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John Jacob Abel, M.D.

. . . . in his laboratory in the old
Physiology Building at Hopkins

John Jacob Ah el, m.d.

A Collection of

Papers by and about

The Father of

American

Pharmacology

John

INVESTIGATOR •

G/

-3

ft 19

Jacob AheL m.d.

TEACHER « PROPHET • 1857-1938

THE WILLIAMS &: WILKINS COMPANY

Baltimore, 1957

}
»

composed and printed by

Waverly Press, Inc.
Mt. Royal & Guilford Aves.

Baltimore 2, Md., U.S.A.

Publishers Foreword

This limited edition of a collection of papers by and about John
Jacob Abel is, like many of Dr. Abel's own endeavors, a labor of love.
It has been prepared and published as a memorial to Dr. Abel on the
occasion of the one-hundredth anniversary of his birth. It is intended
for distribution to members of the American Society for Pharmacology
and Experimental Therapeutics, to others who have been associated
with Dr. Abel and his work, and to friends of ours who will, we think,
be interested.

The brief recitation of a bit of history seems requisite for two rea-
sons of quite unequal importance. The first and least important, is to
justify our association with this enterprise. The second is to exhibit
a facet in the career of Dr. Abel that could easily be quite unknown
to many.

In 1908 or 1909, Dr. Abel conceived the idea of a journal to serve
as means of communication in the field of pharmacology. In his
casting about for means of bringing the idea to practical result, he
encountered Edward B. Passano, then proprietor of a printing concern
called Williams &: Wilkins Co. That company had, a few years earlier,
begun to specialize in the printing of the literature of science; but it
had done no publishing— i.e., it had not assumed the risks of an en-
trepreneur.

Dr. Abel convinced Mr. Passano that American facilities for the
communication of science results were sadly lacking, and persuaded
him that such a field of endeavor could be most rewarding and might
one day be profitable.

The practical result was that the printing company began, in 1909,
to publish The Journal of Pharmacology and Experimental Thera-
peutics, Dr. Abel being its founder and editor (1909-1932), and has
continued to do so ever since. A concomitant result was the inception
during the next decade, under the aegis of Williams & Wilkins, of a
number of new American journals in science. The publishing ven-
ture was extended to books in 1920, and by 1925 it appeared to be of
sufficient volume and extent to justify separate corporate existence.
The old name, with a slight change, was retained for the publishing
business; the manufacturing or printing branch took the style,
Waverly Press, Inc.

Thus Dr. Abel was instrumental in bringing a publishing house
into existence, one that has not been without importance to American
science; at least it did pioneer in a field which, in the early years of the
century, was anything but attractive to business entrepreneurs. To be
sure, Dr. Abel did not work alone. But without his interposition and
his inspiration, nothing would have been done. Many others must
have deplored the lack of publishing facilities as he did. But he had the
percipience to look a little more clearly into the future and the con-
fidence that enabled him to make others share his vision.

Probably Dr. Abel himself would not have counted the establish-
ment of a publishing business among his achievements. Yet it is cer-
tain that he planted the seed from which one grew and equally certain
that he read the future correctly.

The Williams k Wilkins Company
Waverly Press, Inc.

VI

Contents

Abel the Prophet. E. K. Marshall, Jr 1

John Jacob Abel— A Portrait. Paul D. Lamson 8

On the Blood-Pressure-Raising Constituent of the Suprarenal Cap-
sule. John J. Abel and Albert C. Crawford 43

On the Teaching of Pharmacology, Materia Medica, and Thera-
peutics in our Medical Schools. John J. Abel 57

On the Removal of Diffusible Substances from the Circulating
Blood by Means of Dialysis. Jofln J. Abel, L. G. Rowntree,
AND B. B. Turner 73

Crystalline Insulin. John J. Abel 76

Vll

Acknowledgment

Grateful acknowledgement is made to the authors and original
publishers of the articles in this book. Without their permissions to
reprint so extensively from their copyrighted publications this tribute
to Dr. Abel would not have been possible.

Abel the Prophet. E. K. Marshall^ Jr.

Reprinted from "The Johns Hopkins Magazine," Volume 1,
1950.
John Jacob Abel— A Portrait. Paul D. Lamson.

Reprinted from "Bulletin of the Johns Hopkins Hospital," Vol-
ume 68, 1941.
On the Blood-Pressure-Raising Constituent of the Suprarenal
Capsule. John J. Abel and Albert C. Crawford.
Reprinted from "Bulletin of The Johns Hopkins Hospital," Vol-
ume 8, 1897.
On the Teaching of Pharmacology, Materia Medica, and Thera-
peutics in our Medical Schools. John J. Abel.
Reprinted from "The Philadelphia Medical Journal," special
number on Medical Education, September 1, 1900.
On the Removal of Diffusible Substances from the Circulating
Blood by Means of Dialysis. John J. Abel, L. G. Rowntree
and B. B. Turner.
Reprinted from "Transactions of the Association of American
Physicians," Volume 28, 1913.
Crystalline Insulin. John J. Abel.

Reprinted from "Proceedings of the National Academy of
Sciences," Volume 12, 1926.

VIU

Abel the Prophet

E. K. MARSHALL, JR., M.D.

In the fall of 1936, the sulfa drugs were just beginning to be used in
this country. Within a decade, better sulfa drugs were introduced and
less toxic and more effective remedies like penicillin and streptomycin
cured many forms of infectious disease. However, in that autumn of
1936, I knew that few appreciated that the introduction of the sulfa
drugs would completely revolutionize the treatment and importance
of infectious disease, that they would make Ehrlich's dream of a harm-
less magic bullet with which to cure disease almost come true.

On Christmas Eve of that year, I called on my old teacher, colleague,
and friend, John J. Abel, and found him very busy in his laboratory.
Having known him for over a quarter of a century, I realized that the
time was not ripe to sit for a long chat, and without removing over-
coat, I sat down and talked with him for the duration of one cigarette.

When I arose, the old gentleman in a fatherly way put his arm
around my shoulder and very politely piloted me to the door. When
we arrived there, he stopped for a moment and, more as a gesture of
politeness than anything else, he asked me what I was doing now. I
told him I had been very busy all fall with the pharmacology of the
new antibacterial remedy, sulfanilamide. He said, "That's fine," then
jerked up and with a characteristic lift of the eyebrows, "What's this
all about?"

He asked a couple of searching questions and then led me back
into the room. "Sit down, take off that coat, smoke a cigarette, and tell
me all about it."

"Oh, but you're very busy, Professor. I'll come over some other
time," I replied.

"Never too busy to hear about things like this, my boy," he said.

For a half hour or more, I told him what I knew about this new
development in medicine. He asked some very pertinent questions,
and then raised his head and with a faraway look said, "My God,
Marshall, wouldn't Paul Ehrlich turn over in his grave?

This seventy-nine-year-old scientist sa\v at once the great signifi-

cance of what had happened and had such a vision of the future that
the miracles of the next decade might not have surprised him if
he had lived to see them. This breadth of vision in foreseeing im-
portant developments of medicine was one of the qualities which was
responsible for much of Abel's success and greatness.

John Jacob Abel belonged to that small group of men who made
up the first faculty of the Johns Hopkins School of Medicine, and, in
addition, was one of the pioneers who helped build up scientific
medicine in America to the high place which it now occupies in the
world. This is not the place to review Abel's contributions to science,
which covered many subjects during a period no less than half a cen-
tury. However, I shall try to point out many instances of his prophetic
vision in regard to the future developments which were to take place
in medicine.

The life of this first professor of pharmacology in the Johns Hop-
kins University began on a farm near Cleveland, Ohio, on the nine-
teenth of May, 1857, and ended in Baltimore on May 26, 1938, after
a long career in American experimental medicine. His family came
from the Rhine Valley of the Palatinate. He had no scientific fore-
bears on either side. There is reason to believe that he owed his
college education to his initiative

He received his Ph.B. degree from the University of Michigan in
1883, but had an interim of three years in his college course, during
which he served as principal of a high school at La Porte, Indiana,
Avhere he taught Latin, mathematics, physics, and chemistry. Abel
must have looked back on these years with satisfaction, for it was in
La Porte that he met a teacher in his school, whom he once described
as a "very sweet, mild little lady with a great deal of force." This
lady, Mary Hinman, became his wife and was his companion for fifty-
five years. She stood by his side through many tribulations and en-
couraged her husband to acquire a broad medical and scientific edu-
cation. There can be no doubt that Abel's happy family life was a
potent factor in his scientific career.

After graduation, Abel set his course definitely for scientific medi-
cine as his life's work. Two things which he did at that time indicate
his ability to see what scientific medicine was to be like in the future.
He submitted himself to a prolonged, broad, fundamental training,
which consisted of a year with Newell Martin in physiology at the
Johns Hopkins and then seven years with some leading teachers in
the medical schools of Europe. He thus acquired not only a medical

2

degree, but a broad scientific education, and Avas prepared tor scien-
tific medicine in a way which in this country was only recognized as
the correct one some thirty or forty years later.

Also, there can be little doubt that at this time Abel had a clear
vision of what a tremendous role chemistry was to play in the future
of scientific medicine. Irrespective of the expense, which he could
ill afford, he determined to be prepared for this coming development.
While in Europe in 1889, he frequently mentions in his letters the
need of medical chemistry in the hospitals in this country and wants
to come back to the States with some entirely "new line" of work
as well as to get "ready for the twentieth century." Although many
of his colleagues at that time thought his ideas absurd and visionary,
everyone now realizes how justified this vision of his in regard to
chemistry in medicine was.

Very soon after coming to the Hopkins in 1893, his interest de-
veloped in the glands of internal secretion (the endocrine glands)
and indeed in the isolation of their active principles or hormones.
He first tackled the thyroid gland and was busily engaged on this
project when news of Baumann's work on the iodine-containing iodo-
thyroglobulin came out. He stopped the thyroid work, but soon be-
came interested in the hormone of the adrenal medulla, which had a
remarkable blood-pressure-raising action.

When one considers the tremendous importance in medicine of
this field of the endocrines (or hormones) at the present time, one
can only think of Abel's early interest as prophetic. It is now well
recognized that the key to many problems connected with each endo-
crine gland is to be found in the isolation of the pure active principle.
That he early appreciated the importance of stich contributions is
shown by the foUo^ving sentence in one of his addresses: "The actual
finding of definite and specific chemical principles in the organs of
internal secretion has in each case an importance in the way of ex-
plaining and correlating a large number of disconnected facts, only
to be likened to the discovery of the etiological cause of an infectious
disease." He was fond of emphasizing the importance of the powerful
drugs present in the human body in the aphorism, "We are walking
drug stores."

To rettirn to Abel's first published research on the hormones, it
is well known that in 1897, he isolated the active principle or hormone
of the adrenal medulla in the form of a benzoyl derivative. This was
the first instance of the isolation of a hormone of any endocrine gland.
Later, the pure substance was isolated without the benzoyl radical.

3

This substance has been called epinephrine or adrenaline and has
been used in medicine for the past half century.

Scarcely a night passes in the accident room of any large hospital
that patients suffering from asthma are not given an injection of epi-
nephrine, which gives dramatic relief to these sufferers in the course
of a few minutes. Many individuals covered with urticaria (hives)
obtain complete relief from this troublesome condition by an in-
jection of epinephrine. Due to the fact that this substance causes a
marked constriction of blood vessels, it is used thousands of times
every day in connection with local anesthetics. Every time a tooth
is extracted, every time a minor surgical operation is performed, this
substance is used in connection with the local anesthetic.

Opinions may differ as to how much credit should be given to Abel
as the one responsible for the isolation of the first pure hormone. It
is quite true that he did not obtain the hormone of the adrenal
medulla as such but only in the form of a derivative, and it is equally
evident that during the decade in which he was engaged in this
problem, he fell into many pitfalls and made mistakes. It is now
well known that the so-called pure hormone obtained from the ad-
renals is a mixture of two substances, epinephrine and nor-epineph-
rine. Be that as it may no one can detract from the importance of
Abel's pioneering work in making available this valuable medicinal
for research and therapy.

Shortly after the hormone insulin, which has revolutionized the
treatment and progress of diabetes, was discovered, Abel interested
himself in an attempt to obtain the hormone in chemically pure
crystalline form. This he succeeded in doing in 1926, in spite of his
sixty-nine years and his quaint and antiquated methods of chemical
procedure. This was the first isolation in pure crystalline form of a
hormone which must be considered as a protein.

Abel's announcement of the crystallization of insulin was received
with skepticism by many chemists as a final proof of the isolation of
the pure hormone. The criticism was made that the highly potent
true hormone was adsorbed on a crystalline protein. But all criti-
cisms were finally met and Abel's great achievement of the chemical
isolation of insulin in pure crystalline form was soon completely
established. It is amusing to recall that for many months after the
preparation of the crystals, Abel himself was unable to repeat the
performance. He never, however, lost faith. Ultimately, he found the
answer and crystalline insulin is now commercially prepared.

This great optimism in regard to the outcome of his researches is

well illustrated by incidents which occurred during his efforts to
isolate in pure form the hormone of the posterior pituitary gland.
An assistant who was testing Abel's preparations for pharmacological
activity tells me that after he had tested dozens of preparations and
found them all inactive, Abel would come to him with a new one and
confidently say, "I've got it this time." After an evening of testing,
the assistant informed Abel the next morning that the preparation
was completely inactive and was greeted, "It's probably left in the
mother liquor. We'll be sure to get it next time." This abiding faith,
optimism, and enthusiasm in spite of great difficulties and disappoint-
ments marked Abel's career.

In 1913, Abel became interested in a potential method for the re-
moval of diffusible substances from the circulating blood of living
animals by dialysis. At the first inception of the work, he discussed
his idea and plans with his staff at the luncheon table. The author
can clearly recall this particular luncheon meeting. The professor used
small cylinders of bread to illustrate how the apparatus was to be
made and talked glibly about how this "artificial kidney" would be
valuable to provide means for the removal of substances detrimental
to the body in order to relieve the kidneys of their function and tide
over a crisis. At this conception of the idea, he clearly saw the possi-
bility of the use of his "artificial kidney" as a therapeutic measure for
man.

The task was to pass the blood of an animal from an artery through
a series of collodion tubes surrounded by saline solution back into
a vein. Many technical difficulties had to be overcome but in No-
vember, 1913, the first successful experiment was performed on a
rabbit. [See illustration between pages 16 and 17.] When the "old
man" talked of the clinical application of the measure for the treat-
ment of intoxications or to tide over when the kidneys were not func-
tioning, his associates, including the author, considered him a bit of a
visionary. In 1926, Haas of Giessen actually used an "artificial kidney"
on three htmian patients. It was not, however, until 1946 that Kolff in
Holland and Murray in Toronto were able to put the "artificial
kidney" on what appears to be a workable basis. Great technical im-
provement has been made, but the idea and general principles are
the same as those developed by Abel a third of a century before.

In connection with his studies on the "artificial kidney," Abel found
from experiments on dogs that very large quantities of blood can be
withdrawn repeatedly, if the red corpuscles of the blood are separated
and reinjected in salt solution. The paper (1914) dealing with this

5

work contains the following prophetic sentence: "In view of the fact
that mammalian corpuscles retain their stability for three or four days
when kept on ice, a supply of human corpuscles might possibly be kept
in this manner in operating rooms for rapid injection in emergencies
that would otherwise prove fatal." Here we have the fundamental
idea of the "blood bank" which came into use only recently and which
was of such great value in the treatment of wounded soldiers in World
War II.

In the summer and fall of 1921, he became very much interested
in biophysics, and wanted a department established in the Medical
School. Actually, during the academic year 1921-22, biophysics is
listed in the catalogue as a department of instruction. It was in charge
of a lecturer in biophysics but ^vas really under Abel in the Depart-
ment of Pharmacology. Fortunately or unfortunately for the School at
this time, the department only lasted a year, and Abel's attempts to get
his colleagues to continue it proved unsuccessful. Today, biophysics
is recognized as an important University department at Hopkins. It
may be mentioned that at the time of his biophysical enthusiasm,
Abel purchased from his limited funds an infrared spectroscope and
had an assistant for two or three years working with it. Today, infra-
red spectroscopy is recognized as a valuable tool in organic chemistry.

Lastly, in a prophetic way, I can mention his intense interest in
scientific journals and in the organization of national scientific so-
cieties. In view of the fact that he refused to allow himself to be side-
tracked from his devotion to research to figure in the usual accompani-
ments of a successful scientist, medical meetings, committee meetings,
and board meetings, it is somewhat difficult to explain his interest in
scientific journals and scientific societies. The answer appears to be
that he saw clearly the necessities of journals and societies in bio-
chemistry and pharmacology and interested himself in them so that
they might be properly launched.

Abel was first and foremost an investigator. His great enthusiasm
and passionate devotion to research dominated his whole life. In one
of his addresses, after discussing the training necessary for the medical
investigator, wherein an extended chemical training is emphasized,
he writes:

"But to what end is all this preparation for our yoimg man? Is it
solely that he may solve problems whose solution is of practical value
to mankind? Is his mind to shape itself only to the insistent demands of
utility? Even then our method of training will yield the largest profit.

"But it does vastly more than that. Thus trained, our young scholar

6

\vill be able to see beyond the immediately practical problem, even
though it be as great a thing as the discovery of the cause and cure of
the plague that decimates a people. Greater even than the greatest
discovery is it to keep open the way to future discoveries. This can only
be done when the investigator freely dares, moved as by an inner pro-
pulsion, to attack problems not because they give promise of immedi-
ate value to the human race, but because they make an irresistible
appeal by reason of an inner beauty.

"Some of the greatest investigators indeed have been fascinated by
problems of immediate utility as well as by those that deal with ab-
stract conceptions only. Helmholtz invented the ophthalmoscope and
thus made modern ophthalmology possible, and at the same time did
work of the highest order in theoretical physics and wrote on the
nature of mathematical axioms and the principles of psychology. Lord
Kelvin took out patents on great improvements in the compass and on
oversea telegraphy and also made contributions to our knowledge of
the ultimate constitution of the atom and the properties of the ether.

From this point of view the investigator is a man whose inner life
is free in the best sense of the word. In short, there should be in re-
search work a cultinal character, an artistic quality, elements that give
to painting, music, and poetry their high place in the life of man."

John Jacob Abel: A Portrait

PAUL D. LAMSON, M.D.

I

N 1913 I was working at the University of London, the sole occu-
pant of a new chemical laboratory attached to the Department of
Pharmacology. I was swishing salt solution from one end of a dog's
gut to the other, whistling to myself, and dancing a bit to keep warm,
when I chanced to turn around and saw in the doorway with Professor
Cushny a rather tall, thin man dressed in a morning coat, top hat,
and spats, with an umbrella in one hand, a wire cage with two enor-
mous toads in the other, and wearing on his face a composite expres-
sion of interest, surprise, and amusement which I shall never forget.
It was in this way that I first met Dr. Abel, who was looking for
someone who would deposit his precious Bujo agua in the Zoological
Gardens until he demonstrated them at the International Physio-
logical Congress which was to be held that year in London.

Several biographical sketches of Dr. Abel have already been written
(1), the most complete of which is that by Dr. Carl Voegtlin, who
has given us an exceptionally well-chosen outline of Abel's life beside
an expert analysis of his work. Dr. Abel's personal correspondence
from the time of his marriage was carefully saved by Mrs. Abel and
is now in the hands of competent custodians, and it is expected that
these letters from scientific men of all types in all parts of the world,
covering a period from approximately 1885 to the time of his death
in 1938, will be analyzed and published eventually in some form as
an historical document, which should be of great value as giving us a
picture not only of this truly great man but of the times in which he
lived as well.

Although short. Dr. Voegtlin's biography is so complete that when
I was asked to write this note for the Bulletin, I felt that there was
nothing which I could add except my own impressions of Dr. Abel
as I saw him during the years 1914 to 1925. One should realize, how-
ever, that this was a very brief period in Abel's long life, that he
was almost sixty when I first went to his laboratory, and that this was
at a time when he had completed his active years of teaching and

8

organization. In his early life he must have been a very different man
from the one whom I saw. I have heard much from those who came
before me, but it was always the same— amusing anecdotes mixed with
the utmost admiration and in many cases an almost religious devo-
tion for this man whom we all loved.

Dr. Abel's contributions to science were recognized the world over,
as can be seen from the honors which he received. These are sum-
marized as follows by Dr. Voegtlin:

He was awarded the Willard Gibbs, Conne and Kober medals and the medal
of the Society of Apothecaries, London. Honorary degrees were bestowed upon
him by the Universities of Michigan, Pittsburgh, Harvard, Yale, Lwow (Poland),
Cambridge and Aberdeen. He was an honorary fellow or member of the follow-
ing societies: New York Academy of Medicine, Association of American Physi-
cians, Chemist's Club, Institute of Medicine of Chicago, Philadelphia College of
Pharmacy, American Institute of Chemists, Royal Society of Edinburgh, Kaiser-
liche Deutsche Akademie der Naturforscher, Physiological Society of Great
Britain, British Pharmacological Society, Society for Biology of Buenos Aires,
Chinese Physiological Society, Soci^t^ de cliimie biologiques, Wiener Biologische
Gesellschaft. He was a member of the National Academy of Sciences and in 1932
served as President of the American Association for the Advancement of Science.
On the last day of his life he received notification of his election to a foreign
membership of the Royal Society.

John Jacob Abel will be remembered as the first pharmacologist
in this country and a member of that remarkable group of men who
made up the first complete faculty of the Johns Hopkins School of
Medicine, and for the part that he played in the founding of three
of our most important medical publications, the Journal of Experi-
mental Medicine, the Journal of Biological Chemistry, and The
Journal of Pharmacology and Experimental Therapeutics. He was the
pharmacological editor of the first of these, joint editor of the Journal
of Biological Chemistry with Dr. Christian Herter, and the first editor
of The Journal of Pharmacology and Experimental Therapeutics.
He organized both the American Society of Biological Chemists and
the American Society for Pharmacology and Experimental Thera-
peutics. His pioneer work on the isolation of epinephrine, the active
principle of the medulla of the suprarenal gland, is known to every-
one. His ideas of plasmapheresis and his so-called artificial kidney are
equally well known, and his work on the phthaleins which culminated
in kidney and liver function tests should be known by clinicians the
world over, as they use these tests daily. The last work which received
general recognition was his isolation of crystalline insulin. Besides

9

this there were innumerable investigations which cannot be gone into
here.

In order to obtain an insight into Dr. Abel's character it is neces-
sary to consider his early training. As Dr. Voegtlin has done this so
well, with his permission I am quoting him at length:

The life of this true scientist began on a farm near Cleveland, Ohio, where he
was born on the 19th of May, 1857. Little is known about his parents save that
his ancestors came from Germany. ... At the age of 19 he began his college work
at the University of Michigan. It was here that he took a course in physiological
chemistry under Vaughan and physiology under Sewall. His college education
was interrupted for three years during which time he was Principal of the high
school and later Superintendent of Public Schools at La Porte, Indiana. He
received his Ph. B. degree from the University of Michigan in 1883. After gradua-
tion he married Miss Mary Hinman, a teacher in his school at La Porte. . . .

The first academic year after graduation was spent in the Department of
Biology of the Johns Hopkins University under Newell Martin, the able pupil of
Michael Foster. . . .

At this time, in 1884, at the age of 27, he made the important decision to study
medicine in Europe. Throughout his seven years of European study he showed
a remarkable ability to select as his teachers many of the distinguished men of
this period. From 1884 to 1886 he was in Leipzig, studying physiology under
Ludwig and von Frey, histology under His, pharmacology under Boehm, pathol-
ogy under Striimpell, and inorganic and organic chemistry under Wislicenus. At
the same time he completed his doctor's dissertation in Ludwig's laboratory.
The winter semester of 1886-87 was spent in Strassburg under Kussmaul in inter-
nal medicine, under v. Recklinghausen in pathology and infectious diseases.
The following summer semester he studied at Heidelberg with Erb in medicine
and Czerny in surgery. During the summer vacation he attended clinics at
Wiirzburg; 1887-88 brought Abel back to Strassburg where he took courses under
Kussmaul, Naunyn, Hoppe-Seyler and Schmiedeberg. It was Schmiedeberg who
aroused Abel's first interest in pharmacological research, particularly in its chemi-
cal aspects. In 1888 he received his M.D. degree from Strassburg. On October
30th of the same year he suffered the loss of his infant daughter, a severe blow.
It is not unlikely that this loss determined him to leave Strassburg, where he had
found so much inspiration and had made many friends, in order to pursue a year
of postgraduate clinical work in Vienna with Nothnagel and others. But his
yearning for laboratory research found Abel in 1889 to 1890 working in the
laboratory of the outstanding biochemist v. Nencki in Berne, Switzerland. It was
here that Abel obtained his first training in chemical research. In later years he
often enthusiastically referred to this stimulating experience. There can be little
doubt that at that time Abel had a clear vision of what a tremendous part chem-
istry was to play in the future of scientific medicine. Therefore, he resolutely
determined to be prepared, irrespective of the expense involved which he could
hardly afford. In Berne he completed a research on the "molecular weight of
cholic acid, cholesterol and hydrobilirubin." Using Raoult's method he called
attention to the limitations of this method for the purpose in view. Another paper
dealt with the chemical composition of the melanins from hair and melanotic

10

tumors, showing that these pigments did not contain iron in significant amounts.
In Berne he formed a hfe long friendship with Cushny, who at that time was work-
ing in the laboratory of the Physiologist Kronecker.

After this year with v. Nencki, it was Abel's intention to return home where he
expected "to carry on medical practice and to do some research work, if possible,
in internal medicine in connection with one of our American medical schools."
This decision was partly due to the advice given in a letter by H. C. Wood, who,
though recognizing Abel's "extraordinary training," told him he must first be
known in America as a lecturer and independent investigator in order to have a
chance to get a professorship of from $1,500 to $3,000 a year. However, the
outlook for a clinical career would be more "promising." Having used up all his
funds Abel decided reluctantly to enter clinical work. Then in the late summer
while still in Berne, Abel received a cable from Vaughan which was the turning
point in his life. On Schmiedeberg's recommendation Vaughan offered him the
Chair of Materia Medica and Therapeutics in the University of Michigan, with
the understanding that he was to establish a modern department of pharmacology;
materia medica and therapeutics being retained in name only. Here was the
chance Abel had looked for to enter a career in experimental research and with v.
Nencki's advice he accepted the offer to return to his Alma Mater. But before
returning home he induced Vaughan to let him have a last fling at biochemical
research with the able biochemist Drechsel in Ludwig's laboratory. Drechsel
at that time was doing important work on the chemistry of proteins and on pro-
tein metabolism. Drechsel and Abel thus began a joint research on the occurrence
of carbamic acid in alkaline horse urine. This association led to a close friendship
which lasted until Drechsel's death in 1897.

On his homeward journey Abel stopped at Berlin to obtain first-hand informa-
tion on Koch's tuberculin treatment, which had attracted international attention.
This was the subject of his first lecture at Michigan in January, 1891. In a
letter to C. W. Edmunds he writes: "Here at Ann Arbor I was given the oppor-
tunity of starting the first professorship of pharmacology in the United States,
whose holder should devote himself entirely to giving students the best possible
instruction by means of lectures, demonstrations and quizzes, in the manner in
which my European teachers (Schmiedeberg and Boehm) had long carried on
their work. All my energy that was not given to this kind of instruction to
students was devoted to research work and to arousing the enthusiasm of others
for it. . . . There was no laboratory of any kind at my disposal. There was not a
scrap of apparatus, not even a test tube, a flask or a beaker." But soon he had
organized his small laboratory and with a senior student, Muirhead, he imme-
diately gave demonstrations on animals and carried out a research on the occur-
rence of carbamic acid in human and dog urine following the administration of
large amounts of lime water. . . .

While Abel was active in Michigan the Johns Hopkins University under Presi-
dent Oilman began the organization of its medical school. Welch, Osier, Halsted,
and Kelly had already been appointed, and equally outstanding men were needed
to fill the chairs of the preclinical subjects. In January of 1893 Abel received a
letter from Osier inquiring whether he would be a candidate for the chair of
Pharmacology. Ele replied that he was strongly attracted by the prospective
intellectual contacts with Osier, Martin, Welch and Remsen. His main concern,

11

however, was the provision for adequate laboratory facilities. His appointment
to the Professorship of Pharmacology went into effect for the academic year
starting in the autumn of 1893 and with it Abel reluctantly also assumed the
responsibility of giving the course in physiological chemistry. Before assuming
his duties he obtained a few months of leave to complete some research with
Drechsel and to consult his old teachers in Europe.

What was it that caused Abel to make such effort and sacrifices
for this very advanced education, and how was it that he showed
such extraordinarily good judgment in choosing the men with whom
he worked and in training himself along the lines which he did? That
he was not content with a safe and respectable position as Superin-
tendent of Public Schools in a small city shows that at an early age
he was in some way inspired to go further. Was it his association with
Vaughan or Sewall at the University of Michigan which led him to
go to the Johns Hopkins University under Newell Martin, and was
it Martin who suggested that he take up medicine? Regardless of who
may have given him such ideas or advice, it is obvious that Abel was
no ordinary student but one filled with an intense desire for the best.
His ability at the time of his studying medicine, to choose the best
men in the world, was no mere accident, but this trait continued
throughout his long life, and when his life is written in full, it will be
found that the greatest men of these times were among his friends
and correspondents.

In these days it is difficult for us to comprehend the difference
which existed in 1885 between medical science in Europe and in this
country. Here, biological chemistry was not then sufficiently differ-
entiated from physiology to warrant the formation of a separate group
of biochemists, and pharmacology did not exist. It is safe to say that
chemistry was hardly known to the clinicians, who at about that time
were beginning to take up the new field of pathology. As late as 1911
Dr. Reginald Heber Fitz, then Professor of Theory and Practice at
the Harvard Medical School, who was one of the outstanding men in
clinical medicine in those days, advised me strongly not to take up
chemistry in relation to medicine. He said he realized that someday
it was coming into medicine but that he had watched it all his life and
was sure that it never would amount to much in my day. Yet twenty-
five years before this. Dr. Abel with his medical training and medical
degree realized the importance of chemistry and specialized in it. He
was probably one of the very rare men in this country who then had
anything like this training, and it was this knowledge, which others
did not have and could only partially appreciate, that had a great deal
to do with the foresight attributed to him. He had worked in Europe

12

Avith experienced biological chemists and pharmacologists and had
read their journals, all of which impressed upon him the need of
similar organizations and publications in this country. His knowl-
edge of chemistry allowed him to go more deeply into fundamentals
than was possible for many others. Then, too, the whole scientific life
of the remarkable group of German medical men who lived at that
time made a deep impression on Abel. Their almost monastic devo-
tion to medicine, their ability, modesty, the care and exactness with
which they did their work in infinite detail, and their desire to find
out the truth of matters gave him very high standards for his own
development.

To Professor Abel this group always remained different and above
all others. He would speak in a hushed voice of the great Naunyn
or the great Nencki, and in a discussion the last word had always to
be found in a German reference book or article. This was a great
group, and those must have been wonderful times when, as Abel put
it, he "walked the wards with v. Recklinghausen." But all of these
men and these days have gone, and one wonders whether a professor
will ever be as much of a professor as he used to be then, whether the
professorial, broad-brimmed, black felt hat will ever again attract
the same awe and respect that it did, and whether it will be possible
as it then was to determine the departmental rank of a group by
their relative positions as they walked down the street.

Professor Abel's work was largely of a biochemical nature, for ex-
ample, that on the chemical composition of the melanins from hair,
the occurrence of carbamic acid in alkaline horse urine as well as in
human and dog urine, the chemistry of the pigment of the negro's
skin and hair, the isolation of ethyl sulfide from the dog's urine, and
an attempt to isolate the active principle of the thyroid, his isolation
of the active principle of the thyroid, his isolation of the active prin
ciple of the adrenal medulla, his work with Ford on the poison oi
Amanita phalloides, a study of the active principles of the secretion
from the parotid gland of the tropical toad Bufo agua, his classical
experiment demonstrating with his "vividiffusion" apparatus the
presence of amino acids in the blood. Then there was his work with
Pincoffs and Rouiller on the presence of albumoses in the tissues
and in the blood as well as in the gastrointestinal mucosa, his work
with Gelling on Witte's peptone, as well as that on the active prin-
ciples of the pituitary gland, his chemical studies of and isolation of
crystalline insulin. These indicate Professor Abel's real interests. His
work on the phthaleins and their use in kidney and liver function

13

tests, his entrance for a short time into the field of chemotherapy with
his studies of the antimony thioglycollates, his plasmapheresis and
his vividiflfiision ideas were more or less side interests which kept
him from his main line of work for a short time only.

The fact that Dr. Abel had to take over the teaching and laboratory
work in physiological chemistry when he first went to Johns Hopkins
probably had little to do with this biochemical point of view. His
interest was definitely chemical before he went there, and although
he was always attracted to a great variety of problems having to do
with medicine in general, his primary interest seemed to be in the
fundamentals of the living organism rather than in the secondary
changes brought about by disease or intoxications produced by drugs.
It will be noted that, except in very fe^v instances. Dr. Abel paid little
attention to studying the action on the organism of the substances
with which he worked, that is, their so-called pharmacological action.
True it is that he used the reactions of the organism to separate his
various fractions and eventually his pure principles from complex
mixtures, but it was his aim to discover what these principles were
chemically rather than to study the complex reactions of the organism
after their injection.

On returning to this country in 1914 after two years in Europe, I
found that my hearing would not allow me to go on with the clinical
work which I was then doing at the Peter Bent Brigham Hospital in
Boston, and while wondering what could be done about it I suddenly
thought of how Professor Abel looked when I had seen him that
morning with Cushny in London. I immediately wrote to Dr. Abel
and asked if I might come to work in his laboratory. He replied
at once in the most friendly manner urging me to come there, and I
left for Baltimore wondering what I would find to do. After the white
marble walls of the Harvard Medical School and the new Brigham
Hospital, the Johns Hopkins Medical School building of that day
was not an impressive sight. My spirits went down as I climbed the
three long flights of stairs to the pharmacological laboratory where
I found Professor Abel in his small corner room, a test tube in one
hand and a capillary pipette in the other, in the process of adding a
minute drop of some extract to a solution. He immediately put these
down and greeted me with the utmost cordiality. In one corner of
the laboratory was an old, roll-top desk piled high with papers of all
kinds; and every available and unavailable space on the desk, a re-
volving bookcase, and a rather large table was heaped with books and
current periodicals. Within three feet of his desk was a standard

14

chemical bench, behind which was an ordinary canvas army cot.
There was a hood in one corner and a sink next to the door. There
was no room for anything else. There was notliing new in the room;
everything in it looked as though it had been used continuously for
many years. I later found that there was one exception to this— a
new, large Webster's Dictionary which had escaped my attention, as
it was kept rolled up in a green cloth and tied with a string. In spite
of this, however, it was very often used.

After a word or two of greeting I started to tell Dr. Abel about my
forced change of plans, but he interrupted me almost at once, saying,
"That is too bad, but let us put that off until we have an evening at
our house together. If you have no problem on hand at the present
minute, let us start on something which has become of the greatest
importance on account of the war." He then suggested that we at-
tempt to treat pig's blood so that it could be used in man to replace
human blood without causing hemolysis and reactions of one sort and
another. This sounded a bit wild to me, but I did not dare to say so.
He gave me a white coat of his own, hung mine on a hook on his door,
sent the laboratory boy to the nearby slaughter house for pig's blood,
and within fifteen minutes after I came into his room I was actually
at work and on a problem which kept me busy for over ten years al-
though it was not two days before I gave up the pig's blood idea
forever. How many men would have been able to diagnose instantly
the state of confusion brought about by such a change in one's life
and without a word have started one off on a course which effected a
cure almost instantaneously?

At just the time I went there, Baltimore was starting to grow up
and to lose much of its old charm, which, however, has been replaced
by much of beauty. The automobile was just coming in, and a few
people were moving out of town, but many of the best families still
lived in the city and sat on their doorsteps after dinner on warm
evenings; and on the way home it was the custom for one to drop
into the Maryland, Baltimore, or University Clubs, where one was
sure to find friends. The University had not moved out to Home-
wood, and I lived and dined with a very pleasant group at the Johns
Hopkins Club on the corner of Monument and Howard Streets.
Each morning we would walk across town to the School. As we began
our pilgrimage we would pass houses with beautiful doorways, the
brass knockers and nameplates of which were being polished by those
fine old colored men of the old school, and before we had passed
the Washington monument, we were sure to have been greeted with a

15

"good morning, Major, Colonel, General, or Admiral," which, in spite
of slight exaggeration, gave one a sense of importance with which to
begin the day's work. Going over the hill and past the railroad tracks
one saw those marvelous, great horses, eight or ten at a time, which
pulled freight cars through the streets, but after this the glamour
disappeared, as one had to watch his step to avoid the sewage drains
which ran uncovered across the sidewalks in the famous Baltimore
sewage system, and there was nothing left but a long climb up to the
hospital, which tapered off from a very imposing front, to Dr. Welch's
laboratory across the street from Hanselmann's saloon, to which was
attributed the entire success of the early Johns Hopkins group.

Professor Abel was at that time very comfortably settled in an old-
fashioned house with high-ceilinged rooms and a cupola, just off
Charles Street very near where St. Paul Street comes into it. Guilford
itself had not been developed at that time although the streets were
laid and a few houses started. The Professor kept a cow, for which
there was plenty of room, as his land ran down across the railroad
track and up a hill on the other side and must have covered between
ten and twenty acres. I had been in Baltimore for a day or so only
when I was asked to dine at Dr. Abel's house and went there part way
by trolley and the rest by bus and was most cordially greeted by Mrs.
Abel and the Professor. The house was to my mind an almost ideal
place for a professor; everything about it was livable, inside and out.
There was a large study on one side of the front hall, a living room
on the other, behind which was the dining room. In the study there
was an old-fashioned, marble fireplace with a coal grate and a fire
always burning. The walls were very high and completely lined with
bookshelves. The Professor's old-fashioned armchair was pulled up
casually before the fire, and in front of it was a footstool high enough
to make it possible to put one's feet on it and stretch out comfortably
in the chair, which the Professor used to do on less formal occasions.
Pulled up beside the chair was a table piled with books, periodicals,
and papers. The furnishings of his house, like his laboratory, were
ample but simple and looked as though they had been chosen for use
and used. I went to many evening and Sunday dinners at this house,
and those whom I met there were almost always workers in the lab-
oratory or out-of-town or foreign visitors, of whom there were many.
There was always so much of immediate interest going on in Dr.
Abel's mind in connection with his own work or that of his guests
that conversation usually centered about such matters. This always
came about most naturally and was in no way forced.

16

FiGURi: 1. "Artificial Kidney" was envisioned by Dr. Abel years before one was
finally de\eloped which would work on human patients. The \iew abo^•e,, re-
jnoduced from an old drawing, shows the artificial kidney used by Dr. Abel on
animals in 1913. A cannula (tube) was inserted in the animal's artery (A) to lead
blood into the device's apparatus (C), a series of collodion tubes through which
the blood flowed and from which substances in the blood were diffused into a
Huid introduced from outside. A cross-section of these tubes is shown in the
circle at upper left (E). Anticoagulant was introduced through the burette in
center of drawing (D). Blood was returned to vein of animal through upper
cannula at left (B).

First Crystals of Insulin
prepared by
Dr. John J. Abel

1%

s-j

> -tt^'

Figure 2. Dr. Abel was the first to obtain insulin in chemically pure crystal-
line form. He isolated the hormone when he was sixty-nine years old. For
months after he first did it, he was unable to repeat the performance, and many
chemists were skeptical of his achievement. Ultimately he found the answer and
crystalline insulin is now commercially prepared.

Figure 3. How Abel's first insulin crystals (still kept at Johns Hopkins)

appeared under the microscope.

Then, of course, there was the war, at that time in its early stages,
before the United States took part in it. Professor Abel was very
pro-German, which may have been on account of his ancestry but
much more likely on account of what he knew of Germany as he
had seen it. This made it utterly impossible for him to believe that
the Germans were what they were made out to be at that time, and
it was equally hard for me to believe it then. The Avar had a great
effect on the Professor and upset his life tremendously. At first it Avas
very stimulating to him, as the Germans made neAV advances almost
every day, and this Avas reflected in the Avay he Avalked as Avell as talked.
Both Dr. and Mrs. Abel Avere extremely kind to me and treated me
almost as a son. In fact, they asked me after a time to live at
their house Avith them, but I did not accept this invitation for tAvo rea-
sons: one was that although I Avas fond of medicine, I did not Avant to
give up everything in life to the Avhims of this man as all Avho came
very close to him had to do on account of his complete absorption in
Avhat he was doing to the consequent oversight of everything else; the
other Avas that my love for the Germans became less and less, and,
finally, in order that there could be no mistmderstanding on this point
in Professor Abel's mind, I Avrote him a letter telling him that I
thought he should knoAV of my having lost all faith in the Germans
and that I Avas going to take the part of the other side. Although I
did this as kindly as I could, I do not think that the Professor ever
quite got over it.

For a time, after the Avar Avas over, he Avas much depressed and very
bitter, but Avith his usual and extraordinary ability to take reverses
he shook off this depression and Avent to Avork Avith rencAved vigor.
Unfortimately, at just this time the laboratory was overAvhelmed by
a grotip of South Africans Avho were extraordinarily anti-British in
their sentiments. For several years the lunch-table conA^ersation de-
generated into anti-British tales raked up from all possible quarters
by this South African group. I, Avho Avas no historian, could stand this
only so long and then Avould blow up, to be put in my place again on
account of lack of evidence on my side, and since there was no one
there to back me, I became less popular daily. But this group and this
period passed, and in his later years I heard nothing more of the Avar
from Professor Abel. I am sure that his anti-English remarks Avere
purely an attempt to justify Avhat the Germans had done, because he
told me many times that Avhen he retired, his one desire Avas to go
to England and spend his last days Avith "that Avonderful group of
English physiologists."

17

I had been told that it would be a waste of time to go to Baltimore
to work with Abel, because he was always too busy with his own work
and I would see nothing of him. When I arrived, he had just been
asked to write the first Mellon lecture (2) and devoted the better part
of a year to the preparation of this. Anyone wishing to get an idea
of the thoroughness with which he did things, and of the breadth of
view which he had, would do well to read this as well as his other ad-
dresses. This would also give one an idea of Dr. Abel's feeling that
one should give all that one had to whatever was being done. Dur-
ing the first year that I was in his laboratory he carried out almost no
experimental work and would drop in to talk for hours at a time.
We would often leave the laboratory early and drive about the coun-
try, ending up at his house for tea or supper; but after this first year
things were very different, and except when he came out of the se-
clusion of his corner laboratory for lunch or to carry out an animal
experiment in the large laboratory, one saw very little of him.

I shall never forget the day Dr. Abel decided he should move.
A real estate company made plans to develop what is now Guilford.
This involved the house and land where Dr. Abel lived. They tried
to induce him to build another house, but he was afraid of 'being
crowded', as he put it, and decided to go else^vhere. I had an old
car at that time and spent many afternoons driving Dr. and Mrs.
Abel all over the country looking for another house. One afternoon
as the day was getting on and with a violent thunderstorm coming
up, we drove out some ten miles from the middle of the city and up
a hill where there was an enormous unoccupied house very similar
to the one in which he used to live on Charles Street. This was off
the Windsor Mill Road and had fine groimds with wonderful, great
trees, a driveway lined with hemlocks, the same type of cupola on
the house, and goodness knows how many rooms. The house was
by no means in the best state of repair, and neither were the grounds.
The Professor jumped out of the car and rushed into the house, leav-
ing Mrs. Abel and me behind in the rain. Mrs. Abel got slowly out
of the car, stood looking at the house in a horrified manner, and,
turning to me, said in her quiet way, "My goodness. Dr. Lamson,
did you ever see anything so awful?" A few minutes later Dr. Abel
came dashing out of the door shouting, "Mary, this is just exactly
what we want." Mrs. Abel then went in, looked the house over, and
said, "Yes, I think this will do very well indeed." This was typical
of Mrs. Abel. I have never seen such devotion in anyone as she had
for the Professor. It made no difference what his plans might be,

18

they were accepted at once by Mrs. Abel, who not only willingly but
with genuine enthusiasm cooperated with him. If it were a minor
matter such as unexpectedly bringing people to dinner, giving up
engagements, taking a train for other parts, or changing the entire
way of living, it made no difference whatever, Mrs. Abel agreed at
once, and never did any of us hear her complain. Until Mrs. Abel died,
she lived on this hill. At first she had a colored boy to help her, but
he was a character and more trouble than help, and she soon gave him
up.

Among the letters which came to me at the time of Dr. Abel's
death was one from Professor Walther Straub, who told of his com-
ing to this country to lecture and being met at the station by Professor
Abel. It was some minutes after the train came in before Professor
Straub saw him hurrying down the platform; Dr. Abel greeted him
in an excited manner, saying. "I am sorry to be late, but Columbus
only just arrived." Straub said that he was much shocked and thought
that the Professor was losing his mind, and it ^vas only when they
reached the car that he found that Columbus was Dr. Abel's colored
boy.

In these days of new schools and perfect ecpiipment it might be
interesting to consider the surroundings in which Professor Abel
carried out the work which has made him famous the world over.
As I have said before, the Medical School was by no means an im-
pressive sight. Each story was very high, and Dr. Abel's laboratory
was on the third floor. There was no elevator except a small freight
affair which had to be pulled up by hand. There was a hallway
around the stair-well from which the various laboratories radiated.
I have no doubt but that everything Avas done very systematically
when Dr. Abel was younger, but when I reached tiiere, it was a case
of every man for himself, and there certainly was no system about
anything. There was only one kymograph in the laboratory which
worked, and that was a long paper electrical affair, and to do a blood
pressure experiment involved as much as a major surgical operation.
Since I was the youngest and newest arrival, I was not allowed to take
part in such an important event as doing a blood pressure experiment
on a dog, but I was allowed to watch. Dr. Rowntree had just left,
and Dr. Marshall, who at that time did not even know where the
kidney Avas, and a physical chemist from Europe, 'who was not quite
sure whether a dog had a kidney, supervised the operation, which was
done by Charlie Kamphaus.

Outside Professor Abel's laboratory Charlie was the Department

19

of Pharmacology. If you wanted anything, you asked Charlie for it,
and if he happened to be out, you simply did nothing until he re-
turned. I asked him once how it was that none of the large stock
bottles had labels on them, and he said in the most hurt manner
imaginable, "Why, Dr. Lamson, if we had labels on them, everyone
would know what was in them." At another time I asked him to re-
turn something which we had borrowed from another department,
and he said, "Don't do that now. If you wait a little longer, they won't
remember that you have it." Charlie was a German, short, well-fed,
but not fat, then. He was the most good-natured, willing, hard-working
soul I have ever seen. He existed for one thing only, and that was to
serve Professor Abel. Sundays, week days, or holidays the Professor
would merely say, "Charlie, keep your eye on this dog, you must look
at him every two hours," and Charlie would be there day and night.
If the Professor suddenly wanted a dog and there were no dogs in the
animal house, it never occurred to Charlie that this could be anyone's
fault but his own, and with tears in his eyes he would dash about
from one department to another looking for a dog. Charlie liked to
work and confided to me once that the height of his ambition was to
be a waiter in a beer garden where there would be twice as many
people as one could possibly serve, and just as you had supplied one
table with beer they would shout for you to fill up the glasses again,
and you would know that you could not possibly do it.

Charlie was assisted in these blood pressure operations by Charlie,
Charlie Drain, a devout Irish Catholic with the good and bad qual-
ities of a bulldog, very fond of liquor, who died of delirium tremens
during the prohibition period. He worshipped the Professor but was
not as sophisticated as Charlie Kamphaus. His one desire was to find
someone who would say something against Dr. Abel so that he could,
as he put it, "knock his block ofE." Together the two Charlies would
put the dog under ether and hitch up the blood pressure apparatus
and kymograph. Things would usually have worked fairly well had it
not been for the fact that the recording was done by means of glass pens
blown by everyone who had ever been in the laboratory. The experi-
ment would start, and then the pen would weep and the ink run down
the paper, whereupon both Charlies would discuss the advisability of
putting on another pen, and this as likely as not would refuse to write.
In the excitement one or the other Charlie \vould blow through it.
z\fter a very short time both of them were red ink from ear to ear.
If the experiment were a long one and artificial respiration were
needed, another assistant was called in, Mrs. Thomas, the scrub-

20

woman. Mrs. Thomas was getting on in years, was very fat and very
polite, and also a devout Catholic. She would sit on a stool at the dog's
head and pump away on a pair of hand bello^vs, but she had a habit of
dozing oft very frequently and had to be ^vaked up, usually by Charlie
Drain, Avith a polite nudge and the remark, "A little more air, Mrs.
Thomas, please." At one time Mrs. Thomas' husband had to be dug
up and moved, and for years after this during lulls in an experiment
she would describe in great detail just how he looked and the various
colors of his face. This always ended in tears, and w'e had to distract
her with a call for more air. After all was well under way, and while
the chemists were giving general directions, entirely unheeded by the
operating staff, Professor Abel would be ceremoniously called by
Charlie Kamphaus, and he would appear with his little glass evaporat-
ing dish, his capillary pipette, and his notebook. A hush would come
over this scene of blood, red ink, and artificial respiration, and the
Professor, entirely oblivious of everything, would fill a syringe, and
someone ^\•ould make the injection for him.

In the early days when I first went there, Professor Abel wore a
white laboratory coat. Later, he added to this a white apron which
he had become interested in, because Dr. Binger wore these. As time
went on and as the laboratory was none too well heated, Professor
Abel added an ordinary sack coat over the apron, and some years
later discovered a very long, heavy, red rubber apron, 'which he then
wore underneath the white one. At about this time Dr. Abel had his
portrait painted in a gown with which there was a black velvet hat
^vhich pleased him a great deal. He often spoke to me about what a
nice thing this hat was and how he thought it a splendid custom to
wear such a hat. One day a member of the surgical staff came into
the laboratory for luncheon wearing a Avhite operating cap, and I
noticed that Dr. Abel was particularly abstracted that day and kept
looking at our visitor ^^'ith an interest all out of proportion to what the
surgeon's conversation seemed to merit. After lunch the Professor
took me aside and asked if I could manage to get him one of those
little white hats. I did, and he ^vore it to the end of his days.

On the street and around his house Professor Abel was always very
spry and walked with great alertness and rapidity, but for several
years I had been semiconscious of the fact that he went about the
laboratory in a decrepit manner. He would come out of his room and
shuffle across the laboratory with very short steps, almost on his toes,
and ahvays holding his evaporating dish in one hand and his pipette
or his notebook in the other. One day I happened to notice that he

21

held up his apron with one hand, as one would a skirt, and becoming
interested in this phenomenon, I saw that the band around his neck
was so long that the rubber apron nearly touched the floor, and the
string, which should have gone around his waist, tied his knees to-
gether so that it was impossible for him to take a long step. I asked
if I could not shorten the neck band for him and explained what
seemed to me to be the advantage of doing this, but he only looked
at it in a dreamy sort of way and said that it was all right as it was,
and it stayed that way as long as I was there.

When one of these blood pressure experiments was over, the record
was rolled out on the floor, often rimning the entire length of the large
laboratory and even out into the hall. Everyone would very seriously
gather about it and walk up and down the record looking for results.
No one ever seemed to be the least bit aware that this was not the
accepted method of carrying out such experiments.

The laboratory was well equipped for special chemical work, but
except for this one kymograph there was almost nothing in the way of
apparatus. There was one microscope in the department in use, and
that belonged to me. After some ten years when I needed a micro-
scope badly and everyone was using mine, I asked the Professor if
the one which he had in his laboratory could not be turned to gen-
eral use. I had seen this in action only once. It was kept in a wooden
box done up in a brown cloth, tied with a stout cord, and the whole
thing wrapped in an old, white laboratory coat and locked in a case
in Professor Abel's room. He looked very much taken aback at such
a request on my part and asked what was the matter with the one we
were using. I told him that there was nothing the matter with it, but
that it was mine and that we needed another. He said, "But, Lamson,
the microscope that I have is a good one." When I answered that mine
was also, ten years ago before everyone used it, he looked at me hard
without saying anything, and then a quiet smile came over his face,
and he turned and walked away. In a few minutes he came back to
my room with the precious machine of his own and left it without a
word.

We had no shop, and when I tried to make a perfusion apparatus
and needed to make a thermostat, the only tools which could be found
were a hammer with a split handle, a screwdriver, and a keyhole saw
with half the blade broken off. With this outfit I managed to put
together a thermostat made out of a soap box, which worked sur-
prisingly well until one day when I was out of the room I heard a
great commotion and someone shouting, 'Tire!" I came in just in

22

time to see Professor Abel emptying the last of the contents of a large
fire extinguisher into the middle of my precious apparatus, of which
there was nothing left.

At night the heat went off in the laboratory, and it became ex-
tremely cold. Someone broke into the Medical School at one time,
after which rather luiusual precautions were taken to keep a further
break from occurring. These consisted in locking up the gate to the
high iron fence which surrounded the Medical School, and no keys
were given to any members of the faculty regardless of our pleas.
When one came over in the evenings to work, on an icy, snowy night,
and had to climb this high, iron fence with its arrow-shaped spikes,
then feel one's way into the basement in utter darkness, locate the
main switch of the building, turn that on, and then climb three
flights of stairs in the dark on account of an economical lighting
system which had been developed, it often took some time to quiet
one's resentment against the powers that had developed such plans,
especially those who did not have to climb the fence.

In spite of all this, the laboratory was one of the finest to work in
that I have ever seen. Everything was informal, and Professor Abel
had that very rare faculty of being willing to see a change made in
anything at any time. Once while I was there, a plan was developed
to move the Department of Pharmacology to the new Himterian
Building, which to my mind would have ruined the spirit of the
Medical School, as it would have separated biochemistry, physiology,
and pharmacology, but when this was suggested to Dr. Abel, he was
perfectly willing to make the change if others thought it best for the
School, in spite of the fact that it would upset his work for a consider-
able length of time.

If the Professor was a trifle thoughtless about the comforts of his
assistants, he was eqtially thoughtless about his own. For instance,
he had no telephone in his room, and for a long time, in order to use
one, he had to come out into the hallway and squeeze into a horribly
small closet which was a sort of dump for dirty laboratory coats, the
janitors' shoes, etc. For a great many years he had no secretary, and
it took a lot of persuading in order to get him to take on even a half-
time one. The Professor immediately installed a telephone on her
desk, but he himself still had to go through Dr. Marshall's laboratory,
out into the hall, and carry on his telephone conversation in this
stuffy closet. As it became annoying for the secretary to go constantly
to the Professor's room and call him to the telephone, she installed a
buzzer on his desk so that it was only necessary for her to press a but-

23

ton and the Professor would scurry out to the telephone. It was sev-
eral years before we could convince him that he deserved to have an
extension telephone on his desk, which he finally did with great
reluctance.

To me it seemed that Professor Abel lived in the clouds rather than
in this world. However, he was an extremely practical person when
his attention was focused on something, as can be seen from his or-
ganization of scientific societies, journals, his laboratories, and courses
for both biological chemistry and pharmacology. It was he who ad-
vised Mr. Passano of the Waverly Press to specialize in the publica-
tion of scientific periodicals, a thing which had not been done in this
country before and which was followed with very great success, on
account of which Mr. Passano has ^vritten a very fine tribute to Pro-
fessor Abel. But everything having to do with the laboratory, his
work, and science had a supernatural interest for him. When he
would come in to see an experiment. Professor Abel would talk in a
hushed voice. He would speak with the greatest reverence of scien-
tific publications and men, as well as their Avork. He gave to science
a certain halo, which at times seemed out of place in our humdrum
life of America but which corresponded to that aura which enveloped
a German professor in Europe. This was very greatly appreciated by
some who worked with him, and I am sure that it was entirely sincere
and natural to Professor Abel but not in others who attempted to copy
him.

That Dr. Abel had courage is well known to anyone who had any-
thing to do with him. After months of work when he fully expected
that a final experiment would prove what he had been seeking for all
this time and it proved the exact opposite, he would draw himself up,
shake his rather frail shoulders, and say, "Oh, well, there are many
fish in the sea," and immediately begin on his work again. In the
course of his early w^ork on epinephrine an explosion occurred which
filled his eye with glass and must have been an extraordinarily painful
affair, but those who were with him at the time told of his great cour-
age then and during the removal of his eye under local anesthesia.
He almost never spoke of this in any way, but one time did tell me
that it was quite interesting when they cut through his optic nerve.
In minor matters, however, I think he more or less enjoyed having
something happen which made him exert himself against circum-
stances. He used to tell the most extraordinary story of how a nurse
accidentally poisoned him with atropine in the hospital. After he
underwent a rather serious operation at one time and, again, when he

24

broke his leg, there was no reason for, and much against, his hurrying
back to his laboratory, but I think he more or less enjoyed seeing
Avhether he could do it or not.

Dr. Abel belonged to that generation Avhich has just passed, in
which men still liked to think that they might know about everything
althotigh they were perfectly well a^vare of the fact that they could
not. I believe, however, that this irritated Professor Abel consider-
ably. He seemed a trifle jealous of Dr. Welch, who had such an un-
believable memory and who seemed to have had some firsthand ex-
perience with almost everything that had happened in medicine.
When a new edition of the Encyclopedia Britannica came out, he
confided to me that he had heard that Dr. Welch was reading it from
cover to cover, but I know that he read a great deal of it himself
with a great deal of interest, for he used to point out the mistakes in
it and tell me how much better the German encyclopedias ^vere. He
used to like to dabble with Greek and Latin and has sent me post-
cards written in Greek, ivhich I hope were more intelligible to him
than to me. I dropped in on him one time at Randolph, New Hamp-
shire, where he used to spend the summers, and foimd him studying
Latin grammar. He explained to me how he had tramped over the
whole Presidential range with his sons, and another time he told me
how he had spent several smnmers cruising from Baltimore up to the
coast of Maine and back. This was no mean undertaking for a man
unaccustomed to the sea. He apparently went at it with gieat thor-
oughness, however, hired a skipper and a good-sized boat, and took
his family over these many miles of ocean without a mishap. I found,
however, that Mrs. Abel was none too pleased with some of these trips.
When a storm came up, the Professor felt that the deck Avas no place
for a woman, and he not only put her below but shut all the hatches
in a supposedly seamanship manner, and Mrs. Abel admitted that
these were not the best days she had ever enjoyed.

The Professor also had a fondness for mathematics and physics,
but I never realized what a sacred field this was until one day, while
we were having luncheon, Rouiller was extracting a vacuum desic-
cator by means of a very noisy water pump, and Professor Abel got
into an argument with one of the staff members as to Avhether mole-
cules could or could not pass through a hole in the desiccator in a
certain way. I do not remember what the argument Avas about but
only that I heard the Professor say that molecules could not pass
through this hole, and I made the unfortunate statement that I
thought I could make them pass through so fast that they would

25

whistle. My remark was an entirely casual one, based on no knowl-
edge of the matter whatever, but it upset the Professor as much as if
Einstein had said it. He immediately pulled out a pencil and paper
and started to prove to me how I must be wrong. I then became
enough interested to believe that he could not be right, and we dis-
cussed this matter all of one afternoon without leaving the lunch
table. I kept trying to get out of this by saying that it made no
difference what the molecules did, but the Professor kept saying,
"But this is a very serious matter with me. You know I taught
physics once." At about the time we should have left for dinner, I
became exhausted and told the Professor that since he was an older
man I could not say what I wanted to him and I thought that he had
an unfair advantage. Whereupon he said to go ahead and say what
I pleased, which we both proceeded to do for another hour or so, but
when I reached the Johns Hopkins Club after everyone had finished
dinner, I found a group of my associates in the middle of an even
more violent discussion about these molecules, which continued until
well after midnight. When I arrived at the laboratory in the morn-
ing, a bit late after the efforts of the preceding day. Dr. Abel came
into my room with triumph written all over his face and handed
me a book, saying, "Read that and see if I'm not right." On looking
it over, I found it to be a book on how to square the circle.

The laboratory lunch table became famous among the pharma-
cologists and visitors from many lands. Adjoining Professor Abel's
laboratory was a fairly large room in which Dr. Rouiller had a chem-
ical bench and in which Dr. Marshall was carrying out his experi-
ments on the kidney. The lunch table itself was a small kitchen
table covered with a Avhite oilcloth, and, except for the Professor, who
had a chair at the head of the table, we sat on laboratory stools.
Charlie Kamphaus supplied us with a long roll of bread, some cheese,
and "hot dogs" which I would not eat. This irritated the Professor
greatly. He tried for years by every means he could think of to get
me to eat them and usually ended his arguments by saying, "Oh,
well, you are prejudiced, as all Ne^v Englanders are prejudiced."
We made our own coffee. As far as I know, every member of the
staff suggested at one time or another having something else for lunch,
and the Professor always allowed him to try it, but every time we
came back to the bread, cheese, and coffee luncheons, and all agreed
that these were the best. We would have almost finished luncheon
when Professor Abel would appear from his room, having removed
his rubber apron but not his white hat. It was never more than a
26

few moments before he would bring up some topic of conversation
which was always interesting. He had an enormous amount of infor-
mation about matters relating to his work as well as to the work of
others, and he was always very much interested in historical matters,
particularly in relation to the war. When we had such visitors as
Sir Gowland Hopkins, Sir Henry Dale, Barger, and others who were
working on biochemical problems, they would sit at the table half the
afternoon going to the very bottom of these problems. But when
we had visitors of other types who could not discuss fundamentals,
the conversation soon lagged, and it became obvious that the Professor
was anxious to get back to work.

There was nothing formal about these affairs or about the labora-
tory. We were usually surroiuided by several dogs in a state of anes-
thesia due to paraldehyde, whose ureters had been cannulated by
Dr. Marshall for his kidney experiments. The odor from the paral-
dehyde as well as the dogs was not too pleasing, but this made no
difference. There were more roaches in that laboratory than in any
place that I have ever been in, and I have been in bad ones. Several
times we tried concerted gas attacks with sprays on these roaches and
collected several buckets of them, but they came back almost at once.
Then we tried putting the legs of the lunch table in tin cans of kero-
sene to see if that would keep the roaches out of our food, but even
this was none too successful. The Professor always knocked his chair
on the floor and shook out his coffee cup before sitting down. For
years the coffee cups were Cross and Blackwell crockery marmalade
jars. One day I noticed the Professor wiping his knife back and
forth over the oilcloth on the table in a dreamy sort of way when he
suddenly called out, "Charlie, Charlie, what is this? Haven't we
oot a new oilcloth?" When Charlie answered in the affirmative, he
said in his far-off manner, "I thought so. I couldn't hear any roaches
crackle underneath it." The roaches ate the backs off our books.
They were so thick that anyone who had been in the laboratory any
length of time automatically stepped back when opening a door to
allow the roaches to fall, and we all turned the inside bands of our hats
down before leaving for the night and shook the roaches out. I
tried to clean the laboratory once and found that the drawers re-
semljled the streets of Pompeii. They contained layers of papers and
old notebooks between which rats had died, had become desiccated,
and were flattened out by the accumulating material. By such excava-
tions it was almost possible to tell the order in which Dr. Abel's as-
sistants had come to the laboratory. It was only after a Spanish

27

Avoman supplanted Mrs. Thomas as laboratory scrubwoman that we
managed to clean the place up and get rid of the roaches by means
of a roach food rather than a spray.

These remarks may sound a bit exaggerated, but it is a fact that
when in fearful heat I was cleaning out the storeroom in the attic
immediately under the roof on a very hot day with both Charlies,
Charlie Drain was about to toss me a rather large, wooden box when
Charlie Kamphaus shouted at him in a horrified manner and he
stopped. It turned out that this was a box of T.N.T. which had
been put aside and forgotten after a few experiments by Professor
Abel. There was enough there to have removed not only the Depart-
ment of Pharmacology but the entire Medical School as well.

A great deal of Professor Abel's charm was due to his intense in-
terest in his work and, as I have said, his behaving as though every-
thing that went on in the laboratory was on a plane far removed
from everything else on this earth. I shall never forget his experi-
ment on plasmapheresis which I saw when I first went to the labora-
tory. He had already carried out his preliminary work on dogs and
asked me to join Dr. Marshall and Dr. Turner in further experiments
which he wished to have done. Dr. Marshall was at that time an
expert organic chemist with several years' training with Dr. Jones in
biochemistry, but he had not yet had any pharmacology or medicine.
Dr. Turner was a physical chemist from England who appealed to
Dr. Abel's soul by calculating everything that went on, no matter
what it might be. They had just bought a large centrifuge Avith which
to centrifuge the blood taken from the dogs, and Dr. Turner proceeded
to calculate just what would happen if the centrifuge should break
while running at full speed. Each day, with his sleeves rolled up and
a stop watch in his hand, he would push up the starting lever step by
step, which took him the greater part of an hour, and calculate just
where in Baltimore the different parts of the machine would land if
things went to pieces. As Dr. Marshall and I were interested in get-
ting these experiments done and as it took almost an hour to speed
up the centrifuge, we were not so interested in these calculations, but
the Professor, much to my surprise, put the utmost faith in them and
told us never to use the centrifuge except under Turner's directions.
Finally, we slipped in one day when Dr. Turner was away and found
that speed could be obtained in from three to five minutes with
perfect safety, a procedure which was adopted in the future.

After many preliminary trials Professor Abel decided to carry out
one of his plasmapheresis experiments on a patient in the hospital

28

who had nephritis, the idea being to remove a pint or so of blood at
a time, add an anticoagulant, bring it back to the laboratory, centri-
fuge it, and replace the plasma with salt solution, returning the blood
to the patient and repeating the process as often as it was necessary
to do so. It was, of course, necessary to sterilize everything used for
this work. I found that a physical chemist's idea of sterility was a
curious one. Everything was passed through a flame, some slowly,
others fast, depending on their nature, until they were "about sterile."
Having collected a supply of this "about sterile" apparatus, we all
repaired to the hospital. The patient was lying on an operating table
with a donor next to him in case of accident, and the surgical benches
were filled with interested spectators. A surgeon asked the Professor
if he would not care to put on a cap and gown and take part in the
experiment. Dr. Abel stepped up to the nurse and proceeded to get
into his gown backwards, much to the consternation of the nurse.
He finally got it on right side round, then his rubber gloves, and, on
top of all, one of his much beloved operating caps. The Professor
went about on tiptoe, talking in a hushed voice and watching the
drawing of the blood with the greatest interest. During the first part
of the time, he walked about with both hands high in the air, his
mind centered on asepsis, but then he would see someone in one of
the stands to whom he wished to speak, and would go over and take
hold of the iron railing with both hands, and then come back to the
operating table again with his hands held high in the air. It was
difficult for those watching the experiment to restrain themselves
under these circumstances, but they did extremely well. After the
blood was drawn. Professor Abel rushed about in a very excited
manner seeing that everything was ready to take the blood back to the
laboratory, and in a low, excited whisper gave Turner directions as
to just what to do. When all was ready, he disappeared out of the
operating room, with both hands still high in the air. The moment
the door closed there was a sigh of relief, but it was not more than
thirty seconds after this Avhen the Professor came rushing back still
wearing his rubber gloves, his operating gown and cap, but with his
derby hat stuffed on over it. Absolutely unconsciotisly he came up to
the operating table, stood there talking very excitedly in whispers to
the surgeon, and every few moments adjusted his derby hat with
his rubber-gloved hands. About the time we all thought we could
stand it no longer, he dashed out of the room after the blood, and on
looking out of the window, we saw him tearing up Monument Street
after Dr. Turner with his gown flapping in the wind, his derby hat
on the back of his head, and his rubber gloves held high in the air.

29

Tlie laboratory course for the students was something never for-
gotten by anyone who took it. The course was given in a large
laboratory with chemical benches all around the side, and two sets of
these in the center of the room. I always tried to get the Professor
to give the opening lecture in Pharmacology, and he would promise
that he would, but on that particular day something would always
come up, and as far as I can remember he never gave the lecture. He
did, however, give a lecture occasionally, which was the cause of great
excitement throughout the laboratory. Preparation on the lecture
was put off until the last minute, and then everyone was sent rushing
for one thing and another. The Professor would pull out from the
top drawer of his desk a set of very ancient notes in which he would
become deeply absorbed. He would send for twice as many articles
as he could even look at in the time left before the lecture, and when
the time finally did arrive, he was keyed up to such a state of excite-
ment that his voice often broke and he told me, "The only way that I
can lecture is to wait imtil shortly beforehand and then saturate
my mind with material," but the result on the students was worth
seeing. They instantly became absorbed in what he had to say or
it may have been in the man who was saying it. In any case, they
were unanimous in their praise of his lectures. Of course, at times he
would give a special lecture on epinephrine, vividiffusion, or the pitu-
itary, which he would prepare with very great care and exactness.

But to return to the laboratory course. There were laboratory
exercises occupying one afternoon each week. Each year about two
weeks before the course began, the two Charlies would go through the
innumerable cupboards, drawers, research rooms, and so forth, and
pull out what apparatus they could find for the laboratory experi-
ments. Tambours, respiratory tanks, rubber tubing, cannulae, ether
cones, kymographs were all put in a great heap on a large table
in the corner of the laboratory with the idea of sorting these be-
fore the course began, but this was never known to have taken
place. In another corner of the large laboratory there was a small
research room which had been turned into a stock room in which
the unlabeled bottles were kept, and this room had one of those
doors which was cut across the middle so that the bottom could be
kept closed when opening the top. About the time that the students
began to arrive, the two Charlies would appear puffing up the three
long flights of stairs with gunny sacks full of dogs on their backs,
which were unceremoniously dumped over the half door into the

30

corner room, but, like the apparatus, enough dogs were never brought
up before the students arrived, so that half of the students would
leave for the animal house and come trudging back with the dogs of
all sizes, which were also dumped into the corner room.

There was a worse jam at the apparatus table than at a bargain
counter, members of the different groups shouting when they found
a tambour or some other necessary object which all four members of
their group were looking for. The scene around the table took on
the aspects of the stock exchange in a panic, members of the different
groups diving into the melee and signaling or shouting about the
various parts of apparatus which they sought. It was the custom to
shave the dog before operating, but there was only one razor for the
entire class. Elaborate methods of matching or tossing a penny for
the razor were devised to see who could get it first. When you
dump a dozen unacquainted dogs into a small room after they have
been tossed about in a gunny sack together, and let a crowd of excited
students in to see who can get the best dog, the floor is not always in
the best of condition, and after a student managed to get a dog, it
made little difference to him what else he took to the big laboratory.
After this preliminary fight and when the dogs were under ether,
things quieted down for a bit until the injection of drugs began.
The students attempted to obtain records of their experiments, using
German roll paper kymographs, ^vhich one wound up with a key;
the recording was done with the same red-ink pens as were used in
research experiments. These kymographs must have been out of date
when they were bought at the opening of the Medical School in 1893.
It was impossible to make any of them run for any length of time,
and you would hear a cheer from any group which managed to
get a complete record of a single injection of a drug. The spirit of
chance seemed to pervade the whole procedure in the laboratory.
There was not only matching for the razor, the dog, and apparatus,
but you would find different groups betting on whether their kymo-
graph would or would not run through the next injection. In fact,
as only half the class could take the course, there was a good deal of
gambling on how to get into it, and I heard that at one time students
were buying places for as much as twenty-five dollars.

When my turn came to take charge of the laboratory course, I
went to Professor Abel and asked if I might not improve it a bit by
buying new apparatus. Dr. Abel seemed quite hurt and said that as
far as he could see, the course was all right. In those years he never
came into the laboratory. However, as in all things, he was very

31

cooperative and took me to the Dean, who was good enough to let
me buy a whole new set of apparatus, a Harvard kymograph for each
group, and later allowed me to put in a small shop and to obtain
the services of an excellent machinist. Dr. Abel was not anxious to
have the shop and tried to dissuade me by pointing out that there was
no place to put it. When I suggested a corner of the large labora-
tory, he admitted that this would be all right and became quite de-
spondent; but all of a sudden he remembered that the fire escape was
right outside of the window where I proposed to put the shop, and
he told me that it would never do to put it there. When I pointed
out that there was already a chemical bench in front of this window
as well as two shelves and three lines of pipes across it, which made it
impossible to get out, he gave up and let me have the shop.

I spent a great deal of time on this laboratory course, systematized
the whole procedure, and arranged for the entire class to take the
course. I had drawers put in so that each group could lock up its
own set of apparatus, and saw that a razor as well as the necessary
apparatus for each experiment was supplied to each group. The result
was very striking. Everything ran perfectly, the students obtained
good records and went ahead in a very orderly fashion, and I was
extremely proud of what I had done. But one day the Professor
happened to come into the laboratory in the middle of the after-
noon to ask me a question. In the midst of what he was saying,
he suddenly stopped and looked around the room in a dreamy kind
of way at the quietly working students and after a time said, "My
goodness, Lamson, you certainly have ruined this course. The stu-
dents used to have a good time here." There was much in this. Too
much refinement can obliterate all initiative, but where the line is
to be drawn is something for each generation to decide.

After my first year in the laboratory, during which Professor Abel
was largely occupied with the writing of his Mellon lecture, I had a
chance to see him at work on research. He became interested in
secretin and with Dr. Pincoffs made more and more concentrated
extracts of the intestinal mucosa until he obtained fractions that were
^ery active. Endless such fractions were separated, and each needed
io be tested by its effect on the rate of pancreatic secretion in the
dog. Dr. Pincoffs became very expert at preparing these animals.
The pancreatic duct was cannulated, the trachea connected with an
ether bottle, and the dog left to reach a state of equilibrium while
everyone had lunch. Everything worked perfectly for a time, and
then the dogs developed a peculiar habit of dying during the lunch

32

hour. Everyone had his OAvn idea as to why this happened. When
they did die, they died at almost the same minute each day, but
there were certain days on which they did not die at all. This became
a problem of almost as much interest as the nature of secretin itself.
It was solved, as many other things were in the laboratory, by Charlie
Kamphaus, who discovered that the sun came around the corner of
the building at the same time each day, shone on the ether bottle,
and raised the ether concentration to a lethal level.

According to Charlie, it was also he who discovered the fact that
the liver could concentrate phenoltetrachlorphthalein. Dr. Abel and
Dr. Rowntree were working on this substance and studying its pos-
sible action as a cathartic. Charlie was cleaning up after one of
Dr. Abel's experiments and was about to put the dog in a bucket when
he noticed that this dye was pouring out of the bile duct which had
accidentally been cut across. He called Dr. Abel's attention to this,
and if what he says is so, and ^ve could trust Charlie implicitly, we
again have an example of an important medical discovery being made
by chance, combined with the foreknowledge and altertness of the
observer.

Although Dr. Abel's experiments on secretin, Witte's peptone,
albumoses, and so forth, were painstaking and tedious, they were as
nothing compared with his work on the pituitary. The preliminary
pituitary extracts were made by Dr. Rouiller, Dr. Helen Graham,
or Dr. Gelling and then worked up further by Dr. Abel himself. They
were tested either on the blood pressure or on the guinea pig uterus or
both, and here again the pharmacological tests were extremely simple
and needed no complicated apparatus. By that time more modern
methods of doing blood pressures had been introduced into the
laboratoi7, and these were run off in great numbers. I well remember
Professor Abel's great delight when he managed to get rid of a pre-
liminary fall in blood pressure and obtained pituitary fractions which
gave nothing but an instantaneous and beautiful rise of pressure.

The uterine experiments were carried out by Dr. Rouiller, who was
a man for whom I had the utmost respect. He was an ideal person
for Dr. Abel to have associated with him. He was not only an or-
ganic chemist of exceptional ability, but during the years in which he
worked with Dr. Abel he was editing the Section on Organic Chem-
istry of Chemical A hstracts, and it seemed that there was nothing on
earth of which he had not heard. It was Dr. Rouiller who convinced
me that it was impossible to have an original idea. Every time I
had one, it would not be two days before he would come quietly into

S3

my room, an open journal in his hand, and almost apologetically show
me where this had already been done some time before. As far as I
know. Dr. Rouiller never did anything but work, except to read on
the streetcars to and from the laboratory. He was always there the
first thing in the morning and, as far as I know, never left the labora-
tory until at least twelve o'clock at night. He had an even greater
dislike than Dr. Abel for changing methods and an utter scorn for
biological methods, particularly the one on which he worked for some
eight or ten years to the exclusion of all others. This consisted in
comparing the activity of Professor Abel's pituitary fractions with
that of histamine by recording their effects upon the guinea pig
uterus. Although Rouiller was a very quiet and self-contained per-
son, what he had to say about the guinea pig's uterus cannot be
recorded here. Anyone who knows these organs well, knows that it
takes more than a saint to put up with their erratic behavior. They
were strung up in a bath of Locke's solution and tied at one end to a
writing lever, which needed to be constantly agitated so that it would
not stick on the smoked paper of the kymogiaph. In order to produce
this agitation Dr. Abel and Dr. Rouiller devised an apparatus con-
sisting of a pencil stuck through the hole of a rubber stopper, and it
Avas the experimenter's task to sit there and pound the desk with this
rubber stopper, often for five or six hours at a time, while the uterus
was trying to decide whether to behave itself or not. It was utterly
impossible for me to convince either Dr. Abel or Dr. Rouiller that a
mechanical agitator would work just as well, and I will admit that it
was none of my business, but hammering a bench for hours at a time
was one of those things which seemed to me to be obviously incom-
patible with the abilities of a great man.

For many years Dr. Abel carried out this work in spite of continued
setbacks. He used to drop into my room at the end of the day and
talk over his experiments while putting on his coat. Although at
times he was discouraged, it was much more likely that he would say,
"I've got it this time. I'll show it to you in the morning," but in
the morning the fractions of which he had expected so much were
apt to turn out in as disappointing a way as ever. This would never
upset him, and he would begin all over again with as exactly as much
enthusiasm as ever.

For a time Dr. Abel was assisted by Dr. Helen Graham, and as
a sidelight on Dr. Abel's character it might be interesting to record
a remark which he made about her. He said one evening to me,
"Lamson, I have seen a good many women in science, and, to tell

34

the truth, I have not felt that they were particularly well fitted for it,
but Dr. Graham is different. She has upset all of my ideas on the
matter, and she is as good if not better than any man whom I have
ever had with me in the laboratory."

Anyone who has read Dr. Abel's work on histamine, the active
principle of the pituitary gland, as well as his early work on epi-
nephrine, must wonder why Dr. Abel published certain things that
he did, why he was apparently in such a hurry about publication,
and why he was so vague in his description of his work that it is al-
most impossible to repeat it. This seems incompatible with his crit-
ical judgment, the exactness which he required of others, and the
standards which he set for his own journals. Personally, I think
that it was Dr. Abel's terrifically intense interest in the outcome of
his work which allowed him to do this. He was so interested in an
absolutely honest way that this at times warped his judgment. I
know that this was so about his conclusions of the part that histamine
played in the activity of the pituitary gland. He would not listen
to suggestions made to him by Dr. Marshall and others in the labora-
tory but dashed off this paper and published it without showing it to
anyone.

It was very interesting to see the inner workings of The journal of
Pharmacology and Experimental Therapeutics at such times as when
Dr. Abel got hot on the trail of something in which he was particu-
larly interested. Before he reached the end, he would get more
and more excited about his work and become suddenly convinced
that he was going to settle everything the next day. He would call
his secretary, ask for the publishers on the line, and have them hold
the next number of the Journal until hearing from him. The entire
laboratory would then be upset in an attempt to finish his w^ork and
rush a publication through. Every time the expected result was not
found, and after a considerable delay of the Journal, Dr. Abel would
reluctantly give the order to print the next number without his con-
tribution. When a piece of work was really ready to be written up,
the procedme was very different and involved weeks of poring over
endless periodicals by Dr. Abel and his associates. Certainly no one
would accuse him of having done this superficially.

I cannot go into details of the pituitary controversy, but after the
finding that histamine was not the internal secretion of the pituitary
gland and the finding by others suggesting that there were at least
tTVo, if not more, active principles rather than the one which he had
postulated. Dr. Abel set out to sho^v that his opponents could not be

35

right. The discussions at the lunch table took on the character of a
religious controversy, the Professor laying down the law about his
unitarian doctrine and the absurdity of that held by the trinitarians.
He insisted that it was the methods used by his opponents which gave
them their multiple active principles. For years it has seemed that
the Professor could not be right, but recent work indicates that there
is a ray of hope for his doctrine.

In the previous sketches of Dr. Abel's life everyone has referred to
how hard he worked. This, I think, can be gathered from what I
have said already. During my stay in the laboratory Dr. Abel never
spent the evenings there, for he was getting on in years, but I never
dropped in on him at home but what I found him reading either
history or something bearing on his work. I never saw him read a
current novel. I have seen him work when he was so exhausted that
he could hardly stand or speak above a whisper, particularly in the
years after he had undergone an operation. At one time matters
came to such a pass that he could not remember the names of anyone
in the laboratory; he developed a very definite droop on one side of
his face which made his speech indistinct, and I felt almost certain
that if he kept on he would have a cerebral hemorrhage. I was un-
able to induce his clinical colleagues to talk to him about this, for
they felt that it was interfering with his personal affairs, so I finally
wrote the Professor a letter telling him just what I thought might
happen to him if he kept on working as he was doing, explaining that
if he should suddenly die, it would not be such a serious matter, but
that if he were paralyzed, it would be. I also offered to resign from
the laboratory if he did not wish to have someone around who was
interfering with his life. Dr. Abel was indisposed on this day, and
I left the note with Mrs. Abel at his house, wondering what the out-
come would be. At about five in the afternoon Mrs. Abel called me,
saying the professsor read my letter, remained silent for a few mo-
ments, and then said, "Mary, find out when the next train goes to
Atlantic City." After a few weeks' rest he was a different person.

At this particular time Professor Abel had worked himself into a
state of collapse over the matter of a biophysicist. He was then very
much interested in the application of the infrared spectroscope to
the analysis of his pituitary fractions. He was so impressed by the
results of the experiments reported to him (although they were later
found to be valueless, since they were not correctly obtained) and by
the realization of the fact that those trained in physics might add as
much to medicine as those trained in chemistry had already done,

36

that he set out to bring about the organization of a department of
biophysics in tlie Medical School. He encountered great opposition
to his plan, which he attempted to overcome by sheer strength of
character, but this failed, and his efforts nearly killed him. Many
times he said to me that he was going to put this through if it was
the last thing that he did in this world, but finally it was definitely
settled that there would be no such department, and he went back
to work once more. The success of such ventures in other places
since has proven that there was more in what Dr. Abel suggested
than was realized by his colleagues.

After his work on the pituitary he turned to the problem of insulin.
He, Rouiller, and Geiling worked as indefatigably on this as they
had on the pituitary gland. In Dr. Geiling, Professor Abel found
another devoted soul. Dr. Geiling gave up everything else in life
for the Professor, as Mrs. Abel and Charlie Kamphaus both had done.
He tested endless insulin fractions on rabbits, he looked out for all of
Dr. Abel's affairs, both in and out of the laboratory, such as his
traveling arrangements, his tickets, his taxicabs, and countless little
things. He went with him to California for this work. He shared
with Dr. Rouiller the terrible drives that Dr. Abel made on his prob-
lem, which always seemed to come at Christmas, Easter, or during
the summer vacation, when one naturally wished to let down a bit,
but in spite of Dr. Ceiling's remarking that he wished the Professor
could time these drives a little differently, he was always there,
working with as great intensity as the Professor himself. Dr. Geiling
was a very great help to Professor Abel in his latter years.

As said before, I have thought of Professor Abel as a mystic, some-
one whose mind was in the clouds and yet who was absolutely aware
of what was going on in the particular field in which he was interested,
whatever this might be, whether it was medical science, the war, or
historical affairs. No one, whether it was a new assistant, one of his
past associates, one of his colleagues, or a visiting foreigner, ever came
into the laboratory without immediately feeling the friendship of this
man and his real interest in what one came to see him about. If
his visitor was of the first order, himself interested in some problem,
the Professor would spend any amount of time discussing it with him
regardless of his station in life. On the other hand it did not take but
a few moments for Dr. Abel to recognize a second-rate man. He did
not exactly like to turn such a man out but devised a convenient
method of doing this. He ^vould appear in my doorway with the visitor
on his arm and would introduce him to me with the remark, "I

37

want you to meet Dr. Lamson, who is doing some extraordinarily
interesting work whicli I am sure he would be glad to tell you about,"
and with a wink of his one eye he would return to his laboratory.
I would like to know how many such visitors I have had to dispose
of for him in this way.

In his last years, time became the most precious thing for Dr. Abel.
He would not relax but seemed to work harder than ever in the hope
of accomplishing something in what he knew was an ever-diminishing
period of time. He frequently spoke of hoping to last long enough
to accomplish some particular object. We would take our manu-
scripts to him as Editor of The Journal of Pharmacology and Experi-
mental Therapeutics, and although he was critical of outside publica-
tions, he assumed that the papers which we had written were worth
publishing and he hated to waste time on them. I would go into his
room with a manuscript, which he would take very giaciously and
with an air of intense interest. After opening it to one or two pages,
or not at all, he would hand it back with a pat on the back and the
remark, "That certainly is a fine piece of work. Just give it to our
secretary, and we will put it in the next number," and even while
handing it back, he would turn to his work once more. But if some-
thing needed attention, no matter what it was, he would drop every-
thing for it. After I had been in the laboratory for about a year, I
found that shutting off the arterial blood supply to the liver prevented
the production of polycythemia after the intravenous injection of
epinephrine, and I published this work in Dr. Abel's Journal. After
returning to the laboratory I tried to repeat these experiments, and
in the first two dogs which I used I was unable to do so. I was horri-
fied at having published something from Dr. Abel's laboratory that
was apparently not true, and decided that the best thing to do was
to resign and get it over with as soon as possible, so I immediately
went to Dr. Abel and told him what had happened. He listened to
what I had to say with much interest, and to my utter surprise
said, "But, Lamson, you must be right. Have you thrown away the
dogs on which you carried out these experiments?" Such absolute
confidence in an assistant not only endeared him to me for life but
made it an absolute necessity that what I might do in the future must
be well controlled. When I told him that I still had the dogs, he
said, "You must have some collateral blood supply which you did
not tie off." We went out to the laboratory, and he injected dye into
the aorta, and sure enough in both instances the dye immediately
went into the liver, showing that the blood supply had not been prop-

38

erly cut off, and we were able to trace out collateral circulation. It
was not only such trust and kindness as this but Dr. Abel's sympathy
and understanding for all those who had the truth of things at heart
that gave one faith, faith in the value of scientific ideals.

During the many years that I was with him I never heard Dr. Abel
speak of trying to find a man for his laboratory or showing interest
in promising young men who might make good pharmacologists. As
far as I knew, men simply came there as 1 did, delighted with the op-
portunity of being allowed to work there. Everyone always seemed
welcome, and a place was made for him. Dr. Abel's love of foreigners
was obvious. Japanese, Chinese, South Africans, Englishmen, Swiss,
Poles, and Spaniards worked there in even the few years that I was in
the department. His recommendation to his assistants of new ar-
rivals was the closest to falsification that I ever knew Dr. Abel to
come. He brought me one man, for instance, whom he assured me
would be of invaluable assistance, and introduced him as an expert
biological chemist with a splendid training in medicine. This was a
Spanish priest who, beside Spanish, spoke nothing but German and
very little of that. I told this new associate that my work was on
the liver, which seemed to interest him, and he confided to me that
he was a "non-conformist on the liver, that it was the cause of tuber-
culosis." When I asked him why, he replied that he would have to
consult his notebooks, but they were in Spain. On getting to know
him better, I found that he had had five years of lectures in chemistry
and medicine but had never held a test tube in his hand or done a
single experiment of any description. However, he turned out to be
a most delightful person, of whom I became very fond.

With the exception of those who came to work ^vith Professor Abel
on his own problem, men were simply turned loose and allowed to
sink or swim. Some went through a great deal of mental anguish be-
fore finding a problem, but it was surprising how each did, how they
absorbed the spirit of the Professor, and after a very short time were
working day and night. One needs only to go over the list of those
who worked in his laboratory and their accomplishments to see that
whatever the methods of education were which the Professor used,
they certainly were successful.

Finally, I should like to consider what Abel did for pharmacology,
that special field of medicine for which he was responsible. It is
often said that he paid no attention to organization, that he entirely
neglected the training of his assistants as well as the students, and
that in spite of his intense interest in research he let pharmacology

39

run down. There can be no doubt whatever but that pharmacology
did run down in this country during the latter years of Professor
Abel's life, and it is also true that no effort was made by him, during
the years that I was in his laboratory, to see to it that assistants Avere
put through any sort of training or that a policy of any kind was
carried out in relation to the student course. In fact, the Professor
used to preach to me against spending too much time on lectures and
the organization of pharmacology and advised me to put my efforts
into research and let other matters take care of themselves. But was
this not the reaction of a man who had been through much himself
and had forgotten that others did not have the training which he
himself had?

I do not feel that pharmacology would continue to exist as an
entity if all departments were organized as Dr. Abel's was when I was
there, for they would not be headed by Abels; but we must not forget
that the state of pharmacology in his laboratory was more or less the
fault of his assistants rather than of Dr. Abel. He had been through
the years of effort which it took to develop the first pharmacological
laboratory in this country, a series of lectures and demonstrations as
well as laboratory experiments, the organization of a course not only
in pharmacology but in toxicology, prescription writing, materia
medica, and dosage, and a course in pharmacy given by a group of the
best pharmacists in this country. Anyone wishing to obtain an idea
of the care with which he did this needs only to read his papers, "On
the Teaching of Pharmacology, Materia Medica, and Therapeutics in
our Medical Schools" (3), "Report on the Teaching of Pharmacody-
namics, in the Report of the Committee on Medical Education of the
American Medical Association" (4) and "The Education of the Su-
perior Student" (5). There were enough relics of these days in the
Pompeian layers of the laboratory drawers to indicate what had been
done in the past, but Dr. Abel's primary interest was not in organiza-
tion. As soon as he had taken care of the organization of pharma-
cology in this country, not only in teaching but in the provision of a
journal for the recording of experimental work and a society which
would bring pharmacologists together, he left it to others to continue
along the line which he had planned and himself turned to research,
which he kept emphasizing as the basis of everything worth ^vhile.

We are apt to think of Abel as a biochemist rather than what many
consider a pharmacologist to be. I know that Dr. Abel believed most
thoroughly in the method employed by the pharmacologist of using
the reaction of the organism in isolating active principles from plants

40

and tissues. At the time when epinephrine and thyroxin were about
the only hormones known, he fek that we had just made a beginning
in the study of those processes of the body which are under chemical
control. True it is that he Avas not interested in the superficial 'ac-
tions' of drugs, which are studied by many who are satisfied to go
no further. His interest was in the 'nature of things,' the nature of
the great chemical laboratory, the living organism. If he knew that
something in some plant, some animal poison, some gland, or some
bacterial toxin brought about a change when introduced into the
body, he wanted terribly to know the nature of this chemical sub-
stance, as necessarily it must bear some relationship to one of the
chemical constituents of the cell with which it reacted to bring about
the secondary reactions observed, as changes in muscle tone, respira-
tion, and so forth. Abel was as close to the bottom of things as one
could go. He was a biologist of the most fundamental type. If one
wishes to obtain in Abel's own words his concepts of these matters,
they may be found in his presidential address to the American
Association for the Advancement of Science (Science, 1934), as well
as in his letter on pharmacology to Dr. Abraham Flexner, which is
given in Dr. Voegtlin's biography of Dr. Abel (1, p. 397).

During the long life of a man such as Dr. Abel things are certain
to change, and the problems of today are entirely different from those
Avhich he encountered in his most active years. If pharmacology has
retrogressed since Dr. Abel began it in this country, those of us who
have followed should not put the blame on him but on ourselves,
possibly for not taking our share of the organization and the atten-
tion to general principles, which is necessary for the well being of
any medical discipline, and perhaps more than for any other reason
our failure to grasp just what was uppermost in Abel's mind as the
function of the pharmacologist— the solution of the innermost chem-
ical secrets of the living organism.

In all that is going on in the world today, with the utter chaos of
thought, in spite of the terrific increase in scientific knowledge and
technical ability, it is becoming more and more apparent that it is
the man that is needed, rather than knowledge alone, the man with
ideals and the courage to maintain them. But constructive ideals
need knowledge, which can come only with study, training, and ex-
perience. All of these Abel had. It was this which made it possible
for him to see what was best in medicine in his time, and '^vhat prob-
lems were of the most importance for investigation. Abel was ahead
of his time in this country. His desire to get to the bottom of matters

41

showed him the need of chemistry in medicine, and he took the time
and staked his savings to get a training in chemistry before settling
down to work. It was this which made it possible for him to see prob-
lems quite invisible to many of his colleagues and to visualize the com-
ing of the present-day knowledge of hormones and the importance of
chemistry in all life. He was equally well aware of the coming of
physics in medicine but was unable to convince enough others of
this to allow him to do for biophysics what he did for biological
chemistry and pharmacology. When the life of this man is fully
written, students of science as well as of medicine will do well to
study it. Dr. Abel gave the world much by his investigations, but
more than that he has given us ideals— lived up to— which anyone
would do well to follow.

REFERENCES

(1) Clark, W. M.: /. Biol Chem., 124, (n. p.) August 1938.

Dale, H. H.: Obituary Notices of the Roy. Soc. of London, 2, 577, 1939.
Ceiling, E. M. K., and Evans, E. A., Jr.: Scient. Monthly, 47, 185, 1938.
Ceiling, E. M. K., and Evans, E. A., Jr.: Arch, internal, de phartnacodyn.

et de therap., 60, 240, 1938.
Cunn, J. A.: Nature, London, 142, 242, 1938.
Marshall, E. K., Jr.: Science, 87, 566, 1938.
Voegtlin, C: /. Pharmacol, ir Exper. Therap., 67, 373, 1939.

(2) Abel, J. J.

(3) Abel, J. J.

(4) Abel, J. J.

(5) Abel, J. J.

Science, 42, 135 and 165, 1915.
Philadelphia Med. J.. 6, 384, 1900.
A. M. A. Bull., 5, 54, 1909.
/. Che7n. Education, 7, 283, 1930.

42

f^f J-IBRARv '^

On the Blood-Pressure Raising \^
Constituent of the Suprarenal
CapsuM

JOHN J. ABEL, M.D. AND ALBERT C. CRAWFORD, M.D.

B

OTH clinical experience and laboratory research have shown that
the suprarenal capsule is an organ of vital importance.

Physiologistsf have proved that a very small quantity of an aqueous
extract of the medullary substance raises the blood pressure to a great
height above the normal. It has also unequaled power in reviving a
poisoned heart. Gottlieb,]: for example, has shown that it will revive
the heart of a rabbit which has practically stopped beating in conse-
quence of an intravenous injection of chloral hydrate.

Bates§ applied an aqueous solution to the eye and found that it
exerted a marked vaso-constricting action. In numerous cases of con-
gestion a small quantity dropped into the conjunctival sac brought
about an immediate pallor, lasting for some time. According to this
writer the extract is very useful in prolonged operations, for, when
repeatedly applied, haemorrhage is prevented and cocaine anaesthesia
is in consequence indefinitely prolonged. As the result of his two years'
use of the extract Bates concludes "that within the limits of its sphere
of activity there is absolutely no other substance which can take its
place."

Other experiments || go to show that the aqueous extract is a power-
ful poison when injected directly into the circulation and may lead to
fatal results.

* Read before the Association of American Physicians, May 6, 1897.

f Schafer and Oliver, Journal of Physiology, xvi (1894) and xvii (1895); Szy-
monowicz and Cybulski, Wien. med. Wochenschrift, 1896, No. 6.

:|:Arch. f. exp. Pathol, u. Pharmakol., xxxviii, 106.

§ New York Medical Journal, Ixiii (1896), 647.

II Foa and Pellacani, cited in Maly's Jahresb. d. Thier-Chemie, xiii, 129; Marino-
Zuco, ibid., xviii, 231; Gourfein, Rev. M^d. de la Suisse Romande, Oct. 20, 1895;
Compt. rend., cxxi (1895), 311-314.

43

M(\^.

The various extracts that have been used in these experiments were
mixtures of unknown substances, and it is as yet an unsolved question
whether the various actions at present ascribed to the gland are due
to one and the same substance.

We are at present interested in the isolation of the blood-pressure-
raising constituent, for in a purified state, separated from all other
constituents, it might become a therapeutic agent of great importance.

On the chemical side but little advance has been made over Vul-
pian's* striking original contribution more than forty years ago. Vul-
pian observed that the juice expressed from the suprarenal capsule
of many different animals behaved in a striking manner toward ferric
chloride and toward solutions of iodine, giving with the former rea-
gent an emerald green color, and Avith the latter a beautiful rose
carmine tint. No other tissue of the body, so far as investigated by Vul-
pian, gave these reactions.

Virchowf substantiated Vulpian's statements, but added nothing
new. A year after Vulpian's first announcement his second paper ap-
peared in conjunction with Cloez,:}; verifying and extending his first
observations and stating his failure to isolate the chromogenic sub-
stance or substances to which the above reactions are due.

Equally unsuccessful were Arnold§ and Holm.|| Krukenberg,**
years after, repeated the work of Arnold and came to the conclusion
that the chromogen of the suprarenal capsule is a non-volatile, nitro-
genous and ferruginous organic acid which is probably related to the
turacin of the musophagidae and to chlorophyll. He assumed that the
substance giving the green color with ferric chloride is not the chromo-
genic substance of Vulpian, but more likely pyrocatechin accompany-
ing the chromogen. Attention being thus attracted to the possible
occurrence of pyrocatechin in the suprarenal capsule, others took up
the subject.

Brunnerj-f found that an alcoholic extract can be made to give
nearly all of the reactions of pyrocatechin; thus, it gives the well-
known green color with ferric chloride, passing into a fine red on the

* Note sur quelques reactions propres i la substance des capsules surr^nales,
Compt. rend, xliii (1856), 663-665.

fVirchow's Archiv, xii (1857), 481-483.
+ Compt. rend., xlv (1857), 340-343.
§Virchow's Archiv, xxxv (1866), 64-107.

Journ. f. prakt. Chemie, c (1867), 150.
** Virchow's Archiv, ci (1885), 542-591.
-|-f Schweizer. Wochenschr. f. Pharmacie, xxx (1892), 121-123.

44

addition of ammonium tartrate and a few drops of an alkali; it re-
duces silver nitrate at room temperature, and Fehling's solution on
boiling. The addition of an alkali soon causes it to take on a dark
brown color, lead acetate gives a precipitate, nitroprusside and very
dilute ammonia give a wine-red color. All of the above reactions be-
ing given also by pyrocatechin, Brunner concluded that Krukenberg
was right in his belief that pyrocatechin is present in the suprarenal
gland.

After the discovery of the blood-pressure-raising property of the
suprarenal gland, B. Moore,* working in Schafer's laboratory, came
to the conclusion that Vulpian's chromogen and the blood-pressure-
raising constituent are identical. He based his opinion on the fact that
chemical operations which destroy the color reactions by oxidizing the
reducing agent appear also to destroy the blood-pressure-rasing con-
stituent. That the solubilities of the active principle are the same as
those of the reducing agent appears also to support this opinion.

Fraenkelf worked with residues obtained with the help of alcohol
and acetone as solvents. These residues raise the blood pressure and do
not contain pyrocatechin, and on the strength of the ferric chloride
reaction and its reducing po^ver he concludes that the essential prin-
ciple of the residue is a nitrogenous derivative of the or//?odihydroxy-
benzene series.

According to Fraenkel both Krukenberg and Brunner are wrong in
their opinion that the suprarenal gland contains pyrocatechin.
Fraenkel concludes, like Moore, that the blood-pressure-raising con-
stituent and Vulpian's chromogen are one and the same substance.

More recently still, Miihlmann:|: has attempted to prove that the
blood-pressure-raising constituent is a pyrocatechin derivative. He
asserts that on boiling fresh suprarenal capsules with dilute hydro-
chloric acid the active principle is decomposed and the pyrocatechin
which is split off may be taken up with ether. Miihlmann has not,
however, furnished conclusive chemical proofs for his assertion. Both
Miihlmann and Brunner might have settled this point by precipitating
the supposed pyrocatechin with lead acetate and analyzing the lead
salt thus obtained. Pyrocatechin may be present in small amounts in
the gland, but no proof of this has yet been furnished.

There is therefore at present great diversity of opinion as to the

* Journal of Physiology, xvii (1895), Proc. Physiol. Soc, p. xiv.

f Wiener med. Blatter, 1896, No. 14-16.

+ Deutsche med. Wochenschr., 1896, No. 26, 409-411.

45

chemical character of the blood-pressure-raising constituent of the
gland.

Whatever the probability may be of the correctness of this or that
view, it is to be noted that all of the above-named investigators have
based their conclusions on reactions made with aqueous, alcoholic or
acetonic extracts; none of them have even roughly isolated a definite
chemical compound. The subject is one of great difficulty, and our
own work is at present merely preliminary, but we have arrived at the
following conclusions which we believe to be borne out by our ex-
periments.

First, we have found by isolating the blood-pressure-raising con-
stituent in the form of a benzoyl compound and decomposing it, that
the active principle is a substance with basic characteristics and that it
must in all probability be classed with the pyrrol compounds or with
the pyridine bases or alkaloids.

Second, that pyrocatechin cannot be split off from the isolated ac-
tive compound by boiling with acids, as has been asserted.

Third, we have found that a carmine-red pigment can be separated
from the sulphate of the active principle without destroying its
power to raise the blood pressure.

Fourth, in addition to this, we have isolated from the crude benzoyl
product a volatile basic body which fumes in the air and which emits
an odor very much like that of coniine.

Method of Isolating the Active Principle in the
Form of a Benzoyl Compound

We have used sheep's glands in large quantity. The medullary sub-
stance of the fresh glands was scraped out, dried on the water-bath
at 60° C, ground up finely, and extracted with ether for several days
until the fats and the substance known as Manasse's jecorin were re-
moved. In this way a fine dry powder of a grayish white appearance
is obtained, the aqueous extract of which is very active in raising the
blood pressure.

With 100 grammes or more of this powder, representing one kg. in
weight or about 1000 fresh glands, we proceeded as follows: The pow-
der is repeatedly extracted with warm ^vater acidulated with a few
drops of dilute sulphuric acid until the gland has yielded up all of
its chromogenic substances, as tested by Vulpian's reactions. This
aqueous extract is evaporated on the water-bath to a small bulk, a
large excess of strong alcohol is then added and the whole allowed to
stand 24 hours, by which time the proteids have all settled out. The

46

alcoholic fluid is then filtered and the gieater part of the alcohol re-
moved by distillation; the remainder is driven off on the water-bath.
The entire removal of the alcohol is necessary, and in order to avoid
too great concentration of the acid fluid, which seems to destroy some
of the active principle, water has now and then to be added. The
brownish fluid when filtered gives all the well-known reactions char-
acteristic of Vulpian's chromogen, and on neutralizing the sulphuric
acid we found the filtrate to be physiologically very active.

This filtered fluid is next treated with the proper quantity of
benzoyl chloride and sodium hydrate according to the Baumann-
Schotten method of forming a benzoyl compound. There results a
tarry substance of a light yellow color which sticks to the sides of the
separator funnel and which is collected and washed until the wash
fluid no longer gives an alkaline reaction. It is next dissolved as far
as possible in alcohol and the alcohol evaporated. The residue is
then treated with ether, which takes up the greater part of it, the
ethereal solution is filtered and the ether driven off.

The residue, ^vhich is of tarry consistence and amber color, is
taken up in strong alcohol from which all basic substances have been
removed by distilling from tartaric acid. It is then boiled for two hours
with animal charcoal previously well washed with purified alcohol.
After filtration and the evaporation of the alcohol a considerable
quantity of crystalline residue is obtained which is found to consist
of the benzoyl compound of the active principle contaminated with
other benzoyl derivatives and which \\'e may call the crude benzoyl
product. It is insoluble in ^vater, alkalies or acids of ordinary strength,
is soluble in alcohol, ether, glacial acetic acid and concentrated sul-
phuric acid.

It is of interest in this connection to note that benzoyl chloride
effects the complete removal of the blood-pressure-raising constituent
from an aqueous solution. This is proved by the fact that the filtrate
from the insoluble benzoate no longer gives the characteristic chemi-
cal reactions of the active principle, and that chemical manipulations
no longer yield a blood-pressure-raising constituent. Indeed, an injec-
tion of a sufficient amount of the material left after the sodium benzo-
ate and the excess of alkali have been removed, causes a sharp and
sudden fall of pressure instead of a rise.

It was not until long after we had made use of benzoyl chloride as
a precipitant of the active principle that we obtained access to
Fraenkel's* paper. From it we learned that a syrupy substance is

* Wien. med. Blatter, 1896, No. 14-16.

47

thrown out when benzoyl chloride is shaken up with a pyridine solu-
tion of an extract of the gland. Fraenkel did not succeed in crystallizing
this benzoyl compound, nor did he attempt to decompose it in order
to ascertain whether it was in reality a benzoate of the blood-pressure-
raising principle.

Methods of Decomposing the Benzoyl Compound

A quick method always used by us as a qualitative test is as follows:
The compound is dissolved in as little concentrated sulphuric acid as
possible, crushed ice is slowly added, and the benzoic acid which has
been split off is shaken out with ether. On neutralizing the solution
we found it to give the reactions characteristic of aqueous solutions of
the medullary substance. We have not considered this method adapted
to the decomposition of large quantities of the product.

Decomposition of this benzoyl product was effected by means of an
alcoholic solution of sodium alcoholate, and also with strong hydro-
chloric acid and alcohol, but these methods were found to be less
satisfactory in practice than the following, \vhich is the method on
which we now rely. The benzoyl compound is dissolved in glacial
acetic acid, the solution heated to near the boiling point, and an equal
volume of a 25 per cent solution of sulphuric acid actively boiling
is slowly poured into the hot acetic acid solution, the whole being
shaken meanwhile. The flask is now attached to a back-flow condenser
and heated on a small flame for about ten minutes.

The solution is next diluted with water and allowed to cool, the
benzoic acid, which has been thrown out, is filtered off and the rest
is removed with the help of ether.

Mixed with the benzoic acid which has been removed by filtration
is found a dark brittle substance which softens on the water-bath, and
which we assume to be a benzoyl compound of unknown composition
Avhich was apparently unaffected by the dilute sulphuric acid. On dis-
solving it in concentrated sulphuric acid and diluting with crushed
ice, the resulting fluid gives none of the reactions characteristic of
suprarenal extracts.

After decomposing the benzoyl product with hot dilute sulphuric
acid and removing the benzoic acid thus split off, we next get rid of
the acetic acid by repeated partial evaporations, taking care not to
let the solution become too concentrated and thus perhaps injure the
active principle. After the removal of the acetic acid the sulphuric
acid is precipitated with the help of lead carbonate. The lead sul-
phate is removed and the filtrate is allowed to stand in vacuo over

48

sulphuric acid until it has become of tarry consistency. It is then ex-
hausted with ether, acetone and absolute alcohol in succession.

The residue is physiologically very active, and it gives all the reac-
tions characteristic of an aqueous solution of the gland— a beautiful
rose color on the addition of an alkali, a green color with ferric chlo-
ride, reducing silver nitrate, etc.

However, we are not yet dealing with a pure substance. If we neu-
tralize an aqueous solution of the product thus obtained with a free
alkali or with a carbonate of the alkalies, an overpowering odor much
like that of coniine is perceived. As this odor passes that of pyridine
seems to take its place. The basic substance thus liberated fumes in the
air or when a glass rod moistened with hydrochloric acid is brought
into its neighborhood. To remove this basic substance we made an
aqueous solution of the active principle as above isolated, rendered
it faintly alkaline with sodium carbonate and shook out ether sev-
eral times in succession. But this method does not remove all of the
coniine-like substance. To effect this we were obliged to make the
active principle strongly alkaline with sodium hydrate before shaking
out with ether. The acjueous solution, in consequence of the addition
of the free alkali, takes on a deep red color, and carmine red flocks are
thrown out. After the removal of the coniine-like substance with
ether, the fluid containing the red flocks was acidulated with sul-
phuric acid and the carmine-red substance was filtered off. The clear
filtrate, which was a pale straw color, was concentrated in vacuo, and
the active principle taken up in weak alcohol. On account of the in-
solubility of the sulphate of the active principle in absolute alcohol
it is difficult to obtain this entirely free of sodium sulphate. We hope
in future to remove both the coniine-like substance and the pig-
ment ^vith the help of ammonia. The presence of pyridine in our
ammonia prevented our using it for this purpose.

This volatile base of a coniine-like odor has not hitherto been de-
scribed as a constituent of the suprarenal capsule. The beautiful
carmine-red pigment we take to be identical with the red substance
which many other observers have found to be thrown out as a pre-
cipitate when ammonia is added to a concentrated aqueous solution
of the gland, or when a solution is evaporated in the presence of lead
acetate.* Others have believed this red precipitate to be the oxidation
product of the active principle of the gland, but we shall presently
see that the active principle is still present in the filtrate from the

* Holm, Journ. f. prakt. Chemie, c (1867), 150.

49

carmine-red body. We have as yet made no experiments with this pig-
ment except to note that it is but slightly soluble in dilute alkalies
and insoluble in dilute acids, and that iodine destroys the color. Our
method appears to make the further study of this substance possible.

The coniine-like substance we have secured in the form of its hy-
drochlorate, and with it we have made certain studies which will be
published at a later date.

Characteristics of the Blood-Pressure-Raising Constituent

as obtained by decomposing its

Benzoyl Compound

We have now obtained the active principle in the form of a sul-
phate. As thus far isolated it is a hygroscopic, straw-colored residue
which tends to crystallize on standing over sulphuric acid, agglomer-
ates of small crystals forming on the edge of the bowl and the entire
residue taking on a semi-crystalline appearance. This sulphate does
not contain the volatile coniine-like substance, nor do we find the
carmine-red pigment which falls out on the addition of an alkali.
Alkalies no longer liberate the coniine-like substance, nor do they
throw out the red pigment, but they cause a brownish discoloration,
and on heating, alkaline vapors, probably ammonia, are given off.

Our sulphate is very active physiologically. A small quantity suf-
fices to raise the blood-pressure and it is therefore evident that we
have isolated the active principle but slightly contaminated with other
substances.

A final product even more active in small quantities is that whose
action is shown where the mercury is driven out of the manometer.
This more active compound still contains much of the coniine-like
substance, and at once throws out the carmine-red pigment on the
addition of alkalies. The sulphate of the coniine-like substance does
not, as we have seen, raise the blood pressure; it therefore remains
for us to consider whether the carmine-red substance Avhich is pre-
cipitated on the addition of alkalies, either alone or in conjunction
with small quantities of oxidizing agents, has any physiological sig-
nificance or stands in any chemical relation to the blood-pressure-
raising constituent. We incline to the opinion that this substance,
which in the original aqueous solution of the gland gives with iodine
water the "teinte rose-carmin tout a fait remarquable" of Vulpian, is
in nowise connected with the blood-pressure-raising constituent. We
have repeatedly removed or destroyed this substance by boiling solu-
tions containing it with strong ammonia or with sodium hydrate,

50

and have always been able to separate subsequently an active material.
After such treatment with alkalies, care must be taken in the sub-
sequent evaporation of the alcohol with which the active principle
is removed, to keep an acid reaction, as otherwise the greater part, if
not all of it, will be destroyed by oxidation. And unless all evaporations
are carried on under reduced pressure, much material will be lost,
even with the above precaution.

Although somewhat contaminated with its own decomposition
products, this final sulphate has all the characteristics of an active
substance. As shown by repeated experiments, it promptly raises the
blood pressure, it constricts the vessels of an inflamed eye, and when
injected into the dorsal lymph sac of the frog it acts like a narcotic
or cerebrospinal poison.

As freed of the red substance the sulphate of the active principle
behaves as follows: It is very soluble in water, fairly soluble in weak
alcohol (50 per cent), almost insoluble in absolute alcohol, and quite
insoluble in ether, acetone, ligroine and chloroform. Its aqueous solu-
tion, even when freed from adherent sulphuric acid, has a slightly
acid reaction. The addition of iodine water to a neutral solution does
not give a rose-red color. Alkalies added to a strong solution give a
brown color which deepens on heating. Ferric chloride gives a pur-
plish brown, almost black in concentrated solution, which on the ad-
dition of tartaric acid and an alkali passes into a deep red color. Before
the removal of the carmine-red substance the addition of ferric chlo-
ride gives the well-known emerald green color, w^hich passes into red
on the addition of an alkali.

It is evident that our sulphate gives Vulpian's ferric chloride re-
action, though somewhat changed by the removal of what we take to
be the chromogenic substance which gave his iodine reaction. It also
promptly reduces silver nitrate in alkaline solution, but does not re-
duce Fehling's solution even on boiling.

Probable Relation to the Alkaloids

More than a year ago, during our first studies with suprarenal ex-
tract, we were struck with the fact that every extract entirely free of
proteids and physiologically active gave a fine pyrrol reaction when
subjected to dry distillation. This is evidenced both by the odor and
by the pine sliver reaction. A small quantity of the isolated sulphate
also gives the pyrrol reaction when heated either alone or with zinc
dust.

We attach considerable importance to this reaction. As is well

51

known, alkaloids in general give pyrrol on dry distillation; morphine,
for instance, on being heated with 10 parts of zinc dust gives off
pyrrol, ammonia, trimethylamine, pyridine, phenanthrene, etc.* Dur-
ing the past winter we made several attempts to prove the presence of
pyridine among the products of dry distillation of the active principle
as above isolated, as its detection would prove that our principle was to
be classed among the alkaloids.

In attempting to show the presence of pyridine we heated the active
principle with zinc dust in a current of dry hydrogen and passed the
distillation products through a test tube and two small flasks, the tube
being placed in a cooling mixture, the first flask being partly filled
with dilute sodium hydrate, and the second with dilute hydrochloric
acid.

At the close of the experiment the test tube gave off alkaline vapors
that smelled strongly of trimethylamine and had in addition a peculiar
sweetish odor. The contents of the test tube diluted with water gave
a precipitate with bromine water and with copper sulphate, but with
the latter reagent the fine blue color characteristic of pyridine did
not appear. The presence of amines seems to render difficult the de-
tection of small quantities of pyridine. The contents of the third flask
on exposure to the air took on a rose-red color and after a time threw
out a precipitate of the same tint. Both flasks gave off the odor of
benzaldehyde.

The following experiment was also made with a little of the sul-
phate, which no longer gave the rose-red reaction with iodine but
which still contained a little of the coniine-like substance. For two
hours it was kept at 150° C. in a sealed tube with 25 per cent hydro-
chloric acid. On shaking out with ether a considerable crystalline
residue was obtained which, without much purification, melted
sharply at 120° C. and had all the properties of benzoic acid.

In the above decomposition experiments the quantity of material
at command was small, perhaps not more than one-fifth of a gramme
at a time, and not entirely pure. We do not, therefore, lay much stress
on our failure to detect pyridine.

The fact that the nitrogen of our compound is given off in the form
of amines and pyrrol gives strong gTound to believe that our substance
is to be classed with the pyridine bases, using this term in a broad
way. Its basic character, its ability to take up acid radicles, as illus-

* We are well aware that certain salts of glutaminic, pyromuci'c and its re-
lated acids also yield pyrrol on dry distillation. These compounds, however, like
the proteids and their allies, appear to us to be excluded.

52

traced by the formation of a benzoyl product, its reducing power and
its color reaction with ferric chloride are all points which can be urged
in support of this view. Furthermore, cupric acetate, the serviceable-
ness of which as a precipitant of carbo-pyridine bases has been shown
by Gautier and Landi,* also precipitates our active principle; and
iodine chloride, which Dittmarf found to give brown or yellow halo-
gen addition-derivatives with a large number of the alkaloids, gives
with a neutral or slightly acid solution of our active sulphate a brown-
ish flocculent precipitate.

Of less weight in this connection, but nevertheless of some value,
is the fact that its physiological action and its power in small doses is
again in accord with what is known of alkaloids. Strychnine, thebaine
and other alkaloids are readily called to mind as able to raise the
blood pressure, and recently Tunnicliffe;{: has placed piperidine in the
same list. The pyrrol§ bases are also physiologically active, although
less attention has been paid to them.

Pyrocatechin cannot be split off from the
Blood-Pressure-Raising Constituent

As already said, Muhlmann has stated with great positiveness that
the blood-pressure-raising constituent is pyrocatechin joined to some
other substance, probably an acid. Muhlmann does not offer sufficient
proof for his conclusion; and even had he proved the presence of
pyrocatechin in the gland itself, this is a very different thing from
showing that it enters into the chemical constitution of the blood-
pressure-raising constituent.

We have repeated Miihlmann's work and have found that after
boiling the medullary substance with hydrochloric acid, the ether
takes up a trace of Vulpian's substance, as well as a substance that re-
duces Fehling's solution.

The ether residue also gives a precipitate with neutral lead acetate
which, on decomposition with dilute sulphuric acid, sets free a com-
pound that gives with ferric chloride the reaction so characteristic
of pyrocatechin. Our blood-pressure-raising constituent is not pre-
cipitated by lead acetate and could not, therefore, have been responsi-
ble for this result.

*Compt. rend., cxiv (1892), 1154-1159.
f Berichte d. deutsch. chem. Gesellsch., xviii, 1612.
+ Centralbl. f. Physiol., x, No. 25, 777.

§ Jac. Ginzberg, Ueber das Verhalten des Pyrrols, etc., Inaug. Diss., Konigs-
berg. 1890.

53

Furthermore, on decomposing a fairly large quantity of the crude
benzoyl product before referred to and shaking out the resulting
benzoic acid with ether, we have twice found that the ether has taken
up in addition to the benzoic acid a small quantity of a substance
which reduces Fehling's solution and gives a precipitate with neutral
lead acetate. On decomposing the resulting lead compound with
dilute sulphuric acid and neutralizing the filtrate, we obtained a
solution which behaved with ferric chloride in the way characteristic
of pyrocatechin. The quantity of this lead compound obtained has
been too small for analytical purposes.

We consider it, therefore, still imcertain whether or not a little
pyrocatechin is present in the gland.

That the blood-pressure-raising constituent is, however, not a pyro-
catechin derivative seems to us certain. To prove this we used, not the
entire gland nor the medullary substance, but the active principle
itself, as isolated by us by decomposing the benzoyl compound.

We have used large quantities of material representing in each
experiment the active principle of several thousand glands. We have
boiled this with hydrochloric acid of varying strength and for varying
lengths of time, and in no case have we been able to find in the ether
used as a solvent any trace of a substance that would reduce Fehling's
solution or give a precipitate with lead acetate. Inasmuch as some of
the chromogenic substance always passes into the ether from acid
solutions, these two reactions are both necessary to establish the pres-
ence of pyrocatechin. In other words, we have failed to split off pyro-
catechin from the active principle as isolated by us. If present, it
could hardly have eluded our search, for even a minute quantity may
be made to give a precipitate with neutral lead acetate.

We propose during the coming autumn to continue this work. Hav-
ing made arrangements for the use of a large amount of material, we
hope to secure both the benzoate and the sulphate in a form pure
enough for analysis and for further chemical study.

Summary

We may summarize the results of our work as follows:
The blood-pressure-raising constituent of the suprarenal capsule
may be completely precipitated from an aqueous extract by treat-
ment with benzoyl chloride and sodium hydrate, according to the
Schotten-Baumann method.

On decomposing the resulting benzoyl products, a residue is ob-
tained which possesses great physiological activity. It gives the color

54

reactions of Vulpian, reduces silver nitrate and possesses the other
specific qualities of suprarenal extracts.

With the help of alkalies a carmine-red pigment may also be sepa-
rated from these decomposition products. We take this pigment to be
that one of the chromogenic substances of Vtilpian which gives the
rose-carmine color when suprarenal extracts are treated with oxidizing
agents or alkalies.

A volatile, basic substance of a coniine-like odor is always found to
accompany the crude benzoate. When these substances are removed
the active principle is left as a highly active sulphate or hydrochlorate,
as the case may be. It is therefore a basic substance. Its salts give a color
reaction with ferric chloride; they also reduce silver nitrate, but not
Fehling's solution.

It is not possible to split off pyrocatechin from this isolated active
principle. The fact that dry distillation causes the appearance of
amines and pyrrol in abtnidance, taken in connection with its ability
to take up acid radicles, its reducing power, its precipitability by
cupric acetate and iodine chloride, and its physiological action, lead
us to conclude that our active principle is to be classed with the pyri-
dine bases or alkaloids.

Addendum, June 15, 1897

Since the foregoing paper was read before the Association of Ameri-
can Physicians on May 6, 1897, B. Moore has published a paper in the
Journal of Physiology, vol. xxi, Nos. 4 and 5, May 12, 1897, entitled,
"On the Chromogen and on the active Physiological Substance of the
Suprarenal Gland." In this paper it is suggested that the active prin-
ciple may be a pyridine derivative. Moore's conjecture is based, first,
on a formula calculated by him from a combustion analysis of Kruken-
berg, made Avith an impine, hygroscopic, noncrystalline residue ob-
tained by merely decomposing and drying a precipitate seemed oiu
of an alcoholic extract of the gland with the help of basic lead acetate.
The calculated formula, the carbon content of which differs by 1.33
per cent from that actually found by Krukenberg, is C^H^^NO^, and
Moore points out that in it the ratio in which the elements carbon and
nitrogen stand to each other is the same as in pyridine, C5H-N. Now
such a calculation, though suggestive to the investigator, furnishes no
proof of the presence of pyridine, for Krukenberg could not possibly
have had in hand a chemical individual uncontaminated with other
constituents of the gland. Krukenberg himself admits that his ma-
terial was a mixture of unaltered pigment and its decomposition prod-

55

ucts. It is also certain that it was contaminated with other constituents
of the gland. This is proved by the fact that basic lead acetate precipi-
tates several of the constituents of the gland which pass into alcohol,
and also by the fact that the analyzed material contained 0.068 per cent
of sulphur and from 1.18 per cent to 1.44 per cent of ash.

A second reason given by Moore in support of his conjecture is
that when "some suprarenal extract was cautiously fused with caustic
potash so as to avoid charring, the peculiar odor of pyridine was at
once obtained." He admits that proteids were present in this extract,
and that pyridine and its homologues are formed in the destructive dis-
tillation of proteids, but states that the experiment was "conducted
so as to avoid charring," and considers this a sufficient safeguard. This
experiment has also no value, for the odor of pyridine can always be
obtained when a mixture of dry, powdered proteid and po\vdered
caustic potash are fused together so as to avoid charring. This experi-
ment, therefore, must be made with material entirely free of proteids.
Since reading Moore's paper we have fused a little of our active prin-
ciple with caustic potash, but have failed to detect pyridine. If present
in the molecule of the active principle, it is evident that larger quan-
tities of the material must be used to prove it. Only indisputable
chemical proofs can establish the presence of pyridine; the odor is
not enough. We have frequently in various manipulations with the
active substance met with what we took to be the odor of pyridine,
but on shaking out with ether and adding an ethereal solution of
hydrochloric acid and evaporating the ether we have been unable to
detect pyridine in the residue.

On the Teaching of
Pharmacology, Materia Medica,
and Therapeutics in Our Medical
Schools

JOHN J. ABEL, M.D.

I

T WOULD seem unnecessary to define in the columns of a medical
journal what is meant by pharmacology, but the frequent confusion
of this term with pharmacy by those who are not teachers of medicine
must serve as a reason for a brief statement of the methods and aims
of this branch of medical science. The vague and often erroneous use
of the word pharmacology seen in earlier writings, as in the definition
of Nathan Bailey (1736), "a treatise concerning drugs," or in that of
Samuel Johnson (1755), "an equivalent of pharmacy or pharmaceu-
tics," is still frequently met with in our own time. Briefly stated,
pharmacology tries to discover and explain all of the more obvious
functional, and the less noticeable chemical and physical changes
that occur in a living thing that has absorbed a substance capable of
producing such changes, and it is also its province to learn the fate
of the substance thus incorporated. It is not, therefore, an applied
science like therapeutics; it is one of the biological sciences, using that
term in its widest sense.

The interested student of the history of medicine discovers in every
epoch some man far in advance of his contemporaries who may be
looked upon as a leader in one phase or another of our subject. Such
were Erasistratus, Dioscorides, Mesua, Avenzoar, Paracelsus, and Hal-
ler; and when we turn our attention to the modern laboratory methods
of pharmacology and the lasting achievements gained by their aid,
we find that the first great impulse was given by Magendie. That
great experimenter's classical research on the physiological action of
upas, undertaken early in the present century, was the first instance
of the completely successful application of the analytic method in the

57

study of the coarser changes of function which follow on the use of
drugs. As early as 1813 he had also proved that the blood is capable
of taking up and carrying metallic poisons, but it was not until the
middle of the century that the pernicious doctrine of the "action of
poisons by sympathy" received its death-blow. About the middle of
the century, too, the memorable experiments of Claude Bernard and
of KoUiker proving that the paralyzing action of curare centers in the
end plates of the motor nerves gave further evidence of the value of
physiological analysis as applied to the study of drugs.

Brilliant discoveries of a similar character have followed from time
to time, and we have now innumerable instances of the rational analy-
sis and at least partial comprehension of the more obvious functional
changes that follow upon the administration of drugs and poisons.
One has but to recall atropin, pilocarpin, muscarin, eserin, cocain,
digitalis, amyl nitrite, chloral, chloroform, ether, salicylic acid, ergot,
and other well-known drugs and poisons, to appreciate how great is
the store of knowledge relating to the action of drugs which is at the
disposal of the modern student.

It was experiments like those of Magendie and his successors that
induced Mitscherlich (1847) and later Buchheim, to insist on the in-
sufficiency of the mere bedside study of the action of drugs and led to
the erection of special laboratories in which experimenters can build
up their science undisturbed by the intrusive demands of practical
utility. Buchheim's pharmacological laboratory founded at the Uni-
versity of Dorpat in 1849, was the first public institution of the kind
in the world and was long the best equipped in Germany. But it was
not alone in Germany that attention was called to the new methods.
The medical literature of our own country contains some eloquent
pleas in favor of the analyses of medical problems by means of ex-
periments. From among these I would call attention to that of Dr.
R. Cresson Stiles, contained in a ^vorthy but little-known research,
published in 1865, entitled: On the Direct Influence of Medicinal and
Morbific Agents upon the Muscular Tissues of the Bloodvessels. This
physician was interested in the problem as to how the blood, in febrile
conditions, acts upon the circulatory mechanism. He evinced consider-
able experimental skill, as shown by his use of the "surviving" um-
bilical artery in his transfusion experiments, and he seems to have
had some premonitions of our later theories, for he subjected the
umbilical artery to the action of blood drawn from a patient with
typhoid fever and compared the results thus obtained with those
noted when normal blood was used.

58

In one part of his paper he defends and justifies his methods in the
following words: "Moreover, it is not to mere clinical experience
that we must look for a revelation of the laws of disease. The laws of
chemistry were not discovered in blazing fires or crumbling rocks;
the laws of hydrostatics and hydraidics were not revealed in torrents,
tides, or ocean currents, nor those of pneumatics and electricity in
^vinds, whirlwinds, and thunderstorms; much less coidd it be ration-
ally expected that the laws of pathology should be discovered amid
the much greater complexity and more multitudinous conflicts of
elements presented to the physician at the bedside of a diseased or
dying patient. It is in the laboratory, and by artifically contrived ex-
periments that the clue has ever been spun and the torch lighted to
guide through the labyrinths which hide the arcana of nature."

By means of "artificially contrived experiments" we are today en-
abled to demonstrate in detail how drugs act on the various organs
of the body and what is their immediate, specific action on the parts
of a compound mechanism like the circulatory apparatus. Thus we
teach the student of our day the method by which is analyzed the
action of a drug on the heart and arteries, on the vasomotor, cardio-
inhibitory and respiratory centers, on the terminals of the vagus, on
the spinal cord and brain, on the intestines, the uterus, the salivary
and other glands, the iris, ciliary body, etc. Conceptions familiar to
the therapeutician are thus resolved into their elements and made
accessible to the beginner.

The empiricist may perhaps assert that an experimental demonstra-
tion and analysis of the manner in which atropin, for example, causes
dilation of the pupil is of little service to him, that the clinical fact
is all-sufficient. A physician of this practical turn of mind may long
use ^vith safety his corrosive sublimate, his ether, his salicylic acid,
his homatropin, eserin, and other drugs; but, sooner or later, if he
is an observing man, he will find himeslf confronted by doubtful and
obscure questions which directly concern the welfare of his patient,
questions that can only be cleared up with the help of the "artificially
contrived experiment." No branch of practical medicine can afford
to neglect the study of the principles and methods of pharmacology.
For, like other branches of experimental science, it teaches conserva-
tism by pointing out how vastly complex are the phenomena of the
action of drugs and sho^ving how little is clearly understood aside
from the grosser and visible changes which follow upon their ad
ministration. The dogmatic use, in symptomatic treatment, of cardiac
stimidants, depressants, antipyretics, and innumerable other remedies

59

whose extraordinary virtues are lauded in commercial circulars, finds
no justification in the teachings of pharmacology. Its teachings are
not always or immediately convertible into bedside dogmas.

It must be confessed that the therapeutic nihilist who uses only
what is indispensable among drugs, but who is wise in the curative
power of air, water, food, rest, and exercise, will have less to answer
for in the final reckoning than his drug-enslaved colleague who prates
of controlling disease in its every symptom with this or that panacea
and who is guilty of the premature application to practice of what
are only unproved theories.

Pharmacology gives no support to the unthinking worship of ca-
nonical authority. In instances when true specifics and well-founded
remedies are manifestly powerless, the plan outlined by John Locke
is as applicable now as it was when he wrote: "You cannot imagine
how far a little observation carefully made by a man not tied up to
the four humours, or sal sulphur and mercury, or to acid and alkali,
which has of late prevailed, will carry a man in the curing of diseases
though very stubborn and dangerous; and that with very little and
common things, and almost no medicine at all."

In an age which pathology and diagnosis are so far advanced and
in which more genuine help is derived from the rational use of drugs
than ever before in the history of medicine, haphazard drugging is
unpardonable, and still more to be condemned is a fanatical and
conceited adherence to dogmas based on a superficial understanding
of complex physiological principles.

I have spoken thus far only of the older and well-tried methods of
pharmacology, methods that are still fruitful, although newer tend-
encies are now followed and fresher fields are being tilled. The more
detailed examination by means of modern physiological methods of
the respiratory, circulatory, muscular, nervous, and other functional
derangements which are met in "intoxications" will surely lead to
most important results. One of my younger colleagues, who is now
carefully reviewing the list of drugs that act on the heart, tells me
that not a single one of them has been studied on all sides from a
modern physiological standpoint. Digitalis alone of the list has been
the object of a fairly complete physiological examination, but every-
where in this field of the cardiaca there seems to be a great accumula-
tion of physiological facts ready for the coordinating hand of the
pharmacologist. As elsewhere, judgment and special knowledge are
required, and the day has long passed when he who knows the drugs
of the pharmacopeia and their clinical uses and who is able only to

60

set up a kymograph and attach a few registering instruments can
claim to be a pharmacologist. Such an one will not travel far beyond
the region of mere routine, a region chiefly of pedagogical interest.

Thoughtful pharmacologists have also made it the object of their
investigations to understand more fully the chemical and chemico-
molecular phenomena that underlie and accompany the coarser
changes to which reference has already been made. The principles of
physics and chemistry must furnish the pharmacologist with pro-
visional or permanent explanations of these phenomena. Like the
physicist, he is well aware, however, of the "futility of attempting an
ultimate explanation of natural phenomena," and fully recognizes the
limitations of his method. At present we make use of a hundred
terms which convey anything but a clear idea to the mind. Take so
old a drug as ethyl alcohol, for example, and endeavor to explain
why it is not a dynamogenic substance for muscle-tissue. We hide
behind such expressions as "protoplasm poison" and the like. We
know that alcohol is oxidized in the tissues and that liberation of
energy folloAvs, but a more careful study of the subject shows that
oxidizability and the liberation of energy are not alone the measure
of dynamogenic value. A closer study of the intermediate steps in
the oxidation and of the chemico-molecular processes which are in-
itiated by these products and by the alcohol itself will alone clear up
a problem of this sort.

Knowledge of the "chemical architecture" and constitution of a
given drug often enables the pharmacologist to trace it in its passage
through the body, and in studying its chemical fate and final dis-
position, valuable facts bearing on the synthetic, oxidative, reductive,
or splitting powers of various tissues and organs have been brought
to light. In this way, too, intermediate products of metabolism are
discovered and glimpses of hidden chemical processes are obtained
which throw light on deep problems of pathology and clinical medi-
cine. The results of the study of the relation of chemical constitution
to physiological action as yet apply only to certain families of chem-
icals. They have not led to any principles of universal application.
Recently a clearer statement of the action of whole series of drugs
and poisons has been given in the language of physical chemistry.
Thus, this or that feature of the pharmacologic action of many acids
is in proportion to the concentration of their hydrogen ions and de-
pends to a lesser degree on the specific properties of their anions. The
toxic or disinfecting action of a series of dilute metal hydroxides stands
in relation to the concentration of the OH ions. The theory of electro-

61

lytic dissociation, on the other hand, plays but a subordinate part
in determining the toxic properties of phenylic and other compounds.
But whenever this theory is applicable to the problems of our science,
it has put them in a new light. Yet it must be remembered that when
we say the pharmacologic action in a given case is ionic, we are still
far from the last possible analysis and explanation of the observed
phenomena.

A new epoch began with the belief that many diseases are but
instances of acute or chronic intoxication. The growth of the doctrine
of toxins forced upon us by modern experimentation in bacteriology
is seen in pharmacological literature and methods. The recent studies
in the action of toxins and antitoxins, on the nature of immunity, on
the nature and cause of diabetic coma, uremic poisoning, and other
pathologic conditions in which poisons generated within the body
play a role, are all instances of researches in which repeated use of
pharmacologic methods and principles is made. It is evident, then,
that pharmacology deals with the most fundamental conceptions of
medicine, that it conserves and augments a variety of facts, methods
and principles which are of service not alone to every branch of the
medical art, but also to other branches whose subject-matter confines
them to the laboratory, the private study, and the lecture hall.

When and how shall this subject be taught in our medical schools?

First, as to the time when it should be taught. I hold that this
should be when the student begins his clinical studies and not before.
I do not deny that it is often difficult to make room for this subject
in the first clinical year, but the argument which in reality excludes
it is that pharmacology, like physiology, is so capable of illustration
by laboratory experiments and of presentation in the form of lec-
turers, that it can be taught as soon as the student has the needful
foundation in the way of physiologic chemistry, anatomy and phys-
iology.

But this argument ignores the fact that every drug has its clinical
uses, that the teacher of pharmacology is expected to point out what
these uses are, and that it is impossible to avoid reference to diseases
and their symptoms. In the interest of the student, by way of lighten-
ing his work and making it more profitable to him, it is imperative
to teach pharmacology hand in hand with the early clinical Avork.
For now he begins to see drugs used; he notes, for example, how a
patient behaves under ether; for what conditions the clinician pre-
scribes iron, quinin, mercury, salicylic acid, codein, digitalis, potas-
sium iodid, amyl nitrite and the like; what antiseptics and local an-

62

esthetics are used by the surgeon. He perhaps sees an outpatient
with a gangrenous finger due to his having swathed it in 5% carbolic
acid; he learns of mercurial stomatitis, of palsies and neuritic affec-
tions and anemias caused by the heavy metals, of exanthems due to
drugs; he sees examples of iodism, cinchonism, etc., and specimens of
urine that show misleading features in consequence of certain drugs.
Though only a beginner, he meets at every turn Avith some practical
application of the articles of our materia medica. Drugs now have
some significance for him, an interest is aroused in their action,
important data and conceptions are gathered by actual experience.

It must be remembered, too, that a description of the symptoms
that appear when more than the therapeutic dose of a drug is given
is an integral part of the teaching of the pharmacologist. In a word,
toxicology is inseparable from pharmacology, and instruction in this
branch, so far as it is not of a chemical or medicolegal character,
deals with clinical and pathological data. How wasteful of energy is
it to teach this part of the subject at a time when all practical knowl-
edge of such data, with the exception of that gained by experiments
on animals, is lacking! What does the student profit from descrip-
tions, for example, of the nature of cocain, atropin, opium, or arsenical
poisoning, at a time when he has seen nothing whatever of bedside
medicine?

To say that the practical examples of the uses of drugs and of their
toxic action can be as well learned by the student after he has taken
the course in pharmacology is to deny the principle of economy in
intellectual work, and indicates a lack of appreciation of the fact
that the applied and the theoretical parts of pharmacology are not
capable of a sharp separation in courses intended for medical students.

The question as to how we shall teach pharmacology may now be
considered. But first, a few words concerning instruction in toxi-
cology. It has already been stated that, from a scientific point of vie^v,
no sharp line of demarcation can be drawn between this subject and
pharmacology. Only ^vhen the medicolegal, the industrial, or the
chemical sides of toxicology are considered is it advisable to make a
distinction. But these aspects of toxicology should not be neglected
in our medical schools. Even in institutions in which the general
principles and methods of toxicological analysis are taught in connec-
tion with the work in chemistry, or in which extensive courses in legal
medicine and in hygiene are given, there Avill still be left a large field
to be covered by the pharmacologist. In my own experience I have
found it advantageous to give a brief course in toxicology as a pre-

63

liminary to the work in pharmacology. My students begin their work
with me at the conclusion of the first third of their second year, at
a time, therefore, when they have had no clinical work and but little
pathology. The course requires eight weeks, and there are two after-
noon sessions and a Saturday morning recitation or conference. The
points aimed at in the course are: First, the acquisition and compre-
hension of the physiological phenomena of intoxications; second,
certain important phases of the subject regarded as a part of forensic
medicine; third, the more important chronic intoxications which are
met with in the arts and industries; and fourth, the general principles
of toxicological analysis as illustrated by actual practice at the labora-
tory desk.

Nothing in the way of vivisection is done by the student himself
in this course.

The afternoon's work begins with a brief lecture and with demon-
strations of a physiological character. In these a number of circum-
stances bearing on the action of a given substance, whether used as a
poison or as a drug, are clearly set forth. These demonstrations con-
stitute the best introduction to pharmacology. Some of the points
illustrated are the varied symptoms of poisoning, such, for example,
as the paralysis of the respiratory center by hydrocyanic acid or
morphin; the influence of the place of application, as illustrated by
the fact that not all mucous surfaces absorb poisons with equal ra-
pidity; the rapidity of dispersion of poisons throughout the body;
the paths of elimination for drugs and poisons, and the storage of
drugs in various tissues and organs, and the great differences that
obtain in these two fields; changes in the blood; the anatomical lesions
produced by powerful poisons, such as arsenic, phosphorus, nitric
acid, carbolic acid, alkalies, etc. A wide range of demonstrations, in
which organisms ranging from paramecia to dogs and rabbits may
be employed, is at the disposal of the instructor, who has access to
original literature. In this way the beginner receives ocular proof of
the fact that an intoxication, whether acute or chronic, is as complex
a matter as any of the clinical conditions that he will later study in
the hospital; that drugs can produce fever, convulsions, paralysis, and
other symptoms; lesions of the various organs, alterations of the secre-
tions and of the blood— in short, an interest in the manifold problems
of medicine can here be aroused. It is, of course, understood that the
rules of the physiological laboratory in regard to anesthesia are to be
observed in work of the above character. During the first week of this
course the demonstrations extend so far into the afternoon that the

64

student has no time left for laboratory work, and can only arrange
his desk for the chemical work.

The chemical work of the student is so planned that it shall in-
struct him in certain methods which will be of use to him in his
later work in clinical medicine and will enable him also to make at
least the necessary preliminary tests in a case of suspected poisoning.
A small laboratory manual drawn up by the instructor is placed in
his hands and its directions are modified from year to year. The
ground covered in the laboratory includes the methods of isolating
volatile poisons and the analytical methods applicable to the detec-
tion of small quantities of this class of poisons; the search for alkaloids
and glucosids by the methods of Draggendorff, Brouardel, Kippen-
berger, and others, some typical poisons of these classes being mixed
with foods and subjected by the student to processes suitable to their
extraction; the search for metallic poisons and non-volatile acids; a
study of blood-stains and the separation of blood from rust-spots, etc.;
a spectroscopic and simple chemical study of the various hemoglobin
derivatives as methemglobin, hematin, reduced hematin, hematopor-
phyrin, carbon monoxid hemoglobin, etc.; a study of the changes in
the urine induced by drugs.

In a course of this kind a Avise selection of examples must be made
and assistance must be given to the student by means of class demon-
strations and informal talks, as ^vell as by instruction at the laboratory
desk.

In the past few years our students have come to us with a better
preparation in chemistry, and many of them have already had a special
course in the detection of metallic and other poisons.

To avoid repetition we have therefore arranged a few class dem-
onstrations showing the best methods of oxidizing organic matter and
of detecting arsenic, antimony, lead, mercury, and phosphorus, pay-
ing especial attention to the simpler preliminary tests which shall
enable the physician, if need be, to ascertain ^vith certainty whether
one or another of these poisons is present. The object of this chemical
course is, therefore, mainly to give the student a bird's-eye view of the
field, with a certain technic of an elementary sort and to further
improve his chemical knowledge, something for which the modern
physician finds more and more practical uses. Should the student who
has taken such a course ever find himself involved as a medical expert
in a medicolegal case he wdll not be entirely incapable of compre-
hending the controversial points which are agitating the chemical
experts in the trial.

65

Along with this chemical work goes the reading of selected chapters
of a good textbook, recitations, and informal talks by the instructor
on special subjects, as the commoner poisonous plants of the country,
or the intoxications met in the modern arts and industries. The talk
or the recitation, as the case may be, is held early in the afternoon,
before the laboratory work is begun. An hour on one other day on
which no laboratory work is done is also given up to a recitation on
assigned subjects.

It will be seen that there is little in the way of didactic lectures.
The student profits most when, for example, he has himself detected
opium in some mixture and has read his Blyth, Kobert or Lewin and
tiien meets his instructor, to discuss with him, in an informal manner,
the chief points in the physiologic action of the poison in its chronic
use, or in its medicolegal significance and chemical detection. His
previous reading has aroused his interest, and taken in connection
with his chemical experiments and the demonstration on the living
animal, it has prepared him for a conference whose chief aim is to
help him to separate the essentials from the nonessentials.

The remainder of the year is devoted to pharmacology. This course
is only in part a laboratory course, the class working in sections of
four. Even if it is impossible for the student to perform more than a
half-dozen experiments, this kind of work is too valuable to be omit-
ted. Nowadays, when simple apparatus can be had at a comparatively
low cost, it is not a matter of great difficulty to give every four students
out of a class of 75 a number of highly instructive experiments. These
may be so arranged that the student himself learns the chief pharmaco-
logical facts involved, say, in the action of ether and chloroform,
the diuretics and purgatives, atropin, morphin and chloral, or dig-
italis, the nitrites and other agents that have a pronounced action on
the circulatory apparatus.

I would, therefore, urge that at least 5 or 6 topics be made the
subject of laboratory experiments to be preformed by the students
themselves under competent direction. The "artifically contrived ex-
periment" has made the subject what it is; it is that instrument of
knowledge with which the teacher and investigator tests the theories
of the day; it is his very shortest road to certainty of opinion. Why,
then, should it not give a clearer insight to the student also? As
Porter so tersely puts it, "the meat on which professors are nourished
is just the diet for students."

As for the rest of the experimental work, numerous class demon-
strations are necessary. The work in physiology, perhaps going on at

66

the same time, has prepared the student to grasp the principles to be
illustrated by the more complicated experiments and perhaps also
made it unneccessary for the student himself to perform the many
simple experiments to which he is equal, but which can be more
quickly performed for him. For we must keep in mind that as Pro-
fessor Welch has said, "Laboratory methods are extremely time-taking
and are not adapted to teach the whole contents of any of the medical
sciences." I need not recount the list of practicable class demonstra-
tions. There is hardly a drug of importance for which a good demon-
stration is not to be found in the various scientific journals. We know
that the list of drugs in actual use is very large, but if we ask what are
those that have been found to be really indispensable to the surgeon,
the gynecologist and obstetrician, the internist, the ophthalmologist,
dermatologist and other specialists, we can easily reduce our por-
tentous list to some fifty instances. Let these constitute the basis of
instruction and serve as types; take these up in great detail, and when-
ever possible connect with them less important ones of similar action.

But to assist the student to master the contents of his particular sub-
ject should not be the only aim of the medical teacher; he should seek
to arouse an appetite for all that is fundamental in the science of
medicine; he should stimulate to inquiry, to a searching and logical
analysis of the phenomena to be grappled with, be it in the laboratory
or at the bedside. And in striving to carry out this high purpose, his
own life work, his spoken words and his attitude toward his pupils
are his chief means of influence.

I have thus far said nothing on the subject of Materia Medica. I do
not believe that special instruction in this branch is called for. In
the day when the student to the medical school entered with little
knowledge of chemistry, botany, and other sciences, it may have been
^vell enough to give special courses on the physical, chemical, and
botanical characteristics of drugs, but the result in general was to
overburden the student's mind with a multitude of dry details of
interest or value solely to the pharmacist or to the student of pharma-
cognosy. When I began to teach pharmacology ten years ago, I dis-
carded all separate instruction in materia medica. My plan has been
to give only those points which are of actual importance to the stu-
dent of medicine or which he ought to know for historical reasons.
The drugs and preparations which are discussed in lectures and recita-
tions are placed on a table where all may examine them, and the more
important ones are passed from hand to hand while they are being
described. In speaking, for example, of rhubarb, digitalis, cinchona,

67

ergot, or opium, only brief historical remarks, with short accounts
of their chemical composition and their behavior toward solvents are
introduced.

Certainly all unnecessarily detailed description of crude drugs, of
their active principles, or of the modern synthetic remedies, is out of
place in a medical school. The instructor should allow himself but
the briefest introduction as to the physical and chemical properties
of a drug before he begins the more important discussion of its
pharmacological action. Thus, when chloral is the subject, he will
describe its chemical relationship to the other anesthetics and hyp-
notics, its solubilities, its deliquescence, its decomposability by alka-
lies, etc. A rapidly-performed test-tube experiment showing how chlo-
roform is split off when it is brought into contact with an alkali will
prevent the student from prescribing it in this form. Such a method
of treatment consumes but little time and is easily comprehended by
the student who has had a suitable preliminary course in chemistry.
In a word, I would teach materia medica in direct connection with
pharmacology, letting it serve in the case of each drug or class of drugs
as a brief introduction to the latter and giving only such parts as are
indispensable to the physician in his administration of drugs or of
such historical significance that they ought not to be neglected from
the culture point of view. Here, as everywhere in our crowded courses,
wise selection is our only safeguard. With regard to the pharmacopeial
preparations it has always been my plan to require only a knowledge
of the more important ones, the student being requested merely to
read over those of lesser importance. There is much truth in the re-
mark made by William Withering more than a century ago, that "the
ingenuity of man has ever been fond of exerting itself to vary the forms
and combinations of medicines. Hence we have spirituous, vinous, and
acetous tinctures; extracts hard and soft, syrups with sugar or honey,
etc., but the more we multiply the form of any medicine the longer we
shall be in ascertaining the real dose."

Certain chemical and physical points which have a bearing on the
combination of drugs as called for in prescriptions, or official prepara-
tions may be taken up again in a brief course in pharmacy. I cannot
believe that the art of preparing drugs for therapeutic use requires a
prominent place in the better medical schools of the day. The young
physician who is fairly well trained in chemistry can get all that is
necessary in the way of pharmacy out of a course of at most a dozen
or fifteen lectures in which systems of weights and measures, incom-
patibles, and special points relating to prescriptions are dealt with,

68

and in which demonsiiations are given of how pills, tablets, supposi-
tories, tinctures, and other official preparations are prepared.

In schools where the student is admitted with but a poor elementary
training much more than this may be necessary. But, even under the
most favorable conditions the limited course above outlined will
leave much to be desired, even then the physician is not ensured
against the commission of grave enors in prescribing. Without further
study he must often rely upon the friendly hand of the professional
pharmacist to correct his mistakes.

Here, too, then, the question is one of selection, of just how much
will suffice in a field which is occupied by an allied profession.

There are gieat differences of opinion in regard to instruction in
Therapeutics. In teaching pharmacology the therapeutic uses of drugs
must necessarily be considered in more or less detail and pharma-
cological discoveries harmonized Avhenever possible with clinical prac-
tice. It is, therefore, necessary that the teacher of pharmocology shall
be familiar with clinical work and with the actual effect of drugs and
poisons on human beings. It is not necessary, however, that he should
be an active practitioner, and it is only a man of unusual powers and
exceptional training in science who can successfully combine practice
with the demands made on the pharmacologist of the present day as
an investigator and a teacher. In all the leading universities of the
world it is becoming more and more the custom for teachers of physi-
ology, anatomy, pathology, physiological chemistry, and hygiene to
devote themselves wholly to the duties of their chairs, and this practice
will prevail more and more among pharmacologists as the wealth of
medical foundations increases. No one individual, even if he has the
widest clinical experience, can hope to teach the whole art of thera-
peutics. Is it necessary to attempt this? Is not the clinical teacher who
is well grounded in the fundamental sciences the only one who can
rightly train the medical student in the correct choice of drugs and
other agents whose employment falls within his province?

Who, for example, can better teach the student how to treat the
various acute and chronic forms of skin disease than the dermatologist;
who better to treat the diseases of young children than the pediatrist;
who better the details of drug application in diseases of the eye, throat,
and nose than the specialist in these branches; who give wiser coun-
sel in the use of drugs, foods, and other agents in the wide field of the
internist than he who daily grapples with difficult problems in the
cure and alleviation of disease? A practical mastery of therapeutics
can only be obtained from contact with these men and their work.

69

In a limited way, a special course in practical therapeutics in the
field of internal medicine may be given in a medical school, and it is
of great assistance to the medical student who is obliged to enter upon
practice immediately and without the advantages to be derived from
a year or two of hospital practice. A course of this kind is a part of the
curriculum of the Johns Hopkins Medical School and is given by an
instructor in clinical medicine. It occupies a period of 15 weeks and
consists of lectures and demonstrations given twice a week; as stated
in the announcement of the gentleman in charge, this course com-
prises the clinical study of a number of the more common and useful
drugs, their dosage, administration, and effects, methods of prescrip-
tion-writing and illustrative formula, demonstrations of practical
therapeutic measures, the use of hydrotherapy, the preparation of
simple and useful forms of diet, the care of patients considered from
the nursing point of view, the treatment of various emergencies and of
special diseases by climate, rest, and other practical procedures.

The clinical work of the third and fourth years affords abundant
opportunities for further training in practical therapeutics.

This brings me to the subject of lectures and recitations or con-
ferences.

Some didactic teaching, be it in the form of lectures, recitations or
conferences, is necessary in most, if not all, branches of medicine. In
these exercises, the teacher not only clears up doubtful points and sum-
marizes scientific evidence, but he also has an opportunity to so di-
rect "the unwary understanding" of the young, as Sir Thomas Browne
has it, that some perchance will escape intellectual sclerosis at forty.

My own experience with students has led me to believe that they
profit most if they have first read their textbooks before attending a
lecture on a given subject. The teacher's own experience is that he
derives most advantage from a consultation with a specialist in some
other branch of science when he has first informed himself on the
points at issue. It is then that a short talk with a man of wide experi-
ence easily clears up an obscure point. The student should be put
into a similar attitude of mind by proving to him that he will get
more out of an hour with his teacher than out of an hour with his
books at home. If the subject under discussion is one that is well
treated in textbooks, the established points may be passed in rapid
review and then the latest researches, the newer theories brought out
by the instructor. Whenever it is possible to do so, demonstrations
and experiments should be used to illustrate the points under discus-
sion, and these may be given either during the talk or immediately
after.

70

No matter how well a textbook may be written, the teacher who is
himself a ^vorker in the laboratory and who follows attentively the
researches of his contemporaries, will be able to clear up doubtful
points and also to daily anticipate the author's second edition, for the
last chapter of a textbook is hardly completed before the first needs
revision. Aside from this, he is likely to have the advantage of the
author of the book in certain fields, for no man is able to cover the
whole ground with equal authority.

Now as to the student's part. I hold that only the laboratory work
and attendance on such demonstrations as are of the highest impor-
tance should be obligatory. With such attendance and diligent reading
of the best textbooks on the subject, the student will be able to bring
himself up to the "pass" mark, since the examination should only
cover the essential points, aiming like the later State examination to
test and insure an average of attainment and an ability to make use of
acquired knowledge. Of course the student will not in this way get
the utmost possible out of the course, but to do this may not be a part
of his plan of study.

He should be plainly told that he need not attend the lectures and
recitations unless convinced that he will profit by them, and the head
of the department and his corps of assistants will surely be above any
small resentment ^vhen the student accepts this permission in good
faith. The mutual attitude of teacher and student is of far more im-
portance than rigidity of examinations or any tests or credentials what-
ever. I firmly believe in the liberty of both teacher and student. It is
but fair to require of the former that he be a worker in some part of his
held, and that he shall meet Avith enthusiasm and give his best to those
who elect to go deeply into the subject as well as to do his duty to
those Avho choose only the minimum or required work.

The immediate result of this frank understanding between teacher
and student will be that the latter is free to give additional time and
energy to some other line of ^vork for which he may have a decided
bent. But much more, he has the freedom of personal choice, with
all the development that it brings to one who understands his own
mental habits and needs. Petty and irritating restraints are removed
and also the undue weight of authority sometimes attached to a cur-
riculum stipposed to be the result of the wisest judgment of his elders.
We are apt to forget that we are dealing with men and women of some
maturity ^vhose plan for their life-work is made and who have a clear
idea in general, of w^hat their time is worth. They should have, as
Bo^vditch, Mall, and other writers on this subject have pointed out,

71

the advantages of an elective system and also, I maintain, have some
freedom as to method of work in the field chosen.

Have childish restrictions, such as marking for daily attendance,
and all the hateful machinery of the factory time-card system, by
which some teachers attempt diurnal estimates of the student's mental
status, resulted in such a remarkable elevation of the average student,
that we should cling blindly to our present system?

As to examinations, that "necessary evil," I believe it will be ad-
mitted that, in subjects like that now under discussion, they should
not be conducted as if the student were intending to make a specialty
of each branch. They must be fair to the class as a whole. In my own
opinion, a combination of written and oral insures the best results.
Personal knowledge of the student's laboratory work, and also of the
intelligence shown by him in recitations, is of great importance in
enabling the instructor to judge of a student's right to his pass certifi-
cate. The ideal examiner for a given student is not always the man
who has taught him, but may well be a specialist of equal rank in
some other university. Such a change, so stimulating to the intellectual
independence of the student, and so broadening to the teacher, could
only be based on a better agreement than now exists in our country
as to the teaching of a given branch in schools of equal grade. As long as
faculties issue diplomas, they assume a responsibility toward the world
of learning. How they shall discharge this duty is too large a subject
for full discussion here, but it is very desirable that the method used
shall involve a minimum of worry and strain on the part of the student,
and of police duty on the part of the teacher.

72

On the Removal of Diffusible
Substances from the Circulating
Blood by Means of Dialysis

JOHN J. ABEL, M.D.. L. G. ROWNTREE, M.D., AND

B. B. TURNER, M.D.

HERE are numerous toxic states in which the eliminating organs of
the body, more especially the kidneys, are incapable of removing from
the body, at an adequate rate, the natural or unnatural substances
whose accumulation is detrimental to life. In the hope of providing
a substitute in such emergencies, which might tide over a dangerous
crisis, as well as for the important information which it might be ex-
pected to provide, concerning the substances normally present in the
blood, and also for the light that might thus be thrown on intermediary
stages of metabolism, a method has been devised by which the blood of
a living animal may be submitted to dialysis outside the body, and
again returned to the natural circulation without exposure to air, in-
fection by microorganisms, or any alteration which would necessarily
be prejudicial to life. The process may be appropriately referred to as
"vividiffusion."

Essentially, the method consists in passing the blood of an animal
which has been made incoagulable in injection of hirudin from a
cannula connected to an artery through a tube or a series of tubes,
made of celloidin or other suitable dialyzing membrane, contained
in a jacket filled ^vith a saline solution or artificial serum, and back by
another cannula into a vein of the same animal. The tubes and
cannulae before connection are filled with a saline solution approxi-
mating to the composition of the blood, like Locke's or Ringer's
solutions, which is displaced into the system when the circulation is
established. Except that the blood-pressure falls somewhat, according
to the proportion of the blood outside the body, the animal shows no
immediate symptoms, and with due regard to asepsis, makes a rapid
and complete recovery after an experiment that may last several hours.

73

In one instance, where recovery was not aimed at, a dog anesthetized
with chloretone was kept alive during a dialyzing period of sixteen
hours with about one-third of its blood outside the body. At the end
of an experiment the larger proportion of the blood in the apparatus
may be driven back into the body by air-pressure or by means of a
saline solution which is allowed to flow into the dialyzing tubes from
a higher level and which thus drives the blood ahead of it into the
body.

Many experiments have been made to determine the best form of
apparatus combining maximum diffusing surface with minimum vol-
ume, absolute freedom from leaks, ease of construction, uniformity of
flow, minimum exposures to surfaces of glass or other substance liable
to favor clotting, etc. The most efficient type in use at present has
thirty-two celloidin tubes of 8 mm. diameter, 40 cm, long, fastened
by tying with a string to a system of glass tubes branching dichoto-
mously, so that the flow of blood takes place horizontally twice in
each direction through eight tubes in parallel. (An apparatus of this
size can only be attached to animals of at least fifty pounds' weight.)
Flattened tubes and other types are being tried, while very small tubes
will undoubtedly prove valuable when the necessary time and trouble
are not prohibitive. [See illustration between pages 16 and 17.]

Such an apparatus can obviously be used in the solution of many
problems, both therapeutic and physiological, and is especially valu-
able in the latter case because, apart from the necessary anesthetic,
the normal physiological condition is in nowise disturbed, as by
bleeding to obtain large amounts of blood. Diffusible substances,
present in only small proportion at one time, may be isolated in con-
siderable quantities provided they are regenerated in the body as fast
as they are removed. Evidence of this has already been obtained in the
case of the dialyzable (non-proteid) nitrogen which is extracted in
large quantities in prolonged experiments. Determinations by Van
Slyke's method have shown a high proportion of nitrogen in the form
of amino gioups (NHo), and experiments are in progress for the iso-
lation of individual amino-acids by Fischer's esterification method.
Several grams of the esters have been obtained by distillation in a
vacuum of 1 to 16 mm. at temperatures from 70° to 180° C. Bases
precipitated by phosphotungstic acid have also been obtained, but
they apparently constitute a more complex mixture than those usu-
ally obtained in the digestion of proteins by acids, and the discovery
of new bodies, possibly including polypeptids, seems probable.

Quantitative data have been obtained with a view to comparing the

74

efficiency of the apparatus in the elimination of poisons with the
natural kidney. Administering to a rabbit 1 gram of sodium salicylate,
an extraction as rapid as 3 per cent in one-half hour has been observed,
which compares very favorably with the normal action of the kidneys;
in the case of a dog ^vith the same dose, using another apparatus, 4
per cent was obtained in the first hour and a total of about 20 per cent
in sixteen hours. Better results may be confidently expected with an
apparatus having more surface in proportion to the volume. Potas-
sium iodide also passes through the membrane readily as does phenol-
sulphonphthalein. Of the substances naturally present in the body,
sugar, phosphates, diastase and other substances diffuse in notable
amount.

Ethyl sulphide, (C^H5)^S, which is so readily evolved from dogs'
urine on the addition of lime-water or other alkali, may be obtained
in like manner from the diffusate, showing that the mother-substance
of this malodorous compound is freely eliminated by our apparatus.

A wide field of investigation is opened up by the use of this apparatus
in a comparative study of the blood flowing to and from various or-
gans ^vith reference both to the substances which they extract from,
or add to, the general circulation and to the special active principles
(hormones, etc.) which may be present in their internal secretions. A
beginning in this direction has been made by attaching the apparattis
to the portal vein, (four experiments), the blood of which gave by
diffusion considerably more amino-acids (determined by Van Slyke's
method) than that of the carotid. Work in this direction, as well as
in the improvement of the apparatus for the various purposes above
outlined and accumulation of the experience necessary along these
lines, is being pushed actively forward. A full description of the ap-
paratus, with directions for its use, together with the results, will ap-
pear in the January number (1914) of the Journal of Pharmacology
and Experimental Therapeutics.

75

Crystalline Insulin

JOHN J. ABEL, M.D.

In two preceding communications^- ^ it has been told how my col-
laborators and I were induced to attack the problem of the isolation
of insulin and what progress had been made toward its solution to
within a few months past. It was there pointed out that a clue had
been found, the following out of which promised to lead to the desired
goal. This clue eventuated from the observation that when the highly
impure and complex, though therapeutically serviceable insulin ex-
tracts of commerce are boiled for a short time with N/IO sodium
carbonate the resulting physiological inactivation of the extracts is
always associated with an alteration of a part of their sulphur, an ele-
ment which our experiments justified us in believing to be an integral
constituent of the hormone itself. After such treatment ^vith a weak
alkali a new property appears in the altered insulin in that it now
shows an extraordinary sensitivity to very dilute acids which immedi-
ately, and contrary to their usual action, liberate hydrogen sulphide
from it. It was found that inert fractions prepared from such extracts
of the pancreas contain very little of this labile sulphur and a table
was constructed which showed that the labile sulphur of a preparation
is directly proportional to its hypoglycaemic activity for experimental
animals. In other words, the higher the amount of labile sulphur in a
given preparation the greater its potency in lowering the percentage
of blood sugar.

The methods usually employed in fractioning and purifying bio-
logical mixtures have been found to be quite useless in the attempt
to separate the hormone from the numerous impurities that are asso-
ciated with it in even the best of the extracts employed in medical
practice. Equally unsuitable to the purpose in mind was the employ-
ment of the method of isoelectric precipitation from pH 4.7 to 5.0 no
matter how frequently repeated, as likewise the analogous method of
electro-dialysis— a method which has not yielded results of any particu-
lar value in the hands of those who have tried it out on insulin ex-
tracts. We are here dealing with an ampholyte present in very small

76

amount in a solution of other ampholytes whose solubility and pre-
cipitation coefficients lie very close to one another. It seemed worth
while to the writer therefore to employ only weak bases and acids,
more especially such as can act as buffers, in the hope that there might
result from their use such an alteration of solubilities, that impurities
would either fall out of or remain in solution while the hormone in
each case took the opposite course. The successful outcome of the
experiments proved the essential correctness of the idea.

For a description of our earlier methods of purification the reader
is referred to the first paper of this series. The employment of the
simple method there described, led uniformly to the preparation of
an insulin fraction. Fraction IV, with a rabbit unitage of 40 or more
units to the milligram, a unitage that has lately been increased by a
more skilful use of these earlier methods. The next steps in the process
leading directly to the crystallization of insulin are as follows.

One gram, approximately, of the so-called Fraction IV, is dissolved
in a little more than the required volume of N/6 acetic acid, enough
water is added to bring the volume up to 60 cc. or thereabout, and the
contaminating substances (together with some insulin) are then pre-
cipitated by the addition of an acidulated solution of brucine contain-
ing 6 gms. of brucine in 95 cc. of N/6 acetic acid. The resulting clear
supernatant fluid which contains nearly pure insulin is separated
from the precipitate by centrifugalization. Insulin remaining in the
precipitate may be removed by dissolving in N/6 acetic acid and
precipitating with the brucine solution as before. How profitable it
may be to repeat the process has not been determined at the moment.
The clear colorless centrifugalate containing the insulin is then pre-
cipitated ^vith iV/6 pyridine and the precipitate and fluid are immedi-
ately centrifuged. The precipitate which settles out is largely crystal-
line in character, the sides of the tube are found to be coated with
glistening highly refractive crystals and the topmost layer of the pre-
cipitate consists of similar crystals. It is not a difficult matter to remove
this topmost layer of crystals by means of a rubber-mounted pipette
and to free them from adherent pyridine and acetic acid by frequently
washing them with distilled water at room temperature in which
medium pure crystalline insulin is quite insoluble. The crystals may
be recrystallized by dissolving them in N/6 acetic acid and reprecipitat-
ing with N'/6 pyridine. It has been my practice, however, of late to
dissolve this crystalline insulin together with whatever fine granular
material there happens to be mixed with it in M/15 disodium hydro-
gen phosphate. To the clear solution xV/6 acetic acid is added drop by

77

drop with vigorous shaking in order tliat any insulin thrown out will
at once pass into solution again, and this addition of the acid is con-
tinued until a slight amount of turbidity persists permanently. The
flask is then carefully set aside overnight. On the following morning
the bottom of the flask as well as its sides are coated with an abundance
of colorless, highly refractive crystals. The small amount of amor-
phous insulin that falls out in very minute granules or floccules— an
expression of the above-mentioned turbidity— is readily separated by
means of the pipette during the washing with cold water, as the com-
pact crystals obtained by this method sink quickly to the bottom of the
tube like so much sea sand. This process of crystallization may be re-
peated as often as is thought to be necessary. Only a few experiments
have as yet been made with the object of crystallizing the compound
from hot solvents, and to prepare crystalline derivatives.

Professor Swartz of the Department of Geology of the Johns Hop-
kins University has kindly examined samples of the insulin crystals
and reports them as being very uniform in character suggesting a
high degree of purity, as doubly refracting and as belonging to the
rhombohedral division of the hexagonal system. [See illustration be-
tween pages 16 and 17.] The crystals which are allowed to form more
slowly out of acidulated disoditim hydrogen phosphate solution are
very much larger than those precipitated quickly by pyridine out of
an acetic acid solution, such crystals being readily perceptible to the
naked eye as individual crystals. Irrespective of the manner of their
preparation the crystals melt sharply at 233 °C. with slight browning
occurring at 215°C. The melting point has remained constant on re-
crystallization.

Chemical Reactions.— A large fraction of the sulphur of the mole-
cule is in the labile state previously described as characteristic of all
insulin fractions of high rabbit unitage. Quantitative analyses of both
the labile and more firmly bound sulphur are in progress. The com-
pound gives a beautiful biuret reaction passing from a clear pink to a
fine purple on further addition of copper sulphate to the alkaline
solution. Millon's reaction is unequivocal and positive. The Pauly
and the ninhydrin reactions are also positive. This pure insulin is
very sensitive to alkali, as shown by the fact that boiling for 1 5 minutes
with iV/10 sodium carbonate deprives it entirely of its hypoglycaemic
activity. It will be seen that the chemical reactions here described are
of considerable significance as shedding light on the chemical struc-
ture of the compound. It is now being examined in respect to its other

78

physical and chemical properties and efforts will also be made to iden-
tify its various cleavage products.

Animal Experiments.— Numerous tests have already been made in
order to establish the exact rabbit unitage of the crystalline compound.
The rabbit unit employed by us is that fraction of a milligram per
kilogram of body weight which will cause convulsions or lower the
blood sugar to 0.045 per cent within 5 hours. This corresponds to ap-
proximately IV2 times the "clinical unit" used at present.

The exact dosage of the crystalline material has not yet been estab-
lished, but for the present, as is shown in the subjoined table (1),
amounts as small asi^Qgof a milligram per kilo lowered the blood

TABLE 1

Blood Sugar Determinations

Insulin crystals dissolved in M/15 Na2HP04 .
1 mgm. equivalent to 10 cc. solution.
Injections were made subcutaneously.

DOSE PE«

ACTUAL

BLOOD

SUGAR-

-MGM. P

ER lUU C

c.

NO.

WT H
KILOS

KILO
MGM.

DOSE
CC.

TIME

INITIAL

1 HRS.

3 HRS.

5 HRS.

UNITS*

REMARKS

44

2.07

0.016

0.345

11.23

Lost

50

70

88

60

39

1.75

0.0125

0.22

11.29

113

32

54

79

80

42

1.62

0.0125

0.2

11.35

97

50

54

102

80

15

1.54

0.011

0.17

11.38

113

34

39

47

90

29

1.51

0.01

0.151

11.43

110

57

92

110

100

12

1.93

0.01

0.193

11.48

125

48

57

79

100

table 2

14

1.6

0.008

0.13

11.06

119

25

125

Convulsion

46

1.95

0.008

0.15

11.11

115

56

77

111

125

" As defined in the text.

sugar to about the convulsive level, 0.045 per cent. In another series of
experiments 1^25*^^ ^ milligram per kilo produced convulsions in one
rabbit and lowered the blood sugar almost to the convulsive level in a
second animal. (Table 2.) It wall be clear, therefore, that we are deal-
ing here with a hormone which, in very high dilution, influences car-
bohydrate metabolism acting as it were like a catalyst in a chemical
reaction.

With the isolation of this hormone in crystalline forin we are leav-
ing the region of qualitative experiments, and may look forward to
cpiantitative results both in the biological and chemical field which
the future promises to yield.

79

My collaborators in this field of work, Dr. E. M. K. Geiling, Dr.
C. A. Rouiller and Dr. David Campbell and I hope to be able in due
season to publish more extensive reports on the various researches
which naturally arise in the investigation of the properties, chemical
and biological, of the pure product.

^Abel, J. J., and Geiling, E. M. K., Jour. Pharm, and Expcr. Therap., 25, 423,
1925.

"Abel, J. J., Geiling, E. M. K., Alles, G., and Raymond, A., Science, 67, 169,
1925.

80

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