Theory
(American Medicine, October and November, 1914), I was in
Baltimore and had opportunity at Dr. Howard Kelly's private
sanitorium to see a number of cancer cases undergoing radium
treatment. I was also shown photographs some of which re-
vealed really spectacular modifications of malignant growths
under influence of radium, and I received first-hand accounts,
from physicians not directly connected with the work, of cases
in which cancerous growths had magically disappeared appar-
ently as a direct result of the application of radium.

These observations interested me profoundly, and from many
points of view. Not long before I had visited Professor Ernest
Rutherford in his famous laboratory at Manchester, and had
been permitted to study at first hand his radium apparatus, and
to observe his fascinating experiments. I had visited Sir J. J.
Thompson at the Cavandish Laboratory in Cambridge, at the
time when he was making his first photographs of atoms in the
vacuum chamber. I had visited Lenard, the precursor of Roent-
gen, at Freiburg ; and Ostwald at his home in Grossbothen ; and
Arrhenius at the Nobel Institute in Stockholm; and Zeeman in
his wonderful laboratory at Amsterdam; and had discussed the
alluring problems of the ultimate constitution of matter,
the relations of matter and energy, the character of chemical
action and electrical action, and kindred subjects suggested by
the different yet closely allied discoveries for which these men
are famous.

I had also visited and talked with a group of discoverers
in the biological field, and similarly attempted to correlate their
observations — for example, Metchnikoff, at the Pasteur Insti-
tute in Paris, who was then studying conditions in the alimen-
tary tract in their relation to health and longevity; Ehrlich, at
his Frankfort Institution, who had just given the world salvarsan,
and thereby revived hope in specific chemo-therapy ; Sir Aim-
wroth Wright, at St. Mary's Hospital in London, who was
actively elaborating the theory and practice of autogenous vac-
cine therapy, and venturing into another new field in the attempt
to combat hay fever with pollin extracts ; and Professor George
F. H. Nuttall, Quick Professor Biology at Cambridge Univer-
sity, whose fascinating work with the precipitins, through which

107

108 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

he had tested the genetic relationship of hundreds of species of
animals, had recently won him Fellowship in the Royal Society —
a distinction shared, I believe, by no other American.

With the work of these men I had, of course, long been
familiar. Some of the men I had known for years, and visited
on previous occasions. But at this time I was making an espe-
cial effort to correlate the new advances along different lines of
science in the fields of physics, chemistry, and biology. A little
later I sought, through correspondence, the opinions of a thou-
sand leading men of science, actual workers in one field or an-
other, as to what, in their judgment, was the most important
unexplored or half-explored field just ahead. By co-ordinating
these diversified opinions, I thought to attain a clearer view than
had hitherto been possible of the trend of scientific thought in
our day and the probable eventualities of the new scientific era
on the threshold of which we stand.

It was these studies, doubtless, combined with the earlier in-
vestigations that had found expression in my History of Science,
that made possible the crystallization of ideas in my mind rep-
resented by the Proteomorphic Theory. The actual textual for-
mulations of that theory at the particular time when it was
written came about through the accident of my being asked to
make a summary of existing theories of immunization. The
mental co-ordination through which the new and in a sense revo-
lutionary tenets of the Proteomorphic .Theory flashed into my
mind eventuated, rather curiously, one evening as I sat at din-
ner with my daughter in a little restaurant down in llth Street.
The dictating of the twenty-five thousand words of copy com-
prised in the presentation of the theory in American Medicine
was a tour de force begun and completed in the leisure hours
of three or four consecutive days.* But the connotations of the

*I would not seem to imply that the writing of this amount of matter
in the time mentioned constitutes an unusual task. A few months before
the Proteomorphic theory was written I had dictated more than half a
million words of finished manuscript (making eleven fair-sized volumes)
and turned the manuscript over to the printer in a period of fifty con-
secutive days. On almost numberless occasions I have written from
twelve thousand to fifteen thousand words of finished manuscript per day
for days together. One of my large books was begun on Monday morning
and finished Saturday night of the same week. Another (Volume I of my
History of Science) was produced in the midst of exacting duties of a
different character by dictating one hour daily (eight to nine in th<
morning) for twenty consecutive days. I mention these incidents tc
illustrate an habitual tendency to concentrated mental action, in explana-
tion of the seeming anomaly that so comprehensive and even revolutionarj
a doctrine as that comprised in the Proteomorphic theory should have
been produced rather as a mental pastime than as a fixed task. I majl
add, however, that the aftermath of the "mental pastime" in question
has involved me in a series of laborious investigations, of which this
volume gives some intimations, that will probably occupy a large part
of my time for the remainder of my life.

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 109

theory, and the mental associations that made its elaboration
possible, represented a lifetime of study; and the sequential de-
velopments, to which I am about to refer, were equally con-
ditioned on antecedent knowledge acquired through years of in-
vestigation. It is in this connection that I call to mind the
otherwise unrelated incidents just cited.

In particular, I would recall that the thing that impressed me
most in the visit to Ehrlich, above mentioned, was the room in
his laboratory where endless series of glass jars contained can-
cerous mice. Ehrlich himself at the moment was all enthused
over his tentative success with salvarsan, and he made but inci-
dental reference to the cancer mice, but I felt that this was the
problem that would next engage his attention — a problem, in-
deed, that had been interrupted by the other studies. With
peculiar interest, then, I learned a little later of the experiment
in which he had attained at least tentative results in the devel-
opment of a chemical combination, including selinium, that ap-
peared to have a selective action on cancer cells ; a work dupli-
cated, independently, I believe, by Wassermann, in Berlin.

These observations, and the still newer work of Wassermann,
in which he had endeavored to diagnose the presence of cancer
by tests applied to the blood, were fresh in my mind when I
observed the patients, and studied the photographs, at Dr. Kelly's
sanitorium there in Baltimore. I had also in mind the recently
reported experiments of Dr. Leo Loeb with colloidal copper in
the treatment of cancer. And I was, of course, familiar with
various tentatives in cancer treatment that had been made with
biological products, as admirably summarized in Dr. Bainbridge's
book of which just at this time I received a presentation copy
from the author. In particular I had followed with interest the
work of Hodenpyl, partly because I chanced to know personally
the patient from whom the ascitic fluid used by him with such
thought-provocative results was removed.

And as I linked and co-ordinated these various items of knowl-
edge, the thought that was paramount in my mind was that, be-
yond preadventure, it had been demonstrated that the cells of a
malignant neoplasm, notwithstanding their similarity to normal
cells, have essential differences that bring them within the pos-
sibility of selective action on the part of physical or chemical
agencies. The fact that all the methods of practically treating
cancer used hitherto had proved only tentative or utterly dis-
appointing; the fact that the cancer mass seemingly dispelled
by radium treatment might recur and grow with renewed and
fatal activity — these facts seemed to me altogether subordinate
to the great central fact that the cancer cell could, in some
instances, be caused to undergo seemingly autolysis through the

110 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

application of agencies that were not necessarily destructive of
the normal tissues subjacent to the abnormal growth.

This possibility being demonstrated, it seemed to me that the
first great step toward the ultimate successful issue of the con-
test with cancer had been taken.

It appeared to me, however, that radium therapy, as applied
to cancer — and the allied X-ray treatment which I had also
investigated — was subject to one almost insuperable difficulty.
It was hard to conceive how a method could be devised through
which the application of the disruptive rays could be brought
to bear on the cancer cells without bringing an influence on the
cells of healthy subjacent tissues ; and there was ample clinical
evidence that if this influence was carried beyond a certain
stage injury resulted to the healthy cells no less than to the
abnormal ones. The fair inference seems to be that the cancer
cells are of somewhat less stable constitution; that they, there-
fore, yield more readily to the disruptive influence of the radia-
tion; but that the difference between these cells and the normal
cells in this regard is a difference of degree and not a differ-
ence of kind. Such being the case, there is an obvious obstacle
in the use of radium or the X-ray, which by no means bars
these agents from usefulness, but which suggests, as it seems
to me, that they do not give promise of ultimate ideal solution
of the problem.

The ideal would be a chemical agent, biological or other, that
had selective chemical affinity for the cancer cell, with capacity
to effect disruptive activities, somewhat as salvarsan seemingly
has selective affinity for the spirochaete of syphilis.

In particular, at this time, my mind dwelt on the experiment
of Vaughan, with a brief statement of which the original presen-
tation of the Proteomorphic Theory had been concluded, which
showed that the large mononuclear leucocyte produces or con-
tains enzymes capable of splitting up cancer cells. In the con-
cluding paragraph of the Proteomorphic Theory, as originally
published, I suggested the possibility of producing antibodies
from the bodies of leucocytes ; and I had in mind, naturally,
the possible application of such enzymes in the treatment of
cancer (it was well known that Vaughan was working prac-
tically along these lines), and also the more general application
of the method implied in a predicted "extension of serum therapy
and vaccine therapy and the development of a new cyto-therapy."

That the suggested new therapy involved the use of meas-
ures to increase the numbers of corpuscles, and stimulate their
enzymic activities, was everywhere implied, and moreover was
explicitly stated in the discussion of agents calculated to produce
this effect; but the simple method of evoking a corpuscular re-
sponse by parenterally introducing foreign proteins as such did

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 111

not occur to me until later — although the idea lies so near to
hand that, looking back, it would seem that it must inevitably
occur to any one who grasps the fundamental features of the
Proteomorphic Theory. But here, as so often elsewhere in the
field of discovery, the retrospectively obvious may not be obvious
to all from the contemporaneous standpoint.

Nevertheless the idea was apparently very close to the sur-
face of my mind, for it came into clear view, as a vivid reality,
a little later, and was given concrete and tangible expression in
the paper that I published in the New York Medical Journal,
October 2, 1915 — just a year after the original publication of
the Proteomorphic Theory.

The specific observations that led to the clear realization and
application of the Proteomorphic principle had to do with a
series of cases of cancer, part of which had come under my
direct personal observation, and the remainder under observa-
tion at second hand, so to speak, through personal correspond-
ence with the physicians who treated them. The treatment con-
sisted of the hypodermic injection of a vegetable extract, the
nature of which was not at first very clearly divulged, but which
was ultimately known to be produced by macerating a dozen
powdered plant substances in salt solution or in alcohol. The
substances in question, as ultimately revealed, were the follow-
ing: Menyanthes trifoliata, buckbean (leaves); Melilotus offici-
nalis, sweet clover (leaves) ; Mentha crispa, mint (leaves) ; Bras-
sica alba, mustard (seed) ; Anemone hepatica, liver leaf (leaves) ;
Viola tricolor, pansy (flowers and leaves) ; Anthemis nobilis,
camomile (leaves); Citrullus Colocynthis, colocynth (fruit);
Quassia amara, quassia (wood) ; Urtica diocia, nettle (whole
plant except root) ; Rheum officinale, rhubarb (root) ; and Hys-
sopus officinalis, hedge hyssop (whole plant except root).

The formula for this bizarre compound, of unrevealed origin
(and now having only historical interest), had been brought to
this country by a Hungarian layman and used originally as a
poultice in the treatment of superficial epitheliomas and carci-
nomas. The extract in question, made at the instance of some
New York physicians who became interested in the matter, was
used hypodermically, and at first injected directly into the can-
cer mass, the observed effect being supposed to be local.

My attention was called to the matter in February, 1915, soon
after I had observed at first hand the effects of radium in the
treatment of cancer in Dr. Kelly's sanitorium as above related,
and at a time when my mind was actively engaged in consid-
ering various aspects of the cancer problem, and of the pos-
sible application of the Proteomorphic Theory. It is speaking
within bounds to say that I was profoundly impressed with what
I saw of cases under treatment with the vegetable extract at

112 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

the Polyclinic Hospital in New York. The clinical results, par-
ticularly in a case of cancer of the rectum and a case of hyper-
nephroma, struck me as spectacular and in the highest degree
thought-provocative.

But I was impressed also with the observation that — in these
cases and in various others — there appeared to be a congested
condition in the region of the tumor masses, involving both
white corpuscles and red, that was at least inferentially asso-
ciated with the autolytic process.

Meantime the action of the extract was not that of an escha-
rotic. This was fairly obvious even at the outset, when injec-
tion was made directly into the tumor masses; but it became
demonstrative when it was found a little later that the hypo-
dermic injection could be made into distant regions of the body
— say, the upper arm — with apparently the same results in
localized action on a tumor of the breast, the uteras, the stom-
ach, or other region. This seemed to imply a selective action as
between cancer cells and normal cells ; and the observations on
the blood appeared to justify the inference that the corpuscles
were the effective agents through which the selection came about.

Such, at least, was my own inference, biased as I naturally was
by what may be called the Proteomorphic point of view.

Coupled with the collateral observations outlined above, the
matter seemed to be of sufficient importance to merit very care-
ful investigation. I made such investigations in the offices of
the New York physicians who were applying the treatment, and
through correspondence with numerous others. I also visited a
physician in a neighboring city, who had twenty-five or thirty
cases under treatment, carefully inspecting the cases. In the
aggregate, the cases that came under my personal observation
in the half year following the first observations numbered about
three hundred. The reports from other physicians brought the
number to upward of a thousand. And the conclusion forced
upon me was that certain definite and tangible results attended
the administration of the extract. They were results closely sim-
ilar to those that had been attained by the use of various and
sundry of the biological extracts above referred to ; and sub-
stantially identical with those attained by the workers at the
Crocker Research Fund Institution with animal extracts, to
which fuller reference will be made in another connection. But
the method had merits over the antecedent ones in question in
that the extract used could be readily prepared, and lacked the
toxicity that characterized some of the others — for example,
the bacterial extract known as Coley's fluid, the efficacy of
which, in some cases of sarcoma, appears to be beyond question.

When the extract was first brought to my attention I was

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 113

told that no one had any very clear notion as to how it op-
erated, but that it was known to contain chlorophyll, and that
its action was supposed to be due either to this substance or to
some unknown agent of the nature of a vitamine. It was not
until about six months later that I learned the method of prep-
aration of the extract; then the fact was revealed that it con-
tained vegetable proteins in solution. Long before this I had
freely expressed the opinion that there was nothing specific about
the particular vegetable compound used to make the extract, and
had predicted that it would be possible to make extracts from
numberless other vegetables that would be equally effective.
This prophecy was in part based on the supposition that chloro-
phyll was the active agent involved.

But when I learned that the extract contained vegetable pro-
teins, a clear conception of its manner of action crystallized
instantly in my mind, along the lines of force, so to speak, of the
Proteomorphic theory. At once it seemed clear to me that we
had to do with a protein response; that the cohorts of leuco-
cytes and red corpuscles were stimulated into being and into
renewed activities to meet a protein invasion ; and that the ob-
served action on the cancer cells was only an incidental effect
due to the fact that these cells are themselves foreign proteins
and, therefore, fall within the range of activities of the cor-
puscles. The preliminary blood studies that were already under
way, the full details of which will be given presently, appeared
to justify the inference. The observed facts linked with the
Proteomorphic theory, in my mind at any rate, in a way abso-
lutely convincing.

Immediately, and at a single sitting, I wrote the paper explain-
ing the action of the remedy in the light of the Proteomorphic
Theory, which was published in the New York Medical Journal
of October 2, 1915.

I weigh my words very carefully, yet I speak entirely with-
out hesitation, when I express the conviction that a new era
in therapeutics was foreshadowed in that publication.

In speaking thus, I do not mean to refer in particular to the
treatment of cancer. That, as I clearly conceived at the time,
is only an incident. The subject involved is much larger. I
stated this explicitly in the article in question, enunciating the
opinion that a principle of protein response had been (quite by
accident) invoked that would apply against all protein infections.
I expressly stated the opinion that, in the attempt to explain the
rationale of the action through which the vegetable proteins bring
about a beneficent increase in the armies of leucocytes and ery-
throcites, we "gain glimpses of an entirely new field of thera-
peutics and shall be enabled to give at least a proximal explana-

114 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tion of the exact manner of action of a remedy, the introduction
of which, I believe, constitutes the inauguration of a method
that must in future rank with serum therapy and vaccine therapy
— if, indeed, it does not altogether outstrip or totally supplant
both these relatively new additions to the equipment of the prac-
tical physician."

Such a view as this, if presented without both theoretical and
clinical backing, must have seemed heretical. It carried the
clear implication that a non-specific protein might serve as an
antigen capable of decompounding proteins of many types, in-
cluding the bodies of various pathogenic bacteria and various
types of "malignant" cells.

The suggestion ran counter to the dominant medical thought
of the moment. The familiar facts regarding diphtheria anti-
toxin, Wright's anti-typhoid vaccine and allied vaccines, and
Ehrlich's salvarsan (to mention typical examples of three new
types of medication) had revived in the mind of the profession
the old hope that specific medication was to give final answer
to all therapeutic problems. In the cancer field, as well as in
the field of bacteriology, recent effort had nearly all been directed
along the lines either of specific antigens or of remedies having
elective affinity for particular cells. Various attempts to develop
a cancer anti-serum ; Vaughan's use of residual products of the
cancer cell, and Hodenpyl's use of ascitic fluid of a cancer sub-
ject were typical illustrations of one method; and the colloidal
copper treatment of Leo Loeb and selenium experiments of Ehr-
lich and Wassermann were illustrations of others.

It may fairly be said that most workers in the field were so
thoroughly imbued with the idea of specific therapy as to cause
them to look askance at any suggestion of a more general
method.

Perhaps I cannot better illustrate this than by stating that
among the medical men who were most closely concerned with
the introduction of the vegetable extract treatment, there were
those who were inclined to believe that the extract would be
found to contain something having a selective affinity for can-
cer cells, and hence falling within the scope of specific medica-
tion. The thought of a magical "vitamine" was at least vaguely
in their minds. Like the users of Dr. Gwyer's "X-substance,"
which produced analogous results, they were mystified by the
seeming complexity of the agent empirically used. These men
looked with frank scepticism on the theoretical interpretation
of the action of the remedy that I presented in the paper of
October 2, 1915, and did not for some time thereafter accept
the view that a general principle of protein antagonism had been
evoked.

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 115

It is fair to add that I myself was not prepared to demon-
strate at the time when this paper was published that there might
not be other agents, for example, chlorophyll, in the extract that
had a share in the therapeutic action. The demonstration that
the protein alone was the effective agent was the work of later
months, to be narrated in a moment. But the discovery of the
protein principle, and the interpretation of its action in the light
of the Proteomorphic theory, was clearly revealed in this paper
of October 2, 1915. My subsequent work was to elaborate and
demonstrate the principle, but in no wise to change its essen-
tials as presented at this time. There is reason to believe that
the paper found a responsive audience — witness the work in
non-specific protein therapy that a few months later began to
attract attention in the medical journals.

Meantime I had made a statistical study of the results of the
use of the vegetable extract in the treatment of cases of inop-
erable cancer — the only cases to which it was at first applied.
The article in which I summarized the result of this study ap-
peared in the New York Medical Journal of November 13, 1915.
A summary of the results will be presented elsewhere. For the
moment our chief concern is with the theoretical aspects of
the subject rather than with the clinical details. Suffice it that
the clinical experience, statistically summarized, overwhelmingly
sustained the belief that the bodily response, whether or not of
corpuscular origin, was of a nature to antagonize the cancer
cells, and favorably to influence the general conditions of the
patient, as evidenced by decrease or cessation of pain in a large
proportion of cases ; modification or annulment of malodor ; im-
proved appetite, sleep, and sense of well being; and, in a sur-
prisingly large percentage of cases, actual regression of the can-
cer mass itself.

All these clinical changes found explanation, according to my
belief, in the modified numbers and enhanced enzymic activ-
ities of the blood corpuscles, along the lines of the Proteomor-
phic Theory. This opinion found support in the elaborate studies
of the corpuscles, in the counting chamber and on the smear,
which were carried out by me personally, or under my direct
supervision, in the ensuing months.

These studies of the blood were undertaken without prejudice
or preconception. The earlier counts, numerical and differential,
were made under my direction, to be sure, but by an assistant
who had scant knowledge, or perhaps no knowledge at all, of
the Proteomorphic Theory, and who made and recorded obser-
vations automatically, without attempting to classify or sum-
marize them or to draw conclusions. When these observations
were tabulated by me, they at once revealed unequivocally cer-

116 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tain characteristic and very conspicuous modifications of the
blood, comprising, in brief summary, increase of haemoglobin,
increase of the number of red corpuscles, and striking modi-
fication of the differential leucocyte count, in the direction of
lessening the relative number of polynuclears, and markedly in-
creasing the mononuclears, and in particular the large monocytes.
The last-named feature appeared to link suggestively with
Vaughan's observations on the enzymic activities of the large
mononuclears in connection with cancer cells.

Elaborate analyses of the blood count, and of subsequent
studies along these lines, are made in later sections of the pres-
ent work. Here it suffices to call attention to the fact that these
studies from the outset confirmed in my mind the probability
that we had to do with a protein response, and that the Prote-
omorphic Theory supplied a key to the interpretation of the
observed phenomena.

The clinical results hitherto observed were not very different
from those that had been attained by various workers with
different types of animal extracts, sera, and vaccines (Fichera's
autolysate, Hodenpyl's ascitic fluid, Gwyer's X-substance, Coley's
fluid), except that they were carried out on a more elaborate
scale ; but the studies of the blood in this connection were alto-
gether new, and they constituted the determining factor in con-
firming in my mind the belief that the new therapeutic principle
which I conceived to underlie the observed phenomena might
carry us far.

It seemed to me imperative, therefore, that I should put aside
other work and devote my time to the interpretation of this
principle, which appeared to adumbrate vast therapeutic possi-
bilities.

I was more urgently impelled to do so because, with enlarged
experience, it became increasingly evident that the glowing an-
ticipations of some of the earlier users of the vegetable extract
in the treatment of cancer had led to bitter disappointment, in
that patients who seemed at first to be on the highway to re-
covery reached a static period presently and then relapsed and
gradually passed down the characteristic decline to the usual
fatal termination.

I heard over and over the same story, from scores of med-
ical correspondents. At first the improvement of the patient had
been almost miraculous. High hopes were entertained of a
recovery, although previously the case had been regarded as
absolutely hopeless. But now progress was no longer cumula-
tive; the patient perhaps remained more comfortable, with less
pain, less of malodor, but there was a general physical decline;
the tumor's course was no longer checked, the symptoms of

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 117

cachexia were progressive, and the end was obviously at hand.
The life of the patient had undoubtedly been made more comfort-
able, and had almost certainly been prolonged; but the ultimate
result had not been what the friends of the patient had hoped
for, and what the physician had for a time allowed himself to
expect.

There were exceptions to this, it is true. A few cases out of
the hundreds appeared to have gone to a clinical recovery that
seemed to give promise of permanency. But these exceptions,
notable in themselves, were few and far between.

This, of course, was precisely the history of the various ante-
cedent biological measures in the treatment of cancer — the experi-
ence that had led to the abandonment of most of these methods
after a brief term of use. But to me the experience seemed
neither unexpected nor disheartening. I had been careful to
point out in my statistical reports that these were only prelim-
inary and that the final story could not be told for months to
come. I had pointed out that what was being sought was a
scientific medicament and not a magician's wand. I had repu-
diated from the outset the suggestion that the particular vege-
table extract in question had any specific qualities whatsoever
that set it aside from any other extract containing non-toxic
proteins.

And what was still more important — as the sequel will show —
I had conceived the idea that, if the active agent involved was
indeed, as I believed, a protein, as such, there could be nothing
more natural than the gradual immunization of the system against
the particular proteins employed, with the result that the cor-
puscular response would presently cease to be cumulative. This,
as it seems to me, would account for the observed fact that the
patient who had at first shown extraordinary response presently
reached a static condition, and then entered on a period of
decline.

The fact that the use of excessive dosage, or the accidental
or intentional injection of the extract into a vein, with a re-
sultant anaphylactic shock, had been observed sometimes to bring
about a new period of favorable progress in a case that had
reached this static phase, appeared to me to confirm the view
just presented.

The essential fact, as I conceived it, now established irre-
futably, was that the parenteral introduction of a protein could
bring about a response that would produce such clinical modi-
fications. The fact that the response was not indefinitely per-
sistent, and that the ultimate clinical results fell short of the
miraculous, seemed to me a detail. A very tragic detail, to be
sure, for the individual patient ; but by no means condemnatory

118 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

of the procedure as a whole, and assuredly not precluding the
possibility of further development along similar lines.

Therefore I re-entered the laboratory (several years of my ear-
lier professional life had been devoted to chemistry and pathology)
and took up once more the routine of office practice, and the labo-
rious but ever fascinating grind with test tube and microscope. The
dominant thought was to test the protein principle as interpreted
in terms of the Proteomorphic Theory. My published contention
that we had to do with no specific agent, but with a general
principle that could be utilized in all kinds of protein infec-
tions had found a measure of practical support in the success-
ful treatment of a few cases of rheumatoid arthritis and one
almost spectacular case of tuberculosis. The modification of the
blood in these cases had been characteristic; and similar modi-
fications were observed in patients treated with sheep serum.

My belief that the observed modifications are of the nature
of a response to the introduction of a foreign protein, and not
to any particular protein, had become a firm conviction. But
it required further experimental support.

An obvious way to test the matter would be to produce pro-
tein extracts from a variety of non-toxic vegetable substances,
and to observe their effects when used hypodermically. Such
extracts were made from alfalfa seed, millet seed, rape seed,
hemp seed (and subsequently from numerous other sources),
carefully standardized by a nitrogen determination, and clin-
ically tested with a variety of patients, most of whom had long
been under treatment with the original protein extract, but some
of whom had never previously been treated with proteins of
any kind.

The vegetable proteins thus used were at first prepared by
macerating the ground seeds in either salt solution or solu-
tion of sodium hydroxide. A concentration varying from two
to four milligrams of nitrogen to the cubic centimeter was af-
fected by the Kjeldahl method, and ultimately a standardization
on the basis of three milligrams of nitrogen, or approximately
a two per cent, protein solution, was adopted as a satisfactory
and convenient compromise. Sometimes the proteins were used
in the original solution ; in other cases the protein was precipi-
tated from the extract with acetic or hydrochloric acid ; washed,
and redissolved in a solution of sodium hydroxide. In any
event, the extract was always made slightly alkaline with sodium
hydroxide, the slightest degree of acidity rendering it painful
on administration. I had early discovered that this was one
source of irritation that made the administration of the original
extract unpleasant.

Extracts thus prepared were first employed therapeutically in

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 119

July, 1916. They were tested side by side with extracts made
from the conglomerate group of herbs originally employed, or
from this powder with part of the original constituents elim-
inated. Comparative tests were continued for a period of six
months, after which the original extract was entirely aban-
doned, the uncomplicated protein solutions made from alfalfa seed,
alfalfa meal, rape seed, millet seed, hemp seed, and from egg
albumin and milk albumin, used singly or in combination, hav-
ing been demonstrated to produce the same clinical and blood
responses, and bearing about the same relation to the original
clumsy formula that a modern preparation of digitalis bears
to the shot gun formula of the old woman who first used an
infusion of foxglove combined with sundry inert herbs.

In a word, the validity of my early contention that .the re-
sponse was essentially a protein response was abundantly demon-
strated.

Moreover, my expectation that a new protein would produce
a new response, thus supplying means to overcome the stasis
accompanying immunization to the first protein employed, was
also justified in the most gratifying manner. Cases that had
become static after having undergone an original period of prog-
ress, took on a new period of favorable progress on the admin-
istration of the new proteins. The very first patient to whom
alfalfa protein was administered showed the influence of the
new protein in a very striking way. This was a case of meta-
static recurrence after excision of the cancer of the breast.
The neoplasm had regressed under early treatment, but had
become static, with a seeming tendency to take on new growth.
It at once regressed when the alfalfa protein was administered,
and presently nothing remained but a pea-sized nodule just under
the skin, which was excised with local anesthesia. The patient
went on to seemingly complete recovery, and at the present
writing, eighteen months after the disappearance of all symp-
toms or appearances of abnormality, she is in robust condition
and seemingly in complete health.

THEORY TESTED BY PROPHECY

It has been said that the final test of the truth of a theory is
that its application shall enable one to prophesy. It is with
peculiar satisfaction, then, that I make this succinct record of
prophecies fulfilled. Given a therapeutic agent extracted by an
unknown process from a conglomerate mixture of drugs, and
showing clinical response altogether inexplicable by any known
principle of therapeutics ; I predicated the response — guided by
the Proteomorphic Theory — as due to no ordinary pharmaceu-

120 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tical property of any of the ingredients, but as a general response
to the proteins that chanced to be extracted along with sundry
inert constituents ; and — still guided by the Proteomorphic
Theory — I went on to predict that it would be possible to make
numberless extracts having precisely comparable therapeutic ac-
tion from altogether unrelated vegetable products — that, in short,
any non-toxic protein would suffice, in a measure at any rate,
to take the place of the proteins under observation. I predicted
that it would be possible to stimulate a new response by intro-
ducing a new protein after the system had become immunized to
an earlier one. I further suggested that quantitative differences
would be found in the response to different proteins, in accord-
ance with the nearness or remoteness of the individual protein,
botanically speaking, to the proteins of ordinary foodstuffs.

All of these prophecies have been abundantly substantiated
by experiences that now extend over a period of nearly twenty
months, fortified by my personal observation of more than one
hundred carefully studied cases in which clinical manifestations
were constantly checked by blood examinations ; and corrob-
orated by the experience of a body of representative physicians
in all parts of the United States.

Under date of December 1, 1916, I issued a Monograph of
126 pages bearing the title The Proteal Treatment of Cancer and
Allied Conditions; A Practical Study of a New Therapeutic
Principle as Interpreted in the Light of the Proteomorphic
Theory. A portion of the contents of this Monograph is in-
corporated in the text of the present book and may there be con-
sulted in detail. Here I wish to quote from the Foreword a
few sentences that will suggest the confidence which enlarged
experience had inspired — confidence which the yet wider experi-
ence of another fifteen months has abundantly fortified. On
December 1, 1916, then, I felt justified in making the following
emphatic estimate of results attained; which now, fifteen months
later, I reiterate with no less emphasis :

"That proteals, properly administered, assuage the pain of
the cancer sufferer in a large proportion of cases; neutralize
malodor; stimulate the blood count and with it the manifesta-
tions of improved health and comfort ; and in a conspicuous pro-
portion of cases cause unmistakable modifications in the condi-
tion of the neoplasm itself, amounting frequently to marked
regression — is scarcely more open to-day to dispute than that
digitalis stabilizes the heart beat, that quinine antagonizes the
plasmodium of malaria, or that mercury combats the germ of
syphilis.

"There remains, however, a question as to the amount of ben-
efit that may be expected in any individual case; and the all-

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 121

important question as to whether seeming recoveries under the
proteal treatment are complete and permanent recoveries. These
questions will be discussed in the ensuing pages, but with no
suggestion that a final answer as to the permanency of seeming
cures can be made except after the lapse of a long period of time.

"But if the question of the possible cure of cancer by the
new type of medication must be left in abeyance, there is no
occasion for delay in spreading broadcast the knowledge that
the proteals bring a message of new hope for the cancer sufferer,
whatever the form or stage of progress of his malady. The
proteal remedies have already conferred unique benefits upon
not far from 3,000 sufferers ; they have been responsible for
an enormous alleviation of pain in the aggregate, and for a
notable extension of human lives.

"According to recent statistics, cancer accounts for five or
six per cent, of all deaths. That is equivalent to saying that
at least five million people are living in the United States to-day
who must die of cancer unless medical science in the coming
years deals more effectively with the malady than it has known
how to do in the past.

"I dare to hope that the facts cited in this monograph justify
the belief that we are beginning to see a little light in this dark
field.

"I dare even to hope that the beginning of the end of the can-
cer scourge is at hand. Proteal treatment may not offer the
final solution of the cancer problem ; but I verily believe that
it points the way to a solution.

"In any event, the proteal treatment offers to-day a hitherto
unattainable measure of solace, and a message of new hope for
cancer sufferers everywhere in the world."

To be able to write such an estimate, secure in the belief that
the evidence already in hand abundantly justified it, might well
be considered adequate reward for two years of strenuous and
nerve-racking investigation. But in point of fact this was only
the beginning, as I then conceived it, and as I now conceive it.
In the article of October 2, 1915, in the New York Medical
Journal I had expressly repudiated the idea that the protein
response has any specific relation to cancer except in so far as
the cancer mass chances to be composed of protein matter, as-
serting the belief that the province of protein therapy is the
entire .field of protein infection. I purposely refrained from
mentioning bacterial infections as such, for I knew that at best
the suggestion of so general a principle as that implied would
tax the credulity of the profession. But that I had the bac-
terial infections in mind is implied in the fact that these are,
as a matter of course, protein infections; and is explicitly sug-

122 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

gested in the prediction above quoted that the non-specific pro-
tein method "must in future rank with serum therapy and vaccine
therapy — if, indeed, it does not altogether outstrip or totally
supplant both these relatively new additions to the equipment of
the practical physician."

The confidence that underlay this prediction had led me to
urge the use of the non-specific protein extracts in all manner
of toxaemias; and, as rapidly as opportunity offered, the matter
was put to practical tests, in my own practice, and through co-
operation with several hundred progressive physicians to whom
proteals were supplied from my experimental laboratory. As a
result, it has been demonstrated, within two years of the time
when the prophecy was made, that intestinal toxaemias, anaemias,
neurasthenias, rheumatoid conditions (including rheumatoid ar-
thritis), tuberculosis, asthma, and psoriasis fall within the scope
of the protein response no less than cancer, and there is no rea-
son to suppose that even this comprehensive list of maladies
exhausts the possibilities of the method.

OTHER REMEDIAL USES OF THE PROTEALS

The Monograph, though dealing primarily with cancer, made
explicit reference to these wider and, in the aggregate, more
important applications of Proteal Therapy, in part as follows :

It remains to give brief consideration to sundry conditions of
the organism not characterized by the presence of malignant
neoplasms, but associated with organic maladjustments that make
possible the development of such neoplasms; and directly char-
acterized by proliferation of protoplasmic tissues in my judg-
ment comparable with cancer proper — though not commonly
viewed in this light by physiologists or pathologists.

I have in mind various conditions characterized by disturb-
ances of nutrition and assimilation that lead to abnormal growth
of cells in one region or another of the body, all evidencing
conditions of hyperplasia that had certain elements of "malig-
nancy," inasmuch as they are deleterious to the organism, though
varying enormously in the degree of their obnoxiousness.
Among these conditions are : ( 1 ) Anaemic obesity, in which law-
less adipose cells encroach on more useful tissues; (2) pernicious
anaemia and the lymphaemias and myelaemias, characterized by
hyperplasia of the blood-forming tissues; (3) glandular hyper-
trophy, as in goiter, thymus enlargement, and splenomegaly ; (4)
rheumatoid arthritis, characterized by hyperplasia of tissues as-
sociated with joints; (5) general arteriosclerosis, characterized
by hyperplasia of the tissues of the arterial walls ; (6) sundry

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 123

lipomas and fibromas of "benign" character; in addition to (7)
the neoplasms commonly recognized as "malignant."

I venture to associate all these conditions, and to trace them
to a common origin in maladjustments of protein metabolism,
and I suggest that it might not be illogical to group them all
under some such generic title as hyperproteomorphism, or the
cancerous condition. I shall not attempt here to discuss even
in briefest detail the interesting questions in pathology that arise
in connection with the implied association of conditions of such
seeming diversity. Such a discussion will form the basis of
another book. Here I wish to point out very briefly two or
three sets of clinical facts that give at least a measure of sup-
port to the unorthodox conception applied in this classification.

I would first call attention to the familiar fact that a well-
known type of fatty and mucinous hypertrophy known as myx-
oedema is associated with perversions of the thyroid function;
and the further fact that there is believed to be a close asso-
ciation between the integrity of the hormone functioning and
bodily metabolism in general.

Without attempting to point out except in this general way
what I conceive to be the bearing of the observation, I wish to
note that it has been observed by at least one physician who
was administering the mixed proteals in a case of cancer that
an enlarged thyroid disappeared during the treatment.

Observations along this line have not yet reached the point of
readiness for detailed publication. By way of anticipation, how-
ever, we may note that the modification of blood count under
influence of the thyroid serum is singularly like that brought
about by the proteals ; suggesting that the action of the serum
is partly explicable on the basis of its protein content. Doubt-
less there is also an anti-thyroid enzyme element, but the agent
that causes decrease in size of the enlarged thyroid is probably
not this anti-ferment, but the sheep-serum protein.

In the next instance I would note that in a case of cancer
under mixed vegetable protein treatment there existed the com-
plication of severe rheumatoid arthritis. The latter condition
cleared up entirely — a seeming cure being effected under the
protein treatment. This observation led to the administration
of the proteals in several cases of rheumatoid arthritis uncom-
plicated by the presence of cancer ; and the results of such treat-
ment have been highly gratifying. In a recent case the response
to rape seed protein by itself seemed as active as the response
to the combined proteins.

As regards the relation of the new treatment to the form of
nutritional maladjustment manifesting itself in pernicious anae-

124 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

mia, I cannot do better than to quote a letter received not long
ago from a physician in Michigan, which is self-explanatory.

"I have been using vegetable proteins in a late stage of per-
nicious ansemia on purely theoretical grounds. After ten injec-
tions have found an increase of over 15 per cent, in the red
cells with an accompanying favorable alteration in the differential
leucocyte count, and have noted nucleated red cells for the first
time since the treatment was begun.

"The patient, a man over 50 years of age, carpenter by trade,
is without means, having been unable to work for over 18
months. I ordered the remedy for him on my own responsi-
bility, having become familiar with the product through using
it in a supposedly hopeless case of carcinoma of the liver, sec-
ondary to gall bladder carcinoma in my wife's mother. Gall
bladder and neighboring involved liver were removed and re-
ported by pathologist at University of Michigan as carcinoma,
and a hopeless prognosis given."

Vegetable protein treatment was undertaken, and continued
between three and four months ; after which, according to the
report :

"The patient is in better flesh than ever before, is well and
comfortable in every way, and the right lobe of liver, which is
low, feels perfectly smooth and healthy."

It will be observed that this letter has double interest, inas-
much as it bears on the question of the value of combined pro-
teins in the treatment of a "supposedly hopeless case of carci-
noma of the liver," as well as on the question of its value in the
treatment of pernicious anaemia. It is, however, only the lat-
ter point that is at the moment pertinent. I shall not elaborate
the point, however, beyond stating that a letter from the same
physician received several weeks later confirms the observation
that the condition of this patient is benefited by the treatment.
Obviously this is no more than might be expected of the admin-
istration of a remedy which has been observed in a very large
number of cases to produce striking and beneficial modifications
of the blood count.

A further report on the progress of this case comes to hand
in a still more recent letter bearing date of October 19, 1916,
telling of the resumption of the treatment after a considerable
intermission.

"The pernicious anaemia case has shown a remarkable change
for the better since using last package of ampules. This patient,
a county case, was in a somnolent condition, and in fact had been
removed from ward to private room to die. He is now bright,
has lost all the general cedema, eats well, and wishes to be up
and around."

DISCOVERY OF PROTEIN PRINCIPLE IN THERAPEUTICS 125

Just as the physician above quoted was led "on theoretical
grounds," following his observations of the results of the pro-
teal treatment, to inquire whether the remedy might not be of
value in connection with pernicious anaemia, other physicians have
questioned whether its capacity to stimulate the production of
corpuscular enzymes and to bring up the blood count might not
make it of value in the treatment of bacterial diseases.

Very brief but specific reference to such a possibility was,
indeed, made in my paper of October 2nd, in the New York
Medical Journal. In referring to this in the Monograph of
December 1, 1916, the suggestive comment was made that:
"A limited experience in the treatment of tuberculosis appears
to warrant the hope that non-toxic vegetable proteins will prove
available to fortify the defensive mechanism of the body (ac-
cording to the present thesis) by stimulating the corpuscular
activities against the tubercle bacillus. If a non-specific protein
can produce this effect, there would seem to be no reason why
the same protein, or allied proteins, may not give effective aid
in combating all types of pathogenic bacteria."

The above, it will be observed, is in effect a summary of the
stage of development of Proteal Therapy in its wider applications,
toward the close of the year 1916.

The year 1917, following the publication of the Monograph,
saw a rapid extension of the use of Proteals. In the course of a
lecture tour in the west (April 12th to August 19th, 1917), I
delivered over one hundred addresses on Proteal Therapy to
companies of medical men, emphasizing always the wide possi-
bilities of the method in its application to conditions of disturbed
metabolism, and specifically urging the use of the Proteals in
anaemias, toxaemias, rheumatoid conditions, asthma, and tuber-
culosis. Partly as a result of this personal presentation, several
hundred physicians have used the Proteals in these and allied
conditions. More than fourteen thousand ampules of the vari-
ous Proteals were sent from my laboratory to the members of
the profession for such use during the year 1917 and the first
two months of 1918.

A large number of these physicians have reported gratifying
experiences in the use of the Proteals, notably in the treatment
of anaemias, rheumatoid arthritis, asthma, and tuberculosis;
corroborating in a most satisfactory way my personal expe-
rience. Some of these reports will be found incorporated in
the text of the ensuing pages ; which is chiefly devoted, however,
to records gained in my own office, with particular emphasis
on my original hematological studies. The experience of the
co-operating physicians, nevertheless, forms a most enhearten-
ing background, giving assurance that the pioneer results can be

126 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

duplicated everywhere in the hands of the profession at large.
The "entirely new field of therapeutics" covering the domain of
"all protein infections" is no longer an unexplored territory.
Proteal therapy is by way of assuming its predicted rank along-
side serum therapy and vaccine therapy, and the suggestion that
it may ultimately "altogether outstrip both these relatively new
additions to the equipment of the practical physician" seems no
longer hazardous.

If, then, making prophecy possible is the final test of the truth
of a theory, the Proteomorphic theory and its corollary, the
principle of the Protein Response in Therapeutics, have found
abundant justification. I think I am speaking well within bounds
in saying that there are few instances in the entire history of
medicine in which a therapeutic method has had so secure
and so thoroughly scientific a theoretical foundation. In recog-
nition of this fact, it would perhaps be permissible to speak of
the use of non-toxic (non-specific) proteins as antigens in dealing
with all foreign protein invasions and inherent disturbances of
protein metabolism, as utilizing and representing the "Pro-
teomorphic Principle."

The particular application of this principle, which will chiefly
claim attention in the succeeding chapter — the only application,
indeed, which has been tested on an extensive scale up to the
present time — has to do with the vegetable proteins, for which
I have suggested, provisionally, the name of Proteals.

CHAPTER IV
THE SCIENCE AND ART OF PROTEAL THERAPY

If the testimony presented in the earlier chapters of this
book is accepted as conclusive, it will be understood that the
most salient bodily response to the hypodermic administration
of proteins has to do with the regeneration of the blood.

I have observed, as characteristic and almost uniform effects
of proteantigen treatment, increase of haemoglobin, increase in
numbers and modification in quality of the red corpuscles, and
modification of the white corpuscles in the direction of normal
numbers, relative decrease of polynuclears, and relative increase
of mononuclears, in particular the large mononuclears, and of
eosinophiles.

These modifications of the blood are too conspicuous and too
uniform to be considered as accidental. They have been ob-
served in a considerable variety of maladies, including simple
anaemia, secondary anaemia, pernicious anaemia, Graves' disease,
intestinal toxaemia, and other protein toxaemias, rheumatoid
arthritis, chronic articular rheumatism, tuberculosis, mastitis,
and cancer. The aggregate number of cases under observation
is large enough to justify deductions of a somewhat definite
character.

The original studies, and up to the present by far the most
comprehensive ones, bearing on this subject have been made by
the writer himself or under his immediate personal supervision ;
but corroborative testimony as to individual cases has come
from many independent sources, telling of observations of physi-
cians who have administered the proteal treatment to patients
suffering from a variety of maladies. In particular these observa-
tions have had to do with the improvement in haemoglobin and
the increase of the red blood count; since a good many physi-
cians make observation of these matters without taking time
to make careful differential leucocyte count. It is hoped that
physicians in general will pay more attention in the near future
to the blood count in general and the leucocyte count in partic-
ular, partly, at least, as a result of the evidence presented in my
cancer Monograph and in the present volume.

Meantime practitioners who have not facilities for careful
blood examinations may observe the clinical effects of the use
of the new method, which after all is, in the last analysis, the
matter of genuine importance. If the patient looks better, feels
better, has improved appetite and digestion, sleeps better, gains

127

128 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

in weight, strength and energy — practitioner and patient alike
will indulge a measure of satisfaction quite independent of any
microscopical findings to justify their clinical observations.
Nevertheless I would urge that the most intelligent administra-
tion of protein therapy cannot be carried out without the aid
of the microscope, for reasons that have been detailed in earlier
chapters. This is particularly true, as I have pointed out, in
the later stages of treatment. The initial doses of any Proteal
may be given after a routine method, details of which will be
presented more fully in a moment. But determination of dosage
at a later stage of treatment, particularly in case of grave mala-
dies, and questions as to the time when treatment may advan-
tageously be discontinued should be answered by combining
clinical observations with microscopic study of the blood. I
repeat, however, that such observation is not absolutely necessary,
any more than it is in connection with any other line of treat-
ment. But my own studies lead me to feel, in common with other
hematologists, that the microscope should be given a far more
important place in the equipment of the general practitioner
than has yet been accorded it, and I would not overlook this
opportunity to reiterate that opinion.

I would urge the practitioner to carry his studies of the blood
somewhat beyond the elementary stage, and I venture to make
a few practical suggestions based on my own personal studies
before going on to a detailed consideration of the practicalities
of the administration of proteals. I am stimulated to do this
partly because a large correspondence with physicians has shown
a growing interest in the subject, and I feel that by presenting
the matter here I can in effect answer individual inquiries as
advantageously as by personal letter. What I have to say here,
however, must not be taken as a comprehensive study, but only
as a series of practical hints.

At the outset, I would ^suggest that a good deal more atten-
tion might advantageously be given to cells in the counting cham-
ber than is commonly done. A mere numerical count does not
by any means tell the entire story. It is often of interest and
value to note the response of the cells to the influence of the
Toisson solution that is commonly used in counting. Often cells
that at first seem round, full, and normal will presently show
crenated edges, shrivel in size, develop spine-like processes or
fimbriations until they assume the appearance of diminutive sea
urchins, and show other malformations.

It is my opinion that the time required to bring about these
modifications gives at least general clues to the qualitative status
of the red corpuscles; and, in particular, that the corpuscles
suffering, from protein toxaemia (intestinal, cancerous, or what

THE SCIENCE AND ART OF PROTEAL THERAPY 129

not) usually show an exceptional sensitiveness, their bodies be-
coming malformed in the course of a few minutes or a half hour
even though showing normal appearance when the blood is first
drawn. The proportion of cells that take on the sea urchin
form should also be noted as giving a general impression of the
degree of abnormality.

Sometimes it happens that under Proteal treatment the red
corpuscles show a very marked betterment in size and form, so
that there is notable increase in the bulk of these corpuscles in
the aggregate, although the actual number may be decreased.
An interesting illustration of this is shown by a case of cancer
of the stomach under treatment at my office, patient No. 543.
When first examined, before treatment, the blood of this patient
showed 4,900,000 red corpuscles, but the great majority of these
were mere fragments of normal corpuscles, distorted and mis-
shapen, three or four of them scarcely equaling the bulk of a
normal corpuscle. The haemoglobin index was only 60, and the
appearance of the patient was cachetic to the point of ghastliness.
The white cells numbered 13,000.

After one week of treatment with Proteal No. 37 (chiefly pro-
teins of mustard seed, alfalfa seed, and alfalfa meal) there was
a very striking modification in the character of the red cor-
puscles, the dark fragments having disappeared in the main
and their place being taken by corpuscles of fairly normal size
and appearance. The numerical count, however, had dropped
to 4,364,000. Meantime the white cells had been reduced to
8,500.

The haemoglobin index was now 75.

At the end of the second week, 90 per cent, of the red cells
were normal in size and fairly regular in contour, except that a
good many were somewhat oval in shape. Many of the cells
were slightly fringed at the edges, and there were a few small
cells and a good many platelets. In general the red cells were
recorded as presenting an utterly different aspect from the field
of two weeks earlier — a tremendous advance towards normality.
The total number, however, was only 4,120,000. The white cells
numbered 7,200.

At the end of the third week there was farther advance in
the same direction as regards the quality of cells.

At the end of the fourth week, this patient's red corpuscles
showed not more than 10 per cent, of the crenated and mis-
shapen corpuscles after standing two hours in the Toisson
fluid. A large proportion of the cells were full sized and fairly
normal in appearance. And the number had gone up again to
4,954,000. Meantime there had been a further decrease in the
white corpuscles, which now numbers 6,130. The haemoglobin

130 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

index had advanced week by week from the initial 60 to 70,
70 plus, and, at the end of the third week, 80. Modifications
of the differential count and of the qualitative status of the white
cells will be referred to in another connection. Here it suffices
to say that these were of the usual character, involving increase
of the large monocytes and a characteristic change in the staining
quality of the cells.

It is perhaps not unimportant to add that the patient showed
steady improvement in his clinical condition, as might be ex-
pected considering the blood changes. And it should be ex-
plained that the cancer involves the pyloris, closing the aperture,
and that a gastro-enterostomy making an artificial exit through
the anterior wall of the stomach had been performed about five
months before the Proteal treatment was begun, the surgeons
at that time reporting themselves unable to remove the cancerous
mass, which involved not only the stomach but the liver. Since
that time, prior to beginning the Proteal treatment, the patient
had been given the usual variety of drugs, including iron and
arsenic, together with sedatives, yet he had gone from bad to
worse, suffered constantly from gastric disturbances and the
regurgitation of a bitter greenish fluid. He was constantly
hungry, no matter how much food he took, and had wasted
away until, although more than six feet high, he weighed only
128 Ibs. Could sleep little owing chiefly to discomfort in con-
nection with the joints of his legs. The left knee joint was
much swollen, and the patient limped markedly in attempting to
walk.

When the patient came under my observation all drugs taken
by the stomach were discontinued except that rhubarb and soda
mixture was given, together with a daily dose of mineral oil to
aid in regulating the bowels, which had been obstinately con-
stipated. The patient was placed on an exclusively vegetable
and milk diet, and Proteal hypodermics were administered daily
in doses beginning with 3 minims and advancing pretty rapidly
to a maximum of 15 minims. The response was prompt and
stimulative. The patient soon handled his food better and he
gained steadily in strength, presently going about by himself as
he had not done for some time before. The knee joints showed
quite an increase in swelling at first, but before ten days and
subsided to practically normal, and the discomfort in the legs
had disappeared, so that the patient was sleeping well. His com-
plexion changed quite conspicuously, as would be expected,
considering the modification in the blood, and his mental state
was far more comfortable. Meantime palpation showed marked
flattening of the gastric mass, which was hollowed conspicuously
equatorially, and which became slightly tender on pressure, as

THE SCIENCE AND ART OF PROTEAL THERAPY 131

it had not been before. The patient mentioned also having
occasionally experienced a gnawing sensation in the region of
the mass, not especially disagreeable in character, but sufficient
to attract attention.

I have cited details of this case because it is fairly typical.
That the striking modifications of blood and the attendant
clinical evidences of improvement were due directly to the ad-
ministration of the vegetable protein, seems scarcely open to
doubt. It is perhaps equally open to doubt whether any other
treatment hiherto available could be expected to produce modi-
fications similar in character in a late stage of carcinoma of the
stomach which had brought its victim seemingly to the verge
of moribundity.

In such a case as this, it may be said that observation of the
blood in the counting chamber served to give corroborative evi-
dence rather than as a guide in treatment. It should be pointed
out, however, that at a later stage in such cases the microscope
may give the crucial indication as to the time when it is desirable
to change the character of the protein, substituting a new pro-
teal for the one which is losing its effect. Moreover, in many
cases in which the protein toxaemia is of more equivocal char-
acter— anaemias of doubtful origin, mild intestinal toxaemia,
etc. — the microscope may give unequivocal evidence, through ob-
servation of the modification of the red cells above referred to,
that will be of a great value in diagnosis and thereby aid in de-
termining the probable availability of proteal treatment.

Here, for example, is a patient having tumorous masses in
both breasts. Her physician has urged her to have an immediate
operation for the amputation of both breasts. But examination
of the blood shows only 3,200,000 red corpuscles, with extreme
leukopenia, the white cells numbering but 1,800.

With such blood conditions, one could not justify an operation
without preliminary Proteal treatment. The response to this
treatment was immediate and extraordinary. After ten days
the red corpuscles had increased to 5,716,000, and the white
corpuscles to 8,400. The patient's general appearance and sub-
jective feelings had been metamorphosed. From having been
depressed and lethargic, she became exhilarated and buoyant.
She declared that she felt like a girl. Presently her condition
was considered suitable for an operation, and the removal of
the breasts was accomplished, followed by an uneventful re-
covery. After leaving the hospital, however, the patient did
not recover her strength rapidly. Two weeks after the opera-
tion, it was found that the red blood count was 4,516,000. This
was satisfactory enough, but, on the contrary, the white count
showed 16,500, obviously much too high. The Proteal treat-

132 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

merit, which had been interrupted a few days before the opera-
tion, was now resumed. Six days later the blood count showed
the following: red corpuscles, 4,740,000; leucocytes, 13,500,—
telling, obviously, of progress in the right direction. The haemo-
globin index had increased from 80 to 95. Clinically, there was
immediate betterment associated with the resumption of the
proteal treatment ; the patient ceased to have fainting spells, and
gained strength progressively.

It must be obvious that the microscope is an invaluable auxil-
iary in helping to determine the line of treatment in such a case
as this. The same thing is true, as is equally obvious, of cases of
anaemia of various types, and in particular of intestinal and other
protein toxaemias, the clinical symptoms of which may be varied
and lacking in pathognomonic character.

If we turn from the counting-chamber to the blood smear we
find a further exemplification of the same principle. Here the
red cells are still of interest as regards their size, form, and
tendency to dry with smooth contour or with crenated edges
suggestive of amoeboid activity. Their tendency to take on a
copper color on one hand or a bluish cast on the other in the
ordinary Wright or Hastings stain (methylene blue and cosine)
may indicate a condition of alkalinity or acidity as the case may
be that gives at least suggestive hints as to like conditions in
the patient's system. The presence or absence of a tendency to
rupture, with the formation of so-called platelets, is also of
interest, as suggesting the degree of pliability of the cells and
the liquidity of their contents.

According to my own observations, for example, the red cells
of late stage cancer subjects are of such constitution that they
do not tend to disrupt and produce a normal equipment of
platelets on the smear. This is consonant with the tests made
some years ago at the Loomis Laboratory, which showed that
the red cells of cancer subjects are more resistant to haemolysis
than normal cells. I regard the appearance of platelets in normal
numbers under treatment as a favorable indication ; tending at
least to suggest that a modification of the chemical constitution
of the cells is being made in the direction of normality.

Vacuolation of center of the red cell, indicative of paucity of
haemoglobin, and the presence or absence of normoblasts are
conditions that will be observed as a matter of course. It is
not always easy to interpret the precise meaning of influx of
normoblasts. I have known it to occur in an individual previously
in apparent health and undergoing no treatment whatever, in con-
nection with the onset of an acute coryza that did not go on to
a stage of marked infection. In the particular case that I have
in mind there was, however, an accompanying jump in the

THE SCIENCE AND ART OF PROTEAL THERAPY 133

leucocyte count from 5,800 to 13,000, showing that the infection
was really more significant than the clinical symptoms might
have suggested. Obviously there was a marked stimulus to the
blood-forming organs. An interesting feature of this case is
that the presence of normoblasts and of amoeboid red cells taking
a coppery stain was observed two days before the onset of the
symptoms of what appeared to be an incipient influenza, which,
however, proved abortive.

While the observation of the red cells On the smear may thus
give items of highly interesting and important information, it
goes without saying that the chief interest of the smear resides
in the observation of the white corpuscles. No one who has read
the earlier chapters of this book needs to be told that I regard
the differential count as of supreme importance. But I would
emphasize the fact that a good many illuminative things are to
be learned from careful observation of the leucocytes, connoting
their size, form, staining qualities, tendency to agglutinate, and
the like, quite without reference to the differential count, or, better
stated, as supplementary to that count.

It is a not unfamiliar experience, for example, that a series
of slides obtained under closely similar conditions of technique,
and with the same stain, show striking modifications of the
color reaction of the white corpuscles. One slide may show
corpuscles that scarcely take the stain at all ; a second shows the
nuclei with a deep bright blue stain; a third shows corpuscular
nuclei of a purplish color.

Assuming that the stain used is one of the varieties of the
methylene blue and cosine combination (Hastings', for example),
it may be accepted, I believe, that the cells showing the purplish
nuclei are the ones that more closely approximate the normal.
On the other hand, the cells that take the bright blue stain are
somewhat characteristic of conditions in which there is known to
be very marked disturbance of protein metabolism (for example
late stage cancer), and I have come to regard them as in a
measure pathognomonic of disturbed protein metabolism, how-
ever superinduced. As suggesting this condition, they are, I
believe, of distinct diagnostic value.

It is natural to assume that cells that take the blue stain have
an exceptionally acid quality, since they show an affinity for
the basic dye. Frequently such cells show cytoplasm in which
the esinophile granules of the normal cell are invisible or but
very faintly revealed.

I have frequently observed that cells that show these qualities
have a tendency to agglutinate or clump together. Not infre-
quently a smear may show the entire leucocyte population scat-
tered into a windrow at the end, even though the red corpuscles

134 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

may be evenly distributed throughout the length of the smear.
One may assume that corpuscles that show this propensity have
exceptional cohesive properties, suggesting a modification of
their chemical constitution. Of course the amount of pressure
exerted by the spreading slide will modify the distribution of
the white corpuscles under any condition, and in general it may
be expected that the larger cells, notably the large monocytes and
eosinophiles, will tend to be distributed farther down the smear
than the average small lymphocyte. These variations must be
borne in mind; but the experienced hematologist is not likely to
confound modifications of distribution of the corpuscles due to
changes in his technique with modifications connoting variant
systemic conditions of the patient.

If there were any doubt as to this, one may satisfy oneself
that the color reactions and agglutination qualities of the white
corpuscles represent actual differences of systemic conditions by
making a series of slides of three or four patients in succession,
with three or four slides to each patient. It may then be seen
that there are marked and characteristic differences distinguish-
ing each group, lying entirely aside from the minor variations
among slides from the same patient.

Not infreuently a slide that shows the blue-stain nuclei may
show other white corpuscles that scarcely take the stain at all ;
or corpuscles of the lymphoidocyte and plasma cell order, in
which the nucleus remains practically unstained while the cyto-
plasm takes a deep basic stain. There is, I believe, a qualitative
rather than a class distinction between these two types of cells,
— namely, those that take the blue stain distinctly and those
that show exceedingly faint nuclei with or without basophile
cytoplasm. As I interpret it, these are varying conditions of ab-
normal acidity of the cell, associated with a greater or less degree
of activity, or a different stage of activity, in the hydrolyzing
of a foreign or abnormal protein content. The fact that the
cells spoken of as lymphoidocytes and plasma cells, and charac-
terized by unstained nuclei and deep-stained cytoplasm, are in
effect aberrant types of large monocytes and small lymphocytes
respectively adds color to this interpretation, provided of course
the Proteomorphic conception which ascribes to the mononuclear
cells a chief share in dealing with foreign proteins is accepted.

Theories aside, however, the observed variations of cellular
conditions, as regards staining properties, give important clues
to the condition of the patient. Moreover, interesting modifica-
tions of these conditions, in a predictable direction, may be ex-
pected in connection with proteal medication.

A typical case in point is that of patient No. 543, cancer of
the stomach, whose red cell count was above referred to. When

THE SCIENCE AND ART OF PROTEAL THERAPY 135

this patient's blood was examined before treatment, it is found
that the leucocytes stained with very blue nuclei, many of them
taking the stain very badly. Lymphoidocytes and plasma cells
largely took the place of normal cells. There were no normo-
blasts, and no platelets. After a week of Proteal treatment, the
entire character of the white cells had changed. The record
reads: "Polynuclears stained beautifully, with purple nuclei;
cytoplasm granular, moderately acidophile. All lymphocytes
stained typically. No lymphoidocytes or plasma cells. A very
normal collection of white cells, beautifully stained. Numerous
big typical large monocytes. Occasional normoblasts, platelets
numerous."

Two weeks later further modifications in the same direction
had taken place. The white cells were evenly distributed in the
smear, except that a few very large monocytes and myelocytes,
owing to their bulk, dragged toward the end. Nuclei took a
normal purple stain, the cytoplasm of the polynuclears conspic-
uously red-granuled. Platelets were now fairly abundant, and
normoblasts absent or extremely rare.

It is impossible not to associate such modifications of the
cells with the marked improvement in clinical symptoms mani-
fested by the patient. When one has seen similar modifications
take place under Proteal treatment again and again, the belief
that there is a causal relation between the administration of the
Proteals and the changed blood condition, and that the improved
clinical conditions are effects and not accidental concomitants,
becomes a firm conviction.

If the subject to whom the protein extract is administered is,
let us say, a patient with cancer of the uterus, associated with
pain, a fcetid discharge, and marked cachexia, there is likely to
be a very notable modification of symptoms. The pain may
largely disappear after two or three treatments; the character
of the discharge may be so modified that it becomes watery and
inodorous ; and the general physical condition of the patient may
be strikingly modified in a favorable direction. As the treatment
continues, the neoplasm itself may undergo a conspicuous and
unequivocal regression to a greater or less extent.

Similar modifications may be observed in malignant neoplasms
of various types wherever located in the body. There remains,
however, the highly interesting question as to how such changes
are brought about by the hypodermic administration of small
quantities of vegetable proteins.

MODIFICATIONS OF THE LEUCOCYTE COUNT

A further clue to the answer is found in the fact that con-
spicuous modifications of the leucocyte count no less than of the

136 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

red cell count almost invariably follow the administration of the
proteins. These changes are of a kind susceptible of interpreta-
tion in terms of the Proteomorphic theory. But they have a
high degree of interest quite aside from theoretical interpreta-
tions. As gauged by the study of about 200 original cases,
they appear to include a tendency to bring the polynuclear leu-
cocytes and small lymphocytes towards the normal ; whereas the
basophiles and eosinophiles are markedly increased, and the large
monocytes are increased by several hundred per cent.

Before giving details as to these interesting modifications of
the blood count brought about by the administration of protein
antigens, I would again call attention to the highly interesting
laboratory experiments reported by Drs. M. W. Man waring and
Yoshio Kusama, of the department of bacteriology and immunity
of Leland Stanford, Jr., University, as recorded in the Proceed-
ings of the Society for Experimental Biology and Medicine, of
May 24, 1916. These experiments go to show that the blood
corpuscles of a rabbit actively absorb goat serum protein, whether
the goat serum is mixed with the (defibrinated) rabbit's blood in
a receptacle outside the body or whether it is injected into the
system of the living rabbit.

This -observation, obviously, gives strong support to the as-
sumption of the Proteomorphic theory that the blood corpuscles
are the chief agents concerned in dealing with foreign proteins
— the assumption that forms the chief basis for the explanation
of the therapeutic action of the protein remedies with which the
present book is concerned.

In attempting to interpret the meaning of the observed changes
in the blood picture, however, one is entering quite unexplored
territory, and a territory in which the newly observed facts do
not at all times serve as an accurate guide.

Interesting hints as to the mutual relations of the various types
of white corpuscles are given by charts in which the different
groups of cells are represented by graphic lines (see the cancer
Monograph). It is hoped that the study of these in connection
with the protein remedies will throw new light on the obscure
relations of the different types of leucocytes. When a much
larger series of charts is available than at present, it is certainly
to be expected that relations will be observed between the mutual
rise and fall of the different types of corpuscles under treat-
ment that will help to explain the genetic relations of these bodies.

In making such charts, it is desirable to transform percentages
of the differential leucocyte count to actual numbers. When this
is done, one is impressed with the general observation that there
seems a strong tendency, under the Ptoteal treatment, for the
polynuclear leucocytes and the small lymphocytes to be modified

THE SCIENCE AND ART OF PROTEAL THERAPY 137

in number so that, after treatment has been continued for a time,
they fall within normal limits. Here, for example, is one chart
(Case No. 332) in which at the outset the number of neutrophiles
was 5,328, and the number of small lymphocytes 2,131 ; these
numbers representing in each case an excess above the maximum
normal limits, as usually computed. But after treatment had
extended over about 90 days, it was observed that the polynu-
clears numbered 4,356, and the small lymphocytes 1,824; both
these numbers representing a (high) normal count.

But in the meantime, it should be noted that the large mono-
cytes, which at the outset numbered 1,420, had increased to 2,403.
The original count is far in excess of the normal (which seldom
exceeds 400), and the final count exceeds the maximum normal
limits by 600 per cent. The assumption is, according to the pres-
ent thesis, that before treatment the large monocytes had been
stimulated to excessive production under influence of the disin-
tegrated cancer cells; and that the protein treatment effected a
further stimulation.

A similar proportionate increase in the eosinophiles has taken
place, there being none noted at all before treatment and the
number having risen almost continuously until 356 were noted at
the later count, — about double the normal maximum limit.

Whatever the interpretation put upon these facts, it would
appear, as already pointed out, that such a super-normal count
of large monocytes and eosinophiles constitutes a favorable
condition in the organism associated with improved general
health of the patient and a tendency to combat the cancer cells
effectively. Indeed, I never feel that the desired results are
being attained unless this characteristic response is observed.

Another chart illustrates the same principle in a different way;
inasmuch as it was necessary to increase the number of neutro-
philes in order to bring them to a high normal limit. It will be
observed in this chart (Case No. 369) that at the outset the
neutrophiles numbered 4,190 and the small lymphocytes 2,630.
At the end of three weeks' treatment, the polynuclears had risen
to 4,935, and the small lymphocytes had dropped to 1,410. Here,
as before, the final count shows polynuclears and small lympho-
cytes within normal limits.

In the meantime, in this second chart, as in the first, the large
monocytes have risen conspicuously; in this case from 1,150 to
2,608 ; and the eosinophiles have increased from 213 to 329. The
numbers here are substantially in accord with those shown in
the other chart. Such close agreement is a matter of coincidence,
although the same general principle will be seen reiterated in a
large number of cases.

A striking feature of both these charts is the marked modifi-

138 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

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THE SCIENCE AND ART OF PROTEAL THERAPY 139

cation in the number of neutrophiles and small lymphocytes from
the initial dose of the vegetable protein. A question not unnat-
urally arises as to whether there is any mutual relation between
the two groups of leucocytes, or whether the modification of their
numbers has been brought about independently. Glancing at the
first chart, one might think that there must be some mutual rela-
tion, inasmuch as the lines showing modification of the neutro-
philes run almost parallel with those showing modification of the
small lymphocytes. But in the second chart, we find that the
slope of the line is reversed, the neutrophiles showing a rapid rise
after the first dose and the lymphocytes a rapid decline.

It is not impossible to frame a theory that would harmonize
these seemingly contradictory results, but perhaps it is not worth
while to attempt to do so at the moment. Our chief present con-
cern is with the observed facts, which fortunately are unequiv-
ocal. As above outlined, these include a notable departure from
the normal blood picture brought about by the administration of
the protein remedies as evidenced in a relatively enormous in-
crease of the larger monocytes, a conspicuous increase of the
eosinophiles and basophiles ; and a tendency to bring the small
lymphocytes and the neutrophiles within normal bounds.

By way of recapitulation, it is well to recall that Vaughan's
experiment seems to show that the specific enzymes of the large
mononuclears have particular value in proteolyzing the cancer
proteins. Stated otherwise, the large mononuclears would seem
to have particular affinity for cancer proteins ; which is only an-
other way of saying, probably, that they are particularly adapted
to deal with proteins of an embryonic type. The fact that the
large mononuclears abound relatively in the normal blood of the
child may be recalled in this connection.

BLOOD CHANGES IN TUBERCULOSIS

Many instances of spectacular changes in the corpuscular rela-
tions under Proteal treatment are given in the cancer Mono-
graph. Here it is desirable to supplement these records by
citing a few cases representing maladies of different types.

Here, for example, is the case of J. G., a patient in the late
stages of tuberculosis of the lungs. Left lung solidified. Gen-
eral condition extremely cachectic, so emaciated and frail that
his tenure of life seemed very uncertain. His blood showed
3,260,000 red corpuscles of exceedingly poor quality, — variant
in size, malformed in shape. The white corpuscles numbered
14,500, of which 87 per cent, were polynuclears, 7.3 per cent,
small lymphocytes (including plasma cells), and 5.6 per cent,
large mononuclears. The polynuclears are recorded as of red-

140 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

purple nuclei, not sharply defined from the cytoplasm, which was
opalescent, and distinctly reddish. The large monocytes were
typical, dark, with opaque cytoplasm.

This patient was not treated in my office, but by an associated
physician, and a second blood count was not made for six weeks,
at which time the red corpuscles had risen to 4,395,000 in number
and the white corpuscles had come down to 12,500, of which
78.3 per cent, were polynuclears, 7.3 per cent, small lymphocytes
(no plasma cells), and 14.3 per cent, large monocytes. The red
cells in addition to their spectacular increase in number were
much more normal in appearance. A good many platelets had
appeared, and free microblasts, often large, of which there had
been none at the earlier period. The polynuclears were very
acidophile and granular, with full cytoplasm. There was ex-
treme progression to the left in the Arneth sense — that is to say
a very large number of single-nucleated neutrophiles. The large
monocytes were large and fairly typical ; the cytoplasm dark, but
clearly differentiated from the nucleus. The number of these
large monocytes had increased, as will be observed, by 250 per
cent. The change in size and quality was not less conspicuous.

A fairly plausible interpretation of these microscopical find-
ings, and one consonant with the clinical history and the known
pathology of such cases, would be that there was marked bac-
terial infection (indicated by the leucocytosis, with conspicuous
preponderance of polynuclears), but that there was also marked
general protein infection, comparable to the infection from can-
cer, the solidified lung mass having many of the characteristics
of a malignant neoplasm. The response to proteal treatment,
indicated by increase of red corpuscles, decrease of white, de-
crease of the polynuclear preponderance, and marked increase of
large monocytes may be taken as suggesting interesting possi-
bilities of proteal treatment for tubercular cases even at a late
stage of unfavorable development.

In another late-stage case of pulmonary tuberculosis the red
corpuscles before the administration of Proteals numbered only
3,964,000, and were of such quality (90 per cent, diminutive and
misshapen) that their functional efficiency must have been far
more than proportionately reduced. After seventeen days of
Proteal treatment (doses of 3 to 7 minims of Nos. 37 and 45),
the red cells were metamorphosed in character, and increased in
number to 4,500,000. Clinically there was striking improvement.
Temperature and pulse reduced to normal (from 101 and 115,
respectively) ; cough much less ; better appetite and sleep ;
strength and sense of well being so greatly improved that the
patient asked to be allowed to go back to work. Prior to be-
ginning treatment her physician had told her that she had but

THE SCIENCE AND ART OF PROTEAL THERAPY 141

one chance in a thousand to live, and that chance conditioned on
her going at once to the mountains. Nine months later this pa-
tient seemed clinically well, and the blood record was : Haemo-
globin 85; red corpuscles, 5,165,000; white corpuscles, 5,500,—
an absolutely satisfactory numerical count.

TUBERCULOSIS AND PROTEIN POISONING

It is my personal view that an advanced case of pulmonary
tuberculosis represents a condition in which the chief menace
is not from toxins directly developed by the tubercle bacillus
itself, but from toxins generated by mixed infections plus the
toxic products of partial proteolysis of the tissues making up
the lung mass.

Stated otherwise, I regard a tubercular mass as a foreign
growth which may have the same effect on the blood, the blood-
forming organs, and the organism at large as the types of foreign
growths that we term malignant neoplasms. The tuberculosis
patient, like the cancer patient, dies ultimately either of hemor-
rhage or of protein poisoning. In the latter case (and this may
be said to represent the normal progress of pathological events,
if the phrase be permitted), the same kind of strain is put upon
the blood-forming organs, and the same disturbances of the
blood cells are brought about in tuberculosis and in cancer.
Clinically, the cachexia of the late stage tuberculosis patient
and that of the late stage cancer patient cannot be distinguished
one from the other. I have seen two patients side by side, both
cachetic to the verge of moribundity, one having a solidified lung
and the other a carcinoma of the stomach, yet so closely similar
in general appearance that even a practiced eye could not deter-
mine which patient had the injured lung and which the injured
stomach. What could be determined at a glance was that both
patients manifested profound disturbances of metabolism, char-
acterized by lack of good red blood. Both of them have blood-
forming organs that have overworked against persistent protein
invasion until they have reached the stage of sheer exhaustion.

Under the microscope, the blood of these two patients may be
as similar in its abnormalities (decrease of red corpuscles, in-
crease of white, preponderance of polynuclears, qualitative modi-
fications) as their clinical manifestations of malnutrition are
similar.

When we consider the matter in this light, it no longer seems
strange that administration of the same treatment to these two
patients may be beneficial to both. A few drops of Proteal from
the same ampule may be administered hypodermically in succes-
sion to the tubercular and cancerous patients respectively day by

142 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

day; and it may fairly be asserted that each will give evidence,
both clinical and hematological, of an organic response that is
definite and highly gratifying.

As to what will be the ultimate extent of such response, no
predictions can be made in any individual case. It is axiomatic
to say that everything depends upon the degree of involvement
of tissues, both local and general ; the inherent vitality of the
patient; and the responsive capacities of the blood-forming
mechanism. These are matters regarding which no two patients
will be precisely alike, and regarding which the physician cannot
always form an accurate estimate. In particular, that intangible
but highly important thing which we call inherent vitality may
come to the rescue of many a patient whose case seemed hope-
less; whereas another patient whose state seemed less desperate
may not have quite the same recuperative qualities of cellular
tissue. The wise physician will always hold prognosis in abey-
ance and watch for results before forming an opinion in his own
mind as to the outcome.

I would call attention to what I have said in the cancer
Monograph as to the absurdity of hoping to restore cells that
are actually degenerated, reiterating that this can no more be
expected when these cells are part of the liver or pancreas or
lung than when they are part of an amputated arm or leg.
But I would also repeat that we can seldom feel certain as to the
amount of involvement of tissue in any given case where an
internal organ is involved ; and, secondly, that a comparatively
small portion of remaining normal tissue may sometimes show
surprising capacity to take on itself functions of the entire organ.
A familiar case illustrating the latter point is the well-known
capacity of one kidney to do the work of both.

Questions of ultimate prognosis aside, however, we are justi-
fied by present experience in expecting that, in a very large
proportion of cases of the kind just cited (late stage tuberculosis
and cancer), as well as in a variety of other conditions of dis-
turbed protein metabolism that have led to anaemic and cachetic
conditions, the exhibition of Proteals will produce at least a
temporary response of the blood-forming organs that will be
manifested in marked modification of the blood count and in
more or less conspicuous clinical improvement of the patient.

I think I am speaking within bounds when I say that my ex-
perience justifies the conclusion that the Proteals, thus admin-
istered, have such powers of stimulating the blood-forming
mechanism as to place them in a class quite by themselves among
tonic remedies. I have much confidence that the future will
justify my present belief that this form of medication is destined

THE SCIENCE AND ART OF PROTEAL THERAPY 143

to make the old, familiar tonic remedies — notably iron and
arsenic — in their old method of administration, obsolete.

In making this suggestion, I would not have it understood
that I expect to see iron, arsenic, and other old friends of this
category disappear at once from the armamentarium of the
physician. Proteal remedies will not altogether displace these
old friends any more than salvarsan has altogether displaced
mercury. It is not to be expected that any one type of medica-
tion will be applicable to any and every type of case, even where
there are seemingly similar maladjustments of functioning. Yet
I reaffirm the conviction that present experience justifies the
belief that the tonic remedies that have been almost the sole
reliance of the physician in anaemias associated with disturbed
protein metabolism (and hence associated with most of the
disorders of middle life and old age) are rendered obsolescent
by the advent of the new method.

I am aware that such an opinion must seem heretical, perhaps
even fanatical. Yet I express and reaffirm it calmly and with
confidence based on the observation of a series of cases large
enough, and varied enough, in my opinion, to be dependable.

It will be understood that the opinion just expressed is based
on personal, first-hand observation both clinical and microscopi-
cal. The work with which we are dealing is pioneer work. So
far as I am aware, no one but myself and my immediate asso-
ciates have hitherto dealt extensively with non-specific vegetable
proteins as such, either in laboratory or clinic, as therapeutic
agents for hypodermic administration. It is true that several
thousand physicians have administered the original proteal ex-
tract, and I have profited by their clinical experience; but for
the most part the physicians have administered the remedy em-
pirically in accordance with my directions, and comparatively
few of them have watched the blood count. Those who have
done so, however, have reported observations, confirming in the
most substantial manner the original studies with which the
present volume is largely concerned.

Here, for example, is a letter that chances to come to hand the
morning of the present writing, from a prominent physician in
a neighboring city who says ;

"I have now used the Proteal No. 37 for twelve days and have
reached the dose of 15 minims without any local or general reac-
tion. I have increased the dose to 17 minims and will of course
watch for reaction. The only constitutional change thus far has
been a true increase in the mononuclear leucocytes with a de-
crease of the small lymphocytes ; also an increase in the red blood
cell count."

144 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

A pioneer in any line of research work must always await with
interest corroboration of his results by other workers. Naturally
I shall be pleased to have reports at all times from candid ob-
servers, whether by way of corroboration or criticism ; but I
repeat that the evidence already in hand, based on my personal
observation, is so comprehensive, so unequivocal, and so con-
vincing that I await the ultimate verdict of the profession with
absolute confidence.

All this, however, is in effect a digression. Let us again take
up briefly the interpretation of the blood changes that are brought
about by Proteal medication, in so far as they are of practical
interest and importance to the practitioner ; following with some
explicit hints as to the practical administration of the new method
in cases of malnutrition of sundry types, from simple anaemias
to the profound cachexia of tuberculosis and carcinoma.

AN INTERPRETATION OF CORPUSCULAR ACTION

As regards a somewhat more detailed interpretation of the
blood count, and in particular the differential count, there are
certain opinions that I hold provisionally, regarding which more
elaborate publication will be made elsewhere, to which brief
attention may be given. As elsewhere pointed out, this subject
is one in which very little work has been done, and regarding
which the opinions of the pathologists are altogether vague. So
far as I know, the question has not hitherto been asked, let alone
answered, as to why in normal blood the polynuclears number
60 to 70 per cent, of the total leucocytes, the lymphocytes 20 to
25 per cent., and the large monocytes and eosinophiles and baso-
philes make up a relatively insignificant population. Yet there
must be reasons why there is this distribution of corpuscles in
normal blood; reasons associated with the variant functions of
the different types of cells.

In attempting to interpret the observed blood changes under
Proteal treatment, peculiar difficulties are encountered in the
fact that the physiological activities of the corpuscles have been
but vaguely understood.

Ordinarily, the pathologist is guided in the interpretation of
what he sees by known physiological laws. The student of
microscopic pathology has for guide the well-recognized findings
of the histologist. But in the present instance such aid is not
available. We have, to be sure, records as to the relative num-
bers of different types of. blood corpuscles in health and acute
infections. The further fact is available that the polynuclears
appear to be especially concerned in the direct battle against in-
vading bacteria. But with that antecedent knowledge practi-

THE SCIENCE AND ART OF PROTEAL THERAPY 145

cally ends. If one asks, for example, why basophiles, eosino-
philes, and large monocytes are few, whereas small lymphocytes
are relatively numerous, and polynuclears still more so, no an-
swer has hitherto been forthcoming.

It is axiomatic to say that such distribution of numbers must
be consonant with the needs of the average body and with specific
functions of the different types of leucocytes; but as to the
nature of these needs and the character of the function there is
entire silence on the part of physiologists and pathologists alike.

In the first exposition of the Proteomorphic theory, I put
forward the suggestion that the leucocytes as a class have for
their broad general function the hydrolysis of proteins and the
earlier products of protein decompounding. To the mononuclear
cells in particular I ascribed the function of dealing with the
full-sized protein molecule. It was further noted that the large
monocytes appear to have a peculiar relation to the decom-
pounding of such neoplastic cells as those of cancer, and I ven-
tured the suggestion that the small lymphocyte has to do with
the catabolism of normal serum proteins, in rendering them
available for bodily use. But beyond this no detailed interpreta-
tion of the functions of the different leucocytes was attempted.

In the three and a half years that have elapsed since the Pro-
teomorphic theory was conceived and exposited, I have devoted
a large share of my time to studies that brought me directly in
contact with problems of corpuscular activity in disease and in
health. During a considerable part of this time I have devoted
several hours of each day to the microscopic study of blood
corpuscles in counting-chamber and on stained smear. While
chiefly concerned with the blood of persons suffering from
maladies of disturbed metabolism, and in particular with modi-
fications of blood under protein treatment, I have checked these
observations with studies of normal blood under various condi-
tions.

This is not the place to give detailed account of these studies,
which, indeed, have not yet reached the stage where final an-
alysis is desirable. But, by way of preliminary report of matters
hitherto unpublished, it may be worth while to give a brief out-
line of a theory of corpuscular action that seems to be at least
worth considering as a working hypothesis, although confessedly
subject to modification in the light of future evidence. This
hypothesis is only one of numerous suggestions that present
themselves, and which at various times have been entertained in
the course of my investigation. I hold it and put it forward
not in the least dogmatically or as having finality, but in the
thought that it may serve a useful purpose in guiding the inves-
tigations of others,— and I assume that the present publication,

146 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

because of the hematological facts already presented, will stim-
ulate a large number of investigators to take up the study of
the blood with new zest and from new angles.

The working hypothesis which I now suggest hinges on an
assumption that is almost absurdly simple — which may or may
not be a merit. The suggestion is this — that the different groups
of leucocytes, in the order of their numerical abundance, deal
primarily with the successive groups of protein decomposition
products in the order of their numerical molecular representa-
tion. That is to say, the least abundant group of leucocytes
(namely the large mononuclears and binuclears) deal with
full-sized protein molecules ; the next larger group of leucocytes
(namely the small lymphocytes) deal with molecules of the pro-
teose or albuminose order ; the third and most abundant group
of leucocytes (namely the polynuclears or neutrophiles) deal-
ing with protein-product molecules of the peptone order; — it
being understood that the extremely abundant red corpuscles
take up the work of decompounding at the polypeptid stage and
complete the final disintegration into amino acids and toxic by-
products, such as uric acid, urea, and creatinine.

It will be recalled, as giving a sort of apriori plausibility to
the assumption, that the numerical relations between the normal
numbers of different types of leucocytes are, in general terms,
the same as the numerical relations between the numbers of
molecules in the different orders of protein products. This
relation of course does not hold when the red corpuscles are
under consideration, since these are many times more numerous.
But this seeming inconsistency is explicable on the plausible as-
sumption that large quantities of molecules of the polypeptid
order enter the circulation normally, through the intestinal wall.
Indeed, it has been suggested that the red corpuscles may be
called upon under normal conditions to complete the hydrolysis
of the polypeptids wholly or in part, the question as to the pre-
cise condition in which the protein product normally enters the
circulation not being clearly settled.

Even though the enteric enzymes normally reduce the poly-
peptids to the amino-acid stage, it must happen very generally
that they fail to some extent of their complete function, per-
mitting the entrance of a greater or less number of polypeptid
molecules. The same thing is true, of course, of a certain num-
ber of large molecules, including the full-sized protein molecule
itself; but the entrance of the latter must be relatively infre-
quent,— a fact that in itself accounts, we may suppose, for the
relative paucity of large mononuclears in normal blood.

It will be observed that in the above summary, reference is
made to a group comprising mononuclears and binuclears. The

THE SCIENCE AND ART OF PROTEAL THERAPY 147

latter term of course connotes eosinophiles and basophiles.
Very little has been said in recent pages about these two types
of leucocytes, beyond noting that they tend to increase under
proteal treatment just as do the large monocytes. I have long
been disposed to regard the eosinophiles and basophiles as cells
of the same order, representing either stages of individual de-
velopment or modified condition of chemical composition (say
acidity versus alkalinity), in effect no more variant than different
specimens of polynuclear leucocytes some of which show clear
unstained cytoplasm while others are markedly granular and
acidophile.

I am by no means certain that basophiles and eosinophiles are
not to be regarded as matured stages of large monocyte devel-
opment. It is at least within the possibility that a monocyte that
has ingested a certain amount of protein and transformed it, let
us say, into proteose may divide its nucleus and have its enlarged
cytoplasm just prior to disruption assume a condition that mod-
ifies its staining qualities so that its appearance is greatly modi-
fied. On this assumption, the relative scarcity of eosinophiles
and basophiles would be explicable on the ground of their relative
shortness of individual life, it being assumed that the incidence
of the granular condition presages disruption.

It may be recalled in this connection that the Russian inves-
tigators Avrowrow and Timofeeosky have suggested that eosino-
philes are only monocytes that have ingested red blood cor-
puscles.

No doubt many objections could be urged against this linking
of the large monocyte and the eosinophile and basophile as mem-
bers of the same series. I am not aware, however, of any ob-
jection that seems insuperable. Meantime the observed coin-
cidence between increase of large monocytes and increase of
eosinophile and basophiles under proteal treatment (see numer-
ous tables in the Monograph), is at least not inconsistent with
the assumption.

It is consonant with what we know of the mutual relations
of bodily organs to assume that, even if the above interpretation
of the primary action of different types of leucocytes be ac-
cepted, it does not follow that any type of leucocyte is abso-
lutely restricted in its possible activities to the hydrolyzing of
protein products of a particular size. I have already suggested
that the stage of decompounding to which a protein molecule
may be subjected within the leucocyte may depend to some ex-
tent on the amount of pabulum ingested, which in turn would be
a function of the abundance of leucocytes on one hand and of
protein products in the blood on the other.

To illustrate my meaning, we might assume that, granted a

148 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

given prevalence of full-sized protein molecules, when the large
mononuclears are few, they would individually secure large in-
crements of pabulum, and would on the average be disrupted
when this pabulum has reached the proteose stage, thus necessi-
tating a full equipment of small lymphocytes to take up the work
of hydrolyses. On the other hand, if without increase of pro-
tein pabulum, the number of large monocytes is increased, we
may assume that on the average they would carry the work of
decompounding to a lower stage, possibly even to the peptone
stage, and hence be able to turn their product over directly to the
neutrophiles, thus to some extent rendering the presence of small
lymphocytes superfluous. Some blood charts have been pre-
sented which seem to give plausibility to this suggested com-
plementary relation between the activities of the large and small
monocytes.

Applying the same line of reasoning to other types of leuco-
cytes, we may assume that under exceptional circumstances, the
small lymphocyte may be able to deal with the full-sized protein
molecule on one hand and to bring it to something approaching
the polypeptid stage on the other hand ; thus supplementing the
functions of large monocytes and of polynuclears. Cases of
lymphatic leukaemia suggest this possibility. Meantime the poly-
nuclear itself, although ordinarily concerned with transforming
peptones into polypeptids may conceivably on occasion deal with
proteose on one hand and carry the polypeptids toward the amino-
acid stage on the other. A certain complementary relation ob-
servable between the mononuclears, as a group, and the poly-
nuclears, in the charts before referred to, may perhaps thus be
explained. That a full red-cell equipment minimizes to some
extent the need of the services of polynuclears is also at least a
tenable hypothesis.

I have under treatment a patient who for months has main-
tained a clinical status of fairly robust health with a red-cell
equipment of from 2,176,000 to 3,909,000, and a leucocyte count
(chiefly small lymphocytes) ranging from 680,000 to 1,412,000.
On the smear, the small lymphocytes are like bunches of grapes ;
large mononuclears with obscure nuclei are abundant ; but poly-
nuclears are hard to find. Here it is impossible to avoid the
inference that the small lymphocytes perform functions normally
reserved for polynuclears on one hand and erythrocytes on the
other. This interesting case of lymphatic leuksemia will be dis-
cussed in greater detail elsewhere.

It is probable that another factor that may disturb the mutual
relations of the white corpuscles is to be found in the relative
amount of fat to be dealt with in any organism. I have sug-
gested that the polynuclears may have a share in dealing with

THE SCIENCE AND ART OF PROTEAL THERAPY 149

the metamorphosis of fats ; but it is consistent with the above line
of reasoning to assume that the lymphocytes also may have a
hand in this work. Possibly the relative shares of the two
types of leucocytes in dealing with fats may vary indefinitely
under diversified conditions.

A further word must be said about the relation of the various
leucocytes to the type of protein represented in the bodies of
bacteria. At first glance it may seem that the observed fact that
polynuclears deal with bacteria, ingesting them bodily, is incon-
sistent with the assumption that the chief work of the polynu-
clears is to deal with the partially decompounded protein mole-
cule. As to this, however, it will be recalled that the suggestion
was made that the so-called "opsonins," the presence of which
was found by Wright to determine the activities of the leuco-
cytes as ingesters of bacteria, may be enzymes secreted by the
mononuclear leucocytes ; but it is perhaps even more important
to recall that the proteins of bacteria are probably very different
in quality from the proteins of vegetable and animal tissues in
general.

Reference has already been made to the fact that the encase-
ment of the bacteria is of a fatty or lipoid character. It has
been pointed out by Leathes that it is not the cell-membrane
alone of the bacteria that is so constituted, but that the fats enter
into its entire structure. He says: "These fatty substances,
which form a considerable part of the bodies of tubercle bacilli,
not only exhibit a very low iodine value, but offer remarkable
resistance to measures that are commonly efficacious in saponi-
fying fats. And there are reasons for thinking that the vitality
and power of resistance of such organisms is intimately de-
pendent upon the properties of the fat in which their bodies are
enclosed or with which they are impregnated."

In dealing with the bodies of pathogenic bacteria, then, the
organism is not contending at all exclusively with foreign pro-
teins, but with structures in which the protein basis is so in-
corporated with fatty matter as to modify the conditions very
markedly. Moreover, it is probable that the bacterial protein
itself is of a quite different order from the proteins of true
plants and of animals. The low plane occupied by bacteria in
the organic scale suggests the probability that the bacterial pro-
teins have molecules of a relatively simple order, comparable
perhaps in their complexity to peptones or proteoses rather than
to true proteins. On this assumption, as well as in consideration
of the presence of the fat, the recognized capacity of the poly-
nuclears to deal v;ith bacteria is entirely consistent with the
function ascribed to these leucocytes in the above provisional
hypothesis. The instances of observed incapacity of the large

150 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

monocytes to deal with bacteria find further explanation in the
assumption that the bacterial proteins are of a low order of
molecule structure.

Incidentally, this line of reasoning makes it clear that we
are not to expect the same increase in large monocytes from the
use of bacterial proteins as proteantigens that may be expected
from the use of vegetable or animal proteins. The observed
polynucleosis from the injection of bacterial products is quite
what might be expected.

It may be added that if the above hypothesis is valid as to the
assumption that the large monocyte is chiefly concerned with
the full-sized protein molecule, we should not expect so pro-
nounced a large monocytosis from the injection of, for example,
peptones as from the use of the full-sized protein molecUie or
molecules of the proteose order. Practical observation of the
relative response to proteins, proteoses, and peptones, used as
antigens, when carried out on an adequate scale, will go far
toward testing the validity of the above assumption as to the
specific functions of different types of leucocytes. Experiments
directed toward this end are already under way. Comparative
studies are being made, for example, of blood charts in cases
treated with the unbroken protein molecule as compared with
cases treated with the newer Proteals, containing proteoses and
peptones.

A tentative analysis of these tables tends to give a certain
amount of support to the above thesis, inasmuch as the re-
sponse to the partially hydrolyzed proteins appears to include
the polynuclears more markedly and the eosinophiles and bas-
ophiles less markedly than the response to the unbroken mole-
cule. The evidence, however, is not yet sufficiently extensive
to be demonstrative, as only a small part of the material in hand
has been analyzed. Pending the results of such analysis, it will
be well to bear in mind the fact that the generalization as to the
protein blood response enunciated in the first edition of the can-
cer Monograph and throughout the earlier chapters of this book
refer to the unbroken protein molecule.

Meantime the series of tables and charts already in hand,
showing the corpuscular response to the administration of pro-
teantigens for the most part representing the full-sized molecule,
appear to establish the broader outlines of the Proteomorphic
theory as to the manner of handling of foreign proteins in the
parenteral system beyond cavil. No one who studies these tables
even casually is likely to question, I take it, that the prote-
antigen response is directly and strikingly concerned with the
blood-forming organs, and that increase of large mononuclear

THE SCIENCE AND ART OF PROTEAL THERAPY 151

leucocytes on one hand and of red corpuscles on the other are
critical features of that response.

That the characteristic response may be kept up for many
months is adequately demonstrated in tables above presented.
The efficacy of substituting new proteins when the systemic re-
sponse has flagged has been amply proved. Whether there are
any limits to such substitution, and to what extent it is desir-
able to keep up the proteantigen treatment after the seeming
recovery of a patient, are questions for the future to decide. It
would appear that the study of the blood in a large series of
cases must furnish the best clues to an answer.

AGE AND THE BLOOD COUNT

In attempting to account for the observed facts of corpuscular
variation between childhood and adult life, I have been led to
question whether the salient fact that the polynuclear count
increases from about 40 to 60 or 70 per cent, of the total leuco-
cyte count with the advance in years from adolescence to adult
life, may not be merely an evidence of response on the part of
the organism to the perpetual bacterial bombardment to which it
is subjected. It is familiarly known that bacterial products
make up a significant part of the normal faeces ; and, in general,
it is understood that we are perpetually assailed by bacteria
which have become relatively innocuous merely because of their
universal prevalence.

Obviously, in the natural course of events, such infection must
become cumulative; that is to say, we must suppose that on
the average the adult individual is more comprehensively affected
than the average child. On the hypothesis put forward in an
earlier section, it would be the middle products of protein de-
compounding chiefly in excess. Conceivably this may be the
reason why the polynuclear count goes up, reaching in adult life
very frequently a status of approximately double that of the
average of childhood and adolescence.

If this interpretation be correct, the so-called normal leuco-
cyte count of adult life might be said to be in itself a mani-
festation of abnormality. Such a statement sounds paradoxical,
but it may connote an important truth. It is a suggestive fact
that in a patient long subjected to Proteal treatment associated
with careful attention to hygiene of diet and digestion, it is
observed that the polynuclear count very generally comes down
as the patient improves, and may even be reduced to the stand-
ard of childhood — 40 per cent, or thereabouts. In two or three
instances where the patient had been for many months under

152 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

proteal treatment, I have recorded a poly nuclear count of only
39 per cent.

It seems not altogether unlikely that the relatively low poly-
nuclear count of childhood accounts for the susceptibility of
the child to the familiar exanthemata; and that, contrariwise,
the abundance of polynuclears in the adult organism accounts for
the relative immunity of adults to these diseases. It would appear
to be a case where the righting equipment of the body, as directed
against bacteria in general, has been brought to a stage of pre-
paredness in the average adult that makes it possible to attack
and overwhelm the germs of, for example, measles and whoop-
ing cough, whereas the same germs would have been able to
make effective entry into the system of the average child.

A similar line of reasoning may perhaps be applied tc Account
for the observed fact that the red corpuscles are less abundant
in the blood of the child and adolescence than in the blood of
the average adult. Incidentally, this fact in itself would appear
to prove that the red corpuscles have some function other than
the carrying of oxygen, inasmuch as the cellular activities of
childhood and adolescence must certainly be somewhat more than
on a par with those of the adult. Accepting the Proteomorphic
interpretation of the function of the red corpuscles as the agents
concerned in dealing with the end products of protein metabol-
ism, the increase of these corpuscles in adult life might be
interpreted as showing an increased protein infection of a char-
acter to charge the blood with larger quantities of end products
(of the polypeptid order) with advancing years, associated per-
haps with waning power of the digestive apparatus.

The fact that physiologists commonly mention 4,500,000 red
corpuscles as the average normal increment for women and
5,000,000 as the increment for men — a fact hitherto, so far as I
know, entirely unexplained — may conceivably be accounted for
on the supposition that men, on the average, eat larger quanti-
ties of protein food than women. The proverbially daintier appe-
tites of the female sex accord with this hypothesis ; which is here
put forward, however, only as a suggestion. The greater activ-
ity of the male would be an obvious explanation from a more
conventional angle ; but comparative histology robs this explana-
tion of force by reminding us that relatively inactive animals like
the sheep have a high erythrocyte count, whereas excessively
active birds have a low count.

Meantime my personal studies leave me very much in doubt
as to whether there is, in point of fact, an established sex factor
in determining the red cell count — an item of obvious prelim-
inary importance, deserving further investigation.

Whatever the fact as to sex differences, however, it appears

THE SCIENCE AND ART OF PROTEAL THERAPY 153

to be fairly established that the lymphocyte population of the
child's blood, and in particular the large monocyte population,
decreases with advancing age. This would seem to suggest
(holding still to the Proteomorphic interpretation) that the adult
organism is in general called upon to deal less comprehensively
with the full-sized foreign protein molecule than is the organism
of the child. A plausible explanation of this, as already sug-
gested, may be found in the obvious needs of the growing organ-
ism, where nitrogenous tissue is being built up day by day; as
contrasted with the adult organism, where the nitrogenous tissues
are only holding their own, or are actually degenerating.

Incidentally, it may be supposed that the normally large equip-
ment of mononuclear cells in the blood of the child and adolescent
may account in some measure for the relative immunity to the
growth of malignant neoplasms in early life. Contrariwise, the
susceptibility of old age to the growth of such neoplasms may
be associated with the decreased numbers, and, presumably, de-
creased functional activities of the mononuclear leucocytes chiefly
concerned in handling unbroken proteins in general and .lawless
neoplastic cells in particular.

FURTHER HINTS AS TO DIFFERENTIAL FUNCTIONS

Such a suggestion is obviously consonant with the interpreta-
tion of the role of the lymphocyte and the large mononuclears
put forward in connection with the Proteomorphic theory, and
constantly reiterated in the present volume. It must be freely
admitted, however, that our knowledge of the subject is at best
fragmentary, and that a great deal more work must be done
before we can hope for definite answers to many questions that
obtrude themselves whenever one considers a blood smear with
philosophical — that is to say, with childlike — inquisitiveness.

As provisional deductions from my own personal studies, I
have suggested the possibility that one chief role of the poly-
nuclear leucocytes may have to do with the metabolism of fats.
Observation has taught me to expect to find a relative and abso-
lute leucopcenia in examining the blood of obese patients of the
anaemic type. It has just been remarked that bacteria are sur-
rounded by a lipoid covering and have a body structure that
incorporates lipoids. It is familiarly known also that the poly-
nuclear has to do with the fight against bacteria — that being a
classical observation of Metchnikoff that has hitherto stood al-
most alone as an interpretation of specific functions of a par-
ticular type of leucocyte. It is not improbable that lipoids also
enter into the constitution of the cell membrane of the cells of
the normal organism, and of such modifications of these cells

154 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

as go to make up the tissues of malignant neoplasms. If such
is the case, and if the enzymes of the polynuclears have an im-
portant share in the digestion of fats, it may plausibly be assumed
that the polynuclears have an important share in attacking the
cancer cells, thus co-operating with the mononuclears. Reference
was made to this possibility in the Monograph, in connection
with the observation that partially degenerated polynuclears are
observed to congregate, along with the mononuclears, in the
region of a neoplasm that is undergoing disintegration.

It has been observed that large mononuclear leucocytes on
occasion ingest bacteria and yet are unable to digest them. This
may be because the monocyte does not produce an enzyme that
attacks the fatty substances, and hence is unable to penetrate the
cell wall of the bacterium. This initial stage of combating the
bacterium being reserved for the polynuclear, and this function
having been accomplished, the protein content of the bacterium,
whatever its molecular status, may be turned over to the mono-
cytes for further proteolysis, the ultimate product being handed
on to the red corpuscle, according to the hypothesis of the Pro-
teomorphic theory.

It is a familiar observation that a preponderant number of the
leucocytes that spring into being when there is a marked bac-
terial infection are polynuclear in character. This is consistent
with the above supposition that the activities of this particular
type of leucocytes are necessary to begin the destruction of the
bacterium. It has been further observed, however, that at a
later stage of infection there may be a relative and absolute
lymphocytosis. This is at least consistent with the supposition
that the mononuclear leucocytes handle the bacterial proteins
after the polynuclears have made their protein contents available
by dissolving the lipoid membrane.

By way of recapitulation, and condensed summary, it may be
recalled that under normal conditions, according to the provi-
sional hypothesis on which I am working, the polynuclears are
concerned with the handling of the fats normally in the blood,
which somewhat exceed in amount, it may be observed, the
foreign proteins normally present there. The handling of this
normal fat, plus the handling of the bacteria that make perpetual
onslaught, may account for the organic necessity of having the
neutrophile population of the blood about three times as great
as the mononuclear population. The relative paucity of the
mononuclears, and in particular of the large monocytes, may
perhaps be provisionally accounted for as explained by the pau-
city of unbroken foreign proteins in normal blood. In childhood,
when these proteins are abundant, owing to the needs of the
growing organisms, the mononuclears are relatively more

THE SCIENCE AND ART OF PROTEAL THERAPY 155

dant; and we have seen that such is the condition also in un-
treated cases of cancer, and in various other conditions of dis-
turbed protein metabolism, including intestinal toxaemia; subject,
however, to the modifying consideration that an excessive stim-
ulus may for a prolonged period have led to exhaustion of the
blood-forming organs, bringing about a leukopcenia.

As opposed to this line of reasoning, it is perhaps worth con-
sidering that the polynuclear appears to be the most highly dif-
ferential of leucocytes, and that inferentially it might be sup-
posed to deal with the higher proteins rather than with fats and
hydrolysis product. Obviously, the question calls for further
experimental evidence.

As to the different types of large monocytes, I am disposed
to regard lymphoidocytes, myelocytes of the different types, and
cells of the kind designated by Papenheim as leucoblasts, as be-
longing to the same series with typical large monocytes, the latter
being mature and actively functional examples of this type of
cell. It is true that the myelocyte is usually regarded as of the
granular series, and the large monocyte as of the non-granular ;
but, in my opinion, this distinction does not connote an actual
difference of origin or ultimate structure, but only divers stages
of development.

There is another type of large mononuclear leucocytes which
I believe to be merely an overgrown lymphocyte. The presence
of these large lymphocytes indicates activity of development of
the lymphocyte population. Not infrequently in the course of
Proteal treatment it will be observed that all the lymphocytes
increase in average size, and many come to such proportions
as to be classified as large lymphocytes, whereas at the begin-
ning there was but a minimum number, or even none at all, of
this type of actively functional lymphocytes.

Whereas the typical large monocyte (including the so-called
"transitional" type), with its relatively deep-staining nucleus and
basic cytoplasm, is the cell that I like to see represented in in-
creasing coteries under Proteal treatment, I am disposed to
think that the typical large lymphocyte works hand in hand, so
to speak, with its congener in dealing with the foreign proteins.
Whether one type of cell of a preference deals with the un-
broken protein molecule and another with the partially hydrolyzed
molecule (peptone, proteose) is a question regarding which opin-
ion must as yet be held in abeyance, although observations are
in hand that at least prepare the way for the ultimate elucida-
tion of this aspect of the problem.

The fact that under Proteal treatment there is coincident in-
crease in numbers and betterment of quality of large monocytes
and of red corpuscles, suggests a possible common origin for these

156 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

two types of cells in similar regions of the bone marrow. Such
origin would be consistent with the hypothesis that the large
monocytes begin and the red corpuscles complete the process of
protein hydrolysis.

That under normal conditions the large monocytes are few
and the red corpuscles many, may be provisionally explained on
the supposition that a large amount of protein matter normally
enters the blood stream at the polypeptid stage, whereas the
amount of unbroken protein is normally very small; in addition
to which it is to be recalled, of course, that the red corpuscles
have the further function of carrying oxygen.

It is, of course, generally accepted that the polynuclears orig-
inate in the bone marrow ; but the fact that these very commonly
decrease in number while the large monocytes and the red cor-
puscles are increasing under Proteal treatment suggests an in-
dependent site of origin as a possibility ; with the alternative pos-
sibility that the genesis of different types of leucocytes may be
dependent on a different stimulus to the mother cell rather than
upon differences in the mother cells themselves. In any event,
the relative decrease of polynuclears (and their absolute decrease
when they originally were in excess) under Proteal treatment
coincidentally with the clinical improvement of, let us say, a
cancer case in which the neoplasm is regressing, suggests that
whatever share the polynuclear may have in the decompounding
of the foreign protein cell may be accomplished by a normal com-
plement or even a subnormal complement of these particular
agents. The reader who is familiar with the tables published
in the Monograph will recall that the polynuclear count not in-
frequently falls to 55 per cent, or even to 50 per cent, of the
total, and occasionally drops to 45 per cent., and even, in excep-
tional instances, to 39 per cent.

In general, as has been noted, under Proteal treatment, the
polynuclear count tends toward the normal or slightly subnormal
status, the small monocyte population being subnormal, and the
large monocyte showing spectacular increase. For example, a
table published in the Monograph, showing the blood count in
19 cases of cancer after an average treatment of 186 days, gave
these figures: polynuclears, 57.1 per cent.; large monocytes, 24.8
per cent. ; small monocytes, 15.7 per cent. ; eosinophiles and baso-
philes making up the remaining 2.39 per cent. Another table
presenting 31 cases after an average of 152 days of protein
treatment showed : polynuclears, 64.4 per cent. ; large monocytes,
18.3 per cent.; small monocytes, 15.6 per cent. Still another
table, showing 48 cases of various kinds, including hyperthyroid-
ism, intestinal toxaemia, tuberculosis, and cancer under protein
treatment for an average period of 152 days shows the following:

THE SCIENCE AND ART OF PROTEAL THERAPY 157

polynuclears, 63.4 per cent. ; large monocytes, 16.9 per cent. ; small
monocytes, 16.8 per cent.

In each of these groups of cases, it will be observed, the
striking anomaly is the preponderance of large monocytes. That
fact, however, is one that scarcely needs emphasizing for the
reader of the present work. That such an increase does occur,
as the direct result of protein treatment, and that this increase
is associated in a beneficial way with the handling of foreign
protein products in the system, are inferences that constitute
the substructure of this book and the guiding principles of the
investigations on which it is based. They are deductions from a
wide range of original studies, and they are conceived to con-
stitute a significant contribution to physiology, pathology, and
therapeutics. That they constitute valid observations and deduc-
tions, I entertain not the remotest doubt. Nevertheless, I would
repeat, in leaving this aspect of the subject, that there is no
necessary association between the validity of these observations
and deductions and the value of protein medication as a thera-
peutic agency.

In my original studies, clinical observation and microscopical
observation have gone hand in hand. Each has found support
in the other. But I repeat that my pioneer work with the micro-
scope has not as yet been checked by the observation of any
considerable number of cases in the hands of other workers;
whereas the clinical results have been duplicated by some hun-
dreds of physicians administering Proteals from my laboratory
in accordance with my methods. Under such circumstances, it
must freely be admitted that the clinical findings might stand
though the microscopical findings and the theoretical explana-
tions failed of corroboration. As I have stated, no one should
condemn the method merely because he does not agree with the
theoretical interpretation here presented.

Having made that concession, however, let me not leave the
subject without reiterating my expectation that clinical observa-
tion and microscopical observation will both find abundant war-
rant in the findings of any competent observer who makes scien-
tific investigation of the new method ; coupled with the statement
that the interpretation of the observed facts in the light of the
Proteomorphic theory constitutes a working hypothesis that must
hold the field until challenged by some new discovery of which
we have no present inkling. In a word, repeating the phrase
with which this book is introduced, and modifying it to fit the
present purpose, it must be admitted that the observations and
theories of protein metabolism and Proteal therapy presented in
the foregoing pages are important if valid, and I have the utmost
confidence that they are valid.

158 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

If I have dwelt rather longer on this aspect of the subject
than might have been expected in a chapter ostensibly dealing
with practicalities, it is because I would reiterate and emphasize
my belief that protein therapy can be carried out to best advan-
tage only with the aid of the microscope, and with a clear under-
standing of the underlying principles involved. The Proteals
may indeed be administered empirically, by rule of thumb, and
with only clinical results as a guide; but they may be admin-
istered to far better advantage if the clinical findings are checked
day by day or week by week with microscopic observations of
the blood.

RELATIVE NON-TOXICITY OF THE PROTEALS

Let us turn now to matters that to the average reader may
seem of greater interest or at least of more directly practical
character. First and foremost, there is the matter of safety of
administration — implied doubtless in the foregoing pages, but
not hitherto dealt with explicitly and in detail.

The experiments in the administration of proteins to dogs and
guinea pigs are of interest in this connection. It has been re-
ported by independent workers that very small doses of bac-
terial toxins, including Coley's fluid, bring about a condition of
toxicity, with notable cachexia, in the dog, that make it impos-
sible to continue the administration for a considerable length of
time without disastrous consequences. But, on the other hand,
it is possible to administer the vegetable protein edestin in large
doses without producing unpleasant symptoms of any kind, be-
yond a temporary slight chill and rise in temperature.

I have administered various vegetable proteins (extracted from
more than a score of plant species in the aggregate) to guinea
pigs week after week, while the animals maintained perfect health
and normal growth ; the dosage employed relative to the weight
of the animals being from fifty to one hundred times the max-
imum Proteal dose employed therapeutically.

These laboratory observations are obviously in accord with
my experience and that of many scores of associated physicians
who have administered proteals to patients for long periods of
time ; and who have observed, in the vast majority of instances,
a marked improvement in general health, and the disappearance
rather than the onset of cachexia. Let us, however, examine this
vital aspect of the subject somewhat more at length.

In the original presentation of the Proteomorphic theory, as
reproduced in the present book, the idea was elaborated that all
foreign proteins are primarily toxic, and that their relative tox-
icity, in their effect on any particular organism, is determined

THE SCIENCE AND ART OF PROTEAL THERAPY 159

largely by the duration of time and the frequency with which
that organism has been subjected to their presence.

This principle was held to apply to the proteins that serve
for food, and it was suggested that the reason why vegetable
proteins in the foodstuffs are in general less toxic than animal
proteins is that our primitive ancestors doubtless were vege-
tarians for many thousands of generations before they became
flesh eaters. Making a somewhat more elaborate analysis, it is
possible to make the application to many familiar foodstuffs. We
are thus provided, for example, with an explanation of the
familiar clinical fact that patients suffering from intestinal tox-
aemia, with its attendant sequels, may advantageously be placed
on a vegetable diet, and that if animal proteins are allowed milk
and cheese are more wholesome than red meat. It is a familiar
practice with clinicians to permit invalids and convalescents to
partake of these animal proteins, followed in due course by eggs,
fish, and fowl, before permitting the use of beef or mutton ; and
it would appear that this clinical formula finds a certain measure
of support in an analysis of the probable food habits of our
prehistoric ancestors in successive evolutionary eras.

This point of view is recalled in the present connection to
emphasize the fact that I have not overlooked the question of
the toxicity of proteins in the inauguration and elaboration of
the principle of non-specific protein therapy. From the outset,
I have recognized that foreign proteins of every type are toxic
and must be handled with discretion. But I have found them
also to be agents having unique therapeutic possibilities when
administered in proper dosage. And it is hardly necessary to
point out that an element of toxicity is no barrier to the use
of pharmaceutical agents ; else we must forego the use of most
of the best-accredited drugs in our equipment, from opium, bella-
donna, and digitalis to diphtheria antitoxin, typhoid vaccine, and
salvarsan.

Nevertheless, the question of relative toxicity of different pro-
teins is a highly important one. My experience shows that there
is marked difference in the reaction obtained from the use of
vegetable proteins, none of which could be considered toxic ex-
cept in the general sense above outlined. Mustard seed proteins
and rape seed proteins, for example, produce a much less severe
reaction (when using the unbroken molecule) than the proteins
of alfalfa seed and millet seed. It does not follow, however, that
the former are the more valuable agents in therapeutics. Cases
may arise in which it is desirable to produce the more powerful
stimulus of the proteins to which the system has been less fa-
miliarized by past usage. In point of fact, in the case in ques-
tion, the alfalfa and millet seed proteins have, according to my

160 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

observations, far greater therapeutic value than the milder pro-
teins mentioned.

It should be explained that, whereas the introduction of vege-
table proteins therapeutically into the parenteral system has been
practiced extensively for a period of only about three and a half
years, many cases have been under observation in which treat-
ment with an animal protein (sheep serum) dates from a period
much more remote — from five to ten years. The aggregate ex-
perience with the therapeutic use of foreign proteins introduced
parenterally includes upward of four thousand cases directly
observed or more or less definitely reported; and as the treat-
ment of individual cases has usually been extended over terms
of weeks or months, a single patient sometimes receiving up-
ward of 300 doses, it will be seen that practical experience is
sufficiently extensive to justify deductions meriting confidence.

The general conclusion which I wish to state in unequivocal
and emphatic terms is that patients subjected for prolonged
periods to the hypodermic administration of foreign proteins,
including sheep serum and a variety of vegetable proteins, show
no evidence, either clinical or hematological, of toxicity in the
ordinary sense of the word, but, on the contrary, are robust
of physique and normal of blood. Meantime the pathological
symptoms for which the proteins were administered may have
disappeared altogether or have been markedly modified for the
better.

This, after all, is what might have been predicated from a
knowledge of the fact that a certain amount of unbroken pro-
protein from the food finds its way regularly into the parenteral
system from the digestive tract. In other words, every indi-
vidual, in health and in disease, is more or less subject to con-
tinuous cytogenic stimulus from the presence of the food proteins
in his parenteral system. To be sure, it has been suggested (by
Metchnikoff originally) that this fact has to do with the ulti-
mate development of symptoms of senescence with the passing
of the years; and it is my personal belief that the presence
of foreign proteins in excess, taken as food products with the
ordinary diet, is responsible for a large measure of the malad-
justments that are incident to and coincident with the devel-
opment of what we term old age. Be that as it may, however,
the case records cited in this book (together with those epit-
omized in tables of the Monograph) would appear to give final
answer to the question whether a prolonged use of proteanti-
gens in therapeutic dosage constitutes a measure necessarily det-
rimental to the patient. The records seem to show that, quite
on the contrary, such administration may be in the highest de-

THE SCIENCE AND ART OF PROTEAL THERAPY 161

gree beneficial, and that the judicious use of proteantigens may
stimulate the blood-forming mechanism to the effective combating
of toxins both of bacterial and non-bacterial origin against which
no other measure of corresponding efficacy is available.

I have already presented tables showing that the modifications
of the blood count under proteantigen treatment may be, and
frequently are, progressive in what I consider the right direction.
I am preparing for publication in the new edition of the Mon-
ograph more elaborate series of tables in which blood counts of
various patients are arranged sequentially as to time; beginning
with a series of counts of untreated cases, and going on day by
day to cases that have been under treatment for a term of
months. For convenience of observation, these cases are ar-
ranged in successive groups by ten-day periods. This, it will
be understood, is a purely arbitrary division, made merely to
give opportunity to classify results and show at a glance the
general -effect of treatment given a variety of cases for shorter
and longer periods of time. It will be seen that, generally speak-
ing, there is a progressive or cumulative effect observable ; that,
in other words, cases that have been the longest under treat-
ment are, on the average, those that show the most pronounced
modification of the blood count in the direction of (a) higher
haemoglobin index, (b) increase of red corpuscles, (c) modifica-
tion toward the normal of the leucocyte count, with (d) relative
increase of mononuclear leucocytes, and in particular marked
increase of large mononuclears.

If these facts are interpreted in the light of the Proteomorphic
theory, it appears that the conglomerate group of patients here
under consideration have benefited progressively by the prote-
antigen treatment, and that those that have been treated more
or less regularly for periods of six months, a year, and even
two years, are in better condition, as regards their blood count,
than those treated for a shorter period. When it is further stated
that these patients, observed as to their clinical condition, show
a similar status of improvement, the case for the non-toxicity of
proteantigens of types herein referred to (chiefly egg albumen,
milk albumen, sheep serum, and the Proteals) may be considered
to be fairly established.

I may add, by way of auxiliary evidence, that of the hun-
dreds of physicians who have used the Proteals from my labora-
tory no one has ever reported a reaction giving occasion for the
slightest alarm, much less a lethal effect; whereas testimony to
the beneficial effects resulting, seemingly in direct consequence
of the administration of the Proteals, has been so nearly unani-
mous as to satisfy the most optimistic anticipations.

162 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

THE PREPARATION OF THE PROTEALS

It is perhaps unnecessary here to go into details concerning
the various methods of extracting vegetable proteins that have
been employed at one time and another in my laboratory. The
chief facts of importance attach to the method that has super-
seded others, and has been employed in preparing the Proteals
supplied to the profession during the past year, the results of
the use of which are summarized in succeeding pages.

The method consists in the extraction of the proteins by boil-
ing the ground seeds or other plant products in a very dilute
solution of hydrochloric acid. Best results have been attained
with most seeds by using 50 grams of the powder to the liter
of water, and adding from 40 to 80 cubic centimeters of ten
per cent, hydrochloric acid. With plant products other than
seeds, such as alfalfa meal, 20 cubic centimeters of the dilute
acid suffice. The mixture is boiled in a glass flask for four
hours.

The decoction contains, of course, a mass of vegetable detritus
that must be removed by filtering. There is marked variation
in different products in their facility of filtering. With some
it is necessary to refilter two or three times. The final filtrate is
neutralized with 10 per cent, solution of sodium hydroxide. Just
beyond the neutralization point a precipitate forms, part of which
is redissolved. The solution, meantime, becomes of a darker
color, varying from amber to a deep claret according to the
constituents.

Either before or after filtering, as a matter of convenience,
the solution is evaporated at low temperature under a hot air
draft until it bulks about 300 cubic centimeters (varying from
200 to 400 with different products). The solution has usually
become slightly acid again, and it is necessary once more to
neutralize with sodium hydroxide. It is important that slight
alkalinity should be attained and preserved ; otherwise, the extract
will be painful on hypodermic administration.

The Kjeldahl nitrogen test is now made, after which the solu-
tion is either further evaporated or diluted with normal salt
solution, as the case may require, to bring it to the standard
strength of three milligrams of nitrogen to the cubic centimeter ;
indicating a protein content of slightly less than two per cent.

The extract thus standardized is placed in ampules and sealed
in a Bunsen flame ; then sterilized discontinuously for three days
in an ordinary sterilizer.

There are, as a matter of course, tricks of manipulation facil-
itating the preparation of the Proteals that vary somewhat with
the different products ; but, as will be seen, the process is, on

THE SCIENCE AND ART OF PROTEAL THERAPY 163

the whole, a very simple one. It may readily be duplicated in
any laboratory having a moderate equipment for physiological
chemistry.

The proteins thus prepared contain alkali albumens, proteoses,
and a variable quantity of peptones. It is obvious that the rela-
tive percentages of the products of partial hydrolysis will vary
with the degree of concentration of acids in the original medium
and the length of time of boiling. The whole-plant products,
like alfalfa meal, being boiled in weaker acid solution, are less
extensively hydrolyzed, and their proteins have been observed
to be much more likely to produce a local anaphylactic response.
Whether there are compensatory advantages in this is a ques-
tion that I am not as yet prepared to answer definitely; but I
have observed a good many cases in which the local reaction
appeared to be followed by a beneficial systemic response.

In this connection it may be observed that the earlier ex-
tracts, prepared without boiling, in simple salt solution or in
solutions of sodium hydroxide, and containing the full-sized pro-
tein molecule, produced a much more severe local reaction, and
occasionally a general anaphylactic reaction; and that it was at
first supposed that the production of a pronounced reaction was
therapeutically desirable. The independent workers who in June,
1916, and subsequently reported the use of proteoses and of
bacterial vaccines as non-specific agents, as in the treatment of
typhoid fever and arthritis, have employed a dosage (one or two
c.c. of a four per cent, albumen solution) that produced very
marked systemic effects, as well as a pronounced leucocytosis ;
and some of them at least have associated the observed clinical
benefits with the febrile reaction.

I have no doubt that there are cases where heroic dosage is
desirable, but in general the application of Proteal therapy, as
I use it, calls for small doses, not producing marked systemic
reactions.

The Proteal that has been used most extensively during the
past year and a half, and sent out from my laboratory in largest
quantities to members of the profession, is No. 45, the combina-
tion of equal parts of the proteins of alfalfa seed, alfalfa meal,
and millet seed. The same combination with the addition of the
proteins of rape seed and mustard seed bears the laboratory num-
ber 65. A newer combination, much less extensively tested as yet,
contains the proteins of red clover seed, cotton seed, flax seed,
hemp seed, and carrot seed, and bears the number 75. A still
more comprehensive combination, containing equal parts of the
proteins of the ten different types just listed (a mixture, in
other words, of No. 65 and No. 75), is known as Proteal No. 100.

The question naturally arises as to whether there are thera-

164 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

peutic advantages in using a combination of proteins rather than
a single protein. I believe that experience does not as yet
justify a positive answer. I have studied the matter very care-
fully through observation both of clinical symptoms and the
blood response, and I am not prepared to say positively that I
have seen decisive evidence of a difference, qualitative or quan-
titative, between, for example, the use of Proteal No. 39, which
contains only the protein of alfalfa seed, and Proteal No. 45,
which contains also the proteins of alfalfa meal and millet seed.
It is difficult to avoid the feeling that there must be a differ-
ence, but this may be based merely on a preconception. I have
thought it worth while to test the validity of the preconception
by making the elaborate combinations above listed, and numer-
ous others. I think the matter will not be definitely settled until
many thousands of cases have been treated with single proteins
and with proteins in combination. There would seem to be
theoretical warrant for the assumption that, inasmuch as each
protein has its own individual response, a combination of pro-
teins would produce a more varied and, in the aggregate, a more
pronounced response than a single protein. But whether or not
this should prove to be the fact, there is nevertheless abundant
reason for making the combinations, inasmuch as they give oppor-
tunity for the introduction of a new type of protein from time
to time, in accordance with the established therapeutic principle
that it is desirable to change the type of protein, or introduce
a new type, when a certain degree of immunization or cytogenic
apathy has been produced.

A convenient practical method, for example, is to begin treat-
ment of a case, let us say, of tuberculosis, with Proteal No. 39,
alfalfa seed protein; shifting presently to a combination of
alfalfa seed and alfalfa meal (Proteal No. 60), and then in due
course to No. 45, which introduces millet seed protein as an
additional element. A little later the shift may be made to
Proteal No. 65, which, still retaining the alfalfa and millet pro-
teins, introduces also the proteins of rape seed and mustard
seed. Still later an entire shift may be made to No. 75, with its
five new proteins, or to No. 100, which retains the original pro-
teins in relatively reduced quantities and introduces five new ones.

An alternative procedure, which has been observed to work
well in many cases, is to begin with a combination, say No. 45
or No. 65, and after a time to shift to a single one of the con-
stituents. For example, begin with the combination containing
alfalfa seed, alfalfa meal, millet seed, rape seed, and mustard
seed (No. 65), and presently shift to No. 39, alfalfa seed protein
alone, beginning with a relatively small dose and increasing grad-
ually, until, obviously, at maximum dosage the maximum re-

THE SCIENCE AND ART OF PROTEAL THERAPY 165

sponse from that particular protein may be expected. After
that one may shift to millet seed protein (No. 38) or rape seed
protein (No. 42), and so on. The advantages of such a transi-
tion are that it enables one to begin with a mild general response
and presently to get the maximum effect from an individual
protein.

The response to the combined proteins would be, theoretically,
varied and comprehensive ; the response to the single protein
restricted, but relatively intense.

The experienced physician will use his own ingenuity in mak-
ing application of these principles, just as he does in combining
drugs in his ordinary prescriptions. Every skilful practitioner
uses combinations of drugs having allied effects, in the confident
belief that he is attaining certain results at least a little better
than could be secured from any one of the individual constit-
uents. Yet he might find it difficult to prove this. Similarly,
some users of the Pro teals come to feel that they get results
from combinations that they do not get from the individual
proteins. I repeat that it remains for the future, with its analysis
of thousands of cases, to justify or refute this belief.

Meantime it is not in the least in doubt that each type of
protein produces its own individual response, and that one pro-
tein may not be substituted for another indifferently. That a
system immunized to large doses of proteins of one kind or
combination, for example, will show the most vigorous reaction
when a new protein is introduced, has been demonstrated over
and over in my experience, particularly in the early days when
working with the unbroken proteins.

This is tantamount to saying that, whereas the Proteals are
thus standardized on the basis of the same amount of protein
in each, it does not follow that each one is the equivalent of the
other in its therapeutic action. It is my opinion, as the reader of
the foregoing pages is aware, that the protein response is always
similar in character and to be interpreted in the same physiolog-
ical terms. But it has already been pointed out again and again
that some Proteals produce much more active response than
others. The explanation offered has been that proteins to which
the system has longest been accustomed and most continuously
experienced will produce the least striking reaction.

SPECIFIC PROPERTIES OF NON-SPECIFIC PROTEINS

To speak of the specific properties of non-specific proteins
would appear to be, on its face, a contradiction of terms. But
the phrase has definite meanings that are clearly intelligible. The
word "specific" as employed in connection with the use of pro-

166 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tein remedies refers, as is well known, to the use of the bodies
or toxins of definite character of pathogenic bacteria to combat
conditions associated with the activities of the same type of
bacteria. The use of anti-typhoid vaccine either as a preventive
against typhoid fever or as a curative agent when typhoid fever
has actually developed, is the classical illustration of the specific
use of a specific protein remedy.

But the same vaccine may be used, and in point of fact has
been used with apparent effectiveness in the treatment of rheuma-
toid conditions; and in such a case the vaccine is used non-
specifically. In the latter case the response evoked or desired
has no association with the typhoid bacillus, but is a general
protein response. Doubtless there is a specific response also, but
this is purely incidental and does not enter into the calculations
of the therapeutist.

When vegetable proteins extracted from the seeds or sub-
stances of higher plants are used there is obviously no chance
for a specific response in the sense in which the word has just
been defined. Observation shows that there are certain very
characteristic modifications of the blood that occur in response
to the parenteral introduction of any of these foreign proteins,
and that similar modifications are brought about by the intro-
duction of various animal proteins, for example, sheep serum. In
the practical use of the Proteals it has been found possible to
substitute one for another, the selection of the particular type
of protein to be used in beginning treatment of a given case
being to a considerable extent a matter of indifference. I early
observed, however, that some types of vegetable proteins pro-
duced a very much more pronounced anaphylactic response than
others, and I soon found myself selecting one protein or another
with definite reference to the observed condition or suspected
idiosyncrasies of the particular patient.

This obviously implies a recognition of specific differences
among the vegetable proteins used non-specifically.

Further proof of such differences were found in the fact that
an individual patient sometimes responded much more actively to
one type of protein than another. An injection of alfalfa pro-
teins, for example, might cause a marked local reaction, whereas
when mustard seed or rape seed protein was substituted no reac-
tion occurred. Further proof of the specific action — in the usual
sense of the word — was given when it was found that the patient
who had become in a measure immunized to the effect of one
protein showed new response on exhibition of another protein.

Reasoning from analogy, we may suppose that the relative
non-toxicity of proteins from food plants will be shared in some
measure by proteins from botanically related species of plants.

THE SCIENCE AND ART OF PROTEAL THERAPY 167

Thus food plants and their allies would furnish proteins to which
the system was relatively immune; whereas the plants lying bo-
tanically rather far afield from the food plants would furnish
proteins of relative activity or toxicity. Experience, so far as
it has gone, tends to confirm this supposition. In selecting plants
for the development of new Proteals, I am guided by this prin-
ciple. Among the newer extracts, for example, the clover pro-
teins may fairly be expected to produce more pronounced re-
sponse than the proteins of oats and wheat.

It may be added that the theory finds further confirmation in
the fact that the proteins of white of egg and of milk, which
I have used somewhat extensively in alternation with the vari-
ous Proteals, give a still milder reaction, so I was accustomed,
while experimenting with them, to standardize them in a three
per cent, solution and give them in the same dosage that was
employed with the two per cent. Proteals.

All this clearly implies specific differences in the therapeutic
action of the non-specific proteins. If the conclusions just given
are justified, it is obvious that here is a field for investigation
of very wide possibilities. The plants from which I have hith-
erto extracted proteins for therapeutic use number fewer than
thirty species ; it would be difficult to put a limit upon the num-
ber that might advantageously be tested.

THE ADMINISTRATION OF THE PROTEALS

It is my custom to begin the treatment of every new case with
doses of only three or four minims of any one of the proteals;
and administering treatment usually on alternate days, but some-
times daily, to increase minim by minim, or, if there is no reac-
tion, two or three minims at a time till a maximum dose is
attained.

The size of the maximum dose varies with the individual case.
Where there is profound protein toxaemia, as in a well-developed
cancer subject, it is usually desirable to run the dose up rather
rapidly to 10, 15, or even 20 minims ; sometimes a good deal
beyond this. Doses of 60 and even 90 minims of the original
proteal extract have been given. I formerly thought it desirable
to push the dosage until a fairly severe general reaction (rise of
temperature, quick pulse, chill) was produced on at least one occa-
sion. Prolonged experience, however, in which clinical symp-
toms were observed in connection with the blood-count modifica-
tions, leads me to question whether this is usually desirable,
even in cases of malignancy; and it is not in the least degree
necessary to secure a general reaction in dealing with the milder

168 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

types of toxaemias associated with secondary anaemias and neuras-
thenia.

In cases of the latter type a maximum dose of 5 to 8 minims
usually suffices, and often results of the most conspicuous and
well-defined character may be attained with a dosage of only 4
or 5 minims.

In general, my present tendency is to use small doses, and if
necessary give them more frequently, rather than to force the
dosage to heroic proportions. With the new proteals there is no
objection to frequent administration, as the giving of the hypo-
dermic is practically painless.

Probably the most satisfactory method of treatment, whether
of simple toxaemias or malignant ones, is to administer a given
Proteal in gradually increasing doses until the maximum dose
considered desirable in a given case is reached — that is to say, a
dose that produces a satisfactory clinical progress and character-
istic modifications of the blood count; to hold to this maximum
dose for a week or ten days ; and then to shift to another pro-
teal, beginning with a dose of three or four minims and working
up the scale as before. It should be remembered that each pro-
tein elicits its own response, and that a patient relatively im-
munized to, let us say, mustard seed or rape seed proteins may
react vigorously to the protein of alfalfa. The rule is, in begin-
ning with a new protein, to start with a minimum dose, no mat-
ter how thoroughly accustomed the patient is to the administra-
tion of other proteins.

Similarly if the patient has discontinued the Proteal treatment
for a considerable period, and then begins it again, even with
the same Proteal, it is well to start in with a small dose, but
in this case the dosage may be increased much more rapidly
than with a new patient.

It is my routine practice to administer the Proteals by fairly
deep subcutaneous hypodermic injection into the back of the
upper arm. Intravenous injection has sometimes been employed,
but this produces a severe anaphylactic reaction the desirability
of which is doubtful unless in very obstinate and intractable
cases. I do not advocate or practice the method of heroic dosage,
with emphatic anaphylactic reaction, that a few physicians who
in recent months have advocated non-specific protein therapy with
the use of vaccines appear to have employed. My own experi-
ence, based on study of a far larger number of cases than have
elsewhere been treated with non-specific proteins in the entire
world, leads me to conclude that the milder method of admin-
istration is equally efficacious in the end, while being devoid of
unpleasant features.

It is obvious that patients suffering from a simple anaemia

THE SCIENCE AND ART OF PROTEAL THERAPY 169

or a mild intestinal toxaemia would not submit to a treatment
that involved the production of a severe anaphylactic reaction.
In such a case the remedy would be considered worse than the
disease. Fortunately nothing of the kind is either necessary or
desirable. Such a patient undergoing Proteal treatment submits
to nothing more disagreeable than a painless hypodermic, fol-
lowed at worst by a very slight tenderness at the point of injec-
tion, and with no general reaction whatever except the pleasurable
one of increased bouyancy and enhanced sense of well being.

Such, then, are the essentials of the technique of Proteal ther-
apy at present developed. I greatly mistake if the method does
not constitute a marked advance upon any therapeutic measure
hitherto available for treatment of the varied groups of con-
ditions of disturbed protein metabolism — ranging from simple
anaemias to tuberculosis and cancer — to which it is applicable.

Let us now turn from generalities to particulars and consider
very briefly the salient aspects of the application of the Proteal
method to the different types of protein toxaemia in question.

PROTEAL TREATMENT OF CANCER

The reader is aware that the fundamental fact upon which
Proteal therapy is based is that the parenteral administration
of a foreign protein in suitable doses leads to a systemic response
characterized by rejuvenation of the blood corpuscles. The indi-
rect result of such rejuvenation is, in effect, the enhancement
of the phagocytic and enzymic forces with which the body com-
bats protein invasion of all kind. This includes, obviously, cells
of the type called malignant.

Incidentally, therefore, Proteal therapy is applicable in the
treatment of cancer. As I have written another book on this
aspect of the subject, I shall here summarize my experience in
this field very briefly. In so doing, perhaps, I may be permitted
to incorporate matter from a popular article in which I gave a
condensed account of my experience. Possibly the present
reader, sated with technicalities of recent pages, will find this
popular summary a refreshing change. The reader who wishes
fuller and more technical information as to the status of the
Proteal treatment of cancer may turn to the Monograph just re-
ferred to, which under the original title of The Proteal Treatment
of Cancer and Allied Conditions, is about to be issued in a sec-
ond edition.

The condensed popular presentation which, taken in connec-
tion with repeated references in other chapters, seems fairly
adequate for the present purpose, is the following:

Wherever the cancerous condition develops there is always pro-

170 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

found disturbance of the blood, evidenced among other things
by modifications in the quality of the red corpuscles and the rela-
tive numbers of the different types of white corpuscles. Cancer
is never a merely local condition.

To put the matter in untechnical language, the corpuscles fight
the developing cancer cells; if they win, the cancer is eliminated.
The development of a cancer of tangible size is proof positive
that the corpuscles have lost the fight. It may plausibly be
argued that if a way could be found to increase the cohorts of
corpuscles, and to increase their fighting capacity, the tide of
battle might be turned, and the corpuscles, hitherto defeated,
might now become victorious against the cancer cells.

When the Proteals are administered hypodermically, rejuve-
nation of the cohorts of blood corpuscles takes place. That is a
simple matter of fact, which I have demonstrated hundreds of
times under the microscope. My observations have been con-
firmed by numerous independent workers. It has further been
observed that the physical condition of the cancer patient very
generally undergoes a marked change soon after the Proteal
treatment is instituted. Even where cancer had reached a late
stage, perhaps following successive operations, and was now
inoperable and supposedly hopeless, marked changes of favor-
able character have been observed repeatedly.

I have personally collected and published reports of 766 such
cases, treated by more than one hundred and fifty physicians,
showing that, in the estimate of the physicians themselves, 64
per cent, of these "hopeless" cases showed conspicuous improve-
ment under the non-specific protein treatment.

In a certain number of these cases the improvement continued
until the physician regarded the patient as clinically well. The
percentage of such seeming recoveries was small; but that a
single supposedly "hopeless" case could be thus reported in
the early stages of the use of a new method of treatment was
in the highest degree enheartening. To the observers of such a
transformation the result seems to border on the miraculous.

Even where the ultimate results fell short of this there were
temporary effects in a large proportion of cases that seemed
decidedly worth while. For example, in response to a special
request, I received reports at one time from 142 physicians cov-
ering 284 inoperable cases. The reports came from 37 States
and from several provinces of Canada, all the physicians being
men of recognized standing. The specific preliminary results in
this group of cases were as follows:

Where pain was present, it was favorably modified by the
non-specific protein treatment in 77.4 per cent, of all cases. Gen-
erally the use of stupefying opiates could be discontinued. Where

THE SCIENCE AND ART OF PROTEAL THERAPY 171

an offensive discharge was present, it was favorably modified
in 85.6 per cent, of cases. The general health of the patient
was modified as to appetite, sleep, color, weight, or strength in
70 per cent, of cases. Mental attitude was favorably modified
in 71 per cent, of cases. The condition of the cancer mass itself
was favorably modified in 69 per cent, of cases, with marked
regression in size in 27 per cent.

In reporting these results to a professional audience, I added
this comment: "Dealing, as the statistics do, with supposedly
hopeless cases, in the presence of which the physician has hith-
erto stood powerless, and with symptoms mostly not susceptible
of amelioration by any agency hitherto available, this is a showing
at once amazing and enheartening."

A few months later I was able to establish the important
new principle that it is not possible to get cumulative and opti-
mum results from the use of a single protein or combination of
proteins, inasmuch as the system develops a degree of immuniza-
tion. It was found that a case that had become static, after
a period of progress, might take on a new response when a
new type of protein was administered. This principle has been
borne constantly in mind in my personal use of the Proteal treat-
ment, and I have inculcated it persistently in advising with asso-
ciated physicians. Perhaps it will be of interest to reproduce
here a brief history of the patient upon whom the experience of
shifting from one type of protein to another was first made :

Case of Mrs. V. Cancer of the left breast removed by sur-
geon in September, 1915. Recurrence above the clavicle and
about the neck ; pronounced inoperable. Non-specific protein
treatment (hypodermically into the upper arm) begun in Sep-
tember, 1915. Striking modification of the blood, steady im-
provement of general condition, and fairly rapid regression of
the cancerous mass. In June, 1916, only a few small enlarge-
ments remained, but these appeared to be static. A new Proteal,
extracted from alfalfa seed, was administered, and the masses
at once regressed, until only a single gland, as large as the little
finger-nail, was observable just above the clavicle. This was
excised with local anaesthesia, the incision healing promptly.
Occasional doses of Proteal were given at lengthening intervals,
and the patient is still under observation ; but she has been to all
appearance perfectly well for the past eighteen months. She
is of normal weight and appearance; does housework energeti-
cally; reports herself as feeling as well and as strong as ever
in her life. This, it will be observed, two years after the case
had been pronounced hopeless by the surgeons, the diagnosis
of cancer of malignant type having been confirmed with the
microscope.

172 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

The value of a shift from one Proteal to another, illustrated
by the above case, has been demonstrated over and over. Many
types of vegetable proteins are now extracted in my laboratory,
and new ones are constantly being tested. It is routine practice
to shift from one Proteal to another in the treatment of any
intractable case. To a large extent the different vegetable pro-
teins are interchangeable, but no single one can produce optimum
results unaided.

As illustrating the possibilities of the Proteal method in its
present state of development, I may cite the history of a case
even more striking than the one just presented :

Case of Mr. F. Carcinoma of the stomach. Operated on in
September, 1916, by surgeons in Cincinnati, who found a can-
cerous mass completely filling the pyloric end of the stomach
and involving the liver. No attempt made to remove the mass,
but an opening was made in the front side of the stomach and
the intestine attached to permit passage of food. The case was
regarded as absolutely hopeless. The patient came to me for
Proteal treatment five months later, February 25, 1917, in des-
perate condition, regarded by his friends and physicians as be-
yond the reach of medication. The response to Proteal treat-
ment (administered hypodermically into the back of the upper
arm) was immediate. Rapid transformation took place in the
blood conditions, appetite improved, and the capacity to assimi-
late food. Strength was gained from day to day. Painful swell-
ings of the knee joints, which had been a distressing complica-
tion, disappeared. The cancer mass in the abdomen, which could
be readily felt through the emaciated abdominal wall, decreased
rapidly in size until it was not more than one-fourth its original
dimensions. For a time the patient did not gain weight; then
he began gradually and steadily to gain, and in nine months he
had put on twenty pounds. When the treatment was begun in
February, the patient did not attempt to leave the house unat-
tended. Eight months later he made a trip by himself from
New York to his old home in Cincinnati to attend a banquet,
participating actively in all the festivities associated with the
event, and reporting himself, after returning to New York, as
feeling in tip-top condition. He was received by his old friends
and associates almost as one risen from the dead. Whatever the
future progress of his case, there can be little question that the
life of this patient has been extended by many months solely by
Proteal treatment.

To show that similar results may be attained^by physicians who
have had comparatively slight experience with the Proteals, I
may cite a very brief report from a physician in the North-

THE SCIENCE AND ART OF PROTEAL THERAPY 173

west, that chances to come to me just as I am writing this
article :

"Mrs. A. O. Age 53. Cancer of the stomach. Small tumor
at pyloric size of walnut. Under Proteal treatment tumor Dis-
appeared. Stomach symptoms (nausea, vomiting, pain) dis-
appeared. No more blood discharges. Blood picture improved.
Strength and general condition improving."

It will be observed that I have not used the word cure in
connection with the Proteal treatment of cancer. The word
cure is one that I shall not use until at least five years have
elapsed after the clinical recovery of a cancer case. I am hope-
ful, however, that ultimately such reports may be possible. This
hope finds justification in the fact that some of the cases that
have been longest under treatment have shown no tendency to
recurrence. Here, for example, is the record of a case treated
by Dr. E. H. Williams, of Los Angeles, and reported by him in
the New York Medical Journal of October 9, 1915.

Patient with recurrent inoperable cancer of the neck. Treat-
ment begun in June, 1915. Patient made spectacular progress
under hypodermic treatment, the cancer mass regressing rapidly
and altogether disappearing in less than a month. The patient
has now had no treatment whatever for more than two and a
half years, and he continues in apparently perfect health. There
has been no tendency to return of the cancer, and no manifes-
tation of abnormality of any kind.

On the day on which the copy for this chapter goes to the
printer, a letter comes to me from physician number 746 (my
office files), of New Hampshire, telling of a cancer patient, a
woman, treated by him so effectively with the Proteals (No. 45)
that in October, 1917, she was "in fair health and strength, and
able to do very good work in an eating saloon, acting as table
girl," with "no evidence of cancer about her system," and now,
having found the work of lifting the waiters too heavy, she is
occupied regularly in a factory, and has gained fifteen pounds
in weight, is of good color, and seemingly well.

With such reports as this coming from physicians in various
parts of the world, many of whom are quite unknown to me
personally, to fortify my individual observations, I feel amply
justified in reiterating the statement that the results of the
Proteal treatment of cancer are in the highest degree encour-
aging and enheartening. It would certainly seem within bounds
to say that the Proteal method offers new hope for cancer
sufferers everywhere in the world.

In some of my addresses to companies of fellow-physicians
I have gone a step further, venturing the prediction that Pro-
teal treatment will in the immediate future assauge far more

174 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

suffering than the world war causes, and will within the pres-
ent generation save ten lives for every one that the war exacts.

PROTEAL THERAPY AND RHEUMATOID CONDITIONS

Through circumstances with which the reader of earlier parts
of this volume is familiar, the original proteal extracts were at
first administered solely to cases of inoperable cancer. But it
was inevitable that any one who thoughtfully regarded the ob-
served results of this treatment — noting in particular the blood
modifications — should question presently whether maladies of
kindred origin might not fall within the scope of the protein
treatment.

At a very early day I suggested the possibility that a remedy
producing such striking modifications of the blood should be
applicable to the wide range of affections, bacterial and other-
wise, associated with modifications of the blood count. It was
agreed that tests as to this might advantageously be made as soon
as experience was well grounded.

It chanced, however, that the observations tending to confirm
the opinion that the proteal extract might have wider application
were made by a New York physician quite by accident. Among
the patients that came for treatment while the protein method
was still in its infancy was a woman with cancer of the breast,
who also suffered from a severe arthritis of many years' standing.

A published account of this case has described the condition
of the patient before treatment as follows :

"The arthritis had affected the joints of the hands, wrists,
elbows and ankles. The patient had had a variety of treatment
without effect and suffered at the time when she was first seen
more from the pain of the arthritis than from the recurrence of
the malignant growth. The joints of the hands showed the most
deformity, there was a typical ulnar deflection, the articular sur-
faces were enlarged and in some joints eroded, the hands could
not be used for any useful purpose, there were frequent exacer-
bations accompanied by increased swelling and redness of the
joints and increased pain. The affected joints served, in fact,
as so many of them do, as a barometer of the weather con-
ditions."

The case is not the less interesting because, as already noted,
the treatment was aimed entirely at the relief of the returned
cancer of the breast, with no thought, originally, that the rheu-
matic condition would be in any way affected. The treatment,
aside from general hygienic precautions, consisted exclusively
of the hypodermic administration of the original proteal ex-
tract. Note now the sequel :

THE SCIENCE AND ART OF PROTEAL THERAPY 175

"At the time the patient began the treatment she could not
use her hands for any purpose and walked with difficulty. The
injections were administered every second day in gradually in-
creasing doses, beginning with ten minims. During the course
of the first three weeks they were increased to twenty minims.
At this time my attention was called by the patient to the fact
that she now used her hands, for the past week had practically
no pain, was able to button her clothing and was relieved of the
discomforts of the disease to a degree which she had not experi-
enced in years. This improvement continued so that from this
time on the patient practically suffered no more pain from the
diseased joints. The use of the hands gradually returned so
that she was able to write, she could use a needle for sewing
and, while the bony changes were in no way influenced, the
surrounding inflammatory swelling did decrease and she con-
tinued in comparative comfort."

The observer was naturally impressed by these changes in the
joint conditions, and he was quite unable to explain them except
upon the basis of the effect produced by the protein medication.
Very naturally, he recalled the circumstances of this case when a
second patient who was suffering from a rather rapid develop-
ment of arthritis of similar character came under his observation.
This patient was a woman 36 years of age. The history of her
disease extended over a period of two years, the joints involved
being those of the hand, wrists, elbows, ankles, and knees. The
patient had suffered intense pain.

The condition of this patient before treatment is described as
follows :

"The bony changes were not as pronounced as in the case
of the first patient, but the development had been .more acute,
the history extending over a period of approximately two years.
She had already passed through the hands of several physi-
cians who had employed various therapeutic measures, including
careful dieting and observation of the gastro-intestinal tract,
vaccination from cultures obtained from the teeth and a further
course of vaccination with a mixed vaccine originated by
Schaefer. The combined vaccines of Schaefer had given some
relief, but had produced violent constitutional reactions which
had been unfavorable to the general health of the patient. At
the time of her first visit she was suffering so intensely that
she could not walk and was carried into my office. I could not
find a source of infection that seemed adequate to explain the
difficulty."

This patient was at first treated by regulating of diet and atten-
tion to general hygiene, together with the administration of thy-
roid and thymus extracts. In the course of one month some mild

176 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

improvement had resulted from these measures. Then the strik-
ing changes observed in the first patient, as above noted, led to
the decision to administer the Proteal treatment in this second
arthritis case, although the treatment had theretofore been ap-
plied solely to patients suffering from cancer. The administration
of the Proteal extract was begun on the 28th of May, 1915.

The injections were continued over a period of nine months.
At the outset the patient had been taking 40 to 60 grains of
aspirin each twenty-four hours to relieve the pain. The amount
was promptly diminished in the course of the first three weeks
of the Proteal treatment, and in the course of two months the
drug was entirely discontinued.

Here is the report on the treatment and its results:

"During the earlier months of the treatment the injections
were given every second day, during the last four months the
interval between the injections was gradually increased until
finally an injection was given only once a week. The patient's
improvement was gradual but definite, and she finally reached
and maintained a state of health satisfactory in every respect.
The bony changes about the affected joints have never been re-
lieved and it seems very doubtful if they ever will be. How-
ever, the infiltration and thickening of the soft tissues has been
entirely relieved. During the past six months this patient has
had no treatment whatever. She has been in excellent health,
has gained twenty- four pounds in weight during the course of
the treatment, and during the past summer has been unusually
active, playing tennis, swimming and doing a variety of house-
hold work, using her hands with perfect freedom and comfort
for such mechanical operations as writing, fine sewing, etc."

The clinical progress of this case was matched by the modi-
fications in the blood conditions. Starting with a red blood
count of a little over two million and hemaglobin of 70 per cent.,
the records show that on the 17th of September the red blood
count was 3,900,000, the hemaglobin 79 per cent. On the 14th
of December the red count was 4,444,000, the white count 6,700,
the hemaglobin 90 to 95 per cent. On the 27th of December the
red corpuscles numbered 5,280,000, the white corpuscles 8,000.
The differential count, at a time when the treatment was most
actively pursued, showed 53 per cent, polynuclears, 25.5 per
cent, large monocytes, 12 per cent, small lymphocytes, and 9.5
per cent, eosinophiles. At a later date (December 27th), when
the patient was receiving only weekly Proteal treatment, the dif-
ferential count showed polynuclears, 14.5 per cent, large mono-
cytes, 22.5 per cent, small lymphocytes, and 3 per cent, eosino-
philes.

It is significant that two years have now elapsed since treat-

THE SCIENCE AND ART OF PROTEAL THERAPY 177

ment was discontinued in the case under consideration, and
that the patient remains in a condition of normal health. She
was under treatment for hay fever for a short time during the
summer following the disappearance of her rheumatoid difficul-
ties, but there has been no evidence of a tendency to recurrence
of the old malady.

In recent months a number of cases of arthritis of various
types have come under treatment in my office. Reports have
come to me also from other physicians who have used the Pro-
teals from my laboratory in the treatment in cases of rheuma-
tism of various types. The evidence as a whole is not yet in
any wise comparable to the evidence regarding the Proteal treat-
ment of cancer, but in the main it is corroborative of the observa-
tions above recorded. Patients suffering from the most intract-
able forms of arthritis have had their pains banished and their
rigid joints made mobile. Patients suffering from milder types
of rheumatism have shown amelioration of the unpleasant symp-
toms and conspicuous improvement in the general condition —
together with a characteristic regenerative modification of the
blood — almost from the outset. With cases of the latter type
doses of 5 to 10 minims of one of the standard Proteal extracts
— for example, No. 45 — have proved efficacious. For the more
severe cases the dosage has been advanced, gradually, to 15, 20,
and even 30 minims. But I have not thought it necessary or
desirable to force the dosage to the point of producing severe
reactions as a rule. I believe the best results are attainable by
giving relatively small doses for a long period of time.

Spectacular results through the use of one or two heroic doses
have been reported in recent months by physicians using the
proteins of the typhoid bacillus ; but it is my opinion that the
method designed to bring about slow and gradual modifications
in the affected joints will be found in the end more efficacious,
as it is unquestionably the more pleasant method of treatment.

Details of technique aside, -however, it would appear that the
evidence justifies a large measure of confidence in the possibili-
ties of treating rheumatsm and various rheumatoid conditions
with non-specific proteins — associated, as a matter of course,
with general hygienic measures, including low protein (and
chiefly vegetable protein) diet and systematic exercises.

DIETETIC ANOMALIES EXPLAINED

As to diet, however, I would offer a suggestion, which will
perhaps seem anomalous ; but which is based on a wide range of
experience in the first instance, and supported theoretically by
the fundamental principles of the Proteomorphic theory. It

178 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

is to the effect that, whereas I advocate a low protein diet for
people at middle age and later, in health and in toxaemic mala-
dies, and in particular a low animal protein diet, with emphasis
on the exclusion of bearers of purin-bases for rheumatoid cases,
I nevertheless believe it advantageous occasionally to permit the
patient to depart from the rule and indulge in a meal including
a moderate portion of meat — for example, about three cubic
inches of beefsteak.

It is a familiar experience that such a meal, indulged by
exception and not too frequently, has a stimulative or tonic
effect. Haig explains this, as will be recalled by every one
familiar with his oft-berated but never discredited work on Uric
Acid, on the assumption that the beef tends to acidify the liver
and cause that organ to sieve the uric acid out of the blood
temporarily — an explanation that appears to me altogether fan-
ciful and fallacious. Doubtless my own explanation will seem
equally fanciful to any one who has not grasped, or does not
accept, the fundamental thesis of the Proteomorphic theory.
Be that as it may, my explanation is that a certain amount of
the protein of the steak is pretty sure to find its way into the
parenteral system not fully decompounded (experiments cited
in earlier chapters fully warrant this assumption), and will thus
act as a proteantigen stimulating corpuscular response precisely
as if it had been introduced hypodermically. In effect, eating
the steak was equivalent to giving treatment with a protein of a
type which is not familiar (since the meat is eaten only at rather
long intervals), and against which the system is not at the moment
fully immunized.

The corpuscular response includes, according to hypothesis,
increased enzymic activities of the corpuscles ; enhancing, there-
fore, the purin-body-reducing functions of the erythrocytes,
and thus tending to clear the blood of uric acid — in accordance
with Haig's statement of the fact, but not at all in accordance
with his explanation of the modus operandi. The increased
activity of the red corpuscles and their consequent excessive
destruction in the liver might indeed be said to "acidify" that
organ, through increased influx of uric acid, and in particular
urea, from the bodies of the disrupted erythrocytes; but the
"sieving" process, according to the present thesis, would consist
in the increased capacity of the erythrocytes to transform uric
acid into urea (see Chapter I above).

Meantime, of course, the beef protein ingested, if entering
the parenteral system more or less fully digested, but short of
the amino-acid stage, would bring an increment of purin bodies
that would add to the uric acid supply. Where the balance
would be struck, in any individual case, would depend upon the

THE SCIENCE AND ART OF PROTEAL THERAPY 179

quantity of meat ingested and the length of time that had elapsed
since the organism had been habitually invaded by this partic-
ular protein. It is consonant with the Proteomorphic concep-
tion to assume that even when the beef protein-products entered
the blood at the polypeptid stage, they would act as antigens
directly stimulating the mother-cells of the erythrocytes and the
enzymic response of the erythrocytes themselves — provided al-
ways that these cells were not sated by habitual presence of
these particular proteins.

Should intestinal digestion be so perfect that all the beef pro-
tein is reduced to the amino-acid stage before passing into the
parenteral system, there would no such antigenic effect — nor,
in all probability, would purin bodies be included; but there is
reason to believe that enteric digestion seldom is so perfect as
this — particularly in case of persons of rheumatoid diathesis,
since they, almost by definition, suffer from intestinal toxaemia.
Indeed, as was earlier pointed out, it is not quite certain that
the proteins do not normally enter the blood as polypeptids.

Such, then, is the theoretical reasoning through which I find
warrant for the practice of admonishing my patients — rheuma-
toid, anaemic, cancerous, tubercular — to regard an occasional, but
not too frequent, infraction of the purin-free diet rule as a
part of the rule. The radical distinction between such occasional
indulgence and habitual ingestion of the purin-bearing proteins
will be obvious to any one who recalls the oft-reiterated prin-
ciple that an incessant stimulus from the constant invasion of a
protein of any type leads to the corpuscular exhaustion implied
in what has been repeatedly spoken of (though perhaps the
phrase in this connection is not very defensible) as immunization
to the effects of a given protein.

Incidentally it may be noted that the utter satiety that attends
the too continuous ingestion of a single type of foodstuffs is thus
to be explained. So far as I am aware, no other really intelligible
explanation of this anomaly has hitherto been forthcoming. The
oft-cited paradox (doubtless not literally true, yet symbolizing
a profound dietetic truth) that no one can eat a quail a day
for thirty days without utter satiety, thus finds scientific elu-
cidation,

PROTEALS IN THE HANDS OF THE PRACTITIONER

All this, however, is carrying us afield from the question of
the treatment of rheumatoid conditions with Proteals — though,
after all, not far afield, as will appear when an explanation of
the action of the Proteals in this connection is given a little
later. First, however, it will be well, as establishing the prac-

180 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tical status of the Proteals in the matter, to cite a few individual
experiences of physicians using Proteals from my laboratory in
the treatment of familiar types of chronic arthritis. Here, for
example, is an informal letter from physician number 726 (ac-
cording to my office files), of Oregon:

"Mr. F. was the first case treated by me. Had been stiff and
unable to walk for several years. Nervous system run down.
Administered doses as per directions. Noted improvement in
three weeks' time. Health generally better; strength returning.
A maximum dose of twenty-four minims [of Proteal No. 45]
three times with good results. Gave him injections daily. Now
he is able to walk without crutches with the assistance of some
one to steady him." The treatment was given in association
with the use of an electric baking apparatus.

Of similar tenor is a letter from physician number 232 (new
series), of Arkansas:

"The hands — which were contracted so she could not extend
them and could barely get a staff into each hand for walking —
and the feet and hips were so stiff and sore she could not stand
or move except with the twa staffs in hand. She can now ex-
tend fingers, pain almost gone, and walks upright and has thrown
away the sticks."

A little later the same physician made a brief formal report
on his first four arthritis cases under Proteal treatment, which
has added interest because the type of Proteal and the dosage
employed in each case are specified:

Case 1. — Male age 60. Rheumatism of wrists and finger joints.
Pain at night of an aching character causing considerable loss
of sleep. These pains had been persistent and increasing for 10
years. Treatment began with six minims of mixed Proteals
[No. 45 — proteins of alfalfa seed, alfalfa meal, and millet seed]
every other day, subcutaneously in forearms, increased injec-
tions gradually to twenty minims. Ten treatments given and cure
resulted. No general reaction, but there was a marked local
reaction with itching and stinging and marked cutis anserinus
of about two inches surrounding the site of each injection that
persisted about three days each time.

Case 2. — Rheumatic arthritis. Male age 58. Disease affects
hands, elbows, shoulders, and hips. Could walk with difficulty
by means of two staffs, one in each hand. Could barely open
hands sufficiently to get staff (one inch in diameter) into hands.
Tendons badly drawn and joints enlarged and very tender.
Began treatment with six minims of mixed Proteals [No. 45,
as above] every other day. No general reaction, slight local
reaction. Increased the Proteals gradually to twenty minims.
Gave in all twelve treatments, with marked improvement in all

THE SCIENCE AND ART OF PROTEAL THERAPY 181

joints, At close of last treatment patient could walk fairly well
without any staffs and could open hands three-quarters of nor-
mal extension. This patient left the city and must be improving
yet or he would report to me.

Case 3. — Mr. S. Age 48. Rheumatism of the fingers with
deposits about joints, particularly about last joint of right index
ringer, to such an extent he could flex the finger but a trifle
owing to a lump on under and outer side of the joint. Six to
sixteen minims of mixed Proteals [No. 45] gave slow improve-
ment until we were halted by a serious abscess at site of one
injection. A rest of four weeks and then six injections of the
rape seed Proteal [No. 42] on alternate days caused improve-
ment sufficient for him to almost completely flex index finger.
He is in much better health and comfort and frankly attributes
relief to the treatment.

Case 4. — Mrs. M. Age 44. Chronic articular rheumatism of
four years' duration, in feet and ankles, knees, hips, fingers,
wrists, elbows, and shoulders. Had been bedfast several times ;
never much improvement. Suffered greatly with soreness, swell-
ing, and tenderness of joints. Began with six minims of rape
Proteal [No. 42], subcutaneously. Ached and hurt all night
following first injection. Continued and increased the treatment
every other day for two weeks, with steady improvement and
no further reactions. After three weeks the improvement ceased
and I changed to fifteen minims of alfalfa seed Proteal [No.
39]. A very marked improvement followed. Increased the al-
falfa gradually to 25 minims. Four alfalfa injections were given,
when she seemed almost entirely cured. At this time her son
and husband were stricken with typhoid fever. She nursed and
cared for both, until the husband died. During the four weeks
of this unusual strain, she showed no return of the trouble,
but to-day she returned with the report that she begins to have
pains in the feet, ankles, and knees and they are somewhat
swollen, and I have resumed alfalfa, 10 minims.

As representing an initial experience with Proteal therapy,
this record of marked improvement of four consecutive cases of
intractable character in the hands of a single practitioner is
certainly enheartening. The aggregate number of such reports,
giving tangible support to my personal experiences, is already
notable. But in particular there come to me day by day informal
letters from associated physicians that are often more stimulative
than formal reports. For example, here is one that came to
hand in this morning's mail from a physician out in North
Dakota, with reference to a typical case of rheumatoid arthritis
that has been under Proteal treatment for eight months.

"Mrs. — feels that the Proteal treatment is helping her, and

182 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

I can see an improvement, although the affected joints are still
stiffened and sore. She rests much better and has not the con-
stant pain that bothered her so much formerly. She is enthu-
siastic, and wishes to keep up the treatment faithfully."

Another recent letter, this time from British Columbia, tells
that the patient, for fifteen years a sufferer from rheumatoid
arthritis of the most intractable type, has just stood upon her
feet for the first time in ten months, and has found a measure of
relief from pain under Proteal treatment after she had long
despaired of ever finding solace.

I would not be understood to imply, however, that Proteal
therapy has hitherto proved adequate or satisfactory in all rheu-
matoid cases to which it has been applied. I have seen it fail
in at least one case that came under my personal observation.
The patient is a case of chronic arthritis, of progressive type,
who twice came to my office for personal examination, and to
whom the Proteals were administered in varying dosage for a
term of months. On the morning on which I am completing this
chapter, I received (from physician number 767, New York)
the following letter:

"I regret to report that Mrs. — does not show any improve-
ment under treatment with Proteals; I cannot conscientiously
say there has been relief in any of the joints, while the cervical
and lumbar vertebrae seem now to be involved. It is certainly
an obstinate infirmity. Apparently in this particular case the
Proteal does not seem to have developed any protection."

I may add that earlier reports suggest a certain improvement
in general health, which, however, was not of vast significance ;
and that there were modifications of the blood count that led
at one time to favorable anticipations. But apparently in this
case we have failed hitherto to find the source of disturbed meta-
bolism or to counteract effectively the pre-existing maladjust-
ments.

In the contrast with this unsatisfactory showing, I may quote
a letter from another physician concerning a case that also had
come under my personal observation, but which, like the case
just cited, was not treated personally by me, although in both
cases the Proteals used were supplied from my laboratory. Here
is the letter (from physician number 784, Montana) :

"The patient whom you saw when you were lecturing on the
Chautauqua Circuit has shown a remarkable improvement. All
his friends speak about his ease in walking. Perhaps you do not
recall, but he was suffering from chronic arthritis, and of some
of the notables who treated him, Dr. — [a famous Chicago
physician] was the last. The patient has attended two dances
and taken an active part since beginning the Proteal treatment."

THE SCIENCE AND ART OF PROTEAL THERAPY 183

This patient, when I saw him, in August, 1917, did not attempt
to rise from his chair. His arthritic involvement had been
progressive, and had resisted all the conventional lines of treat-
ment, including vapor and mud baths, change of climate, removal
of the tonsils, and careful regulation of the diet under super-
vision of some of the most noted physicians in America. But
improvement was immediate and almost spectacular under use
of the Proteals, fifteen minims of Proteal No. 45 (alfalfa seed,
alfalfa meal, and millet seed) being given as an initial dose. The
letter from the physician above quoted was written after treat-
ment had been continued about two months.

Three months later still a report from the patient himself
tells that he had discontinued using the Proteals for about
four weeks to see what the effect would be, and "although there
was no distinct setback I notice that the swelling began to re-
turn gradually in my hand, and that my feet became more ten-
der." Treatment was therefore resumed, with maximum dosage
of about twenty minims, and the next report received (and the
last one to date) states that the patient is "improving steadily."

In this case the results were so spectacular that they were
known to every one in the community, and a considerable group
of rheumatoid cases have been led to take the Proteal treatment.
There are similar groups in various other communities, developed
in the same way, but I shall not go into details regarding these
or other cases. Full reports and an attempt at the statistical
summary will be given in a book to be issued a little later
under title, probably, of Proteal Therapy in Theory and Prac-
tice. Here I am concerned rather with the general interpreta-
tion, and the fundamental principles of the protein response.
For the present purpose it suffices to have shown that in a
certain number of cases administration of the Proteals has been
followed by modifications of the rheumatoid condition of such
character and under such circumstances as to leave it scarcely
open to doubt that the administration of the protein had a causal
relation to the observed favorable sequence of events.

PROTEAL THERAPY AND ASTHMA AND PSORIASIS
Before attempting a specific interpretation of the action of the
Proteals in rheumatoid cases, in terms of the Proteomorphic
Theory, I would refer to two other types of manifestation of
disturbed protein metabolism, totally different in their localiza-
tion, yet, in my opinion, having a certain setiological relationship.
I refer to bronchial asthma and psoriasis.

Both of these obstinate conditions have been treated, in a
small but striking group of cases, with Proteals from my labora-
tory by associated physicians.

Our practical experience in the treatment of asthma with the

184 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

Proteals is exceedingly limited. Early in the year 1916 I received
a letter from a physician who said that another California physi-
cian, a friend of his, having read an article of mine with ref-
erence to Non-specific Therapy had prepared and used the pro-
teins of white of egg in treatment of his wife, who had asthma,
with seemingly curative effect. I stated this fact to various
physicians in the course of my lecture tour in the West during
the summer of 1917, adding that there are some theoretical grounds
for supposing that the use of the Proteals might be advan-
tageous ; notably, the fact that some physicians associate the
asthmatic tendency with the rheumatoid condition, and that there
is a certain amount of evidence associating asthma with protein
infections, as in those cases that are susceptible to horse serum.
The fact that the blood in many cases of asthma shows a
pronounced increase of eosinophiles, if interpreted in the light
of my own theories as the functions of this type of leucocyte,
is corroborative of the idea of protein infection; the invasion
being, according to my interpretation, conspicuously an invasion
of unbroken protein molecules. Further suggestions along the
same line are to be found in the obvious fact that bronchial
asthma is itself allied to the spasm characteristic of acute ana-
phylactic shock from the introduction of a foreign protein into
a vein, detailed reference to which was made in an earlier chap-
ter of the present work.

Partly at least in response to my suggestions, a number of
physicians have administered the Proteals to patients suffering
from asthma, and the few reports that have come from them
have been of the most encouraging and gratifying character.
My brother, Dr. E. H. Williams, of Los Angeles, California,
who has had very wide experience in the use of the Proteals
in various affections, reports two cases of asthma that have
yielded to the treatment and have reached a stage of seeming
cure. The most spectacular case hitherto reported, however, is
that of a patient in a city of the Northwest (Oregon), a dentist,
who was subject to attacks of such severity that he had been
obliged to discontinue practice of his profession.

Treatment consisted of the administration on alternate days
of five minims of Proteal No. 45, containing in equal parts the
proteins of alfalfa seed, alfalfa meal, and millet seed.

In reporting this case, the physician, who had had consider-
able prior experience with the Proteals from my laboratory and
with whom I had seen a case of rheumatoid arthritis in consul-
tation a few months earlier, wrote as follows, under date of
November 8, 1917:

"I have a very severe case of bronchial asthma to which I have
administered two doses of No. 45 with immediate and pro-

THE SCIENCE AND ART OF PROTEAL THERAPY 185

nounced relief. I wish to give him a regular course of the
treatment."

Under date of December 22, 1917, he sent a personal letter
containing this interesting item : "I want to tell you about the
case of asthma. I used five minim doses of Proteal No. 45
every other day with the most striking results. Patient only
experiences one or two slight attacks toward morning which soon
pass off and he is free all day. Prior to the Proteal he was un-
able to do his practice (he is a dentist). At times I have gone
into his office to find him stretched out fighting for breath. To
show you how well he is feeling — he went duck shooting the
other day and carried a sack of grain across the field to feed
the ducks, with no effect whatsoever on his asthma."

And under date of January 17, 1918, there is this letter: "I
wish to report further on the case of bronchial asthma that I have
been treating with your Proteal. My results are most remark-
able in that the case has resisted every other line of treatment
for years. The patient had not had a whole night's sleep for
three years to my personal knowledge. He reports to-day that
he has been sleeping soundly for the last three weeks, and that
he had no trouble whatsoever; gaining in weight; works at his
profession every day, all day.

"I inject five minims of Proteal No. 45 every third day. I
have not changed the type of protein."

Just a month later, February 17, the final report up to date
states that the patient "is now using eight minims to a dose every
third day, and is absolutely free from all symptoms of asthma
while taking the Proteal that way."

I may add that the same letters that tell of the progress of
this case also report on several cases of rheumatoid arthritis
which "have all improved greatly, although the improvement has
been much slower than in the asthma. I have used the same
Proteal and the same dosage as in the asthma." Also there is
report of a second case of asthma which is "steadily improving
under the Proteal treatment. The asthmatic attacks are much
less frequent, and on the whole she is getting better every day."
This second asthmatic patient is the wife of a physician. Pro-
teal No. 45 has been used in the treatment of this case as in the
other.

I will here supplement this report in specific cases only by
noting that the Proteals are now being tested on a series of
asthma cases in a large city hospital by an associated physician
who reports tentative results that are "really encouraging in
practically every case." Ultimate conclusions from this elab-
orate test will not be reached for some time to come.

As to the treatment of psoriasis with the Proteals. It should

186 TILE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

be noted that this is an application of non-specific protein therapy
in which independent workers have priority. During the sum-
mer of 1917, however, a co-operating physician using Proteals
from my laboratory treated several cases of psoriasis of long
standing with striking success in every case. These were cases
that had proved entirely resistant to antecedent treatment in the
hands of leading Metropolitan skin specialists. The Proteals
were administered in relatively small doses ranging from five to
ten minims. To make the test definitive, there was no change
in the diet of the patient, and no local application whatever was
used. It was reported that in one case there was favorable
change in the eruption in the course of ten days, but that the
others showed no marked change for about five or six weeks;
after which there were rather rapid and progressive modifica-
tions of favorable character, leading ultimately to complete dis-
appearance of the eruption. Only one of the cases was seen
by me personally, but this was a case in which the malady had
been present for about eighteen years. The eruption had ex-
tended over the entire back of the patient at the time when the
treatment was begun; and when I saw the patient about three
months later the skin was perfectly smooth and free from any
kind of eruption.

It is a familiar axiom of medicine that one case may prove
nothing at all, and that a considerable series of cases may prove
quite inconclusive or misleading when checked by more compre-
hensive experience. But when the cases under consideration involve
maladies of such intractability as rheumatoid arthritis, asthma,
and psoriasis, it would appear that such results as those above
noted are at least thought-provocative. Certainly we are war-
ranted in making further tests along similar lines ; and I am
glad to be able to report that tests are being made on a com-
prehensive scale that may be expected presently to justify more
definite conclusions.

How THEORY EXPLAINS PRACTICE

Meantime a few words as to the theoretical ground on which
an explanation of the possible utility of the Proteals in these
conditions of disturbed metabolism may be based. The explana-
tion will readily suggest itself to any one who has read the
earlier chapters of this book attentively. In particular, it should
be recalled that the therapeutic response to the administration
of Proteals involves increase in numbers and (so it is be-
lieved) enhancement of the enzymic activities of the red blood
corpuscles. This implies, further, according to the Proteo-
morphic theory, increased capacity of the organism to deal with

THE SCIENCE AND ART OF PROTEAL THERAPY 187

the end products of protein metabolism, and in particular with
the purin bodies, hypozanthin, zanthin, and uric acid.

Notwithstanding the fluctuations of medical opinion on the
subject, I believe that the uric acid hypothesis is still the most
tenable thesis as to the underlying causation of the rheumatoid
condition that has been put forward. But whatever the view as
to this theory, there is practical unity of belief that the condi-
tions under discussion are associated with disturbances of protein
metabolism. Whether or not the purin bases are chiefly at fault,
there is failure of complete and normal metabolism and elim-
ination of the protein intake. The administration of the Pro-
teals tends to normalize these processes. Very commonly the
blood in these cases shows marked quantitative and qualitative
abnormalities of the corpuscles. The Proteals tend to correct
these abnormalities. Rarely indeed does the patient fail to im-
prove in blood conditions and correspondingly in general clin-
ical condition.

Through such modifica ions, in my belief, the therapeutic ben-
efits of the Proteals are to be expected. I have never for a
moment entertained the thought that the Proteals are specifics
for the rheumatoid conditions. Indeed, I scarcely know what
the word specific may mean in medicine except as applied to
an agent directed against a particular type of microrganism. If
any other use of the word be permissible, it might perhaps be
justifiable to speak of the Proteals as specifics for the condi-
tion of anaemia, so direct and significant is the response of the
blood-forming organs to their stimulus. But anaemia itself is,
after all, a condition or symptom rather than a disease; and no
wise physician would depend upon mere medication in treating
anaemia, without giving thoughtful attention to its underlying
causes, and endeavoring to remove these or modify them by
eliminating sources of infection, counseling proper diet, and
securing the co-operation of proper hygienic measures in general.

If this is true of the simplest anaemia, it is assuredly doubly
true of the complicated anaemias that are associated with the
various maladies of disturbed metabolism that are under consid-
eration in this book. Above all, this is true about rheumatoid
arthritis. This is a malady that makes its encroachments with
almost diabolical persistency. It harks back always, I believe,
to defective enzymic activities of the intestinal tract. As a rule,
it is associated with life-long tendency to constipation. Its ex-
istence implies hereditary vulnerability of the joints, combined
with inherited or acquired deficiency of action of the organs of
digestion and assimilation, probably always associated with
what for the patient in question are improprieties of diet. There
is usually the history of the habitual ingestion of animal pro-

188 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

teins in excess. The use of coffee, tea, and cocoa may often be
credited with an active share in fostering the condition.

One of my patients, now under Proteal treatment, affirmed
that she had been exceedingly moderate in the use of ani-
mal foods and of tea and coffee ; but presently mentioned that
she habitually ate from a quarter to half a pound of chocolate
each day and had been accustomed to do so for many years. It
is probable that this quantity of chocolate would in itself supply
purin bases enough to overwork a set of red corpuscles other-
wise adequate. If this thesis is correct, it is obvious that to
hope to benefit the patient greatly by Proteal or any other treat-
ment without interdicting the use of chocolate would be like
throwing water on a fire with one hand and kerosene with the
other.

In leaving this aspect of the subject, however, I would again
call attention to the fact that a very considerable number of
cases are now on record in my office files in which patients
suffering from rheumatoid conditions (and a smaller number of
cases suffering from asthma and psoriasis) had proved resistant
to every dietetic, hygienic, and medicinal procedure hitherto
available, and yet have seemed to respond to the Proteal treat-
ment so directly and so explicitly as to forbid the supposition
that the observed improvement was only a coincidence. Coup-
ling these observations with the theoretical considerations just
presented, we are justified, I believe, in awaiting with a con-
siderable measure of confidence the results of a more elaborate
investigation as to the use of the Proteals in the treatment of
rheumatoid conditions, asthma, and psoriasis.

PROTEAL THERAPY AND TUBERCULOSIS

Another important malady that has been brought within the
scope of Proteal therapy is pulmonary tuberculosis.

The first case of tuberculosis treated was of a character to
subject the method to the severest possible test. The patient,
a man about 35 years of age, had come back from southern
California in a seemingly hopeless condition. Not only were
lungs involved in the most critical manner, but the tubercular
infection had spread to the larynx and had also involved two
lumbar vertebrae. The case was so obvious that the diagnosis
could have been made by any tyro, but in point of fact
the advice of leading specialists had been sought.

The specialists had agreed in pronouncing an absolutely unfa-
vorable prognosis. Nevertheless the patient showed a certain
amount of response to tuberculin treatment. Recognizing the
limitations of this method, however, as gauged by fairly wide

THE SCIENCE AND ART OF PROTEAL THERAPY 189

previous experience, it was decided, as a last resort, to test
the proteal treatment, which hitherto had been applied only to
cancer and two cases of rheumatoid arthritis ; this decision being
actuated by the observed effects of the remedy in regenerating
the red corpuscles, on the seemingly plausible assumption that a
remedy proved to have extraordinary powers to whip up the
blood-forming organs must be of value in combating an anaemia
of tubercular origin no less than the anaemias of cancer and
rheumatism.

Accordingly the patient was placed under proteal treatment,
early in September, 1915. The original Proteal extract was
administered in the usual way, hypodermically into the arm, in
doses of from 10 to 20 minims, given on alternate days.

The result was nothing less than spectacular. After the treat-
ment was fairly under way the patient declared himself to feel
a sense of exhilaration as if from taking champagne. He gained
in weight, lost his cachetic appearance ; cough and expectoration
subsided. The bacilli disappeared altogether from his sputum,
and physical examination of the chest gave evidence of the
development of reparative processes. After treatment had con-
tinued for about three months improvement all along the line
was so great that the most searching examination failed to
reveal any evidence of active tubercular involvement.

On the 15th of December, 1915, an examination of the blood
showed 90 per cent, haemoglobin ; 5,600,000 red corpuscles, and
8,400 white corpuscles, with 45.5 per cent, polynuclears, 35 per
cent, large monocytes, 10 per cent, small lymphocytes, 4 per
cent, eosinophiles, and 0.5 per cent, basophiles.

The patient's subsequent history was uneventful. The Proteal
treatment was continued for a time, at lengthened intervals, and
then there seemed no necessity for further treatment. The
patient had gone to live in the country, and in the ensuing
summer he was able to take part in rather active phases of farm
work. He has a somewhat weak back, as a matter of course,
from the former involvement of the vertebrae, but his general
health and condition are highly satisfactory. On March 18, 1917,
more than a year after discontinuance of the proteal treatment,
the blood count showed 5,884,000 red corpuscles of normal type,
and 9,400 white corpuscles. Obviously, there is scant suggestion
in such a supernormal count of the tubercular condition, which
had seemed to doom the patient until the proteal treatment was
instituted. The patient's appearance and general condition ac-
cord well with the remarkable blood count.

Another gratifying case of pulmonary tuberculosis is that of
a young girl of 22, whose progress has been so spectacular as
to merit especial record.

190 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

The diagnosis in this case, as in the other, was absolutely
unequivocal. The physical symptoms were typical : violent cough
with profuse expectoration; temperature of 101, and pulse of
115; marked emaciation, and evident, even if not profound,
cachexia. The rales were so conspicuous that they could be heard
without the stethoscope and with the ear at a distance from
the chest. Bacteriological examination of the sputum had been
made, with positive findings, by the New York Board of Health.
The patient's constitution was so undermined that her physician
had told her she had but one chance in a thousand to live, and
that chance contingent on immediate removal to the mountains.

Blood examination before treatment showed 3,954,000 red
corpuscles, but 90 per cent, of these were misshapen or of the
conformation that I am accustomed to speak as the sea urchin
type. The bulk of the red cells was not at all commensurate
with their number, since so high a percentage were misshapen.
The white cells number 9,200, of which 78.5 per cent, were
polynuclears, 11.5 per cent, small lymphocytes, and 9.5 per cent,
large mononuclears, and 0.5 eosinophiles.

X-ray examination of the chest was made before treatment by
a prominent roentgenologist, who reported as follows :

"There are numerous calcified glands in the lung lobes. In
the right lung there are several calcified tubercles scattered
from the base to the apex. Upper lobe is infiltrated, the infil-
tration being most marked around the proximal portion of the
bronchial branches of the upper lobe. On deep inspiration
there is tendency to fixation of the left diaphragm. The left
auricle is moderately enlarged, and the right auricle and ventricle
are moderately enlarged. Diagnosis, tuberculosis of the left
upper lobe."

The administration of Proteal No. 45 (alfalfa seed, alfalfa
meal, and millet seed proteins) was carried out in the usual
way, beginning with 3 minim doses and increasing to 10 minims,
administered hypodermically on alternate days. Changes in the
patient's condition were immediate, striking, and highly grati-
fying. On the eleventh day of treatment it was recorded that
temperature and pulse were normal ; that the cough had almost
disappeared, so that a sample of her sputum was obtained with
difficulty; and that the patient's condition of general health had
been so modified that she expressed a wish to return to her
work. She had gained two pounds weight.

The blood count now showed 90 per cent, haemoglobin, and
4,500,000 red corpuscles, not more than 10 per cent, of which
were of the small, battered, misshapen type which made up
the chief complement of cells before treatment. There were
occasional normoblasts, and some groups of platelets. The white

THE SCIENCE AND ART OF PROTEAL THERAPY 191

cells numbered 9,000, with 77.2 polynuclears, 9 per cent, small
lymphocytes, and 12 per cent, large mononuclears, 1.2 eosino
philes, and 0.25 per cent, basophiles. Thus it will be seen that
the red cells had increased by I2y2 per cent., the large poly-
nuclears by 25 per cent., and the eosinophiles by 300 per cent.
The activity of the blood-forming organs was further evidenced
by the presence of a few lymphoidocytes and plasma cells. The
white cells still showed some defect of staining quality, and a
tendency to clump at the end of the smear ; but, in general, the
modification of the blood fn so short a period was notable.

On the fourteenth day of treatment a second X-ray examina-
tion was made and the report was as follows:

"There is no evidence of an active process in the lungs. The
diaphragm is freely movable and the area of increased density
in the left upper lobe has disappeared. There is probably almost
resolution of the area which gave signs of infiltration at the
examination made twenty days ago."

Thus it appears that the X-ray examination confirms the find-
ings of physical examination, which had shown the most striking
modifications for the better, and is consonant with the observed
modifications of the blood and the conspicuous change in the
patient's appearance and general health. The further history of
this case was absolutely uneventful. The patient continued to
improve, and six months later she seemed entirely well.

As there had been no change of residence or modification of
habits, and as no other treatment had been administered, it seems
impossible not to ascribe the changes thus variously recorded
to the hypodermic injections of the Proteal solution.

Such observations as these are obviously enheartening. It was
natural that I should call attention to these cases in the medical
addresses during my lecture tour of the summer of 1917; and
it is perhaps not surprising that a considerable number of physi-
cians were moved to make a trial of the Proteals in the treat-
ment of tuberculosis. Reports of a very encouraging character
have come from a considerable number of these physicians ; and
no single report in any way contraindicating the use of the
Proteals in cases of tuberculosis.

Meantime my own personal office and consultation experience
has been extended to a fairly representative group of cases of
pulmonary tuberculosis at various stages of development. It
would not be consonant with the plan of the present work to
cite these cases in detail. A case that is fairly typical in its
history and its response to treatment is that of patient Number
2,089, with pulmonary tuberculosis of fibroid type of ten years'
standing. Usual history of forced feeding, temporary change
of climate, and more or less steady progress in the wrong direc-

192 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

tion. Two hemorrhages in the past two years. Temperature
never very high; seldom much above one hundred. Pulse 88 to
100. Haemoglobin 70; red corpuscles 4,088,000, varying in size,
with many microcytes ; white corpuscles 14,000.

Treatment began with three minims of alfalfa seed protein
(Proteal No. 39) ; continued on alternate days, increasing minim
by minim until a dosage of ten minims was reached. A shift
was then made for a few successive treatments to Proteal No.
60 (alfalfa seed and alfalfa meal proteins), one dose of which
produced a rather severe local reaction, which did not recur
with subsequent doses. After about three weeks of treatment
a further shift was made to Proteal No. 45 (alfalfa seed, alfalfa
meal, and millet seed proteins), beginning with five minims, and
gradually increasing the dose to nine minims.

Throughout this period of treatment there was steadily pro-
gressive clinical betterment; a tendency of the temperature to
approximate the normal (falling once to 97.4) ; and of the pulse
to decrease from 98 and 100 of the earlier visits to 84, 80, and,
in the course of six weeks, a fairly constant level of 72. Cough
decreased, and character of sputum changed from thick and puru-
lent to thin and whitish. The patient's color, appetite, and sense
of well-being were conspicuously changed in a favorable direction.

Meantime there had been marked reduction in the quantity of
albumen in the urine, which had been a complicating factor, and
the blood count had shown a steady progression. On the twen-
tieth day the red corpuscles, numbering 4,328,000, and the white
corpuscles held at 14,000. On the tweny-eighth day the red
corpuscles numbered 4,704,000, and the white corpuscles 13,600.
On the forty-third day the red corpuscles numbered only 4,304,-
000, but were large, round, normal-looking for the most part,
very few of them tending to take the purple stain, as many of
them had on a previous examination ; and the white corpuscles
had dropped to 8,000. On the sixtieth day the red corpuscles
numbered 5,168,000, one-third of them remaining smooth and
normal-looking after two hours in the counting chamber, and
another third of large size, though crenated. A fair proportion
of the red corpuscles remained large and fairly smooth after
twenty-four hours in the Toisson fluid. The white corpuscles,
stained for the most part of a fairly pale, opal blue in this fluid,
numbered only 9,000.

Taken in connection with the clinical symptoms, this blood
count of the sixtieth day showed the corpuscles in virtual com-
mand of the mixed infection. An earlier examination had shown
a marked reduction in the tubercle bacilli, only one or two re-
maining to the field. It now seemed desirable to minimize the
total quantity of protein introduced hypodermically, while main-

THE SCIENCE AND ART OF PROTEAL THERAPY 193

taining or accentuating the impulse to the blood-forming organs,
and it was thought that this might be accomplished by using
small doses (three or four minims) of Proteal No. 65, a com-
bination of the proteins of alfalfa seed, alfalfa meal, millet seed,
rape seed, and mustard seed.

Such is the standing of the case at the moment of the pres-
ent writing : Temperature and pulse normal ; blood conditions
all that could be desired ; cough and sputum favorably modified ;
kidney complications minimized; patient's skin with healthy
glow; blood pressure 110; conspicuous physical and mental
buoyancy.

It is perhaps of interest to add that this patient had at the
outset a slight hyperthyroid complication, the right lobe of the
thyroid gland being conspicuously enlarged. The rapid pulse
and a certain nervous hypersesthesia were no doubt in part asso-
ciated with this condition. As an auxiliary to the Proteal treat-
ment, the patient was given one to two drops of a saturated
solution of potassium iodide three times daily for five or six
weeks, at the end of which time the gland had been reduced to
normal size. No other internal medication of any kind was
employed. There had been from the outset a modification of
diet, however. As is my custom with all cases suffering from
protein intoxication, whether or not of bacterial origin, I had
placed the patient largely on a vegetable and milk diet. The
building up of the red cell count and improvement in quality
under Proteal treatment, associated with the cessation of forced
feeding with meat and eggs, is an observation that has been dupli-
cated in many other cases not only of tuberculosis but of various
other asthenic conditions, including cancer. The theoretical ex-
planation is that proteins in large excess overtax the red cor-
puscles (in the handling of the end products), and increase the
anaemia they are supposed to combat. But on the other hand the
protein intake must not be cut too low. The nitrogen balance
must be maintained.

While repeating that I make no attempt here to present, even
in summary, the total experience in the treatment of tuberculosis
with Proteals, I cannot refrain from presenting very condensed
histories of a small group of cases under treatment by an associ-
ated physician in the State of Washington, who, as a result of
these preliminary observations, now has under Proteal treatment
a large group of cases of tuberculosis of which records will ulti-
mately be available. The condensed reports of the three cases
to which the Proteals were first administered are as follows :

(1) Mrs. K. B., 56, Pulmonary tuberculosis. Involvement of
upper half of right lung and upper one fourth of left lung. The
Proteal treatment began with two and a half minims of No. 45,

194 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

increasing one-half minim every other day until seven minims
were given; then dose every fifth day, seven and one-half minims
per dose. Still on Proteal No. 45, fifteen minim dose. Result
after ninety days: Reduction in temperature from 103-104^2 to
99-100^. No more night sweats. No cough. Increased appe-
tite and weight. Haemoglobin increase to 90 per cent., red cor-
puscles to 4,200,000. Considerable fibrosis of both lungs.

(2) Mrs. H. F., age 35. Pulmonary tuberculosis with pleu-
risy, two years' standing, left side. Involvement of apex of right
lung and entire left pleura. Proteal treatment began with four
minims No. 45, increasing one minim every third day till seven
minims were given ; then repeating same dose every five days for
three to four doses before increasing dosage one minim again.
Still on Proteal No. 45, fourteen minim doses. Result after
ninety days : Right apex clear of rales, moisture, and all symp-
toms of infection. One-half left pleura clearing up. Reduction
of temperature, gradually, from 102-103^2 to normal. Increased
appetite. Able to lie on left side for the first time in two years.
Blood picture improved to nearly normal. All symptoms im-
proved.

(3) Mrs. C. D. E., age 20. Pulmonary tuberculosis. Both
upper lobes involved. Proteal treatment began with three
minims No. 45, increasing one minim every other day till eight
minims were given ; then the same dose every third day for three
or four doses, after which the dose increased one minim, etc.
Result of treatment after ninety days: Temperature normal.
Cough decreased. Blood picture same as before treatment.

Such observations as these are certainly stimulative. I have in
hand a considerable body of similar testimony from physicians
in various parts of the country, and fresh evidence' comes to me
week by week. The experience of these associated physicians,
coupled with my personal observations, appears to me to justify
the hope that in the Proteals we have new weapons to aid the
physician in coping with a malady which, although measurably
checked in onslaught in recent years, still has a mortality rate
of about 145 per hundred thousand population — a malady of
which, otherwise stated, claims about 145,000 victims in a year in
the United States alone and not far from a million in the civilized
world.

It will be understood, of course, that no suggestion is made
that the Proteals exercise a specific function in combating the
tubercular condition. Their action here, as elsewhere, is directly
on the blood-forming organs in accordance with the fundamental
principles of antigenic response. But the secondary effect on
the intruding protein masses constituting areas of infection in
the lungs or elsewhere is so natural a consequence that it might

THE SCIENCE AND ART OF PROTEAL THERAPY 195

have been expected, and was in point of fact predicted by me as
a probable sequel — a prediction of so definite and tangible a char-
acter as to have led to the original clincal tests above described,
and, sequentially, to the more comprehensive tests that are now
under way in various sanitariums and hospitals and in the
hands of a large number of private practitioners.

In an earlier section of this book I have called specific atten-
tion to the similarity of the blood conditions in advanced cases
of tuberculosis and of cancer. I would reiterate here the not
altogether unfamiliar doctrine that the tubercular subject does
not as a rule die of direct poisoning by the tubercle germ, but
of secondary infection associated with other types of micro-or-
ganisms, and with the ultimate development of degenerative
protein-product masses in the lungs or elsewhere, partial hydrol-
ysis and absorption of which produces a toxaemia strictly com-
parable to the toxaemia of malignant neoplasms.

There was every apriori warrant, therefore, for the prediction
that the blood corpuscles might be stimulated by protein therapy
to do something toward proteolizing and eliminating from the
system the obnoxious protein masses that owed their inception,
to be sure, to the original invasion of the tubercle bacillus, but
which have now become in effect malignant neoplasms; totally
different, assuredly, from the masses usually classified as cancer-
ous in their histological structure and in the specific type of
irritant associated with their genesis ; yet fundamentally akin to
cancer in that their development was conditioned on relative
failure of the corpuscular activities, and in their inherent tend-
ency to engender progressive exhaustion of the blood-forming
mechanism and ultimately to terminate the life of the individual
in whose body they develop.

The analogy of the observed effect of Proteal treatment of
cancer, therefore, gives additional support to hopeful prognosti-
cations as to the value of the Proteals in tuberculosis, founded
theoretically on the Proteomorphic theory and practically on
observation of a limited number of very striking cases hitherto
subjected to this treatment. By the time my projected book on
Proteal Therapy is ready for the press, there is every prospect
that a body of evidence will be in hand that will answer unequivo-
cally the question as to the ultimate value and the limitations of
Proteal Therapy in its application to tuberculosis.

Meantime, in order to round out this preliminary survey of the
present status of the method, we may now turn to a considera-
tion of the use of the Proteals in those conditions of blood dis-
turbance in which the aetiological factors are so obscure that the
blood conditions themselves have taken rank as specific maladies
under the name of anaemias and leukaemias ; in the antagonizing

196 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

of which conditions the Proteals exercise so direct a function
that here, if anywhere, their action might be said to be specific.
In makng this survey, however, I shall constantly have in mind
the thesis that the anaemias and leukaemias are, in the last analy-
sis, secondary conditions ; the so-called primary anaemias being,
in my belief, usually associated with conditions of intestinal
toxaemia, and being therefore inseparably linked with the other
conditions of disturbed protein metabolism that have all along
engaged our attention. The word anaemia is after all only a
convenient name for a condition that is a necessary precursor or
concomitant of all types of chronic toxaemia. For the moment,
however, we are to focus attention on the blood conditions them-
selves, and to view from a slightly new angle the effect of the
Proteals in dealing with these disturbed conditions.

INTESTINAL TOXEMIA AND THE ANEMIAS AND LEUKAEMIAS
UNDER PROTEAL TREATMENT

In the Monograph of December 1, 1916, I gave a brief prelim-
inary account of an interesting case, in which there was chronic
protein (intestinal) toxaemia in which the red cells had the quali-
tative features of pernicious anaemia, although not reduced in
numbers as in full development of that malady ; and in which
there was pronounced leucocytosis, with embryonic (ontogenetic)
types of cells suggesting a leukaemic tendency.

A typical count before treatment showed 3,850,000 red cells
(crenated, vacuolated ; anocytosis ; poikilocytosis, pronounced
chromophilia ; normoblasts, megalocytes) ; very few platelets;
and 57,000 leucocytes, with 70.6 per cent, polynuclears (full cyto-
plasm, feebly granular, non-acidophile) ; 21.6 lymphocytes
(mostly small and very basophile) ; 5.4 per cent, large mononu-
clears (one-third lymphoidocytes) ; 2.6 per cent, eosinophiles.

After six days of Proteal treatment (four doses of 4 to 8
minims, hypodermically into arm), red cells advanced to 5,012,000
in number and much less abnormal in appearance; normoblasts
exceedingly rare, some groups of platelets ; number of white
cells reduced to 5,100, with 51 per cent, polynuclears, 30.5 per
cent, small lymphocytes, 14 per cent, large mononuclears, 2.5 per
cent, eosinophiles, and 2 per cent, basophiles. Patient's general
condition and subjective symptoms very markedly changed for
the better, as might be expected.

This case appears so remarkable, that I perhaps cannot do
better than to use the record of its blood modification as a text
to guide the brief but explicit study of this aspect of the subject.
Of course it is not to be overlooked that very sudden changes in
the blood count, and even in the quality of the cells, may occur

THE SCIENCE AND ART OF PROTEAL THERAPY 197

spontaneously — the word spontaneous being of course merely
an expression of our ignorance — in cases of pernicious anaemia
and leukaemia. But in the present instance, the patient had been
under observation and under treatment of the conventional type
for a long period before Proteal medication was resorted to, and
we are justified, I think, in feeling a certain measure of confidence
that the blood changes noted were the result of the administration
of the vegetable proteins, and not merely an accidental concomi-
tant of such administration. In any event, it will be of interest to
follow the subsequent history of the case before attempting the
promised interpretation of the observed phenomena.
Briefly summarized, the record is as follows:
Between the sixth and eighth day (following the record above
given), the patient was in the country and had no Proteal treat-
ment. She had departed somewhat from the established dietetic
regimen, among other things eating sausage. On the eighth day
she suffered a clinical relapse. Her head became heavy, and
throbbing. Her ear rang intolerable. She had no appetite.
Her mental condition was depressed and apprehensive. These
were among the symptoms that had characterized her malady all
along. The nausea and vomiting that had also characterized it
did not recur on this occasion. The blood count now showed
4,384,000 red corpuscles, with numerous normoblasts and free
microblasts, and abundant platelets. The white count had
advanced to 12,800, including large numbers of small lympho-
cytes of such diminutive size as to be recognized with difficulty
except under high powers of the microscope. The differential
count showed 15 per cent, polynuclears, 32 per cent, small lym-
phocytes, 8 per cent, large monocytes, and 2.6 eosinophiles.
Thus there was a tendency to increase in polynuclears, a very
marked increase of small lymphocytes, and a reduction in the
large mononuclears. More than half of the large mononuclears
were neutrophile myelocytes.

Proteal treatment was at once reinstated, the particular protein
used on this occasion being an extract of rape seed (No. 42).
On the eleventh day the red cell count showed a marked falling
off, being reduced to 3,708,000. The general aspect of the red
cells was, however, much more satisfactory than at the outset.
Meantime the white cells were now 6,960. The differential
count was highly satisfactory, showing 50.7 polynuclears, 28.5
per cent, small lymphocytes, 18.5 per cent, large mononuclears,
and 2 per cent, eosinophiles. Of the large mononuclears, about
30 per cent, were typical large monocytes and 30 per cent, large
lymphocytes, and 40 per cent, neutrophile myelocytes. As hereto-
fore, the polynuclears tended to stain a rather pale light blue,
but the tendency to clump was not conspicuous as at the outset.

198 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

The patient's physical condition was much better than on the
eighth day, but not so good as on the sixth.

Proteal treatment was continued, in doses of 5 to 10 minims,
on alternate days, and the clinical progress of the patient was so
conspicuous as to be noticed by all her friends. She spoke of
herself as being "quite made over." The distressing giddiness
disappeared altogether ; her appetite was good, and she had no
nausea or other gastric disturbance ; she slept well, felt cheerful
and bouyant, and in general was in a condition that simulated
normal health. On the 28th day of the treatment, her blood
count showed 4,074,000 red corpuscles of fairly normal appear-
ance (totally different in aspect from the original condition),
and 7,150 white corpuscles, of which 52 per cent, were polynu-
clears, 28 per cent, small lymphocytes, 18.5 per cent, large
mononuclears, and 1.5 eosinophiles. The polynuclears stained
blue, but their cytoplasm was distinctly acidophile. The mono-
nuclears were mostly typical large monocytes, with only a few
questionable myelocytes. No normoblasts were seen, but there
was a fair number of platelets. Except that the red cells were
not quite as numerous as might be desired, this blood picture is
in the highest degree satisfactory.

On the 35th day, the defect in the red corpuscles had been
remedied, as these now number 5,328,000. The quality of the
red cells was correspondingly satisfactory, being recorded in the
main very normal, except that some were small. The white cells
now numbered 7,700, with 63.5 per cent, polynuclears, 13.5 per
cent, small lymphocytes, 19 per cent, large monocytes, practically
all of them large lymphocytes or typical large monocytes, 2 per
cent, eosinophiles, and only a negligible number of myelocytes.
It is recorded that the polynuclears were of normal appearance
with cytoplasm taking acidophile stain moderately, and nuclei
staining deeply. Large monocytes and eosinophiles were large
and beautifully typical.

Here it will be noted that the polynuclears were more numer-
ous than in the preceding counts (although far short of their
original percentage), and that this increase had apparently been
made at the expense of the small lymphocytes, the large mononu-
clears being more abundant than on any previous occasion. That
this blood condition was salutary is evidenced by the fact that
the patient's clinical condition continued in the highest degree
satisfactory, notwithstanding that she had been for ten days of
this period under excessive mental strain owing to the critical
illness of a member of her family. It now became necessary
for the patient to go to California, and she accomplished the
journey without incident, although she would have been utterly

THE SCIENCE AND ART OF PROTEAL THERAPY 199

unable to undertake such a voyage six weeks earlier, before be-
ginning the Proteal treatment.

At the end of the journey, the patient was subjected to both
mental and physical strain for a term of weeks, during which
time she had only occasional doses of Proteals, and was not under
observation as to the blood count. It was reported that she
stood the strain amazingly at first, but subsequently, after four
or five weeks, suffered a relapse, with recurrence of spells of
dizziness and a feeling of general debility. Proteal treatment
was resumed, and continued with clinical benefits, after the
patient's return to New York, No. 45 being chiefly used, in
doses of five to eight minims, administered at lengthening inter-
vals, and finally discontinued about six months after the initial
treatment.

On March 30, 1917, the blood picture was : Haemoglobin, 90 ;
red corpuscles, 5,152,000; leucocytes, 5,000, with 56 per cent,
polynuclears, 18.5 small lymphocytes, 24 per cent, large mono-
cytes, and 1.5 eosinophiles. On May 16, the count showed 4,744,-
000 erythrocytes and 5,600 leucocytes. Seven months later (De-
cember 11), with no treatment since June, the blood showed
4,912,000 red cells and 6,000 white; and on January 28, 1918,
fourteen months after the original use of the Proteals, the exam-
ination showed 5,528,000 red cells and 8,600 leucocytes.

Clinically, the patient has attained a condition of fairly robust
health, all the disturbing symptoms having disappeared ; and
such is her condition at the moment of present writing, sixteen
months after the institution of the Proteal treatment and eight
months after it was discontinued.

It is worth while to make inquiry as to whether a satisfactory
theoretical explanation can be found of such striking modifica-
tions of the blood count as are above recorded, in particular with
reference to the spectacular decrease in the number of white
corpuscles at the outset. It should be added that I have had
no closely similar case with equally marked leukaemic tendency
in which so spectacular an effect was observable ; but, on the
other hand, I have numerous records, some of which have al-
ready been presented, of cases in which the white blood cell count
has been very rapidly reduced from 12,000, 14,000, and 16,000 to
the normal by a few doses of vegetable proteins. How shall we
account for this striking phenomenon?

BLOOD CHANGES TENTATIVELY EXPLAINED

It is desirable to say that the explanation about to be given
is put forward tentatively. We know too little about the genesis
and transformations of the blood corpuscles to speak dogmati-

200 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

cally on this aspect of the subject. Nevertheless, I think that
data are sufficient to enable us to suggest at least a plausible hy-
pothesis as to the modus operandi of white cell decrease or modi-
fication in direction of the normal under Proteal treatment. A
clue to the explanation is to be found, it seems to me, in the com-
plementary or compensatory relation that exists between the
white and the red corpuscles. All theories aside, it has long
been known that when there is sudden reduction in the mass of the
blood, through hemorrhage, a rapid leucocytosis supervenes, it
being apparently a more facile matter to increase the leucocyte
population than to bring the red corpuscles back to normal num-
bers. The difference in bulk between the two perhaps explains
this more or less adequately, it being recalled that the red cell
population is normally from 500 to one thousand times the census
of the white corpuscles. It will be recalled, also, that under
normal conditions there is a far wider range of variation in the
number of white corpuscles than in the red. A normal post-
prandial leucocytosis may increase the numbers of white cor-
puscles by 50 per cent; and, contrariwise, a corresponding
reduction takes place a few hours later. No such oscillation
as this occurs under normal conditions in the red cell population.

If the post-hemorrhagic leucocytosis be accepted as in a sense
compensatory, it must be assumed that the leucocytes are able
to some extent to perform the work of the red corpuscles.
Speaking in terms of the Proteomorphic theory, we may assume
that there is no absolutely fixed line of demarcation between the
proteolytic activities of the white corpuscles and red. (I shall
present below the record of a case of leukaemia, that strikingly
emphasizes this view.) The theory assumes that the red cor-
puscles are incapable of dealing with the full-sized protein mole-
cule, and that the white corpuscles cannot adequately care for
the later products of hydrolysis, of the pelypeptid order. But in
all probability there are intermediate stages at which the activ-
ities of the two sets of corpuscles overlap. It is conceivable,
for example, that both the white corpuscles and the red may be
able to deal more or less adequately with molecules at the peptone
stage, and that the white corpuscles may hand the material over,
so to speak, to the red corpuscles at somewhat variant stages of
decompounding under different conditions.

If we assume, as was done in the Proteomorphic theory, that
the disruption of the white corpuscle and the consequent libera-
tion of its contents takes place as the result of osmotic pressure,
and that this pressure is due to the decompounding of the protein
molecules within the substance of the leucocytes, it is at least
conceivable that the stage of decompounding at which disruption
will occur is dependent in a measure on the quantity of protein

THE SCIENCE AND ART OF PROTEAL THERAPY 201

which the white corpuscle has ingested. It will be recalled that,
according to Van't Hoff's theory, each individual molecule, what-
ever its size, presses with equal force in a liquid medium. If,
then, in a given case, a leucocyte has ingested a large quantity
of protein, the decompounding of this protein might produce a
sufficient number of molecules, at, let us say, the proteose stage
to exert a disruptive force on the leucocytic membrane ; whereas,
had the amount of protein originally ingested been smaller,
decompounding to the peptone stage might have been necessary
before an equivalent pressure was exerted.

If this suggestion be accepted, it follows that, given a fixed
quantity of protein papulum in the blood, the larger the number
of leucocytes the smaller would be their average intake of protein,
and hence the more complete the average stage of decompound-
ing before disruption. In other words, the larger the number of
leucocytes, the more efficient their work as protein hydrolyzers.
Where a small number of leucocytes must have turned over their
product to the red corpuscles at the peptone stage, a larger num-
ber of leucocytes may reduce it all to the polypeptid stage, and
thus, seemingly, conserve the resources of the red corpuscles by
limiting the work put upon them.

If such are indeed the relations of white and red corpuscles,
and the hypothesis just suggested be accepted as plausible, a high
leucocyte count such as that recorded in the case of the patient
above reported (57,000) must be accepted as a salutary attempt
on the part of the organism to compensate for the inadequacy
of the red corpuscles, indicated not only by their small number
(3,850,000) but also by their extreme defects of size and quality.
This was a case, seemingly, where chronic intestinal defects of
secretion of the digestive enzymes (pancreatic, biliary, or enteric)
persistently led to the introduction into the blood of protein
products not hydrolyzed to the normal polypeptid or amino-acid
stage. This put an incessant strain on the red corpuscles, which
probably (could the full history of the case be known) were for
a time increased in number, but which ultimately, owing to ex-
haustion of the blood-forming mechanism through long sub-
jection to the same toxin, . became decreased in number and
utterly dyscrasic in quality.

Then came the increase of white corpuscles to endeavor to
compensate the defects of the red cells. The white cells would
accomplish this, according to hypothesis, by handling as effec-
tively as possible the larger protein molecules normally or
abnormally present in the blood. If, however, the intermediate
and later products of hydrolysis continue to intrude themselves
in excessive quantities, the strain on the blood corpuscles would
be cumulative, and even though the white corpuscles were pro-

202 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

duced in larger and yet larger phalanxes, disaster must in the
end result, since no quantity of white corpuscles could compen-
sate altogether for the lack of reds, inasmuch as the red
corpuscles alone are capable of dealing with the end-products
of protein decompounding.

The time would come, apparently, when the increase of white
corpuscles passes the point of maximum efficiency, the amount
of protein papulum for each being so small that a relatively long
life is vouchsafed to each white corpuscle before its contents
reach the stage of disruptive pressure. There would then be
an accumulation of old white corpuscles in the blood, piling up
ultimately in such numbers as to produce the enormous counts
familiar in advanced stages of leukaemia.

On the other hand, under such conditions, the protein content
of each individual white corpuscle would, on the average, be
reduced to an exceedingly low stage of hydrolysis, that is to say,
to the lowest stage to which the leucocytic enzymes can reduce
it; and, on disruption, the leucocytes would supply the red cor-
puscles with, let us say, polypeptids (perhaps dipeptids or mono-
peptids), making the smallest possible requirement on their
enzymic activities. Should something take place that would
cause the disruption even of the major part of the white cor-
puscles in a brief period, the amount of toxicity to the nervous
system that would result would depend entirely on the equipment
of red corpuscles. Moreover, it is not impossible that when the
red corpuscles are abundant, their enzymes may have a catalytic
effect on the white corpuscles, stimulating them to greater
enzymic activity, and thus facilitating their disruption. That
some such complementary relation between the red corpuscles
and the white exists, might reasonably be expected, similar
adjustments between organs of complimentary function being
familiar throughout the organism. An agent which stimulated
the production of increased members of red corpuscles, or one
that increased the enzymic activities of these corpuscles, would
thus, secondarily, result in effecting the more rapid decom-
pounding of the white corpuscles, thereby reducing their number.

I am disposed to think that this line of reasoning explains the
rapid decrease of white corpuscles in the case above cited.
It will be recalled that coincidentally with this decrease in white
corpuscles there was an increase of red corpuscles from 3,850,000
to 5,012,000, — an increase, in other words, of more than 30 per
cent. The size and quality of the individual corpuscle were more
than correspondingly enhanced, so it may plausibly be assumed
that the enzymic capacities and activities of the red corpuscles
as a whole were measurably doubled. The increased red cell
enzymes stimulating white cell catabolism, and the red cells now

THE SCIENCE AND ART OF PROTEAL THERAPY 203

being adequate to deal with the end-products of protein hydroly-
sis thus liberated, the excess accumulation of white corpuscles
would be immediately done away with, and the mother cells of
the leucocytes, being no longer stimulated to excessive activity,
might resume their normal rate of functioning. Indeed, it is
consistent with what has been suggested, to assume that in such
a case as the above, where leukaemia had not been far developed,
the leucocytic mother cells had not acted with extreme prolific-
ness, and that the large leucocytic population was due, in large
measure, to accumulation rather than to over production.

On these assumptions, the only mystery connected with the
matter would be the fact of the extraordinary regeneration of
the red cells themselves under influence of the Proteal remedy.
This is to be explained, according to the Proteomorphic hypothe-
sis, as taking place in connection with the following sequence of
events : ( 1 ) the vegetable protein introduced hypodermically
is quickly absorbed into the blood stream, where (2) it encounters
a multitude of white corpuscles that quickly ingest it and effect
its partial proteolysis. Disruption of the white corpuscles taking
place through osmotic pressure, the polypeptids to which the
vegetable proteins have been reduced (circulating now freely in
the blood) come in contact with the mother cells in the
marrow with the effect of an altogether new stimulus. These
cells, by hypothesis, have become exhausted to the stimulus of
the protein products that come to them through the intestines,
and are performing their functions very inadequately. Now,
however, they respond to the new impulse with alacrity, and
put forth a new generation of red corpuscles totally different
in quality from those that have been their recent progeny. These
new cells are able to deal with the end-products of protein cata-
bolism already in the blood, and with any new increment that
may come; and there is possibility of a re-establishment of
normal conditions of metabolism.

If, now, the patient is placed under proper dietetic restriction,
so that the faulty intake of protein products is in a measure
corrected; and if the Proteal injections are continued day by day,
so that the blood-forming mechanism receives a continuous stimu-
lus, conditions are favorable for a permanent regeneration of the
blood, and for the clinical cure of the patient.

Such, as I see it, is a plausible explanation of the manner of
action of proteantigens in effecting the transformations of the
blood that have been so frequently observed, of which the case
above recorded furnishes an extreme instance.

If this explanation be accepted, it will be clear that the same
line of reasoning applies to any and every type of protein intoxi-
cation. Intestinal toxaemia and cancer are obviously very differ-

204 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

ent conditions (though I venture to doubt if the latter ever
exists without having been preceded by the former), yet the
effects on the blood and on the system at large of protein prod-
ucts absorbed through the intestines and of those liberated from
cancer tissue may be substantially identical. (The high glutamic
acid contents of tumors is worth recalling in this connection.)
It is an observed fact that many diverse conditions, including
intestinal toxaemia, tuberculosis, and cancer, may bring the blood
to seemingly the same stage of abnormality, characterized by
red cells reduced in number and of the pernicious anaemia type,
and by leucocytes increased in number by way of compensation,
with relative neutrophilia. It is not strange, then, that the same
line of treatment may be applicable to all these conditions — and
to numerous other conditions similarity characterized by dis-
turbed protein metabolism — since the fundamental maladjust-
ments are the same in all.

If a fairly satisfactory explanation may thus be found of
the increase of red corpuscles and the decrease of leucocytes
under Proteal treatment, as in the case above cited, it must be
admitted that an explanation of the striking modification of the
differential leucocyte count is not so readily forthcoming.
Nevertheless, it is possible to offer at least a provisional explana-
tion, along the lines of an hypothesis of differential leucocyte
action presented in an earlier section. In examing this hypothe-
sis, we shall have occasion to consider the blood modifications
in an interesting case of leukaemia, already once or twice referred
to. For the moment, however, attention is directed to the modi-
fied leucocyte count in the case of anaemia already discussed.
It will be recalled that the polynuclears at the outset numbered
70.6 per cent of the total leucocyte ; and that after a few days'
treatment their proportion was reduced to 51 per cent. Mean-
time, the small lymphocytes had increased from 21.6 per cent, to
35 per cent., and the large mononuclears from 5.4 per cent, to
14 per cent.

This would appear to tell either of a disproportionate destruc-
tion of mononuclears or of a no less disproportionate production
of mononuclears. And the problem thus presented does not
apply to this case merely, for I have posited a similar modification
of the differential count as a characteristic response to protean-
tigen treatment. Reference to this has been made many times
in the preceding pages ; and tables demonstrating the modification
in series of cases are presented in the cancer Monograph. What
is the explanation of this modification?

Perhaps the simplest explanation of the change of polynuclears
would be that the hydrolytic function of this type of leucocyte
is most directly compensatory of that of the red corpuscles. It

THE SCIENCE AND ART OF PROTEAL THERAPY 205

was suggested above that the polynuclears deal with the proteins
at approximately the peptone stage, carrying hydrolysis to a stage
that fits the protein products for the purposes of the red cor-
puscles. On this assumption, it is logical to suppose that r.s the
red corpuscles are overworked, neutrophile recruits may be
called out to make sure that the largest possible proportion of
proteins in the blood is reduced to the polypeptid stage, thus re-
lieving, as far as may be, the strain on the red corpuscles.

It was noted, however, that the polynuclears unquestionably
had to do with resistance to bacterial invasion ; and it was further
suggested that they perhaps have to do with the decompounding
of fats. These suppositions obviously introduce complications,
which must be borne in mind, but which do not call for more
elaborate consideration at the moment ; inasmuch as, in the case
under consideration, there was no acute bacterial invasion in
question, nor any sudden modification in diet on one hand or the
patient's weight on the other suggesting a change in the needs
of the organism as regards fat metabolism. Yet there was
apparently a very sudden modification in the systemic need of
polynuclear leucocytes. This modification was associated with
very marked increase in the numbers, and presumably in the
efficiency of the red corpuscles ; and a corresponding increase in
numbers and presumptive activities of the mononuclear cohorts.

Viewing the matter with reference to these two essential modi-
fications, the thought obtrudes itself that when mononuclear
leucocytes on one hand and red corpuscles on the other are
working at maximum efficiency, their joint hydrolytic activities
cover the entire range of protein catabolism, leaving the polynu-
clears free for the auxiliary tasks of combating bacteria (with
their large lipoid content) and handling fats in general; possibly,
also, having to do with the catabolism of carbohydrates, — the
latter possibility, however, being mentioned here only parenthet-
ically, as I have purposely refrained from complicating the
problem by reference to this group of alimentary constituents.

Elaborating the view just suggested, we may assume that the
large mononuclear leucocytes begin the hydrolysis of proteins;
and that the small mononuclears, when working at maximum
efficiency, carry it forward to the stage of adequate preparation
for uses of the red corpuscles, which ultimately complete the
work of decompounding ; and that in proportion as this simplified
method of handling is perfected, the need for the services-of the
polynuclears in this connection is minimized.

That this would represent to some extent a conservation of
bodily energies is suggested in the relative complexity of organi-
zation of the polynuclears. Seemingly the mononuclears are cells

206 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

of a more primitive type ; calling for less expenditure of energy,
therefore, in their development.

It will be obvious that there is nothing inconsistent in all this
with the hypothesis of differential leucocyte functions already put
forward. The present view is merely an elaboration and exten-
sion of that hypothesis. It has been urged all along that there
is probably a considerable range of variation or latitude as to
precise proteolytic functions of each type of corpuscle.

This is no more than is observed everywhere in the organism ;
the possibility of vicarious functioning being a necessary safe-
guard to health and to life itself. Thus we find that there is no
single organ that has absolute control over any stage or phase
of food digestion in the alimentary tract. There are more or
less compensatory functions between salivary glands and pan-
creas, and between stomach, liver, and the enteric walls. Even
the highly specialized functions of the kidney are in a measure
duplicated by the functions of the glands of the skin. Moreover,
two kidneys are provided, although a single kidney is amply
competent under ordinary circumstances to meet elimination re-
quirements. Similarly there are two lungs, providing an aggre-
gate alveolar surface vastly in excess of the maximum needs of
the organism.

It is not strange, then, that the corpusclar cohorts should show
a similar margin of safety; and we need not be surprised to ob-
serve that, under exceptional circumstances, metabolic conditions
apparently approximating the normal may be maintained when
there has been a profound disturbance of the observed normal
conditions of the corpuscles, — just as a person with one kidney
or with one affected lung may appear to retain a normal level
of health ; or, to make a still closer analogy, as a patient may be
maintained for a considerable period by rectal feeding, the func-
tions of the normal digestive glands being for the moment
abrogated. I have just had report of such a case where (owing
to a gastric ulcer) rectal feeding has been the sole method of
alimentation for a period of more than ten months.

A CASE OF LEUKEMIA

I am led to emphasize this aspect of the subject because of
certain anomalies forced on my attention by the case of lymphatic
leukaemia to which reference was above made. The patient, a
man of 65, is known to have been leuksemic for several years.
When the patient first came to me for examination, he brought
with him the report of a blood count made two years earlier
which showed 200,000 leucocytes. No blood examination had
been made in the interval, but my examination revealed upward

THE SCIENCE AND ART OF PROTEAL THERAPY 207

of a million leucocytes to the cubic millimeter, with red count
not far above three million ; the smear showing the leucocytes to
be small compact lymphocytes almost exclusively.

The clinical symptoms that led the patient to come for treat-
ment consisted chiefly of extreme enlargement of glands at each
side of the neck, in the region of the parotids ; enlargement of
lymphatic glands at the back of the neck and head, in the axil-
lary regions and inguinal regions and elsewhere ; associated with
severe pains, particularly located in the region of the enlarged
glands at the back of the neck and head.

The patient was placed under Proteal treatment, the mixture
of the proteins of alfalfa seed, alfalfa meal, and millet seed (Pro-
teal No. 45) being administered in doses of from three to eight
minims on alternate days ; a shift being subsequently made to
rape seed protein (Proteal No. 42). There was a very prompt
response, in that general reduction in the size of the enlarged
glands took place. The glands at the sides of the neck were
reduced so markedly as to alter the patient's appearance very
noticeably. The lymphatic swellings at the back of the neck
and head, and in axillary and inguinal regions were greatly re-
duced in size or altogether disappeared. The pain, which had
been persistent, disappeared and has not recurred. Nor has
there been any tendency to return of the glandular enlargements,
except that a temporary swelling appeared in each mastoid region
following an attack of influenza (shortly after convalescing),
which swelling the patient ascribed to "catching cold" through
sitting in a draft.

I shall not go further into the clinical details of this patient's
history in the present connection. We are here concerned with
the blood conditions, which are of the most striking and (in con-
nection with the clinical state), even mystifying character. After
two weeks of Proteal treatment, there was a very marked modifi-
cation in the character of the leucocytes, in that large number
of cells appeared which were two or three times the size of the
prevalent lymphocytes, and which took the stain much more
faintly, and appeared somewhat vague and ragged in outline in
contrast with the sharply rounded, bullet-like lymphocytes that
clustered everywhere so thickly as to remind one of grapes on
the vine. These large cells could not well be classified other than
as large monocytes, although only by rare exception could one
be found that showed a distinct nucleus and dark-stained cyto-
plasm. In general these large cells, like the small lymphocytes,
showed no cytoplasm whatever. They appeared to be all nucleus,
with vague boundaries. They gave one the impression of lying
in the background as it were, and at a different level, from the
protruding grape-like small lymphocytes. The red corpuscles,

208 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

meantime, tended to take a coppery stain. Many of them were
conspicuously vacuolated, and a few showed faint neuclei.

But whereas the mononuclear leucocytes of these two very
distinct types sprinkled every field of the microscope so thickly
as almost to compete with the red corpuscles, it was necessary to
search across a large number of fields in succession before finding
a single polynuclear. Now and again, however, one did appear ;
and the character of this rare exhibit was altogether unequivocal.
The nucleus was usually of bizarre type, but distinct and clearly
defined ; and there was a normal quantity of clear cytoplasm. In
running clear across the smear, one might come upon a single
polynuclear, or two or three at most ; but at the very end of the
smear, in a dense windrow, one might find a mass of cells many
of which had the appearance of being degenerated polynuclears.
Their structure, to be sure, was ill defined ; their seemingly
nuclei were jumbled and as it were compacted; and they were
crowded together in such fashion that no trace of distinct cyto-
plasm remained. These cells took the stain faintly, like the large
monocytes already referred to ; yet they showed traces of nuclear
structure not to be seen in the large monocyte, and one felt that
they were of a different type. These cells did not appear in the
earlier smears ; and I am led to question whether perhaps their
presence suggests a tendency to restocking of the blood with the
hitherto minimized neutrophiles.

It is further notable that in the most recent smear I detected
a single gigantic eosinophile, with three discrete nuclei, the cyto-
plasm abundant and sharply defined, and taking a brick-red color,
the individual granules very small. In this most recent smear,
also, there appeared to be larger numbers of large monocytes
that show a fairly distinct nucleus differentiated from the cyto-
plasm. The total number of the large monocytes, as contrasted
with the lymphocytes, has also conspicuously increased. In a
single field of the microscope, for example, using the 1.9 milli-
meter objective and Number 10 eyepiece, and further minimizing
the field by lengthening the tube, the count showed fifteen small
lymphocytes and twenty-one large monocytes, with not far from
one hundred red corpuscles. Another field showed only eight
small lymphocytes and twenty-three large monocytes. Such a
preponderance, however, was unusual ; and fields could be found
where the relative numbers were reversed. Thirty fields in suc-
cession revealed only a single polynuclear.

The total leucocyte count at this time is 1,048,000, as against
a red-cell count of 2,324,000. Yet it is an astonishing fact that
this patient, aside from the still noticeable enlargements at the
sides of the neck (which, however, are no longer extremely con-
spicuous), might readily pass under fairly close inspection as a

THE SCIENCE AND ART OF PROTEAL THERAPY 209

man with the appearance of robust health. His skin has a good
healthy glow, his actions are vigorous and energetic; and he
reports himself as feeling exceedingly well. His appetite is so
good that he has to curb it to prevent overeating ; he sleeps well
(although obliged to get up several times to empty the bladder, —
the urine, however, showing no abnormality on analysis) ; and
he is able to perform fairly vigorous labor, such as wood-sawing,
shoveling snow, and the like, and in general to execute the duties
incident to keeping his modest country establishment in order,
without experiencing shortness of breath or undue fatigue. His
pulse, during his visits at my office, has ranged from 72 to 80;
and the blood pressure from 145 to 130, — a fairly characteristic
reduction under Proteal treatment. In a word, the clinical symp-
tom-complex is that of a man substantially normal, well pre-
served, and more than moderately active and robust for his age.

All this, it will be observed, with a total corpuscular count of
about three and a third millions, of which leucocytes comprised
more than a million; leaving (according to the most recent
count) only 2,324,000 erythrocytes ; and providing a haemoglobin
index of 70.

Incidentally, I may suggest that the fact that this patient
appears not to suffer in the least from lack of oxygenation of the
tissues gives strong support to the Proteomorphic thesis that the
full normal equipment of red corpuscles is by no means necessary
for the carrying of oxygen ; for of course it is not to be supposed
that the leucocytes can compensate the red corpuscles in this
regard ; moreover, even if they were able to do so (no such sug-
gestion is made), the total number of corpuscles is still not much
above three-fifths of the normal. However, cases of other
types are common enough in which an erythrocytic equipment of
3,000,000 or even 2,000,000, suffices to oxygenate the tissues.

The anomaly is, that the universal processes of food hydrolysis
and of bodily metabolism in general in this case have been carried
out for a term of years with a corpuscular equipment so strangely
maladjusted.

But the mystery is to some extent clarified if we accept the
general thesis of the Proteomorphic theory and the special inter-
pretation of that thesis just elaborated, according to which the
functions of the different types of leucocytes overlap or are
complementary, permitting what might be described as team
work, through which weakness in one leucocytic department may
be effectively compensated in another ; and that similar team work
is possible between the white corpuscles and the red, as regards
the proteolytic functions of the latter.

These theoretical assumptions, considered in the light of such a
case of lymphatic leukaemia as that just recorded, give us at least

210 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

suggestive clues as to the origin of this obscure disorder. A
tenable hypothesis would appear to be that degenerative changes
had taken place in the particular cells of the bone marrow that
normally produce polynuclear leucocytes; involving also, to a
less extent, associated mother-cells of the erythrocytes. To
meet this deficiency, unusual cohorts of small lymphocytes were
called into action; and as the need persisted, and was perhaps
progressively aggravated with progressive degeneration of the
cytogenic apparatus in the bone marrow, there was hyperplasia
of the entire lymphatic system (roughly analogous to the compen-
satory hypertrophy of heart muscles to maintain an obstructed
circulation), of which tangible evidence was given in the observ-
able enlargement of the lymphatic glands in many regions.

Observation of the smear before Proteal treatment was admin-
istered, taken in connection with the clinical symptoms, appears
to justify the inference that small lymphocytes in superabundance
may on occasion perform the totality of leucocytic labors plus
a certain amount of the work of the red cells, maintaining a fair
semblance of normal bodily metabolism.

It would appear that the Proteals stimulated the mother-cells
of the large monocytes effectively, and that these cells were able
to take the work off the small lymphocytes to such an extent that
the enlarged lymphatic glands could be reduced ; such reduction
being perhaps facilitated by direct activities of the large mono-
cytes, as has been repeatedly observed in cases showing malignant
metastatic involvement of the lymphatics.

The appearance of increased numbers of polynuclears, albeit
in an embryonic or degenerative condition, suggests that possibly
the Proteals have been able to stimulate to some extent the ex-
hausted mother-cells of this type of leucocytes. Such stimula-
tion has apparently not been very effective hitherto, however, and
the stimulus to the mother-cells of the erythrocytes has seemingly
been even less effective, since the number of these cells, although
fluctuating (at one time reaching 3,400,000), has on the whole
failed to increase. It should be remarked, however, that the
possibilities of Proteal stimulation in this direction have been
by no means exhausted ; inasmuch as the dose administered has
not been increased above eight minims. The treatment has been
carried out under somewhat disadvantageous circumstances, the
patient coming to my office only occasionally, and in the main de-
pending upon home administration. Moreover, it has been
thought well to advance cautiously in view of the extraordinary
blood conditions to be dealt with.

Fuller history of the case awaits later presentation ; I have
dwelt on it here because of the interesting sidelights that it throws
on the Proteomorphic theory, and because of the conspicuous

THE SCIENCE AND ART OF PROTEAL THERAPY 211

clinical betterment that attended the use of the Proteals in a
case well calculated to puzzle the therapeutist. All questions
of blood picture aside, the progress of the case, as viewed from
the patient's standpoint, has been exceedingly gratifying. Paro-
tid glands that constituted a conspicuous deformity have been
reduced to less than half the original size, ceasing to be very
unpleasantly noticeable; lymphatic nodules larger than hickory
nuts have been reduced to the vanishing point; persistent pain
in connection with these enlargements has totally disappeared,
without recurrence up to the present, and the patient's general
health, though never greatly impaired, has been raised to a
higher level of seeming vitality, while the sense of well-being
has naturally increased with the vanishing of pain.

STUDYING THE BLOOD SMEAR

I have a few additional suggestions to make as to compen-
satory relations of the different types of leucocytes versus the
army of erythrocytes ; but before going on to these, I would
like to call attention to certain practicalities of the study of the
blood smear that are highly essential if one is to gain a really
accurate knowledge of the actual conditions which the smear
is capable of revealing. This section can have no great interest
for any one who does not work with the microscope, but I be-
lieve it will be found to have genuine importance by a good
many observers who regard themselves as accomplished students
of microscopical blood conditions. Experience has taught me
that some very elementary considerations in the study of the
smear are often overlooked, and that skilful hematologists may
employ methods of making the differential count that necessarily
vitiate or invalidate their results.

It is a not uncommon error, for example, as a good many
smears sent me for examination show, to use too large a drop
of blood, so that the smear runs off the end of the slide. Differ-
ential results are entirely vitiated in such a case, if, as often
happens, the white corpuscles have an agglutinative quality and
thus tend to clump at the end of the smear — since, in this case,
the end of the smear will be altogether lacking. It is impossible,
in such a case, to gain more than a vague notion of the true
character of the differential count from the most careful exam-
ination of the smear. The data for an accurate accounting are
absolutely lacking.

Assuming, however, that the smear is properly made, the entire
content of the drop placed on the slide being available for obser-
vation, it is still possible to examine it in such a way as to
draw entirely unwarranted conclusions as to the differential leu-

212 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

cocytic relations. I have known an observer, for example, to
make the count by running up and down the field, thus taking
in cross sections, instead of working backward and forward
laterally along the entire length of the smear. A moment's con-
sideration makes it clear that if the leucocytes are not evenly
spread on the smear, such a method may give a record that
quite negatives the facts.

It is true that strictly normal blood may show a fairly even
distribution of the different types of leucocytes at different stages
of the smear. But the distribution is probably never absolutely
uniform, and with the blood of a patient suffering from a pro-
tein toxaemia of any type there is likely to be the most striking
unevenness. Not infrequently the small lymphocytes are nearly
all left near the beginning of the smear, whereas the polynu-
clears and large lymphocytes, and in particular the large mono-
cytes, are dragged along toward the end of the smear. In such
a case the result of a cross-section examination (up and down
the field as the examiner views it, instead of from side to side),
will depend very largely upon the particular point that chances
to be brought under observation. If the survey is made near the
beginning of the smear, the report will show a tremendous pre-
ponderance of small lymphocytes, if, on the other hand, it is
made near the end of the smear, there will be a corresponding
preponderance of polynuclears or large monocytes. In either
case, the accounting is worse than worthless ; it conveys an en-
tirely wrong impression of the facts.

But the difficulties of such a case are not entirely solved merely
by making the lateral survey. It is true that such a survey will
put one on the trail of the different types of leucocytes and will
ultimately bring all types into the field, whether they have stopped
at the beginning of the smear or have been carried to its extrem-
ity— provided, of course, that the entire length of the smear is
examined. But a point I have never seen emphasized is that,
quite obviously — when your attention is called to it — you do not
get an accurate record if you discontinue counting while in the
midst of the smear. It is perfectly clear that such is the case,
if you are going once across the smear only, since in that case
you may not have come to the portion of the smear that contains
the chief bulk, of, let us say, the large monocytes. But a mo-
ment's reflection will make it clear that if, after going across
the smear, you turn about, in the regular way, and proceed in
the reverse direction, you must now go clear back to the begin-
ning of the smear, else you will not give proper enrollment to
the small lymphocytes that were largely left near the bginning.

However often you repeat the process, you must never stop
short of a complete traversing of the smear, if you are to give

THE SCIENCE AND ART OF PROTEAL THERAPY 213

proper enrollment to the differently distributed types of leu-
cocytes.

Yet I venture to surmise that nine observers out of ten dis-
regard this truism, and ultimately stop their count when they
have registered an arbitrary number of corpuscles, say two hun-
dred or three hundred, regardless of the fact that the field with
which they abandon the count may lie at the middle of the smear.

If the smear is a short one, so that a good many tours have
been required to make up the requisite count of two hundred or
three hundred, the miscalculation will not be very notable, but
if a long smear is under observation, or if there is a marked
leucocytosis, so that only two or three sweeps of the smear are
necessary to complete the count, the inaccuracy may be highly
significant. Smears are not infrequent, for example, in which
practically all small lymphocytes are in the first half and prac-
tically all the large monocytes in the second half. If, now, the
sweep of the field begins at the beginning of the smear, and two
and a half tours of the field are required, the region of the
small lymphocytes will have been traversed three times, whereas
that of the large monocytes will have been traversed only twice,
and the record will show a seeming preponderance of small
lymphocytes in excess of the actuality — somewhat in the ratio
of three to two. But if, contrariwise, three and a half tours
of the field were required, then we shall have traversed the region
of the large monocytes four times and the regions of the small
lymphocytes only three times, and the record will show a ficti-
tious preponderance of large monocytes.

In a word, where the method is employed — and it is almost
universal — of counting a definite number of leucocytes, it can
occur only in the exceptional instances where the count happens
to be finished at the extremity of the field, that the result is as
accurate as it might be and should be. The degree of error will
vary with the length of the smear (a short smear being pref-
erable) and with the aggregate number counted; the larger the
number, naturally, the closer approximation to accuracy. But
the method is inherently faulty and, in my opinion, should be
abandoned.

The only correct way to make the differential count, as I see
it, is to work clear across the field from right to left and from
left to right, several times, preferable at considerable longi-
tudinal intervals, so that in the end practically the entire area
of the smear has been sectioned, and to stop counting, not
when an arbitrary number has been reached, but at the end of
a complete tour across the smear, whether that tour be the first
or the twentieth. A single or double sweep across the field, with
an aggregate count of, let us say 137 leucocytes, would be, in

214 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

my opinion, more accurate in its results, particularly where a
long smear is in question, than an arbitrary count of 200 or
even of 300 cells; although, of course, it is not open to dis-
pute that, other things being equal, the larger the count the closer
the approximation to accuracy. Other things are not equal in
the supposititious cases in question.

The method of counting an arbitrary even number of cells
has nothing whatever to recommend it except ease in computing
percentages. Every other advantage lies with the method of
counting clear across the field, letting the aggregate number be
what it may (but continuing, of course, until the aggregate is
reasonably large), and the additional labor of computing per-
centages with this method should not weigh for a moment against
the enhanced value of the results.

INTESTINAL TOXEMIAS AND THE CORPUSCULAR BALANCE

Turning now from this parenthetical excursion into the region
of microscopic technique, which I trust was not altogether un-
warranted, let us make further examination of the corpuscular
balance, with particular reference to the response to protein
invasions from the intestinal tract. Let me say at once that
the observations of the blood falling within this classification
are likely to be very discordant. We have considered cases in
which intestinal toxaemia was associated with very pronounced
leucocytosis. There are other cases in which there is a pro-
nounced leucopcenia. Sometimes, at least, the conflicting evi-
dence may be reconciled by considering the degree of chronicity
of the cases involved ; recalling that habitual stimulation of the
cytogenic apparatus throughout a long period may lead to exhaus-
tion. I have records of several cases of rheumatoid arthritis,
of many years' standing, in which the outstanding feature of the
blood count is a conspicuous paucity of leucocytes. Usually with
these cases there is a history of life-long tendency to constipa-
tion, associated with habitual over-indulgence in proteid foods.

Presumably, in these cases at an early stage, there was over-
stimulation of production of leucocytes to meet the protein inva-
sion. Exhaustion has followed, and the leucocytes, performing
their functions inadequately, have put an excessive burden on
the red corpuscles. In general the erythrocytes have appeared
able to meet in some measure the recurring emergency, as shown
by their relatively large numbers, but the inadequacy of their
ultimate action is evidenced in the incomplete metamorphosis
and elimination of protein end products, in particular uric acid.
The weak spot in the heredity armor of the individual being the
fibrous tissues and serous membranes of the joints, deposits of

THE SCIENCE AND ART OF PROTEAL THERAPY 215

urates occur here, with the gradual development of the char-
acteristic malformations of chronic arthritis.

There is nothing in these end-product deposits to give new
stimulus to the mother-cells of the leucocyte. The case is differ-
ent, however, with an individual, who, with the same aetiological
conditions, as to protein invasion, has an hereditary predisposi-
tion to hyperplasia of cells under stimulus of a local irritation
which may lead to the development of a malignant neoplasm.

I have elsewhere developed the thesis (see the Monograph)
that the essential characteristic of malignancy in a neoplasm
is that its cells are more or less subject to proteolysis by the
corpuscular enzymes. According to this view, the cancer cells,
in thus undergoing hydrolysis, stimulate the blood-forming mech-
anisms and lead thus to leucocytosis, and in particular to large
monocytosis. Whether the sequel will show complete hydrolysis
and elimination of the cancer cells or not depends upon the per-
sistence of the local irritative stimulus, the degree of develop-
ment of the cancer cells themselves, the responsiveness of the
blood-forming mechanism, and other factors that do not here
concern us. What is here significant is that one does, in point
of fact, find a leucocytosis, and a relative monocytosis, as the
almost constant accompaniment of a cancerous invasion; and
that the stimulus given by the disintegrating cancer cells them-
selves may be supposed adequately to explain the condition, in
contrast with the leucopcenia of the arthritic patient who lacks
this stimulus. But I repeat that, could we have seen the arthritic
patient at an earlier stage, we should probably have found that
the protein invasion (usually from the intestines) had produced
a leucocytosis that long persisted before exhaustion of the cyto-
genic mechanism came about. In substantiation of this view, we
not infrequently find a leucocytosis, and in particular a notable
large monocytosis, present in young individuals suffering from
intestinal toxaemia, in whom the cytogenic apparatus is still re-
sponsive. Moreover, such an increase has been observed in cases
of intestinal toxaemia that have not undergone proteal treatment ;
although in other cases of this type (as above noted) the large
monocyte count is low.

Here, for example, is a man of 26, who has suffered all his
life from intestinal toxaemia. So poor is his assimilation that,
even when in best condition, he is almost skeletal, carrying no
excess avoirdupois whatever. His stomach is his perpetual en-
emy. His differential count shows 50 per cent, polynuclears,
34.3 per cent, small lymphocytes, 22 per cent, large mononuclears,
and 0.6 per cent, eosinophiles. It is observed that the small
lymphocytes are mostly relatively large and with abundant cyto-
plasm, so that one is constantly tempted to classify them as large

216 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

lymphocytes; yet even so the number of cells registered as
unequivocal small lymphocytes is at a high normal limit. Mean-
time the large mononuclears, which are seen to stain deeply and
with ill-defined nuclear bounds, represent 22 per cent, of the
leucocyte count, a proportion seldom observed except under the
stimulus of proteantigen treatment. The nuclei of all the white
cells stain very poorly, a second staining with methylene blue
being required to bring them out at all clearly.

An explanation of these peculiarities, consonant with the hy-
pothesis all along expounded, would be that in this case sto-
machic and intestinal digestion are so defective that relatively
large numbers of unbroken protein molecules find their way
through the intestinal walls. This invasion is met by a large
mononuclear population, and in particular by the extraordinary
aggregation of large monocytes. The condition here is strictly
comparable to the conditions that obtain where there is a well-
developed cancer; in each case there is constant intrusion of
fully formed proteins into the circulation, and the increase in
large monocytes shows the response of the defensive mechanism.
The relative effectiveness of response in this case may be ex-
plained, perhaps, by the fact that the patient is young and hence
has a more resilient cytogenic apparatus than the average cancer
subject.

The particular case of intestinal toxaemia in question is known
to me only by report and from a blood smear sent to me from
a distance, so I am not able to record the results of Proteal
treatment, which would be of obvious interest. I have had
numerous cases of intestinal toxaemia more or less similar to
this, however, under treatment, and I am able to report that
the results of Proteal treatment have in most instances been
as satisfactory as the theoretical consideration above outlined
might lead one to anticipate. As a rule, these cases do not have
a high large monocyte count at the outset, presumably because
their digestive protein products are at an intermediate stage of
decompounding before they penetrate the intestinal walls. The
red cells, however, whether or not they are reduced in number, are
likely to show very marked abnormalities of form, suggestive
of perverted function ; and the white cells, frequently increased
in number, tend to take the stain very badly, and to have an
agglutinative quality that leads to their clumping and assembling
in windrows at the end of the smear. Very commonly the red
cells in the Toisson solution show a large proportion of small
or misshapen cells, battered looking, crenated, or covered with
spicular pseudopodia, giving them an appearance that I am accus-
tomed to liken to that of a miniature sea urchin. There may be

THE SCIENCE AND ART OF PROTEAL THERAPY 217

curious vacuolations or typical modifications of the structure
giving a figured appearance.

All these things, to be sure, may be seen more or less in rela-
tively normal blood cells; but the proportion of cells showing
such aberrant conditions is very greatly increased in cases of
intestinal toxaemia, particularly when associated with rheumatic
sequels. One cannot well doubt that there are profound chem-
ical changes in both red and white cells of such a subject.

A typical case recently under treatment is that of a young
woman whose clinical symptoms included "general debility," poor
circulation associated with cold hands and feet, lack of appe-
tite, lassitude and depression, and a tendency to enlargement and
pain of the finger joints of "rheumatic" character.

The blood count showed 3,571,000 red corpuscles of character-
istic abnormal quality, and 9,690 white cells of the faint-staining,
clumping variety. The polynuclears represented 82.6 per cent.,
small lymphocytes 9.6 per cent., the large mononuclear 7 per
cent., and the eosinophiles 0.6 per cent.

After three weeks of Proteal treatment (Nos. 37 and 45 in
doses of 3 to 6 minims on alternate days), there was marked
improvement all along the line in clinical symptoms, including
conspicuous change in the patient's appearance and feelings, and
the blood count showed more than 6,000,000 red cells which at
first seemed normal, but afterward became picturesquely modi-
fied along the lines just referred to. The white cells had been
reduced to 5,800, and there was most striking modification of
the differential count, which now showed 59.5 per cent, poly-
nuclears, 26.5 per cent, small lymphocytes, and 14 per cent, large
mononuclears. Occasional normoblasts and groups of platelets
were now present. A modification of the chemical condition
of the whites was suggested in the fact that the nuclei now
stained deep purple, the cytoplasm being markedly acidophile.
The individual leucocytes were large, and there was not much
clumping.

This patient, obviously, requires a long course of proteal treat-
ment to bring about permanent modification of the disturbances
of metabolism, but the changes effected in so short a period are
striking and gratifying. The case is still under treatment.

BY WAY OF SUMMARY

The reader of the Monograph on The Proteal Treatment of
Cancer is aware that the theory that underlies my interpretation
of most of the phenomena of protein therapy traces a large part
of the ills of middle life to disturbances of protein metabolism.

218 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

It will be recalled that I listed lymphatic and myologenous leukae-
mias and pernicious anaemia, and such seemingly diverse con-
ditions as anaemic obesity, Graves' disease, arthritis, arterio-
sclerosis, and neoplasms of all types under a common heading
as evidence of the "cancerous condition." The detailed expo-
sition of a certain number of typical cases in recent pages has
been intended to illustrate in some measure the validity of this
classification. In my original exposition of the principles of
protein therapy, so often referred to in these pages, I spoke of
the proteantigen response as applicable to all types of protein
infection. The present entire volume is but an elaboration of
that thesis.

It is perhaps unnecessary to detail further individual cases
to emphasize the opinion that disturbances of the blood grow-
ing out of abnormal alimentation may be aetiologically connected
with many types of maladies that have not hitherto been asso-
ciated in the mind of the average practitioner. It should be
axiomatic to say, however, that abnormal modifications of the
blood must have wide and various implications in disturbed
functionings of the bodily organs. It is scarcely too much to
say that there are no maladies that are not to some extent asso-
ciated with disturbances of metabolism that must register them-
selves in the blood, whether or not we are able to read the record.

Every practical physician knows how prevalent are anaemias
of various types, whether or not associated with recognized
sources of protein infection. But the manner of association —
the universality of disturbed protein metabolism as a factor in
producing anaemias — was perhaps never so adequately explicable
on any other hypothesis as it becomes when interpreted in the
light of the Proteomorphic theory. And assuredly there is no
remedial agent hitherto available that so directly and so explic-
itly goes to the source of disturbance and tends to correct it as
do the proteantigens.

It will be a little difficult for the profession to accustom
itself to the idea that the same line of treatment, modified to
meet individual cases, may be applicable to maladies recorded
under such diverse headings as intestinal toxaemias, anaemias,
arthritis, psoriasis, asthma, tuberculosis, and cancer. But when
the idea is clearly grasped that there are important underlying
causal factors that are the same for all these conditions, the
logicality of the protein treatment will be obvious.

And I predict with much confidence that the practical physi-
cian, whatever his attitude toward theories of therapeutic action,
will feel that Proteal medication places in his hands a new
weapon of unique value in the treatment of a wide range of
maladies of middle life and old age that hitherto have proved

THE SCIENCE AND ART OF PROTEAL THERAPY 219

intractable. When he has seen the blood count in an anaemic
patient change more radically after a week or ten days of treat-
ment than he would otherwise have been able to change
it in as many months, he will come to recognize the Proteals as
indispensable additions to his equipment, compared with which
the entire list of specific serums and vaccines have minor sig-
nificance.

In speaking thus, I have no intention to disparage the value
of specific serums and vaccines. I have been from the outset
an enthusiastic advocate of these methods. I have only in mind
the thought that the diseases to which they are applicable are
relatively rare; whereas the maladies herein under considera-
tion, as associated with disturbed protein metabolism and more
or less amenable to Proteal medication, are so prevalent that
they claim by death three-quarters of a million individuals in
the United States each year. I think it is not quixotic to express
the belief that a more intelligent application of dietetics com-
bined with the rational use of Proteal therapy may modify very
conspicuously the mortality statistics of the not-distant future.

I bring this outline of the development and present status of
protein therapy to a close with a full sense of the inadequacy of
the presentation that has been given. I have not so much as
referred to the recent literature that shows how actively the
minds of many physicians in various parts of the world are
turning toward the subject. My intention throughout has been
to give a resume of the pioneer work in this field; my own
experience and the experience of co-operating physicians still
constituting, no doubt, by far the largest body of evidence in
existence as to the therapeutic use of non-specific proteantigens.
It suffices to say that the reports that have come from a number
of independent workers in this country and in Europe during
recent months, although covering only a part of the field of our
researches, have been singularly corroborative of our results. In
particular, the work of Miiller and Thanner and their associates
in Berlin in the use of milk protein and an "albumose prepara-
tion" in the treatment of infective maladies of the eye, including
those of syphilitic, of rheumatic, and of gonorrheal origin, have
peculiar interest. Such extensions of the method will excite
no surprise in any one who has grasped the principles of the
therapeutic action of the proteantigens, as originally detailed in
my paper of October 2, 1915, and as elaborated throughout this
book. Disturbed protein metabolism underlies a great variety
of maladies, particularly in middle life and old age ; and, as my
original presentation stated, protein therapy is directed "against
all protein infections."

Even where the infection is specifically bacterial there is

220 THE PROTEOMORPHIC THEORY AND THE NEW MEDICINE

theoretical warrant for the administration of agents that stim-
ulate the blood-forming mechanism to effective activity, since
"good blood" is always at a premium. Moreover, it is plausible
to suppose that when the cytogenic apparatus is thus rendered
active, its functionings will result, under proper stimulus, in a
maximum production of specific anti-bodies directed against the
toxins of a particular bacterium, as well as of general enzymes
to deal with the proteid bodies of the bacteria themselves.

It appears fairly certain, then, that the range of application of
non-specific protein therapy overlaps the field of specific therapy,
and has even wider connotations than those included in the prac-
tical use of the method up to the present. Yet even as the case
stands at the moment, protein therapy, of proved value in condi-
tions ranging from anaemia and intestinal toxaemia to typhoid
fever and tuberculosis, and from rheumatism to cancer — a
method, in short, that combats every form of protein toxaemia
by fortifying the bodily defensive and offensive mechanism as
represented in blood-forming organs and blood corpuscles — may
without exaggeration be said to constitute the most general and
the most comprehensive procedure known to modern scientific
therapeutics.

It is my confident belief that in the very near future non-
specific protein therapy — and in particular Proteal therapy — will
be so generally employed as to modify the mortality statistics of
the degenerative diseases of middle life and old age not less
conspicuously than the mortality of diphtheria has been modi-
fied by specific serum therapy and the mortality of typhoid fever
by the anti-typhoid vaccine. In its ultimate application, Proteal
therapy will find a prominent place among preventive measures
and in the incipiency of disorders of nutrition. In its earliest
application to the later stages of the most malignant of disorders
of disturbed metabolism, it showed astonishing efficacy; but the
full measure of its value can be taken only when it is generally
used to counteract disorders of nutrition in their incipiency —
simple anaemias, neurasthenias, mild autointoxications, "run-
down" conditions — or at a stage short of profound cachexia and
permanently degenerated organs. The present book will have
served its purpose if it arouses the profession to a realization of
the enheartening possibilties along these lines now made available
by protein therapy in its wider aspects.

PART II

CANCER: INTERPRETED IN THE LIGHT OF THE

PROTEOMORPHIC THEORY AND THE

PROTEIN RESPONSE

The ensuing pages reproduce with occasional modifications about
two-thirds of the text of the Monograph so frequently referred to in
this book, as published December i, 1916, under title of The Pro-
teal Treatment of Cancer and Allied Conditions: A Practical Study
of a New Therapeutic Principle as Interpreted in the Light of the
Proteomorphic Theory.

• I have thought that it might be of historical interest to include
the dedication of that work, which is therefore reproduced overleaf.

mmtograpl)

telling or a humanitarian work that vitally concerns the lives
and welfare of one-sixteenth of the world's total popula-
tion,— a work carried forward in the face of fanatical op-
position, under almost insuperable difficulties, and at great
personal sacrifice, — •

(0 DcDf CfltcD

to the memory of five of my New England ancestors —
representing four patronymic generations in direct line —
who were Regular physicians of distinction, namely:

(i) My great great grandfather ^ THOMAS WILLIAMS,
A.M. (Yale),M.D. (1718-1775), Colonial surgeon in the
French and Indian wars and brother of the founder of
Williams College; my great grandfathers (2) WILLIAM
STODDARD WILLIAMS, M.D. (1762-1828), of Deer-
field, Mass., and (3) JOSEPH GOODHUE, M.D., of Ports-
mouth, surgeon in the Federal Army; (4) my grandfather,
STEPHEN WEST WILLIAMS, A.M., M.D. (1790-1856),
Professor and Lecturer upon Medical Jurisprudence, the
Theory of Medicine, and Medical Botany, in the Berkshire
Medical Institute, in the College of Physicians and Surgeons
in New York, in Dartmouth College, and in Willoughby
University; author of numerous books; personal friend of
Valentine Mott and Oliver Wendell Holmes ; close associ-
ate of N. S. Davis in the organization of The American
Medical Association; and (5) EDWARD JENNER WILLIAMS,
M.D. (1823-1881), my father, a man endowed with rare
qualities of mind matched by yet rarer qualities of heart:

Each of them perennially active in the service of human-
ity; each of them in the forefront of the medical progress
of his time; each of them a life-long zealot for the best
traditions of medical ethics; each of them honored by all
who knew him in life, and in death epitaphed simply and
justly with the words:

"He was a skillful practitioner and an honest man."

PART II

CANCER: INTERPRETED IN THE LIGHT OF THE

PROTEOMORPHIC THEORY AND THE

PROTEIN RESPONSE

SECTION I
THE NATURE OF CANCER

In the paper of October 2, 1915, in the New York Medical
Journal, I suggested the following definition and interpretation
of cancer:

One might define cancer, in the light of the present theory,
as a systemic condition characterized by the development of
neoplastic cells of a somewhat embryonic type, in conjunction
with an excess of leucocytes in the blood and a deficiency [actual
or relative] of red blood corpuscles.

It must further be postulated that the neoplastic cells are of a
type susceptible to the attacks of leucocytic enzymes, so that there
is a constant tendency to disintegration of some of these cells
under the attacks of the white blood corpuscles. Meanwhile, the
deficiency [actual or relative] in red blood corpuscles makes it
impossible for the system to deal adequately with the partially
hydrolyzed protein products resulting from the breaking down
of some of the new cells under the attacks of the leucocytes.
The net result is a condition of protein poisoning or autointoxi-
cation which, when fully developed, constitutes the characteristic
"cancer cachexia," and ultimately causes the death of the patient.

It should be observed that this new definition of cancer explains
the hitherto obscure fact that almost any kind of new growth
in the organism may on occasion take on the characteristics of
malignancy. A fibroid tumor of the uterus, for example, is not
ordinarily "malignant" because its tissues are of a type that the
leucocytic enzymes cannot readily attack — largely, perhaps, be-
cause of their slow development and firmness of texture. Yet
on occasion, as is well known, portions of a fibrous growth may
become susceptible to disintegration under the attacks of the
bodily enzymes ; and in such a case, should the red blood^ cor-
puscles fail of their appointed task, a condition of veritable
malignancy is attained, and the aforetime fibroid becomes a
cancer.

Ordinarily, however, the neoplastic growth is from the outset
composed of such cells as are more or less susceptible to the

223

224 THE PROTEAL TREATMENT OF CANCER

action of the leucocytes; and, from a pathological standpoint,
it is permissible to regard all such growths as nascent cancers.
In a vast majority of cases, however, the neoplasm is denied
opportunity of considerable growth, because of the immediate
attacks of the leucocytes, which are backed up by the erythrocytes
to such good effect that the neoplastic proteins are completely dis-
sociated and eliminated from the body without producing harmful
results, and, indeed, as a rule, without being given any considera-
tion whatever.

It is probable that there -are scores of nascent neoplasms that
are dissociated and obliterated for every one that attains mastery
over the corpuscular bodily defenders and becomes a tangible
neoplasm. It is probable, in other words, that every insignificant
lesion of the bodily tissues that calls for the development of new
cells in the process of repair, might be regarded as an incipient
malignant neoplasm; and is prevented from becoming an actual
menace only by the efficient activities of the corpuscles that are
normally present in adequate numbers for the bodily defense.

In elaboration of the idea underlying this conception of can-
cer, I now suggest the following expanded definition :

Hyperproteomorphism, or the Cancerous Condition, is a sys-
temic condition characterized by a profound disturbance of pro-
tein metabolism involving originally the blood and blood-forming
mechanism ; evidenced by disturbances of the corpuscular balance
and the abnormal proliferation of cells of one type or another;
frequently, but not necessarily, associated sequentially with local
neoplasms comprising cells that are partly subject to hydrolysis
under influence of the enzymes developed by the white and red
corpuscles.

As elaborating the definition, I suggest the following classifi-
cation of the varied manifestations of the cancerous condition:

(1) Lymphatic and Myelogenous Leukaemias and Pernicious
Anaemia, where the hyperplasia involves the blood-forming
tissues.

(2) Anaemic obesity, characterized by excessive fat-founda-
tion and deposit, at the expense of more useful tissues.

(3) Proteoid hypertrophy, as in Grave's Disease and myxoe-
dema, where the lawless new growth involves glandular and
lymphatic tissues.

(4) Chronic rheumatoid arthritis, where the maladjustment
of metabolism manifests itself in a tendency to new growths in
connection with the cartilage of the joints.

(5) Arterio-sclerosis, where the localized evidence of nutri-
tional maladjustment involves the tissues of the circulatory
apparatus.

(6) Benign neoplasms, where a local irritation in association
with the disturbance of protein metabolism has led to a prolifer-

THE ORIGIN OF CANCER 225

ation of localized tissues not freely subject to proteolysis by the
corpuscular enzymes.

(7) Malignant neoplasms, or true cancer, where a localized
irritation or abrasion has cooperated with protein maladjustments
to cause a proliferation of epithelial, endothelial, or connective
tissues constituting a more or less conspicuous neoplasm the tis-
sues of which are to some extent subject to hydrolysis by the
corpuscular enzymes. Here the development of the neoplasm
in itself evidences the disturbed conditions of protein metabolism
in the body (deficiency of corpuscular enzymes), and the new
cells tend further to disturb that maladjustment by presenting
additional protein material for hydrolysis.

I am fully cognizant that so revolutionary a definition and
classification as the above, in which it is suggested that the can-
cerous condition is not necessarily associated with the presence
of such a neoplasm as is commonly supposed to constitute the
essentials of the disease, must excite surprise and opposition. But
I venture to believe that the more closely the matter is consid-
ered, the more valid will seem the reasoning on which the inter-
pretation is based. It will appear presently that there is also an
important body of clinical evidence that gives support to the view
above presented.

SECTION II
THE ORIGIN OF CANCER

What I have to suggest as to the origin of cancer follows as a
matter of course from the theory just outlined as to the nature
of the disease.

Whatever tends to disturb protein metabolism in the body may
be considered as a predisposing cause of the malady. Familiar
causes of such disturbance are (1) lack of exercise, (2) excess
of protein food, particularly of animal proteins, (3) inadequacy
of the protein intake.

It is obvious that the second and third of these causes of pro-
tein maladjustments are mutually exclusive. They must both
be borne in mind. An excess of proteins in the diet, resulting
in a putrefactive mass in the bowels and the entrance of a cer-
tain amount of unbroken protein into the parenteral system may
overwhelm the blood corpuscles and produce an anaemic condi-
tion comparable to that due to a lack of adequate protein for the
building up of fresh supplies of blood corpuscles.

It will be recalled, of course, that there is constant destruction
of the red corpuscles in the spleen and liver, through which

226 THE PROTEAL TREATMENT OF CANCER

(according to the proteomorphic theory) byproducts of protein
metabolism that are toxic in character are excluded from the
system. To compensate this destruction, there must be a constant
building of new corpuscles, implying fresh protein supplies and
an enormous aggregate expenditure of energy. If the necessary
protein supplies are brought in excessive quantities, it follows that
the red corpuscles have an excess of byproducts (of the poly-
peptid order) to deal with and are necessarily destroyed in
excessive numbers. To keep up the supply, calls for an increased
expenditure of energy, putting a needless tax on the bodily ma-
chine that may manifest itself in an abnormal blood count,
increased blood pressure, and ultimately in one or another of the
conditions of localized maladjustment above listed.

But it does not by any manner of means follow that the only
cause that can produce such maladjustments is an excess of pro-
tein in the digestive tracts. It has already been implied that a
marked deficiency might lead to a corresponding sequence of
events. The presence of large numbers of bacteria in the intes-
tinal tract is in itself a factor that makes constant work for the
red blood corpuscles, resulting in a steady nitrogen loss and
necessitating a constant restocking with nutritive proteins. So
protein starvation might be quite as disastrous as protein reple-
tion. The happy mean, here as elsewhere, constitutes the road
to health.

As to exercise, a somewhat similar line of reasoning applies.
Every physician nowadays recognizes the necessity for a certain
amount of exercise in normalizing the processes of metabolism.
But it must not be overlooked that excessive exercise, carried to
the point of exhaustion, may have a devitalizing influence that
will lead to conditions closely comparable to those resulting from
entire lack of exercise. Doubtless a hundred persons suffer from
lack of exercise, however, where one suffers from over exercise.
So the practical lesson that one is commonly called upon to
inculcate is that exercise is the road to health.

Vigorous exercise is a recognized factor stimulating formation
of blood corpuscles ; which fact, according to the present theories,
suggests a fairly direct association between exercise and preven-
tion of the disturbances of protein metabolism that are here
postulated as constituting the true cancerous condition.

Whereas lack of exercise and improper diet are, in my opinion,
the chief causes that lead to the maladjustments of metabolism
constituting the cancerous condition, there are, as a matter of
course, many minor causes of disturbance. Conspicuous among
these is the loss of blood which many women suffer at the meno-
pause ; a condition that no doubt contributes very markedly to the
genesis of malignant neoplasms; a condition, therefore, which

THE ORIGIN OF CANCER 227

should always receive careful attention from the physician. Any
condition that causes persistent anaemia should be viewed with
solicitude in this connection.

A greater or less degree of instability conditioned on heredity,
is implied as a matter of course, as determining a "tendency" to
cancer. Hormone disturbance (e. g., thyroid inefficiency) may
also constitute a predisposing element.

As to causes that determine the localized development of a
neoplasm, when the cancerous condition eventuates in such
development, elaborate studies have been made, and there is vir-
tual unanimity of opinion among authorities. Any chronic source
of irritation may result — and indeed must result — in stimulus to
growth of new cells. A callous on the thumb and a corn on the
toe illustrate this principle as tangibly as an epithelioma on the
lip where a clay pipe has long been held, or a carcinoma of the
breast that developed from a nipple irritated by a corset steel.
But the thumb callous and the corn are "benignant" growths
because their tissues are not of a character to be broken down
by the bodily enzymes. The same is true of an ordinary
overgrowth of fibrous tissue in the interior of the body, as a
fibroid of the uterus or a fibroma located, for example, on the
forearm.

The new growth, let it be emphasized, becomes malignant only
when its character is such that its cells can to some extent be
hydrolyzed by the bodily enzymes (including, prominently, ac-
cording to present thesis, the enzymes of the white and red cor-
puscles). Moreover, even cells falling within this definition are
not necessarily a menace to the system, provided the supply of
enzyme- forming corpuscles is adequate and in good working
order ; for in that case misplaced new cells are at once dissociated
and the products of such dissociation utilized as animo-acids or
eliminated from the body. According to the proteomorphic
theory, the early stages of such dissociation are effected by the
white corpuscles, and the later (polypeptid) stages by the red
corpuscles ; but details as to this are not essential to the present
thesis. What is essential is the recognition that if the enzymes
that are competent to hydrolyze cells, whenever these cells are
present in excess, are normally abundant in the system, there will
be no development of a malignant neoplasm.

Stated otherwise, the presence of the tangible "malignant"
neoplasm is in itself evidence that there was antecedent disturb-
ance of the processes of protein metabolism in the body, charac-
terized specifically by inadequacy of the enzymes that deal with
proteins not needed by the system.

Viewed from a slightly different angle, it appears that any
proliferation of new cells, however induced e.g., in repair of an

228 THE PROTEAL TREATMENT OF CANCER

ordinary traumatism — is a potential malignant neoplasm; the
question as to whether it becomes an actual menace being deter-
mined solely by the antecedent conditions of bodily metabolism.
As illustrating the truth of this, it is familiarly known that normal
blood antagonizes cancer cells when introduced from without, as
in the case of an inoculation experiment in animals. It is known,
too, that transplantation experiments are facilitated by bleeding
the animal in advance of transplantation.

Summarizing the matter, we may say that three factors are
always present and in cooperation when a malignant neoplasm
develops in the human subject. There is (1) the factor of dis-
turbed protein metabolism, which I have spoken of as the can-
cerous conditions; there is (2) the factor of local irritation, — a
pipe stem on the lip, an injury to the breast, hot food in the
mouth or stomach, chronic intestinal irritation, a laceration of the
cervix uteri; and there is (3) the factor of inherent suscepti-
bility, hereditary or acquired.

It is the old story of stress and resistence. The same irrita-
tion being applied in the same place in the case of two individuals,
one individual suffers no obvious inconvenience, because his
defensive mechanism is in good working order; and the other
individual develops a fatal "cancer" because his defensive mech-
anism is not in effective fighting condition.

This view harmonizes the contentions of those theorists who
have on one hand alleged the general origin and on the other,
the local origin of cancer. In a sense both theorists are right,
inasmuch as there would probably never be a local neoplasm
developed in any individual case, unless there was some source
of irritation. So there is every reason why careful attention
should be paid to sources of local irritation, and to local injuries
of every character. But it is sheer folly, while treating these
local conditions, to ignore the underlying systemic maladjust-
ments, correction of which (where this is possible) would make
the danger from local irritation negligible.

In other words, in the pro founder view, the problem of the
origin, and therefore the problem of the prevention, of cancer
implies attention to the bodily processes of metabolism — diges-
tion, assimilation, nutrition. Mere attention to local conditions
partakes of the character of what Thoreau called clipping at the
twigs of the tree of evil while the roots remain untouched. The
root of the cancerous condition is disturbed protein metabolism,
and not mere local irritation.

I shall have occasion to point out rather obvious corollaries of
this view in their application to the question of the surgical treat-
ment of cancer, as well as to make what I hope may be consid-
ered important deductions as to more effective general treatment
of the malady.

LOCAL TREATMENT OF MALIGNANT NEOPLASMS 229

SECTION III

THE LOCAL AND SURGICAL TREATMENT OF
MALIGNANT NEOPLASMS

We have seen that the development of a local neoplasm implies
defective conditions of general blood supply.

Such deficiencies may be accentuated by local perversion of
circulation, as, for example, where the capillaries and veins are
rendered patulous by the persistent application of heat, as in the
use of a clay pipe, or of the abdominal heaters carried by certain
natives of the Orient.

In a slightly different way, the presence of an excess of adipose
tissue, may interfere with the circulation, and tend to produce a
local anaemia even while the general blood supply is fairly
adequate.

In a case in which the general conditions of protein metabolism
were just at the border line, so to speak, of the cancerous condi-
tion,— that is to say, of out-and-out abnormality, — a compara-
tively slight interference with circulation at some local point may
give opportunity for the development of a neoplasm that other-
wise would be held in check.

Such a condition is found, for example, in nearly all scar tis-
sue. Every pathologist knows that scar tissue is poorly supplied
with blood vessels, and that it tends rather readily to break down
under irritation. In other words, it has not a normal degree of
resistance. Doubtless this lack of resistance is closely associated
with the defective blood supply. If, now, in addition, there is
some source of irritation that tends to stimulate the growth of
the cells (as all irritation does tend to do), conditions are favor-
able for the development of a neoplasm, which will be non-
malignant or malignant according to the general condition of the
blood, or according to the precise character of the new tissue
itself.

If the balance of leucocytes is right, and there is an adequate
supply of red corpuscles to deal with the later products of protein
decompounding, the new tissue will be cared for by the system,
and the condition of malignancy cannot develop.

If, on the other hand, the red cells are inadequate either in
number or in activity, the development of the new cells will
almost of necessity result in a condition of malignancy.

Even when at the outset the red cells are adequate the growth
of the new tissue may be so rapid as to supply a larger amount
of protein than can be dealt with (particularly if the red cells

230 THE PROTEAL TREATMENT OF CANCER

are over-burdened by an excess protein diet), and a condition that
at first was non-malignant will gradually grade into malignancy.

Such a change from a benign to a malignant condition is a mat-
ter of common observation. As an illustration, note how ulcer
of the stomach tends to develop into cancer of the stomach. The
presence of the ulcer tends in itself to interfere with digestion and
assimilation, and thus to superinduce the systemic maladjustment,
as regards protein metabolism, which I have all along spoken of
as the cancerous condition. In this case, the initial cause of the
entire difficulty may have been the ingestion of a morsel of hot
food. The local abnormality here precedes the systemic one ; but
it should be recalled that in such a case, if the person swallowing
the hot morsel of food was in normal health, the original stomach
lesion was an ulcer of "benign" character, and its ultimate malig-
nancy was sequential to the general condition of protein malad-
justment, as in the case of every other malignant neoplasm.

Cancer of the stomach, however, is a case apart, complicated
by the fact that the stomach is the channel of intake of foods to
nourish the body in general. With malignant neoplasms in gen-
eral, it is a safe presumption that there are usually deficiencies of
local circulation to supplement the defects of the general blood
supply. The uterus depleted by hemorrhage is an illustration
in point.

It follows that anything which tends to facilitate the circula-
tion of the blood in and about the malignant neoplasm may be of
remedial value, provided that the enzymic conditions of the blood
have not shrunk to too low a level.

So we find that a local inflammation may sometimes have cura-
tive effects at the early stage of development of a malignant
neoplasm. The cardinal symptoms of inflammation — pain, red-
ness, and swelling — are associated with an engorgement of the
blood vessels, and thus with an increased local capacity to deal
with the protein elements. The true explanation of inflammtion
has probably never hitherto been available as clearly as the
proteomorphic theory reveals it. Hitherto no one has understood
just why there should be an accumulation of red blood corpuscles
at a source of inflammation. That the process was curative or
beneficial for the individuals could be taken for granted, but as to
just what the nature of the benefit conferred might be, has hitherto
been only inferential. Now that the province of the red cor-
puscles in dealing with the end-products of protein metabolism
is understood, the benefits of the inflammation induced, for
example, by bacterial onslaught are clearly explicable. The
province of the red blood corpuscle is to cooperate with the white
corpuscles by carrying away and further proteolyzing the later
products of protein decompounding.

LOCAL TREATMENT OF MALIGNANT NEOPLASMS 231

Where the protein in question is new tissue of cancerous char-
acter, the process of decompounding and elimination is of course
entirely comparable. The leucocytes (in particular, probably,
the large mononuclears) begin the process of hydrolysis, and the
red corpuscles continue it beyond the polypeptid stage and carry
away the toxic by-products.

So we might expect a certain amount of relief, and even in
favorable cases an actual curative process, to be engendered by
local inflammation, however induced, in the region of a malignant
neoplasm at an early stage. Such an expectation is occasionally
justified. I have recently had called to my attention at first hand
a case in which, seemingly, an accidental streptococcus infec-
tion resulted in the disappearance of an epithelioma of the lip
quite without treatment; and this observation is by no means
unprecedented. Doubtless there are scores of irritative or caustic
compounds that have in exceptional instances produced the "cure"
of a local epithelioma, or of a carcinomatous ulcer of the breast,
through inducing such a local inflammation.

Such cases, however, would obviously be exceptional, and in
general it is to be hoped that a local inflammation will prove
curative in any case of a well-developed malignant neoplasm only
in occasional instances. As an adjunct to general treatment, how-
ever, the application of a local irritant may be of value. But at
best this treatment must be considered as an adjunct only.

It is my belief that much the same statement may be made
with regard to the efficacy of the treatment of the local neoplasm
with the knife. I am aware that this view is heretical, but it
follows as a natural conclusion from the line of reasoning above
outlined.

To be sure, it is current surgical doctrine that if cancer can be
removed early enough, and removed in its entirety, the patient
is cured.

But in point of fact, if the present thesis as to the nature of
cancer is tenable, the surgeon who has removed a malignant
neoplasm, — even in its earlier stages, and even though the removal
had been as complete as is ever feasible, — far from curing the
malady, has not really treated the malady at all. He has removed
a local manifestation of the essential systemic abnormality that
is the true "malignant condition," but at best the treatment is a
tentative dealing with symptoms, and has no reference to the
essential disease itself.

It is true that the removal of the local neoplasm takes away a
certain amount of tissue that, through partial dissolution, is
poisoning the system ; and thus may be a valuable aid in the treat-
ment of the amaladjustment in the process of nutrition, which
constitutes the essential character of cancer. But to treat the

232 THE PROTEAL TREATMENT OF CANCER

local condition, and imagine that in so doing one has cured the
malady, is hardly less futile than would be the supposition that
one has cured a case of syphilis because one has excised a syphili-
tic wart or healed a chancre or a tertiary ulcer by local cauteriza-
tion.

The futility of even the most drastic surgical interference is
unequivocally illustrated by the history of a case examined and
diagnosed by me in which both breasts and the axillary glands had
been removed because of the presence of small nodules which were
pronounced of doubtful malignancy by a competent microscopist ;
yet in which the blood six months later recorded 17 per cent, of
large mononuclear leucocytes, half of them myelocytes, leucoblasts,
and lymphoidocytes ; together with red cells showing poikilocytosis
and polychromasia, and not infrequent normoblasts, evidencing a
condition of myelogenous excitation that — in connection with the
history of the case — left one not at all in doubt as to the existence
of the cancerous condition. Here surgery had been given the best
possible chance, and had obviously failed. The patient died, un-
treated, six months later.

It does not follow that the surgeon's knife should be held in
abeyance. On the contrary, there is the most logical reason for
using the knife, and removing as much as possible of the local
neoplasm that evidences the systemic disturbance. But such a
procedure should be but a small part of the process of treatment
of the cancerous condition. In every case where a malignant
neoplasm is removed by the surgeon's knife, there should be the
most careful examination of the blood, with full count of the
corpuscles both red and white, and differential count of the lat-
ter. There should be the closest scrutiny of the patient's habits
of living, with notable reference to the diet, the condition of the
bowels and kidneys, and the general processes of assimilation and
bodily metabolism. Only by attention to these, and the readjust-
ment of the perturbed process of assimilation, can there by any
reasonable grounds for hope that the excised neoplasm will not
recur.

It is partly because surgeons usually fail to give such attention,
that the neoplasm does return after surgical removal in so pre-
ponderant a proportion of cases. That it ever fails to recur must
be ascribed to the good luck of the patient, or to his chance obser-
vation by an internist of discrimination and judgment, rather
than to any merit of the average performer of the operation.

I shall have something more to say presently about the pre-
operative and post-operative treatment of malignant neoplasms,
suggesting, among other things, that any surgeon who fails to
avail himself of therapeutic measures now available for general
treatment of the case in connection with his operations must be

BIOLOGICAL MEASURES IN THE TREATMENT OF CANCER 233

judged guilty of gross negligence, amounting to malpractice. But
this presentation of the case may advantageously be delayed until
discussion has been had of the new therapeutic measures in
question.

SECTION IV

"BIOLOGICAL MEASURES" IN THE TREATMENT
OF CANCER

As preliminary to such discussion, it will be well to take a brief
survey of various tentatives in the direction of the general treat-
ment of cancer, made in recent years, that have seemed to have
scientific foundation and to meet with a certain measure of suc-
cess in a limited number of cases ; to the end that we may inquire
whether there is a point of contact between these different kinds
of treatment.

The discovery of such a point of contact would obviously give
interesting clues to the further investigation of the subject.

The very brief examination necessary in the present connec-
tion may advantageously be conducted along the lines of the
classification or synopsis given by Bainbridge, who summarizes
what he refers to as "biological measures" for the cancer treat-
ment under the following headings: (1) Bacterial toxins, (2)
Antitoxic sera, (3) Antitoxins, (4) "Toxins" or "Fluids," (5)
Vaccines, (6) Residues, Extracts, and Emulsions, (7) Serous
Exudates (Sera), (8) Opotherapeutic measures.

Among the examples of antitoxin, antitoxic sera, and bacterial
toxins, the following are named: (1) Blastomycetic antitoxic
serum of Sanfelice, based upon the theory that cancer is due to
blastomycetes ; (2) Wlaeff's Serum, made from cultures of
blastomycetes from cancerous inoculated into pigeons; (3)
Serum of Emmerich and Scholl, made by inoculating sheep with
Streptococcus erysipelatosus; (4) Doyen's Serum, from Micro-
coccus neoformans; (5) Schmidt's Serum, from Mucor muccdo
(Cancroidin, Antimeristem) ; (6) Wyeth's Toxins of Strepto-
coccus; (7) Coley's Fluid — Mixed toxins of Streptococcus
erysipelatosus and Bacillus prodigiosus.

Among the vaccines named are the Mlcrococcus Neoformans
Vaccine (Doyen), used in connection with the serum made from
the same organism, and the Bacterial Vaccine of Jacob and Geets,
made from cultures of the same micrococcus sterilized and
standardized according to the opsonic theory.

234 THE PROTEAL TREATMENT OF CANCER

Residues, Extracts, and Emulsions, include Coca-Gilman Ex-
tract, or Emulsion; Vaughan Residue; the Fichera Emulsion,
and Autolyzed Cancer or Normal Tissue.

Of serous exudates and body fluids there is a long list, includ-
ing Hodenpyl's Ascitic Fluid from a cancer subject; Normal
human Blood Serum; blood serum of the horse and donkey;
Hydrocele Fluid; Spermatocele Fluid; Ascitic Fluid from the
subject of alcoholic cirrhosis; Ascitic Fluid from the subject of
cardiac insufficiency ; and Pleuritic transudate resulting from
broken compensation.

Of Opotherapeutic Measures (organotherapy) the examples
include (1) "Antituman" of Oestriech made from embryological
cartilage and arteries from which a supposedly immunizing sub-
stance chondroitin-sulphate is extracted; (2) Thymus Gland
Extract; (3) Extract of Sheeps' Thyroids; and (4) Pancreatic
enzymes, Trypsin and Amylopsin as widely exploited a few years
ago under the auspices of Beard.

As to the status of these various treatments, perhaps I cannot
do better than to quote Bainbridge's summary to the effect that :
"Many of the agents have been discarded, with practically a con-
sensus of opinion against their efficacy ; others continue to receive
a certain amount of attention, largely because no definite test of
their value has been made upon a convincing basis; while still
others are being given careful consideration by a sufficient num-
ber of skilled clinicians to warrant the hope that a decision, pro
or con, will be soon forthcoming."

I would add, however, that there is a considerable body of
evidence to show that a good many of these diverse agents have
seemed to produce beneficial effects in a certain number of cases,
and that several of them are still actively employed and enthusi-
astically championed by a number of physicians. Note, for
example, the report of Klinger in the Correspondenz-Blatt fur
Schiveizer Aerzte for Sept. 23, 1916, on the results obtained
with autolysates, to which fuller reference will be made in another
connection. That no one of them fully meets the hopes and
expectations of its originators may, doubtless, be accepted as
fairly demonstrated. But I think it must also be clear that even
tentative results would hardly have been attained with so great
a variety of animal extracts unless some general principle was
involved that gave the different treatments affinity.

It is my belief that the principle in question is the presence of
animal or bacterial proteins in all of the various compounds in
question. In the case of Beard's Pancreatic Enzymes there are
also present digestive ferments closely comparable to those known
to be evolved by the white blood corpuscles, the manner of action
of which will be dealt with presently.

BIOLOGICAL MEASURES IN THE TREATMENT OF CANCER 235

For the moment, the point that I would emphasize is that the
entire group of biological cancer remedies as above outlined com-
prises agents of very diversified origins that have at least one
prominent point of contact in the presence of organic proteins.

If we add that among all the numberless agents that have been
used in the general treatment of cancer, there is not one at present
commanding the slightest scientific consideration that does not
contain protein, we are at least put in the way of an interesting
and suggestive line of thought.

The ideas thus engendered are naturally linked with the reflec-
tion that many students of cancer have attempted to associate
the genesis of the disease with defects of protein assimilation;
and also with the very interesting studies of Bulkley in the treat-
ment of cancer by careful regulation of the diet with reference
to the protein intake.

The full bearing of the observation, however, is appreciable
only when we reflect along the line of the now familiar physio-
logical principle that the introduction of a foreign protein paren-
terally leads to a development by the body of antibodies to
antagonize the toxic influence of that protein; and the further
reflection that the antibodies in question are produced by the
system in excess of the quantity required merely to neutralize
the foreign agent.

A classical illustration of this is found in the use of the anti-
typhoid vaccine, which leads to the production of antibodies in
such excess as to give the individual immunity to the typhoid
virus for a term of months or years.

A moment's further reflection shows that the antibodies thus
produced when a foreign protein is introduced in the body must
be of a character to effect the decompounding of the protein
molecule. If the thesis of the Proteomorphic theory is accepted,
it follows that the introduction of a foreign protein will result
in the increased activities of the white and red blood corpuscles
and of the organs that produce these corpuscles. Specifically, we
may expect that after introduction of a foreign protein there
will be observable a modification of the blood count in the
direction of an increase of large mononuclear lymphocytes and
red blood corpuscles. We may assume that there is a responsive
increase in the quantitative enzymic activities of these corpuscles,
and that the aggregate effect exceeds the immediate needs of the
system as induced by the invading protein.

In other words, there will remain a residual quantity of en-
zymes in the blood capable of decompounding proteins.

These residual enzymes obviously constitute an agent capable
of attacking other foreign proteins, unless we assume that they

236 THE PROTEAL TREATMENT OF CANCER

are of so specific a character that they can affect only the par-
ticular protein that has invoked them.

Have they such specificity?

This, obviously, is an important question. But I think there
can be no doubt about the answer. The enzymes that begin the
decompounding of the protein molecule are of a tryptic character,
closely comparable apparently whether secreted by the digestive
glands or by the white corpuscles, and their action is very general.
The same enzyme can affect the decompounding of animal and
vegetable proteins of the most varied character, as the normal
digestion of an ordinary meal in the intestinal tract sufficiently
demonstrates. Moreover, it is specifically observed that the white
blood corpuscles can attack and destroy bacterial proteins of
many types. There are abundant reasons to believe, then, that the
enzymes developed as antibodies to any one of the wide range of
foreign proteins introduced parenterally may be able to effect the
decompounding of other proteins than the particular one intro-
duced.

If, now, we reflect that the cells of a malignant neoplasm are
made up of protein which, notwithstanding its close general simi-
larity to that of normal tissues, is in a sense a foreign protein;
and, moreover, that these cells because of their newness and rapid
growth lack something of the stability of matured normal cells,
it is readily explicable that they may be attacked by the protein
antibodies in the blood and decompounded.

As suggesting a chemical basis for the expectation that an agent
might be developed that would differentiate between normal cells
and cancer cells, we may note the researches tending to show
that cancer cells have a mineral content in excess of the normal;
and, specifically, that the more malignant types of cancer cells
are relatively rich in potassium, less malignant ones showing a
relative preponderance of calcium ; also the fact, to be dealt with
in another connection, that cancer tissue is reported as showing
only 70 per cent, of the nitrogen content of normal tissue.

If the protein antibodies in the blood come in sufficient quanti-
ties, it is even conceivable that the cells of the neoplasm may be
altogether dissociated, and the neoplasm itself thus eliminated.
But of course so radical a result as this could be expected only
in very exceptional cases in which the balance between the normal
activities of the corpuscles and the activities of the cells of the
neoplasm had not been too profoundly disturbed.

This is perhaps equivalent to saying that success might be
expected somewhat in proportion to the stage of advancement of
the cancerous condition in general and of the neoplasm in
particular.

A highly important complication is found, however, in the fact

BIOLOGICAL MEASURES IN THE TREATMENT OF CANCER 237

that the animal and bacterial foreign proteins now under discus-
sion as furnishing the agents to stimulate the corpuscular en-
zymes, are in themselves more or less toxic bodies. All foreign
serums have elements of toxicity, and this may be so pronounced
that the aggregate effect of introduction of the foreign proteins
may be the opposite of remedial. As a case in point, the intro-
duction of a foreign blood serum may cause active haemolysis,
so that the blood count goes down instead of up. But this, prop-
erly interpreted, is in itself an evidence of such activities of a
foreign protein as are above postulated, the destruction of the
red blood corpuscles evidencing exactly such activities in connec-
tion with the elimination of the byproducts of hydrolosis of for-
eign proteins as is postulated in the Proteomorphic Theory.

But it is obvious that from a therapeutic standpoint the relative
toxicity of the protein introduced is of paramount importance.
And this observation furnishes the clue to a comprehensive criti-
cism of the entire list of biological agents, above referred to as
comprising the various cancer remedies. The bacterial agents
employed in making the various serums of Emmerich and Wyeth
and Coley are confessedly toxic; and the various and sundry
animal serums are all known to have active toxicity when intro-
duced into heterologous parenteral systems.

Hence in practice it happens that in using any of these various
vaccines and serums we are introducing agents capable, to some
extent, of combating the cancer cell (indirectly), but also agents
that put a severe tax on the enzyme- forming organs (blood cor-
puscles and cytogenic apparatus) they are designed to aid. In
using these agents, then, there is always danger that when we
take one step up the hill we shall slip back the length of two
steps. In other words, while we are by way of "curing" the can-
cer, we may kill the patient.

As I have already suggested, it is only in a small residual mini-
mum of cases that we can hope to find the balance of nutritional
conditions in the system such that, when by a happy chance we
stumble on the right dosage of foreign protein, the aggregate
results of our effort is beneficial, and the local neoplasm is caused
to regress.

Nevertheless, the evidence of these scattered and isolated cases,
in the midst of the great mass of failures, is in the highest degree
encouraging and enheartening, because, properly interpreted, it
tends to establish the general principle that the use of foreign
proteins may be of value in the treatment of the cancerous con-
dition. Even though the entire list of "biological remedies"
should stand condemned, these tentative remedies will have served
a useful purpose in pointing the way to a line of medication which
retains their advantages and eliminates their disadvantages.

238

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THE EVOLUTION OF THE PROTEIN PRINCIPLE 239

SECTION V
THE EVOLUTION OF THE PROTEIN PRINCIPLE

Charles Darwin was accustomed to emphasize the value of
hypothesis as an aid to scientific discovery. This value is, indeed,
so evident that the statement of it is almost a truism. Yet it is
equally true that a false hypothesis may constitute one of the most
hampering of obstacles in the way of progress.

I was forcibly reminded of this, when, a few weeks after the
issue of the first edition of the Monograph so frequently referred
to, I came upon a report that had hitherto escaped my attention,
in which an account was given of some very remarkable experi-
ments in the treatment of cancer in the human subject with an
alleged "X" substance said to be extracted from thymus of the
calf. The report appears in a volume issued by Columbia Uni-
versity Press in the year 1913 captioned "Studies In Cancer and
Allied Conditions," and said to be issued from the department of
zoology, surgery, clinical -pathology, and biological chemistry
under the auspices of the George Crocker Special Research Fund
at Columbia University.

This is one of a series of volumes with which I had consider-
able familiarity, but I had failed to note the essential part of the
particular report in question; otherwise I should very eagerly
have welcomed it as giving support to a quite different theory
from the one that the authors of the investigations were pursuing.

The report in question bears title "The Relation of Certain
Internal Secretions to Malignant Tumors." The investigation
was said to be conducted "with the idea of throwing some light
on the relation of some of the internal secretions to malignant
tumors." But in point of fact, the part of the report to which
I refer has, in my opinion, no essential relations to the subject
of internal secretions. The investigation was indeed conducted
with the aid of extracts made from the thymus gland ; but in my
opinion that fact was merely incidental, and precisely the same
results would -have been attained had the extracts been made from
any one of a score of other tissues of the animal body.

In other words, in my opinion — and indeed, in the light of new
evidence, I think it hardly open to doubt — the observations made
had reference to the results of introducing foreign proteins into
the parenteral system, though the authors themselves make it
positively clear that they had no such conception. Probably they
will repudiate the suggestion now that it is made. Nevertheless
I believe the suggestion to be entirely valid.

240 THE PROTEAL TREATMENT OF CANCER

The results achieved, in the treatment of 49 cases of inoperable
cancer in the human subject, were so striking that I shall have
occasion to summarize them in a moment, and to make brief
quotations from the case records. I shall cite also results attained
by Klinger in the treatment of cancer with his animal autoly sates,
for comparison with the results attained in the use of vegetable
proteins. It will be clear, I think, that there is at least a strong
presumption — when we note the striking similarity of these inde-
pendent reports as to the effect on the pain of the cancer subject,
on the character of the discharge from the tumor, and on the
tumor itself — that a common principle is involved in the three
types of therapeutic procedure. And it -seems to 'be scarcely open
to question that the most plausible hypothesis — to put the case
mildly — as to the character of this common agent is the assump-
tion that it is a protein or a protein derivative.

Had the authors of the paper in question conceived that pro-
teins were indeed the active agent in their remedy, their entire
outlook on the subject would have been changed, and in ev^ry
probability they would have gone forward to perfect a discovery
at the verge of which they paused. That they missed the dis-
covery, yet missed it narrowly, is revealed almost pathetically in
the summary of conclusion with which they finished their paper,
when, following deductions that are not pertinent to the present
aspect of the subject, they conclude:

"(3) That there is a substance common to many tissues, but
present in varying degrees, which has a positive influence in
immunity and cure in animals.

"(4) That the application of these results to the treatment of
human tumors results in a temporary improvement in some cases,
and in some few cases in an apparent cure.

"(5) That there is still lacking something which will carry
improvement observed to a successful issue. In what direction
search for such a substance or for an explanation of the problem
is to be made is at present unknown."

The concluding sentence makes it unqualifiedly clear that the
authors were entirely at sea ; that their observations were merely
empirical ; and that they came to no generalizations that could by
any possibility be claimed as constituting the discovery of the
protein principle. Had they made such a generalization, the
entire history of the cancer problem would have been changed
from that moment ; and, quite incidentally, my own work in this
field would have been unnecessary and would never have been
undertaken.

Looking back, in the light of recent developments, it seems
strange that the authors should have failed of the prevision, the
imagination, that would link their observations one with another

THE EVOLUTION OF THE PROTEIN PRINCIPLE 241

and reveal a unifying principle. But this is the history of every
discovery in science when viewed in retrospect. The reader of
my History of Science will be familiar with numberless instances
in point. He will recall that the usual difficulty is that the
imagination is hampered by preconceptions of the experimenter
based on a false hypothesis of one type or another.

In the present instance, the hampering hypothesis was the
thought that the "substance common to many tissues . . .
which has a positive influence in immunity and cure in animals,"
and even in the alleviation of pain in inoperable cancer in the
human subject, is an obscure substance, the method of extraction
of which was supposed to be known only to a single individual —
namely, Dr. Frederick Gwyer, of New York — and which was of
so problematical a character that the name "X" -substance was
given to it. We are told that "the chemistry and method of
isolation of this active substance being preeminently the field of
Dr. Gwyer, we shall not speak of it." So it appears that the
experimenters were working with something -which they regarded
as mysterious ; of which, to be sure, they knew the general origin,
but regarding the precise methods of preparation of which they
were altogether in the dark.

This was peculiarly unfortunate, both because it savors of an
unscientific method of procedure, and because the secrecy in this
case probably stood in the way of progress ; for it is hardly con-
ceivable that, had the method of extraction employed by Dr.
Gwyer been made known to all of the workers, there should not
have been some one of them who would have fathomed the open
secret, — devining, what the originator of the process doubtless
himself altogether failed to surmise, that the "X-substance,"
interpreted in scientific terms, is merely protein, or a product of
partial protein hydrolysis.

But the minds of the operators were under sway of the "X-sub-
stance" hypothesis, and hence they were not in the least en-
lightened when animal tissues various and sundry were subjected
to observation "to see if the 'X'-substance is widely spread in
tissues or if limited to the thymus," and were informed that it
could be found in a great variety of animal tissues. A table is
given, naively showing that Dr. Gwyer has extracted — by a
method "not yet published" — varying quantities of the "X" sub-
stance from macerated human embryo, uterine fibroid, chronic
cystic masstitis of the breast, and liver of chronic congestion in
the human subject ; from muscle, thyroid, thymus, testes, spleen,
pituitary, adrenal, and ovary of beef creature ; from carcinoma,
heart, stomach, spleen, kidney, sarcoma, lung, liver, intestines,
and testes of the rat ; and from fluid from a carcinomatous cyst,

242 THE PROTEAL TREATMENT OF CANCER

abdominal ascitic fluid from a tumor, and from carcinoma in
the mouse.

Furthermore "Gwyer next examined several of the reported
curative agents for cancer and found 'X' substance in all those
mentioned, namely (1) Ascitic fluid from a case of stationary
carcinoma in the human; (2) calf thymus; (3) sheep thyroid;
(4) rat carcinoma tissues prepared after Vaughn's method;
and (5) rat carcinoma tissues prepared after the method of Coca
and Gilman."

Still another table is published which shows "the interesting
fact that immune animals contain more of this 'X' substance than
non-immune." It appears from this table that the quantitative
differences in question are very slight, the range of variation
being given as .011 1/10 to .014% grms. per gram of dried body
weight; and we are given no analysis of methods to assure us
that these variations do not lie within the limits of experimental
errors. The figures serve, nevertheless, to show that Gwyer's
tests were apparently not applied for the detection of the full-
sized .protein molecule as such, but to some derivative product.
The fact stands out, however, and from the present standpoint
is all-essential, that all the experiments in question deal with
tissues or substances rich in- proteins. This of course does not
by itself establish proteins, as such, as -the active agents in the
remedial process ; but it does raise a strong presumption — taken
in connection with the mass of new evidence presented in the
present book — that either the protein molecule or one of its
derivative products in the form of proteoses, peptones, or poly-
peptids is the active principle involved. There seems no present
need of invoking an "X" substance.

Unfortunately, however, this mysterious substance was invoked,
and hence the physicians who administered the treatment were,
in their own estimation, performing what was in effect a mysteri-
ous rite. If we appluad the freedom from prejudice — altogether
unusual in men of their position — that permitted them to employ
what they regarded as a secret agent, of unknown method of prep-
aration, in the treatment of a human malady, we must at the
same time deprecate their unfortunate thraldom to superstition
in focalizing ^attention on the supposed mysterious agent, when
there was every warrant for a simple scientific deduction to the
effect that they were really dealing with agents familiar to every
physiological chemist.

Be that as it may, 'however, the mistake was made, and so
it unfortunately resulted that, notwithstanding the very interest-
ing and, properly interpreted, important results achieved, nothing
of permanency or real significance came of the investigation. It
being seen that the magical "X" substance did not ultimately act

THE EVOLUTION OF THE PROTEIN PRINCIPLE 243

with necromatic efficiency, notwithstanding its early promise, the
experimenters seemingly abandoned it, and, standing with numer-
ous other agents of similar potency in their hands — had they but
known it — they make the bewildered declaration : "That there is
still lacking something which will carry the improvement observed
to a successful issue"; and, almost wilfully shutting their eyes
lest the truth be revealed to them, they add : "In what direction
search for such a substance or for an explanation of the problem
is to be made is at present not known."

And this bewildered confession of defeat is printed on a page
opposite which lies a table telling of really remarkable results
achieved in the treatment of human carcinomas and sarcomas,
all inoperable and supposedly hopeless, in which two cases were
apparently cured; twenty-two cases "greatly improved for a
period" ; five cases "slightly improved for a period" ; and only
sixteen cases treated without effect. This table summarizes the
text in which we are told explicitly what was the character of the
improvement noted. Here are some of the effects : "The tumor
becomes gradually smaller, softer, and in some cases ulcerated,
and large portions may be sloughed off. In those cases where
there has been a large amount of discharge, notably in the uterine
cases, this discharge has markedly decreased and in some cases
stopped. The pain is relieved to a most remarkable extent; in
one case, for example, where morphine was given in doses of 2
grains in twenty-four hours, 5 mms. per day of the extract were
sufficient to enable the patient to do without the morphine until
her death four months later. Some tumors that were ulcerated
on beginning treatment after slight reduction in size became
covered with normal epithelium."

It is quite true that the report continues with this statement:
"Unfortunately, however, aside from the relief of pain, these
results do not persist in all of the cases. The improvement noted
goes on from 4 to 8 weeks and then there is a gradual return to
the old conditions." But it is added : "The tumor, however, does
not grow as fast as would be expected and some of the cases have
lived longer than ordinary clinical experience would indicate as
the expected period of life." Moreover, detailed case histories
are given of a recurrent carcinoma of the breast in which : "The
mass grew steadily smaller and after fifteen injections dis-
appeared. There has been no recurrence to date, which is sixteen
months after treatment; and of a case of inoperable carcinoma
of the corpus of the uterus which became operable under treat-
ment and apparently as a direct result of the treatment, in which
the patient was free from recurrence twenty- four months after
operation, although she died thirty months after operation, of re-
currence, the thymus injection not being kept up after operation."

244 THE PROTEAL TREATMENT OF CANCER

Viewing such results in retrospect, and recalling that a positive
statement is made: "All of the patients treated, 49 in number,
have been declared surgically inoperable and the growth positively
malignant, both clinically and microscopically," it seems almost
incredible that the record of such results, achieved under the
auspices of a great university and published with the authentica-
tion of an important bureau for cancer research, should have
aroused no interest on the part of other workers, and have led
to no practical result looking toward the solution of the cancer
problem. And I think we must feel that the barrenness of the
effort was largely due to the unfortunate hypothesis with which
the striking results were linked in the minds of the experimenters
and in the minds of the readers of their report.

Here were results attained with an alleged "X" substance of
mysterious origin, of unknown composition, a subtsance that no
one knew how to duplicate — the private property, as it were, of
the physician who had discovered it. Under the circumstances,
other searchers in the cancer field probably felt that they could
do nothing except await further reports from the alleged dis-
coverer himself; and as these reports were not forthcoming,
progress in that direction was at an end. It seems regrettable
that some one did not raise the query as to whether the alleged
mystery of the "X" substance were not mythical, and, by making
similar experiments with thymus extract prepared in a non-
mysterious way, following these up with other extracts, carry the
experiment forward a step farther along the lines of conquest of
cancer.

In point of fact, k appears that at least one experimenter did
do this, although whether he knew of the work of the "X" sub-
stance experimenters or not I cannot say. I refer to Klinger,
the Swiss physician whose work with animal autolysates was
referred to in an earlier part of this volume. He, in effect, did
precisely what has just been suggested. He tested animal extracts
of no mysterious character, using them hypodermically quite as
the 'Columbia University experimenters had used the "X" sub-
stance. Like them he produced striking results in the early stage
of treatment of cases of inoperable cancer. Like them he saw
that it was necessary to find other substances which "will carry
the improvement to a successful issue." But, unlike them, he did
not feel that "the direction of search for such a substance or for
an explanation of the problem was quite unknown." In some
way he divined that it might be worth while to test other animal
extracts after the efficiency of the first one had been exhausted.
In so doing he found that a new term of improvement followed.
Thus he was one stage nearer the final goal.

And, as the reader is aware, at the same time that this ex-

THE EVOLUTION OF THE PROTEIN PRINCIPLE 245

tension of methods was being employed by Klinger in Switzer-
land, my associates and I were working quite independently along
precisely similar lines, using vegetable proteins for the most part
instead of animal proteins, with strikingly analogous results.

Klinger's results are published in the Korrespondenz-Blatt fiir
Schweizer Aerzte, September 23, 1916. A lengthy summary of
the article appears in the Journal of the American Medical Asso-
ciation for November 4, 1916. No one could fail to note the
similarity of the description of Klinger's results with his auto-
lysates to my previously published reports of results obtained with
vegetable proteins. For example, he says, as condensed in the
Journal of the American Medical Association:

"Quite a number of cases have been reported of complete cures
or essential improvement under Autolysate treatment of previous-
ly inoperable cancer. In Betrand's case an extensive recurrence
of a mammary cancer was completely cured. On suspension of
the treatment after several months of daily injunction, the tumor
began to grow again. The resumption of growth on suspension
of the treatment apparently shows that the cure was not a spon-
taneous subsidence of the tumor but was actually the work of the
treatment. Such brilliant results are exceptional. But even in
the only improved cases the inflammatory infiltration may sub-
side and the tumor may cast off necrotic masses, the edge of the
ulceration healing over. Cancers bleeding and suppurating pro-
fusely may have the bleeding and secretion arrested. The tumor
often grows so much smaller that the esophagus or the rectum
may become permeable once more. Pains caused by the infiltra-
tion subside as this retrogresses. In many cases the growth be-
comes operable after a few weeks of Autolysate treatment."

All this, obviously, might have been written of the effects of
administering the vegetable proteins instead of the animal pro-
teins of the autolysates. Note also the following:

"Klinger regards intravenous injection as the most effectual
route. There does not seem to be any danger of an anaphylaxis,
he says, but sometimes the autolysates seem to lose their power.
This can be avoided by changing the material."

The striking analogy here with what has been pointed out in
detail again and again in the present book about wearing out the
effect of one Pro teal and changing to another will be obvious to
every reader. Even more striking are the analogies suggested by
the theoretical explanation offered as to the action of the auto-
lysates, as follows:

"The results of Klinger's own research and experience confirm
the possibility of influencing the growth of a tumor by injecting
certain products of the breaking down of albumin. These auto-
lysates supply the body with ready-made ferment while at the
same time exerting a stimulating action on the blood-producing

246 THE PROTEAL TREATMENT OF CANCER

tissues, whipping them up to increased production of the tumor
cell-destroying substances. As cancers consist essentially of al-
buminoid substances, it seems evident that their retrogression and
absorption depend on the intensification of certain disintegration
processes."

Here, it will be observed, the ideas which furnish the essential
thesis of the present monograph — to the effect that protein an-
tigens stimulate the blood-producing tissues, and that these in
turn produce the substances that destroy the tumor cell — are
stated as if they were matters of common or accepted knowledge.
If Klinger reached these conclusions independently, and without
having seen my papers of October and November, 1914, and
Ocober 2, 1915, his estimate will obviously have peculiar value
by way of corroboration.

I mention this, not because questions of priority have con-
siderable significance or even interest, but because the main thesis
involved has vast importance, and because the judicious reader
cannot fail to be impressed by the fact that certain Swiss physi-
cians working with animal proteins should have obtained results
so strikingly in accordance with results obtained by American
physicians working with vegetable proteins. It does not appear
that Klinger recognizes the response of the blood-forming organs
as essentially a protein reaction, but that detracts nothing from
the corroborative value of his observations.

My own work has been carried forward, as the reader is well
aware, under guidance of an hypothesis — the hypothesis, namely,
that results were attained through the administration of proteins
or protein by-products, as such; that the patient immunized
against one protein may be given a stimulus by the use of another
protein, and ultimately by yet another; and that there is nothing
mysterious connected with the matter, except in so far as all
biological processes are mysterious.

It is vastly important that this thesis should be sustained or
repudiated at the earliest possible moment. All my recent ex-
periences tend to confirm the thesis ; to establish it more firmly in
my mind. In bringing forward the reports of other workers,
therefore, as I am doing in the present section, the only thought
is to present to the reader as wide an array of evidence as possible,
not because there is the remotest element of doubt in my own
mind as to the validity of the argument, but because I am aware
that the discovery in itself seems so simple as to be almost un-
believable; and because, therefore, I wish to fortify this in the
mind of the reader as completely as data at present available
permit.

It is a familiar experience in medicine that innovators appear
to get results with a remedy that others cannot duplicate. There-

THE PROTEIN RESPONSE INTERPRETED 247

fore, I have wished to show that the protein method is one that is
in no wise dependent upon the operation of any individual or com-
pany of individuals. I wish to show that any physician can
utilize the method and get initial results. I wish also, however,
to emphasize the fact that the initial results will not be maintained
in the vast majority of cases, if a single protein is adhered to,
and that it is necessary to follow up the method along scientific
lines, guided by results not only clinical but microscopical (with
especial reference to the relative status of the corpuscles) ; and
to point out that this opinion is not the result merely of my own
experience, wide though that be, but is fortified by the experience
of other workers with proteins, including those who had no
definite idea as to the real character of the work they were
carrying out.

SECTION VI.
THE PROTEIN RESPONSE INTERPRETED

The paper of October 2, 1915, which announced to the medi-
cal profession the introduction of a fundamentally new method
in therapeutics, — namely, the use of non-specific protein antigens
as such, — as interpreted in the light of the Proteomorphic
theory, had to do specifically with the interpretation of the action
of non-toxic vegetable proteins in their relation to malignant neo-
plasms, but clear intimations were given that the therapeutic prin-
ciple believed to be involved had much wider application. The
action of the extract was explained as chiefly due to its protein
content (the relatively non-toxic vegetable proteins acting as anti-
gens to stimulate the enzymic activities of the corpuscles and new
corpuscle-production by the cytogenic apparatus), and the con-
clusion was expressly stated that the remedy "is not merely a
cancer redemy ; it is a remedy against all protein infections."

I further stated the belief that in the attempt to explain the
rationale of the action through which the vegetable proteins bring
about a beneficent increase in the armies of leucocytes and ery-
throcytes, "we shall gain glimpses of an entirely new field of
therapeutics, and shall be enabled to give at least a proximal ex-
planation of the exact manner of action of a remedy, the intro-
duction of which, I believe, constitutes the inauguration of a
method that must in future rank with serum therapy and vaccine
therapy — if, indeed, it does not altogether outstrip or totally sup-
plant both these relatively new additions to the equipment of the
practical physician."

I have elsewhere referred to the sceptical attitude of the pro-
fession toward this confident prophecy. It will be obvious from

248 THE PROTEAL TREATMENT OF CANCER

the words quoted, however, that in my own mind the matter was
perfectly clear. To me it seemed that the Proteomorphic theory
offered through basis for interpretation of the observed phe-
nomena. It has been observed that, following the hypodermic
injections, in cases of inoperable cancer, pain was modified or
annulled, the malodor disappeared, and in many cases the cancer
mass itself was modified in character or progressively decreased
in size.

I had not only observed these clinical changes at first hand,
but had gathered statistical data regarding them (published in
detail in a subsequent article in the New York Medical Journal
of November 13, 1915). • As to the facts, there could be no doubt.
The explanation of the facts seemed to me equally unequivocal.
Scientific caution led me to concede that some other constituent
of the plant extract employed — for example, chlorophyll, lipoids,
or chromophyl — might in a measure be operative. But the chief
action I ascribed unhesitatingly to the protein content; and the
explanation was given in terms of the Proteomorphic theory, in
part as follows :

It is well known that foreign proteins of whatever character,
when introduced into the parenteral system, constitute antigens
that stimulate the body to the producion of defensive enzymes,
that tend to proteolyze the antigen itself and to neutralize its
toxic products. According to the Proteomorphic theory, the chief
agents in the production of these proteolytic and antidotal
enzymes are the white and red blood corpuscles, the latter being
concerned with the end products of the polypeptid order. Ac-
cording to the theory, large numbers of the red corpuscles them-
selves are destroyed in the liver, in the process of eliminating the
toxic end products of protein metabolism from the system. This
explains, for example, the pernicious anaemia that may result
from the absorption of toxins of protein origin, as in bothrio-
cephalus poisoning.

Similar destruction of the red corpuscles, in their attempt to
rid the body of toxins, explains, according to the present thesis,
the pernicious anaemia that generally accompanies malignant neo-
plasms. The animal protein cell does not break down without the
production of toxic molecules, and wherever animal proteins of
any type are being split up parenterally, such destruction of the
red corpuscles must occur, with the result that the cytogenic
apparatus may finally be overtaxed and find itself unable to keep
up the supply.

It seems probable, however, that vegetable proteins, notwith-
standing their chemical similarity to animal proteins, are less
likely to produce toxic by-products during disintegration. It is a
familiar doctrine that animal proteins rather than vegetable are

THE PROTEIN RESPONSE INTERPRETED 249

the source of intestinal putrefactions. There is theoretical war-
rant, according to the Proteomorphic theory, for the assumption
of the less toxicity of vegetable proteins, in the fact that they
doubtless have constituted the food of our ancestors for a much
longer period than have animal proteins. Probably the remote
ancestors of men were eaters of vegetables for millions of genera-
tions before they became eaters of animal foods. And, according
to the thesis under discussion, the toxicity of any type of protein
is directly proportional to the newness, so to speak, or the in fre-
quency with which the organism has come in contact with it.
Toxicity is not a thing per se, but a matter of relativity. In-
herently, all proteins are poisonous to every organism except the
one producing them. A few drops of eel's blood injected into
the veins of a dog will cause death.

Doubtless there is great diversity among vegetable proteins
themselves as to the matter of toxicity ; but the ones actually in-
troduced are of a type to produce a minimum of toxicity while at
the same time acting as vigorous antigens, stimulating the cyto-
genic mechanisms to the rapid production of white and red blood
corpuscles. Doubtless these corpuscles proteolyze the vegetable
protein itself, but in so doing the red corpuscles are not destroyed
in large numbers, because they have a minimum of toxic by-
products to deal with.

The large mononuclear leucocytes, which have been shown to
produce enzymes that are peculiarly active in the splitting up of
cancer cells, are usually found to increase very markedly in the
blood. There is also increase of the lymphocytes, which are
credited with an active share in the splitting up of animal pro-
teins, and of the eosinophiles. The enzymes generated by these
protein fighters begin the disintegration of cancer cells (which,
because of their embryonic character, are more susceptible to dis-
integration than are the cells of normal tissue), and the products
of such disintegration are liberated into the blood stream, where
the red corpuscles, now banded in adequate numbers, continue
the work of proteolysis and elimination.

Of course, the disintegrating cancer cells liberate toxic mole-
cules, and in dealing with these the red corpuscles are of neces-
sity destroyed in large numbers in the liver. But this temporary
reduction in the numbers of the erythrocytes is compensated
almost immediately by the stimulative effects of a succeeding
dose of protein, so that unless the breaking down of cancer
tissues goes forward very rapidly indeed, the aggregate count of
red cells increases from day to day. It is not unusual to find
the count above five million, after the treatment is well estab-
lished. The enzyme-forming capacity of the red cells is probably
increased proportionately.

250 THE PROTEAL TREATMENT OF CANCER

The chill and rise of temperature that mark the characteristic
reaction, and serve as guides to the clinician, probably mark
the period when the cumulative action of the leucocytes has
taxed the blood with more polypeptid by-products than the red
cells can for the moment handle, so that the ranks of the latter
have been momentarily depleted, and the chill gives warning
that the system is feeling the effects of toxicity. But the rise of
temperature is compensatory, since this in itself stimulates the
activity of the cytogenic apparatus, so that in a short time there
are usually enough of the corpuscular defenders present to take
care of the obnoxious protein products.

If compensation does not take place quickly, the delay serves
as a warning to the clinician that he should let a longer interval
elapse before giving the next dose, or administer the remedy in
smaller doses.

If the foregoing reasoning is accepted, it is clear that we can
form a tolerably vivid mental picture of the processes through
which the regression of the malignant tumor is brought about
under the influence of the vegetable protein antigens. The ob-
served phenomenon of the cessation of pain, which is one of the
most uniform and gratifying immediate results, is explicable as
due to the softening and disintegration of the peripheral cancer
cells that have encroached upon the nerve fibrils. The time re-
quired for the pain-annulling effects to make themselves manifest
would appear to depend upon the exact site of the cancer, and
the extent to which its cells have involved the nerves. As the
cancer tissue steadily regresses, it is withdrawn more and more
from interference with the nerves, and the cessation of pain is
lasting.

There is very commonly experienced a sensation of gnawing
or digging at the site of the tumor, which is not exactly agreeable,
but which the patient cheerfully tolerates because he regards it,
doubtless quite correctly, as an evidence that salutary changes
are taking place within the tissues of the neoplasm.

The cessation of odor in superficial ulcerative neoplasms or
in the discharge from uterine or other masses, is readily under-
stood, according to the present thesis, as due to the activities of
the hitherto depleted but now adequate army of red blood
corpuscles. The decomposition products that produce the bad
odor are precisely of the character of the protein products that,
according to hypothesis, the red blood corpuscles deal with
habitually. The odor was, therefore, directly due to the in-
adequacy of the supply of red blood corpuscles, and it disappears
almost as a matter of course when this defect is fully compensated.

VEGETABLE PROTEIN IN CANCER TREATMENT 251

SECTION VII.

VEGETABLE PROTEINS IN CANCER TREATMENT

It seems perfectly clear, and even obvious now, in the light of
later experience, that the above interpretation is valid. But at
the time when it was made, the interpretation was fortified by my
own belief in the Proteomorphic theory rather than by demonstra-
tive evidence. I was presently able, however, to bring forward
substantive evidence of more tangible character through de-
velopment of a new series of antigens of known composition,
made for the express purpose of testing the assumption that the
observed action of the original extract above referred to was
essentially due to its protein content. An analytical laboratory
investigation had been made in which it was shown that each of
the twelve constituents contributed a fractional quantity of pro-
tein to the extract ; but that the major part of the protein came
from the mustard seed, as might be expected.

It was at first contemplated to make clinical observations with
each of the individual proteins, to determine whether any one of
them or any particular combination of them had exceptional value
in stimulating a characteristic physiological response of the or-
ganism. But since this, obviously, would involve an enormous
expenditure of time and labor, it was thought that a short-cut
might be effected by making the provisional assumption that any
foreign protein of non-toxic character might produce an effective
enzymic response. Theoretically, in the light of the Proteomor-
phic theory, it should be so. I determined to find out whether
it was so in practice.

A large variety of vegetable substances were used as the source
of new extracts, among others alfalfa seed, alfalfa meal, hemp
seed, and rape seed, and, later, clover seed, cotton seed, timothy
seed and various others, and sundry foodstuffs.

The practical stimulus to the development of the new proteins
was the fact that in a large number of cases patients suffering
from inoperable cancer who had responded strikingly to the treat-
ment with the original combination of vegetable proteins came
finally to a seemingly static period, at which they snowed notable
improvement over their previous condition, yet now seemed no
longer to respond actively to the stimulus of the remedy. Seem-
ingly they were immunized against further enzymic response to
the particular proteins in question. But there seemed to be at
least a possibility that they might take on fresh response if new
proteins were administered.

This expectation was justified in a considerable number of cases
to which the new proteins have been administered, singly or in

252 THE PROTEAL TREATMENT OF CANCER

combination, during subsequent months. It was found that
patients who were virtually immunized to the combined proteins,
taking large doses without tangible response, showed marked
anaphy lactic reaction when small doses of the new proteins were
administered. Such being the case, it was not surprising that
there should be a corresponding -modification of clinical symptoms
and a characteristic modification of the differential blood count
to which- 1 shall refer more in detail in a moment.

In the New York Medical Journal of November 13, 1915, I
summarized the preliminary results attained in the treatment of
766 cases of inoperable cancer by 152 physicians using the orig-
inal vegetable protein extract.

These were all cases of far-advanced malignancy, mostly post-
operative. Many of them had been X-rayed and radiumed. All
were pronounced inoperable before the protein treatment was
undertaken ; and this treatment was used to the exclusion of any
other. The preliminary results, as tabulated in the article in
question, showed that 16.5 per cent, of the cases in question were
reported as having died ; 19.5 per cent, as being unimproved ; and
64 per cent, as being improved to a greater or less extent.

Following the summary, this comment was made :

"As most of the patients in question have been under treat-
ment for periods of only from two weeks to two months ; and
as by far the greater majority of them were in a very desperate
state at the time when the treatment was undertaken, it must be
admitted that this is a very gratifying showing. It is perhaps
unnecessary to add that, despite the favorable showing, most of
these cases are not as yet at a stage where prediction can be made
as to the ultimate outcome."

It will be of interest, I think, to introduce here in tabular form
a summary of the reports made by a group of co-operating physi-
cians in response to a questionnaire I sent out under date of
October 25, 1915. The letter was accompained by a blank form,
covering details as to the type of cases of inoperable cancer
treated, and the general and special results observed.

This form was sent to about 275 physicians, located in various
parts of the United States. In the course of a few days, replies
were received from 144 physicians. This was perhaps as high a
percentage as could be expected. The number is large enough to
give fairly satisfactory statistical data; and there is no reason to
believe that the essential character of the report would be changed
had the entire number responded. Be that as it may, the reports
received are printed here serially, each bearing the number that
the physician's name bears in my office files. Results are tentative,
but the aggregate report is at least highly suggestive.

VEGETABLE PROTEIN IN CANCER TREATMENT

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253

254 THE PROTEAL TREATMENT OF CANCER

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VEGETABLE PROTEIN IN CANCER TREATMENT 255

256

THE PROTEAL TREATMENT OF CANCER

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VEGETABLE PROTEIN IN CANCER TREATMENT 257

If we summarize the above table, and condense the findings
into a single table aggregating total results, we have the
following :

Total number of physicians, 144, residing in 37 states and in
several provinces of Canada; including 63 members of the
American Medical Association and 29 other physicians who are
members of State Medical Associations.

Total number of cases treated, 284; of which 209 were carci-
nomas, 52 epitheliomas, and 17 sarcomas, 6 being unclassified.

General results of treatment:

(1) Died, 43, or 15.2 per cent, of the total cases.

(2) Unimproved, 60 (21 deteriorated and 39 unchanged), or
21.3 per cent, of total cases.

(3) Improved, 179, or 63.1 per cent.

(4) Of favorable prognosis, out of danger, or clinically well,
48, or 16.2 per cent, of total cases.

(5) Unclassified as to general resuks, two cases.

Results as to special symptoms:

(1) Pain present in 221 cases; favorably modified by treat-
ment in 171 cases, or 77.4 per cent.

(2) Offensive discharge, present in 111 cases; favorably
modified in 96 cases, or 85.6 per cent.

(3) General health of patient: Seemingly uninfluenced by
treatment in 77 cases ; favorably modified as to appetite, sleeping,
color, weight or strength in 180 cases, or 70 per cent.

(4) Mental attitude: Seemingly uninfluenced in 74 cases;
favorably modified in 180 cases, or 71 per cent.

(5) Condition of the neoplasm: Seemingly uninfluenced in
79 cases, or 27.8 per cent. ; favorably modified in 171, or 60
marked regression in size in 76 cases, or 26.8 per cent.

Dealing, as the statistics do, with supposedly hopeless cases,
in the presence of which the physician has hitherto stood power-
less, and with symptoms mostly not susceptible of amelioration
by any agency hitherto available, this is a showing that is amazing
and enheartening.

In- the period of thirty -months that has elapsed * since the
reports thus tabulated were received, I have been constantly in
touch with a considerable number of physicians who 'have used
the Proteals in the treatment of inoperable cancer. Their reports
have come in the form usually \}f personal letters, — letters not de-
signed in any case for publication, and for the most part written
in the interest of the individual patient, asking advice as to some
detail of treatment very commonly, and containing expressions
of opinion as to the progress of the case of precisely the character
a practitioner would make in seeking the advice of a special con-
sultant.

258 THE PROTEAL TREATMENT OF CANCER

It must be evident, I think, that reports made under such cir-
cumstances have peculiar value. In the nature of the case, they
are candid, frank, and uncolored.

On the other hand, it must be borne in mind that, by the same
token, these men are for the most part not specialists of wide
experience in the treatment of cancer cases. A number of them
are such, to be sure, but in the main the physicians of the group
under consideration are general practitioners. But in a way
that makes their testimony all the more important, inasmuch as
it shows what the new line of treatment may be expected to
accomplish in the hands of the average practitioner. One of the
greatest merits of the Proteal treatment is that it enables isolated
physicians, in the remotest hamlets, to do something tangible and
definite toward ameliorating the condition of the cancer patient
who has passed beyond the reach of the surgeon.

Thanks to the new treatment, the most inexperienced practi-
tioner can do more to-day for the amelioration of the condition
cf a late stage, inoperable cancer case that could hitherto be
accomplished by the most experienced practitioner in the best
metropolitan cancer hospital.

The substantial unanimity of opinion as to the character of
results attained in their own practice by some hundreds of phy-
sicians scattered about the country, and in foreign countries, is
so striking a phenomenon that it is susceptible of but one inter-
pretation. It is impossible that all these men should be mistaken.
Their individual observations, when aggregated, pile mountain
high the evidence that the proteal treatment has remarkable effect
in relieving pain of the inoperable cancer subject; removing the
bad odor of cancerous discharges; improving the general health
of the patient ; and conspicuously modifying the condition of the
malignant neoplasm.

After carefully scrutinizing the evidence, it is difficult to avoid
the conclusion that these beneficial effects of the proteal treat-
ment, in varying degree, may be observed in an overwhelming
proportion (not less, in my opinion, than 80 per cent.) of cases
of inoperable cancer, wherever located, in which the remedy is
administered in .suitable doses.

This, it will be observed, postulates nothing as to the ultimate
effects of the treatment. It says nothing as to the "cure" of
cancer. As to that, I shall have something to say in detail a
little later. Here it suffices to note that the records under con-
sideration tell of definite and unequivocal improvement of the
most tangible character in a large proportion of cases ; such im-
provement amounting in a certain number of cases to seeming
clinical recovery.

THE BLOOD IN CANCER SUBJECTS 259

SECTION VIII
THE BLOOD IN CANCER SUBJECTS

It will be recalled by those who have read the original presenta-
tion of the Proteomorphic Theory that the theory ascribes to the
lymphocytes in the blood the function of beginning the decom-
pounding of protein molecules. It will be recalled also that ex-
periments (of Vaughan) are cited which seem to show that the
large monocytes have power to produce enzymes that bring about
the decompounding of cancer cells.

It is of pecular interest, then, to inquire as to the modifications
of the blood count that are associated with the cancerous con-
dition, and the further modifications that are brought about by
therapeutic application of protein antigens.

It has long been recognized by pathologists that there are
marked modifications of the blood count in nearly all cases of
malignant disease. Most observers have been content to note the
reduction of the haemoglobin index and of the red blood count,
and the marked leucocytosis that usually characterizes the condi-
tion, at least in its advanced stages. A number of observers,
however, have fortunately made more elaborate studies, and rec-
ords are available in the literature covering a considerable body
of cases in which complete blood counts were made that furnished
the basis for a comparative study in connection with the original
observations that I am about to record.

Dr. Price Jones has published detailed results of the study of
29 cases of cancer, including carcinomas of the breast, stomach,
intestine, generative organs, tongue, and larynx, and variously
located sarcomata. His results show an average of 3,838,000 red
blood cells and 10,409 white cells to the cubic millimeter. The
differential count showed 73.7 per cent, of polynuclears, 10.38
per cent, large monocytes, and 13.6 small lymphocytes. Eosino-
philes and basophiles are not recorded, but by exclusion are shown
in the aggregate to represent 2.32 per cent, of the leucocyte census.

Another interesting series of cases comprises cancer in which
there were bone matastases, recorded by different observers, and
aggregating 22 cases fully reported. Here the average red blood
count was found to be 2,808,000 ; the average white blood count,
14,214 (increased by the presence of a few cases in which the
leucocytosis was extreme). The differential count shows 58.11
per cent, polynuclears ; 14.89 per cent, large monocytes ; 25.86 per
cent, small lymphocytes; 0.87 per cent, eosinophiles ; and .027
per cent, basophiles. A considerably modified average is found
if we consider only the first count in each of the 22 cases, the re-
sult being: red corpuscles, 2,744,000; white corpuscles, 11,500

260

THE PROTEAL TREATMENT OF CANCER

(the aberrant case being omitted); poly nuclear s, 65 per cent.;
large monocytes, 11.7 per cent; small lymphocytes, 22 per cent.;
eosinophiles, 1 per cent.

These results may be compared with the table, herewith pre-
sented, of our own untreated cases. It will be seen that there is
close general agreement. I would call special attention to the

TABLE II— THE BLOOD COUNT IN CANCER
TWENTY-NINE CASES OF DR. PRICE JONES \t THE MIDDLESEX HOSPITAL, ENGLAND

Nature of Case

No.
of
Cases

Red
Blood
Corpuscles

White
Blood
Cor-
puscles

Poly-
nuclears

MONONUCLEARS

Large

Small

9
7
2
6
1
1
4

4,230,000
3,770,000
4,600,000
4,160,000
3,780,000
2,400,000
4,490,000

10,400
9,700
14,600
14,280
18,600
6,300
10,930

7,115
7,070
11,478
10,038
13,974
4,365
. 7,847

1,324
835
1,446
1,671
1,711
819
1,158

1,661
1,598
1,490
2,103
2,845
1,091
1,694

Card, of the Stomach
' of the Intestine

' Generative Organs
' of the Tongue

" of the Larynx

Weighted averaged of 29 cases.

3,838,000

10,409

7,664

73.7%

1,077
10.38%

1,421
13.6%

TABLE III— TWENTY-TWO CASES OF CANCER WITH BONE METASTASES
REPORTED BY DIFFERENT PHYSICIANS

Observer

Hemo-
globin

Red
Blood
Cor-
puscles

White
Blood
Cor-
puscles

Poly-

nu-
clears

MONONUCLEARS

Eosino-
philes

Baso-

philes

Large

Small

1. Hawley

75
62
49

35'
60
15
25
60
21
40
105
46
65
50
115
85
56

45'
20
50

3,172,000
2,751,000
2,300,000
1,056,000
1,600,000
1,940,000
1,550,000
1,825,000
4,320,000
900,000
1,984,000
4,452,000
2,168,000
4,760,000
4,920,000
4,725,000
5,615,000
3,850,000
3,020,000
2,150,000
1,000,000
3,000,000

7,300
2,500
6,700
10,200
14,000
3,500
20,000
9,100
19,700
9,220
16,400
7,600
6,000
10,800
9,000
3,700
8,500
20,300
120,000
22,000
30,000
6,000

63.0
56.4
54.0
78.0
63.0
60.0
66.0
48.5
86.1
64.5
82.0
58.6
66.0
50.7
68.9
51.0
68.0
60.0
96.17
59.0
78.8
56.7

10.0
20.0
9.2
9.5
17.6
14.0
12.0
31.4
7.0
19.0
8.7
4.6
8.2
17.4
6.5
4.6
11.4
14.0
1.25
8.5
15.6
12.7

27.0
19.6
36.2
11.0
16.7
21.0
22.0
19.2
6.2
15.0
8.2
35.1
19.0
31.2
23.3
42.2
21.4
23.0
2.16
31.0
4.6
30.5

0
1.6
0.6
1.6
0.7
4.0
0
1.0
0.7
1.0
1.2
0.8
0
0.6
0.8
0.4
0.2
3.0
0.42
1.0
0.5
0.1

0
0
0
0
0
0
0
0
0
0.5
0
1.6
0
0
0.5
1.8
0
0
0
0.5
0
0

2. Harrington
8. Houston

4. Parkes
6. Harrington
6. Parmentier
7. Wolfer

8. Kurpjuweit
9. Kurpjuweit
10. Frese

11. Schleip
12. Schleip ..

13. Naegeli...

14. Ward
15. Ward...

16. Ward

17. Ward
18. Ward
19. Kast
20. Turnbull
21. Hirschfeld
22. Bloch

53.3

2,744,000

11,500

65.26

11.7

22.06

1.0

0.2

column showing the percentages of large mononuclear leucocytes.
Recalling that in normal blood the large monocytes number only
2 or 3 per cent., as a rule, with perhaps 5 per cent, as maximum,
it will be noted that in Price Jones' series of cases these cells num-
ber 10.35 per cent, of all leucocytes ; in 22 cases of bone metasta-

THE BLOOD IN CANCER SUBJECTS

261

ses, as first counted, they number 11.7 per cent.; in one of our
series (26 cases) they number 13.5 per cent., and in another of our
series (22 cases) they number 14.05 per cent. It should be under-
stood that the large mononuclear leucocytes do not constitute a
homogenous group. They include, in an ordinary cancer case, not
only large lymphocytes and normal large monocytes (the macro-

TABLE IV — ORIGINAL CASES
THH BLOOD COUNT m 26 UNTREATED CASES OP INOPERABLE CANCER

Case No. |

Name

Nature of Case

j

Red
Blood
Corpus-
des

White
Blood
Cor-
pus-

cles

ll

Mono-
nucleara

it

1

Large

Small

846
361
378
335
310
394
349
333
316
356
375
327
358
224
325
344
362
331
312
355

341
339

Mrs. C....
Mr. C
Mrs. DeB..
MissD
Mr. E
Mrs.L.....
Mrs. G
Mrs.H....
Mr. K
Mr. L
Miss Me...
MisaM....
Mr. U
Mrs.S
Mr. S
Mrs.S
Mrs. St....
Mr. S
Mrs. Y
Mrs.S
Mr. M
Mr. G
Dr. L
Dr. McG..
Mr. P
Mrs.T

Card, of Breast...
" " Jaw

90
90
100
80
65
100
95
85
75
85
90
90
95
95
85
90
85
70
46
85
45
90
100

95

85

4,630,000
4,568,000
4,272,000
2,464,000
3,920,000
5,280,000
4,564,000
3,824,000
4,096,000
4,640,000
3,872,000
5,160,000
5,272,000
5,088,000
4,288,000
4,684,000
4,016,000
3,744,000
2,730,000
3,376,000
1,424,000
5,360,000
4,096,000

4,992,000
4,920,000

9,320
6,230
8,000
10,650

9,566
7,700
8,650

9,880
7,880
9,220
7,550
9,000
7,240
9,220
8,100
9,780
16,600
8,660
11,550
8,430
10,000

9,800
9,680

63
77
57
70.6
82
65.5
46.6
50
61
75.5
70.6
64
52.5
78
77
80.6
71.3
67
66
74.3
68
57
67
79.3
62
53.3

12
9.6
18.3
8.6
11
10
13.6
19
23
12.3
13.3
12.6
20.75
13
8
12.6
13
10
16
14.3
8
20
13.5
9
9
21.3

25
13
21.6
7.6
6
20
39
28
15
12.3
14.6
21.6
21.5
6.5
15
6.6
15
23
16
10.3
22
21.5
9.5
6.6
22
25

0
.3
3
2.6
1
4
.6
3
1
0
1.3
1.6
4.75
2.5
0
0
0
0
2
1.3
2
1.5
10.
4.6
7
0.3

0
0
0
0.3
0
0.5
0
0
0
0
0
0
0.5
0
0
0
0.6
0
0
0
0
0
0
0
0
0

" "Uterus
" " Breast

" " Bladder
" Breast

" " Uterus
" Breast

Epithe. of Palate
Card, of Stomach
" Breast
" "Mediastinum..
Sarc. of Peritoneum
Epithelioma
Card, of Larynx
" " Breast

" " Coscum
Mixed Parotid Cancer...
Card, of Uterus
" "Intestine
Doubtful Diagnosis
Card, of Uterus

Ep. of Tongue
Card, of Stomach

Average for abov
Average for 22 ca
Weighted average
Unweighted "

e26 cases
ses in Table VI

81.4
81.9
s:}.2
73.2

4,258,000

4,271,000
4,264,000
3,777,000

9,240
8,840
9,080
10,000

67.5
67.95
67.72
68.6

13.5
14.05
13.77
12.45

17

16
16.6
17.16

2
1.69
1.8
1.56

.07
.07
.07
.11

a for 48 cases
" 99 "

The above 26 blood counts of cases of inoperable cancer constitute a fairly representative
group, presented here together because they chance to be cases in which only a single blood
count was made. They are otherwise unselected. The averages of this group may advanta-
geously be compared with those of a second group of untreated cases detailed in Table VI. A
combination of these charts gives the averages for 48 untreated cases of inoperable cancer.
For purposes of comparison, the averages of the 29 cases of Price Jones and the 22 cases of
bone metastnses reported by various investigators are also presented. It will be seen that
there is dose general agreement. The relatively low red corpuscle count in the bone cases may
perhaps be due in part to direct involvement of the marrow. The Price Jones cases were
hospital cases. The original cases were ambulatory, although late stage inoperables. Thus
we have a fairly representative group of 99 cases, and, in so far as any generalizations are
justified from so small a number, we may take the grand average as suggesting a typical blood
picture in advanced stages of the cancerous condition.

phages of Metchnikoff), but myeloctyes (neutrophile, eosinophile,
and occasionally basophile), leucoblasts, and lymphoidocytes.
For the moment, however, it will be convenient to group all of
these together, in consideration of their probable similarity of
origin, and their obvious similarity of structure,

262 THE PROTEAL TREATMENT OF CANCER

Striking the (unweighed) average for these 99 cases, we find
the large mononuclears (of these various groups) aggregated to
represent 12.45 per cent, of the total leucocyte count. This is
about two and a half times the normal maximum percentage ; and
it would appear that we may accept some such modification as
this of the large monocyte count as typical of advanced cases of
malignant neoplasms. Individual cases, as a matter of course,
show exceptions, but there appear not to be more than five or
six cases in the entire 99 in which the count of large monocytes
was found as low as the normal maximum limit.

We are justified, then, I think, in regarding a marked increase
of the large monocytes as a typical manifestation of the presence
of malignant neoplasms in an advanced stage. These clinical
observations in the human subject find support, it may be added,
in Price Jones' observations of cancerous mice in which also a
very marked increase of the large monocytes was noted. It should
be observed, however, as having interest in another connection,
that the percentage of large monocytes in the blood of the normal
mouse is far higher than in the human subject. The figures
given by Price Jones are, for normal mice, 21.5 per cent.; for
cancerous mice 32.2 per cent, of the total leucocyte count.

The question at once arises as to whether the observed increase
of large monocytes in the cancerous condition is to be regarded
as a part of the disease process, or whether, on the other hand,
it manifests a salutary modification indicating nature's attempt to
combat the invasion of the lawless cancer cells.

In view of the known functions of the leucocytes in guarding
the body against bacterial invasions, we may, I think, unhesitat-
ingly accept the increase of leucocytes in general in the cancerous
condition, and of the large monocytes in particular, as represent-
ing a salutary process. The fact that Vaughan's experiments
showed that enzymes produced by the large monocytes bring about
at least partial decompounding of cancer cells naturally comes to
mind in considering the observed fact of the increase of these
monocytes in the cancer subject.

It seems at least a justifiable inference that the presence of the
cancer cells has directly stimulated the production of large mono-
cytes, just as the presence of foreign pathogenic bacteria stimu-
lates the increased production of phagocytic polymorphs.

If this view is accepted, it is permissable to suppose that in a
very large number of cases incipient malignant neoplasms are
nipped in the bud, so to speak, by the activities of the large mono-
cytes ; and that the presence of a tangible cancer demonstrates the
fact that, in this individual case, the body has been unable to pro-
duce the defending corpuscles in adequate numbers to overmaster
the invading cancer cells ; although, at the same time, it must be

THE BLOOD IN CANCER SUBJECTS

263

observed that the presence of the increased number of monocytes
shows that the bodily organism has not given up the fight.

THE BLOOD COUNT AS MODIFIED BY PROTEIN ANTIGENS

When charts, based on the study of original cases, showing
the results of such blood counts in about 150 original cases under

TABLE V — ORIGINAL CASES

48 UNSELECTED CASES APTER AN AVERAGE PEBIOD OP 102 DATS OP PBOTEIN
TREATMENT.

Case No. I

Name

Nature of Case

No. of Days

j

Red
Blood
Corpus-
cles

White
Blood
Cor-
pus-
cles

tj

Mono-
nuclears

it

j

Large

Small

106
311

271
223

135
133
167
8
192
353
305
88
209
186
261
250

221

395
307
48
326
207
372
40
165
264
283
259
268
274
281
298
43
24
208
159
407
25
32
47
247
382
44

Miss A...
Mrs. A...
Miss A...
Mrs. B...
Mrs. B...
Mr. B ...
Fr. B....
Mrs. B...
MissD..
Mrs. D. .
MissD..
Mrs. D. .
MissE...
Mrs. E...
Miss P.. .
Mr. F...
Mrs. G...
Mrs. G..
Mrs. H. .
Mrs. H. .
Mr. H...
Miss K..
Mr. K...
Mrs. K. .
Mrs. L...
MissL...
Mrs.L...
MissMcG
Mrs. M..
Sr. M....
Mr. N...
Mrs.Q...
Mr. R...
Mrs. S...
Mrs.S. .
Mr. S.. .
Mrs.S. .
Mrs.S. .
Mrs. S. .
Mrs. T. .
Mr. V. .
Mr. W. .
Mr. W. .
Miss W .
Mr. W...
Mrs. Wn
Mr. Wk..
Mrs. D..

Thyroid. ..

195

4

IB
(i!»
40

84
84
7:{
205
18
59
15
Jll

r,n
90
52
144

65

61
68

111
75
9(i
98
201
101
151
84
137
52
88
42
1!»
131
ll:(
9H
75
6<

2ir

22<
119
62
6(
19(

00
90
00
65

85
90
95

oo

85
90
85
90
80
00
00
85
85
95
SO

90
00
75

00
90
00
95
00
75
90
00
95
70
70
80
81
90
90

100
100
95

80

6(

95
95

5,376,000
5,250,000
4,480,000
3,328,000
4,064,000
5,600,000
5,296,000

5,632,000
4,370,000
4,032,000

4,640,000
2,848,000
5,440,000
5,600,000
3,976,000
5,000,000
4,032,000
4,032,000
5,320,000
4,490,000
5,440,000
3,840,000
5,296,000
4,928,000
4,040,000
4,576,000
4,524,000
4,960,000
4,028,000
4,784,000
5,308,000

3,400,000
2,168,000
3,856,000
4,160,000
5,450,000
4,496,000
4,620,000
5,664,000
5,728,000
4,250,000
3,440,000
3,804,000
5,324,000
4,444,000

8,000

6,700
10,250

8,400
8,100

6,400

6,500
9,620
7,300

8,000
7,700
9,340

7,200
11,300

7,220
7,100

5,720
6,600
8,300
9,200
7,100
6,300

6,400

7,930
7,800
8;330

7,000
9,000
7,600
10,250

7,500
6,700

61.5
66.5
58
79.3
80.6
45.5
55.6
67
55.5
66
43
64.3
58.5
77.6
60
70
57
72
47.5
67
74
62
62.5
68
50
62
52
55
49
52.5
59.6
62
77
62.5
84
68.5
70
62
64
61.25
78.5
77
68
73
77.6
63.5
44.3
54

20
19
13.5
8.3
10.6
35
20
16
24.5
18
24.5
16
24
13.6
20
14.5
8.3
11.6
24
13
13.3
23
14
11
15
22.5
15.6
20
19.6
21.5
20
23
14
24
4
11.5
11.6
12
14
15.5
15
9
15
11
13.3
15.5
30.3
25

15
22.5
23
10.6
8.6
10
20.3
16
18.5
14
29
17.3
16.5
5
18.5
13
33.3
12.6
25
18
11.6
13
18.5
20.5
35
14.5
24.6
16.5
26
24.5
9.3
14
7.5
12.5
8.6
14
10
26
21
18
6
13
16.5
15
6.3
18.0
23.5
16.5

16.8

3.5
2
4.5
1.6
.6
4
3.3
1
1.5
2
3.5
3.3
1
3.6
.5
2
.3
3.6
2.5
1
1
2
5
.5
0
1
7.6
8
5.5
1.5
1
1
1
1
2.6
6
2.6
0
1
3.75
.5
1
0.5

2.6
2.
2.3
4.5

.5
.6
0
0
0
)
0
0
0
0
.5
0
0
0

1

0
0
0
0
0
0
0
.5
0
0
0
0
.5
0
.6
0
0
0
0
1.5
0
0
0
0
0
0
0
0

Thyroid

Thyroid

C. of Uterus
Tuberculosis

Diabetes
Carci. of Breast

Thyroid
Carci. of Breast

Thyroid
Carci of Breast

Thyroid

Carci of Breast

Thyroid

Thyroid

C. of Uterus . . .

Thyroid

C. of Intestine

Thyroid . .

Indigestion

C. of Uterus
Thyroid

Thyroid

Thyroid
Thyroid
C. of Breast

" " (Esophagus
" " Breast
Toxaemia
Endoth. of Throat
Carci. of Uterus
Sarc. Testicle
Carci. of Breast
Thyroid
Carci. of Breast

Thyroid
C. Mediastinum

Thyroid...
Thyroid
C. of Tongue
C. of Breast

Rheumatoid Arthritis. . .

Averai

;e

102

89

4,673,000

7,830

63.4

16.9

2.33

-1

protein treatment were available, it was at once evident that there
were very striking and characteristic modifications of the dif-
ferential count coincident with the administration of the vege-
table proteins; and that these were curiously similar to changes
coincident with the administration of an anti-thyroid serum.

264 THE PROTEAL TREATMENT OF CANCER

A typical, yet somewhat extreme, case, for example, was that
of a patient suffering from carcinoma of the throat whose blood
on the 8th of October, 1915, at an early stage of the treatment
showed 7.3 per cent, of large mononuclears to 18 per cent, of
small ones ; and whose count about six weeks later (on the 22nd
of November) was almost precisely reversed as regards these
particular elements, showing 18.3 per cent, of large mononuclears
to 7.6 per cent, of small ones.

Other specific cases show the proportion between large and
small mononuclears as follows : 19 to 20.6 at an early stage of
treatment and 34 to 11.5 at a later stage; 14 to 31.6 at an early
stage, and 27.75 to 15 at a later stage; 9 to 16 at an early stage,
and 21.5 to 8 at a later stage; and 10.5 to 29 at an early stage,
against 31 to 15.5 after three months of treatment.

A typical thyroid case showed the balance between large and
small mononuclears as 8 to 19.6 on the 12th of October, and
shifted to 25 to 19.5 on the 17th of December, after two months
of use of anti-thyroid serum.

It seems a fair inference that, since vegetable proteins on one
hand and anti-thyroid sheep serum on the other produce precisely
the same results in human subjects that Vaughan observed in
case of the sheep inoculated with cancer tissue, the principle in-
volved is the response to the protein antigen as such rather than
a specific response to any particular type of protein.

This, it will be observed, would be fully in keeping with the
assumption that the mononuclear leucocytes are the agents chiefly
involved in beginning the decompounding of foreign proteins in
general when brought in contact with the blood.

Be the theoretical explanation what it may, however, the thing
that has peculiar significance in the present connection is the ob-
served fact that the hypodermic administration of proteins (inde-
pendent of any other treatment) has been demonstrated to bring
about a very marked modification of the leucocyte count, in the
direction of the increase of the large mononuclears. Cases in
which no favorable modifications of this kind have taken place
under Proteal treatment have not been observed to make favor-
able clinical progress.

Fairly typical of desired results in case number 348, who on
the 15th of October (before beginning treatment) had a haemo-
globin index of 80 per cent., a red count of 3,168,000, a white
count of 9,880; with 78.6 poly., 10.6 large monocytes and 8.3
small lymphocytes; and who on the 1st of December showed a
haemoglobin index of 90 per cent., a red count of 4,944,000, and
a white count of 7,500; with 66.5 per cent, poly., 21 per cent,
large monocytes, and 10 per cent, small lymphocytes.

THE BLOOD IN CANCER SUBJECTS

265

TABLE VI— ORIGINAL CASES
BLOOD COUNT IN 22 CASES OF INOPERABLE CANCER BEFORE TREATMENT

| Case No. II

Name

Nature of Case

H*m-
*

Red
Blood
Corpus-
cles

White
Blood
Cor-
pus-
cles

A

Mono-
nuclears

II

I

Large

Small

369
888

3(iO
315
309
381
313
354
359
322
371
332
317
318
3M
37(3
301
318
287
399
371
317

Mrs.B...
Mrs.C....
Mr. D
Mr. D
Dr. G
Mra.H....
Mrs. K...
Mrs. M
Mrs. Me...
Mr. N
MissN....
Miss V
Miss W
Mr. E
Mr. Me. . . .
Mrs. T....
Mrs.B.. .
Mr. E
Mr. H
Mrs. M
Mr. T
MissW

Carci. of Breast

Epithe. of Jaw. .... . ! .
Carci. of Larynx

90-95
90
90
90

100

4,480,000
3,976,000
3,776,000
4,668,000
5,056,000
4,752,000
4,960,000
5,064,000
3,608,000
3,212,000
4,456,000
5,008,000
4,137,000
3,168,000
4,704,000
4,600,000
4,200,000
3,168,000
3,592,000
5,120,000
4,130,000
4,137,000

8,220
9,330
7,880
8,350

7,600

8,i50
9,100

7',906
8,880

9,880
5,250
8,300

9,880
13,500
9,300
10,000

61
65.6
51
79
75
80.5
61.5
73.3
63.6
74
65
64
66.6
78.6
74
70.3
48
78.6
81.6
75.5
53.6
63.6

14
14.3
17.5
15
17
7.6
23.5
12.6
16.3
9
15.6
16
14.3
10.6
15
12
18
10
7
15
15.6
14.3

31.6

17.3
23.5
6
6
8.6
14
13
18
17
16.3
24
20.6
8.3
11
15.2
31
8.3
11.3
8.5
23.3
20.6

2.6
2.3
7.75
0
2

;i.3

1
1
2
0
3
0
.6
2.3
0
2
0
2.3
0
1
8.8
0.6

.6
.3
.25

.6
.3

0
0.3
0.6

Sarc. Abdomen

Carci. of Breast

Epithe. of Face.."!.'.'.'
Carci. of Breast

90
95
90
60
90-95
85
85
80
90
85
80
80
80
95
85
85

" " Stomach. ....
Epithe. of Mouth
Car. Gall Bladder
Carci. of Larynx
" Stomach
Sarc. of Testicle
Carci. of Breast

Sarc. of Jaw
Care, of Breast

Average

81.9

4,271,000

8,840

67.95

14.05

16

1.69

.07

THE SAME 22 CASES AFTER AN AVERAGE PERIOD OF 41 DAYS OF PROTEAL TREATMENT

4

£

3

T ' 1

White

Mono-

$

I

Q

.5

Hed
Blood

Blood

£>i

nuclears

i 8

^

I

Name

Nature of Case

•5
6
X

I

Corpus-
cles

Cor-
pus-
cles

1!

jl

1

Large

Small

369

Mrs. B . . .

Carci. of Breast

21

100

5,724,000

6,500

45.3

32

18.3

3

1.3

368

Mrs.C....

29

95

4,112,000

8,500

64.6

19

12.3

3.6

.3

360

Mr. D

EP. of jaw .....;.;;

89

95

4,384,000

6,600

52.6

17.3

20.6

9

.3

345

Mr. D

Card, of Larynx... .

21

90

4,720,000

7,880

73

16.6

5

4.6

0

309

Dr. G

Sarc. of Abdomen .

11

3,412,000

7,850

59

22.5

16

2.5

0

381

Mrs.H....

Melanoma

30

166

4,500,000

8,200

81

12.5

5

1

.5

313

Mrs. K

Card, of Breast . . .

80

100

5,564,000

8,000

60

19.3

17.3

3.3

0

354

Mrs. M

7:J

100

5,500,000

7,800

60

23

14

2

1

359

Mrs. Me...

41 Cl tl

57

100

4,384,000

7,200

59

16.5

19

4.5

.5

322

Mr. N

Ep. of Face

71

85

4,192,000

7,700

51.5

19.5

26.5

2.5

0

371

MissN....

Carci. of Breast

84

95

4,352,000

8,600

59.5

16.5

21

8

0

332

Miss V

90

100

5,656,000

8,900

48.5

27

20.5

4

0

317

Miss W. . . .

«< « «

88

85

4,944,000

7,330

56.6

21

18.6

3.6

.3

348

Mr. E ...

" Stomach '. '. '.

47

!)()

4,944,000

7,500

66.5

21

10

2.5

0

314

Mr. Me... .

Ep. of Mouth

81

85

4,888,000

8,650

68.3

19.3

11.6

.6

0

376

Mrs. T

C. Gall Bladder

62

100

4,896,000

9,600

62

15.5

19.5

2.0

0

301

Mrs. B

Card, of Larynx

82

90

3,724,000

7,270

75

14

11

0

0

348

Mr. E

"Stomach...

48

90

4,944,000

7,500

66.5

21

10

2.5

0

287

Mr. H

Sarc. of Testicle

4

85

3,256,000

8,500

73

12.3

14.0

0.6

0

399

Mrs. M... .

Carci. of Breast

8

100

4,896,000

9,500

69.5

14.5

13.5

1.5

0

374

Mr. T

Sarc. of Jaw

32

95

4,864,000

8,300

70.5

18.

6.

5.5

0

317

Miss W

Card, of Breast

86

85

4,944,000

7,330

56

21

18.6

3.3

0.3

Average

40.4

93. r

4,667,000

8,000

62.6

19.06

14.94

2.95

0.2

Modification of the blood count following the administration of fairly vigorous Proteal
treatment. Particular attention is called to the notable increase in the large mononudears.
Such a modification is certainly one of the most characteristic, and perhaps the most impor-
tant, of the changes brought about by the proteal treatment. Note also the increase in
haemoglobin and in red corpuscles, and the decrease in white corpuscles as a whole and in the
percentage of polynuclears.

These cases are grouped together simply because they are cases in which an original blood
count, made before treatment, was supplemented by a subsequent count after treatment.
They are otherwise quite unselected, and are strictly comparable to the cases shown in the
earlier chart. The blood picture of the treated cases shows wide departure from the type-
picture supplied by the 99 untreated cases.

266 THE PROTEAL TREATMENT Of CANCER

The average results of fourteen unselected cases under the
protein treatment are summarized thus: At the beginning of
treatment haemoglobin index 89 per cent., red corpuscles 4,500,-
000, white blood corpuscles 8,878 ; with 68 per cent, polymorphs ;
14.9 'per cent, large monocytes ; 14 per cent, small lymphocytes ;
.65 per cent, eosinophiles ; and 0.32 basophiles. At a later stage
after an average of 42 days of protein treatment, haemoglobin
index 96 per cent.; red corpuscles 4,930,000, and white blood
corpuscles 8,107; with 62 per cent, polymorphs; 18 per cent,
large monocytes ; and 16 per cent, small lymphocytes ; 3 per cent,
eosinophiles ; and 0.35 basophiles.

SOME PRACTICAL HINTS

It is almost axiomatic to say that observation of the blood
count must in future be regarded as indispensable as a guide to
dosage and frequency of administration in carrying out the pro-
teal treatment of cancer. This is particularly true, however, after
treatment has been continued for a period of five or six weeks.

Up to that time, there is almost certain to be favorable progress
of the case if the remedy is pressed pretty actively from the outset,
the doses being carried to the point of securing a pronounced gen-
eral reaction on at least one occasion, and subsequently modified
so that there is a mild reaction.

During this stage, there will usually be observed a pronounced
increase of red blood corpuscles; but this is no more notable than
the lymphocytosis, with marked preponderance of the large cells.

It should be observed, however, that the activities of the mono-
cytes in beginning the decompounding of cancer cells may be so
great as to put so severe a tax on the energies of the red blood cor-
puscles that their numbers will be for a time materially reduced,
even when the case is progressing favorably.

A very good illustration of this is furnished by case 309, in
which there was a large abdominal sarcoma located near the spine,
which had been declared irremovable after an exploratory incision.
On the 19th of September, 1915, two days after beginning the
Autolysin treatment, this patient showed a red blood count of
5,066,000 ; with 75 per cent, polymorphs, 17 per cent, large mono-
cytes ; 6 per cent, small lymphocytes and 2 per cent, eosinophiles.
Two weeks later the red blood count had decreased 3,412,000; but
in the meantime the polynuclears had decreased to 59 per cent. ;
there being now 22.5 per cent, large monocytes, 16 per cent, small
lymphocytes, and 2.5 per cent, eosinophiles.

Taken by itself, the decrease in red blood corpuscles might seem
alarming; but that the above interpretation of this decrease is
correct is suggested by the fact that the patient went ahead stead-

THE BLOOD IN CANCER SUBJECTS 267

ily and rapidly to clinical recovery with apparent entire regression
and disappearance of the tumor, so far as could be determined
by palpation. The case was supposed to be hopeless by the sur-
geon who attempted the operation; yet progress was so spectac-
ular under the protein treatment (exclusively) that a few weeks
later the patient returned to his home and took up once more his
accustomed work as a practising physician.

Such a reduction in the red blood corpuscles under the Proteal
treatment as that just noted would be regarded with equa-
nimity, however, only where there was, as in the instance cited, a
large tumor mass undergoing rapid disintegration. And even then,
it is questionable whether, as a rule, it would be desirable to carry
forward the disintegration of the tumor mass so rapidly as to
produce a marked reduction in the red blood corpuscles. A bet-
ter way, ordinarily, would be to regulate the dosage so as to
secure only such amount of hydrolysis of cancer cells as can be
dealt with by the red blood corpuscles without reducing their
ranks much below the five-million mark.

Cases are reported where the dosage of proteins was pressed
so actively from the outset that the breaking down of a pelvic
cancer was effected so rapidly that the system could hardly have
been expected to withstand the shock had there not been oppor-
tunity for exterior discharge and drainage. One physician de-
scribed the results attained in such a case as reminding him of
the effects of a curette, so rapid was the removal by exfoliation
of the cancer tissue.

In such a case, there is obvious danger of severe hemorrhage.
This danger would be obviated, at least in a measure, if the dosage
were so regulated that the decompounding of the cancer cells was
less rapid.

I have elsewhere pointed out that the critical period in the
treatment of cancer cases comes after an interval of several
weeks, when the systemic response has been carried to the maxi-
mum. Almost invariably, the question then arises as to the best
manner of continuing treatment, in order that the effects may be
cumulative, and the case carried to the favorable termination that
seemed promised by the early response.

It is now that constant appeal should be made to the microscope
to determine the precise status of the red blood corpuscles and
the various leucocytes. An endeavor should be made to keep the
former as near as possible to the five-million mark ; while it is to
be hoped that the lymphocytes will continue to represent at least
one-third of the leucocyte count, and that the large mononuclears
will outnumber the small ones.

A typical satisfactory blood count is shown by patient number
239 (carcinoma of the breast), whose blood on the 8th of Janu-

268

THE PROTEAL TREATMENT OF CANCER

ary, 1916, after about six months' treatment, showed 100 per cent,
haemoglobin, 5,096,000 red blood corpuscles, and 8,000 leucocytes
with 60 per cent, polys., 23.5 large monocytes; 13 per cent, small
lymphocytes; 2.5 eosinophiles, and 1 per cent, basophiles.

At the time when this count was made, the patient was steadily
progressing, and she went ahead to seemingly complete clinical
recovery.

TABLE VII— ORIGINAL CASES

THIRTY-ONE UNSELECTED CASES OF INOPERABLE CANCER AT EARLIER AND LATER STAGES

OF PROTEIN TREATMENT
FIRST COUNT AFTER AN AVERAGE PERIOD OF NINETY DAYS OF TREATMENT

Case No. |

Nature

Nature of Case

No. of Days |

I

Red
Blood
Corpus-
cles

White
Blood
Cor-
pus-
cles

a

Mono-
nuclears

W a

Large

Small

294
366
278
16
153
263
270
94
233
239
131
258
248
235
64
149
370
84
289
242
138
163
347
193
280
296
23
168
251
189
391

Dr. A
Sr.A
Mrs. B....
MissD....
Mrs. G....
Mrs. H....
Mrs. H....
Mrs. H....
Mrs. L. . . .
Mrs. M . . .
Mrs.N....
Mrs. N....
Mr.O
Mr.P
Mr.P
Mrs.R....
Mrs. R....
MissR....
Mr».S....
Mrs. S
Mrs.F.S..
Mrs.S....
Mrs. S...
Mr.S
Mrs.S....
Mr. Von E.
MissW...
MissW. . .
Mrs. W. . .
Mr. M....
Mrs.W...

Ep. of Tongue
C. of Breast

43
106

Kir,

I li:i
87
12G
5

96
95
90
90
88
90

4,864,000
4,448,000
4,400,000
4,464,000
4,656,000
3,744,000

7,330
8,200

7,500

74.6
66
58.6
59
73
58
73
56
65
64.3
62
59
71
68.3
72
63.5
72.6
71.76
51.5
60
56.3
65
42
63
74
64
60
6U

77.6
52.0

7.3
13.5
19
17
13
20
17
26
19.5
16.3
18.6
18
9
14
9.5
21
14
11.5
20
10.6
17
20
28
19.6
15.6
20
13
11.6
11
11.6
25.5

18
16
20.6
24
12
20
9
14
15
15.6
18.3
23
16
9
18.5
15.5
10.6
16.25
25
29
24.3
16
30
20
6.6
26
27
20
11
10.6
14

0

3.75
1.6
0
0
2
1
4.5
.5
3.6

0
.3
4
0
0
2.6
.5
3.5
.5
2.3
0
0
1.5
4
0
0
2
4
0.6
8.0

;; Uterus'.'.'.'.'. !
" Breast

Ep. Forehead
C. of Breast

" Uterus'.'.'.
" Breast
Sarc. of Test
C. of Jaw. . .
Ep. of Cheek

190
28
141
171
47
72
05
115
79
5
170
38
G!)
129
21
90
165

ir,!»

24
124

88
63

83
60

95

'96
100
90
85

"so

86
95
95
90
75
85
75
76
100
100
90
80
80
85
80
100

5,160,000

4,680,000
3,376,000
5,964,000
5,330,000
4,352,000
4,352,000
4,240,000
4,570,000
4,896,000
5,128,000
4,616,000
2,800,000
3,654,000
4,226,000
4,280,000
3,936,000
4,460,000
4,730,000
4,440,000
4,448,000
3,570,000
4,312,000
4,116,000

8,300

7,200
7,600

10,200
10,200

9,000

8,440
7,600
7,200

8,800

C. of Breast
" Skin
Chond-Sarc
C. of Breast

Ep. of Face
Sarc. ofPhar
C. of Breast

" Jaw. . .'
" Thyroid...

Sarc. of Leg
C. of Breast

" Rectum'.'.'.
" Ovary

Average

90

88.6

4,400,000

8,270

63.69

16.37

17.72

1.7

This table may advantageously be compared with earlier tables showing blood condition
in untreated cancer cases, and with the table on the opposite page, showing later history of
the same cases.

It will be of interest to contrast this blood count with another,
No. 399, which chanced to be made on the same day, in which
the haemoglobin test was also 100 per cent, and in which the red
blood count was 4,896,000, but in which the leucocyte count was
9,500 (more than could be desired), polymorphs representing 69.5
per cent., and large monocytes, only 14.5 per cent., as against 14.5
per cent, small lymphocytes, together with 1.5 per cent, eosino-
philes and 1 per cent, basophiles.

THE BLOOD IN CANCER SUBJECTS

269

Here, it will be observed, there is substantial uniformity be-
tween the two counts except as regards three factors : namely ( 1 )
the total leucocyte count, which was 9,500 in the second patient
against 8,000 in the first ; (2) the polynuclear count, which was
69.5 against 60; and (3) the large monocyte count which was
14.5 against 23.5. These differences, however, are highly sig-
nificant, in view of the studies of the blood count above outlined.

TABLE VIII — ORIGINAL CASES

THE SAME 31 UNSELECTED CASES AFTER AN AVERAGE OP 152 DAYS OF
PROTEIN TREATMENT

Case No.

Name

Nature of Case

No. of Days

!

Red
Blood
Corpus-
cles

White
Blood
Cor-
pus-
cles

4

Mono-
nuclears

ft

}

Large

Small

294
366
278
16
153
263
270
94
233
239
131
258
248
235
64
149
370
84
289
242
138
163
347
193
280
296
23
168
251
189
391

Dr. A...
Sr. A

Ep. of Tongue
C. of Breast

87
134
193
215
170
112
122

-"'!

172
207
1 50

i«;2

91

1 'JO

LG9
67

L88

102

HO

175

i74

!so

55
if!
98

152

90 5,288,000
100 4,160,000
100 4,832,000
100 5,252,000
90 3,840,000
100 3,424,000
95 5,696,000
955,240,000
1005,652,000
1005,096,000
955,124,000
100 4,800,000
90 5,404,000
905,200,000
903,904,000
1005,600,000
904,130,000
100 4,928,000
100 5,184,000
100 4,672,000
954,640,000
1004,928,000
602,326,000
1004,376,000
1005,230,000
100 4,640,000
1004,960,000
100 5,650,000
95 4,288,000
80 4,072,000
95 5,632,000

9,800
6,700
6,100
7,500
7,500
7,700
6,800
8,000
8,600
8,000
8,300
9,400
8,300
8,880
11,700
6,800
12,000
10,000
7,300
7,200
8,000
7,000
10,500
6,900
7,400
7,800
9,000
9,200
8,600
7,520
8,100

73
48
54.5
61.5
55
72.5
72.5
58.5
76.5
60
62
58.5
71.5
87.6
84
74
77.5
57
61.5
50.5
53
61.5
40
60
72
60.5
72
64.5
64.5
69.3
54

64.4

18.3
26
34
13
22
10
17.5
18
13.5
23.5
20.5
26.5
20.5
7.3
10.5
13.5
15
13.5
16
31
11
22.5
19
16.5
18
20
16
18
19.5
11.6
25

18.3

7.6
24.5
11.5
24
20.5
15.5
5.5
21.5
8.5
13
16.0
13.5
8
4.6
4.5
9.5
6.5
28
20
15.5
32.5
13
39
21
7
14.5
9
17
18.6
18.6
17.5

15.6

2.6
1.5
0
1.5
2.5
2
4
2
1
2.5
1.5
1.5
0
.3
1
8
1
1.5
2.5
3
2.5
2.5
1
1.5
2.5
1.5
2.5
.5
3.3
.3
3.5

L9

1
0
0
0
0
0
0
0
.5
1
0

0

0
0

0
0
0
0
0
0
.5
1
l
.5
.5
.5
0
.3
0
0

0.2

Mrs. B....
MissD. ..
Mrs. G

Mrs.H....
Mrs. H
Mrs-H....
Mrs. L....
Mrs. M....
Mrs. N . . .
Mrs. N....
Mr. O. ..
Mr. P...
Mr. P
Mrs. R. ..
Mrs. R. . . .
MissR....
Mrs. S
Mrs. S
Mrs. F. S. .
Mn».S
Mrs.8
Mr. S
Mrs. S
Mr. Von E .
MissW....
Miss W
Mrs.W....
Mr. M
Mrs. W. . . .

" " Breast" !

Ep. Forehead
C. of Breast

" " Uterus .

" " Breast .

Sarc. Testicle
C. of Jaw
Ep. of Cheek
C. of Breast
" " Skin
Chond-Sarc
C. of Breast
Ep. of Face
Sarc. of Phar
C. of Breast

" " Jaw
" "Thyroid
Sarc. of Leg
C of Breast

" " Rectum
" Ovary

Average

95.5

4,782,000

8,270

Comparison with the preceding table will show characteristic progress during this period
of fourth and fifth months (on the average) of Proteal treatment.

Nothing more would have been necessary to make the two
counts identical as to their leucocyte percentage balance than to
take the 9.5 per cent, in excess of polymorphs in the second case
and transfer them to the large monocyte column. I am greatly
disposed to believe that had the Proteal treatment been able to
effect such a modification of blood count, there would have been
a modification in the production of the leucocytic enzymes that
might have turned the scale in the patient's favor. As it was,
however, the second patient developed a small metastasis in the
neck while undergoing the treatment, which so alarmed her that

270 THE PROTEAL TREATMENT OF CANCER

she went to another city for X-ray treatment. A few months
later her death was reported.

What might have been the progress of the case had the Proteal
treatment been continued is oi course only conjectural. But
the blood count showed that the case was not progressing under
the proteals as satisfactorily as could be desired; whereas the
blood count of the other patient gave every warrant for the favor-
able prognosis that was presently justified.

Incidentally we may note that both these cases were cancers of
the breast.

In another connection, I have suggested that when a patient
under the Proteal treatment has been carried to a stage of very
marked improvement, progress may be retarded by excessive
dose, putting a tax upon the corpuscles that is not compensated
by further stimulus to the blood-forming organs. Obviously, the
guide as to this must be found in the blood count.

In general, I would suggest that when the red-cell count has
been brought to approximately five millions, and the differential
leucocyte count to the status above suggested, in which there is
marked lymphocytosis with distinct preponderance of the large
mononuclears, the physician should be chary of giving large doses
of protein.

It may be desirable to discontinue treatment altogether for a
time; but it is usually preferable to restrict the size of dosage,
and extend the intervals between doses. A dose of 5 or 10
minims given weekly or semi-weekly may keep the corpuscular
response at a maximum, and foster progress that would be im-
possible under larger or more frequent doses. Yet the same case
may have required dosage of 40 or 50 minims daily or on alter-
nate days at an earlier stage.

All therapeutic rules have exceptions, however; so I must add
that it appears sometimes to be advantageous to give a patient
who has reached the static period the shock of a large dose, or
of an intravenous injection, which produces a vigorous reaction.
A case was recently reported in which, quite by accident, part
of a dose was given into a vein. There was anaphylactic reac-
tion within a few minutes, and subsequently the neoplasm began
rapidly to regress, although it had for some weeks been static,
after having passed through an earlier stage of favorable progress.

All this, however, only emphasizes the point made in an earlier
section, to the effect that any one who can administer a hypo-
dermic injection may begin the proteal treatment of a case of
cancer, and for a time secure gratifying results ; but that, even in
cases that have larger possibilities, these possibilities can be rea-
lized only when the subsequent administration of the remedy is
carried forward along scientific lines. One object of the present

CANCER AND THE LYMPHOID SYSTEM 271

section has been to suggest that the scientific administration in
question necessarily connotes repeated observation of the blood
count as modified by the administration of the proteal antigens.

SECTION IX.
CANCER AND THE LYMPHOID SYSTEM

There is one profoundly important aspect of the problem of
treating cancer with proteins to which incidental reference has
been made in this monograph, but which, so far as I am aware,
has never been elsewhere suggested.

The point in question is this: Every cancer patient has been
subjected to a spontaneous course of protein treatment before he
comes into the hands of the surgeon or physician.

Such, at least, must be considered the fact if the thesis as to
the nature of cancer that furnishes the basis of this monograph
is accepted. According to that thesis, as elsewhere elaborated,
there is incessant warfare from the outset between the blood cor-
puscles and the neoplastic cells, with the consequent destruction
of combatants on both sides.

If the corpuscles win, the lawless cells are entirely eliminated,
and no tangible neoplasm will result.

But if the new cells win, they ultimately constitute an aggre-
gate that we call a tangible cancer. Meantime, there has been
an effort on the part of the bodily defenders — namely, the white
and red corpuscles — that has profoundly disturbed their status
as health-defending agents. And needless to say this profound
disturbance has extended to the organs that produce the blood
corpuscles,— namely the bone marrow, the lymphatic system, and
the spleen. Abundant proof of this is found in the presence of
myelocytes, normoblasts, and abnormal lymphoid corpuscles in the
blood stream.

The manner of change that brings about this modification of the
blood conditions may be illustrated by a quotation from Dr.
Ward's book on Bedside Hamatology. In the chapter on "Gen-
eralized Affections of Blood-forming Tissues"— in which there is
no specific reference to cancer — he says:

"It is well known that the most powerful and efficient stimu-
lants of blood regeneration are the products of blood destruction.
This is well shown in the case of Addisonian [pernicious] anaemia
and in the results of injections of very small quantities of blood
in cases of anaemia. We need not then be surprised if after this
destruction we find excessive formation. We do, as a matter of
fact, find both excessive formation of white cells and the pres-

272 THE PROTEAL TREATMENT OF CANCER

ence of the products of excessive destruction in the urine. The
next step in the pathology will be the reversion of the cell- forming
organs to a more primitive type as a result of the continued strain
on them. This also we find in lymphsemia as we do in Addisonian
anaemia. Here, however, the analogy ends for the reversion in
the case of lymphsemia may proceed in the extent of resurrecting
tissues whose cell-forming days were over."

Elsewhere in the same chapter, the salient aspect of the sub-
ject is elaborated as follows :

"In the group of diseases now to be discussed the common and
distinctive feature is involvement of all the blood-forming or-
gans by a growth or overgrowth that is similar in each organ.

"In the first sub-group, the leukaemias, not only the adult blood-
forming organs, marrow, spleen, and lymph glands are effected
but in other situations tumors may appear which are composed
of tissue identical with that in the marrow, etc. These tissues
are the embryonic and infantile blood-forming organs, the liver
and thymus, .and, secondly, connective tissue wherever met with.
This extraordinarily wide distribution of lesions in some cases is
the more readily explained when we remember that all mesoblastic
tissue is potentially Wood-forming — i.e., blood-cell-forming — just
as it is potentially sarcomatous or fibromatous."

To understand the subsequent sequence of events, we have to
recall that overstimulation of any organ leads presently to ex-
haustion. So the same stimulus that at first produces an excess
of blood corpuscles may presently result in marked decrease. Note,
for example, what Pappenheim says as to this:

"Leucopenia is not diametrically opposed to hyperleucocytosis
even when it appears from the first as a leucopenia, e.g., in typhoid.
It ought rather to be regarded as differing in degree only, since
high degrees of leucocytosis, or leucocytosis of long standing, may
merge into leucopenia. When this occurs, especially if accom-
panied by the presence of early forms [leucoblasts, myelocytes,
normoblasts] in the blood, it indicates commencing exhaustion of
the overtaxed bone marrow."

Such are the recognized effects of a persistent stimulation of
the organs of blood regeneration by the products of blood de-
struction. It must be obvious, then, that in every far-advanced
case of cancer, or at any rate in every case in which a neoplasm
has assumed considerable proportions, there must be a greater or
less degree of what Ward refers to as "hyperprophy of the lym-
phocyte-forming tissues," including spleen and marrow. Ac-
cording to the present thesis, the increased formation of lympho-
cytes and early myelogenous forms in response to the stimulus of
the cancer cells is a salutary process, — an attempt on the part of
the organism at spontaneous cure of the malady. But the net
result, when the new growth is too active, is that ultimately the
organs of blood- formation have reached their maximum response

CANCER AND THE LYMPHOID SYSTEM 273

to that particular antigen, and through prolonged overstimulation
a general myelogenous and lymphatic maladjustment is produced
which is in many respects comparable to the general leukaemias
of different origin. "Many people," says Ward, "consider that
leukaemia is of the nature of a malignant growth as, for instance,
cancer of the stomach is a malignant growth." Again he says:
"That there are analogies between cancer and the leukaemias no
one will deny." He adds that in his opinion these analogies are
not sufficient to bring the two into the same class ; admitting at the
same time that theories in the matter are at present only tentative,
and going on to say that: "If leukaemias are cancer, then the
metastases of cancer are not due to emboli from a primary growth
nor to spread by direct continuity along lymphatics, but are pri-
marily formed in each situation in which they occur under the
influence of the same stimulus that produced the original tumor."
To be sure, Ward thinks that most pathologists will not subscribe
to this view of cancer metastases, and so will reject the analogy
which suggests that leukaemia is to be regarded as a form of new
growth of the bone marrow or glands. He adds, however, that
"the theory and the analogy form a fascinating and possibly pro-
ductive field for discussion and research."

There is no occasion here to enter into detailed discussion of
the pathological questions involved. My object in referring to
it is to emphasize the view that the presence of a cancerous
growth implies a profound dyscrasia of the lymphoid tissues.
There is of course nothing new in this view, although it may per-
haps be said that there is novelty in the explanation of the fact
just offered, — the suggestion, namely, that the lymphatic hyper-
trophy may be a direct result of the response to the antigenic
stimulus of the decompounding cancer cells.

From a practical standpoint, the importance of the matter lies
in the fact that a full recognition of the conditions will prevent
anyone from supposing that he has effectively treated a case of
cancer when he has merely removed a local neoplasm.

More specifically, the matter is important in the present con-
nection as emphasizing the view that a cancer patient, before he
comes into the hands of the physician, has undergone a radical
course of protein treatment. This fact is immensely significant
in its bearing on the practicalities of a subsequent course of pro-
tein treatment at the hands of the physician.

If the view just presented is accepted, for example, it becomes
obvious that any further treatment based on the administration
of cancer proteins (and such treatment has been suggested and
extensively tested) would be illogical in the highest degree. All
that cancer proteins can accomplish as antigens has already been
accomplished, and the net result is that the patient still has a

274 THE PROTEAL TREATMENT OF CANCER

neoplasm associated with a responsive dyscrasia of the blood-
forming organs. Hence the futility of the autolysate treatment
of Fichera and allied attempts to treat cancee with so-called"
"vaccines" made from the tissue of neoplasms.

A disturbance of the blood count, or a deviation from the nor-
mal, in token of cytogenic dyscrasia, may be expected as a matter
of course. If the neoplasm is small, as in case of a epithelioma
of the mouth, the antigenic stimulus of the cancer cells may be of
so relatively slight a character that the blood picture, at the time
when the patient comes under observation, may be identical with
that which has been presented in an earlier chapter as typically
favorable. The red blood count may be above five million ; the
white count about 8,000; and the mononuclears may constitute
35 or 40 per cent of the leucocytes with a preponderance of large
monocytes; and there may be relatively high percentage of eos-
inophiles.

This would indicate, according to the present thesis, that the
patient in question is receiving spontaneous protein treatment that
is accomplishing valuable results in retarding the progress of the
malady.

More commonly, however, as records of our counts have shown,
the patient at the time of first examination has reached a stage
at which the corpuscular balance is much less favorable. The
stimulus to the cytogenic apparatus (in particular the bone mar-
row), followed by exhaustion, is revealed in a relative monocy-
penia, but with marked preponderance of the small lymphocytes,
associated with a deficiency of eosinophiles, and, usually, with a
marked decrease of the red corpuscles. Commonly there is marked
general leucocytosis, but with preponderance of the polynuclears.
Myelocytes, leucoblasts, and normoblasts may be present in
greater or less profusion. The poly nuclear commonly show
marked deviations from the normal as regards the conformation
of the nucleus (S-shaped nucleus, ring-form, spiral contortion,
etc.), with in general a marked tendency toward "progression to
the left," — speaking in terms of the Arneth formula.

This pciture suggests that a spontaneous cancer-antigen treat-
ment has passed its maximum of efficiency, and that relatively
rapid and unfavorable progress of the neoplasm must now be
expected unless a new and different stimulus can be brought to
bear on the defensive mechanism of the body.

Such a new stimulus may be supplied by the X-ray, by radium,
or by the administration of proteins of a type quite different from
the proteins of cancer.

In discussing the action of X-ray and radium elsewhere I have
suggested that the beneficial effect of these rays may be in part
at least due to their general influence on the blood count. I wish

CANCER AND THE LYMPHOID SYSTEM 275

now to emphasize this aspect of the matter in the light of the
statement above quoted from Ward to the effect that : "It is well
known that the most powerful and efficient stimulants of blood
regeneration are the products of blood destruction."

I am inclined to think that a large measure of the benefits
sometimes unquestionably attained in cancer from the use of X-
ray and radium may be explained as due to their destructive in-
fluence on the blood corpuscles. It is well known that in general
leukaemias, the number of white corpuscles may be reduced by
X-ray treatment. It is also known that radium exercises a de-
structive influence on the blood corpuscles. It follows that these
influences must stimulate the blood-forming mechanism, inasmuch
as their use tends to saturate the blood, more or less, with "the
products of blood destruction."

In point of fact, I have observed that patients that had un-
dergone X-ray or radium treatment before applying for Proteal
treatment sometimes show a blood picture precisely of the
kind that we have come to regard as favorable, and as indicating
the best possible response to the proteal treatment itself. I am
strongly inclined to the opinion that in many cases this favorable
blood picture is directly due to the use of X-ray or radium, and
that the beneficial effects of these treatments are in a large meas-
ure due to this general modification of the blood quite as much as
to any local effect on the neoplasm.

Indeed I think it is an open question whether it may not be
possible to get the good effects of X-ray or radium by treatment
applied generally, or to the bones or to the spleen, rather than
by prolonged application to the site of the neoplasm itself. This,
however, is a matter that need not be discussed in detail in the
present connection. It suffices to emphasize the opinion that pro-
longed exposure to X-ray or radium at the site of the neoplasm
is inadvisable ; and that the danger of local burns, with their
characteristically disagreeable and resistent ulcers, may be obvi-
ated without sacrificing any of the expected benefits, by shifting
the locus of treatment.

Incidentally, it may be noted as a matter of interest that radium,
when introduced into the animal organism, is believed to have
something like an elective affinity for the bone marrow, taking
permanent lodgment there. So, at least, I have been informed
by one of the most experienced workers in this field, who stated
this as a matter of fact, quite without reference to any theory as
to the action of radium on the blood-forming mechanism.

It is the commonly accepted opinion of pathologists that, where-
as the X-ray exerts a temporarily beneficial effect in the treatment
of leukaemias, the effects cease to be cumulative after a time, and
ultimately the beneficial response ceases, and the patient goes

276 THE PROTEAL TREATMENT OF CANCER

on to a period of decline, which the X-ray now seems powerless
to retard.

We must expect, I think, that the same thing will ordinarily be
true of the X-ray or radium treatment of the type of lymphaemia
or myelaemia associated with the presence of malignant neoplasms.
It was above suggested that the neoplasm assumes significant pro-
portions only when the blood-forming mechanism has ceased to
respond effectively to the antigenic stimulus of the "cancer pro-
teins. When this has occurred, a new stimulus may be given to
the blood-forming apparatus by X-ray or radium treatment. In
a certain number of cases, this new stimulus may be sufficient to
turn the scale in favor of the bodily defenders, and against the
neoplasm ; with the result that the lawless cells are totally disinte-
grated, and a condition of at least clinical cure is effected. But
in a much larger proportion of cases, it cannot be hoped that the
new stimulus given by the radiation treatment will serve to turn
the tide so effectively. In a vast preponderance of cases, the neo-
plasm will be found to be so thoroughly fortified that it offers suc-
cessful resistence to the best fighting equipment that the body
can develop under the new stimulus.

Even where the local neoplasm seems completely to disappear
under the new stimulus, it is a matter of unfortunate observation
that either direct or metastatic recurrences presently reveal them-
selves, showing that the profound lymphatic dyscrasia, however
modified, has not been eliminated.

In such a case (and this is equivalent to saying, in practically
all cases of cancer), it is desirable to seek still other methods of
stimulating the cytogenic apparatus, and thus further to fortify
the fighting equipment of the body. The therapeutic agents avail-
able for this purpose include: (1) Hygienic measures, such as
proper food, exercise, massage, and cold baths; and (2) An in-
definite series of foreign proteins, animal, bacterial, and vegetable.

SECTION X.

ANIMAL EXPERIMENTATION AND PROTEAL
THERAPY

About the year 1908 workers at the Loomis Laboratory
were experimenting with transplantable tumors in dogs. They
found that with dogs, as with rats and mice, some individuals
seemed immune to the transplantation of such tumors. In
other cases, the tumor after transplantation grows for a time
and then "spontaneously1' regresses. In yet others, it continues
to grow until it brings about the death of the animal. As with

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 277

rats and mice, the dog that had recovered through "spontaneous"
regression of a tumor appeared to be immune to subsequent
transplantation.

It occurred to the experimenters to test the effect of transfusing
the blood of such an immunized animal into the vascular system
of a dog in which the transplanted tumor was progressing.
Experiments were first made with the blood serum of the im-
munized dog; and the results were negative. But when, subse-
quently, transfusion was made of the whole blood of the dog, a
curative result was abserved, the tumor in the affected animal
regressing, and the dog going on to complete recovery.

It seemed fairly obvious, then, that there was something in the
entire blood of the animal that was not conveyed with the serum
alone that served as an antagonist to the cancer cell. It is re-
called that on one occasion a not unnatural suggestion was made
by a visiting physician who had witnessed the results of these
experiments to the effect that possibly this curative principle
might reside in the bodies of the leucocytes. The suggestion was
recognized as having interest and plausibility, but the trend of
thought at the moment was in the direction of chemical explana-
tions of a less tangible kind, and no immediate attempt was made
to verify or refute the leucocytic hypothesis. The matter came
naturally to mind, however, when several years later, observation
was made of the modification of blood count under influence of
the protein treatment of human cancer subjects.

When the series of blood counts made in my experimental
laboratory had reached the stage at which it became evident
that there were highly interesting modifications of the leucocyte
count (specifically characterized by an increase of mononuclear
leucocytes, and in particular of the large mononuclears), it
became a matter of interest to examine the literature of experi-
mentation in quest of records of analogous experiences.

Then it became apparent that there is a peculiar paucity of
observations on the differential count of the white corpuscles in
an otherwise expansive literature ; due, no doubt, to the fact that
most workers have been concerned with the biochemical rather
than the histological aspects of the investigation. It was, I think,
the late Elbert Hubbard— voicing a familiar conclusion— who
made the cogent observation that, in matters of science, we
appear always to progress from the complex to the simple, and
that the obvious is the last thing to be observed. Experiments
in cancer inoculation with animals would seem to furnish another
illustration of the truth of this observation, inasmuch as very
tangible and obvious modifications of the blood count have for the
most part been overlooked by workers who were concerning
themselves with intricate problems of bodily metabolism involv-

278 THE PROTEAL TREATMENT OF CANCER

ing chemical conditions susceptible of investigation only by the
most delicate of biological methods.

Fortunately, however, there are a few workers who appear to
have been impressed with the histological aspects of the problem,
although even these have for the most part considered this aspect
of the subject as having only subordinate interest.

Among the earliest and most important observations that asso-
ciate the leucocytes with the process of immunization of animals
against cancer inoculation are those of Bashford, Murray and
Cramer, working under the auspices of the Imperial Cancer
Research Fund, in England. In a report published in the Pro-
ceedings of the Royal Society of London for 1909, dealing with
the general subject of resistant cancer inoculation, in mice, they
make the following highly interesting observations:

"The phagocytosis of formed cellular elements plays an im-
portant role in inducing resistance; serum is impotent to induce
resistance, blood corpuscles do so. The energetic phagocytosis
which accompanies the spontaneous absorption of transplanted
tumors, and which occurs in absorption after exposure to radium,
speaks strongly for the conclusion that the processes are the same
in kind when blood or tumor cells, being absorbed, produce
resistence. But we are as yet unable to determine the extent to
which agencies directed against the tumor cells themselves may
assist in determining their early death in protected animals."

At an earlier stage of the series of investigation, the role of
the leucocyte had been under consideration, as shown by a report
made by Bashford, Murray, and Bowen, in the Proceedings of
the Royal Society for 1906. In this report the authors say :

"Of course the cells presenting complete degeneration are no
longer capable of giving rise to tumors. In fact they are rapidly
taken up by the phagocytes in the days immediately preceding
transplantation, and it might be concluded that growth was con-
tinued by cells which never tended to degenerate."

Incidentally it is of interest to note that in connection with this
report the authors show a drawing of inoculated tumor tissues
undergoing degeneration, in which portions of the mass that stain
lightly are surrounded 'by cells with dark-staining nucleus and
protoplasm of a type closely similar to cells that I have observed
and studied in detail in a patient's blood taken from the im-
mediate substance of a cancerous mass.

In continuance of the same line of observation, we find Da
Fano in the Fifth Scientific Report of the Imperial Cancer
Research Fund, issued in 1912, referring to the round cells that
occur in the margin of a tumor that is retrograding, and along
the strands of actively proliferating connective tissue. De Fano
suggests that the development of tumor immunity in mice is
coincident with the general reaction of the connective tissue
throughout the organism. He observed that the polynuclear leu-

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 279

cocytes appear first at the place of the implanted tumor, and
undergo degeneration, without showing phagocytic activity. The
lymphocytes then appear in large numbers in the region of the
inoculated tumor, gradually diminishing after immunity is estab-
lished. According to his observation, inoculation of dead tumor
cells was not followed by round cell infiltration nor by the de-
velopment of tumor immunity. The observations were thought
to establish a close relationship between the leucocytosis and the
development of tumor immunity.

Dr. F. W. Baeslack, of Detroit, Mich., was led to take up a
specific investigation of the modifications of the leucocytic blood
count in mice suffering from transplanted tumors. The results of
his researches were published in the Zeitschrift fiir Immunitats-
forschung for 1913. He points out that the observation of the
increase of leucocytes in cancer was made as long ago as 1843
by Andrae, and confirmed in detail by Liidke in 1867. The latter
observer concluded "that the increase in the number of leucocytes
was a sign that the disease had become general and involved the
whole body." Reference is made to other workers who have
made observations on the leucocytes in cancer, but the list is a
surprisingly short one considering the enormous bulk of cancer
literature in general.

Dr. Baeslack's experiments had to do with several series of
inoculated cancer mice. He states that his count of the blood
Icells included the large mononuclears and the eosinophiles, but
his percentages and charts are given only for polynuclears and
small lymphocytes. As to these he says:

"It is of interest to note that the small mononuclear lympho-
cytes decreased during the period of active tumor growth, while
the polymorphonuclear leucocytes increased, and that shortly be-
fore the retrogression of the tumor became noticeable the rela-
tionship between these two classes of cells was entirely changed."

The charts presented give graphic illustration of the observa-
tion that when the polynuclear leucocytes went up and the small
lymphocytes went down, the case was progressing badly. In
one case at an early stage the polynuclears went up to 55 per
cent, and the lymphocytes went down to 26 per cent. (It must
be recalled that the polynuclears are relatively sparse — 16.9 per
cent., according to Price Jones — and lymphocytes relatively
abundant — 59.7 per cent. — in normal mouse-blood). But at a
later stage, when the tumor was undergoing regression, the
polynuclears went down to 16 per cent, (substantially normal),
and the small lymphocytes advanced to 48 per cent, of the total
leucocyte count, a number probably within the limits of normal
variation.

280 THE PROTEAL TREATMENT OF CANCER

It is unfortunate that details are not given as to the remaining
types of leucocytes, but it is obvious that a simple computation
shows that at the earlier stage of this experiment, when the tumor
was seemingly overmastering the system, the large mononuclears
and the eosinophiles together aggregated only 19 per cent, of the
leucocyte count; whereas at a later stage, when the tumor was
spontaneously regressing, the large monocytes and the eosino-
philes together must have aggregated 36 per cent, of the total
count, a number far in excess of the normal, which, according
to Price Jones, is represented by 21.5 per cent, of large mononu-
clears and 0.14 of eosinophiles.

These observations of general lymphocytosis in cases of mouse
tumors that are progressing to recovery have obvious interest as
supplementing the observations of Da Fano to the effect that
lymphocytes appeared in great numbers about inoculations of
immunizing material during the evolution of resistance, and that
in growing carcinomata the presence of the lymphocytes in great
numbers was clearly associated with a local healing.

Further association between the corpuscles and the processes
of immunization was suggested by the observations of Lambert
and Haynes that rat sarcoma would grow in the plasma of immu-
nized mice quite as vigorously as in that from normal or tumor-
bearing animals, — an observation that obviously links with the
observations on the curative properties of entire blood versus
serum, as recorded at the beginning of this chapter.

From the present standpoint these observations as a whole have
quite exceptional interest because they reveal modifications of the
leucocyte count in mice in which tumors are undergoing regres-
sion that are singularly comparable to the records of the favorable
case of human cancer under protein treatment observed by me
and recorded in great detail before I had so much as heard of Dr.
Baeslack's experiments. It will be recalled that charts were pre-
sented to illustrate graphically the fact that in cases that pro-
gressed most favorably under -Proteal treatment the polynuclears
and the small lymphocytes tended to approach the normal in
numbers, whereas the large monocytes increased very markedly
and held at high level.

It would appear that the same formula could be applied to Dr.
Baeslack's convalescing mice; although -the observer himself ob-
viously failed to appreciate the significance of the large monocyte
count, his attention being fixed solely on the polynuclears and
small lymphocytes. Possibly he had overlooked, or was not aw-are
of, the normal balance of leucocytes in mice (which, as just noted,
is very different from that of the human subject), and hence did
not realize that the fall of polynuclears to about 16 per cent, and
the rise of lymphocytes to about 50 per cent., represented only

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 281

approximations to the normal ; whereas the really significant fea-
ture of this count had to do with the large monocytes, which rose
far above normal as the case progressed favorably (as we learn
by subtracting the polymorphs and lymphocytes from the total
count), yet which he did not think it worth while specifically to
enumerate.

This correspondence between clinical experience with the
human subject and laboratory observation of mice, as regards the
modifications of leucocyte differential count when the system ap-
pears to be getting the better of a cancer invasion, is at least
highly suggestive.

That Price Jones should have noted a rise of large monocytes
in cancerous mice presumably not progressing favorably is ob-
viously consistent with the thesis concerning the response to the
presence of cancer cells exposited in detail in an earlier chapter
of the present work ; and it may be observed that the mice in ques-
tion, as studied by Price Jones, showed increase in polynuclears
also, precisely as did Baeslack's mice that were not recovering.

Of course it will not be overlooked that rise of polynuclears,
taken by itself, is a phenomenon familiarly associated with bac-
terial infections, and that the latter may occur as a complication
in many cases of malignant involvement. But it will be obvious
that the modification of the differential count recorded in the
protein-response tables is quite different from that induced by
bacterial infection, inasmuch as a characteristic feature is the
reduction rather than the increase of both relative and absolute
polynuclear numbers.

Meantime it should be observed that students of the infections
have tended to focus attention on the polynuclear "microphages"
to the neglect of the mononuclear "macrophages." Even where
the latter were counted, the possible significance of modifications
of their numbers, is frequently overlooked or ignored. Thus in
the very interesting and important studies of Gay and Claypole,
as recorded in the Archives of Internal Medicine for November,
1914, in which the leucocytosis induced in normal and immunized
rabbits by the injection of Bacillus typhosus is studied differen-
tially, stress is laid entirely on the increase in polynuclears, al-
though the facts recorded permit interesting inferences regarding
the large mononuclears also, since the actual count of these cells
twenty-four hours after inoculation showed an increase per cubic
millimeter from 670 to 3,014 — a four-and-a-half-fold advance.
It is true that the advance of polynuclears was even more over-
whelming (from 5,226 to 60,480) ; but on the other hand, the
small lymphocytes advanced only from 7,370 to 11,340, an in-
crease of but 54 per cent, suggesting by contrast that the four-
and-a-half fold advance of the large lymphocytes is not to be

282 THE PROTEAL TREATMENT OF CANCER

explained as a mere incidental result of general excitation of the
blood-forming mechanism.

It is noteworthy in this connection that German clinicians (for
example Von Domarus) cite an increase of large mononu clears
as a typical feature of the secondary stage of a so-called "leu-
cocyte-curve" of infections, such increase following the primary
advance and recedence of the polynuclears, and preceding the
advance of the small lymphocytes. Conceivably this macrocytosis
is to provide for the hydrolysis of the protein products with which
the blood has been flooded by the disintegration of the micro-
phages (polynuclears) with their increment of partially digested
bacteria. Such at any rate, might be a plausible explanation of
the later aspects of the "leucocyte curve" if the proteomorphic
thesis as -to the proteolytic activities of large and small lympho-
cytes is accepted.

In general, it would appear that a relative monocytosis be-
tokens a non-bacterial protein invasion as clearly as a neutrophile
increase betokens a bacterial infection. Probably the diagnostic
value of the monocytosis is not less than that of the polyneu-
closis, although hitherto quite unrecognized.

Further pursuance of the subject here, however, would carry
us too far afield from the present theme, which concerns malig-
nant neoplasms rather than general infections. Let us again
take up the analysis of the results of animal experimentation in
the cancer field, with an eye to the correlation of these results
with our own clinical and laboratory experience with cancer in
the human subject.

CART BEFORE HORSE

In considering various of the observations above cited, and
numerous others in the literature of transplantable tumors in rats
and mice, one is led to reflect on the power of preconception and
the difference that may result from a changed point of view.

If a person who had seen automobiles moving about the streets,
but who now for the first time saw a horse and carriage, were to
describe what he had seen, he would doubtless tell of an auto-
mobile that pushed before it a strange animal. He might even
note with amusement that the animal was obliged to move very
rapidly to keep ahead of the vehicle that tends to overrun it.
Probably he would be led to query why it would not be more con-
venient to tie the animal behind the vehicle and thus avoid the
danger of injuring it.

Now such a description of the locomotion of the horse-drawn
vehicle would, in my opinion, be strictly comparable to the descrip-
tions that have appeared in the literature of cancer in connection
with the question of the transplantation of tumors and the giving

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 283

of immunization. As a case in point, note the comment of a very
industrious and laborious compiler, reviewing the literature of the
subject, when referring to the experiments of De Fano, above
noted, as follows :

"As lymphocytes appeared in great numbers about inoculations
of immunizing material during the evolution of resistance, their
relation to this condition could not be denied. ... In growing
carcinomata they were to be found only in places where local
healing was in progress. A carcinoma cell seemed to exert some
sort of specific influence on the lymphocyte, and the latter to
spread the resistant state throughout the organism."

In the light of the interpretation of the action of the lympho-
cytes that furnishes the chief thesis of the present monograph,
which will be elaborated presently, such a phrasing seems not less
ridiculous than the suggestion that the horse is pushed before the
carriage.

To say that lymphocytes "were found only in places where
local healing was in progress" is a little as if one were to note
the curious coincidence that, in a certain house, rats were to be
found only in places where cheese was disappearing.

Scarcely less absurd seems the interpretation that has been put
upon the widely heralded experiments of Ehrlich, as repeated by
others, in what has come to be known as the zigzag transplanta-
tion of tumors. It will be recalled that in this experiment a tumor
from a mouse is transplanted to the body of a rat, where it grows
for a time, and then begins to undergo regression. Before it has
entirely regressed, it is taken from the body of the rat and trans-
ferred to the original host, where it again takes on more or less
energetic growth. It will be recalled that Ehrlich explained this
with an elaborate theory of so-called atrepsia, according to which
there are certain chemical constituents in the organism of the
mouse that are essential to the growth of the mouse tumor; that
a certain quantity of this material is transferred with the tumor
to the body of the rat, and that when this transferred portion is
exhausted, the growth can no longer continue in the body of the
rat.

In the light of the present thesis, the explanation of zigzag
transplantation would be simply that the transplanted tumor grew
for a short time in the body of the rat because a certain time was
required to muster the companies of corpuscles to combat the law-
less cells. When the corpuscular defenders had been aggregated
in sufficient numbers, the fight with the cancer cells would turn
in favor of the host, and the cancer would begin to regress. Now,
however, the remainder of the cancer cells are retransferred to the
mouse, where, as a matter of course, they continue to grow be-
cause it had already been demonstrated that the body of that par-
ticular mouse was not competent to produce corpuscles and their

284 THE PROTEAL TREATMENT OF CANCER

enzymes in sufficient quantity to combat the activities of the cancer
cells.

A similar explanation, obviously, may be found for the ob-
served fact that an animal may be rendered immune to inocula-
tion experiments not merely by inoculation with the cancer tissue,
but with tissues of various kinds, including heteromorphous ones.
For example, Dr. Isaac Levin reported the immunization of rats
by treatment with mouse tissue. (Proceedings of the Society for
Experimental Biology and -Medicine, 1910.) Other experimenters
have produced immunization with the tissues of liver, spleen, and
other organs. The evidence seems to justify the expectation that
immunity may be developed by the introduction of various protein
substance, whether derived from the tissues of animals of the
same species, or of other species. In a word, it would appear
that we have to do with a general protein reaction. Couple these
observations with the observations of Bashford and his associates
and of Baeslack, and we might fairly expect — were not our minds
turned in the opposite direction — that an essential modification
of the leucocyte count would be found in all of these cases ; and
we might justify the inference that such modification had an im-
portant relation to the process of immunization.

When, now, we turn to the human subject, and study the modi-
fications of the blood count in cancer cases, and in particular can-
cer cases under protein treatment, as reported in the present mono-
graph, it is obvious how all these observations of the animal ex-
perimenters harmonize with the results shown in our charts ; and
the conclusion seems inescapable that we have to do with a gen-
eral principle of protein reaction, and with a response of the
blood-forming organs one prominent feature of which is an in-
crease in the phagocytic or enzymic activities of the corpuscles.
This, after all, is only giving specific application, in terms of the
proteomorphic theory, to the general conclusion stated by Levin
in the paper above cited on the immunization of rats with mouse
tissue, to the effect that: "The explanation must be sought in
some protective substance within the host created under the
influence of the implanted mouse tissue."

PHAGOCYTIC ACTIVITIES

Before going on to a more detailed exposition of what I con-
ceive to be the character and manner of action of this "protective
substance," I would introduce a quotation from Starling's stand-
ard work on Physiology to remind the reader of the really ex-
traordinary part that phagocytic activities play in physiological
processes.

"We have seen," says Starling, "that the leucocytes from what-
ever animal they may be taken present two phenomena, viz., that of

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 285

amoeboid movement and that of ingesting foreign particles which
may be presented to them. On account of this power of eating
up foreign particles they are frequently spoken of as 'phagocytes,'
in this respect resembling unicellular organisms and the undif-
ferentiated cells of many kinds of tissue. All the phenomena con-
nected with the process of inflammation in higher animals are
directed to the assemblage of leucocytes at the spot which is the
seat of injury or of infection, so that they may devour and remove
either the injured tissue or the invading micro-organisms. This
process plays therefore an important part in determining the im-
munity of any animal against infection; though in the higher
animals it is assisted by a number of other mechanisms directed
towards the same e"nd, which we shall have to discuss in a subse-
quent chapter. The use of phagocytosis is not, however, confined
to the protection of the organism against infection. Wherever
any effete or dead tissue has to be cleared away, whether as the
result of injury or in the course of metamorphosis of organs, the
leucocytes play an important part. Thus in the great rearrange-
ment of tissues which occurs in the larval state of insects, the re-
moval of the muscle fibres which are no longer required is effected
by the accumulation of phagocytes around them. The phago-
cytes may send processes into the muscle substance, which dis-
solve this tissue and then take it up. The absorption of the tail
of the tadpole is effected in the same way by means of phagocytes.
In mammals, including man, the moulding of the long bone which
occurs in the process of growth is effected by continual and coin-
cident processes of absorption and new formation of bone. The
absorption is carried out by means of spinal phagocytes formed by
the aggregation of a number of leucocytes, the well-known 'giant
cells' or myeloplaxes which form so prominent a constituent of
bone-marrow.

"The blood-corpuscles represent the wandering phagocytes of
the body. There are fixed phagocytes of which the myeloplaxes
just mentioned may be regarded as a type. Other members of
this class are the endothelial cells (Kupfer's 'Sternzellen') which
line the capillaries of the liver. If a suspension of carmine or of
micro-organisms be injected into the blood stream these endo-
thelial cells are found a little later to have taken up large numbers
of the foreign bodies. Under normal circumstances these cells
as well as some similar cells in the spleen take up effete red blood-
corpuscles and destroy them. During the process of ^degeneration
of a peripheral nerve brought about by its separation from the
ganglion-cells of which its fibres are the processes, a marked pro-
liferation of the nerve-nuclei takes place. These become sur-
rounded with protoplasm and act the part of phagocytes, loading
themselves with the fat globules set free by the degeneration of
the myelin sheath. To the same class of fixed phagocytes may
possibly be ascribed certain of the plasma-cells of the connective
tissues.

"That the polymorphonuclear leucocytes are endowed with
these phagocytic properties is universally acknowledged, but some

286 THE PROTEAL TREATMENT OF CANCER

doubt still exists as to how far the other types of leucocytes which
we have described can function as phagocytes. It is probable that
the lymphocytes, and certainly the large mononuclear or hyaline
corpuscles, are endowed with these properties. The granular cor-
puscles, namely, eosinophile and basophile, are thought by some
to function as unicellular glands and to react to infection, not by
englobing the micro-organisms, but by discharging substances
stored up in their granules which have a poisonous effect on the
micro-organisms, and so prepare them for subsequent ingestion
by the polymorphonuclear leucocytes."

A very striking illustration of the phagocytic activities of leuco-
cytes is given in certain abnormal conditions, notably in so-called
phagocytic anaemia. This condition is characterized by active
phagocytosis of blood cells by other blood cells of normal or ab-
normal type in the circulating blood. Ward says of this : "The
resulting blood picture is very striking. In one case the phago-
cytosis was so pronounced that it was calculated that if all the
cells were as actively phagocytic as one which was observed ac-
tually in perfect cells on the warm stage, the whole of the red
cells of the body would have been destroyed in less than two
hours. In this case the destruction produced a fatal anaemia.
Other cases have followed transfusion or have been associated
with some known haemolytic process such as cholaemia. Isolated
phagocytic cells may be met with in malaria and leukaemia and
no doubt in other diseases."

The active share that the large mononuclear leucocyte takes in
this process is noted by Ward and graphically depicted in a draw-
ing showing large mononuclear phagocytes, "Many of them con-
taining several cells or portions of cells which have been caught."
One of these mononuclear phagocytes appears to have engulfed
no fewer than seven red corpuscles. Another has engulfed two
large cells that have the appearance of polynuclears. The picture
gives graphic support to the nomenclature of Metchnikoff, who
designated the polynuclears as microphages and the large mon-
onuclears as macrophages.

These activities of phagocytes may be recalled in connection
with the observations already cited of similar functioning in the
removal of the detritus of cancer cells, as noted by Bash ford and
his associates. It may be noted also that Walker, in dealing with
the effect of certain serums on carcinoma in mice, observes that
if pieces of tumor are placed in the serum of a rat which has been
injected with extract of mouse testis, degeneration of the cancer
cell takes place, the cells being invaded and replaced by leuco-
cytes. It does not appear that this observation has been verified
by other workers, 'but it has obvious interest in connection with
the not dissimilar observations of the other workers already cited.
In particular, note the observation of Bash ford, Murray, and

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 287

Cramer as to the "energetic phagocytosis which accompanies spon-
taneous absorption of transplanted tumors, and which occurs in
absorption after exposure to radium," and the observation of two
of the same workers that cancer cells presenting complete degen-
eration "are rapidly taken up by phagocytes in the days imme-
diately succeeding transplantation."

All in all, it would appear that there is abundant warrant for
the assumption that the leucocytes have an important share in the
attempt of the organism to combat the invasion of cancer cells.
Probably the evidence justifies the belief that they have the im-
portant share, though the co-operation of the red corpuscles is
so essential (according to the present thesis) that these agents
can scarcely be said to be subordinate.

If this conclusion is justified, it would seem to follow as a mat-
ter of course that a medicinal agent to combat cancer should be
sought along the lines of a stimulus to the blood-forming organs.
It does not appear, however, that any one definitely formulated
such an idea until an agent clinically observed to benefit the cancer
subject was found to have acted through stimulation of the blood
count — in particular increasing the numbers of red corpuscles and
large mononuclears.

TYPES OF LEUCOCYTES

It will have been observed that throughout the foregoing dis-
cussion we have been concerned with concrete and tangible facts.
Let us supplement these facts by recalling the series of tables in
which it was demonstrated that the administration of vegetable
proteins brings about, in the average cancer case, a conspicuous
and progressive increase of the large mononuclear leucocytes,
which were seen to advance from the normal maximum of four
or five per cent, of the leucocyte count to 15 per cent., 18 per cent.,
19 per cent., and 25 per cent., on the average, in successive groups
of cases ; reaching a much higher figure in individual cases.

With these series of facts for background, it will not be with-
out interest to make inquiry as to the manner of action through
which the increased armies of large monocytes exercise their an-
tagonistic influence against cancer cells, and thus benefit the
patient.

At the outset I would suggest the advisability of not drawing
too sharp a line of distinction between the two types of mononu-
clear leucocytes, namely, the small lymphocytes and large mono-
cytes. It must be recalled that there are still differences of opin-
ion as to the origin of the large monocytes, some physiologists
contending that they are merely overgrown lymphocytes. A more
popular view, probably, is that they are of bone-marrow origin,

288 THE PROTEAL TREATMENT OF CANCER

and the progenitors of the polymorphonuclear leucocytes. But
whichever view is correct, it is scarcely in question that the mon-
onuclear leucocytes represent a somewhat more primitive type of
cell than the polynuclear. The polymorphs, eosinophiles, and
basophiles are of granular structure, and it is held that the gran-
ules have a secretory function, generating enzymes that escape
into the blood plasma. In keeping with this function, these cells
have in general a relatively large cytoplasm, and their nuclear
structure, although elaborated and differentiated in form, is rela-
tively sparse, particularly in case of the fully developed poly-
morph.

Meantime, the typical lymphocyte is almost exclusively com-
posed of nuclear structure ; and the typical large monocyte has a
relatively enormous nucleus and a relatively small amount of cyto-
plasm, as contrasted with the typical polynuclear cell. There is,
however, a type of large mononuclear with nucleus less basic in
stain than the typical large monocyte, and with full clear cyto-
plasm, which my personal studies lead me to associate with the
cancer-cell destroying process, and which I am disposed to regard
as of lymphoid origin — in effect an overgrown lymphocyte. Fuller
discussion of the status of this and other types of large mononu-
clears is reserved for a later chapter.

In substantiation of the idea that the mononuclears are of a
somewhat more primitive type than the polynuclears, we find the
former relatively abundant in lower animals — for instance, the
rabbit, with 60 per cent, of mononuclears ; and the mouse, as al-
ready cited, with 80 per cent, or more of mononuclear cells, one-
fourth of them large monocytes, and 17 per cent, of polynuclears,
contrasted with the 70 per cent, of the latter in the human subject.

Witness also the fact that children show a relatively high per-
centage of mononuclears, at once evidencing the primitive char-
acter of these cells, and suggesting that they in some way func-
tionate in connection with the control of rapidly growing tissues.
In the first and second years of childhood, according to Von
Domarus, the polynuclears represent only about 42 per cent, of
the total leucocyte count, the small lymphocyte representing 47
per cent., the large monocyte (including transitionals) about 8
per cent., and the eosinophiles about 3 per cent. By the fifteenth
year, the polynuclears have risen to more than 56 per cent., and
the lymphocytes have dropped to about 28 per cent., but the large
monocytes and transitionals are slightly more abundant than in
infancy, representing about 9 per cent, of the leucocyte count,
while the eosinophiles have risen to not far from 6 per cent. Be-
tween puberty and adult life there are further changes, result-
ing ultimately in giving the polynuclears a census not far from
three-quarters of the total leucocyte count; the lymphocytes being

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 289

about one-third as numerous, and the large monocytes dropping
to relative obscurity with a count of from two to four per cent.

It would appear, then, that the physiological conditions in the
body of the normal mouse call for about five times as many large
monocytes, proportionately, as are required in the body of an
adult human being; and that the normal human being during
childhood and adolescence requires about twice as many mono-
cytes as are subsequently called for.

Note now the suggestive fact that, according to the observations
of Cramer and Pringle, the tissue of a cancer (in mice) is of an
embryonic type, as shown by the fact that its cells contain only
about seventy per cent, of the nitrogen content of the average
tissues of the host. Cramer had indicated the similarity between
the growth of cancer and the growth of the foetus, and prelim-
inary experiments by Dr. Lochstad had shown that a rapidly
growing tissue (foetus) has a lower nitrogen value than the ma-
ternal organism. These experiments obviously confirm the old
idea that cancer tissue is of somewhat embryonic character, and.
suggest the possibility that chemical or other agents might be
found that would serve to decompound the cancer cells without
injuring the normal surrounding tissue.

NATURAL IMMUNITY AND ARTIFICIAL IMMUNIZATION

Consider now for a moment the attitude — if the word be per-
mitted— of the normal organism toward intruding cancer cells.
Here the evidence must come largely from the field of animal ex-
perimentation, but it offers suggestive hints that may be applied,
with due reserve, to the human subject.

It is familiarly known that the pioneer work of Hameu and
Morau, expanded a little later by the work of Jensen and Leo
Loeb, made possible a new era of investigation by showing that
carcinomas and sarcomas of white mice and rats could be trans-
planted into other animals of the same species. It is equally well
known that all experimenters are agreed that a certain number
of individual animals show resistance to such transplantation,
tumors embedded in their tissues regressing and disappearing
"spontaneously" instead of continuing their lawless growth.

Thus it is shown, as Dr. Isaac Levin has phrased it, that "the
growth of the implanted tumor depends upon the correlation be-
tween the virulence of the implanted cell and the resisting power
of the organism of the host."

It was further shown that an artificial tumor used for inocula-
tion appears to acquire increasing virulence as it is passed from
one animal to another. But, on the other hand, it is possible to
induce a condition in the body of an animal which at first is sus-

290 THE PROTEAL TREATMENT OF CANCER

ceptible that will render it immune to further transplantation.
This was done by Ehrlich and his associates by making an orig-
inal inoculation with a tumor known to possess a low degree of
virulence. Such a tumor being absorbed "spontaneously," it was
observed that the animal in which such spontaneous absorption
had occurred was now immune against inoculation with tumors
of a more virulent type which would almost certainly have grown
had not the animal been given added powers of resistance by the
original inoculation.

What is of peculiar importance from the present standpoint is
the fact that it was shown presently that inoculation with normal
tissue, such as liver, spleen, and blood produced a degree of im-
munity comparable to that produced by the inoculation with a
mild type of cancer cell. And most interesting of all is the ob-
servation of Dr. Levin and others that identical results as to in-
duced immunity may be brought about by inoculation with so-
called autolyzed tissue, that is to say, with tissue "of which the
cells are killed in such a manner as to leave the endo-cellular
enzyme-like substance uninjured and active."

I have quoted Dr. Levin's own phrase as to the use of auto-
lyzed tissues, chiefly because it probably expresses the general
attitude of mind of experimenters toward this particular aspect
of the subject, in that it inferentially ascribes the immunizing
influence of the autolyzed tissues to their "enzyme-like substance."
It is hardly necessary to tell the reader of the present monograph,
however, that in my own opinion the success of the experiment
was due not to the presence of any specific enzymes, but to the
fact that the tissue used— cancer tissue, liver tissue, spleen, blood,
or what not — had the all-important advantage of being protein-
bearing tissue.

This conclusion, to be sure, is inferential; but I think it will
be admitted to find strong support in the fact that all manner of
tissues, including even the tissues of an animal of another species
(mouse tissues introduced into the rat, for example), can produce
seemingly the same condition of immunity.

Note, now, the very significant fact that when a dog was cured
of a transplanted tumor by the transfusion of blood of an im-
mune animal in the later experiments made at the Loomis Lab-
oratory, it was shown that decompounding and absorption of the
tumor itself was an essential part of the immunizing process.
This was proved by the fact that it was not found possible to
render a dog immune to transplantation of a tumor by transfusing
blood before such transplantation. It was only after the tumor
had actually been transplanted and begun its growth, that the
transfusion sufficed, through the process of destroying the tumor,
to give the animal immunity against further inoculation.

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 291

Perhaps the most plausible explanation of this is found in the
suggestion that the transfused blood contained corpusclar or en-
zymic substances that could begin the decompounding of the
cancer cell, and that through such decompounding a stimulus was
given to the blood-forming organs of the animal that led to an
elaboration of the defensive mechanism that would not otherwise
take place. The permanent modification of the conditions in the
dog's system that made it resistant to future inoculation would
thus be attributable to activities stimulated by the cancer pro-
teins, acting virtually as autologou-s- antigens.

In this view immunity thus .induced is closely comparable to
immunity induced by inoculation wkh autolyzed tissues.

No doubt it has occurred to a large number of workers, that,
as Dr. Levin phrases it, "to induce en immunity to cancer growth
may indicate the way to rational treatment of cancer, since such
an immunity would prevent the occurrence of metastases, after
the primary tumor is removed." But doubtless most such
workers have felt, as Dr. Levin felt, that "it is self-evident that
the results obtained cannot be transferred as yet to human
pathology."

Had it occurred to any one, however, that the active agent
involved was merely protein matter as such, and not enzymes
specifically associated with or antagonistic to the cancer cell,
there would have been no such embargo on transferring the re-
search to human pathology.

But as the experimenters failed to gain this conception, the
inviting possibilities were unrealized, and the clues to a solution
of the problem were found in a quite different way. I have told
the story in some detail elsewhere and 4t need not be repeated
here.

THE VALUE OF EARLY TREATMENT

Among the most important of the observations of the animal
experimenters, in their possible application to the human subjects,
are those showing that (1) there is a marked distinction to be
drawn between the original susceptibility of an animal to inocula-
tion with cancer and the resistance to growth of the tumor in the
same animal at a later period ; and (2) the correlated fact that the
same tumor appears to develop increasing virulence as it is
brought through section and transplantation from the body of
one animal to another.

As illustrating the first point, it is noted that a pregnant mouse
is very insusceptible to inoculation with a tumor transplanted
from another mouse, yet once the transplantation has been suc-
cessfully effected, the tumor grows with extraordinary vigor.

A possible explanation of this would be that the pregnant ani-
mal has a system relatively well fortified against protein invasion,

292 THE PROTEAL TREATMENT OF CANCER

due to the fact that there is a certain amount of proteid absorp-
tion from the placenta (the experiments of Abderhelden in this
connection will be recalled), which led to a leucocytosis, and to
the presence of an increased enzyme titer in the blood. In a word,
the organism is well equipped to fight against the invasion of the
protein cells represented by the cancer inoculation. If, however,
in spite of this condition of preparedness, the cancer cells grow
with such vigor that they prevail against the defending host, then
it is not surprising that they take on very rapid development, be-
cause of the relatively large amount of nourishment that must be
present in the blood and lymph channels of the pregnant animal
to provide for the growth of the embryo.

It will be recalled that investigators have shown the chemical
affinity between the rapidly growing tumor and the embryo — each
of them containing a relatively low nitrogen content. In a sense,
the foetus is in itself a foreign tumor, and one that takes on ex-
traordinary rapidity of growth. Like the malignant tumor, the
foetus has capacity for almost indefinite growth ; and were it not
possible presently to extrude the foetus it would become as great
a menace to the life of the mother as the cancer itself. That
thought need not be expanded here, however. From the present
standpoint, the important thing is to recall that there is a distinc-
tion between the initial resistance to the early growth of a tumor
and subsequent resistance to its later growth.

It is probable that this variation is not due solely to conditions
in the system of the animal, but that it is also dependent in part
on changed conditions of the tumor itself. This idea finds strong
support in the observed increasing virulence of tumors as they
pass from one organism to another. It seems plausible to sup-
pose that this increasing virulence is at least in part a function
of age; and to infer from this that cancer tissues in the same in-
dividual may gain increasing virulence as they grow older. The
familiar fact that cancer cachexia appears only at the later stage
of development of the malady in the human subject; coupled with
the fact that metastatic secondary tumors very commonly grow
with exceptional vigor, gives added support to this suggestion.

The obvious application of this line of reasoning is that there
is an enormous premium on early treatment of cancer in the hu-
man subject — not merely treatment in the sense of cutting out
the new growth as soon as it is discovered — though in many cases
that may be desirable — but also in the sense of fortifying the de-
fensive mechanism of the body by every available means. There
is abundant clinical warrant for the belief that the protein treat-
ment, for example, may accomplish results when administered to
a patient having a new cancerous growth that could not be hoped
for were the tumor a post-operative recurrence ; the obvious ex-

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 293

planation being, in the light of what has just been said, that, on
one hand, the new tumor is probably relatively non-virulent and,
on the other hand, that the system of the patient has not had time
to undergo so profound a condition of metabolic disturbance as
accompanies the progress of the malady.

Results attained with relative ease at an early stage become al-
most impossible at a later stage, in which the cancer cells were
additionally fortified and the bodily defenses progressively weak-
ened. Stimulated by the presence of the abnormal cells, the
blood-forming mechanism may ultimately reach a point of ex-
haustion which permits only a feeble response to new proteins.
Myelocytes, leucoblasts and lymphoidocytes take the place of
normal large monocytes; normal polymorphs are replaced by
those of small, immature type; the lymphocytes are devoid of
cytoplasm— a "starved" type; the red cells poikilocytic or
nucleated.

This, assuredly, is not a hopeful picture. Yet even under such
circumstances modifications in the blood in the direction of nor-
mality, and corresponding improvement in the general condition
of the patient, together with modifications of the neoplasm, are
sometimes effected by protein treatment within a relatively brief
period, though not with spectacular suddenness. In one of my
recent cases (No. 488), for example, a recurrent cancer of the
breast rapidly developing about one year after removal, the blood
count before treatment showed 33 per cent, of large mononuclear
leucocytes, but very few of these were normal monocytes, the
major part of them being of the leucoblast type. In the san?e
count the polynuclears represented 53.3 per cent, and the small
lymphocytes only 8 per cent., the eosinophiles 4.9 per cent.

After five days'treatment with rape protein, there was a very
remarkable transformation. The leucoblasts had disappeared, pos-
sibly being transformed into polynuclears, since the latter now
represented 69 per cent, of the white cell count. Large mono-
nuclears were now only 4.6 per cent., but these were of the normal
type, either of true monocytes with large nucleus and basic cyto-
plasm or of Ehrlich's transitionals. Meantime, there had been,
seemingly, very active stimulation of the lymphatic system, since
the small lymphocytes now numbered 23.5 per cent. Many of
the lymphocytes were fairly large, and with a relatively large
amount of cytoplasm. The eosinophiles were now only 1.5 per
cent., but there were granular cells that stained dark, resembling
the eosinophiles in structure rather than true basophiles, to the
additional number of 4.3 per cent.

After another interval of five days, the leucocyte count had
progressed still farther in the direction of normality, as regards
the quality of the cells, the typical large monocytes now num-
bered 7.2 per cent. ; the polynuclears 60.2 per cent. ; lymphocytes

294

THE PROTEAL TREATMENT OF CANCER

TABLE IX.— ORIGINAL CASES

A GROUP or CASES or INOPERABLE CANCER STILL UNDER OBSERVATION AND IN ROBUST
CONDITION AFTER PROLONGED PERIODS or PROTEAL TREATMENT
(251 TO 632 DAYS; AVERAGE, 424 DAYS)

1

J

Name

Nature of Case

1 No. of Days II

i

Red
Blood
Corpus-
cles

White
Blood
Cor-

s:

ll

a

Mono-
nuclears

It

SO

Large

Small

278

Mrs. B

Rec. C. of Breast. .

105

90

4,400,000

68.6

19

20.6

1.6

9

180

100

5,408,000

7,600

72

17.3

8.6

2

0

194

100

4,832,000

6,100

54.6

34

11.5

0

0

475

57.4

13.7

26.8

1.7

0.7

16

MiMD....

Rec. C. Of Breast. .

93

90

4,464,000

59

17

24

0

0

198

95

5,664,000

7,600

66.5

21.5

20

2

0

215

100

5,252,000

7,600

61.6

13

24

1.5

0

627

3,705,000

6,240

60

13.3

26.6

0.6

•

881

Mrs. H....

Melanoma

2

100

4,752,000

7,600

80.5

7.6

8.6

8.3

0

16

100

4,448,000

8,000

78

10.5

7

4.5

0

30

100

4,500,000

8,200

81

12.5

6

1

.5

48

100

5,184,000

8,000

77.5

9.5

11

2

0

324

67.5

21.5

8.5

.6

1.5

239

Mrs. M...

Car. of Breast

142

90

5,376,000

7,200

64.3

16.3

15.6

3.6

•

156

95

4,800,000

8,800

62.3

21.5

13

2

1

172

100

5,096,000

siooo

60

23.5

13

2.5

1

405

58

16

22

4

0

870

Mrg.R....

Ep. Car. of Hand..

5

95

4,896,000

10,200

72.6

14

10.6

2.6

0

20

90

4,556,000

10,400

74

10

12

3.5

Ji

45

90

4,130,000

12,000

77.5

16

6.5

1

0

811

58.4

30.3

5.8

5.4

.1

242

Mrs.S

Ep. of Face

69

75

2,800,000

60

10.5

29

.5

0

144

95

4,672,000

6,600

65.5

28

14.5

1

155

100

4,672,000

7,200

60.6

31

15.5

8

•

460

51

9

38.5

1.5

882

MrfcV.W.

Rec. C. of Breast. .

50

85

5,008,000

8,880

64

16

24

0

9

62

100

4,522,000

7,600

58.6

18.6

19.3

2.3

I

76

100

4,448,000

7,400

65

17.6

15

2.6

0

90

100

5,656,000

8,900

48.5

27

20.6

4

0

394

39.3

17.6

41.6

1.3

0

455

100

5,600,000

6,900

61

29.5

18.5

1

0

605

100

5,610,000

6,600

168

Miss W. . .

Rec. C. of Breast. .

88

80

4,448,000

66.3

11.6

20

2

0

112

95

4,240,000

8,000

67.3

21.6

10

.6

.3

121

100

4,650,000

9,200

64.5

18

17

.6

0

486

52.6

20.3

26

1.3

0

251

Mrs.W...

Rec. C. of Breast. .

632
63

100
85

5,177,000
3,570,000

9,100

74

11

11

4

0

138

85

5,280,000

9.400

68

16

9.5

6.5

0

155

95

4,288,000

8,600

64.5

19.6

12

8

1

467

63.6

9

20

6.6

609

6,044,000

60.3

8.3

22.6

8.8

868

MmC....

Rec. C. of Breast. .

1

90

3,976,000

9,330

66.6

14.3

17.3

2.3

.3

29

95

4,112,000

8,500

64.6

19

12.3

3.6

.3

44

100

4,576,000

8,900

72

14.5

13

.6

0

60

100

4,096,000

8.000

61.5

19.5

18

1

0

312

55.3

16.6

28.3

2

0

643

Mr. P

C. of Stomach....

0

60

4,956,000

12,200

57

11

30

2

0

7

75

4,364,000

8,500

59.5

19

21.5

0

•

17

70

4,012,000

7,200

24

80

4,974,200

6,138

29

63.8

18.5

16.5

1

.5

33

80

5,000,000

6.900

50

25.6

23.6

.6

41

85

4,938,000

8,800

228

4,644,000

8,200

70

12.5

12.5

4.6

243

85

4,848,000

9,600

261

4,320,000

6,400

ANIMAL EXPERIMENTATION AND PROTEAL THERAPY 295

24.4 per cent. ; eosinophiles 5.6 per cent. ; basophiles 1.2 per cent.
At this time study of the red cells showed a great abundance
of normoblasts and free microblasts. Two weeks later, however,
these had altogether disappeared (October 18th). The large
monocytes, of normal type, now numbered 9.6 per cent. ; the poly-
morphs stood practically unchanged at 59.6 per cent. ; the lym-
phocytes had fallen to 19.6 per cent., and there were only 1 per
cent, each of eosinophiles and basophiles. A month later (No-
vember 16th), the count showed continued progress, the poly-
nuclears having fallen to 55.3 per cent., whereas large mononu-
clears had risen to 13.3 per cent., small lymphocytes to 27.3 per
cent., and eosinophiles to 4 per cent.

The significant feature of this blood modification was the
transformation from abnormal types to normal types of large
mononuclears and the very notable increase of lymphocytes. The
patient's general condition had meantime improved and there was
a tendency to softening of the tumor mass in the breast, flattening
of a large lymph node in the axilla, and marked regression of a
subclavicular mass. It was not to be expected, however that very
marked regression of the tumor would occur until the large mono-
cyte count had been brought to a much higher state. The ulti-
mate result must be left for future record. I mention the case
here merely to illustrate a rather exceptional modification of the
blood count, and to emphasize the point that in a case of such
chronicity, in which the lymphatic system is seriously involved,
with metastases, one must be content to go slowly, expecting no
such spectacular metamorphosis as was recorded in the letter
above quoted.

By way of contrast, note the progress of another recent case
(No. 497) in which there was primary involvement of both
breasts not far advanced. A surgeon had advised removal of both
breasts, yet malignancy was considered doubtful by me until the
blood count showed the following : polynuclears, 48.9 per cent. ;
large mononuclears (including myelocytes), 16.6 per cent.; small
lymphocytes, 30.5 per cent.; eosinophiles, 4 per cent. The re-
sponse to the proteal treatment was immediate; the patient re-
ported a transformation in general health, and the blood count
after three weeks of treatment (November 16, 1916) was: poly-
nuclears, 43.6 per cent. ; large monocytes, 21 per cent. ; small lym-
phocytes, 33.6 per cent.; eosinophiles, 1.6 per cent.

The rapid response of this patient as contrasted with the pre-
ceding one may be ascribed, in all probability, to the early stage
of development of the neoplastic growths.

With the emphasizing of this point, I may perhaps advantage-
ously leave this aspect of the subject, reiterating the opinion that:
here, as in so many other fields of pathology, there is a tremen-

296 THE PROTEAL TREATMENT OF CANCER

dous premium on early treatment. Proteal remedies have indeed
proved capable of giving, solace in extraordinary measure to late
stage inoperable cases of the most hopeless type; but the full
measure of what may be expected of the new treatment can be
gauged only when the Proteals have been administered to a large
number of cases at an earlier stage of development.

SECTION XI
THE PREVENTION AND CURE OF CANCER

If the essential thesis of this paper as to the nature of cancer
is accepted, and it is further accepted that the administration of
vegetable proteins hypodermically tends to stimulate the enzymes
capable of protein hydrolysis, certain practical suggestions as to
the prevention of cancer; as to possible cure of the cancerous
condition ; and as to the obviation of its recurrence, follow almost
as matters of course.

Since, however, things that seem obvious after one has devoted
much thought to a subject are not always quite so plain to those
who have thought along different lines, perhaps it may not be
amiss to present here, partly by way of summary and recapitula-
tion, a brief practical discussion of the prevention and the pos-
sible cure of the condition which I have characterized as hyper-
proteomorphism, with particular reference to that phase of the
condition characterized by the presence of a malignant neoplasm
or true cancer.

As to prevention, I shall speak only in the briefest terms.
Whatever tends to maintain the general good health, keep the
blood count normal, promote the normal digestion and nutrition,
and keep the muscles (including those of the arterial walls) plas-
tic, tends to ward off the cancerous condition.

No single expedient, in my judgment, is more important than
habitual and vigorous exercise, particularly for persons in middle
life and (modified in intensity) in old age. Keep the muscular
system in really vigorous condition ; avoid excess proteins in the
food, in particular animal proteins ; drink plenty of water ; avoid
all sources of general systemic irritation as well as local irritation,
and there is at least a large measure of probability that the can-
cerous condition will never develop.

Once it has developed, however, and in particular when it has
formed a local neoplasm of the type that we term epithelioma,
carcinoma, or sarcoma, as the case may be, is there a possibility
of a cure of the condition?

THE PREVENTION AND CURE OF CANCER 297

The answer must be, I think, that there is nothing inherent in
the nature of the malady that makes it necessarily fatal (the re-
sults of animal experimentation appear to justify this verdict) ;
but that, on the other hand, it is implied in the very nature of
the condition that unless there can be a radical readjustment of
the relations of the individual to his environment, the case is
hopeless.

Merely to cut out the local neoplasm, and hope thus to cure
the disease, is a childish procedure. The surgeon tells you that if
you make the incision early enough and radical enough, all will
be well. But, of course, you can never make the incision early
enough nor radical enough. You could, to be sure, eradicate
cancer of the uterus by universal hysterectomy in childhood, and
annul cancer of the breast by universal amputation of infantile
mammae. But such a procedure would have no conspicuous bear-
ing on the cancerous condition, and would not in any way shield
the organs that remained.

It is true that most surgeons claim a considerable proportion
of "cures" following their operative procedures, particularly for
cancer of the breast. But very few surgeons have cared to pub-
lish statistics as to the post-operative history of their cases, ex-
tending over a term of years. One surgeon of my personal ac-
quaintance admits that when he attempted to follow up his cases
he found that very few indeed were living three years after the
operation, and only a single case after a lapse of five years.

Whether or not we accept that as a typical experience, it will
be denied by no one that the usual and, so to say, expected his-
tory of a cancer case after operation is characterized by meta-
static recurrence ; that after a second and perhaps a third opera-
tion the case reaches an inoperable stage; and that inoperable
cancer is universally regarded as among the most hopeless of
conditions.

Speaking with the utmost conservatism, we can now say that
experience justifies the statement that the Proteal treatment has
come with at least a message of hope for these supposedly hope-
less cases. As regards actual and permanent eradication of the
diseased condition, doubtless this applies to only a small percen-
tage of the cases hitherto treated by the new method. But that
is merely equivalent to saying that the major part of the cases
thus treated have been individuals whose systems were in so
profound a state of disrepair that in the nature of the case they
could not be mended.

Researches at the Mayo Clinic have made it clear to what an
alarming extent changes that may be considered cancerous in
character occur in other organs of the body than those directly
effected either by the original neoplasm or by definite metastases.

298 THE PROTEAL TREATMENT OF CANCER

These observations are obviously in keeping with the present
thesis as to the general character of the cancerous condition.
They accord also with a wide range of clinical experience. It is
almost axiomatic to say that no two cases could be precisely alike
as to the exact degree of involvement of the various organs and
tissues of the body. Inherent susceptibilities of hereditary char-
acter, combined with accidental conditions of local irritation,
would determine that in one case the liver, in another the pan-
creas, in a third the kidneys would have suffered most from the
condition of nutritional maladjustments, in a series of cases in all
of which the seat of the "primary cancer" might be, let us say,
the breast, the stomach, or the uterus.

It is equally axiomatic to say that the precise location of me-
tastatic masses and the precise relative degree of involvement of
various organs affected without metastasis must be vastly im-
portant in its bearing on the prognosis of the case as regards im-
minence of the fatal issue.

Obviously, then, each case must be a law unto itself. If it is
hazardous to generalize regarding conditions described merely as
"cancer of the breast," "cancer of the uterus," etc., it is equally
hazardous to attempt predictions as to the possible curability of
any individual case thus described.

No one speaking with authority in connection with the Proteal
treatment ever made such- a prediction or held out the expectation
of cure in any individual case. From the outset, in my publica-
tions and medical addresses on- the subject, I have urged that a
conservative attitude must be maintained as regards ultimate
prognosis.

No one speaking with authority has suggested or expected that
the proteins would perform the necromantic feat of restoring de-
generated and decompounded cells of liver or spleen or kidneys
or pancreas or intestinal glands. As well ask the surgeon to re-
place a lost arm or leg. Yet without such regeneration, in a large
proportion of cases, it would be utterly futile to hope for the
restoration of normal conditions of protein metabolism absolutely
essential to health.

If, in such a case, the Proteal -treatment favorably modified the
blood count and made possible a temporary improvement in
metabolism, thereby relieving the patient's distress, nullifying
the obnoxious odors of a cancerous -discharge, inducing a sense of
well being, and prolonging life by a term of weeks or months
while at the same time giving comfort — everything has been ac-
complished that could rationally be expected ; everything, perhaps,
that can never -be hoped for in connection with the treatment of
cases at so advanced a stage.

It should be added, however, that it is seldom possible to de-

THE PREVENTION AND CURE OF CANCER 299

termine with accuracy the precise stage of advancement of any
given case, for the obvious reason that we cannot examine the
structure of the various organs even if quantitative tests of their
degree of involvement were available. A case that seems pro-
foundly cachectic, and even almost moribund, may in reality have
tissues less vitally involved than those of another case that has
been tangibly affected for a much briefer period and in which the
visible symptoms seem less alarming.

Hence it occasionally happens that a case in which the most
optimistic estimate of a skilled observer would predict a very early
demise responds to the treatment with unexpected vigor and ral-
lies in a way which enthusiastic observers have not hesitated to
speak of as "almost miraculous."

In a considerable number 'of instances, cases of this character
have gone on, under the Proteal treatment, to a stage of improve-
ment which may with validity be spoken of as clinical recovery.
Whether or not the conditions of bodily metabolism have been
permanently readjusted in such wise that the proliferation of mis-
placed cells will be prevented in future, must be left to the future
to decide.

It may fairly be said, I think, that where a cancerous mass has
thus retrogressed under the Proteal treatment there is greater
inherent probability of non-recurrence than if it had disappeared
under local treatment or through surgical interference ; inasmuch
as an improved condition of general bodily metabolism is implied
in the results attained by the hypodermic method.

When treatment consisting exclusively of hypodermic injection
into the tissue of the upper arm has resulted in the regression of a
tumor mass in the pelvis, no argument is required to show that
there has been profound modification of the condition of the body
fluids. It is perhaps permissible to hope that this modification
may have an element of permanency, or that it may be kept up
by occasional administration of the hypodermic remedy, and that
recurrence or metastasis of the localized cancerous mass will thus
be prevented.

I repeat, that this is a matter for the future to decide. But I
would suggest also that every practitioner who has successfully
treated a case with Proteals should feel it incumbent upon him
to urge his patient to have a blood count made at intervals of
two or three months so long as he lives, and to submit himself
to a new course of treatment should the blood show the slightest
deviation from the standard. Doubtless it would be safer to take
an occasional course of the treatment whatever the blood condi-
tions. In any event, the treatment should not be discontinued for
a good many weeks after the disappearance of the neoplasm.

That there should be most careful attention to the diet with

300 THE PROTEAL TREATMENT OF CANCER

particular reference to the nitrogen balance, goes without saying.
Careful attention should be given to all hygienic measures tend-
ing to promote general health. But in particular a regime of life
should be adopted that includes daily systemic exercise of the
most vigorous type consistent with the patient's condition of
muscular tract. In my opinion, no single measure is more im-
portant than this ; indeed, no other measure except that concern-
ing the protein diet, approaches it in importance.

But these, after all, are matters regarding which the wise physi-
cian scarcely needs counseling. When it is clearly apprehended
that the cancerous condition is due to a maladjustment of protein
metabolism, it follows as a matter of course that all the measures
commonly recognized as tending to reestablish the normal adjust-
ment of such metabolism must be, in the first instance, preventa-
tive of cancer ; in the second instance, invaluable as auxilliaries
during the treatment of the malady, by whatever method; and,
in the third place, indispensable as measures directed against re-
currence of the malady.

But while all this, stated in general terms, seems fairly axio-
matic, there goes with the suggestion the implication that no type
of malady could give greater opportunity for the exercise of pro-
fessional skill than the treatment of the cancerous condition. I
have urged the futility of surgical treatment which is content
merely to wield the knife and disregard all general measures. I
would now urge that it would be only a degree less fatuous to
suppose that adequate treatment of a cancer case by the protein
method implies merely the random administration of a hypo-
dermic. Yet a -good many physicians who have used proteins have
seemed to labor under this misapprehension. The correspondence
is filled with letters from physicians of acknowledged standing
who state that they have administered a dozen ampules, or two
dozen ampules, of Proteals with remarkable results, and who now
wish to ask if it is necessary to continue treatment.

A typical instance of -this kind concerned a case of uterine can-
cer, originally operated upon and, after recurrence, pronounced
inoperable at one of our most important metropolitan cancer hos-
pitals, and subsequently radiumed without benefit and pronounced
hopeless. Proteals had been turned to as a last resort, and
eighteen doses had been administered in a term of about six
weeks. And then the physician, without show of emotion, calmly
inquires whether there is any necessity for further treatment, — a
cure having seemingly been effected !

Needless to say the physician was urged to continue the treat-
ment.

I cite this instance as illustrating how vague may be the con-
ception of the true character of cancer in the minds of well-in-

THE PREVENTION AND CURE OF CANCER 301

formed physicians. Perhaps this is not surprising, considering
that the available authorities differ so widely in their estimate of
the nature of cancer. The fact that Metchnikoff advocated the
theory of the germ origin of cancer no doubt has "had great
weight ; and doubtless there are physicians who, in accepting this
view, and having also in mind the conceivability of destroying
disease germs at a single dose, or at the most with two or three
doses, as was at first expected of Salvarsan, have thought that
the Proteals might act in similar manner. Their expectations seem
to be justified when the administration of two or three doses pro-
duces very striking modification in symptoms, including change
in the character of the discharge, and a softening and tendency
to regress in the neoplasm itself.

Even were cancer a germ disease (which I altogether disbe-
lieve), and were it therefore possible to conceive a treatment that
would eradicate the cause of the disease at a single coup, by the
slaughter of bacteria, there would still remain the neoplasm itself,
a proteid mass, to deal with. To expect that medication of any
character would lead to the dissolution of the mass, when it is a
large one, without profound systematic disturbance would be to
misconceive the nature of the essential physiological conditions.
It is neither to be expected nor desired that the protein matter
making up the cancer should be hydrolyzed all at once, nor even
with great rapidity. Were the enzymic attack on the cancer cells
too active, the blood must become charged with the products of
protein decompounding, and a tax would be put upon the cerebral
tissues and the organs of elimination that they might not be able
to withstand.

It follows that the carrying of a case of cancer under the pro-
teal treatment to a favorable issue, even in the least complicated
cases, is a matter demanding full measure of professional skill.
I recall once hearing a somewhat distinguished artist say that any-
one can begin the painting of a picture, but that it takes an artist
to finish it. Similarly it may be said that any one can begin the
proteal treatment of a case of cancer. Whoever can administer
a hypodermic with ordinary aseptic precautions can secure defi-
nite results that are conspicuous and even notable in a great ma-
jority of cases. But to carry the case forward so that the effects
are cumulative, and ultimately to secure the largest measure of
benefit possible, requires skill of a high order.

If the best possible results are to be attained, it will be neces-
sary not only to administer the treatment with constant observa-
tion of results as a guide to dosage and frequency of administra-
tion and the shifting from one proteal to another ; but also to in-
voke, in many cases, the aid of supplementary measures.

First and foremost among these supplementary measures, is

302 THE PROTEAL TREATMENT OF CANCER

the knife of the surgeon. It is true that the Proteals have hitherto
been applied almost exclusively in inoperable cases. But in more
than one instance it has happened that, under the influence of the
remedy, a cancerous mass too widely extended for removal has
regressed until the remaining mass is readily operable. In such a
case, I would strongly urge that the co-operation of the surgeon
should be sought, and the mass excised. By so doing, we relieve
the system of the patient of the burden of absorption of a mass
of protein tissue.

It will not usually be necessary, however, to make the surgical
operation so radical, when Proteals are used, as it otherwise must
be ; inasmuch as the metastatic glands and the neighboring tissues
— which at best the surgeon can remove but inadequately — are
peculiarly subject to the proteolytic enzymes evoked by the ad-
ministration of the hypodermic remedy.

It goes without saying, now that Proteal therapy supplies a
means hitherto not available, to stimulate the production of the
blood corpuscles and whip up their enzyme-forming capacities,
that no surgeon of judgment will think of performing an opera-
tion for cancer without supplementing his surgical procedure with
the use of Proteal remedies before and for some time after the
operation.

It is essential, of course, to bear in mind the familiar phenom-
ena of anaphylaxis, and to continue the administration of any
given protein daily, or at intervals of two or three days at the
most, until immunization is attained. It would obviously be in-
advisable, after administering a given protein, to wait ten days
or two weeks before administering a second dose of the same
protein ; since it is precisely under such conditions that the phe-
nomena of anaphylaxis in its alarming form are likely to be
developed. One protein, as is well known, does not fully im-
munize the system against another. Indeed, it is precisely this
fact, as already pointed out, that furnished the basis for the
theoretical administration of a series of proteins along the lines
just suggested.

It has been pointed out that there is a wide range of variation
among patients as regards their response to a given quantity of
any foreign protein. The degree of susceptibility of individual
patients must be determined by experiment.

It should be recalled, however, that in giving maximum doses
one is introducing a relatively large quantity of foreign proteins
and that these proteins must be dealt with by the bodily enzymes.
So it may be accepted as a general principle of medication that
the smallest dose that will produce a vigorous enzymic (corpus-
cular) response is the best dose.

There may come a time in the course of any individual case,

THE PREVENTION AND CURE OF CANCER 303

at which the enzymic response has reached the maximum. If,
then, the administration of large doses of Proteals is continued
at short intervals, the demands put upon the corpuscles in dealing
with the proteins thus introduced may exhaust their resources,
tending to induce a condition of pernicious anaemia.

The rational procedure in such a case is to discontinue for a
time the administration of the protein to which the body has
become "immunized" ; either giving no treatment at all for a time
(days or weeks, according to the progress of the case), or else
substituting small doses of different proteins. In either case, the
dose of the original protein should be small when its use is
resumed. Patients who had discontinued the treatment for a
term of weeks have repeatedly been observed, on resumption of
the treatment, to react as vigorously to the small doses as if
taking it for the first time.

From all this it will appear that no mere rule of thumb can be
applied in determining the dosage, interval of administration, or
length of treatment with protein antigens of any individual case
of cancer. In general, it may be said that the dose to be aimed
at is that which will carry the red blood count and the haemo-
globin test to the normal, and keep the large mononuclear leuco-
cytes in adequate cohorts.

It should be recalled that no treatment can hope to produce
better general systemic conditions than the individual patient ex-
perienced during his normal life; hence that every one who has
suffered from cancer must always be more or less liable to recur-
rence,— unless, indeed, it should ultimately be shown that a meas-
ure of immunity results from regression of the neoplasm.

In other words, the cancer would not originally have developed
had there not been certain inherent defects in the bodily mech-
anism of the individual. Often these defects are hereditary.
Usually they are associated with the on-coming of old age, prema-
ture or otherwise. They mark a condition in which the capacity
of the organism to deal with protein metabolism is waning. So
this individual will probably always need the prop of an artificial
stimulant to the cytogenic apparatus from time to time. Proteals
supply such a prop. Their use will probably become routine prac-
tice not only in the post-operative treatment of cancer subjects,
but in the after-year treatment of cases that have had the neo-
plasms removed by the action of Proteals themselves.

Obviously the same thing applies to cases treated successfully
with X-ray and radium.

In a word, it may be expected that the province of Proteal
therapy will be by no means confined to the treatment of cancer,
but will have a place at least as important, and conceivably more
important, in the prevention of recurrence after the local neoplasm

304 THE PROTEAL TREATMENT OF CANCER

has been removed by any means whatsoever ; and, ultimately also,
no doubt, in prophylaxis applied to any person who through mal-
nutrition, combined with some local source of irritation, has rea-
son to fear the development of cancer.

Meantime this method gives to the individual cancer sufferer,
whatever the stage of his malady, and to the physician who is
called upon to treat him, the most enheartening message of hope
that pres«nt-day therapeutics can offer.

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