Nobel Prize Winners In Medicine And Physiology 1901 1950

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Nobel Prize

Winners

in

Medicine and Physiology
1901-1950

A Volume in The Life of Science Library
Number 29

Nobel Prize

Winners
in

MEDICINE

and

PHYSIOLOGY

1901-1950

by

Lloyd G. Stevenson,
M.D., Ph.D.

Henry Schuman New York

Copyright 1953 by Henry Schuman, Inc.

Manufactured in the United States of America by H. Wolff

Library of, Congress Catalog Card Number: 53-10370

PREFACE

A HALF-CENTURY OF ACHIEVEMENT IN MEDICAL SCIENCE IS

reflected in the awards of the Nobel Prize for Physiology and
Medicine. One-fifth of the interest on Alfred Nobel's fortune is to
be given annually "to the person who shall have made the most
important discovery" in this domain. "Winners are selected by the
Caroline Medico-Chirurgical Institute in Stockholm. Each Nobel
laureate is judged to have made a personal contribution of first-rate
importance. Behind and around him there is always a constellation
of scientists who have taken part in the same work. Their pre-
liminary researches have made it possible, or their subsequent
eiforts have made it more fruitful. The winner of the Prize is
therefore not only a discoverer in his own right, but a representa-
tive by virtue of his outstanding contribution of those who have
worked toward the same or a similar goal. The configuration of the
heavens may be roughly indicated by mapping the principal stars,
but the sky would be dim indeed without the rest,

In the following pages each Prize Winner is represented, first,
by a short biographical sketch; second, by a passage in which he
describes the Prize discovery in his own words; and third, by a
brief editorial explanation of the meaning and importance of the
work. For the most part the quotation is an excerpt from the Nobel
Lecture delivered in Stockholm at the time of the presentation of
the Prize.

These Lectures are given to general audiences and should there-
fore be suitable for general readers, as many of them are. Unfortu-
nately this is not always the case. When the Lecture has been very
technical in form, some less complicated version of the same story
has been sought for elsewhere in the author's works. Sought for,
but not always found. Happily there are only a few cases Profes-
sor Gullstrand's is one in which the very nature of the discovery
requires that the reader should have extensive background knowl-

$)

Vi PREFACE

edge before he can hope for a competent understanding. These few
instances must be left to those who can grasp them. The majority of
the discoveries are easy to comprehend in outline. No more than
this is aimed at here.

Occasionally, too, the Prize Winner has grown bored with his
own discovery long before reaching Stockholm he may have de-
scribed it already fifty times and has chosen to talk about some-
thing else. Pavlov and Florey are examples: both of them preferred
to speak of more recent work. Again, a modest laureate may devote
most of his time to expounding the related discoveries of other
scientists. In all such cases it is obvious that the Nobel Lecture
would have been an unsuitable choice for the present purpose.
Actually most of these Lectures are precisely what is needed. Some-
times, too, the choice has been determined by the way in which the
work of one Prize Winner can be linked with that of another: as
they are here represented, Sherrington's physiological discovery
leads on from an anatomical finding by Golgi; there are also other
examples.

Except where otherwise shown, all translations have been pre-
pared for their present use. I am grateful to my colleagues, Dr.
R. J. Rossiter, Dr. J. A. F. Stevenson, Dr. George Stavraky, Dr.
R. G. E. Murray, Dr. Murray L. Barr and Dr. T. H. Coffey for
their help and advice.

Lloyd G. Stevenson, M.D.
October, 1952

CONTENTS

YEAR PRIZE WINNER PAGE

Preface v

1901 Emil von Behring i-- 3

1902 Ronald Ross / 10

1903 Niels Ryberg Finsen 15

1904 Ivan Petrovich Pavlov 20

1905 Robert Koch >* 25

1906 Camillo Golgi 32
Santiago Ramon y Cajal

1907 Charles L. A. Laveran 41

1908 EHe Metchnikoff

Paul Ehrlich 46

1909 Emil Kocher 57

1910 Albrecht Kossel 62

1911 Allvar Gullstrand *-*' 68

1912 Alexis Carrel ., 73

1913 Charles Richet 7 8

1914 Robert Barany 84

1915 No Award

1916 No Award

1917 No Award

1918 No Award

1919 Jules Bordet 5

1920 August Krogh 9^

1921 No Award

CONTENTS

1922 Archibald Vivian Hill * 02
Otto Meyerhof

1923 Frederick Grant Banting 109
John J. R. Macleod

1924 Willem Einthoven H5

1925 No Award

1926 Johannes Fibiger 120

1927 Julius Wagner- Jauregg 125

1928 Charles Nicolle 13

1929 Christiaan Eijkman *34
Frederick Gowland Hopkins

1930 Karl Landsteiner 143

1931 Otto Warburg 148

1932 Charles Sherrington 154
Edgar Douglas Adrian

1933 Thomas Hunt Morgan 165

1934 George Hoyt Whipple 171
George Richards Minot

William Parry Murphy

1935 Hans Spemann 180

1936 Henry Dale 186
Otto Loewi

1937 Albert von Szent-Gyorgyi 196

1938 Corneille Heymans 204

1939 Gerhard Domagk 209

1940 No Award

1941 No Award

1942 No Award

1943 HenrikDam^ 216
Edward A. Doisy ,

1944 Joseph Erlanger 223
Herbert Spencer Gasser

1945 Alexander Fleming % 229
Ernst Boris Chain

Howard Walter Florey

CONTENTS

1946 Hermann Joseph Muller 238

1947 Bernardo Albert Houssay 244
Carl E Cori

Gerty T. Cori

1948 Paul Muller 255

1949 Walter Rudolf Hess 260
Egas Moniz

1950 Edward Calvin Kendall 272
Philip Showalter Hench

Tadeus Reichstein

Index 285

Nobel Prize

Winners

in

Medicine and Physiology
1901-1950

1901

EMIL VON BEHRING

(1854-1917)

ff For Ms work on serum therapy, especially its
application against diphtheria, by which he has
opened a new road in the domain of medical sci-
ence and thereby placed in the hands of the physi-
cian a victorious weapon against illness and death."

BIOGRAPHICAL SKETCH

EMIL ADOLF (VON) BEHRING WAS BORN IN DEUTSCH-EYLAU,
Germany, in 1854 and studied in Berlin. He entered the Army
Medical Corps and was lecturer in the Army Medical College,
Berlin, in 1888. The following year he became assistant in Robert
Koch's Institute of Hygiene. In 1891, when Koch became chief
of the new Institute for Infectious Diseases, von Behring accom-
panied him. Meantime (1890) he had published his important
papers on serum therapy. The consequences in medical practice
were sensational and von Behring was soon famous. In 1894 he
accepted the chair of hygiene in Halle, but a year later transferred
to a similar position in Marburg. He received many distinctions
and several monetary prizes. In Marburg he established works for
the manufacture of antitoxins and a remedy for the tuberculosis
of cattle. He died in 1917.

4 NOBEL PJOZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"As already proved by Loffler, then Roux and Yersin, there are
animals naturally immune to diphtheria; I have confirmed by my
own investigations that this is true of mice and rats, and that
these animals tolerate, without appreciable damage to their health,
inoculations with cultures which have a sure and deadly effect
on much larger animals, such as the guinea pig, rabbit, and
wether. . . .

"Furthermore, one can make animals immune which were orig-
inally very susceptible to diphtheria. . . .

"i. One of the immunization methods, which I can show to be
very reliable on the ground of my own research, has been described
exactly by Prof. C Frankel [1861-1915; an assistant of Koch's
who became professor of hygiene at Halle and did much original
work in bacteriology and immunology]. ... It depends on the
use of sterilized cultures, and with the help of this method one can
make guinea pigs nonsusceptible in 10-14 days to inoculations
that are certain death to normal guinea pigs. . . .

"2. [Von Behring next describes a method of his own, using in
place of the sterilized cultures of Frankel cultures weakened by the
addition of iodine trichloride in small amounts. A feeble culture
was succeeded by a more active one. Finally a fully virulent culture
was tolerated.]

"In both the methods just mentioned, immunity is brought about
by the metabolic products bred by diphtheria bacilli in cultures.

"3. But it is also possible to produce immunity through the
same metabolic products engendered from diphtheria bacilli in
the living animal organism. If one investigates animals dying of
diphtheria, one finds an extremely abundant transudate in the
pleural cavity. . . .

"In more than 50 separate cases investigated, this transudate
never contained diphtheria bacilli; but it possesses properties poi-

* Translated from Emil von Behring, " Untersuchungen iiber das Zustandekom-
men der Diphtherie-Immunitat bei Thieren," Deutsche medicinische Wochen-
sckrift, Vol. 16 (December n, 1890), pp. 1145-1148.

1901: EMIL VON BEHRING 5

sonous for guinea pigs. The degree of toxicity is not always the
same. . . .

"Those [few} guinea pigs which survive an injection of [10 to
15 c.c. of} transudate . . . are regularly sick for a long time;
[here follows a description of their symptoms}.

"Now when I awaited the complete recovery of those animals
which displayed the symptoms just described to a pronounced de-
gree, then ... I could establish that they endured without harm
inoculations that would kill healthy animals in 3 to 4 days. . . .

"4. An[other} immunization method, one not hitherto em-
ployed, can also be traced to the operation of the metabolic prod-
ucts of the diphtheria bacilli.

"It consists in first infecting the animals and then doing away
with the deleterious effect through therapeutic management. [This
was exceedingly difficult. Of the many drugs tried, most were use-
less. Mention is made, however, of certain compounds which
appeared to have cured infected guinea pigs, notably iodine tri-
chloride. Behring reported that treatment with this drug prior to
infection did no good.}

"5. [It was reported that prior treatment with hydrogen per-
oxide seemed to confer some immunity. This alleged success had
nothing to do with immune products resulting from the metabolism
of bacilli.}

"All five of the methods of immunization against diphtheria
thus far described are in my opinion not practicable at least in
the form I have given them for humans.

"But from the scientific viewpoint, and ... for the under-
standing of the occurrence of diphtheria immunity, they are capable
of affording us worth-while service.

"That is to say, immunity having somehow occurred and I do
not exclude natural immunity all diphtheria-immune animals
have certain characteristics in common which distinguish them
from non-immune animals.

"First of all, the living immune animals, as a whole, not only
possess protection against infection with the living diphtheria
bacilli but are also protected against the deleterious effect of the
poisonous substances formed by the diphtheria bacilli in cultures
and in the animal body.

6 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"I have undertaken the proof of this in various ways. First I
tried it with the solution of an albuminous substance which I
separated from old cultures with acidified alcohol; however, I was
unable to remove the acid from the resulting preparation without
impairing the poisonous effect; I also think it no easily soluble
problem ... to separate other precipitating agents from the
precipitate produced. But for the purpose in question I scarcely
needed to go after the diphtheria poison, or, perhaps more cor-
rectly, the diphtheria poisons; filtrates of old cultures afforded me
all I wanted.

"Using my cultures grown in alkaline bouillon, with 10 c.c.
normal alkali per liter, I found that after 10 weeks they contained
so much poisonous substance that, having been rendered germ-free
by filtration, they already called forth characteristic symptoms of
diphtheria poisoning with a dose of i c.c. in medium-sized guinea
pigs; these symptoms did not entirely disappear for 3 to 4 weeks.
Furthermore, 3 to 4 c.c. were enough to kill larger guinea pigs in
3 to 8 days . . .

"Now all guinea pigs with established diphtheria immunity
endured 3 to 5 c.c. without any discernible disease symptoms
or local reaction whatever; on the other hand, guinea pigs that had
still not quite recovered from an infection proved to be only very
little more poison-resistant than they normally would be. ... It
is very noteworthy that the immunity can be lost again through
the subcutaneous injection of considerable and repeated quantities;
this happens with all the more certainty, the less the immunity has
been 'established.' At all events, guinea pigs under the influence
of the poisonous, germ-free diphtheria culture fare as before
against diphtheria infection under unfavorable conditions.

'The first thought to arise could be this, that the resistance to
poison here described depends on 'habituation/ as in the case of
alcoholics, morphine addicts, arsenic eaters. . , .

"But such an interpretation is at once controverted by the fact
that animals which have never had anything to do with diphtheria
poison also possess diphtheria poison resistance.

"If we start out again with the xo-week culture rendered germ-
free, then, calculating on the basis of body weight, it is deadly for
guinea pigs in the ratio of about i :ioo; but mice endure the poison

1901: EMIL VON BEHRING 7

without any harm when it is injected into them in the ratio of i :ao,
and I have injected rats on several successive days with 4 c.c. at a
time without the appearance of a reaction worth mentioning.

"A further argument against accepting habituation to the poison
{as the explanation] is the circumstance that I have never suc-
ceeded, despite the most cautious increase in the dosage of poison
from a quite harmless to a higher one, in protecting animals against
the diphtheria poison, except insofar as they have later been able
to endure a little more of it than they normally could.

"These observations and considerations led me to approach
closer to the question whether the origin of the poison resistance
really does not depend at all on a characteristic of the living cellular
parts of the organism, but rather on a peculiar property of the
blood, freed of living cells.

"In order to decide this question I withdrew blood from rats 3
hours after they had had large amounts of diphtheria poison in-
jected into their abdominal cavities, and injected it, or the serum
obtained from it, into the abdominal cavities of guinea pigs; no
trace of the symptoms of poisoning occurred, whereas the blood
of diphtheria-susceptible animals which had received the diphtheria
poison, when injected into the abdominal cavity in like amount
(4 c.c.), did not, indeed, kill the guinea pigs, yet clearly made
them sick.

"For the future, then, I attach importance to the fact that the
extravascular blood of diphtheria-immune guinea pigs also has
the capacity of making the diphtheria poison harmless. To what
extent this occurs, and to what extent therapeutic results can be
obtained with the blood of immunized animals on these points I
propose to contribute later. ..."

CONSEQUENCES IN THEORY
AND PRACTICE

In No. 49 (December 4, 1890) of the Deutscke medicimsche
Wochenschrijt (German Medical Weekly), von Behring and his
Japanese colleague, Shibasaburo Kitasato (1852-1931) announced
the discovery of tetanus antitoxin. It was shown that "immunity
to this disease . . . depends on the capacity of the blood to render

8 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

harmless the poisonous substances produced by the tetanus bacilli/*
"In that work/* wrote von Behring, "the same was also affirmed
for diphtheria immunity, in just the same way as for tetanus, but
without the communication of separate investigations, which had
shown for diphtheria, too, the equivalent mechanism of the occur-
rence of immunity." The work had already been done in part by
von Behring, and one week later, in No. 50 (December n, 1890)
of the same journal, there appeared the classic paper from which an
excerpt is quoted above. It is interesting that a large part of this
paper concerns preliminary investigations and relates the way in
which von Behring reached the conclusion that the power of resist-
ing the disease does not reside in the cellular constitution of the
body but rather in the cell-free blood serum. (This contention was
so amply proved a little later that Metchnikoff's discovery of the
part played by white blood cells in combating infection was at first
rather ill received. See below, pp. 49-50.)

As suggested by the last sentence of the longer quotation, much
remained to be done in studying this phenomenon. About a year
after publication of the quoted paper the first human case was
treated with diphtheria antitoxin. This was a child in Bergmann's
clinic in Berlin, Geissler making the injection on Christmas night,
1891. The method was soon widely used and its success was phe-
nomenal. The death rate from diphtheria, as reported by one of the
Berlin hospitals, fell from 48 percent to 13 percent, and even better
results soon were achieved. Before the discovery of antitoxin the
fatality rate in general was about 35 percent, and in laryngeal cases
about 90 percent. Since this discovery, mortality has fallen to
approximately 5 percent, and in laryngeal cases to 15 percent.

Ability to measure dosage was largely the result of the brilliant
work of Paul Ehrlich (see below, pp, 52-55). Further progress
was made when the Health Department of New York City adopted
the use of cultures for diagnosis and for control of the period of
isolation; this was done in 1893 under the direction of Park. In
1913 Schick described the intradermal toxin reaction (skin test)
for the determination of individual immunity. In the same year
von Behring introduced the use of injections of toxin-antitoxin
mixtures in children for active immunization against diphtheria.
This proved a most effective means of protection. In 1924, Ramon

1901: EMIL VON BEHRING 9

brought forward his formalized toxin or anatoxin, commonly
known as toxoid, which has largely replaced toxin-antitoxin mix-
tures.

Not only did von Behring make the most important contribu-
tions to the conquest of diphtheria but his introduction of sero-
therapy opened a whole new field to medicine.

REFERENCES

BULLOCH, WILLIAM. The History of Bacteriology (London and New
York: Oxford University Press, 1938), and the literature cited there,
especially E. Wernicke, "Die Immunitat bei Diphtheric," Handbuck
der pathogenen Mikroorganismen von Kolle-Wassermann, 1913.

1902

RONALD ROSS

(1857-1932)

"For his work on malaria, by which he has shown

how it enters the organism and thereby has laid the

foundation for successful research on this disease

and how to combat it! 9

BIOGRAPHICAL SKETCH

RONALD Ross CAME OF A THREE-GENERATION ANGLO-INDIAN
family. He was born at Almora in the Kumaon hills, northwest
Nepal, on May 13, 1857, the eldest of ten children. His father was
General Sir Campbell Claye Ross. In 1874 Ronald Ross began the
study of medicine at St. Bartholomew's Hospital Medical School.
He obtained the M.R.CS. diploma in 1879 and for a time traveled
between London and New York as a ship's surgeon. He then
entered the Madras Medical Service and took part in the Burma
War. On leave in 1888, he studied bacteriology in London under
Klein, and took the D.P.H. Returning to India, he began, in 1892,
to take especial interest in malaria; he had already studied mosqui-
toes on his first tour of service. In 1894 Patrick Manson, the great
pioneer of tropical medicine, showed him the malarial parasites
discovered by Laveran in 1880. Returning to India in 1895 after
his second home leave, Ross carried on an exhaustive study of the
problem of the transmission of malaria, constantly advised and
encouraged by Manson. A series of frustrations, due to the failure
of the authorities to support his work and their maddening tend-

10

1902: RONALD ROSS 11

ency to transfer him at crucial moments in his research, dogged him
for years. He nevertheless achieved the great success described be-
low. Ross was later sent to Assam to investigate kala-azar. In 1899
he was appointed lecturer in tropical medicine at the Liverpool
School and retired from the Indian Medical Service; in 1902 he
became professor. In 1912 he left Liverpool to act as physician for
tropical diseases at King's College Hospital. He served in various
capacities as a consultant during the First World War and after
1918 he practiced in London. He traveled widely, chiefly to advise
on antimalaria measures. In addition to his scientific writings and
his Memoirs, he published books of verse and several romances. In
1911 he became a Knight Commander of the Bath, and in 1918
Knight Commander of the Order of Saint Michael and Saint
George. The Ross Institute and Hospital for Tropical Diseases,
founded in his honor, was opened at Putney in 1926. He died there
in 1932.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"Towards the middle of August [1897] I had exhaustively
searched numerous grey mosquitoes and a few brindled mosquitoes.
{Unable to obtain literature on mosquitoes, Ross made a working
classification of his own and invented simple names. His grey
mosquitoes belonged to the genus Culex, his brindled mosquitoes
to the genus Stegomyia.*} The results were absolutely negative; the
insects contained nothing whatever. . . .

"I had remembered the small dappled-winged mosquitoes
{genus Anopheles^ but as I could not succeed either in finding
their larvae or in inducing the adult insects to bite patients, I
could make no experiments with them. On the ijth August, how-
ever, one of my assistants brought me a bottle of larvae, many of
which hatched out next day. Among them I found several dappled-
winged mosquitoes, evidently of the same genus as those found
about the barracks, but much larger and stronger. Delighted with
this capture I fed them (and they proved to be very voracious) on

* From Ronald Ross, "Researches on Malaria," Les Prix Nobel en 1902.

12 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

a case with crescents in the blood. Expecting to find more in the
breeding bottle and wishing to watch the escape of the motile fila-
ments in this new variety, I dissected four of them for this purpose
immediately after feeding. This proved to be most unfortunate, as
there were no more of these insects in the bottle, and the results
as regards the motile filaments were negative. I had, however, four
of the gorged dappled-winged mosquitoes left; but by bad luck two
of the dissections were very imperfect and I found nothing. On
the 2oth August I had two remaining insects both living. Both had
been fed on the i6th instant. I had much work to do with other
mosquitoes, and was not able to attend to these until late in the
afternoon when my sight had become very fatigued. The seventh
dappled-winged mosquito was then successfully dissected. Every
cell was searched, and to my intense disappointment nothing what-
ever was found, until I came to the insect's stomach. There, how-
ever, just as I was about to abandon the examination, I saw a very
delicate circular cell apparently lying among the ordinary cells of
the organ, and scarcely distinguishable from them. Almost in-
stinctively I felt that here was something new. On looking further,
another and another similar object presented itself. I now focussed
the lens carefully on one of these, and found that it contained a
few minute granules of some black substance exactly like the pig-
ment of the parasite of malaria. I counted altogether twelve of
these cells in the insect, but was so tired with work and had been
so often disappointed before that I did not at the moment recognize
the value of the observation. After mounting the preparation I
went home and slept for nearly an hour. On waking, my first
thought was that the problem was solved; and so it was.

"Next morning . . . the eighth and last dappled- winged mos-
quito . . . was killed and dissected with much anxiety. Similar
bodies were present in it. . . . The objects lay, not in the stomach
cavity of the insects, but in the thickness of the stomach wall. . . .

"These two observations solved the malaria problem. They did
not complete the story, certainly; but they furnished the clue. At a
stroke they gave both of the unknown quantities the kind of mos-
quito implicated and the position and appearance of the parasites
within it"

1902: RONALD ROSS 13

CONSEQUENCES IN THEORY
AND PRACTICE

In July 1897 MacCallum discovered the sexual phase of the
reproduction of the malarial parasite. Manson at once recognized
that Ross's pigmented cells were the fertilized female cells, becom-
ing motile after fertilization and burrowing into the insects* tissues
for further development. In July 1898 Ross discovered the sporo-
zoids of Proteosoma, a malarial parasite attacking birds, in the
salivary glands of mosquitoes. The route of infection was thus re-
vealed and the story was virtually complete. Grassi extended the
discovery from bird malaria to human malaria, and Italian malari-
ologists worked out most of what remained to be learned. Ross
optimistically expected that his discoveries were "to save human
life in the gross, perhaps to open continents to civilization/* a
confidence widely shared. It was largely doomed to disappointment,
for the problem has turned out to be an enormously difficult one.
Economics, agriculture, and the social conditions of great masses
of people have proved important, and often intractable, factors
in the control of malaria. Furthermore, there appear to be epi-
demiological considerations which are not well understood even
today. For example, no entirely satisfactory explanation has yet
been advanced for the almost complete disappearance of malaria
in certain areas, such as parts of the United States and Canada,
where Anopheles mosquitoes continue to thrive. Nevertheless the
discovery made by Sir Ronald Ross has borne fruit in such measures
as the drainage or oiling of swamps and in the "malaria discipline'*
which, properly inculcated and enforced, has been shown capable
of providing a large measure of protection to armies fighting in
the tropics. This has been of great value to other groups and
individuals exposed to the same danger; combined with the use of
quinine, and more recently with other drugs, especially atabrine, it
has reduced, although by no means abolished, the greatest hazard
of the malaria-infested regions of the globe. The introduction of
DDT (see below, pp. 255-259) and other insecticides has given
the malariologist new weapons against the mosquito. In several

14 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

malarial districts, notably in Cyprus, the most recent results have
been very encouraging.

One may be tempted to suggest that Ross's work inspired Walter
Reed, Charles Nicolle, and later discoverers of insect vectors in
disease; but it should be remembered that earlier workers, notably
Theobald Smith and Manson, had already performed a similar
service. It will not be forgotten that General W. C. Gorgas, by
exterminating mosquitoes in the Panama region, was able to control
both malaria and yellow fever.

REFERENCES

MEGROZ, R. I. Ronald Ross, Discoverer and Creator (London: Allen

& Unwin, 1931).
Ross, RONALD. Memoirs: With a Full Account of the Great Malaria

Problem and Its Solution (London: J. Murray, 1923).

1903

NIELS RYBERG FINSEN

(1860-1904)

ff ln recognition of Ms contribution to the treatment
of diseases, especially lupus vulgaris, with concen-
trated light rays, whereby he has opened a new
avenue to medical science"

BIOGRAPHICAL SKETCH

NIELS RYBERG FINSEN WAS BORN DECEMBER 15, 1860, AT
Thorshavn, capital of the Faroe Islands, and received some of his
early schooling at Reykjavik, Iceland. He studied at the University
of Copenhagen for eight years and took his degree in medicine in
1890. In the same year he was appointed professor of anatomy in
the Surgical Academy. As an undergraduate he had already become
interested in the influence of light upon living organisms. His work
followed researches of Downes and Blunt on the influence of light
upon bacteria, and those of Widmark on the power of the actinic
rays to cause inflammation of the skin. In 1893 he published his
first essay on the red-light treatment of smallpox. This was fol-
lowed by other papers on the biological effects of light, including
accounts of his work on the treatment of lupus vulgaris, a form of
tuberculosis affecting the skin, especially that of the face. In 1895
he established the first Light Institute, at Copenhagen, which re-
ceived patients from many parts of the world. Originally built and
supported by private philanthropy, this Institute was later assisted
by the state. When awarded the Nobel Prize, Finsen placed half

15

16 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

the prize money at interest for the benefit of his family and donated
the other half to the Institute. He died at the age of forty-three,
on September 24, 1904.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"Thanks to the work of Downes and Blunt, of Duclaux, Arloing,
Roux, Geissler, Buchner, etc., it is at present [1897] well estab-
lished that light possesses an energetic bactericidal power. Thus
everything argues, at least theoretically, in favor of the use of light
in the treatment of superficial cutaneous diseases caused by bac-
terial infection, and yet this therapeutic procedure has remained
unused ... to this day. . . . {Finsen here reviews some refer-
ences in the literature to earlier attempts to use light in this way in
the treatment of lupus. In some cases this apparently had been con-
ceived as nothing more than a form of heat treatment; in general,
Finsen concludes, the light source had been too feeble, the treat-
ments too short and too few.]

"These isolated instances of the use of light for the treatment
of lupus are thus of little value and can scarcely provide a basis for
further researches. Consequently I have thought it my duty to re-
undertake the study of this important question from top to bottom.

"As light only exerts its bactericidal effects very slowly, it is
necessary ... to concentrate it by means of mirrors or lenses, at
the same time excluding the heat rays of the spectrum, the infra-
red, red, orange, and yellow, because when concentrated they cause
burning of tissues. This exclusion, moreover, curtails the bac-
tericidal action of the light only a very little, for on examining the
question more closely one finds that the majority of observers have
asserted that the bactericidal qualities are due to the most refractive
rays, a fact which my own experiments have confirmed. . . . [At
this point Finsen describes the filters he used for this purpose, the
means he employed for "straining" and concentrating sunlight, and
the apparatus he devised for making use of artificial sources of
light to produce "blue-violet" rays. His chief resource for filtering

* Translated from Niels Ryberg Finsen, La. Phototherapie (Paris: G. Carre et
C Naud, 1899), pp, 85-96.

1903: NIELS RYBERG FINSEN 17

sunlight was a hollow planoconvex lens filled with an ammoniacal
solution of copper sulfate; when he used an electric arc lamp, the
rays were made parallel by two planoconvex lenses.}

"Before having this apparatus constructed and perfected, I
assured myself by a series of experiments that the bactericidal action
of light is really augmented in the degree that its rays are concen-
trated ... I made use of flat, rectangular vessels, coating their
walls inside with peptone-gelatin or peptone-agar which I sowed
with pure cultures [of bacteria]. On the outside of each flask I
stuck a sheet of paper, white on one side and black on the other, the
white surface being turned to the light in order to prevent the
absorption of heat rays, and the black surface applied to the glass to
prevent the light from influencing the culture. In addition I cut
round holes in this paper across which I wrote on the glass of the
vessel . . . figures indicating the time in minutes during which
these parts were subjected to the action of light.

"Two identical flasks prepared in this way were simultaneously
exposed . . . one to direct sunlight, the other to concentrated sun-
light. . . . [The cultures were allowed to grow in the dark for
a day or two. It was then found that the concentrated light had had
a greater inhibitory effect than direct sunlight. Finsen performed
other experiments of a similar nature to test this point. He also
found that his blue-violet rays, when passed through the pinna of
the ear, had no effect on photographic paper; but that if the ear
were compressed between plates of glass until partly exsanguinated
i.e., deprived of blood the rays then seemed capable of pene-
trating it. For this reason he devised glass discs to be bound firmly
with tapes to the surfaces he wished to expose; these were supposed
to prevent blood from absorbing too much of the radiation by
forcing it out of the areas under treatment.}

"I have employed the method of treatment by concentrated
chemical rays in different infectious skin diseases, but above all in
lupus vulgaris, an affection which presents particularly favorable
conditions for putting this therapeutic procedure to work. It is
known that lupus vulgaris is caused by the tubercle bacillus, that it
is a local and quite superficial malady. On the other hand it is well
established that light is capable of killing the tubercle bacillus. . . .

"When a plaque of lupus has been subjected for a long enough

!8 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

time to the action of concentrated chemical rays, its margins^ pre-
viously elevated, become smooth, the redness progressively dimin-
ishes, the skin regains its normal color, and ulcerations, when they
exist, are cicatrized/ 1

CONSEQUENCES IN THEORY
AND PRACTICE

Finsen's use of concentrated radiation from the sun or an arti-
ficial light source, with the heat rays eliminated, made available the
most refractive rays, the blue and especially the ultraviolet. Ultra-
violet light continues to hold a place in the treatment of lupus vul-
garis and a few other types of skin disease. The apparatus used
and the details of treatment have changed, but the principle re-
mains. X-ray treatment has been substituted in some cases of lupus,
particularly in those with marked ulceration and hypertrophy, but
the Finsen method, although time-consuming and costly, yields the
least disfiguring scars. Sometimes both X rays and Finsen rays are
used, and radium, too, has been employed. Local treatment with
drugs and the surgical removal of severe localized lesions have
been recommended, in combination with the systemic treatment of
tuberculosis. Despite variations, a leading place is still reserved for
ultraviolet irradiation. The approach to therapy has been altered,
however, by the recent introduction of cortisone and ACTH.

The therapeutic use of other forms of irradiation has probably
been inspired in part by Finsen's success. Ultraviolet light is now
used for a variety of other purposes, including the partial steriliza-
tion of a limited, enclosed space; attempts have also been made to
reduce the number of upper respiratory infections by ultraviolet
irradiation of working places, but with limited and rather dubious
success. (The importance of sunlight for health has been confirmed
by the discovery that vitamin D 2 is produced by the ultraviolet ir-
radiation of ergosterol, a substance derived from yeast and other
plant sources, but also found in animal tissues, notably in the skin;
hence the rarity of rickets in sunny climates. ) Meanwhile, Bernhard,
Rollier, and a number of later workers have extended the use of
phototherapy in surgical cases and in several different forms of
tuberculosis.

1903: NIELS RYBERG FINSEN 19

Finsen had earlier (1893) described a method for the preven-
tion of pitting in smallpox by keeping the patient in a red-lighted
room, the chemical rays at the other end of the spectrum being
excluded. This procedure is now seldom mentioned in the text-
books.

1904

IVAN PETROVICH PAVLOV

(1849-1936)

ff ln recognition of his work on the physiology of

digestion, by which, in essential respects, he has

transformed and enlarged our knowledge of this

subject"

BIOGRAPHICAL SKETCH

IVAN PETROVICH PAVLOV, WHO CAME OF A FAMILY OF POOR
country priests, was born September 26, 1849, in the city of Riazan,
in Russia. He began his education in the church school and con-
tinued it in the theological seminary. Discovering an interest in
the natural sciences, he left the seminary in 1870 and entered St.
Petersburg University, where Mendeleev and Butlerov were among
his teachers. Subsequently he entered the Medico-Chirurgical
Academy and was graduated in 1879. The influence of Professor
E. von Cyon and the fame of Sechenov are said to have determined
his future career. After graduation he served as Professor S. P.
Botkin's chef de laboratoire in the Clinic of Internal Medicine at
the St. Petersburg Military Medical Academy, where he continued
to study physiology and carry on research. In 1884 ^ e went abroad
to study, spending two years in further training, partly with Lud-
wig at Leipzig, partly with Heidenhain in Breslau. He returned to
the Military Medical Academy in 1886. In 1888 he discovered the
secretory nerves to the pancreas; in 1889 he described his experi-
ments in sham feeding (see below) . Not until 1890 did he obtain

20

1904: IVAN PETROVICH PAVLOV 21

a chair, becoming professor of pharmacology. A year later he was
also appointed director of the Department of Physiology of the
Institute of Experimental Medicine. In 1895 ^ e g ave U P his chair
of pharmacology for that of physiology in the Medico-Chirurgical
Academy, which he retained until 1924. In 1902 Bayliss and
Starling announced the discovery of secretin, the hormone which
incites the pancreas to secrete its digestive juice. The discovery was
confirmed in Pavlov's laboratories, but Pavlov himself had con-
centrated on nervous correlations and the introduction of a humoral
(blood-stream) factor seems to have cooled his interest in diges-
tion. At any rate he now turned to his famous work on the condi-
tioned reflex. For the next thirty years he devoted himself to the
reflex activity of the cerebral hemispheres. His death occurred in
1936.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"In the year 1852 Bidder and Schmidt had observed that, under
certain circumstances, one needs only to excite a dog by the sight of
food in order to call forth a secretion of gastric juice. ... In
recent times the French physiologist Richet has had the opportu-
nity of making observations on a patient on whom the operation
of gastrotomy had been performed for an incurable stricture of the
oesophagus [i.e., a permanent opening had been made from the
stomach to the exterior to permit feeding]. Soon after the patient
took anything sweet or acid into the mouth, Richet was able to per-
ceive a secretion of pure gastric juice. . . . [These] observations
prove . , . that the gastric glands are influenced through nerves
by "distant effect/ since the phenomenon comes to pass without any
immediate contact between the food and the gastric mucous mem-
brane. It only remained to make the experiment constant and sim-
ple; in other words, to facilitate its reproduction and seek out its
proper interpretation.

"As a matter of fact, I am now able to demonstrate experiments
to you which yield absolutely constant and unequivocal results. We

* From J. P. Pawlow, The Work of the Digestive Glands, translated by W. H.
Thompson (London: C. G. Griffin, 1902), pp. 49'5* 54 7*-

22 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

have here before us [this is a demonstration lecture] a dog . . .
[which] possesses an ordinary gastric fistula with metallic cannula
[tube], and has had its oesophagus divided as well, so that the
mouth is cut off from all communication with the cavity of the
stomach. Its stomach has been washed out . . . and . . . not a
single drop of fluid escapes from the fistula. I give the dog food.
The animal eats greedily, but the whole of the food swallowed
comes out again at the oesophageal opening in the neck. After
feeding in this way (. . . f sham feeding') for five minutes, per-
fectly pure gastric juice makes its appearance at the fistula, the
stream steadily becomes greater and greater, and now, five minutes
after the commencement of secretion, we have already 20 c.c. of
juice. We may continue to feed the dog as long as we wish, the
secretion will flow at the same rate for one, two, or more hours.
... It is obvious that the effect of the feeding is transmitted by
nervous channels to the gastric glands.

". . . We will [now] carry our experiment a step farther by
dividing the vagi nerves. ... In the case of this dog, at the time
of making the gastric fistula, the right vagus nerve was divided
below its recurrent laryngeal and cardiac branches. In this way,
only the pulmonary and abdominal branches on the side in ques-
tion were thrown out of function, the laryngeal and cardiac fibres
remained intact. About three hours before the present lecture, I
prepared the left vagus free in the neck, passing a loop of thread
round the nerve, but not dividing it. I now pull gently on the
thread to draw the nerve outwards, and sever it with a sharp snip
of the scissors. At present the pulmonary and abdominal vagi on
both sides are paralysed, while on the right side the laryngeal and
cardiac fibres are intact. . . . The dog . . . shows no indication
whatever of a pathological or otherwise uncomfortable condition.
. . . We again off er the dog food to eat, which it eats with increas-
* ing greed . - . but in sharp contrast to the previous sham feed-
ing, we do not see a single drop of juice flowing from the stomach.
We may feed the dog as long as we wish, and repeat our experi-
ment ... as often as we desire, but never again shall we see a
secretion of gastric juice in this animal as the result of sham feed-
ing. . . ,

"[In another dog in the same state] the peripheral end of the

1904: IVAN PETROVICH PAVLOV 23

[left vagus nerve in the neck] had been prepared free, placed on
a ligature, and for the time being preserved under the skin. After
three to four days the stitches were carefully removed . . . when
the nerve lay free before us. In this way we avoided appreciable
discomfort to the animal before exciting the nerve. By such pre-
cautions we invariably succeeded in obtaining a secretion of juice
from the empty stomach when the nerve was subsequently excited
by slow induction shocks at intervals of one to two seconds. . . .
"[In still another case] we begin to get ready a meal of flesh
and sausage before the animal [with gastric fistula and divided
oesophagus] as if we meant to feed it. ... Precisely five minutes
after we begin to tease the animal in this way the first drops of
gastric juice appear in the fistula. The secretion grows ever stronger
and stronger, till it flows in a considerable stream."

CONSEQUENCES IN THEORY
AND PRACTICE

Apart from his later work on the conditioned reflex (which he
discussed in his Nobel lecture, although the Prize had not been
awarded with this in mind), the experiments described in the
quotation are probably the most famous of the many which Pavlov
performed. His great surgical skill contributed to his success, and
he is credited with the introduction of aseptic surgery and the
"chronic" experiment into physiology. His new experimental pro-
cedures included esophagotomy combined with gastric fistula, as
well as a new type of stomach pouch designed to preserve blood
and nerve supply; he also used new methods of faradization (ap-
plication of an induced, or faradic, electric current) and was
responsible for a number of other innovations or modifications in
experimental techniques. His studies of the secretions of the salivary
glands, the stomach, the pancreas, and the intestine indeed, of
almost every aspect of digestive secretion are too far-ranging for
brief summation; hence a portion of his work on gastric secretion
has been selected as a specimen of his achievement. Professor Bab-
kin summarizes the facts established under ten headings: **( I ) &
was demonstrated beyond doubt that vagus was the secretory nerve
of the gastric glands. (2) It was shown that 'psychic' gastric secre-

24 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

tion was a fact of extreme importance. (3) A typical course of
gastric secretion in response to different food substances meat,
bread, milk was established. (4) For the first time it was demon-
strated that the peptic power of the gastric juice varied with the
nature of the food ingested and the phase of gastric secretion.
(5) The constancy of the acidity of the gastric juice was demon-
strated. (6) The stimulation of gastric secretion by food intro-
duced directly into the stomach was shown to be due not to the
mechanical but to the chemical stimulation of the gastric glands.
(7) New secretagogue substances, e.g., water and meat extract,
were discovered. (8) The ability of starch to stimulate a greater
output of pepsin was shown. (9) The inhibitory effect of fat on
gastric secretion was established. (10) The three phases of gastric
secretion the nervous, the pyloric, and the intestinal were dis-
closed/'

This represents only a part of Pavlov's work on digestion; one
therefore feels no surprise at Babkin's further statement that the
sum of this work "is the foundation on which modern normal and
pathological gastroenterology is based."

Pavlov's discovery of the part played by the vagus nerve was
an important contribution to general knowledge of the autonomic
control of internal organs and directed further attention to this
interesting question. The reflexes described above are uncondi-
tioned reflexes. But it is already apparent, in the references to
"psychic secretion/ 1 that Pavlov was feeling his way toward his
concept of the conditioned reflex, initiated by a stimulus in-
herently meaningless but rendered effective by association. This
concept in turn has had widespread influence on physiology, psy-
chology, psychiatry, and even education.

REFERENCES

BABKIN, B. P. Pavlov: A Biograpby (Chicago: University of Chicago

Press, 1949).
STAVRAKY, G. W. "Ivan Petrovitch Pavlov/' Archives of Neurology

and Psychiatry, Vol. 33 (May 1935), pp. 1082-1087.

1905

ROBERT KOCH

(1843-1910)

ff For his investigations and discoveries in regard to
tuberculosis"

BIOGRAPHICAL SKETCH

BORN DECEMBER n, 1843, IN KLAUSTHAL, HAHOVER, ROBERT
Koch was the son of a mining official and the third of thirteen
children. He attended the Gymnasium of his native town and at
the age of nineteen began his medical studies at Gottingen. Here
he was influenced by the teaching of Jacob Henle, who had pro-
posed a theory of contagion in 1840. In 1866, at the age of
twenty-three, Koch received the M.D. degree. He then interned
at the Hamburg General Hospital and in 1869 commenced practice
at Rakwitz, in Posen. The following year he volunteered for
medical service in the Franco-Prussian War. He resumed civil
practice in 1872 in the town of Bomst (pop. 4000), in Wollstein,
Polish Prussia; soon he became district physician, assuming respon-
sibility for a large territory. Despite the heavy pressure of his day-
to-day work, he found time for microscopy and conducted original
research. His first triumph was his demonstration, in 1876, of the
complete life cycle and sporulation of the anthrax bacillus. This
historic piece of work was the first demonstration of a specific
microorganism as the cause of a definite disease. Koch's ingenious
contributions to the technique of bacteriology isolating, mount-
ing, staining, and photographing bacteria facilitated his own later

25

26 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

studies. In 1880 he was made a member of the Imperial Board of
,Health. This enabled him to give up his country practice and devote
his time to research. The results, which were almost immediate,
were of prime importance. In 1881 he introduced steam steriliza-
tion. On March 24, 1882, at a meeting of the Berlin Physiological
Society, he announced his discovery of the bacillus of tuberculosis.
From 1885 to 1891, he was professor of hygiene at the University
of Berlin, where much of his time was given up to teaching; in the
latter year he became the first director of the Institute for Infec-
tious Diseases, turning his full energies to research. In 1883, as
head of the German Cholera Commission, he visited Egypt and
India and discovered the cholera vibrio. Later travels in India, Java,
Africa, and Italy were occasioned by his studies of trypanosomiasis,
malaria, plague, and a variety of other diseases. He and his col-
laborators were able to show that bubonic plague is transmitted to
human beings by the rat-flea. He came back repeatedly to his labors
on tuberculosis. Koch died at the age of sixty-seven, on May 27,
1910. His body was cremated and the ashes placed in the Berlin
Institute for Infectious Diseases.

DESCRIPTION OF THE PRIZE-WINNING
WORK*

"{Jean Antoine] Villemin's discovery that tuberculosis is trans-
missible to animals [1865} has found varied confirmation, as is
well known, but also apparently well-founded opposition, so that,
up to a few years ago, it remained undecided whether or not tuber-
culosis is an infectious disease. [It was commonly blamed on nutri-
tional disturbances.} Since then, however . . . inoculations into
the anterior chamber of the eye ... and in addition, inhalation
experiments . . . have proven the transmissibility of tuberculosis
beyond a doubt. . . .

"Attempts have been made repeatedly to investigate the nature
of tuberculosis thoroughly, but up to now [1882] they have been

* From Berliner klinische Wochenschrijt, Vol. 19 (1882), pp, 221-230; reprinted
in Medical Classics (Baltimore: Williams & Wilkins, 1938), Vol. n, pp. 821-
852 (translation on pp. 853-880). The translation given here is modified slightly
from that of Dr. W. de Rouville in Medical Classics.

1905: ROBERT KOCH 27

fruitless. The staining methods so frequently used with success for
the demonstration of pathogenic microorganisms have left this
disease in the lurch, and the attempts made to isolate and cultivate
the virus of tuberculosis up to the present cannot be regarded as
successful. . . .

"In my investigations of tuberculosis, I at first followed the
known methods without obtaining any explanation as to the true
nature of the disease. However, several opportune observations
caused me to abandon these methods and to adopt others which
finally led me to positive results. . . .

"The material to be examined is prepared in the usual manner
for examining for pathogenic bacteria, and either spread on the
cover slip, dried, and heated or cut into sections after fixation in
alcohol. The cover slips or sections are placed in a staining solu-
tion of the following constitution: 200 ex. of distilled water are
mixed with i c.c. of a concentrated alcoholic solution of methylene
blue, shaken up, and then 0.2 c.c. of a 10 percent solution of potas-
sium hydroxide is added with repeated shaking. This mixture must
show no precipitate after standing for several days. The materials
to be stained remain in this solution for 20 to 24 hours. By heating
the solution to 40 C in a water bath this time can be shortened to
^ to i hour. Following this the cover slips are covered with a con-
centrated aqueous solution of vesuvin, which is filtered each time
before using, and after i to 2 minutes rinsed with distilled water.
When the cover slips come from the methylene blue, the attached
layer appears dark blue and is markedly overstained. During the
treatment with vesuvin this blue color is lost and it appears stained
a faint brown. Under the microscope all the constituents of animal
tissue, that is, the cell nuclei and their products of disintegration,
appear brown, while the tubercle bacilli, on the other hand, stain
a beautiful blue. Moreover, all other bacteria which I have investi-
gated to date, with the exception of the lepra bacilli [discovered
by Hansen in 1875], take on a brown color with this staining
method. The color contrast between the brown stained tissue and
the blue tubercle bacilli is so striking that the latter, which are
present often only in very small number, are nevertheless to be
found and identified with the greatest certainty. ..."

{Koch indicates the diseased tissue, both human and animal.

28 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

examined by him in his search for the bacilli. He studied not only
a large number of cases of spontaneous tuberculosis, but also many
animals infected by inoculation.}

"On the basis of my numerous observations I state it to be
proved that the bacteria designated by me as the tubercle bacilli are
present in all cases of tuberculous disease of man and animals, and
that they may be differentiated from all other microorganisms by
their characteristic properties. It does not necessarily follow from
this coincidence of the tuberculous disease and the bacilli that the
two phenomena have an original association. . . .

Tfn order to prove that tuberculosis is a parasitic disease caused
t>y the invasion of the bacilli . . . the bacilli had to be isolated
from the body and cultivated in pure culture . . . and, finally,
through transfer of the isolated bacilli to animals, the same clinical
picture of tuberculosis as is obtained by the injection of naturally
developed tuberculosis material had to be produced.

"The solution of the problem} depends on the use of a solid,
transparent culture medium which retains its firm consistency
at incubator temperature [a method previously introduced by
Koch}. . . .

"Serum of cattle or sheep blood ... is poured into cotton-
stoppered test tubes and daily, for six consecutive days, is heated
to a temperature of 58 C for an hour at a time. By this means
it is possible to sterilize the serum completely in most instances.
. . . Then it is heated to 65 C for several hours. . . .

"On this solidified blood serum, which forms a firm transparent
culture medium at incubator temperature, the tuberculous material
[excised from diseased organs with disinfected instruments} is
placed ... by means of a just previously flamed platinum wire
fused into a glass rod. Naturally the cotton plug is removed for
only the shortest possible time. . . .

"The test tubes . . . are placed in the incubator and must re-
main there constantly at a temperature from 37 to 38 C . . . The
cultures resulting from the growth of tubercle bacilli first appear
to the naked eye in the second week after inoculation, usually not
until after the tenth day, as very tiny points and dry scales. . . .
The markedly slow growth which is attained only at incubator
temperature, the peculiarly dry and scale-like condition of these

1905: ROBERT KOCH 29

bacillary colonies occur in no other known type of bacteria, so that
confusion of the cultures of tubercle bacilli with those of other
bacteria is impossible; and after only a small amount of practice
nothing is easier to detect at once than accidental contamination of
the cultures. ..."

{The pure cultures thus obtained were used by Koch in a series
of animal inoculations, described in detail. The nature of the ex-
periments and the results attained are indicated briefly in Koch's
summation.]

"If one looks back over these experiments, it is apparent that
a not inconsiderable number of experimental animals that had re-
ceived the cultures of bacilli in various ways, that is, by simple
inoculation into the subcutaneous tissue, through injection into the
abdominal cavity, or into the anterior chamber of the eye or directly
into the blood stream, had been rendered tuberculous without a
single exception; and, indeed, had developed not only a solitary
tubercle but an extraordinary number of tubercles proportionate
to the large number of infectious germs introduced. In other ani-
mals it was possible by the injection of a minimal number of bacilli
into the anterior chamber of the eye to produce a tuberculous
iritis. . ."

CONSEQUENCES IN THEORY
AND PRACTICE

Tuberculosis is a protean disease, which can affect a number of
organs and show a number of different results. Nevertheless some
clinicians, notably the great Laennec, inventor of the stethoscope,
had been able to draw upon clinical observations to combine all
tubercular processes into a single morbid unity. Later, however,
under the influence of Rudolf Virchow, this unity was destroyed
and a dualistic conception of tuberculosis grew up on the basis of
pathological findings. On March 24, 1882, Koch informed the
Berlin Physiological Society that he had discovered the tubercle
bacillus. Laennec's views were thus confirmed and the work of
Villemin and other experimenters verified; the dualistic doctrine
vanished. Koch could demonstrate tubercle bacilli not only in the
lungs but in other infected organs intestines, bones, kidneys,

30 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

lymph glands, and skin. A variety of diseases were thus shown to
be one and the same. Improvements in staining technique, intro-
duced by Ehrlich and Ziehl, speeded up the detection of the organ-
isms. Soon thousands of examinations were being made and the
classification of these tubercular diseases became clear and certain.
All were forms of tuberculosis. The clinical aspect of the disease,
once complicated, was greatly simplified. "Chronic pneumonia/'
"apex catarrh/' "apex pneumonia/' etc., disappeared from the
books.

In the tubercle bacillus doctors had a trustworthy diagnostic sign.
Found in sputum or urine, it left no doubt of the diagnosis. Fur-
thermore its presence or absence could be used to check on the
effectiveness of treatment and on the patient's progress.

Isolation of the exciting cause of tuberculosis made it possible
to study the nature and reactions of the responsible organism. All
new therapeutic agents must be tried on the bacillus itself, in vitro
(i.e., in a test tube) first, then in vivo (i.e., in the living body) . At
the present time a number of promising new agents are being in-
vestigated and there appears to be a strong likelihood that effective
chemotherapeutic remedies will in course of time be found.

In 1890 Koch announced that he had found a substance that
would check the growth of tubercle bacilli both in vitro and in vivo.
This was tuberculin, a glycerine extract of a pure culture of tubercle
bacilli; although it proved disappointing as a remedy, substances
not unlike it have since been found of real value in diagnosis. It is
also possible that the work on tuberculin, which attracted universal
attention, may have served as a step toward the discovery of the
antidiphtheria serum.

As shown in the quotation above, the tubercle bacillus is difficult
to stain and difficult to cultivate on artificial media. It was Koch's
great technical ingenuity that enabled him to devise a staining tech-
nique by which he could detect the bacillus and a culture technique
by which he could grow it. Also worthy of note are the steps by
which he proved it to be the causative factor in the disease. As a
pioneer in staining, in the use of solid culture media, in steriliza-
tion by steam, and in many lesser technical matters, Koch was the
principal founder of modern laboratory bacteriology in all its
means and methods. He also imposed upon the growing science

1905: ROBERT KOCH 31

certain rigid requirements, known as "Koch's postulates/* by
which to establish proof of a causative relationship between mi-
crobe and disease. Among his own discoveries of this kind, none
was more important, or more productive of good results, than his
discovery of the tubercle bacillus.

REFERENCES

HEYMANN, B. Robert Koch. Leipzig, 1932.
KIRCHNER, M. Robert Koch. Vienna, 1924.
LOBEL, J. Robert Koch: Gescbicbte ernes Glucklicben. Zurich, 1935.

1906

CAMILLO GOLGI

(1844-1926)

SANTIAGO RAMON Y CAJAL

(1852-1934)

ff ln recognition of their work on the structure of
the nervous system! 9

BIOGRAPHICAL SKETCH

GOLGI

CAMILLO GOLGI WAS BORN IN CORTENO, IN BRESCIA, ITALY, IN
1844, the son of a medical practitioner. He received his medical
training at the University of Padua, where he was graduated in
1865. During his postgraduate hospital course he was attracted to
the Psychiatric Clinic of Cesare Lombroso, and his first publica-
tions were in the field of psychiatry. It was at this time, however,
that Virchow's Cellular Pathology (1858) was exerting a great
influence on medical scientists. Golgi began to work in the Pavian
laboratory of Giulio Bizzozero, the histologist, where he conducted
his first studies on the lymphatics of the brain and on the nature
of the neuroglia. In 1872 circumstances forced him to take a post
in the small hospital for incurables at Abbiategrasso, but despite
disheartening conditions he carried on his researches and developed
his famous silver-impregnation method of staining nervous tissues

32

1906: GOLGI AND CAJAL 33

(1873) . He applied this method to the central nervous system, dis-
covering the "Golgi cells" and providing evidence for the neuron
theory. Meanwhile he had also done useful work in neuropathol-
ogy. In 1879 he was appointed professor of anatomy at the Uni-
versity of Siena, but left the following year to return to Pavia as
professor of histology and general pathology. He continued to
conduct important studies in neuroanatomy, but much of his later
work was in pathology. In a series of publications from 1886 to
1893 he established the cycle of development of the parasites of
quartan and tertian malaria. He received many honorary degrees as
well as other awards and was probably the best-known Italian
medical scientist of his time. He died in 1926.

RAMON Y CAJAL

SANTIAGO RAMON Y CAJAL WAS BORN MAY i, 1852, IN PETILLA,
an isolated village in the Spanish Pyrenees, where his father was
"surgeon of the second class." The elder Ramon later extended his
studies and in time became professor of anatomy at Zaragoza. The
son's unfortunate early schooling, under tyrannical teachers, failed
to reveal his gifts. It was followed by apprenticeship, first to a
barber, then to a shoemaker. His father then undertook to teach
him, particularly in osteology, which revealed the boy's talent as a
draftsman. Thereafter he studied medicine at Zaragoza and was
graduated in 1873. Then came compulsory service in the Spanish
army, chiefly in Cuba, until 1875; during this interval he suffered
severely from malaria and dysentery. After taking a medical de-
gree at Madrid, he became a demonstrator and then, in 1877, pro-
fessor of anatomy at Zaragoza; but he was soon forced to interrupt
his work because of pulmonary tuberculosis. He married in 1879
and in 1884 was called to the chair of anatomy at Valencia. For a
time he worked at bacteriology and serology, but turned to his
proper field, histology, and in 1887 was given a chair in that subject
at Barcelona. Learning of the Golgi silver stain from Luis Simarra,
a neuropsychiatrist of Madrid, Ramon y Cajal developed an im-
provement of his own which he began to use in the study of the
nervous system. This was the first of his several important innova-
tions in staining technique. In 1889 he demonstrated his work

34 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

before the German Society of Anatomists, was praised by Kolliker,
and was soon acclaimed by German histologists generally. In 1892
he was appointed professor of normal histology and pathologic
anatomy at Madrid. International honors now accumulated. There
followed many years of intensive labor. By 1923 he had already
published 237 scientific papers. He also wrote a large number of
books, including not only comprehensive works on the nervous sys-
tem but popular essays, a treatise on color photography, etc. He
died on October 18, 1934, at the age of eighty-two.

DESCRIPTIONS OF THE PRIZE- WINNING

WORK

GOLGI *

"I have found two quite different kinds of nerve-endings in the
tendons:

"(a) The one is represented by peculiar bodies which are quite
characteristic in appearance, form, structure, and type of connection
with the nerve fibrils, and are unlike any other in the known
nervous end-apparatus of our organism; it is very probable, then,
that their significance lies in correspondence with the function
which muscles and tendons have to perform in common. Since
they are at times associated with muscles, at times with tendons,
one must, I think, confer on them the name of nervous musculo-
tendinous end-organs.

"(&) The other type is represented by bodies which likewise
have a peculiar and striking appearance, but which, on the whole
. . . find their counterparts in other known nervous end-organs
of our bodies, which they resemble not only in anatomical struc-
ture but probably in function also. I want to remark at once that
I here refer to the so-called end-bulbs of the conjunctiva, the
glands, etc.

* Translated from Camillo Golgi, "Uber die Nerven der Sehnen des Menschen
und anderer Wirbelthiere und liber ein neues nervoses musculo-tendinoses Endor-
gan," Untersttchungen uber den feineren Bau des centralen und penphenschen
Ffervensy stems . . . iibersetzt von Dr. R. Teuscher (Jena: G. Fischer, 1894),
pp. 207-209.

1906: GOLGI AND CAJAL 35

"Just as these two kinds of end-organs are distinguished one
from another by form, structure and nerve-fibril connections, so,
too, do they differ from one another in their location. The first are
always found in deep layers of the tendon origins, at the transition
point where muscle becomes tendon; always, too, in relation to
the muscular fasciculi. The second, on the contrary, lie as a rule in
the superficial layers of the tendons or in the tendinous extensions.

". . . [The} principal anatomical characteristics [of the mus-
culo-tendinous organs] may be summed up briefly as follows:

"In general they are spindle-shaped, and one of their ends is
always connected with the fasciculi of the muscle fibers, with the
sarcolemma [or sheath} of which their stroma [framework} ap-
pears to be in direct union; the other end, occasionally single but
usually double, follows the course of the tendon fasciculi and
gradually blends with them over a considerable distance.

"Their size varies within fairly wide limits, from 70-80 \i In
breadth \ji is short for micron, the millionth of a meter or thou-
sandth of a millimeter} and 300-400 \JL in length to 100-120 p in
breadth and over 800 /z in length; the latter, especially if stained
with gold, can easily be distinguished and isolated with the help of
a simple lens.

"Their outline tends to be very distinct and even appears at times
in the form of a slender, glittering border, along which one catches
sight of nuclei. . . .

"As far as the structure is concerned, if one disregards the medul-
lated nerve fibers, which penetrate from without in varying num-
ber, one must believe them to consist simply of fibrillary connective
tissue with nuclei scattered through it. ...

"The nature of the connection of the little bodies described here
with the nerve fibrils is characteristic.

"For the most part there is only one fibril allotted to each of
these little bodies, but fairly often two, three, and even four
medullated fibrils enter a single one. Entry can take place either at
one end, regularly at that which blends with the tendon fasciculi,
or also at the side, and indeed precisely at the thickest part of the
spindle.

"However large the number of fibrils entering, they proceed to
separate, in that they advance to the middle of the body and eacb

36 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

fibril of the second or third order, while retaining the character
of a medullated fibril, diverges from the others and turns toward
the periphery. . . . All this can be perceived with the simplest
means of observation. . . . The further, ultimate conduct of the
separate fibrils can only be made clear by the gold reaction. With
this method one can now make the following observations.

"After the medullated fibrils have changed to nonmedullated,
these bifurcating branches diverge helter-skelter and pursue their
further course to the periphery of the body. Having reached it,
they form at short intervals, by means of still finer and more
frequent divisions, numerous circumscribed, longish, reticular
plexuses, which lie parallel with the surface. . . ."

RAMON Y CAJAL *

"From the sum of my researches springs a general concept which
comprehends the following propositions:

"The nerve cells are morphologic units, the neurons, to use the
word sanctioned by the authority of Professor Waldeyer. This had
already been demonstrated, as regards the dendritic or protoplasmic
extensions of the nerve cells, by my illustrious colleague Professor
Golgi; but when our researches began there were only conjectures
more or less tenable regarding the way in which the ultimate divi-
sions of the axons and nerve collaterals are arranged. Our observa-
tions, with Golgi's method, which we applied first in the cerebel-
lum, then in the spinal marrow, the brain, the olfactory bulb, the
optic lobe, the retina, etc. of embryos and young animals, revealed,
in my opinion, the terminal disposition of the nerve fibers. These,
in their ramifications to several junctures, incline constantly toward
the neuronal body and toward the protoplasmic expansions, around
which arise plexuses, or nerve nests, very close-woven and very
rich. The . . . morphologic dispositions, which vary in form ac-
cording to the nerve centers one studies, attest that the nerve ele-
ments have reciprocal relations of contiguity and not of continuity,
and that communications, more or less intimate, are always estab-
lished not only between the nervous arborizations but between the

* Translated from Santiago Ramon y Cajal, "Structure et Connexions des Neu-
rones," Les Prix Nobel en 1906.

1906: GOLGI AND CAJAL 37

ramifications of one part and the body and protoplasmic extensions
of another part. . . .

'These facts, recognized in all the nerve centers with the aid of
two very different methods (Golgi's and Ehrlich's) . . . involve
three physiological postulates:

"(i) Since nature, in order to assure and amplify contacts, has
created complicated systems of ramifications around the cells (sys-
tems which would become incomprehensible by the hypothesis of
continuity), it is necessary to admit that the nervous currents are
transmitted from one element to another by virtue of a sort of in-
duction, or influence at a distance.

"(2) It is also necessary to suppose that the cellular bodies and
the dendritic prolongations, like the axis cylinders, are induction
apparatus, since they represent intermediate links between the
afferent nerve fibers and the axons mentioned. This is what Bethe,
Simarro, Donaggio, we ourselves, etc., have confirmed quite re-
cently, in demonstrating, with the aid of neurofibrillary methods, a
perfect structural concordance between the dendrites and the axis-
cylinder prolongation.

"(3) Examination of the transmission of nerve impulses in the
sense organs, such as the retina, the olfactory bulb, the sensory
ganglions and the spinal marrow, etc., show not only that the pro-
toplasmic expansions play a conducting role but also that the move-
ment of the nerve impulse in these prolongations is toward the cell
body, whereas in the axons it is away from the cell body. This prin-
ciple, called the dynamic polarization of neurons, formulated a long
time ago by van Gehuchten and us as an induction drawn from
numerous morphological facts, is not contrary to the new researches
on the constitution of nerve protoplasm. In fact we shall see that
the framework of neurofibrils makes up a continuous reticulum
from the dendrites and the cell body to the axon and its peripheral
termination."

CONSEQUENCES IN THEORY
AND PRACTICE

The investigations of Golgi and Ramon y Cajal were to a large
extent complementary, although on many points they disagreed.

38 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

(Golgi's Nobel lecture was largely a series of qualifications of the
neuron theory as set forth above by his Spanish colleague.) Ramon
y Cajal began his work on the nervous system using the Golgi stain.
Between the two men, they worked out the finer details of the
structure of nervous tissue in a thorough and comprehensive man-
ner.

In 1873, using his new method, Golgi gave his description of
the two main types of nerve cells, since known as Golgi cells type
I and type II, the long and short axon nerve cells respectively. In
1874 he described the large nerve cells of the granular layer of the
cerebellum, which are also known by his name. He likewise de-
scribed the structure of the olfactory bulb. His name is attached to
the internal reticular apparatus of cells, the nature and function of
which have not been fully determined even yet. In addition to this
he discovered the muscle spindles which are described in the quota-
tion above. This passage has been selected as a characteristic and
important piece of work, and also because knowledge of the recep-
tor organs in muscle was the starting point for a valuable contribu-
tion to neurophysiology made by Sir Charles Sherrington (see
below, pp. 156 ff; 162).

The discoveries in normal histology mentioned here are only
the best known among a large number. Golgi also contributed to
the knowledge of nerve pathology. He was able to show, for ex-
ample, that the disease called chorea is not due to a mere functional
disturbance but is associated with definite lesions in the nervous
system. It was Golgi, too, who pointed out the microscopic char-
acteristics which distinguish sarcomas from gliomas, two kinds of
brain tumor which previously were often confused; this was of
practical importance, for gliomas, although "malignant" from
their location, do not metastasize (i.e., establish cellular colonies
in other parts) , as do the more dangerous sarcomas. Here again, it
is possible only to single out one or two among Golgi' s major con-
tributions to neuropathology. His work on the structure of the
kidney and other organs and his important studies of malaria
parasites fall outside the limits of the Nobel citation.

The quotation from Ramon y Cajal has been selected as the
latter's attempt at a general summation of an important part of his
work. The neuron theory, here presented in a condensed form, was

1906: GOLGI AND CAJAL 39

firmly established by his researches. Its importance to subsequent
investigators can hardly be assessed in a few words. It underlies the
exceedingly important work of Sir Charles Sherrington. It guided
the thought of Egas Moniz, who introduced prefrontal leucotomy
(see below, pp. 264-270) . It is one of the basic theories of modern
biological science.

Ramon y CajaFs contributions are also too numerous and too
complex for summary treatment. As he himself said, "Unfortu-
nately it is absolutely impossible to condense in a few pages
morphological facts the description of which occupies a large num-
ber of brochures with hundreds of drawings." It may be men-
tioned, however, that another Nobel laureate, Robert Barany (see
below, pp. 84-88), in attempting to connect the function of the
labyrinth apparatus of the ear with cerebellar function, was initially
dependent on the Spanish histologist's account of the nerve con-
nections involved. It is safe to say that there is no neurologist or
neuroanatomist of recent times who does not owe him a similar
debt.

"Even more lasting than his wealth of recorded observations will
be the improved methods of Cajal and his disciples. First, in 1888,
he increased the applicability of the Golgi stain. In 1903 he de-
veloped his own reduced silver nitrate stain. . . . In 1913 he in-
troduced the gold sublimate stain. . . . His eminent pupils Achu-
carro and Hortega [introduced] the silver carbonate stains. . . .

"These methods in the hands of Cajal and his students have
clarified much of the embryology of each cellular element in the
nervous system. Furthermore, the finer details of gliomas revealed
by these stains, with the accumulating light from embryology, have
given the neurosurgeon useful correlations of structure and biologic
characteristics of brain tumors." *

* Wilbur Sprong, "Santiago Ramon y Cajal: 1852-1934," Archives of Neurology
and Psychiatry, Vol. 33 (i935) PP* 156-162.

40 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

REFERENCES

GOLGI

CHOROBSKI, JERZY. "Camillo Golgi: 1843-1926," Archives of Neu-
rology and Psychiatry, Vol. 33 (1935), pp. 163-170.

DA FANO, C. "Camillo Golgi," Journal of Pathology and Bacteriology,
Vol. 29 (1926), pp. 500-514.

RAMON Y CAJAL

CANNON, DOROTHY F. Explorer of the Human Brain: The Life of

Santiago Ramon y Cajal (1852-1934) (New York: Schuman, 1949).
RAMON Y CAJAL, SANTIAGO. Recollections of My Life, translated by E.

Home Craigie and Juan Cano (Philadelphia: American Philosophical

Society, 1937), 2 vols.
SPRONG, WILBUR. "Santiago Ramon y Cajal: 1852-1934," Archives of

Neurology and Psychiatry f Vol. 33 (1935), pp. 156-162.

1907

CHARLES LOUIS ALPHONSE
LAVERAN

(1845-1922)

"In recognition of Ms work regarding the role
played by protozoa in causing diseases"

BIOGRAPHICAL SKETCH

ALPHONSE LAVERAN WAS BORN IN PARIS ON JUNE 18, 1845. His
father, a military surgeon, was a professor at the school of Val-de-
Grace. Having completed his preliminary education in Paris,
Laveran matriculated as a medical student at Strasbourg, where he
was graduated in 1867 with a thesis on regeneration of nerves. In
1874 he, too, joined the staff of the Val-de-Grace School of Mili-
tary Medicine. In 1878 he was sent to Algeria, where he remained,
in the service of the French army, until 1883. During this period,
while at Bone and at Constantine, he carried out his studies of
malaria, which led to the discovery of the causative organism, the
malarial parasite. In 1884 he was appointed professor of military
hygiene and clinical medicine at Val-de-Grace, where he remained
for ten years. For a short time he was engaged in administrative
medical and sanitary work at Lille and at Nantes, but with a view to
resuming his scientific studies he retired from his administrative
position in 1897. He then entered the Pasteur Institute. Here he
soon became a professor, and devoted the rest of his life to a con-
tinuation of his work in tropical medicine and parasitology. The

41

42 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

recipient of many scientific honors, he was one of the founders, and
first president, of the Societe de Pathologic Exotique. His work was
terminated only by his death, which took place in Paris on May
18, 1922.

DESCRIPTION OF THE PRIZE- W INN ING
WORK*

"On arriving at Bona in 1878 I had the opportunity of making
autopsies on subjects who had died from pernicious attacks, and
I was struck with the fact that melanaemia [the presence of a black
pigment in the blood, causing a brown coloration of certain organs}
was a lesion peculiar to and very characteristic of paludism [i.e.,
malaria, or marsh fever, from the Latin palus, marsh}; my atten-
tion was naturally directed to this lesion, which I had never met in
any other disease. [Although often described in connection with
malaria before this time, the color change here mentioned had not
generally been considered either as constant, or as peculiar to the
disease.}

"Melanaemia is specially very pronounced in individuals who
died from acute paludism (pernicious attacks); the colour which
it gives to certain organs, particularly to the spleen, the liver, and
the grey substance of the brain, is almost always sufficient to
show from microscopic examination if death is the result of
paludism. . . .

"Some observers have been able to maintain that occasionally no
single characteristic alteration was found in individuals who had
died of pernicious fever,

"This assertion does not stand a strict examination, and could
only be put forward at a time when the importance of melanaemia
was not known. It might be affirmed on the contrary, that in these
cases there always remain lesions specially pronounced in the spleen
and liver. The spleen increases in volume and weight, but the in-
crease is not always considerable. . . . The shape of the organ is
modified, the edges are rounded; the spleen tends to take a globular
form, which is explained by the softening, the pulpiness of the

* From Alphonse Laveran, Paludism, translated by J. "W. Martin (London: New
Sydenham Society, 1893), pp. 5-9.

1907* CHARLES LOUIS ALPHONSE LAVERAN 43

splenic parenchyma [the specific substance of the spleen, supported
and held together by fibrous elements}. It often happens that the
mere act of grasping the spleen to pull it out from the abdomen
causes rupture of the distended and thin capsule; the fingers sink
into splenic pulp.

"The colour is characteristic; instead of the normal red colour the
spleen shows in the inner parts, as well as on the surface, a brown-
ish tint which has been compared to chocolate and water.

"If you examine a drop of splenic fluid with the microscope you
will find in the midst of the blood, and the elements proper to the
spleen which are separated, the existence of pigmented elements in
great numbers, and free granules of pigment; the pigmented ele-
ments are either leucocytes [white blood cells] loaded with pig-
ment [i.e., "melaniferous," the term used hereafter}, or hyaline
bodies of irregular shape: one finds in those preparations of the
spleen pigmented granules much more numerous than in blood
taken from the vessels of other organs. . . .

"[Similar changes are then described as they are seen in liver,
kidney, and brain tissue.] The other tissues have a normal tint,
but by histological sections it is easy to see that the capillary vessels
contain pigmented elements more or less numerous, and that
melanaemia is really, as the etymology implies, a general alteration
of the blood, which is only more pronounced in the spleen, in the
medulla of bones, and the liver than in the other viscera, which
is naturally all the more apparent as the tissues are more vascular.

"When one examines a drop of blood taken from the dead body
of a palustral subject in the ordinary conditions of autopsy that
is to say, twenty-four hours after death one sees in the midst of
the blood numerous pigmented bodies. Many of these elements are
melaniferous leucocytes, the nuclei of which can be coloured and
stained with carmine; but besides these leucocytes, hyaline pig-
mented irregular bodies are seen, which can only be coloured
slightly, or not at all, by carmine, and which do not contain any
nuclei. These latter elements have great analogy in their dimen-
sions, and often in their shape, with melaniferous leucocytes, and
it can easily be understood that they may have been confused with
them. If the blood is taken shortly after death the parasitic elements
characteristic of paludism can be recognised.

44 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"In 1880, as I was trying to account for the mode of formation
of the pigment in the palustral blood, I was led to see that besides
melaniferous leucocytes, spherical hyaline corpuscles without
nucleus could be seen, and also very characteristic crescent-shaped
bodies.

"I had proceeded thus far with my researches, and was still
hesitating whether these elements were parasites, when on No-
vember 6th, 1880, on examining the pigmented spherical bodies
mentioned above, I observed, on the edge of several of these
elements, moveable filaments or flagella [literally, "whips"}, whose
extremely rapid and varied movements left no doubt as to their
nature.

"I published in 1881 the observation of the patient in whose
blood I saw the flagella for the first time. . . .

"The very fact that I can quote the day on which I observed the
flagella for the first time shows how characteristic these elements
are. It was natural to suppose that these parasitic elements, for the
most part pigmented, were the cause of palustral melanaemia, and
also the cause of the phenomena of paludism. Numerous facts soon
came to confirm this hypothesis/'

CONSEQUENCES IN THEORY
AND PRACTICE

The citation for the Nobel Prize in 1907 refers to the sum of
Laveran's work "regarding the role played by protozoa in caus-
ing diseases." (The protozoa include all the unicellular animal
organisms. Literally the word means "first animals/') Since the
terms which govern the award require that it be given for recent
work, or for work recently seen to be of importance, it is probable
that this phrasing was chosen to comply with the rule by including
Laveran's later studies; nevertheless it was in fact the reward for
his quarter-century-old discovery of the malarial parasite. It is, of
course, quite true that this discovery, the first of the kind, stimu-
lated interest in protozoal disease agents, and that although Laveran
himself made no other such epochal discoveries he did open the
field to other workers and he also made solid contributions of his
own toward extending our knowledge of similar organisms. Dur-

1907: CHARLES LOUIS ALPHONSE LAVERAN 45

Ing his years at the Pasteur Institute he collaborated with Profes-
sor Mesnil, and together they published an important work on
trypanosomes and trypanosomiasis. (G. H. Evans and D. Bruce
were chiefly responsible for showing that trypanosomes cause
sleeping sickness.) Laveran likewise published the first treatise on
leishmaniasis (leishmania are protozoans which cause kala-azar,
oriental boil, etc. ) and investigated many of the flagellate parasites
of man and animals.

Laveran's discovery of the malarial parasite did not receive im-
mediate recognition from all authorities, but his findings were soon
confirmed and extended by others, and his own pathological,
clinical, geographical, and therapeutic studies all tended to estab-
lish the role of the organisms he had discovered, which later came
to be known as plasmodia. Their presence in the blood of malaria
patients, their disappearance after treatment with quinine, their
absence in healthy persons, and their association with the character-
istic malaria pigment made it highly probable that they were in-
deed the long-sought causative organisms of malaria. This could
not be readily demonstrated, as in bacterial diseases, according to
"Koch's postulates" (see above, p. 28), because in contrast with
bacteria the plasmodia could not be cultivated outside the living
body. But further evidence, strongly supporting Laveran's view,
was provided by another Nobel laureate, Camillo Golgi (see above,
PP- 33> 3 8 )> wno showed that some plasmodia require forty-
eight hours to develop to the stage when the red blood cells are
broken down and the parasites are released, that others need
seventy-two hours, and that these periods correspond exactly to the
af ebrile intervals of tertian and quartan fever. The different types
of plasmodia and the stages in the plasmodial life cycle were
worked out by Italian, American, and English scientists. These
workers, including the early Nobel laureate Sir Ronald Ross, built
upon the foundations laid by Laveran. The practical significance of
knowing what the causative organism is (Laveran) and how it
spreads (Ross) has been briefly discussed in an earlier section (see
above, pp. 13-14).

1908

ELIE METCHNIKOFF

(1845-1916)

ff ln recognition of his work on immunity"

(The award for 1908 a/as shared with Paul Ehrtich, see
below, pp. 51-55.)

BIOGRAPHICAL SKETCH

ILIA ILICH MECHNIKOV, BETTER KNOWN AS ELIE METCHNIKOFF,
son of an officer of the Imperial Guard, was born in the province
of Kharkov, Little Russia, on May 16, 1845. Privately tutored at
first, he later entered the lycee at Kharkov, where his scientific in-
terests, already formed, were stimulated in the direction of physi-
ology and zoology. He found little to satisfy such interests at the
University of Kharkov, but after graduation did independent and
original work in Helgoland and at Giessen. He was then given a
scholarship by the Russian Ministry of Public Instruction, which
enabled him to travel and study abroad. He worked for a time at
Naples, in association with the young Kovalevsky, then at Got-
tingen, where he spent a short interlude with Kef erstein and Henle.
At Munich his preceptor was von Siebold. In 1867 he returned to
Russia to become docent at the new University of Odessa. He soon
shifted to St. Petersburg as professor of zoology, but worked at
intervals in Messina and elsewhere. In 1886 he became director of
the Bacteriological Institute in Odessa, but left in 1887 and went
to Paris, where he resided till the end of his life. He carried on his
work at the Pasteur Institute, of which he became subdirector. His

46

1908: METCHNIKOFF AND EHRLICH 47

first paper on phagocytosis was read at a congress in Odessa in
1883; the initial observations and experiments had been made at
Messina earlier in the same year.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"Occupied with the origin of the digestive organs in the animal
world, we were struck by the fact that certain elements of the
organism which do not take any part in the digestion of food are
nevertheless capable of engrossing foreign bodies. To us it ap-
peared that the reason for this was that these elements formerly
participated in the digestive function. . . .

"Certain lower animals, transparent enough to be observed in
the living state, show clearly in their interior a host of little cells
provided with mobile extensions. The least lesion of these animals
brings an accumulation of these elements right to the spot which
has been injured. In the little transparent larvae, one can easily
ascertain that the mobile cellules, gathered at the point of injury,
often contain the debris of foreign bodies.

"Similar facts, on the one hand tending to confirm our supposi-
tion of the origin of the migratory elements, on the other hand
suggested the idea that their accumulation in the neighborhood of
lesions constitutes a sort of natural defense of the organism. It was
necessary to find some method of verifying this hypothesis. Finding
myself at this time more than twenty-five years ago at Messina,
I turned my attention to the floating larvae of starfish. . . . Large
enough to undergo some operations, they are, however, sufficiently
transparent and can be observed under the microscope in the living
state.

"Having introduced pointed splinters into the bodies of these
[larvae}, I was able next day to see a mass of mobile cellules en-
closing the foreign body, forming a thick layer. The analogy of this
phenomenon with that which takes place when a man pricks him-
self with a splinter, bringing on inflammation accompanied by
suppuration, is astonishing. Only in the starfish larva, the accumu-

*Elie Metchnikoflf, "Sur 1'etat actual de la question de rimmunite dans les
maladies infectieuses," Les Prix Nobel en

48 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

lation of mobile cellules around the foreign body takes place with-
out the least concurrence of blood vessels or nervous system, for
the simple reason that these animals possess neither the one nor
the other. So it is thanks to a sort of spontaneous action that the
cellules are gathered round the splinter.

"The experiment which I have just presented to you shows the
first step, so to speak, of an inflammation in the animal world.
But ... in men and the higher animals, this phenomenon is
almost always the result of the intervention of some pathogenic
microbe. . . .

"It was therefore necessary ... to find some higher animal
sufficiently small and transparent to be observed alive by the
microscope and ... to subject to some microbe disease.

"After several attempts in this direction, it became possible to
study the progress of an infection among the fresh-water animals
commonly known as "water fleas/' These little crustaceans are very
widespread in all sorts of stagnant waters and are subject to sev-
eral diseases. One of these is occasioned by a little microbe which
has the peculiarity of producing spores in the form of needles.
Swallowed by the water flea . . . these spores easily wound the
intestinal wall and penetrate into the body cavity. But once they
have stolen into the organism, the spores provoke around them an
accumulation of mobile cellules which correspond to human white
blood corpuscles. A struggle occurs between the two kinds of ele-
ments. Sometimes the spore succeeds in germinating. A generation
of microbes is then produced which secrete a substance capable of
dissolving the mobile cellules; but these instances are rather rare.
Much more frequent, on the contrary, are the cases in which the
mobile cellules kill and digest the infectious spores, thus assuring
the immunity of the organism. . . .

"Having established the basis of the theory of immunity, it was
necessary to apply it to higher organisms and to man himself. The
conditions here being incomparably more complicated than among
the little transparent animals, all sorts of difficulties sprang up on
every side. Because of the impossibility of submitting even the
smallest vertebrate animal, such as a newborn mouse, to direct
microscopic examination, it was necessary to proceed by a more
complicated route, combining the results of researches on the blood

1908: METCHNIKOFF AND EHRLICH 49

and on organs removed from the organism, and linking them by
thought. Now under these circumstances the door is wide open to
all sorts of errors.

'The study of several infectious diseases of man and the higher
animals has shown from the first that the facts observed accord well
with the theory based on the research on transparent lower animals.
In all cases where the organism enjoys an immunity, the introduc-
tion of infectious microbes is followed by an accumulation of
mobile cellules, white blood corpuscles in particular, which incor-
porate the microbes and destroy them. The white corpuscles and
the other cellules capable of bringing about this result have been
designated 'phagocytes' that is to say, voracious cellules [i.e.,
eating cells] and the sum of the function which assures immunity
'phagocytosis/ "

CONSEQUENCES IN THEORY
AND PRACTICE

MetchnikofTs theory that bacteria are destroyed by "eating cells/'
or phagocytes, at first met with strong opposition. The view was
then current that resistance to bacterial infection depends upon
chemical properties of the blood, and indeed antibodies had already
been demonstrated in blood serum. A long controversy ensued, in
which, as it now appears, both sides were partly right. In 1903 two
British scientists, Almroth Wright and Stewart Douglas, found that
the serum of immunized animals contains substances which appear
to prepare bacteria for ingestion by the white blood cells; these
substances were named "opsonins," from the Greek verb meaning
"to prepare food/' The opinion then grew up that phagocytosis can
take place only when the microbes have first been "buttered/* as it
were, with specific antibodies. The phagocytes were thus restricted
to a secondary role.

In the last ten years, however, the Metchnikoff theory has been
partly rehabilitated, and the functions of antibodies and phagocytes
have been distinguished more clearly. Most bacteria that cause acute
infections injure the human body only when they are outside of
cells; the bacteria that cause chronic infections, on the other hand,
do damage within the cells. The former are readily engulfed and

50 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

digested, except when they have outer capsules which protect them
from phagocytes; the latter, although readily ingested by phago-
cytes, can go on living inside. Phagocytosis as a defense mechanism
is therefore of much greater importance in acute than in chronic
diseases. When the bacteria of the acute diseases are well protected
by a capsule, this armor may be broken down by the appropriate
antibody. But patients treated with "sulfa" drugs and other anti-
biotics often recover several days before antibodies can be detected
in the blood. The drug slows the multiplication of the bacteria, and
phagocytes may then destroy them without the aid of antibodies,
provided there is a suitable surface upon which to operate. In lung
tissue, for example, the white cells pin the bacteria against the
walls of the alveoli (air sacs) and then ingest them. The strands
of fibrin, which are a common feature of the inflammatory reaction,
also provide suitable surfaces for promoting phagocytosis; or the
bacteria may sometimes be trapped against the walls of small blood
vessels. The proportion of fluid to phagocytic cells during infection
limits the efficacy of this process, for phagocytes diluted in fluid
are unable to engulf fully encapsulated bacteria. In the peritoneal
cavity of the abdomen, and in other "open" sites, phagocytosis is
relatively inefficient, since the white cells do not have sufficient
contact with one another and with tissue surfaces.

In the intracellular infections, caused by viruses, some bacteria,
and certain protozoa, phagocytosis is not of primary importance,
because the parasites can survive and even multiply inside the white
cells. But in a great many acute infections, caused by extracellular
parasites, the invaders may be slowed down by drugs and destroyed
by phagocytes before the relatively slow process of the manufacture
of antibodies has taken place. Phagocytosis is thus the first line of
defense in acute infections.

This summarizes the current view of the importance of Metchni-
koff 's phagocytes and of the way in which they operate. The activi-
ties of the white cells continue to be investigated, however, for
there is much which yet remains mysterious about the body's reac-
tion to invading microorganisms.

1908: METCHNIKOFF AND EHRLICH 51

REFERENCES

METCHNIKOFF, OLGA. The Life of Elie Metchnikof, 1845-1916 (Lon-
don: Constable; Boston and New York: Houghton Mifflin, 1921).

PETRIE, G. F. "The Scientific Work of Elie Metchnikoff," Nature
(London), Vol. 149 (1942), p. 149.

WOOD, W. BARRY, JR. "White Blood Cells v. Bacteria," Scientific
American, Vol. 184 (Feb. 1951), pp. 48-52.

PAUL EHRLICH

(1854-1915)

"In recognition of his work on immunity."

(The award for 1908 was shared with Elie Metchnikof; set
above, pp. 46-51.)

BIOGRAPHICAL SKETCH

PAUL EHRLICH WAS BORN AT STREHLEN, A SMALL TOWN IN
Silesia, in 1854. He received his early education in his native
town and at the Gymnasium at Breslau. He also spent his first
university semester at Breslau, studying scientific subjects, and then
proceeded to Strasbourg, where he took up the study of medicine.
While still an undergraduate he attracted the attention of Waldeyer
by his application of aniline dyes in histology. After graduation he
worked for a year in the Pathological Institute under Cohnheim
and Heidenhain. In 1877 he was appointed chief assistant in
Frerichs's clinic in Berlin. In 1886 he found that he had contracted
tuberculosis, apparently as a result of accidental infection in the
course of his researches, and was forced to give up his work for

52 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

a year and a half, which he spent in traveling abroad. Returning
to Berlin, he worked for a time in a small private laboratory, then
obtained a post in the Institute for Infectious Diseases, which he
held for several years. When the new Serum Institute at Steglitz
was opened, in 1896, Ehrlich was appointed director. From 1899
until his death in 1915 he was director of the Royal Institute for
Experimental Therapy in Frankfurt am Main. He was raised to the
dignity of Privy Councilor with the title "Excellent" in 1911. It is
convenient to divide Ehrlich's work, as W. Bulloch does, into
three parts: (i) the application of stains to the differentiation of
cells and tissues for the purpose of revealing their function (1877-
1890); (2) immunity studies (1890-1900); (3) chemothera-
peutic discoveries (1907-1915). He was the founder of modern
hematology, one of the chief early contributors to immunology,
and, by virtue of the discovery of "606," the founder of chemo-
therapy.

DESCRIPTION OF THE PRIZE -WINNING
WORK*

"At the very beginning of my theoretical work on immunity I
made it my first task to introduce measures and figures into investi-
gations regarding the relations existing between toxine and anti-
toxine. From the outset it was clear that the difficulties to be
overcome were extremely great. The toxines, i.e., the poisonous
products of bacteria, are unknown in a pure condition. So great is
their potency, that we are obliged to assume that the strongest solid
poisons which are obtained by precipitating toxic bouillon with
ammonium sulphate, represent nothing more than indifferent
materials, peptones and the like, to which the specific toxine at-
taches itself in mere traces beyond the reach of weighing. . . .

"Their presence is only betrayed by the proof of their specific
toxicity on the organism. For the exact determination, e.g., of the
amount of toxine contained in a culture fluid, the essential condi-
tion was that the research animals used should exhibit the requisite
uniformity in their susceptibility to the poison. Uniformity is not

* From Paul Ehrlich, "On Immunity with Special Reference to Cell Life," Pro-
ceedings of the Royal Society of London, Vol. 66 (1900), pp. 424-448.

1908: METCHNIKOFF AND EHRLICH 53

to be observed in the reaction of the animal body to all toxines.
Fortunately in the case of one important body of this nature, viz.,
the diphtheria toxine, the conditions are such that the guinea-pig
affords for investigations the degree of accuracy necessary in purely
chemical work. For other toxines this accuracy in measuring the
toxicity cannot be attained. It was necessary for me to try to
eliminate, as far as possible, the varying factor of the animal body,
and bring the investigations more nearly into line with the condi-
tions necessary for experiments of a chemical nature. . . . The
relations were simplest in the case of red blood corpuscles. On
them, outside the body, the action of many blood poisons, and of
their antitoxines, can be most accurately studied, e.g., the actions
of ricin, eel-serum, snake-poison, tetanus toxine, etc. In an experi-
ment of this kind, in which are employed a series of test-tubes con-
taining definite quantities of suspended blood corpuscles, each
test-tube represents as it were a research animal, uniform in any
one series, and one that can be reproduced at will. By means of
these test-tube experiments, particularly in the case of ricin, I was
able, in the first place, to determine that they yielded an exact
quantitative representation of the course of the processes in the
living body. The demonstration of this fact formed the basis of a
more extended application of experiments of this nature. It was
shown that the action of toxine and antitoxine took place quantita-
tively as in the animal body. Further, these experiments yielded a
striking series of facts of importance for the theoretical valuation
of the reaction between toxine and antitoxine. It was proved in the
case of certain toxines notably tetanus toxine that the action of
antitoxines is accentuated or diminished under the influence of the
same factors which bring about similar modifications in chemical
processes warmth accelerates, cold retards the reaction, and this
proceeds more rapidly in concentrated than in dilute solutions.
. . . Yet again insurmountable obstacles seemed to present them-
selves. . . .

"When, in the case of diphtheria toxines of different stocks, that
quantity of toxine bouillon which is exactly neutralized by a certain
definite quantity of diphtheria antitoxine (the official German im-
munity unit . . . ) was determined, so that every trace of toxic
action was abolished, the figures obtained were not in accord. Of

54 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

one toxine bouillon 0.2 c.c., of another 2.5 c.c,, were so neutralised
by one immunity unit. Such a relation need not have given rise to
surprise, because it was well known that the diphtheria bacillus,
according to outside circumstances, yields in the bouillon very
different quantities of toxine. It was therefore allowable to infer
that the different quantities of toxine bouillon, which were satu-
rated by one immunity unit, were exact expressions of the toxicities
of the various bouillons, or, to use other words, indifferently
whether the bouillon was strongly or feebly toxic, the same multi-
ple of the minimal lethal dose would be constantly neutralised by
one immunity unit, so that in every case the law of equivalent pro-
portions would hold good.

"But when looked into more closely, the relations showed them-
selves to be by no means so simple. In what manner could one
obtain a satisfactory estimation of the strength of a toxine? As the
constant factor in such an estimation, it was only possible to pro-
ceed from a previously determined standard reaction in the case of
a definite species of animal, and so we came to regard as the 'toxic
unit' that quantity of toxic bouillon which exactly sufficed to kill,
in the course of four days, a guinea-pig of 250 grammes weight.

"When we employed this standard unit, or 'simple lethal dose/
to estimate the amount of toxic bouillon neutralised by one Im-
munity unit/ the facts which presented themselves were far more
surprising than it was possible to have foreseen at the outset. These
results were, that of one toxine, perhaps 20, of a second, perhaps
50, and of yet a third, it might be 130 simple lethal doses were
saturated by one immunity unit. Since, however, we had previously
assumed that the simple lethal dose alone afforded a standard on
which reliance could be placed in determining the combining rela-
tions of toxine and antitoxine, it appeared from these results that
the neutralisation of toxines by antitoxines did not follow the law
of equivalent proportions, and, notwithstanding all earlier work in
agreement with such a conception of the action, we were obliged to
conclude that between toxine and antitoxine a purely chemical
affinity did not exist. The seemingly inexplicable contradiction be-
tween the results just stated and previous work was very soon ex-
plained. When the neutralisation point of toxine and antitoxine
was investigated for one and the same sample of poison, the fol-

1908: METCHNIKOFF AND EHRLICH 55

lowing results were obtained. Immediately on its preparation, fresh
from the incubator, it was found that one immunity unit neutralised
a c.c. of toxic bouillon, and this quantity represented /? simple
lethal doses. When the same toxic bouillon was examined after a
considerable interval, the remarkable fact was discovered that
exactly a c.c. of the toxic bouillon were again neutralised by one
immunity unit; but that these a c.c. now represented only ft x
simple lethal doses. It therefore followed that the toxic bouillon
had retained exactly the same combining affinity but possessed
feebler toxicity. From this it was evident that the toxic action on
animals and the combining capacity with antitoxine represented
two different functions of the toxine, and that the former of these
had become weakened, while the latter had remained constant."

CONSEQUENCES IN THEORY
AND PRACTICE

This is not the place to discuss the importance of Ehrlich's
studies on the staining of bacteria, nor his related studies of animal
cells, especially blood cells, nor his work in. chemotherapy. Like
these studies, his investigations in immunology, for which the Prize
was awarded, were of basic importance. By the researches described
above he established the principles of the standardization of bac-
terial toxins and antitoxins. The practical methods still in use are
essentially the same as his. The first disease to which this contribu-
tion applied was diphtheria: an exact gradation of the efficacy of
antidiphtheritic serum was achieved. In this regard the conception
outlined in the last paragraph above is a fundamental one that
the lethal action of a toxin and its antitoxin-combining power are
two separate functions. In his work with the vegetable poison
known as ricin, Ehrlich discovered that a latent period exists be-
tween the injection of the stimulating "antigen" and the produc-
tion, as a protective response, of the specific "antibody." He also
studied the serum fluctuations in the course of the development of
antibodies. Moreover, he investigated the transmission of im-
munity, which is not truly hereditary, through the placenta and the
milk. In the course of this study he was able to distinguish between
active immunity, a more or less lasting condition due to the active

56 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

manufacture of antibodies in response to antigens, and passive im-
munity, a transient state due to the transmission of antibodies in
the ways already mentioned or by the injection of a ready-made
antitoxin. When Bordet's work on hemolysis appeared (see below,
pp. 90-95 ) it was taken up, confirmed, and extended by Ehrlich
and Morgenroth, who introduced the terms "complement" and
"amboceptor."

This is no more than an indication of the main headings for an
appreciation of Ehrlich 's work in immunology.

REFERENCES

BULLOCH, WILLIAM. The History of Bacteriology (London: Oxford

University Press, 1938).

MARQUARDT, MARTHA. Paul Ehrlich (New York: Schuman, 1951).
MUIR, R. "Paul Ehrlich," Journal of Pathology and Bacteriology, Vol.

20 (1915-1916), pp. 350-360.
Paul Ehrlich: Eine Darstellung Seines Wissenschaftlichen Wirkens

(Jena: G. Fisher, 1914). Essays on Ehrlich's achievements in science

by thirty-seven contributors.

1909

THEODOR KOCHER

(1841-1917)

"For bis work on the physiology, pathology, and
surgery of the thyroid gland"

BIOGRAPHICAL SKETCH

THEODOR KOCHER WAS BORN ON AUGUST 25, 1841, IN BERNE,
Switzerland. He was educated in his native city, and after his
graduation there in 1865 he spent some time in Berlin, London,
Paris, and Vienna. In Vienna he was a pupil of Theodor Billroth
(1829-1894), the most famous surgeon of his time. Kocher be-
came professor of clinical surgery at the University of Berne In
1872 and for forty-five years was head of the University Surgical
Clinic. The first of his contributions to surgery to attract attention
was that In which he worked out the method now known by his
name for the reduction of a dislocated shoulder. He afterward
devised new methods, or modifications of older methods, for
operations upon the lungs, the stomach, the gall bladder, the intes-
tine, cranial nerves, hernia, and so on all this in addition to his
famous work on the surgery of the thyroid gland, described below.
He also invented many instruments and appliances. "Kocher's
forceps" remain in general use. It is an Indication of his scientific
objectivity that he was always ready to abandon any of his own
techniques or gadgets in favor of improvements introduced by
other surgeons. Thus it is said that in his later years he performed
the Bassini operation for hernia In preference to his own. In his

57

58 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

work on the thyroid, Kocher showed himself to be not only surgeon
and anatomist but also physiologist and pathologist. He was diligent
and original in research, expert in operating, and effective in
teaching, although he left no surgical "school" behind him. His
clinic was for many years a mecca for visiting surgeons from all
parts of the world. "With the death of Kocher," wrote Sir Berkeley
Moynihan in the British Medical Journal obituary in 1917, "the
world loses its greatest surgeon."

DESCRIPTION OF THE PRIZE -WINNING
WORK*

"It was due . . . [in part] to strict asepsis that one of the most
difficult, before Lister [one of] the most dangerous, operations,
the removal of the thyroid gland, so often appearing urgently neces-
sary because of severe respiratory disturbances, could be performed
without substantial danger. We ourselves have contributed a series
of three hundred and more goiter operations without a death. Im-
portant as this result has been for suffering humanity, it has been
far surpassed by the knowledge of the vital physiological function
of the thyroid, growing up afresh on practical and clinical grounds.
... In the spring of 1883, at the Congress of the German Sur-
gical Society [Gesellschaft fur Chirurgie], we announced that some
thirty of our first one hundred thyroidectomies, which we could
follow up and investigate, presented a quite definite, characteristic
disease-picture, which we designated simply with the name cachexia
strumipriva [literally, a bad condition due to removal of a struma,
or goiter}. This appeared in its completely distinct form only in
those patients from whom we had removed the whole thyroid
gland; with no more than transitory signs, on the other hand, where
all goiter tissue had supposedly been removed, but where in point
of fact a piece had remained behind, which grew larger.

"Isolated observations on the connection of cretinoid disturb-
ances with changes in the thyroid gland had already been made by
early investigators. . . . [Kocher here mentions the observations
on sporadic cretinism of Felix Plater (1536-1614), but not those

* Translated from Theodor Kocher, "Uber Krankheitserscheinungen bei Schild-
drusenerkrankungea geringen Grades," Les Prix Nobel en 15)09.

1909: THEODOR KOCHER 59

of Paracelsus, who linked cretinism and endemic goiter. Also men-
tioned are T. B. Curling, who in 1850 suggested that cretinism
was due to thyroid deficiency, Hilton Fagge, Sir William Gull,
W. M. Ord, etc., and his own contemporaries, the Reverdins, who
in 1882 published a short notice on the "bizarre" changes displayed
by certain patients after thyroid operations. J. L. Reverdin (1842-
1908), also a Swiss surgeon, was best known for his plastic opera-
tions, particularly skin grafting.}

"At the time (April 1883) when, in Berlin, I described cachexia
strutnipriva as the constant result of total excision, on the ground
of numerous observations, and warned against such excision be-
cause it always leads to consequences displaying a well-marked
cretinoid character, a brilliant discourse was delivered at the same
congress by a first-rate surgeon on the advantages and technique of
total excision. . . .

"Further corroborative information on the nature and conduct
of the new disease soon followed my contribution. On reviewing
their operations the Reverdins recognized the relation of cachexia
strumipriva to the myxedema of the English [Gull, Ord, etc.}.
... At a famous meeting of the Clinical Society in London
(November 23, 1883) Felix Semon . . . referred to my work and
mentioned a confirmatory case, following total excision by Lister;
and Ord read a letter I had written to him on the etiology of the
disease and the connection of myxedema with cachexia thyreopriva.

"The impulse was thereby given for the splendid investigations
of the Clinical Society Committee, which came to the conclusion
that myxedema and sporadic cretinism are identical, and probably
cachexia strumipriva also, and that close connections exist with
endemic cretinism. . . ."

CONSEQUENCES IN THEORY
AND PRACTICE

Myxedema, due to deficiency of thyroid secretion, had been
given its name by W. M. Ord, who read Kocher's letter to the
Clinical Society. Cretinism, a form of idiocy and dwarfism with the
general symptoms of myxedema, is due to congenital atrophy or
absence of the thyroid gland and is also called congenital myxe-

<$0 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

dema. Cachexia strumipriva, following total excision of the thyroid,
is operative myxedema. As indicated in the text above, it was
Kocher's description of the latter condition, together with his per-
ception of its cause and its relation to other forms of thyroid de-
ficiency, which made possible the grouping of all these "entities"
under a single head. This clarified not only the terminology of the
subject but also the thinking and the therapy of both physicians and
surgeons. Moreover, Kocher was able to point out that hypo-
thyroidism can be traced not only to absence of the gland, whether
congenital or due to an operation, but also to a goiter which has
made the gland stop working. Incomplete and debatable evidence
as to the function of the thyroid could now be reviewed and sup-
plemented, and in. the years which followed Kocher's first pro-
nouncement on the subject great advances were made. Murray,
Gley, and Vassale administered thyroid in various forms to over-
come deficiency. Attempts to produce the essential constituent, the
hormone, in a pure state were long unsuccessful but resulted in
showing that iodine plays an important part. In 1914 E. C Kendall
finally isolated the hormone or the effective part of it called
thyroxin, which was later synthesized by C. R. Harrington and
G. Barger. Meanwhile the nature of hyperfunction or dysfunction
of the gland, causing exophthalmic goiter, was elucidated by Victor
Horsley and others, providing a sound basis for surgical interven-
tion. Kocher did much to perfect the technique of the operation
and performed more than two thousand thyroidectomies with less
than 5 percent mortality; this represents the resultant of a reduction
of mortality from 18 percent to less than -J percent, the ultimate
rate in his clinic. He was also a pioneer in stressing the importance
of blood-picture change and coagulation time as means of early
diagnosis and prognosis both in hyperthyroidism and hypothy-
roidism. Finally, he made extensive and careful studies of malig-
nant tumors of the thyroid gland.

In the days before anesthesia and antisepsis, thyroidectomy was
so dangerous that it was performed only in cases with severe suf-
focative symptoms. The control of bleeding remained a serious
problem, and only from 1870, when the hemostatic forceps came
into general use, was the operation a practical one. Understanding
of thyroid physiology and pathology extended the range of surgical

1909: THEODOR KOCHER 6^

intervention. Kocher made important contributions to this under-
standing.

The prophylactic value of small amounts of iodine in the
prevention of goiter has been shown by D. Marine and others.
Thiouracil and related compounds have been introduced for the
medical treatment of thyrotoxicosis (poisoning by an excess of
thyroid secretion) . Radioactive iodine has found a similar use. Yet,
whatever the future holds in the prevention and treatment of the
various forms of thyroid disease, surgery is still of predominant
importance today.

1910

ALBBJECHT KOSSEL

(1853-1927)

tf ln recognition of the contributions to the chem-
istry of the cell made through his work on proteins >
including the nucleic substances."

BIOGRAPHICAL SKETCH

ALBRECHT KOSSEL, ELDEST SON OF A MERCHANT AND PRUSSIAN
consul, was born in Rostock on September 16, 1853. After attend-
ing the Gymnasium there, he studied medicine at the University of
Strasbourg, where he was much influenced by E. F. Hoppe-Seyler
(1825-1895), one of the pioneers of modern physiological chemis-
try; he also attended the University of Rostock. He passed his state
examination for practice in 1877 and became doctor of medicine
in the following year. After assisting Hoppe-Seyler for a time, he
was summoned by E. Du Bois Reymond to the Physiological Insti-
tute in Berlin. In 1895 he became professor of physiology and
director of the Physiological Institute at Marburg, where he re-
mained until 1901, when he took over the Heidelberg chair made
famous by Willy Kiihne and Helmholtz. A physiologist by train-
ing, Kossel devoted his researches almost entirely to chemical sub-
jects. His early investigations were concerned with the nucleic acids;
later he turned his attention to the protamines of fish roe (first
investigated by Miescher), which are comparatively simple pro-
teins, and made a special study of their six-carbon cleavage prod-
ucts, containing nitrogen, called "hexone bases." He reached a
position of pre-eminence by his substitution of the exact methods
of organic chemistry for the less precise means employed by older
physiologists. He had a number of distinguished pupils, including
the Englishman H. D. Dakin. His son, Walther, became a well-

62

1910: ALBRECHT KOSSEL 63

known theoretical physicist. Professor Kossel died in his seventy-
fourth year, after a brief illness, on July 5, 1927. At the time of
his death he was emeritus professor of physiology at the University
of Heidelberg and director of the Heidelberg Institute for Protein
Investigation. For more than thirty years he had been editor of the
Zeitscbrift -fur physzologische Chemie, in which most of his writ-
ings appeared.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The first observations in this field [the chemistry of the cell
nucleus] were undertaken on the nuclei of pus cells during the
sixties of the last century in Hoppe-Seyler's laboratory. It fell to
Miescher, a pupil of Hoppe-Seyler's, to isolate this nucleus, and he
found in it a substance very rich in phosphorus, which he desig-
nated 'nuclein/ [This substance is now known to have been nucleo-
protein. Friedrich Miescher (1844-1895) is regarded as the
founder of our knowledge of the chemistry of the cell nucleus.}
A suitable object for the continuation of this work presented itself
in a structure arising from the transformation of the nucleus and
preserving its chemical nature, obviously a fundamental part of the
physiological functions also namely, in the head of the sperma-
tozoon. In the course of the next decades evidence accumulated to
show that 'nuclein/ or 'nuclein substance/ is actually peculiar to
the nucleus. [This view has had to be altered. See the commentary
below.} Still other objects were found, which in some way lent
themselves to the isolation of the nuclei, e.g., the red blood cor-
puscles of birds, the cell body of which is soluble in water. Further-
more, the nuclear substance isolated from them could be submitted
to chemical investigation in sufficient quantity, and now the char-
acteristics of the nuclear substance were further revealed. Micro-
chemical work completed the demonstration. At the same time it
showed that the nuclein substance appertained to a definite part of
the substance of the nucleus, which separates itself in the trans-

* Translated from Albrecht Kossel, "Uber die chemische Besdhaffenheit des
Zellkerns," Les Prix Nobel en 1910.

*64 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

formation processes in a very characteristic way, the quantity of
which varies in different nuclei, and which has obtained the name
'chroinatin' because of its reaction to certain dyestuffs. [The ques-
tion of the distribution of nuclear constituents is not yet settled, but
-chromosomes are considered to be almost exclusively nucleopro-
tein.] Only one difficulty presented itself at first for this doctrine.
This was the finding of 'nuclein substance' in animal products
which contained no nuclei, and indeed in the vitelline discs [yolk}
of eggs and the casein of milk. Strange hypotheses had already been
advanced in an attempt to make these facts intelligible, when exact
chemical investigation brought enlightenment.

'The chemical structure of these nuclein substances exhibits
-some peculiarities, which are found in many of the organic con-
stituents of protoplasm, especially in those which take a lively part
in metabolic processes. It was observed that such combinations
teadily break down into a definite number of complete atom groups,
which have been compared to building blocks. Such building
blocks/ in large number and variety and apparently combined ac-
cording to a definite plan, build the molecule of albuminoid or
protein material, also that of starch and glycogen. . . .

"The nuclein substances also exhibit a combination of this kind.
Chemical analysis showed first of all that the nuclein substances
can in many cases be separated into two parts, one of which bears
the character of a protein or albuminoid material. This possesses
no other atom groups than the usual albuminoid substances. So
characteristic is the structure of the other part that it has received
the name nucleic acid. It fell to me to obtain from it a series of
fragments, which may in part be detached from the molecule even
ty gentle chemical procedures and which are characterized by a
quite specific group of nitrogen atoms. There are here side by side
four nitrogen-containing atom groups: cytosine, thymine, adenine,
and guanine.

"One of these four bodies, guanine, was already known earlier
-and in different tissues of the animal organism; e.g., it had been
discovered by Piccard in the spermatozoa of salmon. . . . The
knowledge of their origin from nucleic acid, which was unexpected
and was at first assailed by lively opposition, at once made intel-
ligible separate phenomena which had been encountered without

1910: ALBRECHT KOSSEL 65

explanation; e.g., it had been observed that guanine and its kindred
are found in large amounts in the blood in leukemia. Now this
form of disease is distinguished by the fact that unnucleated red
blood corpuscles [adult cells} are replaced by {young} nucleated
forms. But these latter fall prey in large numbers to decomposition,
and accordingly the body fluids are inundated with the disintegra-
tion products of the nuclein substances. So, then, the bases named
or their nearest conversion products are to be met with in large
amounts in the body fluids. Also the contradiction previously men-
tioned, which seemed to lie in the alleged presence of nuclein sub-
stance in vitelline elements and in milk, was now solved. An exact
chemical investigation proved that these elements, which because
of their unusual behavior and their phosphorus content had been
proffered earlier as nuclein substances, possessed another kind of
chemical structure. The building blocks rich in nitrogen which I
have just named are altogether absent from them. . . . [Nucieo-
proteins are nevertheless present in eggs, and embryonic tissues are
rich in nucleic acids.}

"Now the more was known of the relation to the nucleus of the
nitrogen-rich substances, the more also must the question arise of
the arrangement of the nitrogen and carbon atoms in their mole-
cule. Two of the four bodies named, adenine and guanine, belong
to a group of chemical compounds which today are usually grouped
together under the names of alloxur or purine derivatives. . . .
Both thymine and cytosine showed a simple composition; analytical
and synthetic research lead to the result . . . which the following
schema express:

[A number of workers, notably Emil Fischer, contributed to the
establishment of these formulae; the mode of writing them has
here been altered slightly to conform to recent usage.}
NH 2 O NH 2 OH

A 4 > n A H

/Vn H-/V-CH, /VN<* / C-N/

A C-H A C-H b C-N^ 6 &-xS

- - /\/ /\/

H N H 2 N N

...A

Cytosine Thymine Adenine Guanine

66 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

CONSEQUENCES IN THEORY
AND PRACTICE

The study of the biochemistry of the nucleic acids, in which
Miescher, Altmann, and Kossel were among the pioneers, has
assumed ever-increasing importance. Knowledge of the presence
or absence of these compounds in certain organic substances has
been much extended since Kossel's day, so that some of his asser-
tions, quoted above, are now outdated; nudeoprotein is not peculiar
to the cell nucleus, as was then supposed, but is also found in pro-
toplasm. Pentosenucleic acids of the type found in yeast were once
thought to be characteristic of plants, deoxypentosenucleic acids
of the type found in the thymus gland to be characteristic of ani-
mals; but both have been found in plants and animals alike and the
distinction of source has been shown to be largely false.

The metabolic activity of che nucleic acids is of great importance.
The rate of renewal in different parts of the body varies with age,
with X radiation, and with other factors. Questions of growth and
of both the normal and pathological function of the organs are
involved in the study of these substances. Formation of the body's
proteins takes place through the mediation of the nucleic acids.
Genes and chromosomes consist of nucleoproteins. A great deal of
current research on cancer is also centered on the study of the
nucleoproteins. Bacteria are particularly rich in nucleic acids, and
nucleoproteins form the substance of plant and animal viruses and
of the bacterial virus, bacteriophage. Indeed all self -reproducing or
protein-synthesizing units in living organisms are believed to be of
this chemical constitution. Studies in the biochemistry of nucleic
acids are expected to yield valuable information, not only concern-
ing the mode of action of bacteria and viruses but also concerning
genetics, embryology, the normal physiology of the cells, and the
pathological deviations from the normal, including cancer.

This general field of biochemical research is of primary impor-
tance for the basic knowledge which underlies medicine. Immediate
practical applications may appear at any time or, on the other hand,
may be long postponed. The fact that thymine, one of the
pyrimidine bases discovered by Kossel, has proved clinically effec-

1910: ALBRECHT KOSSEL 67

tive in cases of pernicious anemia is probably less important for
this immediate reason than because there is some possibility that
the basic biochemical defect which results in the disease may be
elucidated through the use of thymine. Cellular pathology, initiated
by Rudolf Virchow nearly a century ago, gives promise of new and
greater usefulness as the mystery of chemical events within the
cell is gradually penetrated.

REFERENCES

B., G., "Prof. Albrecht Kossel." Nature (London), Vol. 120 (1927),
p. 233.

DAVIDSON, J. N. The Biochemistry of the Nucleic Acids (London:
Methuen; New York: Wiley, 1950).

EDLBACHER, S. "Albrecht Kossel zum Gedachtnis," Hoppe-Seyler's
Zeitschrift fur physiologische Chemie, Vol. 177 (1928), pp. 1-14.

GRAY, GEORGE W. "The Mother Molecules of Life," Harper's Maga-
zine, April, 1952, pp. 51-61.

RlESSER, OTTO. "Albrecht Kossel/* Deutsche medizinische Wochen-
scbrift, Vol. 53 (1927), p. 1441.

1911

ALLVAR GULLSTRAND

(1862-1930)
"For his work on the dioptrics of the eye."

BIOGRAPHICAL SKETCH

ALLVAR GULLSTRAND WAS BORN AT LANDSKRONA, SWEDEN,
on June 5, 1862. He studied at the University of Uppsala, for one
year at Vienna, and finally at Stockholm, where in 1888 he passed
the examinations for the license to practice medicine. He sustained
his thesis for the doctorate in 1890, and was named decent in
ophthalmology in 1891. He was later called to the new chair of
ophthalmology at Uppsala. In geometric and physiological optics
he was self-taught. His thesis of 1890 ("A Contribution to the
Theory of Astigmatism* ') already contained the foundations of
his most notable work, elaborated in three subsequent publications
(1900, 1906, and 1908). One of his most remarkable contribu-
tions to ophthalmology was the discovery of intracapsular accom-
modation, described below; he also invented a number of impor-
tant instruments and made useful modifications in the design of
others. He died in 1930.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"It is ... necessary to remember that the lens fibers are at-
tached both anteriorly and posteriorly, describing in their course

* From Allvar Gullstrand, "Mechanism of Accommodation," an appendix to
Helmholttfs Treatise on Physiological Optics, translated from the third German
edition by James P. C Southall (Rochester, N. Y.: Optical Society of America),
Vol. i, pp. 388-390.

68

191 1 : ALLVAR GULLSTRAND 69

arcs which are convex toward the equator. When the points of
attachment of the fibers are separated from one another by the
increase of thickness of the lens, the arches must be spread, involv-
ing the greatest amount of dislocation of particles in the parts of
the fibers farthest from the points of attachment. If the lens were
always symmetrical, a centripetal shifting would have to occur at
the equator. If the point of maximum centripetal shifting on each
lens fiber were determined, and a surface passed through all these
points, this surface of maximum accommodative shifting would
coincide with the equatorial plane. But since the passive lens is
asymmetrical, and the change of shape is particularly marked on
the anterior surface, the surface of maximum accommodative shift-
ing must be concave toward the front. This conclusion, drawn
entirely from the anatomical structure of the lens with respect to
its asymmetrical accommodative change of shape, may also be de-
duced directly from . . . mathematical analysis. The slight change
of form of the posterior surface of the lens demonstrates that the
points of attachment of the lens fibers adjacent to this surface
must, on the average, be less separated from one another during
accommodation than those of the fibers lying on the anterior sur-
face. Since, on the whole, the fibers of the posterior surface have
their points of attachment situated more toward the periphery on
the anterior surface, and toward the center on the posterior surface,
and as these conditions are reversed in the case of the fibers of the
anterior surface, the distance of the posterior pole of the lens from
the anterior point of attachment of the Zonula Zinnii must be rela-
tively less changed during accommodation than the distance of the
anterior pole from the posterior point of attachment. As a result,
the shifting at the anterior point of attachment must occur in a
direction approximately corresponding to a tangent to the surface.
Consequently, it follows from the anatomical structure of the lens
that the increase of curvature of the anterior surface of the lens
during the accommodative change of form is accompanied by an
axi petal shifting of the anterior point of attachment of the zonule.
Mathematical investigation demonstrates the presence of a
corresponding shifting in those parts of the largest closed iso-
indicial surface that are nearest to the point of attachment.

"As the surface of maximum accommodative shifting contains

70 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

cross or slightly oblique sections of the lens fibers, the rapidity of
the centripetal movement of these sections during accommodation
must be greater at a point nearer the axis than in the vicinity of
the equator. ... It is true, this mechanism might be impeded by
the fact that the fibers lying nearer the axis would be cut obliquely
by the surface of maximum shifting in the passive state and per-
pendicularly during accommodation, provided the centripetal
movement could occur to a sufficient extent. But in order to com-
pensate the suggested difference of centripetal shifting, the oblique
section must make an angle of 60 with the perpendicular section;
and this is manifestly impossible. Another consequence, therefore,
of the anatomical structure of the lens is that the equatorial diam-
eters of the smaller iso-indicial surfaces must be proportionately
more shortened in accommodation than those of the larger. But
according to the mathematical investigation, this is an expression
of an increase of the total index; and hence the increase in total
index during accommodation, as proved by physiological-optical
investigations, may be deduced directly from the anatomical struc-
ture of the lens. The so-called S-shaped curvature of the lens fibers
is inferred from the fact that the projection of such a fiber on the
equatorial plane is not a straight line; and the reason why in this
discussion of the anatomical structure of the lens the possibility of
a change in this curvature has not been mentioned is that the only
thing which could modify it would be radially directed elevations
and depressions. This is a necessity due to the mode of attachment
of the lens fibers in rows, so that any mutual shifting of the indi-
vidual fibers at these points is impossible. On the other hand, it
follows again from the anatomical arrangement of the lens fibers
that during the accommodative change of form, such elevations and
depressions must either originate in the iso-indicial surfaces or must
be reversed there, if they are already present. Else they would
undergo a reduction of superficial area during accommodation. This
might perhaps be possible if the lens were composed of freely
movable particles, but is actually impossible because the capability
of movement is restricted by the arrangement of the fibers. How-
ever, a necessary mathematical consequence of this accommodative
change of the iso-indicial surfaces is the variation of the star-shaped
appearance of a luminous point.

1911: ALLVAR GULLSTRAND 71

"A slight increase of the index at any given point may result
from the interpenetration of individual fibers between others, even
though the physical indices of the individual fibers are not altered.
This explains why the smaller iso-indicial surface ... is appar-
ently a little nearer the anterior pole of the lens during accommoda-
tion, because the superficial extent of that portion of it which is
nearest the axis is augmented by the forward displacement, and
this must involve an interpenetration of fibers from the central
region.

"Thus, the dioptric investigation of the lens in accommodation
has resulted in finding out the accommodative variations that
occur in the substance of the lens. At the same time, it appears that
these changes, which for convenience may be grouped together
under the name of the mtracapsular mechanism of accommodation,
are not only in complete agreement with the anatomical structure of
the lens, but also establish and explain the causal connection be-
tween this structure and the variation of the total index of the lens
as proved by the change of refraction that occurs when the lens is
removed or during the process of accommodation."

CONSEQUENCES IN THEORY
AND PRACTICE

For a proper understanding of Gullstrand's contributions to
ophthalmology, a thorough knowledge of the anatomy of the eye
and of geometric and physiological optics is essential. Certain
points, however, may be noted here as of primary importance. The
heterogeneous structure of the lens, described in the quotation, had
never before been explained on physiological grounds. According
to the classical (Helmholtz) theory of accommodation, the action
of the ciliary muscle increases the convexity of the lens, especially
of the anterior surface, and no function is ascribed to the non-
uniformity of the internal parts of the lens structure. Accommoda-
tion, representing a gain in the refractive power of the lens, makes
it possible to focus on the punctum proximum, or "near point/*
which varies with the amount of accommodation possessed by the
eye and is determined clinically by noting the shortest distance at
which it is possible to read the smallest test type. Gullstrand was

72 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

able to show that this gain in refractive power is only about two-
thirds dependent on the increase in surface curvature of the lens;
the remaining third is due to a rearrangement of internal elements,
as set forth above. This means that approximately two thirds of
accommodation is "extracapsular," one third "intracapsular."

Gullstrand's investigation of optical reproduction, begun on the
level of pure physics and extended to physiological optics, led him
to modify, or supplement, the theory of co-linear reproduction,
enabling him to give improved explanations of anisotropic coma
and monochromatic aberration. In applying his findings to the
human eye he contributed also to present knowledge of the struc-
ture and function of the cornea.

In practice, Gullstrand invented improved methods for estimat-
ing astigmatism and corneal abnormalities and for locating para-
lyzed muscles. He improved the design for corrective glasses after
removal of the cataractous lens. He devised a reflex-free oph-
thalmoscope. Perhaps the best known and most useful of his in-
ventions is the slit-lamp. It supplies a brilliant light condensed
into a beam, which traverses the parts to be examined, the re-
mainder of the eye being in darkness; the illuminated area is then
examined with the binocular microscope. The combination of slit-
lamp and corneal microscope makes possible the minute examina-
tion of changes in the anterior part of the eye. Exact localization
in three planes or dimensions is obtainable with this instrument.
Thus the examiner can locate the site of a foreign body or deter-
mine the depth of an ulcer. Lens opacities can be located and their
progress watched. The very earliest signs of serious inflammations
may often be seen with the aid of Gullstrand's slit-lamp. Sometimes
a differential diagnosis of great importance can be made when
ordinary methods of examination leave doubt. The slit-lamp is
now considered an indispensable part of the ophthalmologist's
apparatus.

1912

ALEXIS CARREL

(1873-1944)

"In recognition of bis works on vascular suture and
the transplantation of blood vessels and organs."

BIOGRAPHICAL SKETCH

ALEXIS CARREL WAS BORN IN LYONS, FRANCE, ON JUNE 28,
1873. He became a bachelor of letters of the University of Lyons
in 1889, bachelor of science in 1890, and doctor of medicine in
1900. He interned in a Lyons hospital, then taught anatomy and
operative surgery at the university as a prosector. He began his
experimental work in surgery in 1902 in Lyons, whence he went to
Chicago at the end of 1904. In 1906 he became attached to the
Rockefeller Institute for Medical Research in New York, where he
conducted most of the experiments for which the Nobel Prize was
awarded him. This was the first Nobel Prize in medicine for the
United States. He was made a fellow of the Institute in 1909, a
member in 1912, and retired in 1939 as member emeritus.

During the First World War, Carrel served as a major in the
French army medical corps and helped to develop the well-known
Carrel-Dakin antiseptic solution for sterilization of deep wounds.
In 1935, with Col. Charles A. Lindbergh, he announced the de-
velopment of a mechanical "heart," in which the heart, kidney, etc.
of an animal could be kept alive for study in glass chambers sup-
plied by circulation of artificial blood.

73

74 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

When the Second World War broke out, Carrel joined a special
mission for the French Ministry of Public Health (1939-1940).
At the time of his death, which took place in Paris, on November
5, 1944, he was director of the Vichy government's Carrel Founda-
tion for the Study of Human Problems.

His writings included the best-selling Man, the Unknown, and
he was joint author with Georges Dehelly of Treatment of Infected
Wounds and with Charles Lindbergh of The Culture of Organs.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The idea of replacing diseased organs by sound ones, of put-
ting back an amputated limb or even of grafting a new limb on to
a patient who has undergone an amputation, is far from being
original. Many surgeons before me have had this idea, but they
were prevented from applying it, owing to the lack of a method
for re-establishing immediately a normal circulation through the
transplanted structures. It was of fundamental importance to first
discover a suitable method of uniting the blood vessels of the new
organ to those of its host. In 1902, therefore, I began to investigate
by what means a vascular anastomosis {union between blood ves-
sels] might be effected without producing either stenosis [narrow-
ing], or thrombosis [plugging by clot formation]. Many surgeons
had previously to myself performed vascular anastomosis, but the
results were far from satisfactory. I began by using Payr's and
Murphy's methods, after which I proceeded to study the principles
for a new technique on human cadavers. I next performed some
vascular anastomoses on living dogs at the University of Lyons
in the laboratory of Prof. Soulier and with the collaboration of
Dr. Morel. This study was continued at the University of Chicago
in Professor Stewart's laboratory and with the collaboration of
Doctor Guthrie. Later, at the Rockefeller Institute for Medical Re-
search, the causes of all possible complications were analysed and
greater perfection of methods was obtained. With this modified
technique a great many experimental operations were performed

* From Alexis Carrel, "Suture of Blood- Vessels and Transplantation of Organs/'
Les Prix Nobel en 1*912.

1912: ALEXIS CARREL 75

and their clinical and anatomical results were observed during a
period of three and four years. . . .

"In operations on blood vessels certain general rules must be
followed. These rules have been adopted with the view of eliminat-
ing the complications which are especially liable to occur after
vascular sutures, namely, stenosis, haemhorrhage and thrombosis.
A rigid asepsis is absolutely essential. Sutures of blood-vessels must
never be performed in infected wounds. It seems that the degree of
asepsis under which general surgical operations can safely be made
may be insufficient for the success of a vascular operation. It is
possible that a slight non-suppurative infection, which does not pre-
vent the union of tissues 'per primam intentionem' ['by first in-
tent'], may yet be sufficient to cause thrombosis. The obliteration
of the vessel also follows injuries to its walls. The arteries and
veins can be freely handled with the fingers without being injured,
but it is often harmful to use forceps or other instruments. If a
forceps be used, it must take between its jaws nothing but the
external sheath. When temporary haernostasis [control of bleed-
ing] is obtained by means of forceps or clamps, these instruments
must be smooth-jawed and their pressure carefully regulated. The
desiccation of the endothelium [lining membrane] may also lead
to the formation of a thrombus. Therefore, during the operation
the wall of the vessels must be humidified ... or be covered with
vaseline. ... As perforating stitches are always used, the en-
dothelial layer is necessarily wounded by the needle. These wounds,
however, are rendered as harmless as possible by the use of very
fine and sharp round needles. Extremely small wounds are made.
The threads are sterilized in vaseline and kept heavily coated with
it during the suture. . . . The operating-field is circumscribed by
a black Japanese silk towel on which the fine threads can easily be
seen. . . .

""The termmo-termmal [end-to-end] anastomosis is effected by
bringing the extremities of the vessels into contact, no traction
being necessary. The ends are united by three retaining stitches
located in three equidistant points of their circumference. By trac-
tion on the threads the circumference of the artery can be trans-
formed into a triangle, and the perimeter can be dilated at will.
Then the edges of each side of the triangle are united by a con-

76 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

tinuous suture whilst they are under tension. During the suture
great care is taken to approximate exactly the surfaces of section of
the wall. Before the last stitch is made, the remaining vaseline is
removed by pressure from the lumen [cavity] of the vessel. In
venous anastomoses the ends of the veins are also united by three
retaining stitches. A venous suture, however, requires more stitches
than an arterial suture, on account of the thinness of the walls. The
union of the extremities is made by eversion of the edges, which
are united not by their surface of section, but by their endothelial
surfaces. An inversion of the edges would be very dangerous and
would provoke the formation of a thrombus/'

CONSEQUENCES IN THEORY
AND PRACTICE

Aiming at successful replacement or transplantation of organs,
Alexis Carrel perceived that the chief difficulty was the re-establish-
ment of circulation without hemorrhage or thrombosis. He there-
fore worked out the method described above; then he proceeded to
apply it. Using his new techniques he was able to remove entire
organs, such as the spleen or kidney, and replace them either in the
original location or occasionally, in still more spectacular opera-
tions, in different parts of the body, where they functioned fairly
well. He was even able to replace an amputated limb.

Before the introduction of citrate to prevent blood from clotting
(see below, p. 146) , vascular suture was used in blood transfusions,
a donor blood vessel being anastomosed to a recipient vessel. This
method has since been abandoned, but it is repeatedly necessary, in
the surgery of injuries and wounds, to restore the continuity of
divided blood vessels. Here the Carrel technique finds application.

Vascular surgery is now an important specialty. As a result of a
congenital malformation, the greatest of the arteries, the aorta, may
be so constricted at some point that the blood supply to the lower
half of the body becomes inadequate. This condition is often over-
looked, as the patient may be active for years and experience little
or no difficulty; but the average duration of life is only about thirty-
five years. In 1944 C Crafoord, and in 1945 R. E. Gross, per-
formed the first operations for this condition, known as coarctation

ALEXIS CARREL 77

(narrowing) of the aorta. The local constriction is removed and
the Carrel method makes it possible to join together the two ends
and thus provide an aortic lumen of adequate size.

Certain other kinds of congenital heart disease may now be
remedied by somewhat similar techniques. The "blue baby" opera-
tion, introduced in 1944 by A. Blalock and H. G. Taussig, involves
a rerouting of congenitally misdirected blood flow, using a piece
of vein to form a new link between two arteries. In this way it is
possible to direct a larger proportion of the blood through the
pulmonary circuit, originally by-passed in part, and so to assure
sufficient oxidation of the blood as it circles through the lungs.

The domain of vascular surgery is undergoing remarkable exten-
sion. Among the surgical techniques which have made this possible,
the suture method devised by Carrel Is of basic importance. Even
with the full resources of present-day surgery the transplantation
of organs has not yet become generally practicable. At the present
time kidney transplants are being attempted, but the value of this
procedure remains in doubt. It appears that tissues do not fare
well for the most part when removed from one individual and
implanted in another; corneal transplants, having nothing to do
with vascular surgery, are the obvious exceptions.

1913

CHARLES RICHET

(1850-1935)
' f ln recognition of his work on anaphylaxis.'

BIOGRAPHICAL SKETCH

CHARLES RICHET WAS BORN ON AUGUST 26, 1850, IN PARIS,
where his father, Alfred Richer, was professor of clinical surgery
In the Faculty of Medicine. He was graduated in medicine in 1876,
and then worked under Marey at the College de France. In 1887 he
was appointed professor of physiology at the University of Paris.
An industrious and versatile worker, he did not limit himself to
the usual confines of physiology but also published papers on
physiological chemistry, experimental pathology and pharmacology,
and normal and pathological psychology. He did original work on
gastric secretion. He also investigated the relation between respira-
tion and the area of body surface, and carried out extensive research
on animal heat. In addition he studied the effect of chloride dep-
rivation on epilepsy, and of a diet of raw meat in the treatment of
tuberculosis. Work begun in 1887 led Richet to the concept of im-
mune serum, and in 1890 he performed the first serotherapeutic
injection on a human subject. Richet's attempt to follow this clue in
his work on tuberculosis was disappointing, but von Behring and
Kitasato pursued it with greater success in studies of tetanus and
diphtheria. In 1898, with his collaborator, Hericourt, Richet stud-
ied the effect of eel serum on dogs, observing that a condition of

78

CHARLES RICHET 79

hypersensltiveness could develop. This was followed by his work
with P. Portier in 1902 and his own later independent studies of
anaphylaxis, described in part below, for which he received the
Nobel Prize. In his later years Richet's inclination toward the
study of psychology increased. Side by side with this, he nurtured
an interest in clairvoyance, telepathy, and materialization an
interest that he did not find incompatible with rigid mechanistic
determinism. He followed the development of aeronautics very
closely and actually designed an airplane. He was the author of a
number of novels and plays. He was also active in pacifist move-
ments. Richet died of pneumonia on December 4, 1935.

DESCRIPTION OF THE PRIZE -WINNING
WORK*

"Phylaxis, a word but little used, means, in Greek, protection.
And the word anaphylaxis will then signify the contrary of pro-
tection. Thus, through its Greek etymology, anaphylaxis means a
state of the organism in which . . . , in place of being protected,
[it] has become more sensitive. [Richet coined the word ana-
phylaxis in 1902.}

"To state the ideas precisely, we are going to examine what takes
place In an Individual receiving a poison.

"Let us suppose the dose a moderate one, and the individual
restored, after some days, to his original state, at least to all appear-
ance. If, then, the same dose of the same poison is injected anew,
what is going to happen?

"We can suppose three cases.

"The first, the simplest, is that nothing has been changed in his
organism, and that on receiving the same dose as a month ago,
exactly the same phenomena will reappear under the same condi-
tions. . . .

"The second possibility is that the organism may have become
less sensitive. In other words, a certain state of habituation, or
insensibility, has been produced by the preceding intoxication; so
that a stronger dose has become necessary, at the second injection,

* Translated from Charles Richet, "Conference Nobel sur 1'anaphylaxie," Les
Prix Nobel en 1913.

80 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

to produce the same effect. It is the case of immunity (rela-
tive). . . .

* These two cases: unmodified sensitivity or stability, diminished
sensitivity or habitation, had been known for a long time. But I
have shown that very frequently, under certain conditions which
I have been able to specify, a third modality is seen: it is increased
sensitivity, of such a kind that the first injection, in place of pro-
tecting the organism, makes it frailer, more susceptible, it is
anapbylaxis.

"Let me tell you under what circumstances I observed this
phenomenon for the first time. I may be permitted to enter into
some details on its origin. You will see, as a matter of fact, that it
is not at all the result of deep thinking, but of a simple observation,
almost accidental; so that I have had no other merit than that of
not refusing to see the facts which presented themselves before me,
completely evident.

"In equatorial seas one comes across Coelenterates [a sub-king-
dom of animals comprising the Actinozoa and Hydrozoa] called
Physalia (Portuguese men-of-war). These animals are formed
essentially of a sac full of air, which allows them to float like a
leather bottle. Associated with this sac is a bucco-anal cavity, fur-
nished with very long tentacles, which hang down in the water.
These tentacular filaments, sometimes two or three meters in length,
are armed with little "gadgets" which adhere like suckers to objects
which they encounter. And in the interior of each of these in-
numerable suckers there is a sharp little point, which penetrates
the foreign body touched. At the same time this point imparts a
subtle poison, very active, contained in the tentacles; so that the
contact of the Physalia' s filament is equivalent to a multiple injec-
tion of poison. The moment you touch a Physalia, you feel an in-
tense pain, owing to the penetration of this venomous liquid. . . .

M Now, in the course of a cruise made on the yacht of Prince
Albert of Monaco, the Prince advised me, as well as our friends
Georges Richard and Paul Portier, to study the poison of these
Physaliae. We saw that it dissolves readily in glycerine, and that
on injecting this glycerinated liquid one reproduces the symptoms
of Physalian poisoning.

1 'Having returned to France, and no longer being able to obtain

CHARLES RICHET 81

Physaliae, I thought of studying comparatively the tentacles of
Actiniae [sea anemones} . . . which can be obtained in abun-
dance; for the Actiniae swarm on the rocks of all the European
coasts.

"Now the tentacles of the Actiniae, treated with glycerine, yield
their poison to the glycerine, and the extract is toxic. Working with
Portier, I then sought to determine the toxic dose. This was diffi-
cult enough, because this poison acts slowly, and one must wait
three or four days before knowing whether or not one has reached
the fatal dose. With the solutions that I was using, a kilo of
glycerine to a kilo of tentacles [a kilo, or kilogram, is a little more
than two pounds}, it required, after filtration, about o.i of liquid
per kilo of live weight to bring about death.

"But certain dogs escaped, whether because they had received
too weak a dose, or from some other cause. And at the end of two,
three, or four weeks, as they seemed altogether restored to their
normal state, I made use of them for a new experiment.

"Then an unforeseen phenomenon presented itself, which to us
appeared extraordinary. If the dog, injected beforehand, received
an extremely weak dose, for example 0.005 per kilo, he imme-
diately exhibited dreadful symptoms: vomiting, bloody diarrhea,
syncope, loss of consciousness, asphyxia, and death. Repeating on
different occasions this fundamental experiment, we were able to
establish, in 1902, these three principal facts, which are the very
foundation of the story of anaphylaxis: first, an animal injected
beforehand is enormously more sensitive than a new animal; sec-
ond, the symptoms which supervene on the second injection, char-
acterized by a rapid and total depression of the nervous system,
have no resemblance to the symptoms produced by the first injec-
tion; third, this anaphylactic state requires an interval of three or
four weeks to establish itself. It is what is called an incubation
period.

"After the initial facts of anaphylaxis had been solidly estab-
lished, the domain was enormously enlarged at once, thanks to the
beautiful experiments of clever investigators.

"In 1903, Arthus, of Lausanne, showed that if a rabbit is given
an intravenous injection of serum, this first injection of serum is
anaphylactogenic that is to say that three weeks after the first

82 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

injection the rabbit has become very sensitive to the second injec-
tion. Thus the phenomenon of anaphylaxis was generalized; and
in place of being particular to toxins and toxalbumin was extended
to all albumins, whether toxic on first injection or not. [Albumin-
protein. Arthus observed a local reaction since known as the
""Arthus phenomenon/]

"Two years later, two American physiologists, Rosenau and
Anderson, established in a remarkable memoir that the anaphy lactic
phenomenon is seen after every injection of serum, even when the
quantity injected is minuscule, be it o.ooooi c.c, the tiniest quantity,
but sufficient to give an animal anaphylactic sensitivity. They gave
examples of anaphylaxis with all the organic liquids: milk, serum,
egg, muscular extract. They indicated the specificity of this reaction,
and finally they clearly established that of all animals the guinea
pig appears to be the most sensitive to the anaphylactic reaction.

"In 1907, I made an experiment which notably clarified the
pathogenesis [the mode of origin] of anaphylaxis. In taking the
blood of a sensitized animal, and injecting it into a normal animal,
the anaphylactic state is developed. Thus the anaphylactogenic poi-
son Is a chemical substance contained In the blood.

"Such, as it seems, are the principal phases through which our
knowledge has passed.'*

CONSEQUENCES IN THEORY
AND PRACTICE

Ricfaet was not the only investigator to report intensified results
from a preliminary conditioning expected to create, if anything, a
state of Immunity. Thus Edward Jenner had long ago noticed a
similar occurrence In performing vaccinations, and von Behring
had observed that a second injection of diphtheria toxin seemed at
times to have a greater toxic effect than anticipated. But the regu-
larity of the phenomenon was Richefs discovery; he not only ob-
served and named it but clearly expounded as a general principle
what had been noted from time to time in the past as an exceptional
and bizarre occurrence. Furthermore, he showed that it was not a
mere intensification of an ordinary toxic action but was a specific
effect with characteristic signs and symptoms.

1913- CHARLES RICHET 83

The term "anaphylaxis" may refer to increased susceptibility to
an injection under the conditions described above; more commonly
It means the reaction to a foreign substance, usually a protein such
as animal serum, following a previous introduction, by Injection
or otherwise, of the same substance. The effect is the same regard-
less of what substance is used to cause it, but the conditioning Is
specific for each substance. Often the preliminary Introduction of
the substance In question has taken place accidentally or obscurely,
or the sensitivity may be inherited; in other cases there is a clear
history of the previous introduction. Because spontaneous or hered-
itary cases occur, and because the history and other indications are
often unreliable, test doses are Introduced into the skin or the eye
before serums are Injected. Anaphy lactic shock, which is sudden
and often fatal, or the slower * 'serum sickness/* may be avoided by
the use of a type of serum different from the one previously Intro-
duced. The risks connected with serum treatment may also be over-
come, as A. Besredka has shown, by desensitization that is, by
beginning with extremely small doses and gradually Increasing
them.

Antigens causing reactions akin to those of anaphylaxis may gain
entrance to the body by Ingestion, by inhalation, by injection, from
a focus of infection, or from external contacts. Proteins are the com-
monest, but not the only, antigens. The list includes the pollens,
danders and many other air-borne substances of animal and vege-
table origin, foods, drugs, therapeutic serums, and bacteria and
their products. Diseases of allergy now form an important division
of internal medicine. They Include not only asthma, hay fever, and
serum sickness but also contact dermatitis in a wide variety of
forms. This whole domain of medical science and practice finds its
starting point in the investigations of Charles Richet.

1914

ROBERT BARANY

(1876-1936)

"For Ms work on the physiology and pathology of
the vestibular apparatus."

BIOGRAPHICAL SKETCH

ROBERT BARANY, AN AUSTRO-HUNGARIAN, WAS BORN IN
Vienna, on April 22, 1876. He was educated chiefly in the city of
his birth, and was graduated in medicine in 1900. After two years
spent at various German clinics in the study of internal medicine
and psychiatry, he returned to Vienna, where he soon restricted his
work to otology (the study of diseases of the ear) and related prob-
lems as they affect certain parts of the brain. He became famous for
his studies of the vestibular apparatus in the ear and of the cerebel-
lum (the "little brain," or that part of the brain behind and be-
neath the larger cerebrum; see below). In 1913-1914 he was
awarded a number of international prizes, culminating in his selec-
tion as Nobel laureate. The confusion which accompanied the out-
break of the First World War caused postponement of the 1914
award until 1915. At that time Barany was a Russian prisoner of
war in Siberia. Through the intercession of the Swedish Red Cross,
however, he was released, and the award presented to him through
diplomatic channels. After 1917 his work was done at Uppsala
University. He died in 1936, at the age of sixty.

84

: ROBERT BARANY 85

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"As a young otologist I practiced in the clinic of Privy Councillor
Professor Politzer in Vienna. Among my patients there were many
whose ears I had to flush out. A number of these patients com-
plained of dizziness after the flushing procedure. It naturally oc-
curred to me to examine their eyes, and there I observed marked
nystagmus [involuntary, spasmodic motion of the eyeballs, a jerky
rolling of the eyes]. I made a note of this observation. After a
while, when I had collected about twenty observations, I compared
them and was surprised to find the same observations recorded
every time. Then I recognized that a general law must underlie
these observations. I did not yet know, however, the basis of the
conformity to law. Chance came to my aid. One of the patients
whom I syringed explained to me: 'Doctor, I only get dizzy when
the water is not warm enough. When I flush out my ears for myself
at home and use warm enough water, I don't get dizzy/ There-
upon I called the attendant and instructed her to give me warmer
water for the flushing process. She explained that the water was
warm enough. I retorted that if the patient found the water too
cold, we had to adjust ourselves to the patient. The next time she
put very hot water in the bulb of the syringe. When I syringed the
patient, he cried out: 'But Doctor, the water is much too hot; now
I'm becoming dizzy again/ Hurriedly I observed the patient's eyes,
and noticed that now the nystagmus was exactly opposite in direc-
tion to that seen earlier when syringing with water that was too
cold. Then in a flash it became clear to me that naturally the tem-
perature of the water was responsible for the nystagmus. I drew
some conclusions from this at once. If the temperature is to blame,
then, to be sure, water of exactly body temperature must produce
no nystagmus and no dizziness. Experiment confirmed this conclu-
sion. I said further, if it is a matter of water temperature, then
nystagmus must be producible by syringing in normal people, too,

* Translated from ' "Nobel- Vortrag . . . von Dr. Robert Barany," Les Prix Nobel
en 1914-18.

*86 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

and not merely in people with suppurations of the ear. This in-
ference also proved to be right.

"On the ground of my previous studies, I did not doubt for a
moment that as regards this nystagmus it was a question of a reflex
initiated in the semicircular canals. [The three semicircular canals,
or ducts, which are membranous, are contained in corresponding
bony canals in the internal ear within the skull; the canals lie in
planes approximately at right angles to one another. Their func-
tion, briefly stated, is to initiate the reflexes which cause us to right
ourselves involuntarily by compensatory movements, in response to
changes in velocity or direction of motion. These reflexes effect
movements of eyes and limbs. There are also reflexes which influ-
ence the tone, or steady, continuous action, of the muscles respon-
sible, in their coordination, for posture.} Thence the further
conclusion was also obvious that the semicircular canals being
destroyed, this reflex must fail to appear. I now sought a case of
this kind in the rich material of the Vienna ear clinic. I had soon
found a case of severe suppuration of the middle ear, showing no
nystagmus reaction on long-continued flushing with quite cold
water. I diagnosed destruction of the labyrinth (with respect to the
semicircular duct apparatus) ; in point of fact the operation showed
the expected finding. This made clear the significance of the new
reaction for the diagnosis of diseases of the inner ear. Yet a series
of cases was required for corroboration. This was forthcoming.
, . . I had already perceived the significance of the caloric reaction,
and yet I did not know how to explain it. I thought it over in vain.
Then one day an idea struck me. I remembered the water heater,
and my astonishment, as a child, when I found the water just
above the fire quite cold, but right at the top the bath-oven was so
hot it burned the fingers. The labyrinth now represented in my
mind the water heater i.e., a vessel filled with fluid. The tempera-
ture of this fluid is naturally 37 C the body temperature. I squirt
cold water at one side of the vessel. What must happen? What
must naturally occur is that the water lying against this wall is
cooled down; in this way it acquires a higher specific gravity than
the surrounding water and sinks to the bottom of the vessel. On
the other hand, water still at body temperature takes its place. If I
syringe the ear with hot water, then the motion must be precisely

I9I4 : ROBERT BARANY 87

contrary. But the motion of the fluid must be altered if I alter the
position of the vessel. And it must be changed to the exact opposite
if I turn the vessel through 180. The test which had to be the
crucial experiment for this theory occurred to me at once. If syring-
ing, be it with cold fluid or hot, succeeded in evoking nystagmus
precisely opposite in direction for two positions of the head differ-
ing by 180, then the theory must be the right one. I now went to
the clinic and undertook the experiment. As it turned out, the
anticipated result appeared with the greatest clearness. Two posi-
tions of the head, encompassing between them 180, gave directly
opposite nystagmus reactions. . . ."

CONSEQUENCES IN THEORY
AND PRACTICE

"Barany's caloric test/* the first result of his study of the vestib-
ular apparatus, consists in irrigating the canal of the external ear
with either hot or cold water. This normally causes stimulation of
the vestibular apparatus resulting in nystagmus. In vestibular
disease, the response fails relatively or entirely. This method for
diagnosing disease of the semicircular canals is the most widely
used of several "Barany tests" and has borne his name to clinics
and hospitals the world over. But this was not the end of his investi-
gations. Starting from the work of Ramon y Cajal (see above, pp.
33-40), who traced the communications of the vestibular nerve,
and from the studies of the Dutch comparative anatomist Louis
Bolk, Barany concluded that influences on the musculature of the
whole body which result in disturbances of equilibrium pass from
the semicircular ducts by way of the cerebellum. The study of these
disturbances, and the belief that there is definite localization in
the cerebellum for movement, led him to devise certain tests for the
integrity of the control centers, as reflected in movement of the
extremities and even of particular joints. A normal subject with
his eyes shut will "past point" to the right beyond the spot he
attempts to touch, if the right vestibular apparatus has been stimu-
lated with cold water. The direction of "past pointing" is always
opposite to the direction of nystagmus. But Barany found that
spontaneous "past pointing" sometimes occurred. If the patient

88 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"past pointed' ' to the right, stimulation of the vestibular apparatus
to induce a swing to the left failed to work; it merely caused the
patient to point correctly. Barany assumed that "there are in
the cerebellum four centers . . . namely, a center directing to the
right, one to the left, one up, and one down. ... At any time
two of these centers work like two reins, between which the arm,
for instance, moves. If both of these reins are stretched equally
taut, then the arm moves without fail to each point desired. But
now I can pull one rein harder than the other. This happens if I
stimulate the semicircular duct apparatus." It is obvious that a lesion
of some sort, a local sickness in one of these centers, will act like
the cutting of a rein. Attempts to "pull" this rein will fail, as in
the instance of spontaneous "past pointing" mentioned above.
Hence it is possible to use Barany tests not only for diagnosing cer-
tain ailments in the inner ear but also for investigating some of the
activities of the cerebellum.

1915-1918

No Award

191,

JULES BORDET

(1870- )
ff For bis discoveries in regard to immunity. 9

BIOGRAPHICAL SKETCH

JULES (JEAN BAPTISTE VINCENT) BORDET, FAMOUS BELGIAN
bacteriologist and immunologist, was born on June 13, 1870, at
Soignies, Belgium. He studied at the University of Brussels, where
he was graduated as doctor of medicine in 1892. In 1894 he went
to the Pasteur Institute, Paris, where he was attache or preparateur
in MetchnikofPs laboratory until 1901, when he founded the
Pasteur Institute in Brussels and became its director. In 1907 he
was appointed professor of bacteriology at the University of Brus-
sels. His numerous and important contributions to immunology
made him widely known. He was elected a foreign member of the
Royal Society in 1916. His colleague, Octave Gengou, co-author of
the paper quoted below, was also a Belgian; he afterward (1902)
extended the work on complement fixation which is described
in the quotation. From the considerable range of Bordet's work in
immunology this particular contribution has been selected as of
outstanding importance to medicine.

DESCRIPTION OF THE PR IZE -WINNING
WORK*

"The serum of numerous animals contains alexin {now gen-
erally known as "complement/' the name given to it by Ehrlich},

* Translated from J. Bordet and O. Gengou, "Sur 1' existence de substances
sensibillsatrices dans la plupart des serums antimicrobiens," Anncdes de I'lnstitut
Pasteut, Vol. 15 (1901), pp. 289-302.

90

JULES BORDET 91

that is to say, an ill-defined material, its chemical constitution still
unknown, to the presence of which is attributed that property
which serums in general possess of exercising a destructive influ-
ence on diverse cellules and on certain microbes. The alexin loses
its activity when the serum which contains it is heated to 55. This
material is to be met with, in quite comparable amounts, in the
serum of normal animals and in that of vaccinated animals: arti-
ficial immunization does not modify it appreciably, either in
quantity or in character.

"When an animal is vaccinated against the cholera vibrio [bac-
teria}, the organism elaborates a particular substance, the preven-
tive or sensitizing material [amboceptor}, the presence of which
can be detected in the serum and which resists quite elevated tem-
peratures. By itself, it is not at all bactericidal for the vibrio. But
it favors considerably, and in a specific way, the destructive action
which the alexin can exercise on this microbe. One can also say
that the specific vibrio-killing property of cholera serum, although
due primarily to alexin . . . , results from the collaboration of
two substances, on one hand the alexin, on the other the favoring
(sensitizing) material with which only the serum of vaccinated
individuals is endowed in large degree. . . . [These ideas were
established by Bordet in 1895. He applied them, first, to cholera
serum, secondly, to specific hemolytic serums. He supposed the
phenomenon to occur more generally, but the method he had used
for these instances was not generally applicable. In brief it was
this. Cholera vibrios are destroyed (bacteriolysis) to a very marked
degree by immune serum from a vaccinated animal, to a very slight
degree by normal serum. The power of either serum may be
abolished by 55 of heat. But adding to normal, feebly active serum
a small amount of preheated immune serum, inactive in itself,
results in a strongly bactericidal mixture. Hence, the conclusion, as
above, that it contains a "sensitizer" (amboceptor) which adds to
the otherwise slight power of the "alexin" (complement) in the
normal serum. A similar method applied where hemolysis } rather
than bacteriolysis, was the revealing change. But where neither of
these changes took place another method was needed.}

"As a preliminary, we must recall to the reader an experiment

92 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

related a year ago in these Annales [Bordet, in May 1900}, and of
which the following is the principle:

"If one adds to a suitable quantity of the serum of a normal
animal, such as the guinea pig (serum recently obtained, unheated,
thus containing alexin), some red cells (of a rabbit for example)
{which have been] strongly sensitized (that is to say, mixed with
some hemolytic serum, active vis-a-vis these cells, and which has
been heated to 55 ), one observes . . . the destruction of the
corpuscles. At the end of a certain time some sensitized cholera
vibrios (added to cholera serum preheated to 55) are added to
the mixture, which is incubated at 37. One ascertains that the
vibrio . . . retains its normal form. Consequently one can affirm
that at the moment when the vibrios were introduced, the mixture
no longer contained alexin. . . . [This could be reversed i.e.,
the "alexin" could be used up by "sensitized** vibrios and would
then fail to hemolyze "sensitized" corpuscles.}

"These experiments have established . . . two quite distinct
ideas: (i ) Corpuscles or microbes, under the influence of sensitiza-
tion } acquire the power of absorbing alexin avidly, and thus of
making it disappear from the surrounding liquid. (2) In the same
serum, the same alexin can provoke either hemolysis or bacterioly-
sis. . . . {The authors assert as the aim of the present paper to
show that} to denote the existence of a sensitizer in an antimicrobic
serum one can use the property with which this substance is en-
dowed of causing the absorption of the alexin by the microbe which
it affects . .

"[Serum from a horse vaccinated against bacillus pestis, the
cause of plague} is heated to 56 for half an hour, at the same time
as some serum from a normal horse; this heating renders the alexin
inactive. A 24-hour culture of bacillus pestis on gelose [gelatinous
part of agar-agar, a solidifying agent used in culture mediums} is
diluted in quite a small amount of a physiological solution of
NaCl; one thus obtains a very turbid emulsion, rich in microbes.
Some serum is also prepared, well cleared of corpuscles by cen-
trif ugatioa, from a normal guinea pig bled the day before. This is
the alexic serum [i.e., serum containing alexin, or complement}.
The following six mixtures are prepared in test tubes: (a} This
tube contains: 2/10 c.c. alexic serum; 4/10 c.c. bacillus pestis emul-

1919 : JULES BORDET 93

sion; 12/10 c.c antiplague serum (preheated to 56). (b} [The
same as a except that] it contains, in place of antiplague horse
serum, 12/10 c.c. of normal horse serum (preheated to 56).
(c) [The same as a but without bacillus pestis emulsion.] (d)
[The same as b but without bacillus pestis. These four mixtures
contain the same dose of alexin.] (e] Contains 4/10 c.c. plague
emulsion; 12/10 c.c. antiplague serum. (/) Contains 4/10 c.c.
plague emulsion; 12/10 c.c. normal horse serum. These last two
tubes are the same, respectively, as a and b, except that they do not
contain alexin.

"One waits about five hours, while the mixtures remain at lab-
oratory temperature (15-20). Then one introduces into the dif-
ferent tubes, at the same moment, 2/10 c.c. of the following mix-
ture: 2 c.c. of serum (previously heated for half an hour to 55)
from a guinea pig treated in advance with three or four injections
of 4-5 c.c. of defibrinated rabbit blood; 20 drops of defibrinated
rabbit blood. In other words each tube receives two drops of very
strongly sensitized blood.

"Here is the result of the experiment: Hemolysis appears very
quickly, with very similar rapidity, in the tubes b, c 3 d. After 5-10
minutes these mixtures no longer contain intact corpuscles. In the
tube a, which contains, besides alexic serum, the bacilli and the
antiplague serum, hemolysis does not occur. The corpuscles remain
intact for days at a time. They also remain intact ... in the tubes
e and /, which do not contain alexin. Thus we see, first, that the
bacillus pestis mixed with normal horse serum does not absorb
alexin (or absorbs it only to an insignificant degree) ; second, that
the same bacillus, in the presence of antiplague serum from a vac-
cinated horse, fixes the alexin with great avidity, and makes it dis-
appear from the surrounding liquid; third, the antiplague serum,
without the addition of bacilli, leaves the alexin perfectly free.

"Consequently it is necessary to conclude that the serum of a
horse vaccinated against the bacillus pestis contains a sensitizer
which confers on this microbe the power of fixing alexin [comple-
ment]."

94 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

CONSEQUENCES IN THEORY
AND PRACTICE

Bordet and Gengou formed an effective team and worked to-
gether for years. (The organism called Hemophilus pertussis, the
cause of whooping cough, was originally known as the "Bordet-
Gengou" bacillus, after its discoverers; it was first described by
them in 1906-1907.) But the fundamental work which made pos-
sible the discovery set forth in the above quotation had been car-
ried out by Bordet some years earlier. His publication of 1895 had
shown two different substances to be involved in the phenomenon
of bacteriolysis. That the terminology has changed makes little dif-
ference. It was Bordet who discovered that two factors, not a single
antibody as previously supposed, are concerned in the lytic (de-
structive) action. One of these substances is present both in normal
and fresh immune serum and is thermolabile (subject to alteration
or destruction by heat) 9 the other is peculiar to the immune serum
and is thermostable (heat-resistant). He called these, respectively,
"alexine" (from the Greek alexo, "I ward off") and "substance
sensibilisatrice." These terms have been replaced by the names
given to the substances by Ehrlich, "complement" and "ambocep-
tor." It was found, chiefly as a result of Bordet's further experi-
ments, that lytic action is not limited to bacteria. Red blood cells
are destroyed by a similar mechanism, hemolysis.

"The possibility of ... a practical test [using immune serum}
was first made known by R. Pfeiffer (1894), who found that the
bacteriolytic destruction of cholera vibrios in the peritoneum was
so specific that this method could be employed for the differentia-
tion of cholera vibrios from vibrios otherwise indistinguishable.
Bordet (1895) utilized this principle and applied it in vitro [in
the test tube] instead of in vivo [in the living animal}. . . .

"Of particular medical importance is the so-called complement
fixation test . . . Gengou (1902) showed . . . that 'sensitizers'
(amboceptors) are developed in the blood-serum of animals which
have been injected with milk, and that such sensitizers are also
capable of fixing complement. . . . [I.e., Gengou further gen-
eralized the discovery.}

JULES BORDET 95

"These facts were extended by C Moreschi (1905), who
showed that complement fixation occurs in the presence of normal
serum mixed with the serum of an animal injected with normal
serum, and he demonstrated that extraordinarily small quantities
of serum (1/100,000 c.c.) can be detected by this method of
diagnosis. M. Neisser and Sachs (1905) recommended the method
for the diagnosis of blood in medico-legal work. In 1906 Wasser-
mann, Neisser, and Bruck published their historic account in which
they described the discovery of antibodies to syphilis antigen in
the serum of syphilitic monkeys. In the same year Wassermann and
Plaut (1906) , by demonstrating syphilitic antibodies in the cerebro-
spinal fluids of general paralytics [see below, p. 126], proved this
disease to be syphilis, and Wassermann, Neisser, Bruck and Schucht
(1906) demonstrated similar antibodies in the blood-serum of
syphilitics. Since that time the 'Wassermann reaction' has been prac-
tised to an enormous extent in the diagnosis of syphilis and is re-
garded as a test of deadly accuracy. The complement fixation test
has been permanently accepted also in the case of the diagnosis of
glanders." *

* William Bulloch, The History of Bacteriology (London and New York:
Oxford University Press, 1938), pp. 281-283.

1920

AUGUST KROGH

(1874-1949)

fe For Ms discovery of the regulation of the motor
mechanism of capillaries."

BIOGRAPHICAL SKETCH

AUGUST KROGH WAS BORN AT GRENAA, IN JUTLAND, DENMARK,
on November 15, 1874. He studied zoology at the University of
Copenhagen, receiving the M.A. degree in 1899. Even before this,
beginning in 1897, he had been carrying on research in the physi-
ology laboratory under Christian Bohr, with whom he continued to
work for some years. In 1902 he took part in an expedition to
Greenland to study arctic animals. Krogh early turned his attention
to studies in gaseous pressures, first in natural waters, afterward in
animal physiology. His doctoral thesis (1903) dealt with the
respiration of frogs. Much of his subsequent work on the pressures
of oxygen and carbon dioxide in the blood was carried out in col-
laboration with his wife, Dr. Marie Krogh. That the affinity of
blood for oxygen depends upon carbon dioxide pressure was
demonstrated in 1904 by Bohr, Hasselbalch, and Krogh. In 1908
Krogh became associate in animal physiology at the University of
Copenhagen, but had no laboratory until 1910 and did not become
titular professor until 1916. His investigations, in some of which
Lindhard was associated, were concerned chiefly with the physi-
ology of respiration and blood circulation, but covered a wide
range of interests.

96

1920:

AUGUST KROGH

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The current view of the capillary circulation, at least until a few
years ago, was . . . that blood is flowing continuously through
all [capillaries] at rates which are determined by the state of con-
traction or dilatation of the corresponding arterioles, and that the
dilatation of an arteriole will cause a rise of pressure in the cor-
responding capillaries, which will become passively expanded, to
contract again by their own elasticity when the pressure is reduced.
An increase in [arterial and arteriolar] current must always
be accompanied by a corresponding increase in capillary pressure^
and when the requirements are small the quantity of blood in a
large number of the capillaries would serve no useful purpose. A
much more effective distribution would obviously be obtained if
the capillaries themselves were contractile, if in a resting organ only
a limited number of capillaries . . . were kept open. . . . This
hypothetical conception was to me personally the starting point and
guide in the experimental study of capillary contractility. . . .

[Krogh here reviews earlier work on the subject, beginning with
S. Strieker (1865) and extending to H. H. Dale and A. N.
Richards (1918). Most of this work was based on direct micro-
scopic observations of capillaries. Sources of error inherent in the
method were not sufficiently guarded against. V. Ebbecke, however,
and at the same time (1917) Cotton, Slade, and Lewis, had pub-
lished evidence based on the local vasomotor reactions of the skin
and internal organs, and Dale and Richards had compared the ac-
tions of three "depressor" drugs, leading to the conclusion that
two of them, histamine and adrenaline, must produce relaxation of
the capillary wall.]

"My own first contribution to the problem ... was published
in Danish in 1918 ... and appeared in the British Journal of
Physiology ( 1919) .... I found it possible to observe at least the
superficial capillaries of muscles both in the frog and in mammals
through a binocular microscope. . . . Resting muscles observed

* From August Krogh, The Anatomy and Physiology of Capillaries (New Haven:
Yale University Press, 1922), Silliman Memorial Lectures, Lecture II.

98 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

in this way are usually quite pale, and the microscope reveals only
a few capillaries at fairly regular intervals. These capillaries are so
narrow that red corpuscles can pass through only at a slow rate
and with a change of form from the ordinary flat discs to elongated
sausages. When the muscle ... is stimulated to contractions a
large number of capillaries become visible and dilated. . . . Since
capillaries, even in a group fed by the same arteriole, do not all
behave in the same way, the changes obviously cannot be due to
arterial pressure changes. . . .

" [Measurements showed the average distance between open
capillaries in resting muscle to be much greater than in muscle
which had just contracted.] The measurement of distances between
open capillaries made upon living specimens could not, of course,
be very accurate. ... I had, therefore, to try and devise a method
by which the state of the vessels at any given moment could be
studied after fixation. This I succeeded in doing by injecting an
India ink solution . . , [made] isotonic with the blood and [freed
from] toxic substances. . . . When a suitable quantity of India
ink is introduced into the circulation of a living anaesthetized ani-
mal it is evenly mixed with the blood, and if the animal is suddenly
killed by stopping the circulation a few minutes later, and prepara-
tions are made from the muscles and other organs, these show the
capillaries which were open at the time.

M 0n frogs I found by this method that there were large differ-
ences between different organs in the number of open capillaries.
The skin, liver and brain [organs which are constantly active} were
always well injected, with all, or nearly all, capillaries open. The
tongue was generally white and nearly bloodless, when not stimu-
lated before being removed. The empty stomach and intestines
had only a small number of open capillaries. The injection of mus-
cles was variable, but in most of the resting muscles few capillaries
only were open, while muscles which had been [stimulated} before
stopping the circulation were almost black from the large number
of injected capillaries/'

1920: AUGUST KROGH 99

CONSEQUENCES IN THEORY
AND PRACTICE

It was stated above, in the biographical sketch, that a large part
of Krogh's work was concerned with the physiology of respiration
and circulation. His primary interest appears to have been respira-
tion, and many of his studies of circulatory mechanisms were aimed
at finding out how the circulation carries oxygen to the tissues.
Some of his earlier studies had dealt with gas exchange in the
lungs. When the organism is under stress, breathing quickens and
deepens. In determinations of the amount of blood which the heart
pumps around the blood-vessel circuit in one minute, Krogh had
found that when muscular work is performed there is a marked
increase in the blood flow. Thus the extra oxygen taken in is passed
along to the tissues. But a problem remained. Under these condi-
tions of stress the oxygen of each cubic centimeter of blood is used
up more quickly than when the body is at rest, so that obviously the
demand for extra oxygen is not being met solely by the greater
cardiac output. In the experiments described in the quotation,
Krogh found that there was a great variation in the number of
capillaries which might be open at a given moment. The num-
ber of patent vessels was directly related to the activity of the tissue
at the time, being much larger in active than in resting muscle.
Sometimes in resting muscle he could observe that a tiny vessel was
so constricted that the oxygen-bearing red corpuscles could not enter
it, the plasma alone being allowed to pass. (This he called "plasma
skimming/') In active muscle, on the other hand, a larger number
of vascular channels were opened, and they were opened more
widely, so that as many red corpuscles as possible might carry their
oxygen to the tissues. The extra blood supplied by the greater blood
flow through the whole body was passed into as many as possible of
the small channels where oxygen is given up in those parts of the
body needing it; elsewhere the capillaries were constricted. Krogh
considered that these changes play an important role in the mech-
anism for the regulation of the oxygen supply to tissues.

The physiology of the capillaries is a subject of great importance
to medicine. Studies in normal and disordered blood pressure re-

100 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

quire minute and accurate knowledge of the behavior of the
smaller divisions of the arterial tree. Inflammatory symptoms and
allergic reactions of certain kinds depend on capillary changes. The
permeability of capillary walls is altered in some hemorrhagic
diseases. Accumulations of fluids in dropsical maladies are also
determined in this way, and changes in the state of the capillaries
explain many of the symptoms of shock. August Krogh has made
raluable contributions to this basic knowledge of the anatomy and
physiology of the capillaries.

REFERENCES

REHBERG, BRANDT P. "August Krogh, November 15, i874-September
13, 1949," Yale Journal of Biology and Medicine, Vol. 24 (1951),
pp. 83-102*

1921

No Award

1922

ARCHIBALD VIVIAN HILL

(1886- )

"For his discovery relating to the production of
heat in the muscles"

OTTO MEYERHOF

(1844-1951)

ff For Ms discovery of the fixed relationship between

the consumption of oxygen and the metabolism of

lactic acid in muscle' 9

BIOGRAPHICAL SKETCHES

HILL

ARCHIBALD VIVIAN HILL, DISTINGUISHED BIOPHYSICIST, WAS
born in England in 1886 and was educated at BlundelFs School,
Tiverton. He won scholarships to Trinity College, Cambridge,
where he studied mathematics. One of his teachers was W. M.
Fletcher, who was then associated with F. G. Hopkins in investi-
gating the formation of lactic acid in muscle. Hill apparently turned
to physiology on Fletcher's urging, and J. N. Langley suggested
that he undertake the work for which he afterward received the
Nobel Prize. In 1910-1911 he studied in Germany under Biirker

102

1922: HILL AND MEYERHOF 103

and Paschen. He continued his work at Cambridge until the out-
break of the First World War, in which he served from 1914 to
1919. In 1920 he was appointed to the chair of physiology at
Manchester, and from 1923 to 1925 he was Jodrell Professor of
Physiology, University College, London. In 1926 came his ap-
pointment as Foulerton Research Professor of the Royal Society.
As an Independent Conservative he was M.P. for Cambridge Uni-
versity from 1940 to 1945. He was also a member of the War
Cabinet Scientific Advisory Committee, as well as of many other
scientific and defense committees.

MEYERHOF

OTTO MEYERHOF, ONE OF THE PIONEERS OF PRESENT-DAY Bio-
chemistry, was born in Hanover on April 12, 1884. His family
moved to Berlin and he attended the Wilhelms-Gymnasium there,
then studied medicine in Freiburg, Berlin, Strasburg, and finally
Heidelberg, where he was graduated in 1909, having written a dis-
sertation in psychiatry. He then busied himself chiefly with psy-
chology and philosophy, publishing a book entitled Contributions
to a Psychological Theory of Menial Diseases and an essay called
"Goethe's Methods in Natural Philosophy." Under the influence
of Otto Warburg, he transferred his attention to physiology; while
in Heidelberg he also worked at physical chemistry. In 1912 he
went to Kiel. Lectures delivered in England and the United States
appeared as a book, The Chemical Dynamics of Living Matter,
which helped to make him widely known. Meyerhof occupied a
variety of distinguished positions in German science before Ger-
many's scientific and political decline. By 1929 he had become head
of the Department of Physiology in the Institute for Medical Re-
search in Heidelberg. Forced to leave Germany in 1938, he con-
tinued his work at the Institut de Biologic Physico-Chimique in
Paris. After the invasion of France, in 1940, he escaped with his
wife to the United States, where he was appointed research profes-
sor at the Department of Physiological Chemistry, University of
Pennsylvania. Professor Meyerhof died in Philadelphia on October
6, 1951.

104 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE- WINNING

WORK

HILL *

"In the study of thermal changes [in muscle] the most con-
sistent and valuable results have been obtained by utilising the
isometric contraction of the sartorius muscle of the frog. [The
sartorius is a straplike thigh muscle. "Isometric contraction" refers
to the fact that the two ends of the muscle are fixed, so that the
effort of contraction does not actually shorten it.] ... The
isometric contraction has the advantage, firstly, that energy is not
liberated in it in any other form than heat . . . and secondly, that
. . . movements of the instruments are prohibited. ...

"The fundamental difficulty . . . is the smallness of the changes
involved and their rapidity. In the muscle twitch of a frog's sar-
torius at 20 the rise of temperature is not more than 0.003 C
and the time occupied in the earlier phases (as distinguished from
the recovery process) is only a few hundredths of a second. The
first requisite therefore is a very sensitive thermometric apparatus
and great freedom from temperature changes, the second is ex-
treme rapidity and lightness in the recording instruments. . . .
[Hill then discusses thermometric apparatus and concludes that a
very light, delicate, and sensitive thermopile is the only possibility.
A thermopile is a kind of battery, made of alternating pieces of two
different metals; heat applied to the junctions, or couples, gives rise
to an electric current, the strength of which is measured by a gal-
vanometer; an indirect measure of the heat is thus provided, and
very minute temperature changes are detectable. Because of the
nature of the apparatus, these readings cannot be accepted at face
value, but the factors which distort the results can be eliminated by
a control experiment.] Fortunately it is possible to make a direct
calibratioa of the instruments [i.e., to scale them in such a way that
results may be read as degrees of temperature] by liberating in the
same muscle, in the identical position on the thermopile at the close

* From A. V. Hill, "The Mechanism of Muscular Contraction," Les Prix Nobel
en 1923,

1922: HILL AND MEYERHOF 105

of an experiment, a known amount of heat . . . [first killing the
muscle].

"One of my earliest observations on the subject was that the
galvanometer deflection persists much longer in a live muscle than
in a control experiment. . . . This phenomenon can be due only
to a delayed production of heat, and I found that this Recovery*
heat as we called it is appreciable only in oxygen, being abolished
by keeping the muscle in nitrogen, or by previous exercise violent
enough to use up the oxygen dissolved in the muscle. ... A
rough estimate of the magnitude of the recovery heat production
made it approximately equal to the total initial heat. [Hill's later
work, with the help of W. Hartree, showed its magnitude to be
1.5 times the total initial heat.} This estimate appeared to answer
unequivocally a question long debated, on the fate of lactic acid in
the recovery process. Fletcher and Hopkins had found [in 1907}
that lactic acid is removed in the presence of oxygen, though the
same muscle at the end of the recovery process can liberate during
exercise or rigor the same amount of lactic acid as before. Was
lactic acid removed by oxidation, or by restoration to the precursor
from which it came? Previous experiments of my own had shown
that the production of one gramme of lactic acid in rigor leads to
the liberation of about 500 calories. . . . Peters had proved that
the production of i gramme of lactic acid in exercise . , . leads
to the liberation of about the same quantity of heat. Hence, if the
recovery heat were equal to the initial heat, the oxidative removal
of one gramme of lactic acid would lead to the production of
about 500 calories, which is less than i/yth of the heat of oxidation
of the acid. The conclusion . . . seemed to me to be inevitable
that the lactic acid is not removed by oxidation. . . .

"The most important point brought out by - . . analysis of the
initial heat-production is that relating to the influence, or rather to
the absence of influence, of oxygen. . . . No difference whatever
can be detected between the curves obtained (a) from a muscle in
pure oxygen and (b) from one which has been deprived of oxygen
in the most rigorous manner for several hours. The conclusion is
important and supplements the observations previously described
on the recovery heat-production. Oxygen is not used in the primary
break-down at all: it is used simply in the recovery process."

106 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

MEYERHOF *

"Let us first of all consider an excised frog's muscle, working
in a maximal supply of oxygen; chemical analysis then reveals only
this, that a definite amount of glycogen disappears from the muscle,
while a quantity of oxygen is taken up and carbonic acid given off
quite adequate for this oxidation. [Glycogen is a compound carbo-
hydrate, 'animal starch/ found in most of the body tissues, espe-
cially in the liver and muscles.] But we can analyze the connection
of events more closely if we first let the muscle work under anaero-
bic conditions [i.e., without oxygen] and then expose it to oxygen.
During the anaerobic phase of work, lactic acid accumulates in the
muscle, approximately in proportion to the work done. Simultane-
ously a corresponding amount of glycogen disappears. ... In the
second oxidative phase, on the other hand, the lactic acid which
had been formed disappears, while a quite definite amount of extra
oxygen is taken up, and actually the disappearance of lactic acid
during this period bears an exact proportion to the increased con-
sumption of oxygen. Meantime the oxygen suffices for the oxida-
tion of no more than a fraction of the vanished lactic acid; the rest,
in total fatigue about three quarters of the whole lactic acid, reverts
quantitatively into glycogen. I may say ... that this ratio of
oxidized lactic acid to the acid which has disappeared is not con-
stant under all conditions."

CONSEQUENCES IN THEORY
AND PRACTICE

The complex of chemical events through which every physi-
ological activity is carried on is a tangled skein to undo, and while
a great deal is known about the body's chemistry, it is generally the
case that each particular process is understood only up to a point; to
push beyond this point is, of course, the object of research, and
explanations which remain true in principle are constantly being
revised in detail. This is what has happened in the case of Meyer-

* Translated from Otto Meyerhof, "Die Energieumwandlungen im Muskel,"
Les Prix Nobel en 1923.

1922: HILL AND MEYERHOF 107

hof 's discovery. A fundamental point of great importance in muscle
physiology was revealed by the work for which he won the Nobel
Prize; but the chemistry of muscle is rather more complicated than
it appeared at the time, and the work of other chemists, with his
own later work, has brought about some revision and extension in
the explanations which were given then. Hence the brevity of the
quotation above.

Some fifteen years before Hill and Meyerhof delivered their
Nobel lectures, W. M. Fletcher and F. G. Hopkins (the latter to
become a Nobel laureate in 1929 for his work on vitamins) had
shown that lactic acid is an essential part of the muscle machinery.
It appears only gradually in a resting muscle, but rapidly during
work. It accumulates more and more, until, when it reaches a con-
centration of a few tenths of one percent, the muscle becomes in-
capable of further contraction. This lactic acid disappears in the
presence of oxygen; the fully recovered muscle is then able to work
again and to produce as much lactic acid as before.

These changes of accumulation or removal of the acid could be
detected only after evoking a series of responses in the muscle.
Each change actually represented a summation of many changes.
To study the transformations taking place in a muscle fiber during
and immediately after contraction, to study the instantaneous and
contemporary events, seemed beyond the reach of chemistry. The
only change recorded in this flash-of -lightning way was the con-
traction itself; but this muscle twitch is merely the final result, the
end product of activity. The mechanical record of a unit response
told little; the chemical record was apparently not to be had. But
the investigation of heat production seemed promising, for heat is
associated with the chemical events which cause contraction. In the
manner, and with the results, so clearly set forth above, A. V. Hill
made use of this approach. It then appeared that the working phase
of muscular activity, the actual contraction, is not dependent on
oxygen, which is required, rather, for the recovery phase. The
oxygen requirement for an exertion may even be met after the
event; the body may assume an "oxygen debt," which explains the
heavy breathing of an athlete when the race is over. Hill's thermal
data had now to be fitted into the larger picture of chemical hap-
penings in muscle.

108 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Meyerhof found that as lactic acid accumulates a corresponding
amount of glycogen disappears, no oxygen being supplied. This
disappearance of glycogen was also observed in the presence of
oxygen, but without the accumulation of lactic acid. Carbon dioxide
was given off and more oxygen was consumed; but the increased
oxygen consumption was only enough to account for the oxidation
of a small part of the lactic acid. What happened to the rest? At
the time of its disappearance the glycogen content was found to
have increased. Meyerhof concluded that glycogen breaks down
to form lactic acid in a contracting muscle, that lactic acid plays
the dominant part in the actual contraction, and that the small part
of it which is then oxidized supplies energy for the reconversion of
the remainder into glycogen. That this is not the whole story was
soon revealed, and the biochemistry of muscle has commanded
much attention ever since. A series of complicated enzymatic reac-
tions has been discovered; furthermore, considerable differences
have been found between the mechanism of these events in frog
muscle and in mammalian muscle. Embden, Lundsgaard, and
Szent-Gyorgyi have made important contributions to the increas-
ingly complex development, and Meyerhof himself published
further studies (1938) on glycogen resynthesis. Half of the Nobel
Prize for 1947 was awarded to C. F. and G. T. Cori jointly "for
their discovery of how glycogen is catalytically converted" (see
below, pp. 248-253).

Although Parnas and Wagner (1914) had shown that glycogen
was the precursor of lactic acid, it was Meyerhof who demonstrated
that the disappearance of the lactate could not be attributed to
oxidation, and who first advanced the view that it undergoes re-
synthesis to form glycogen. Despite later extensions of knowledge
this has remained a basic contribution to the understanding not
merely of muscular action but of carbohydrate metabolism gen-
erally, (On further contributions of both Hill and Meyerhof, see
below, pp. i93>2530

REFERENCES

H. [ILL], A. V. "Otto Fritz Meyerhof," The Lancet, Oct. 27, 1951, pp.
790-791.

1923

FREDERICK GRANT BANTING

(1891-1941)

JOHN JAMES RICHARD
MACLEOD

(1876-1935)
"For their discovery of insulin."

BIOGRAPHICAL SKETCHES

BANTING

FREDERICK G. BANTING WAS BORN ON NOVEMBER 14, 1891,
near Alliston, Ontario. He was educated In local schools and then
attended the University of Toronto, where he registered as a stu-
dent of divinity but soon transferred to medicine. He completed
his medical studies in 1916 and served overseas as a medical officer
from 1917 to 1919. In 1918 he was awarded the Military Cross for
heroism under fire. Following a year of the study of orthopedic
surgery in Toronto, he commenced practice in London, Ontario,
but remained less than a year. Carrying out part-time teaching
duties at the University of Western Ontario, he became interested
in diabetes. In 1921 he returned to Toronto to undertake research
on this problem in Professor Macleod's laboratory, where he was
associated with C H. Best, J. B. Collip, and a number of others.

109

110 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

His research and its successful issue are described below. Insulin
was isolated in 1921 and the first patients were treated in 1922.
In 1923 Banting became professor of medical research. The Bant-
ing Institute was opened in 1930 and Banting was knighted in
1934. In later years he was particularly interested in cancer re-
search. In February 1941, while acting as liaison officer between
British and North American medical scientists in the Second World
War, he was killed in an aircraft disaster in Newfoundland.

MACLEOD

J. J. R. MACLEOD WAS BORN IN CLUNY, PERTHSHIRE, SCOTLAND,
on September 6, 1876. He was educated at the Aberdeen Grammar
School and the University of Aberdeen, studying medicine at
Marischal College. He was graduated in 1898, was awarded the
Anderson Research Travelling Fellowship, and studied biochem-
istry in Leipzig under Siegfried and Burian. In 1900 he became
attached to the London Hospital Medical College, as demonstrator
in physiology under Leonard Hill. In 1903 he was appointed
professor of physiology at the Western Reserve University, Cleve-
land, Ohio, where he remained for fifteen years; during most of
this time he carried on investigations in carbohydrate metabolism.
In 1918 he accepted the position of professor of physiology at the
University of Toronto, where the work on insulin was performed.
In 1928 he returned to Scotland as professor of physiology at the
University of Aberdeen. Here he continued his research both
within the University and at the Rowett Research Institute. He also
served on the Medical Research Council. In his later years Professor
Macleod fell victim to a crippling arthritis. His health gradually
became worse and he died on March 16, 1935. His scientific,
literary, and educational work was very extensive. He was the
author of several books* including a well-known text, Physiology
and Biochemistry in Modern Medicine. He was very successful as
a teacher, and some of the most distinguished medical scientists
of the present day in the United States and Canada were trained
in Macleod's laboratory.

1923: BANTING AND MACLEOD 111

DESCRIPTION OF THE PRIZE- WINNING

WORK

BANTING *

"On October 3oth, 1920, I was attracted by an article by Moses
Baron, in which he pointed out the similarity between the degenera-
tive changes in the acinus cells of the pancreas following experi-
mental ligation of the duct, and the changes following blockage of
the duct with gall-stones. [Acinus cells secrete a digestive juice and
are distinct from hormone-producing cells.} Having read this arti-
cle the idea presented itself that by ligating the duct and allowing
time for the degeneration of the acinus cells, a means might be
provided for obtaining an extract of the islet cells free from the
destroying influence of trypsin and other pancreatic enzymes. [The
islet cells secrete the hormone.}

"On April 14111, 1921, I began working on this idea in the
Physiological Laboratory of the University of Toronto. Professor
Macleod allotted me Dr. Charles Best as an associate. Our first step
was to tie the pancreatic ducts in a number of dogs. At the end of
seven weeks these dogs were chloroformed. The pancreas of each
dog was removed and all were found to be shrivelled, fibrotic, and
about one-third the original size. Histologkal examination showed
that there were no healthy acinus cells. This material was cut into
small pieces, ground with sand, extracted with normal saline. This
extract was tested on a dog rendered diabetic by the removal of the
pancreas. Following the intravenous injection the blood sugars of
the depancreatized dogs were reduced to a normal or subnormal
level, and the urine became sugar free. There was a marked im-
provement in the general clinical condition as evidenced by the fact
that the animals became stronger and more lively, the broken down
wounds healed more kindly, and the life of the animal was un-
doubtedly prolonged. . . .

"The second type of extract was made from the pancreas of
dogs in which acinus cells had been exhausted of trypsin by the
long continued injection of secretin. [See above, p. 21}

* From F. G. Banting, "Diabetes and Insulin," Les Prix Nobel en 1924-2$.

112 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

'The third type of extract used in this series of experiments was
made from the pancreas of foetal calves of less than four months
development. Laguesse had found that the pancreas of the new-
born contained comparatively more islet cells than the pancreas of
the adult. Since other glands of internal secretion are known to
contain their active principle as soon as they are differentiated in
their embryological development, it occurred to me that trypsin
might not be present since it is not used till after the birth of the
animal. Later I found that Ibrahim had shown that trypsin is not
present till seven or eight months of intrauterine development.
Foetal extracts could be prepared in a much more concentrated solu-
tion than the former two varieties of extract. It produced marked
lowering of blood sugar, urine became sugar free and there was
marked clinical improvement. Its greatest value however was that
the abundance in which it could be obtained enabled us to investi-
gate its chemical extraction.

"Up to this time saline had been used as an extractive. We now
found that alcohol slightly acidified extracted the active principle,
and by applying this method of extraction to the whole adult beef
pancreas active extracts comparatively free from toxic properties
were obtained. . . .

"The extracts prepared in this way were tried on depancreatized
dogs and in all cases the blood sugar was lowered. . . . Diabetic
dogs seldom live more than 12 to 14 days. But with the daily
administration of this whole gland extract we were able to keep a
depancreatized dog alive and healthy for ten weeks.

"The extract at this time was sufficiently purified to be tested on
three cases of diabetes mellitus in the wards of the Toronto Gen-
eral Hospital. There was a marked reduction in blood sugar and
the urine was rendered sugar free. . . ."

"The invariable lowering of the blood sugar which was ob-
served to result from the administration of insulin in animals
rendered diabetic by pancreatectomy, raised the question as to

* From J. J. R. Macleod, "The Physiology of Insulin and Its Source in the
Animal Body," Les Prix Nobel en 1924-25,

1923^ BANTING AND MACLEOD 113

whether such would also occur in those forms of hyperglycaemia
which can be induced by other experimental procedures, such as
the injection of epinephrin, piqure or asphyxia. As the first step
in the investigation of this question, Collip injected insulin into
normal rabbits and found the blood sugar to become lowered, thus
furnishing a valuable method for testing the potency of various
preparations and, therefore, for affording a basis for their physi-
ological assay. At the same time it was found that neither piqure,
nor epinephrin, nor asphyxia caused any hyperglycaemia in rabbits
in which, as a result of injection with insulin, the blood sugar was
at a low level to start with.

"Peculiar symptoms (convulsions and coma) were observed in
many of the injected animals, and it was soon possible to show that
these were related to the lowering of the blood sugar and that
they usually supervened when this was about 0.045 per cent. Some-
times the animals recovered spontaneously from these symptoms,
but more frequently the coma became so profound, with marked
fall of body temperature, that death occurred. That the lowering of
blood sugar is closely related to the occurrence of the symptoms,
was proved by finding that the subcutaneous injection of a solu-
tion of glucose was followed, almost immediately, by complete re-
covery, even in cases in which death was imminent from deep
coma. It has been found, in collaboration with Noble, that glucose
is remarkably specific in this regard. . . /'

CONSEQUENCES IN THEORY
AND PRACTICE

Long before 1922 the dietary treatment of diabetes had been
developed to a high degree of refinement. This treatment, although
it helped to minimize symptoms and prolong life, was far from
satisfactory, since only the milder cases could be kept under con-
trol and even these very often grew worse. Diabetes was then a
severe debilitating disease, ultimately fatal in a great majority of
cases, usually rapidly fatal in children. Infections of various kinds
were very likely to supervene, surgery was most hazardous, and
childbearing was dangerous to both mother and child. After the
introduction of insulin it became possible to control most cases,

114 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

and all the incidental dangers were diminished or removed. Life
was greatly prolonged and useful activity restored. Unfortunately
the diagnosis of the disease and the use of the remedy have not
been universal even in the Americas and Europe. Full realization
of the benefit of the discovery has therefore never been attained.
None the less the transformation in the therapy of diabetes has
been as striking as any single advance in modern medicine.

At the time when Banting, Best, Macleod, and Collip were
carrying on their research in Toronto, other workers were pursu-
ing the same end in several other centers. After the discovery was
announced a further impetus was given to this research and valu-
able results were achieved in the study of carbohydrate metabolism.
On the practical side, H. C. Hagedorn and D. A. Scott were re-
sponsible for the production of protamine-zinc insulin, which has
a prolonged effect. On the side of "pure" research, B. A. Houssay,
in the year after insulin was discovered, began his related studies
of the function of the pituitary body (see below, p. 244) . These
are only two examples of the work which followed the stimulus of
the Toronto discovery. A "working cure" for diabetes, a therapy
of replacement of the deficient hormone, had been introduced by
the Toronto group, and the search for underlying factors in the
genesis of the disease had been given not only a new stimulus but
a new basis in added knowledge from which to proceed.

REFERENCES

HARRIS, SEALE. Bantings Aiiracle (Philadelphia: Lippincott, 1946).
STEVENSON, LLOYD. Sir Frederick Banting (Toronto: Ryerson Press;

Springfield, 111.: Thomas, 2nd ed., 1947).

1924

WILLEM EINTHOVEN

(1860-1927)

"For Ms discovery of the mechanism of the electro-
cardiogram"

BIOGRAPHICAL SKETCH

WILLEM EINTHOVEN WAS BORN ON MAY 21, 1860, IN THE
Dutch East Indies, where his father was a practicing physician.
When Wiilem was ten years old his father died; his mother
returned to Holland with her six children and settled in Utrecht.
In 1878 Einthoven began the study of medicine at the University,
where his teachers included the physicist Buys Ballot, the anatomist
Koster, and the great physiologist and ophthalmologist F. C.
Donders. He became doctor of medicine in 1885 and was called
to Leyden in the same year to succeed Heynsius in the chair of
physiology; until 1905 his department was also responsible for
the teaching of histology. Einthoven approached physiology as a
physicist, no doubt partly, at least, as a result of his training in
Utrecht; but his knowledge of anatomy, histology, and optics
was also of great value to him in his famous work of devising the
modern electrocardiograph and interpreting the data obtained by
its use. This naturally led him toward pathological physiology
and clinical medicine. Einthoven died in 1927.

115

11<$ NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE-WINNING
WORK*

"The string galvanometer consists of a delicate thread, conduct-
ing electric current, stretched like a string in a magnetic field. As
soon as the thread is electrified, it deviates from its equipoise in
a direction at right angles to the direction of the magnetic lines of
force. The magnitude of the deviation is proportional to the
strength of the current flowing through the thread, so that this
can be easily and exactly measured. . . . [This instrument, in-
vented by Einthoven, is the essential part of the modern electro-
cardiograph. The "string" of the latter is a fiber of finely spun
silver-coated quartz glass, 0.002 mm. in diameter, or about -J of
the diameter of a red blood cell; platinum has also been used in
place of silvered quartz. A beam of light, directed through holes
in the arms of the magnet, throws the shadow of the string on a
photographic plate or film, or on sensitive paper, through a series
of lenses which magnify the image. This photographic surface, in
a camera of special design, moves at an appropriate speed to
record the successive positions of the string in its lateral move-
ments, or deflections. The sensitivity of the string is standardized so
that a deflection of a certain magnitude represents a certain strength
of current. The record is marked out in horizontal lines (to meas-
ure the magnitude of deviation, and hence the strength of cur-
rent) and vertical lines (to indicate the time intervals). Various
technical refinements have from time to time been introduced.}

'"Just as every muscle in its contraction generates an electric cur-
rent, so also in the heart there is an evolution of electricity with
every systole [contraction]. This was first described by Kolliker
and Miiller. The English physiologist Augustus D. Waller then
showed that differences in potential developed in the heart are con-
ducted to different parts of the body, and that with a sensitive
measuring instrument, the capillary electrometer, one is in a posi-
tion to observe the variations in potential of the human heart.
[The capillary electrometer consists of a capillary tube filled with

* Translated from Willem Einthoven, "Das Saitengalvanometer und die Messung
der Aktionsstrome des Herzeos," Les Prix Nobel en 1924-1925.

1924: WILLEM EINTHOVEN 117

weak acid; a globule of mercury, placed in the center, moves to-
ward the negative pole when an electric current is passed through
the tube, and the image of the mercury is projected for photo-
graphic record.} One needs only to lead the current from the
hands and feet to the measuring instrument in order to see the
variations in electric current, which show the same rhythm as
the heart action.

"If one records the deviations of the measuring instrument one
obtains a curve, which was called the electrocardiogram. But be-
cause of the imperfections of the capillary electrometer the curve
directly recorded does not portray in an exact manner the actual
variations in potential that have occurred. To get an exact picture,
one must construct a new curve based on the peculiarities of the
instrument used and the data of the recorded curve, work requir-
ing considerable time. This circumstance stood in the way of the
practical application of electrocardiography to the investigation of
cardiac patients, and general interest in the ECG first developed
later, after the string galvanometer made it possible to register the
required pattern directly, easily, and quickly, and with satisfactory
accuracy. ..."

CONSEQUENCES IN THEORY
AND PRACTICE

Einthoven first constructed a string galvanometer in 1903. From
1906 to 1921 he gradually improved it. It came into fairly general
use in hospitals, and the modern electrocardiograph is based on the
same principles. By 1906 Einthoven had observed that different
types of heart disease show different, and distinctive, tracings on
the electrocardiogram. Between 1908 and 1913 he worked on the
interpretation of the normal tracing, so as to provide a secure
basis for the understanding of deviations from the normal result.
His interpretation of each wave and complex in the recorded curve
was worked out during this period, and the Prize was actually
awarded not for the invention of the string galvanometer, but "for
his discovery of the mechanism of the electrocardiogram."

Einthoven's work was confirmed and extended by a number of
other scientists, particularly by Thomas Lewis. Analysis of the

118 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

symptoms of heart disease as seen in the electrocardiogram was
developed in detail by a generation of cardiologists who had been
provided by Einthoven with a precise tool for their study. This
method often makes for quicker and more reliable diagnosis. When
recorded serially, electrocardiograms may provide decisive evidence
in questionable cases of coronary thrombosis. They aid in localizing
the site of the area affected by obstruction of a coronary vessel
(the area of "infarction") . In this and other forms of heart disease
they establish the nature of the disturbances of the heart's rhythm or
mechanism. Often they are of great value in following the course
of healing, and so help to determine the nature of treatment.

1925

No Award

1926

JOHANNES FIBIGER

(1867-1928)
' f For Ms discovery of the Spiroptera carcinoma.

BIOGRAPHICAL SKETCH

JOHANNES ANDREAS GRIB FIBIGER WAS BORN IN SILKEBORG,
Denmark, on April 23, 1867. He finished his medical studies in
1890. From 1891 to 1894, after hospital work and some further
study with Koch and Behring, he was assistant to C J. Salmonsen
in the bacteriology laboratory of the University of Copenhagen.
Then, until 1897, he was associated with the Hospital for Con-
tagious Diseases in Copenhagen, meanwhile (1895) obtaining his
doctoral degree with a thesis on the bacteriology of diphtheria.
After 1897 he worked at the Institute of Pathological Anatomy of
the University and in the army bacteriological laboratory. In 1900
he was named professor of pathological anatomy and head of the
Institute. He carried out a large number of official commissions and
took part in the direction of numerous institutes and societies. He
was co-editor, as well as one of the founders, of Acta Pathologica
et Microbiologica Scandinavica; he was also co-editor of Zieglers
Beitrage. Fibiger died on January 30, 1928, in Copenhagen, after
a short illness.

120

1926: JOHANNES FIBIGER 121

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The researches I am going to communicate started out from
some observations I had occasion to make at the end of the year
1907. At the autopsy of three wild rats . . . which originally had
served for subcutaneous injections of tubercle bacilli, the stomach
showed itself in the three animals to be the site of severe lesions.
The stomach was greatly enlarged, heavy, and of firm consistency.
The exterior surface was rough, especially at the fundus [the
cardiac end of the stomach, where food is received] and divided
by means of furrows into slightly elevated parts, gray-yellow in
color. After opening it, one found only localized lesions in the
fundus, while the pyloric region was normal. The wall of the
stomach was greatly thickened at the fundus . . . the mucous
membrane arching toward the stomach cavity in the form of folds
and of stout, irregular ridges, prolonged in out-juttings, and of
papillomatous polyps [see below], . . .

"Microscope examination ascertained that the enormous thicken-
ing of the walls was caused essentially by a very marked epithelial
hyperplasia [excessive growth of the surface layer] and by a severe
papillomatosis [overgrowth of tiny, nipplelike processes normally
present at the surface] and also, but in a less pronounced manner,
by acute and chronic inflammatory lesions. . . .

"At the histologic examination one was struck to see that here
and there, in a small number of sections, the superficial epithelium
contained cavities of different shapes: circular, oval, or cylindrical.
Continuing the researches, it was found that in other preparations
these cavities were filled by peculiar bodies, not found in the parts
of stomachs first examined. . . .

"These bodies had very distinct contours and complicated struc-
ture, making the supposition a probable one that this was a matter
of the more highly organized animal parasites. . . .

* Translated from Johannes Fibiger, "Recherches stir un nematode et sur sa
faculte de provoquer des neoformations papillomateuses et carcinomateuses dans
Testomac du. rat," Academie Royale des Sciences et des Lettres de Danemark:
Extrait du Bulletin de I'Annee 1913, No. i.

122 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

[In an effort to determine the frequency of this disease, which
Incidentally had nothing to do with tuberculosis, and also to find
new cases for further study, Fibiger examined 1144 rats, with nega-
tive results. Back in 1878, M. Caleb had described a nematode, a
threadlike worm, as parasitic in rats' stomachs. He had shown that
this appeared to be the same nematode already described as early as
1824 as a parasite In a common kind of cockroach, Periplaneta
orientates. Feeding nematode-infested cockroaches to rats, Galeb
was able to parasitize them. So Fibiger looked for rats and cock-
roaches together, then examined the stomachs of the rats, but
without success. He fed large numbers of cockroaches to rats. No
luck.}

"At last, informed that in a locality of the city [Copenhagen]
(a great sugar refinery) rats and cockroaches were found en masse,
I resolved to examine the rats of this district, too, although the
cockroach in question was not the Periplaneta orientates spoken of
by M. Galeb, but a different species, the P. americana. . . .

"Contrary to all expectation, the result of the examination was
positive. . . . [Thus Fibiger's studies could be continued. As it
turned out, Galeb's nematode was not the same. Nor, on the other
hand, was P. americana a necessary part of the story, as Fibiger
naturally supposed at first, for the commoner P. orientates would
likewise serve his purpose; so that when the sugar refinery burned
down, his work was only temporarily interrupted. He had found
the required nematode again, and he could show that only a part
of Its life cycle takes place in the rat, rat-to-rat transmission never
occurring. Eggs passed by rats were fed to cockroaches, and the
cockroaches were fed to rats. There then appeared to be a propor-
tional relation between the number of parasites and the duration
of their life In the stomach, on the one hand, and the degree of
anatomic change on the other.}

"In general, the successive development of the anatomical altera-
tions can be represented in the following manner: as the initial
phenomenon, simple epithelial hyperplasia, ordinarily followed by
acute inflammation. The inflammation ever increasing, the growth of
the epithelium in depth, the formation of epithelial papillomata and
heterotopia \beter os s other -f- topos, place: the presence of these
cells in parts where they are normally absent] are added to these

1926: JOHANNES FIBIGER 123

phenomena. As the terminal stage: severe papillomatosis, develop-
ment of large epithelial crypts with the more or less extensive de-
struction of the stomach wall. As deviations from this course of
development: (i) some cases in which the inflammatory processes
are little pronounced or totally absent ... (2) some cases in
which the process becomes malignant in the proper sense of the
word, by the development of a cancroid having the faculty of pro-
ducing metastases [new growths in parts of the body remote from
the original tumor}."

CONSEQUENCES IN THEORY
AND PRACTICE

Fibiger's discovery of Spzroptera carcinoma appeared to be a clear
confirmation of the view of Rudolf Virchow, the great pioneer of
cellular pathology, that cancerous growths are due to chronic irrita-
tion. Here was a tiny worm, a nematode, apparently the source of
both mechanical and chemical irritation, and it seemed that Fibi-
ger's careful experiments, only partly indicated in the abstract
above, had conclusively shown it to be the cause of a particular kind
of cancer in rats. Some believed this was due to non-specific irrita-
tion; Fibiger thought it due to specific toxins. There was, it is true,
some question raised about the real nature of this disease. Parasites
of other kinds were known to cause proliferative diseases, but
these came to be regarded as noncancerous. The part originally
diseased might set up colonies, so to speak, in remote parts of the
body; but these were not true "metastases," resulting from the in-
herent ability of morbidly overactive cells to establish new foci and
multiply afresh, for in each of the new locations parasites were
found. Like scattered abscesses, these areas represented the migra-
tions of the causative organism. But the metastases seen in Fibiger's
disease were true metastases, containing no parasites: the cells
themselves had become malignant. There was likewise some dispute
over the microscope evidence of the cells (the finer points of the
histology have not been given above) . But in the course of time
it was generally agreed that the tumor was a true malignant, or
cancerous, growth. More recently doubts have been raised about
the role of the nematodes. It has been suggested that a vitamin

124 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

deficiency was responsible for Fibiger' s results, since A. Y. Fuji-
makl was able to produce stomach tumors, some benign and some
malignant, by feeding rats on a vitamin-deficient diet. A. Borrel,
who anticipated Fibiger in suggesting that parasites might be con-
cerned in causing cancer, continued to maintain his original view
that such parasites could only be the carriers of a virus, the real causa-
tive agent.

In earlier studies of cancer it had sometimes been found possible
to transplant malignant growths to other animals of the same
species. But these studies did not show the origin of the tumors,
and the earliest stages of their growth could not be followed. It
therefore appeared of great importance to have a method at hand
for producing a form, of cancer experimentally, although this had
been done a short time before in the experiments of J. Clunet by
X irradiation. Two years after the publication of Fibiger' s work,
other scientists, perhaps encouraged by his success, were able to
produce experimental cancer in rabbits by the use of coal tar. A
number of carcinogenic (cancer-causing) substances have since
been isolated from coal tar and have been shown to be related
chemically to sex hormones, bile acids, and other substances of
biological importance.

Fibiger expressed the hope that some forms of human cancer
might be shown to be caused by parasites. He did not believe that
he had discovered a general principle of broad application, but only
that some small part might be found for parasitology in the genesis
of human cancer. Even this modest hope was doomed to disap-
pointment. Bilharziasis, a tropical disease caused by a small worm,
produces cancers of the bladder or rectum in about 5 per cent of
cases; and cancer of the liver is known to follow another kind
of infestation. These instances were recognized before the time of
Fibiger's work. The vast majority of cancers cannot be explained
in this way.

REFERENCES

OBERLING, CHARLES. The Riddle of Cancer. Translated by W. H.
Woglom. Revised ed. (New Haven: Yale University Press, 1952),
pp. 65-74.

1927

JULIUS WAGNER-JAUREGG

(1857-1940)

"For his disco-very of the therapeutic value of

malaria inoculation in the treatment of dementia

paralytica."

BIOGRAPHICAL SKETCH

JULIUS WAGNER- JAUREGG WAS BORN IN WELS, IN UPPER Aus-
tria, on March 7, 1857. (The hyphen in " Wagner- Jauregg" takes
the place of 'Von/' the distinction of nobility discontinued by the
socialist regime after the First World War.) He received the de-
gree of doctor of medicine in 1880 from the University of Vienna,
where he began his scientific career in the Department of Experi-
mental Pathology and Internal Medicine. In 1883 he joined the
star! of the psychiatric clinic. This was apparently a second choice,
forced upon him by circumstances, but he soon became deeply inter-
ested in psychiatry and was later renowned not only for his research
but also for his activity as a teacher. In a publication of 1887 ^ e
proposed to produce febrile diseases deliberately as a treatment
for psychiatric patients, using malaria and erysipelas. His pre-
liminary trials did not proceed far. From 1889 to 1893 he was
professor of psychiatry and neurology at the University of Graz
(Austria). In 1890 Koch introduced tuberculin, and Wagner-
Jauregg tried it as a fever-producer on patients at Graz. These ex-
periments were stopped because tuberculin had come to be con-
sidered dangerous. At this time he was recalled to Vienna as head

125

126 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

of the University Hospital for Nervous and Mental Diseases, and
in 1894 he resumed his work with tuberculin. The first malaria
inoculations for dementia paralytica were given on June 14, 1917.
Wagner- Jauregg published many early contributions on physi-
ology and pharmacology. Later he was interested in forensic psy-
chiatry, in cretinism, myxedema, and the prevention of goiter. He
retired from his professorship in 1928, and he died October i,
19405 in his eighty-fourth year.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"Progressive paralysis {also called paresis, general paralysis of
the insane, dementia paralytica] has always been considered an
incurable disease, leading in the course of a few years to dementia
and death.

"Nevertheless there was on record a series of cases of progressive
paralysis which had been cured; cases in which all the symptoms
had disappeared so completely as to permit those affected to be
independently active for years, in life and employment. And even
if such cases were quite extraordinarily rare, there was a compara-
tively frequent occurrence of remissions of some duration, in which
there was a retrogression, greater or less in degree, of symptoms
already developed. Thus, in principle at least, progressive paralysis
had to be a curable disease. . . .

"The observation was now forthcoming that in the rare cases of
healing and in the frequent remissions of progressive paralysis, a
febrile infectious malady or a protracted suppuration often pre-
ceded the improvement in the state of the disease.

"Therein lay a hint. These cures following febrile infectious
diseases, of which I myself had witnessed striking cases, induced
me as early as the year 1887 to propose that this natural experiment
be imitated by deliberately producing infectious diseases, and at
that time I named malaria and erysipelas as suitable diseases. As a
particular advantage of malaria, I stressed the fact that it is possible
to interrupt the disease at will with quinine, and did not yet suspect

* Translated from "Nobel- Vortrag von Julius Wagner- Jauregg," Les Prix Nobel
en

1927: JULIUS WAGNER- JAUREGG 127

at that time to what extent the expectation would be fulfilled
through inoculation with malaria.

"Apart from an unsuccessful experiment with erysipelas, I did
not proceed as yet to the direct execution of this proposal, and
furthermore I would scarcely have had the authority at that time
to carry it through.

"Instead, starting in 1890, I attempted to imitate the action of
a febrile infectious disease by the use of tuberculin, just introduced
by Koch, at first not only in progressive paralysis but also in other
mental derangements, and as a matter of fact with favorable results
in not a few cases. {This was to some extent a forerunner of the
protein therapy which later attained great development.}

"Since there were some cases of progressive paralysis among
them, my interest soon concentrated on this disease, for a favorable
result could not so easily be considered an accident here as in other
psychoses.

"After ... it had been established that the paralytics treated
with tuberculin . . . showed more, and more lasting, remissions
than an equal number of untreated paralytics, this treatment was
carried out systematically . . . and at the same time an energetic
iodine-mercury cure, later combined with injections of salvarsan,
was instituted. . . .

"The remissions which were obtained by the mercury-tuberculin
treatment did not differ qualitatively from those to be obtained by
inoculation with malaria. . . . But the number of relapses was
large; the lasting remissions were in the minority.

"I tried to enhance the action of the nonspecific treatment by
the use of different vaccines . . . without much effect on the fre-
quency of the discouraging relapses.

"In the course of this therapeutic research, I could repeatedly
make the observation that particularly complete and lasting remis-
sions took place in just those cases in which, concurrently with the
treatment, some incidental infectious disease occurred, for instance
pneumonia {or} an abscess.

"Consequently, in 1917, 1 set about the execution of the proposal
I had made in the year 1887, and inoculated nine cases of progres-
sive paralysis with tertian malaria.

"The result was gratifying beyond expectation: six of these nine

128 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

cases obtained extensive remissions, and in three of these cases the
remission proved lasting, so that this year [i9 2 7] I was able to
present these cases ... as having carried on their occupations
without interruption for ten years. After the outcome of this first
experiment had been followed for two years, I undertook, in the
autumn of 1919, to pursue this therapeutic research on a large
scale. . . ."

CONSEQUENCES IN THEORY
AND PRACTICE

Wagner- Jauregg appears to have contemplated the use of malaria
In treating paretic dementia for many years, and when, in 1917, a
patient with tertian malaria appeared in one of his wards he con-
sidered this as a sign of fate and proceeded to carry out his plan.
The tertian variety of the disease is still preferred, although the
quartan type has also had its advocates.

Dementia paralytica, perhaps more commonly known as GPI
(general paralysis of the insane), or simply general paresis, is a
progressive disease of the brain and meninges (brain coverings)
due to syphilis. In adults it is usually a late result of an untreated
or inadequately treated antecedent syphilis; a juvenile form (juve-
nile paresis) usually is due to congenital syphilis. The proper treat-
ment of the early stages of syphilis is the only sure means of pre-
vention. Fever therapy is indicated in all cases of GPI, as well as
in paresis sine parese, meaning the same disease before paralytic
signs have occurred but where the mental symptoms and laboratory
indications point to neurosyphilis.

Fever therapy since Wagner- Jauregg has taken various forms,
ranging from sodoku (rat-bite fever), killed typhoid bacilli,
preparations containing colloidal sulfur, and continuous hot-air
and hot-water baths, to diathermy. A variety of nonspecific proteins
have been employed. Although fever cabinets are widely used,
some psychiatrists consider it doubtful that any other fever-produc-
ing agent gives results as good as does the malaria treatment. The
mortality from malaria is low and it is claimed that about 30 to 40
percent of those so treated show permanent recovery (more than
five years). It is especially during the earliest stage that the in-

1927*. JULIUS WAGNER- JAUREGG 129

volvement of the central nervous system is amenable to treatment;
no treatment of any kind is capable of restoring damaged brain
tissue. Fever therapy, however, combined with an antisyphilitic
drug (especially tryparsamide) tends to prolong life and arrest
deterioration. The newer drugs for the treatment of syphilis may
alter the picture somewhat; but as yet there is no likelihood of dis-
pensing with fever treatment, as introduced nearly thirty-five years
ago by Wagner- Jauregg.

1928

CHARLES NICOLLE

(1866-1936)
"For his work on typhus"

BIOGRAPHICAL SKETCH

CHARLES NICOLLE WAS BORN SEPTEMBER 21, 1866, AT ROUEN,
where his father practiced medicine. He first attended the lycee in
his native city, then studied medicine in Paris. In 1893, at the
conclusion of his studies, he was named to the faculty of the Medi-
cal School in Rouen and appointed physician to the Rouen hospitals.
At the instigation of his brother, Maurice Nicolle, a microbiologist,
he took the Pasteur Institute course in microbiology in 1892. In
1902 he succeeded Adrien Loir as director of the Pasteur Institute
in Tunis. Here he carried out the work on typhus described below,
in which he demonstrated the role played by the louse, A later
achievement of importance was the distinction he helped to draw,
after a visit to Mexico, between classic, louse-borne epidemic typhus
and the murine variety, which has its reservoir in rats and is trans-
mitted sporadically to man by the rat flea. (The murine type, under
the name of tabar ditto, has appeared epidemically in Mexico.
Nicolle has been credited in France with distinguishing murine
from classic typhus. It appears, however, that the most important
contributions to the knowledge of murine typhus were made by
Maxcy, Dyer, Rumreich, Badger, Mooser, Castaneda, and Zinsser. )
In 1932 Nicolle took the place of d'Arsonval in the chair once held
by Claude Bernard, Magendie, and Laennec at the College de

130

1928: CHARLES NICOLLE 131

France. He carried out extensive work on a variety of infectious
diseases. In addition to being known for his studies of typhus he
was chiefly distinguished for a number of innovations in technique.
He was the founder of the Archives de I'Institut Pasteur de Tunis.
He wrote not only scientific but literary and philosophic works. He
died February 28, 1936.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The center of my observations was the native hospital of Tunis.
When I visited this hospital I often stepped over the bodies of
typhus patients who had come to be admitted and had fallen down
from exhaustion at the door. Now there was a singular event tak-
ing place in this hospital, the significance of which no one had
understood, and which impressed me. The typhus patients were
lodged at this time in the common medical wards. As far as the
doors of these rooms they scattered the contagion. Typhus devel-
oped on contact with them in the families where they were received,
and the doctors required to visit them became infected on contact.
Moreover the contagion struck the personnel of the admitting
offices of the hospital, the employees whose duty it was to collect
the clothes and linen, and the laundresses who washed them. And
for all this, a typhus patient once admitted to the common ward
did not contaminate a single one of his ward neighbors, not an
attendant, not a doctor.

'This observation was my guide. I asked myself what happened
between the hospital door and the sickroom. What happened was
this: the typhus patient was relieved of his clothes and linen, and
was shaved and washed. The agent of the contagion was therefore
something attached to his skin, to his linen, and something of
which soap and water rid him. This could only be the louse. . .

"If it had not been possible to reproduce the malady in animals
and consequently to verify the hypothesis, this simple determina-
tion would have sufficed to make clear the mode of propagation of

* Translated from "Conference Nobel par Charles Nicolle," Les Prix Nobel en
1928.

132 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

typhus. Fortunately it was possible to bring experimental proof to
bear upon it.

"My first attempts to transmit typhus to laboratory animals, con-
sisting of little monkeys, failed, like similar attempts of my prede-
cessors, and for reasons which it is easy for me to explain to myself
today.

"I asked my mdttre, M. Roux, to procure a chimpanzee for me,
thinking that an anthropoid might be more sensitive than animals
of other kinds. The very day I received it, I inoculated it with the
blood of a patient. . . . The chimpanzee showed a fever. With its
blood, obtained during this fever, I inoculated a macaque (M.
sinicus}, which also showed a fever. On this macaque I fed lice
which I transferred to other macaques. These were infected and
later showed themselves to be vaccinated against a trial inocula-
tion. . . . {Monkeys are expensive animals for experiment and
Nicolle discovered that guinea pigs, rats, and mice are also sus-
ceptible to typhus; most of his later work was done on guinea pigs.
He found that lice are incapable of spreading contagion until
about a week after taking up blood; he also found that develop-
ment occurs meanwhile in the digestive tract of the louse, and that
the feces become virulent.}

"Typhus is characterized in man by a symptomatic triad; fever,
eruption, signs of nervous involvement. In animals, fever is the
only sign of infection. ...

"It sometimes happens, especially when one uses blood, that in a
lot of guinea pigs, inoculated with the same dose of the same ma-
terial, certain ones do not show any fever. At first I attributed this
failure to a fault in technique, or else to a greater individual resist-
ance. The repetition of negative results did not permit me to accept
these too facile explanations for long. The animals for which the
vims is pathogenic present a picture of variable sensitivity, which
runs from the very severe, often fatal, typhus of the European
adult to the merely theraiometric fever of the guinea pig, passing
through all the intermediate degrees: typhus of the adult native,
benign typhus of the children, still more benign in monkeys. I
asked myself if there did not exist, below the already very feeble
sensitivity of the guinea pig, a yet slighter degree in which the
only sign of infection would be the virulent power of the blood

1928: CHARLES NICOLLE 133

during the period when the more sensitive animals show the char-
acteristic fever. It was indeed so."

CONSEQUENCES IN THEORY
AND PRACTICE

Nicolle transformed the fight against typhus into a fight against
the louse. For many years the methods of delousing were elaborate,
laborious, time-consuming, and not altogether effective. To a large
degree they worked; the difficulty was to apply such methods on a
broad enough scale. Particularly in winter, when lice are favored by
heavy clothing, crowding, and infrequent bathing, it proved im-
possible to put a quick stop to outbreaks of typhus, at least among
civilian populations. In the past ten years, however, such outbreaks
have been effectually suppressed on several occasions by the liberal
use of DDT (see below, p. 258) .

Nicolle also gave a convincing demonstration of what he called
"inapparent disease." He showed that there are instances in which
no symptoms whatever appear, yet the blood is virulent on inocula-
tion. This fact has been brought forward to explain the mystery of
how the contagion survives between epidemics.

It is interesting that Theobald Smith, Patrick Hanson, David
Bruce, and the members of the Yellow Fever Commission demon-
strators of insect vectors in disease were not rewarded with the
Nobel Prize. Possibly the theoretical aspect of Nicolle' s work, to-
gether with its importance in combating typhus during the First
World War, influenced the decision to honor him with the Prize.

Typhus has been known for centuries as one of the great epi-
demic diseases. It has been associated with a massing of people in
cities, armies, prisons, and ships. Its alternative names ship fever,
jail fever, prison fever, camp fever, hospital fever are revealing.
It has also been known as war fever, since fatal epidemics have
attended most of the great wars. To an important degree typhus is
a social disease, requiring a lousy population to feed upon. Present
ability to cope with it in an emergency depends less upon prophy-
lactic vaccination and modern treatment than upon powerful new
insecticides. Nicolle convicted the louse; Paul Miiller, of DDT
fame, discovered the means to kill it.

1929

CHRISTIAAN EIJKMAN

(1858-1930)
"For Ms disco-very of the antineuritic vitamin*

FREDERICK GOWLAND
HOPKINS

(1861-1947)

"For his discovery of the growth-stimulating
vitamins"

BIOGRAPHICAL SKETCHES

EIJKMAN
THE SON OF A SCHOOLMASTER, CHRISTTAAN ElJKMAN WAS BORN

on August ii, 1858, in Nijberk, a small town on the Zuyder Zee.
He began his studies at the University of Amsterdam in 1875 and
was for some years assistant to the professor of physiology there.
In 1883 he |oined the colonial army in the Dutch East Indies but
he was invalided home two years later and resumed his laboratory
work, this time as a bacteriologist. In 1886 he returned to the
Dutch East Indies as a member of the Pekelharing-Winkler Com-
mission to study beri-beri This group vainly sought a bacterial

134

1929: EIJKMAN AND HOPKINS 135

cause for the disease. When his colleagues returned home, Eijkman
remained in Batavia as director of a new laboratory for bacteriology
and pathology, taking charge of the medical school for native doc-
tors as well. It was during this period that he carried out the work
on beri-beri described below. He later studied "tropical anemia/'
denying it separate existence as a disease entity. He also challenged
the assumption that metabolism varied greatly with climate. Among
the more important investigations of his later years were his study
of fermentation tests and the demonstration of the presence of the
colon bacillus in water (Eijkman's test). Ill once again, Eijkman
returned home in 1896 and became professor of hygiene at the Uni-
versity of Utrecht; he held this post until 1928. In 1930 he died.

HOPKINS

FREDERICK GOWLAND HOPKINS WAS BORN JUNE 20, 1861, IN
Eastbourne, in Sussex, England, where he spent the first ten years
of his life alone with his widowed mother, attending a dames*
school from the age of six and playing with his father's microscope
from the age of eight or nine. After 1871 they lived in Enfield
with his mother's brother, James Gowland. For nearly four years
Hopkins attended the City of London School, but despite a good
record at first he had ultimately to withdraw because of truancy
ft sheer boredom" was his own explanation. He then attended a
private school. At seventeen he entered an insurance office, but re-
mained for only six months; he then became an articled pupil to
an analytical chemist. Later he attended the Royal School of Mines
at South Kensington and worked for a few months as assistant in
a private laboratory. A few courses at University College and suc-
cess in examination for associateship of the Institute of Chemistry
brought an invitation from Dr. (later Sir Thomas) Stevenson,
Medical Jurist at Guy's Hospital and Home Office expert, to assist
in his laboratory. While working there, Hopkins took a degree
extramurally from the London University. In 1888 he began to
study medicine at Guy's. In 1894 he qualified and obtained the
London M.B. He then joined the school staff at Guy's but left in
3:898, going to Cambridge at the invitation of Michael Foster to
develop teaching and research in physiological chemistry. There he

136 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

spent the rest of Ms life, at first with meager facilities, but after
1925 in a well-endowed institute. He was everywhere recognized
as facile princeps of English biochemistry, which he established
almost singlehanded. His honors included knighthood, in 1925;
the Copley Medal, in 1926; the Nobel Prize, in 1929; presidency
of the Royal Society, in 1931; and the Order of Merit, in 1935. He
retired in 1943 and died in 1947. In addition to his dietary studies,
his work on glutathione and tissue oxidation, on muscle chemistry,
and on uric acid are very well known.

DESCRIPTION OF THE PRIZE- WINNING
WORK

EIJKMAN *

"An accident set me on the right road.

"In the chicken-run of the laboratory in Batavia there suddenly
broke out a disease which was in many ways strikingly similar to
human beri-beri, and hence invited penetrating study. . . . [Eijk-
man here gives a detailed account of the symptoms shown by the
birds: unsteady gait, muscular weakness resulting in falls, collapse,
progressive paralysis finally affecting the respiratory muscles,
cyanosis, or blueness of comb and skin resulting from insufficient
oxygen in the blood, stupor, subnormal temperature, and death.]

"As may already be guessed from the symptoms and the course
of the disease, and as microscopic study confirmed, it was a question
of a polyneuritis [multiple neuritis affecting the nerves generally
and not merely in the local area}.

"As regards etiology, our original supposition that, considering
the striking epizootic commencement of the disease [epizootic =
animal epidemic], we had to do with an infection was not con-
firmed. Search for infection, using material from side animals or
those that had died of the disease, gave no clear result, while all
the hens, including those kept separate as controls, were affected.
JNfo specific microbe was found, nor any higher organized parasite.

"Then all at once our opportunity for further researches dis-

'* Translated from Chrlstlaan Eijkman, "Antmeuritisches Vitamin und Beri-beri/'
Les Prix Nobel en 1929.

1929: EIJKMAN AND HOPKINS 137

appeared, as the disease came suddenly to a stop. The sick hens got
better and no new cases appeared. Fortunately suspicion was then
directed toward food, and indeed rightly, as it presently turned
out.

"The laboratory was still temporary, and very meagerly housed
in the military hospital, although it was administered under the
civil authority. The laboratory attendant, his motive economy, had
now, as I first learned later, obtained cooking rice from the hos-
pital kitchen to use as chickenfeed. Then, the cook having been
transferred, his successor objected to military rice going to civilian
hens. So it happened that the hens were fed with cooking rice only
from the loth of June to the aoth of November. But the epizootic
began on the i oth of July and ended in the last days of November.

"Deliberate feeding experimentation was then undertaken,
aimed at further proof of the presumable connection between food
and sickness. This definitely showed that the polyneuritis had its
origin in the cooking-rice feed. The hens were thereby subjected
to the disease after 3-4 weeks, or not uncommonly somewhat later,
while the controls fed with unhulled rice remained healthy. We
also not seldom succeeded in restoring animals already sick by a
suitable change in feeding.

"This difference between rice that had been hulled, and likewise
polished, and whole rice did not consist in a lessening in the quality
of the former through storage, for cooking rice freshly prepared
from whole grain could also call forth the disease. It turned out
that rice half hulled i.e., freed only of the thick hull which
spoils much more easily [and] is attacked by mites, molds, etc.,
proved harmless in feeding experiments. This rice, which is ob-
tained through simple pounding, still has the inner hull, the so-
called silver skin [Silberhautchen] (pericarp), and contains the
germ, wholly or in large part. As could then be concluded from
many different experiments, the effective antineuritic principle
occurs particularly in these parts of rice and of cereal grains gen-
erally. It can easily be extracted with water or strong alcohol and
can be dialyzed [i.e., the crystalloid and colloid elements of the
extraction can be separated by diffusion through a membrane}. I
was able to establish further that it can be used as a remedy either
by mouth or by injection."

138 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"Early in my career I became convinced that current teaching
concerning nutrition was inadequate, and while still a student in
hospital in the earlier eighteen nineties I made up my mind that
the part played by nutritional errors in the causation of disease was
underrated. The current treatment of scurvy and rickets seemed
to me to ignore the significance of the old recorded observations. I
had then a great ambition to study those diseases from a nutritional
standpoint; but fate decreed that I was to lose contact with clinical
material. I had to employ myself in the laboratory on more aca-
demic lines. I realised, however, as did many others at the last cen-
tury's close, that for a full understanding of nutrition, no less than
for an understanding of so many other aspects of biochemistry, fur-
ther knowledge of proteins was then a prerequisite; and when I was
first called to the University of Cambridge I did my best to con-
tribute to that knowledge.

"As an ultimate outcome of my experiments dealing with the
relative metabolic importance of individual amino acids from pro-
tein my attention was inevitably turned, without, I think, knowl-
edge, or at any rate without memory, of the earlier work, to the
necessity for supplying other factors than the then recognised basal
elements of diet if the growth and health of an animal were to be
maintained. This indeed must at any time come home to every
observer who employs in feeding experiments a synthetic dietary
composed of adequately purified materials. ... A good many
investigators using synthetic dietaries have, it is true, from time to
time expressed doubts upon the point, but we now know that it
was because the constituents they used were not pure and not free
from adherent vitamins. In 1906-7 I convinced myself by experi-
ments, carried out . . . upon mice, that those small animals at any
rate could not survive upon a mixture of the basal foodstuffs alone.
I was especially struck at this time, I remember, by striking differ-
ences in the apparent nutritive value of different supplies of casein
in my possession. One sample used as a protein supply in a syn-

* From F. G. Hopkins, "The Earlier History of Vitamin Research/' Les Prix
Nobel en

1929^ EIJKMAN AND HOPKINS 139

thetic dietary might support moderate growth, while another failed
even to maintain the animals. I found that a sample of the former
sort, if thoroughly washed with water and alcohol, lost its power
and also, if added to the samples originally inadequate, made them
to some degree efficient in maintaining growth. I found further at
that time (1906-7) that small amounts of a yeast extract were
more efficient than the casein extracts. Similar experiences were en-
countered when otherwise adequate mixtures of amino acids were
used to replace intact proteins. By sheer good fortune, as it after-
wards turned out, I used butter as a fat supply in these early experi-
ments. Upon the evidence of these earlier results I made a public
statement in 1907 which has been often quoted. I cannot, how-
ever, justly base any claims for any sort of priority upon it, as my
experimental evidence was not given on that occasion. It was indeed
not till four years later that I published any experimental data. In
explanation of this delay I would ask you to consider the circum-
stances of the time. The early experiments of Lunin and others had
been forgotten by most; the calorimetric studies held the field and
tentative suggestions concerning their inadequacy were, I found,
received with hesitation among my physiological acquaintances. It
seemed that a somewhat rigid proof of the facts would be neces-
sary before publication was desirable. Thus came the great tempta-
tion to endeavour to isolate the active substance or substances before
publication, and I can claim that throughout the year 1909 I was
engaged upon such attempts, though without success. At this time
I was using what is now the classic subject for vitamin studies,
namely the rat. As I was concerned with the maintenance of growth
in the animal, the tests applied to successive products of a frac-
tionation took much longer than those which could be used in
studying the cure of polyneuritis in birds by what we have learned
to call Vitamin BI, so the work occupied much time. I may perhaps
be allowed to mention what was for me a somewhat unfortunate
happening in the beginning of 1910, as it is instructive. A commer-
cial firm had prepared for me a special extract of a very large
quantity of yeast made on lines that I had found effective on a
small scale. With this I intended to repeat some fractionations
which had appeared promising. I thought, however, upon trial
that the whole product was inactive and it was thrown away. The

140 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

real explanation, however, was that instead of using butter, as in
earlier experiments, I at this moment determined to use lard, and
my supply of this, as I learned to understand much later, was
doubtless deficient in Vitamins A and D; I was now giving my
animals in the main the B Group alone. If I had then had the
acumen to suspect that any of the substances I was seeking might
be associated with fat I should have progressed faster. Later in
1910, if I may intrude so personal a matter, I suffered a severe
breakdown in health and could do nothing further during the year.
On my return to work I felt that the evidence I had by then ac-
cumulated would be greatly strengthened by a study of the energy
consumption of rats, on the one hand when failing on diets free
from the accessory factors (as I had then come to call them) , and,
on the other hand, when, as the result of the addition of minute
quantities of milk, they were growing vigorously. These experi-
ments took a long time, but they showed conclusively, as at that
time It seemed necessary to show, that the failure in the former
group of animals was not due primarily, or at the outset of the feed-
ing, to any deficiency in the total uptake of food.

"My 1912 paper . . . emphasizes on general lines the indis-
pensable nature of food constituents which were then receiving no
serious consideration as physiological necessities."

CONSEQUENCES IN THEORY
AND PRACTICE

Eijkman and Hopkins are among the half dozen pioneers in the
study of vitamins. Eijkman, however, did not at once appreciate
the full significance of his important discovery. He did not visualize
beri-beri as a deficiency disease, but thought of it as a sort of poi-
soning, due to a nutritional error, an excess of carbohydrate in a
diet of rice; this he considered was counteracted by a protective
element, or neutralizing substance, in the rice bran. In 1901, how-
ever, G. Grijns put forward the view that the cortical substance in
rice filled a universal need for the protection of health; this view
was later adopted by Eijkman and the vital substance was eventu-
ally identified as vitamin BI. Since beri-beri, which is characterized
by multiple neuritis, edema, atrophy of muscles, and heart symp-

1929: EIJKMAN AND HOPKINS 141

toms, often co-exists with other nutritional deficiencies, there has
been some debate as to whether or not one specific factor is the sole
cause; there is no doubt, however, that persons with beri-beri are
greatly benefited by vitamin BI therapy. It took a long time before
the practical value of Eijkman's observations for combating beri-
beri was appreciated, although on this point Eijkman himself had
recognized the significance of his findings. The outlook for a case
of beri-beri, if diagnosed early and adequately treated, is nowadays
very good. Prevention, dependent on a well-balanced diet, is a
more difficult matter, since it calls for the education of the ignorant
masses of the people in the eastern countries, where the disease is
most prevalent, and for the raising of their economic level two
very large orders. It is asserted, however, that prevention of the
overmilling of grain would go far to solve the problem.

Although there are other claimants for the honor, it is now
widely accepted that E G. Hopkins was the first to realize the full
significance of the facts and to recognize the necessity for "acces-
sory factors" in the diet. The important work which has since been
carried out in vitamin research was initiated by his discoveries.
Osborne and Mendel, and McCollum and his co-workers, distin-
guished between "water-soluble" and "fat-soluble" vitamins. It
was shown by McCollum and Davis (1913) that the growth-pro-
moting effect of milk demonstrated by Hopkins depended on two
factors: fat-soluble vitamin A and water-soluble vitamin B. Vita-
min B was later shown by Goldberger to consist of a mixture of
several vitamins. One of these, vitamin BI, protects against beri-
beri; another is the pellagra-preventing vitamin.

It is not possible to review the later history of vitamin research
in a brief space. Rickets, and also scurvy, were added to the list of
diseases proved to result from specific deficiencies; there were
soon several others. Many contributions have been made by physi-
ologists, pathologists, and chemists to the increasing knowledge
of nutritional deficiencies. Attention has been given not only to the
vitamins but to the need for small amounts of other substances,
particularly minerals. Study of these various substances, and the
vitamins most of all, has greatly increased our knowledge of physi-
ology as well as our clinical knowledge of disease (for an example
in physiology, see below, p. 197, in the article on Szent-Gyorgyl).

142 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Several Nobel Prizes, in medicine and chemistry, have been
awarded for work on vitamins. (For Dam's discovery of vitamin
K and the hemorrhagic states related to it, see below, p. 218.)
Eijkman and Hopkins were among those who opened the gates of
an important field in medicine.

1930

KARL LANDSTEINER

(1868-1943)
"For Ms discovery of the human blood groups*

BIOGRAPHICAL SKETCH

KARL LANDSTEINER WAS BORN IN VIENNA, ON JUNE 14, 1868.
He entered the University of Vienna in 1885 and was graduated as
doctor of medicine in 1891. He received his chemical training in
the laboratories of Hantzsch in Zurich, Emil Fischer in Wiirzburg,
and E. Barnberger in Munich. Thereupon he turned to bacteriology
and pathology, but his approach to these subjects was derived from
his thorough training in the fundamental sciences, especially chem-
istry. In 1896 he became assistant under Dr. Max von Gruber in
the Institute of Hygiene at the University of Vienna. From 1898
to 1908 he was an assistant under Professor A. Weichselbaum at
the Pathological Institute. In 1908 he was prosector at the Wil-
helminspital, where he then served as pathologist from 1909 to
1919, with the rank of professor. After the First World War he
left Vienna and went to Holland, to be pathologist at the R. K.
Ziekenhuis, the Hague, from 1919 to 1922. In 1922 he became
a member of the Rockefeller Institute for Medical Research, in
New York, where he continued to work for more than twenty years.
In 1939, having reached the mandatory age for retirement, he was
made an emeritus member of the Institute, but continued his re-
search with undiminished vigor. Stricken by heart disease while
busy in his laboratory, he died two days later, on June 26, 1943, at

143

144 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

the Rockefeller Institute Hospital. He had just completed the
preparation of a new edition of his book The Specificity of
Serologlcal Reactions, which was already a classic. Landsteiner pub-
lished about 330 papers on his investigations In chemistry, in
pathological anatomy, in experimental pathology (infectious dis-
eases), and in serology and immunology. His studies of syphilis
and poliomyelitis were particularly important. Probably his most
far-reaching work was in immunochemistry, a branch of science
which he did much to establish.

DESCRIPTION OF THE PRIZE-WINNING
WORK*

'The difficulty of dealing with substances of large, complex
molecules accounts for the fact that we are still far from the goal
of characterizing and determining the constitution of proteins,
which rank as the most important constituents of living beings. So
it was not the usual methods of chemistry but the application of
serologic tests which led to an important general result in protein
chemistry, to the knowledge that the albuminous substances differ
in the separate kinds of animals and plants and are characteristic
for each kind. The diversity is increased still more in that the dif-
ferent organs also contain particular proteins, and consequently
special building materials seem to be necessary for each particular
form and function of living organisms, in contrast to artificial
machines, which can be produced for greatly varied performance
from a limited number of materials.

"The question which was raised by the discovery of the bio-
chemical specificity of kinds, and which formed the basis of the
investigations to be discussed, was thereupon formulated with the
aim of seeing whether differentiation extends beyond the limits of
species, and whether the separate individuals of one kind also ex-
hibit similar, if at the same time slight, differences. In the absence
of any observations pointing to a circumstance of this sort, I chose
the simplest among the research arrangements which offered, and
that material which at first glance lent itself to useful application.

* Translated from Karl Landsteiner, "liber Individuelle unterschiede des mensch-
lichen Blutes," Les Prix Nobel en

1930: KARL LANDSTEINER 145

Accordingly the research which I undertook consisted in letting the
blood serum and red blood corpuscles of different people react on
one another.

"The result was only in part what was expected. In many tests
there was no change to be observed, just as if the blood cells had
been mixed with their own serum, but often a phenomenon called
agglutination took place, the serum causing the cells of the stranger
to form clumps.

"The surprising thing was this, that the agglutination, when
present at all, was just as pronounced as those reactions already
known, which occur with the interaction of serum and cells from
different kinds of animals, while in the other cases there seemed
to be no difference in the blood of different people. So first of all
there was still the consideration that the required individual physi-
ological differences had not been found, and that the phenomena,
when seen, too, in the blood of healthy people, could be caused by
illnesses which had been overcome. But it soon became apparent
that the reactions conform to a law which is valid for everyone's
blood, and that the peculiarities found in separate individuals are
just as characteristic as the serologic signs for an animal species.
The main point, of course, is that there are four different kinds of
human blood [Landsteiner first described three}, the so-called
blood groups. The number of the groups is due to the fact that in
the erythrocytes there exist substances (isoagglutinogens) with two
different structures, of which both may be lacking or one or both
may be present in a man's erythrocytes. That alone would still not
explain the reactions; the effective substances of the sera, the
isoagglutinins, must also occur in a definite distribution. This is
actually the case, for each serum contains that agglutinin which
acts on the agglutinogens that are not present in the cells, a note-
worthy fact, the cause of which has not yet been established with
certainty. From this arise definite relations among the blood
groups. . . ."

146 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

CONSEQUENCES IN THEORY
AND PRACTICE

Serum from the blood of an animal was known to be capable of
causing flocculation (hemoagglutination) and dissolution (hemoly-
sis) of red blood corpuscles in the blood of another animal of
different species. That this might also at times occur in mixing
serum from one individual with red blood cells from another indi-
vidual of the same animal species (isoagglutination) was observed
in 1900 by Ehrlich and Morgenroth. In the same year (1900),
Karl Landsteiner and Samuel Shattock, working independently,
reported on the incompatibility of different types of human blood.
By 1901 Landsteiner had enough data to distinguish three groups
and was able to give a clear account of isoagglutination. In 1902,
his associate, A. Sturli, working with A. von Decastello, described
the fourth group.

The discovery of the human blood groups had important results
in (i) clinical medicine and surgery; (2) forensic (legal) medi-
cine; and (3) anthropology.

Isoagglutinogens of two different structures, A and B, occur in
red blood corpuscles, either separately, or together ( AB) . Both may
be absent (the O group) . An individual's serum cannot normally
agglutinate his own blood corpuscles or those of others who belong
to the same blood group. Serum from a member of the O group
agglutinates the red cells in all the other groups, but the red cells
of O group are not affected by any of the four kinds of serum
(A, B, AB ? O) . Serum from a person belonging to A group agglu-
tinates the cells of B-group blood, but not those of A or AB groups.
Conversely, serum from B-group blood agglutinates cells of A
group but not those of B or AB groups. This knowledge formed
the foundation for the development of blood transfusion. Agote,
Jeanbrau, and Lewisohn demonstrated the efficacy of adding sodium
citrate to prevent coagulation of collected blood before injection
into the recipient, a method which helped to make transfusion more
generally available. Transfusions are now used for a wide variety
of purposes. Lives are saved daily by this means following hemor-
rhage from injury, operation, gastric ulcer, ruptured ectopic preg-

1930: KARL LANDSTEINER 147

nancy, bleeding after childbirth; in bleeding due to hemorrhagic
diseases of the blood; and in cases of severe anemia, leukemia, etc.
Carbon monoxide gas has a great affinity for the hemoglobin in
the blood; an infusion of fresh blood provides unaltered hemo-
globin. Transfusions have proved beneficial in some cases of
chronic sepsis, and ''Immunotransfusions' 9 have been used against
scarlet fever, typhoid, and septicemia. Whole blood transfusion is
especially effective in cases of traumatic or postoperative shock due
to loss of blood in an accident or during an operation.

In 1910 E. von Dungern and L. Hirszfeld discovered that the
groups are inherited according to Mendel's laws, A and B being
strongly dominant. In cases of disputed paternity this fact may be
of great value. Although a man cannot be proved to be the father
of a child by means of his blood group, it is often possible to
prove that he is not the father. The blood-group determination may
also be of use when bloodstains are brought in evidence In criminal
cases.

Since the blood groups are unevenly distributed In the various
races, Landsteiner's discovery has been useful to anthropology. In
experiments on primates he showed that the blood of anthropoids
Is more closely related than that of lower monkeys to human blood
and stated that his results tf seem to agree with the theory that man
and apes are descendants of a common stock rather than that man
evolved from one of the apes/*

In 1927 Landsteiner discovered additional agglutinogens In
human blood, two of which, M and N, have been of importance In
forensic medicine. In 1940 Landsteiner and A. S. Wiener discov-
ered the Rhesus, or RH, factor, which has since assumed great
significance. Incompatibility in this respect in the blood of the
parents is the cause of a fetal disease (Erythroblastosis foetalis)
which may result in abortion, miscarriage, or a dangerous illness of
the newborn child.

1931

OTTO WARBURG

(1883- )

ff For Ms discovery of the nature and mode of action
of the respiratory enzyme."

BIOGRAPHICAL SKETCH

OTTO HEINRICH WARBURG WAS BORN IN FREIBURG (BADEN) ,
on October 8, 1883. His father was the physicist Emil Warburg
(1846-1931). After studying chemistry under Emil Fischer, War-
burg obtained his doctorate in 1906 with a dissertation on polypep-
tides. In 1911 he became doctor of medicine as well, his thesis deal-
ing with problems of oxidation. He has concerned himself chiefly
with life processes, insofar as they can be investigated by the
methods of physics and chemistry; by his own account he has striven
to trace the events of life to the events of the inanimate world. He
has never taught, except for imparting instruction to younger in-
vestigators working with him, but has devoted his entire time to
scientific research. For the past twenty years, apart from a brief
sojourn in the United States, he has worked in Berlin-Dahlem in
the Kaiser- Wiihelm Institute for Cell Physiology, erected in 1930
by the Rockefeller Foundation. He is best known for extensive
investigations on intracellular en2ymes and on the metabolism of
tumors.

148

OTTO WARBURG 149

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"That iron occurs in all cells, that it is vital, and that it is [the
oxygen-transporting part of] the oxidation catalyst of cellular
respiration was first apprehended in recent times. It is the valence
change of an iron compound the oxygen-transporting respiratory
ferment on which catalytic oxidation in living substance de-
pends. . . .

"In the investigation of the chemical constitution of the oxygen-
transporting ferment, analytical chemistry according to the usual
methods has been abandoned, since in view of the almost infinitely
small concentration . . . and the fragility of the ferment, they
appear hopeless. . . . j[This opinion determined the adoption of
other methods, but Warburg has since concluded that isolation of
this substance is not impossible.] One looks for substances which
specifically and reversibly stop the operation of the oxygen-trans-
porting ferment that is to say, the oxidation in living substance.
Now it cannot be otherwise than that a substance which inactivates
the ferment reacts with [it] chemically, so that conclusions can be
drawn about the ferment's chemical nature from the kind of re-
tarding substances and from the circumstances to which the retarda-
tion is subject. ... It is an advantage that by so doing one
investigates the ferment under natural conditions, in the intact,
breathing cells. . , .

"The blocking of intracellular respiration by hydrocyanic acid
. takes place through a reaction of the hydrocyanic acid with
the iron of the oxygen-transporting ferment. . . . Hydrocyanic
acid retards the reduction of the ferment iron. . . . [That carbon
monoxide also inhibits intracellular respiration was discovered by
Warburg in 1926.} In accordance with the carbon monoxide and
oxygen pressures a greater or smaller part of the ferment iron is
eliminated from catalysis by combination with carbon monoxide.

* The first quotation is translated from Otto Warburg, "Das sauerstoffiibertragende
Ferment der Atmung," Les Prtx Nobel en 1931. The second consists of excerpts
from Otto Warburg, Heavy Metal Prosthetic Groups and Enzyme Action, trans-
lated by Alexander Lawson (Oxford: Clarendon Press, 1949)-

150 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

. . . Carbon monoxide bars the oxidation of the ferment iron.
... [It was well known that CO acts on hemoglobin by expelling
the oxygen from its union with iron. The inference as to the iron
content of the ferment is based on analogies of this kind, and on
the evidence, mentioned below, of its absorption spectrum.]

"If one adds carbon monoxide to the oxygen in which living
cells are breathing, then . . . respiration ceases. If one exposes
[this] to light . . . then respiration is resumed. By exposing liv-
ing, breathing cells to light, and, alternately, darkening them, one
can cause respiration to appear and disappear. In the dark, the iron
of the oxygen-transporting ferment is bound to carbon monoxide;
In the light, the carbon monoxide is split off from the iron, and
the iron is thereby again free for oxygen-activation. This was dis-
covered in 1926 [by Warburg] with Fritz Kubowitz."

[Best known of the iron pigments In the body is hemoglobin,
consisting of a protein, globin, to which is added an iron compound
called a "heme," or "hematin." Such a chemical group or com-
pound attached to a molecule is called a "prosthetic group.'* Al-
though it was once thought that the body contains no iron apart
from hemoglobin, MacMunn in 1885 asserted, on the basis of
spectroscopic examination, that all animal cells contain heme
compounds. Warburg's discovery of 1926 was an extension of
discoveries made by earlier investigators in the 1890*5. The photo-
chemical dissociation of certain iron compounds had been dis-
covered in 1891 by Mond and Langer; a few years later J. S.
Haldane and J. L. Smith had observed that light upsets the equilib-
rium of hemoglobin, carbon monoxide, and oxygen, in favor of
oxygen. Other biological iron pigments were later found to behave
in this way too, and Warburg found the same result with the
respiratory enzyme. This suggested that the enzyme contained a
prosthetic group with the properties of a heme.}

"Probably all carbon monoxide-iron compounds are light-sensi-
tive. . . . On the other hand, up till now it has not been possible
to decompose by light a carbon monoxide compound in which the
carbon monoxide was joined to any metal other than iron. , . .
{What follows Is an account of the action of light on the carbon

ILLUSTRATIONS

EMIL VON BEHRING

RONALD ROSS

IVAN PETROVICH PAVLOV

NIELS RYBERG FINSEN

ROBERT KOCH

CAMILLO GOLGI

SANTIAGO RAMON Y CAJAL

CHARLES L, A. LAVERAN

ELIE METCHNIKOFF

PAUL EHRLICH

EMIL KOCHER

ALBRECHT KOSSEL

ALLVAR GULLSTRAND

ALEXIS CARREL

CHARLES RICHET

ROBERT BARANY

JULES BORDET

AUGUST KROGH

ARCHIBALD VIVIAN HILL

OTTO MEYERHOF

FREDERICK GRANT BANTING

JOHN J. R. MACLEOD

WILLEM EINTHOVEN

JOHANNES FIBIGER

JULIUS WAGNER- JAUREGG

CHARLES NICOLLE

CHRISTIAAN EIJKMAN

FREDERICK GOWLAND HOPKINS

KARL LANDSTEINER

OTTO WARBURG

CHARLES SHERRINGTON

EDGAR DOUGLAS ADRIAN

THOMAS HUNT MORGAN

GEORGE HOYT WHIPPLE

GEORGE RICHARDS MINOT

WILLIAM PARRY MURPHY

HANS SPEMANN

HENRY DALE

OTTO LOEWI

ALBERT VON SZENT-GYORGYI

CORNEILLE HEYMANS

GERHARD DOMAGK

HENRIK DAM

EDWARD A. DOISY

JOSEPH ERLANGER

HERBERT SPENCER GASSER

ALEXANDER FLEMING

ERNST BORIS CHAIN

HOWARD WALTER FLOREY

HERMANN JOSEPH MULLER

CARL F. CORI

GERTY T, CORI

PAUL MULLER

BERNARDO ALBERT HOUSSAY

EGAS MONIZ

WALTER RUDOLF HESS

EDWARD CALVIN KENDALL

PHILIP SHOWALTER HENCH

TADEUS REICHSTEIN

193*- OTTO WARBURG 151

monoxide inhibition of respiration in yeast cells.] A 75-watt metal
filament lamp is placed under two conical manometric vessels {a
manometer is an instrument for indicating the pressure of gases}
which are shaken in a thermostat. Each vessel contains 2 c.c. of a
dilute yeast suspension. The gas space contains nitrogen and oxygen
or carbon monoxide and oxygen. The light is switched on and off
for periods of 20 minutes. . . . The light in the nitrogen-oxygen
mixture has no effect on the respiration. The respiration inhibited
by carbon monoxide, however, increases with the light and de-
creases in the dark. [The gas pressures in the manometer indicate
the respiration taking place; see commentary below,} This means
that the carbon monoxide compound of the oxygen-transporting
enzyme is decomposed by light. ... In order to verify the influ-
ence of wave-length on the reaction we selected four regions of
the spectrum, made their intensities the same and irradiated yeast
cells, the respiration of which had been inhibited by carbon mon-
oxide. Thus with light of the same intensity but different wave-
length, we found [in the blue part of the spectrum, strong action;
in the green and yellow, weak action; in the red, no action}. This
is the experiment which gave rise to the method for the determina-
tion of the absorption spectrum of the oxygen-transporting en-
zyme/' [The 'ferment bands* were compared with the bands
shown by a variety of hemes, and the close coincidence of the
values in certain instances confirmed Warburg's view as to the
nature of the prosthetic group of the enzyme.}

CONSEQUENCES IN THEORY
AND PRACTICE

Lavoisier believed that oxidation takes place in the lungs. It has
long been known, however, that the chemical events summed up
in the word "respiration" actually occur in the cells, to which molec-
ular oxygen Is transported by the hemoglobin of the red blood
corpuscles. In the preface to Heavy Meted Prosthetic Groups and
Enzyme Action, Warburg writes: "Ever since it has been known
that cells respire, the chief problem connected with respiration has
been to determine which part of the living matter is auto-oxidizable
[i.e., which part undergoes spontaneous oxidation}. If the com-

152 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

bustlble substances in the cell are not auto-oxidizable, and If the
ceil material itself is not, with what then does the molecular oxygen,
which is absorbed by the respiring cell, react? The answer to the
problem lies In the auto-oxidizable ferrous iron complex which is
oxidized to ferric iron by molecular oxygen and transformed again
to ferrous Iron by the reducing action of the cell constituents."
This Iron complex is the active part of Warburg's Atmungsjer-
ment; the latter, according to him, is "the enzyme which has con-
tributed more than any other to the explanation of life."

In 1925, D. Keilln confirmed and extended the spectroscopic
studies of MacMunn, mentioned above (p. 150). He attributed
three of the MacMunn bands to three heme compounds, which he
called cytochrome a s cytochrome b, and cytochrome c The word
"cytochrome," which is sometimes used alone to comprehend all
three variants, means simply cell pigment. Keilln at first identified
cytochrome with Warburg's respiratory ferment, but in 1927 War-
burg suggested that the oxygen-transporting ferment oxidizes the
cytochrome, which thus forms another stage in the process, a view
in which Keilin concurred. Disputes arose, however, first as to
whether or not the enzyme is really In part a heme compound, and
secondly as to the range of application of Warburg's theory. War-
burg himself has discovered that in certain plants the oxygen is
transported not by iron but by copper; other heavy metals may at
times substitute for iron. He also discovered the first of the "yellow
enzymes/* which do not contain iron, but he states that "In the
aerobic cells . . . the yellow enzymes are intermediate members of
the enzyme chain at the head of which stands oxygen-transporting
iron."

Warburg has made very important contributions toward under-
standing the complicated mechanism by which oxidation and reduc-
tion, essential to all life, are brought about. The importance to
biology and medicine of intracellular chemistry has already been
discussed in another connection (see above, p. 66). It may be
mentioned here that peculiarities of respiration have been observed
in tumor cells and that Warburg's methods have been applied to
the study of tumor metabolism. Warburg has designed a mano-
metric apparatus which is now widely used by chemists and bio-
chemists. His "inhibition technique," employing carbon monoxide,

OTTO WARBURG 153

etc., has been used in other respiration studies; and he has demon-
strated an ingenious method for determining the absorption spectra
of unisolated substances which are present in cells in very small
amounts. His "tissue slice" technique is well known to biochemists.

REFERENCES

WARBURG, O. Heavy Metal Prosthetic Groups and Enzyme Action,
translated by Alexander Lawson (Oxford: Clarendon Press, 1949).

, ed. The Metabolism of Tumours, translated by F. Dickens

(New York: R. R. Smith, 1931).

1932

CHARLES SHERRINGTON

(1857-1952)

EDGAR DOUGLAS ADRIAN

(1889- )

ff For their discoveries regarding the function of
the neurons! 9

BIOGRAPHICAL SKETCHES

SHERRINGTON

CHARLES SCOTT SHERRINGTON WAS BORN IN LONDON, ON
November 27, 1857. He was educated at Queen Elizabeth's School,
Ipswich, matriculating in 1881 at Cambridge, where he was ad-
mitted to Gonviile and Caius College. There he came under the
tutelage of Sir Michael Foster and worked in association with Bal-
f our, Gaskell, Langley, Newell Martin, and Sheridan Lea. He pub-
lished his first paper on the nervous system in 1884, with Langley.
After receiving his degree in medicine (M.B.) from Cambridge in
1885, he went to Spain and Italy to study cholera. He continued his
work in pathology at Berlin, first with Virchow but for a longei
period with Koch. Returning to London, he was made lecturer in
physiology at St. Thomas's Hospital, and in 1891 he was appointed
Professor-Superintendent of the Brown Institute for Advanced
Physiological and Pathological Research, where he succeeded Sir

154

1932: SHERRINGTON AND ADRIAN 155

Victor Horsley. Between 1885 and 1895 Sherrington made several
visits to Strasbourg to study under the physiologist Goltz, whose
chief interest lay in the function of the central nervous system. In
the latter year Sherrington accepted the chair of physiology in the
University of Liverpool, where he remained for eighteen years,
until he went to Oxford as Waynflete Professor of Physiology. In
1893 he was elected a Fellow of the Royal Society, of which he
became president in 1920. He was knighted in 1922. In 1891 he
married Ethel Mary Wright. They had one child, Carr E. R. Sher-
rington, who became a distinguished railroad economist and author.
In addition to his scientific papers, Sherrington wrote on more
general topics, including public health and the history of medicine,
and published a book of verse. His death occurred on March 4,
1952, in his ninety-fifth year.

ADRIAN

EDGAR DOUGLAS ADRIAN WAS BORN IN LONDON, ON NOVEMBER
30, 1889. He was educated at Westminster School and entered
Trinity College, Cambridge, with a science scholarship, in 1908.
He studied physiology for Part II of the Natural Sciences Tripos
and was awarded a first class in 1911. His first research was done
in collaboration with Keith Lucas. It was followed by an investiga-
tion of the "all or none" principle in nerves, for which he was
elected to a fellowship at Trinity College in 1913. Adrian became
the ninth Fellow of Trinity to be awarded a Nobel Prize. He took
a medical degree in 1915 and worked at clinical neurology, return-
ing to Cambridge in 1919 to lecture on the nervous system. He was
made a fellow of the Royal Society in 1923. Two years later he
began investigating the sense organs by electrical methods. In 1929
he was made Foulerton Professor of the Royal Society. Probably
his best-known works are The Basis of Sensation (1927), The
Mechanism of Nervous Action (1932), and The Physical Back-
ground of Perception (1947). He has received many honors, in-
cluding the rare distinction of the Order of Merit, which was also
awarded to Sherrington. Succeeding G. M. Trevelyan, the his-
torian, Adrian is now Master of Trinity.

156 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE -WINNING

WORK

SHERJUNGTON *

"The receptors played upon by the events of the external world
supply their 'drive' to the muscles. In reflex action they do so far
more simply and for far more simple purposes than when the trains
of reaction they set going have to thread the mazes of the higher
brain, and, so to say, obtaining mental sanction, issue in acts re-
moter from the original stimulus. Yet in both cases the muscles lie
at the behest of the receptors, as instruments of their hand.

"We should go too far, however, did we infer that the muscles
themselves are instruments entirely passive under drive of the
receptors acting on them from without. That they are agents not
purely passive is shown by their possession of receptors of their
own. On their own behalf they send messages into the central ex-
changes. This must mean they have some voice in their own con-
ditions of service, perhaps ring themselves up and ring themselves
off. Let us attempt to penetrate into the significance of this their
'receptivity/

"It is a receptivity differing obviously from that of other recep-
tors, rightly more commonly chosen to exemplify receptive func-
tion, such as retina, ear, tongue, tactile organs, and so on, for in
the case of the receptors of muscle, instead of being stimulated
directly by agents of the external world, they are stimulated by
happenings in the microcosm of the body itself namely, events in
the muscles themselves. In muscular receptivity we see the body
itself acting as stimulus to its own receptors. The receptors of
muscle have therefore been termed "proprioceptors/ [This term
was coined by Sherrington.j

"Following the functional scheme of all receptors, we may be
sure that the central reactions provoked by the receptors of muscle

* From C. S. Sherrington, "Problems of Muscular Receptivity," Linacre Lecture,
Nature (London), June 21 and 28, 1924. Reprinted in D. Denny-Brown, ed.,
Selected Writings of Sir Charles Sherrington (New York: Paul B. Hoeber, 1940),
PP- 385-390.

1932: SHERRINGTON AND ADRIAN 157

will be divisible into, on the one hand, the purely reflex, and on
the other hand, those which subserve mental experience.

"Let us turn to the simpler of these divisions, the purely reflex.
For that purpose, appeal can be had to what may with justification
be regarded as a partially surviving animal an animal which, Its
cerebral hemispheres having been removed, is a wholly inconscient
and purely reflex automaton. From it no sight or sound evokes
evidence of perception. There is total inability to evoke from it any
sign of mentality, of emotion, let alone intelligence. It remains
motionless hour after hour; yet if planted upon its feet in the up-
right position it stands, and statuelike continues to stand.

"Now, standing is a postural act, and one of course of high
importance. In maintaining posture the muscles, though they per-
form no external work, are active with an activity often technically
termed 'tonus/ a postural contraction. In this maintenance of the
erect posture by the decerebrate animal, we meet a co-ordinated
posture involving many separate muscles harmoniously co-ordinated
reflexly. For this reflex postural act of standing some stimulus must
be at work evoking and maintaining it. We have to ask what that
stimulus may be.

"If the afferent nerves that pass from a limb to the spinal centres
be severed, the standing posture in that limb is no longer fully
executed or maintained. The stimulus exciting the posture in that
limb must be something which is applied to the receptors of that
limb itself. The skin surface of the limb is rich in receptors, one
region especially rich being the sole of the foot. On the receptors of
the skin of the sole of the foot the external world may evidently
be acting as a stimulus in the form of pressure from the ground
upon the skin. To test whether that is the source of the reflex
posture, the skin of the foot can be deprived of all its receptors
by severing their nerves. This is found to exert no obvious influence
upon the posture. Nor does severence of all the receptive nerves
from the skin of the whole limb, nor, indeed, from that of all the
four limbs. The stimulus producing and maintaining the posture
is therefore not pressure of the skin against the ground, nor indeed
any cutaneous stimulus whatsoever. On the other hand, if, even
without interference with the skin nerves, the receptive nerves of
the limb-muscles the motor nerves, of course, remaining intact

158 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

be severed, the reflex posture disappears at once from the limb.
The stimulus which produces and maintains the posture is some-
thing which is acting on and exciting the receptive nerves of the
muscles of the limb.

"What are the muscles which, by their contraction, execute this
postural act? The posture keeps the head and neck from sinking,
the trunk straightened and the spine supported, the tail from droop-
ing, the limbs from yielding and folding under the superincumbent
weight of the body. In a word, this habitual reflex posture counter-
acts in the various parts of the body the effect of gravity on them in
the erect attitude. Experimental analysis shows that throughout the
muscular frame of the animal all those muscles, and only those, are
In action, the activity of which counteracts gravity in the erect atti-
tude for example, in the hind-limb the muscles which extend hip,
knee, and ankle. The muscles which execute the reflex we may, in
short, term 'antigravity' muscles. Even the jaw is included; the
lower jaw, which, but for its postural tonus, would drop, is held
lifted against the upper.

"If in the limb the receptive nerve of one of these antigravity
muscles be cut, that muscle no longer contributes to the reflex pos-
ture. On the other hand, severance of the receptive nerves of all
the other muscles does not destroy the postural reflex of the muscle
the receptive nerve of which remains intact. The stimulus which
is the source of this reflex standing is therefore one acting on the
receptors of those limb-muscles which are themselves executants
of the posture.

"The excitability of a receptor is selective. That is, construction
fits the receptor to respond to stimuli of one particular kind only,
the so-called 'adequate' stimulus; thus, the retina to light, a taste
papilla to "sweet/ and so on. Hence Pavlov's term 'analyser* for
the receptors, because by them the various complex events which
play upon the body and cause reactions of it through the nervous
system are to some extent analysed. A wave breaking on the shore
excites the retina by its reflected lights, the ear by sound vibrations,
and, maybe, the skin by the spray dashed up. The wave as 'object*
and stimulus from the external world is thus partially analysed by
the receptors.

1932: SHERRINGTON AND ADRIAN 159

"Seeing that the receptors of muscle are an appendage of an
organ mechanical in function, a near supposition is that their ade-
quate stimulus is of mechanical kind. What is the adequate stimulus
at work in these antigravity muscles in their posture of standing?

"A muscle representative of the whole antigravity group is the
extensor of the knee. Suppose it isolated from the rest and its freed
tendon attached to a stiff spring, and to the spring a light lever so
fixed that movement of the lever-point is photographically re-
corded. If then, by its bony attachments, the muscle be pulled
against the spring, we can passively stretch the muscle and record
the tensile strain developed in it by the stretch. Let us take the
case of the muscle paralysed by severance of all nerves both afferent
and efferent which connect it with the nerve-centres. The tension
developed in the muscle as it is stretched yields a curve resembling
that given by various fibrous and elastic tissues of the body, not
unlike that given by a strip of indiarubber. Let us repeat the obser-
vation, but with the difference that the muscle retains unimpaired
its purely efferent motor nerve. The stretching produces the same
tensile curve as before, a curve practically indistinguishable from
that of the wholly paralytic muscle. Then let us make the observa-
tion, with the further difference that the muscle this time retains
not only its motor nerve but its receptive nerve as well. We find
the muscle yields now a completely different curve of tensile strain.
The tension developed by it is much greater, and its curve under
equable progressive increase of the stretch runs, tensions being
ordinates, convex instead of concave to the abscissa line. The mus-
cle in response to the stretch now replies not merely by passive
strain but also by active contraction of its muscle-fibres. In the
muscle with its reflex arc intact, the passive pull provokes a reflex
contraction of the muscle."

ADRIAN*

"The sense organs respond to certain changes in their environ-
ment by sending messages or signals to the central nervous system.
The signals travel rapidly over the long threads of protoplasm

* From E. D. Adrian, "The Activity of the Nerve Fibres/' Les Przx Nobel en
1932.

160 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

which form the sensory nerve fibres, and fresh signals are sent
out by the motor fibres to arouse contraction in the appropriate
muscles. What kind of signals are these? . . . [This question]
would have been answered correctly by most physiologists many
years ago, but now it can be answered in much greater detail. It
can be answered because of a recent improvement in electrical
technique. The nerves do their work economically, without visible
change and with the smallest expenditure of energy. The signals
which they transmit can only be detected as changes of electrical
potential, and these changes are very small and of very brief dura-
tion, . , .

"The revolution in technique has come about not from any in-
crease in the sensitivity of galvanometers and electrometers but
from the use of [amplifiers like those employed in radio] to am-
plify potential changes. . . . Many workers have contributed to
the introduction of this technique in physiology, notably Forbes
of Harvard, Gasser of St. Louis [later of New York, winner of
the Nobel Prize with Erlanger in 1944], who was the first to use
very high amplification, and Mathews of Cambridge. . . .

"Seven years ago [i.e., in 1925] it became clear to me that a
combination of the capillary electrometer * with an amplifier would
permit the recording of far smaller potential changes than had been
dealt with previously, and might enable us to work on the units of
the nerve trunk instead of on the aggregate. . . . The problem
was then to limit the activity to only one or two nerve fibres. [The
difficulty of interpreting the irregular effects from a whole nerve,
due to the fact that impulses in the various nerve fibers do not
come simultaneously and can therefore nullify or amplify one an-
other, has been likened by Professor Liljestrand to an attempt to
construct the separate conversations by listening to the various
wires in a telephone cable simultaneously. It was necessary to try
to obtain impulses corresponding to one single conversation or one
sending station.] In this I was happy to have the co-operation of
Dr. Zotterman of the Caroline Institute. We found that the sterno-
cutaneous muscle of the frog could be divided progressively until it
contained only one sense organ; this could be stimulated by stretch-

* See above, pp. 116-117.

1932: SHERRINGTON AND ADMAN 161

Ing the muscle, and we could record the succession of impulses
which passed up the single sensory nerve fibre.

". . . [The signals] consist of nerve impulses repeated more
or less rapidly. . . . The waves [recording potential changes} are
of constant size and duration, but they begin at a frequency of
about 10 a second, and as the extension increases, their frequency
rises to 50 a second or more. The frequency depends on the extent
and on the rapidity of the stretch; it depends, that is to say, on the
intensity of excitation in the sense organ, and in this way the im-
pulse message can signal far more than the mere fact that excitation
has occurred. [There had previously been 'good reason to believe
that the nerve impulse was a brief wave of activity depending in
no way on the intensity of the stimulus which set it up/}

tf ln all the sense organs which give a prolonged discharge under
constant stimulation the message in the nerve fibre is composed
of a rhythmic series of impulses of varying frequency. . . . With
some kinds of sense organ there is a rapid adaptation to the stimu-
lus and the nervous discharge is too brief to show a definite rhythm,
though it consists as before of repeated impulses of unvarying size.

"The nerve fibre is clearly a signalling mechanism of limited
scope. It can only transmit a succession of brief explosive waves,
and the message can only be varied by changes in the frequency
and in the total number of these waves. Moreover the frequency
depends on the rate of development of the stimulus as well as on
its intensity; also the briefer the discharge the less opportunity
will there be for signalling by change of frequency. But this limita-
tion is really a small matter, for in the body the nervous units do
not act in isolation as they do in our experiments. A sensory stimu-
lus will usually affect a number of receptor organs, and its result
will depend on the composite message in many nerve fibres. . . .
[It has been shown in specific instances that} the impulses in each
nerve fibre increase in frequency [when the stimulus increases}
and more fibres come into action. Since rapid potential changes can
be made audible as sound waves, a gramophone record, will illus-
trate this, and you will be able to hear the two kinds of gradation,
the changes in frequency in each unit and in the number of units
in action."

162 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

CONSEQUENCES IN THEORY
AND PRACTICE

The contributions of Sir Charles Sherrington to neurophysiology,
like the contributions of Ramon y Cajal to neuroanatomy, are so
numerous and varied that they are difficult to summarize.* One of
Sherrington's earlier achievements was to analyze the distribution
of the ventral (motor) nerve roots, recording the muscles activated
by each; similarly he mapped out sensory distribution for dorsal
roots, with results which have formed the basis of all later work on
sensory levels.

Prior to 1894 it was generally assumed that all nerves going to
muscle were motor nerves. In that year Sherrington published a
paper in which he maintained that one third to one half of the
nerve fibers in skeletal muscle nerves are sensory. It was not then
established that Golgi's spindles (see above, pp. 34-36) were
actually sensory. Sherrington cut ventral nerve roots so as to deprive
a particular muscle of motor supply, and found that the spindles
remained intact with their myelinated fibers; but interruption of
dorsal (sensory) roots at a corresponding level caused these end
organs to degenerate and disappear. He found that dorsal root sec-
tion, unlike the severing of cutaneous nerves, caused an animal to
lose awareness of the position of its limbs in space, to lose tendon
reflexes (such as the knee jerk) and to become ataxic i.e., to
lose the power of muscular coordination. These experiments laid
the foundation of knowledge of the "proprioceptive" system, the
mechanism for the sense of position and equilibrium, with the fine
adjustment of muscular movements depending on stimuli originat-
ing within the organism (Latin proprius, one's own) . The term is
Sherrington* s and the whole concept is based largely on his work.
These experiments incidentally served to explain ataxia in the
clinical condition known as tabes dorsalis, in which sensory path-
ways at dorsal root level are impaired. In a somewhat similar man-
ner many another Sherrington experiment has explained the find-

* These paragraphs about Sherrington are based in part on John F. Fulton,
"Sherrington's Impact on Neurophysiology/* British Medical Journal, Vol. n
(i947) PP- 807-810.

1932: SHERRINGTON AND ADRIAN 163

ings and guided the thought of the clinical neurologist; his writ-
ings have also proved source books for the general physiologist and
the psychologist.

Sherrington next studied the reflexes in the spinal and decerebrate
state and the reciprocal innervation of antagonistic muscles i.e.,
the reflex mechanism which results in the coordinated action of
muscles of opposing tendency, such as a flexor and an extensor of
the same part. This reflex behavior of antagonistic muscles led to
the concept of integration, a theme developed in the Silliman Lec-
tures delivered at Yale in 1904, first published in 1906 under the
title The Integrative Action of the Nervous System (latest edition,
1947) . This is one of the classics of modern physiology, embracing
a wide range of work on nervous integration.

Another important contribution was the mapping of the motor
areas of the cortex in a more exact manner than had ever been done
before. His observations in this field at once accounted for the
clinical picture of hemiplegia (paralysis of one side of the body)
and for the manner in which recovery takes place. The rigidity
(contracture) of hemiplegia was explained by Sherrington's studies
of decerebrate rigidity, to be caused by the unantagonized activity
of subcortical centers. He then turned to the study of special re-
flexes, such as the swallowing reflex, and in 1924 discovered the
"stretch reflex,** which accounts for the constant activity of the
antigravity muscles. On the nature of cortical inhibition he pub-
lished his principal paper in 1925; on the ultimate unit of reflex
action, in 1930.

This rapid listing of achievements has taken little account of
many observations on the physiological anatomy of the tracts of
the spinal cord, of investigations of binocular flicker and sensual
fusion, of extensive work on general sensation, and of a host of
other special contributions. Sherrington has given to medicine not
only a multitude of exact and important observations, but new
theoretical concepts of the greatest value and striking advances in
laboratory technique, as well as in the teaching and practice of
mammalian physiology in general. His work and his ideas have
entered into the whole structure of the physiology of the nervous
system.

The work of E. D. Adrian built upon and extended Sherring-

164 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

ton's researches and demonstrated their value. The latter had
shown that stimuli from different points can weaken or reinforce
a reflex; he had also determined the effect of repeated stimulations
at the same point. A motor neuron receiving impulses from many
directions discharges its impulse in one way only, through its axon;
of several indications for action, "nociceptive," or pain, reflexes
predominate, apparently as a protection for the organism. What is
the nature of the nerve impulse in afferent and efferent limbs of a
reflex? Adrian and his co-workers answered this question in the
manner set forth above, working with the "stretch reflex" originat-
ing in a single end organ. By repeated stimulations at the same
point Sherrington had demonstrated temporal inhibition and sum-
mation. Adrian showed that sense organs can adjust themselves so
that a stimulus which produces a rapid succession of impulses when
first applied has a weaker effect when sustained. Adrian and Zotter-
man demonstrated the increase in frequency of the signals sent in
to the central exchange as the stretching of a muscle becomes
greater; with D. Bronk, Adrian showed that heightened activity in
the motor limb of the reflex, or of motor nerves generally, is accom-
panied by an increase in the number of impulses per second. This
analysis of the nerve impulses served to explain earlier results, in-
comprehensible because of their complexity, by the isolation of
functional units; synthesis following analysis put the complex pat-
tern together again. Adrian's work threw much light on the adjust-
ment capacity of the nerve action and the sense organs. His work
on the electrophysiology of nerve impulse has been complemented
by that of two other Nobel laureates, Erlanger and Gasser (see
below, pp. 223-228).*

* For more recent developments see Harry Grundfest, "Potentialities and Limita-
tions of Electrophysiology," a symposium, in D. Nadhmansohn, ed., Nerve
Impulse: Transactions of the First Conference, March 2-3, 19^0 (New York:
Josiati Macy Jr. Foundation, 1951).

1933

THOMAS HUNT MORGAN

(1866-1945)

"For Ms discoveries concerning the junction of the
chromosome in the transmission of heredity.*'

BIOGRAPHICAL SKETCH

THOMAS HUNT MORGAN WAS BORN IN 1866 AT LEXINGTON,
Kentucky. He attended the University of Kentucky and was gradu-
ated in 1886. He then entered the Johns Hopkins University, where
he studied morphology with Professor W. K. Brooks and physi-
ology with H. Newell Martin. In 1890 he received the Ph.D. de-
gree and was Bruce Fellow for the following year. In 1891 he was
appointed associate professor of biology at Bryn Mawr College,
where he remained until 1904; in that year he was named professor
of experimental zoology at Columbia University. In 1928 he be-
came head of the KerckhofT Biological Laboratories of the Cali-
fornia Institute of Technology, Pasadena, California. From 1909
on, Morgan attracted to his laboratory a brilliant group of workers,
including C B. Bridges and A. H. Sturtevant, with both of whom
he shared the Nobel Prize money, and H. J. Muller, who was later
awarded the Prize himself for his discovery of X-ray mutations
(see below, pp. 238-243). The result of the combined efforts of
Morgan's team was a great extension of the knowledge of genetics.
Morgan's work and influence were acknowledged by the award of
many honors, including foreign membership in the Royal Society.
He died at the age of seventy-nine, on December 4, 1945.

165

166 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"Mendel's paper was recovered in 1900. [In 1866 J. G. Mendel
published an account of his experiments with garden peas, setting
forth "Mendel's laws" of heredity. According to the first of these,
two different hereditary characters, after being combined in one
generation, will again be segregated in the next i.e., in the new
sex cells. The latter being fused with others, new and independent
combinations can be formed; this is Mendel's second law, that of
independent assortment. No notice was taken of his paper until
1900.} Four years later Bateson and Punnett reported observations
that did not give the numerical results expected for two independ-
ent pairs of characters. For instance, when a sweet pea having
purple flower-color and long pollen grains is crossed to one with
red flowers and round pollen grains, the two types that go in to-
gether come out together more frequently than expected for inde-
pendent assortment of purple-red and round-long. They spoke of
these results as due to repulsion between the combinations purple
and long and red and round, that came from opposite parents. To-
day these relations are called linkage. By linkage we mean that
when certain characters enter a cross together, they tend to remain
together in later generations, or, stated in a negative way, certain
pairs of characters do not assort at random.

"It would seem, then, so far as linkage holds, that there are
limits to the subdivision of the germinal material. For example in
the vinegar fly [also called fruit fly], Drosophila melanogaster,
there are known about 400 new mutant types that fall into only
four linkage groups.

"One of these groups of characters of Drosophila is said to be
sex-linked, because in inheritance the characters show certain rela-
tions to sex. There are about 150 of these sex-linked mutant char-
acters. Several of them are modifications of the color of the eye,
others relate to its shape or its size, or to the regularity of the dis-
tribution of its facets. Other characters involve the body color;

* T. H. Morgan, The Theory of the Gene (New Haven: Yale University Press,
rev. ed., 1928), Silliman Lectures, pp. 10-14, 19-20.

1933 : THOMAS HUNT MORGAN 167

others the shape of the wings, or the distribution of its veins; others
the spines and hairs that cover the body.

"A second group of about 120 linked characters includes changes
in all parts of the body. None of the effects are identical with those
of the first group.

"A third group of about 130 characters also involves all parts of
the body. None of these characters are the same as those of the
other two groups.

"There is a small fourth group of only three characters; one
involves the size of the eyes, leading in extreme cases to their total
absence; one involves the mode of carriage of the wings; and the
third relates to the reduction in size of the hairs.

"The method of inheritance of linked characters is given in the
following example. A male Drosophila with four linked characters
(belonging to the second group), black body color, purple eyes,
vestigial wings, and a speck at the base of the wings, is crossed to
a wild type female with the corresponding normal characters, that
may be called gray body color, red eyes, long wings, and absence
of speck. The offspring are wild type. If one of the sons is now
crossed to a stock female having the four recessive characters
(black, purple, vestigial, speck), the offspring are of two kinds
only, half are like one grandparent with the four recessive char-
acters, and the other half are wild type like the other grandparent.

"Two sets of contrasted (or allelomorphic) linked genes went
into this cross. When the germ-cells in the male hybrid matured,
one of these sets of linked genes went into half of the sperm-cells
and the corresponding allelomorphic set into the wild type half of
the sperm-cells. This was revealed, as described above, by crossing
the hybrid (Fx) {first generation} male to a female pure for the
four recessive genes. All of her mature eggs contain one set of four
recessive genes. Any egg fertilized by a sperm with one set of the
dominant wild type genes should give a wild type fly. Any egg
fertilized by a sperm with the four recessive genes (which are the
same as those in the female here used) should give a black, purple,
vestigial, speck fly. These are two kinds of individuals obtained.

"The members of a linked group may not always be completely
linked as in the case just given. In fact, in the FI female from the
same cross, some of the recessive characters of one series may be

168 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Interchanged for wild type characters from the other series, but
even then, since they remained united more often than they inter-
change, they are still said to be linked together. This interchange
is called crossing-over, which means that, between two correspond-
ing linked series, there may take place an orderly interchange in-
volving great numbers of genes. . . .

"A study of crossing-over [in Drosophila] has shown that all
possible percentages of crossing-over occur, up to nearly 50 per
cent. If exactly 50 per cent of crossing-over took place, the nu-
merical result would be the same as when free assortment occurs.
That is, no linkage would be observed even though the characters
involved are in the same linkage group. Their relation as members
of the same group could, nevertheless, be shown by their common
linkage to some third member of the series. If more than 50 per
cent crossing-over should be found, a sort of inverted linkage would
appear, since the cross-over combinations would then be more fre-
quent than the grandparental types.

'The fact that crossing-over in the female of Drosophila is
always less than 50 per cent, is due to another correlated phenom-
enon called double crossing-over. By double crossing-over is meant
that interchange takes place twice between two pairs of genes in-
volved in the cross. The result is to lower the observed cases of
crossing-over, since a second crossing-over undoes the effect of a
single crossing-over/'

CONSEQUENCES IN THEORY
AND PRACTICE

Professor Morgan began his career as a zoologist on strictly
morphological lines i.e., as a student of form and structure. He
became, however, a distinguished experimentalist, particularly in
genetics. Deeply interested in evolution, on which he wrote exten-
sively, he was distrustful of Darwin's theory of natural selection
and preferred the mutations theory of De Vries as an explanation
of the origin of species. That is to say, he was inclined to think new
species the consequence of spontaneous, inheritable changes due
to aberrations of the chromosomes, threadlike intracellular struc-
tures which had been suggested as the carriers of hereditary char-

1933 : THOMAS HUNT MORGAN 169

acters (genes). This suggestion, made at the beginning of the
century by W. Button and T. Bovery, seemed to fit the scheme of
Mendelian heredity. Prior to cell division each chromosome splits
longitudinally into two daughter chromosomes; when cell division
actually takes place, one of these becomes part of the structure of
each new cell, which is thus endowed with the same combination
of chromosomes as the original cell. Maturation division, however,
which occurs in mature sex cells, is of a different kind: here the
number of chromosomes is reduced by one half. When male and
female sex cells come together and fuse, the original chromosome
number is again restored, but now one half of each pair is derived
from the male, the other half from the female, sex cell. If chromo-
somes were actually the carriers, as Sutton and Bovery suggested, of
the hereditary elements, the genes, here was a mechanism to account
for the Mendelian ratios in breeding experiments. But of this there
was no proof.

It was about this time that Morgan began to work with Droso-
phila. The fruit fly of this name had already been shown by Lutz ?
Payne, and others to be amenable to culture in the laboratory. It is
particularly well suited for studies in genetics because it breeds very
rapidly (ten days from egg to egg) and because its cell nucleus
contains only four chromosomes. Morgan found that Drosophila
did not give rise to new species, in accord with the theory of De
Vries, but rather provided valuable material for the study of
Mendelian segregation.

As indicated in the quotation, Mendel's second law is subject to
certain exceptions. These were accounted for by the doctrine of
linkage. But linkage is not perfectly constant and factors are some-
times separated which usually occur together. Morgan's explana-
tion was that chromosomes belonging to the same pair may
exchange genes immediately before the maturation division. One
or more breaks occur in each chromosome and the parts are then
reunited crosswise. This is the mechanism of the crossing-over al-
ready described. The probability that a break will occur between
genes when a chromosome is segmented in this way is increased by
the distance separating the positions of two such genes; the more
commonly such genes break off, the more commonly the factors
they represent will be recombined in offspring.

170 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

All this assumes that the genes are arranged in straight lines,
and not, for example, in circles. If this assumption is made, there
is an exact correlation to be expected between the rate of occurrence
of these recombinations and the relative distance between the genes
in question in a chromosome. Charts of chromosomes have been
established in this way, showing the positions of the genes. (Com-
pare H. J. Muller's explanation of X-ray mutations; see below,
pp. 239-241.)

Morgan's school of geneticists has been able to present con-
vincing evidence that the chromosome is actually the carrier of the
genes. This evidence is of several kinds. There are four chromo-
somes in Drosophila; there are also four linkage groups. But per-
haps the most conclusive evidence is that which comes from the
loss or from the addition of one of the small fourth chromosomes
of Drosophila. Genetic indications can in this case be verified
directly by the microscope.

The Morgan doctrines which are here sketched in outline were
built up by the patient and comprehensive work of many years.
They have been confirmed by other scientists in studies of both
animals and plants. In the human being, too, it has been possible
to identify linkage groups. It is now obvious that legal medicine
owes a debt to genetic science. In the investigation of hereditary
tendency to disease or physical defect it is likewise impossible to
proceed without the aid of the bask contributions of laboratory
geneticists. The study of mutations in genes and chromosomes is
a promising part of current cancer research. Not only in medicine
but also in agriculture and stock breeding the "theory of the genes,"
which owes so much to Morgan and his school, has shown itself to
be a concept of great practical importance*

1934

GEORGE HOYT WHIPPLE

(1878- )

GEORGE RICHARDS MINOT

(1885-1950)

WILLIAM PARRY MURPHY

(1892- )

"For their discoveries concerning liver therapy
against anemias."

BIOGRAPHICAL SKETCHES

WHIPPLE

GEORGE HOYT WHIPPLE WAS BORN IN ASHLAND, NEW HAMP-
shire, on August 28, 1878. He was educated at Andover Academy
and Yale University (A.B., 1900) and received his M.D. degree
from the Johns Hopkins University in 1905. With the exception of
one year (1907-1908) as pathologist at the Ancon Hospital,
Panama, Dr. Whipple was at the Johns Hopkins Medical School
from 1905 to 1914, as assistant in pathology, instructor, associate,
and associate professor. From 1914 to 1921 he was professor of
research medicine at the University of California Medical School,
and director of the Hooper Foundation for Medical Research, Uni-

171

172 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

versity of California. During the year 1920-1921 he was dean of
the University of California Medical School. In 1921 Dr. Whipple
became professor of pathology and dean of the School of Medicine
and Dentistry of the University of Rochester. Much of his research,
from the time when he was a junior in the Johns Hopkins Depart-
ment of Pathology under Dr. William H. Welch, has dealt with
normal and pathological liver function. Dr. Whipple has conducted
penetrating studies of the origin, function, and fate of bile pig-
ments and other body pigments in health and disease. He has made
contributions of basic importance to our knowledge of the anemias.
He has also studied plasma protein regeneration and iron metab-
olism. He became a Trustee of the Rockefeller Foundation in 1927,
a member of the Board of Scientific Directors of the Rockefeller
Institute in 1936, and a Trustee of the Institute in 1939.

MINOT

GEORGE RICHARDS MINOT WAS BORN IN BOSTON, ON DECEMBER
2, 1885. He attended Harvard University, receiving the A.B. in
1908, theM.D. in 1912, and the honorary degree of S.D. in 1928.
After serving as medical interne at the Massachusetts General Hos-
pital 5 he worked at the Johns Hopkins Hospital and Medical School
under William S. Thayer and William H. Howell. In 1915 he re-
turned to Boston, being appointed assistant in medicine at the
Harvard Medical School and Massachusetts General Hospital. In
1922 he became physician in chief of the Collis P. Huntington
Memorial Hospital of Harvard University; later he was appointed
also to the staff of the Peter Bent Brigham Hospital. In 1928 he
was made professor of medicine at Harvard and director of the
Thorndike Memorial Laboratory, as well as visiting physician at
Boston City Hospital. Although he published papers on a wide
variety of subjects, including cancer, arthritis, and dietary deficiency
(e.g., the role of dietary factors in "alcoholic" polyneuritis), his
chief interest lay in disorders of the blood and the function and
dysfunction of bone marrow. He contributed to knowledge con-
cerning coagulation of the blood, the blood platelets, various hemor-
rhagic disorders, the blood picture in certain industrial poisonings,

1934 : WHOTLE, MINOT AND MURPHY 173

leukemia, disorders of the lymphatic tissue and polycythemia, as
well as the anemias. His most significant contributions were his
studies of the anemias, and especially pernicious anemia.

MURPHY

WILLIAM PARRY MURPHY WAS BORN IN STOUGHTON, WISCON-
sin, on February 6, 1892. His early education was received in the
public schools of Wisconsin and Oregon. He received his A.B.
from the University of Oregon in 1914 and then for two years
taught physics and mathematics in Oregon high schools. After one
year in the University of Oregon Medical School, Portland, and a
summer session at the Rush Medical School, Chicago, he entered
the Harvard Medical School and received the M.D. degree in 1922
as of 1920. After two years as house officer at the Rhode Island
Hospital, he became assistant resident physician at the Peter Bent
Brigham Hospital under Prof. Henry A. Christian for eighteen
months, then junior associate, and later associate in medicine at the
same institution. He was assistant in medicine at Harvard from
1923 to 1928, instructor from 1928 to 1935, and associate from
1935 to 1948. Since 1948 he has been lecturer. Dr. Murphy has
been an active practitioner of medicine since 1923.

DESCRIPTION OF THE PRIZE- WINNING

WORK

"At the University of California (1914), Dr. [C W.] Hooper
and I took up a careful study of bile pigment metabolism by means
of bile fistulas in dogs and investigated the effect of diet upon bile
pigment output As these studies were continued ... it became
apparent that we could not understand completely the story of bile
pigment metabolism without more knowledge about the construc-
tion of blood hemoglobin in the body. Blood hemoglobin is a most
important precursor of bile pigment and it was necessary to under-

* From G. H. Whipple, "Hemoglobin Regeneration as Influenced by Diet and
Other Factors," Les Prix Nobel en 1934-

174 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

stand what factors influenced the building of new hemoglobin in
the dog.

'Tor this reason we produced simple anemia in dogs by means
of blood withdrawal and in short experiments followed the curve
of hemoglobin regeneration back to normal. These experiments
with Dr. Hooper were begun in 1917 and it was found at once
that diet had a significant influence on this type of blood regenera-
tion. Because of our interest in liver function and injury we soon
began testing liver as one of the diet factors and could readily
demonstrate that it had a powerful effect upon hemoglobin re-
generation [1920]. These short anemia experiments were relatively
crude and gave at best qualitative values for the various diet factors.

"After the transfer of the anemia colony of dogs from San
Francisco to Rochester, New York (1923), Dr. Frieda Robscheit-
Robbins and the writer began to use a different type of anemia.
Dogs were bled by aspiration from the jugular vein and gradually
reduced from a normal hemoglobin level of 140-150 per cent to
about 1/3 normal, or 40-50 per cent, and this anemia level was
maintained a constant for indefinite periods by suitable removal of
new-formed hemoglobin. The potency of the diet factor was then
accurately measured in terms of the grams hemoglobin removed to
preserve the constant anemia level. The stimulus presumably was
maximal and uniform, and the reaction of a given dog to a diet
factor was shown to be uniform when repeated time after time.

"Much effort and time were spent in devising a basal ration ade-
quate for health and maintenance during these long anemia periods
lasting throughout the entire life of the dog (5-8 years). . . .
[Such a diet] permits of minimal new hemoglobin regeneration
and therefore gives a low base-line hemoglobin output from which
to measure the increased output due to liver, kidney, gizzard or
other favourable diet factor. . . .

"{From the results] it is obvious that liver . . . stands out as
the most potent diet factor. . . . Gradually various diet factors
were standardized and this information was placed at the disposal
of physicians who were concerned with the therapeutic treatment
of human anemias. Iron was found to be the most potent inorganic
element.

"Pernicious anemia, examined from the point of view of the

1934 : WHIPPLE, MINOT AND MURPHY 175

pathologist, was described in 1921 [publication 1922} as a disease
in which all pigment factors were present in the body in large
excess but with a scarcity of stroma-building material or an abnor-
mality of stroma-building cells." [The "stroma" is the framework,
or structural basis, of an organ, tissue, or cell. In pernicious anemia
the factors needed to form blood pigment are present, but the red
blood cells, the necessary vehicle, do not form properly.}

MINOT *

"The idea that something in food might be of advantage to
patients with pernicious anemia was in my mind in 1912, when I
was a house officer at the Massachusetts General Hospital, as is
noted in certain case records there. . . .

"The study of the patients' diets was begun in 1915 in an at-
tempt to determine if some sort of dietary deficiency could be
found. The similarity of certain symptoms and signs of pernicious
anemia to those in pellagra, sprue and beriberi was appreciated, as
was the fact that certain sorts of anemia were occasionally associated
with a faulty diet. Elders., among others, suggested in 1922 that
such a state of affairs existed in pernicious anemia. Furthermore,
the almost constant occurrence of achlorhydria [absence of hydro-
chloric acid in the gastric juice} in pernicious anemia . . . led me
to wonder if this disorder of the digestive system had something to
do with the condition which might be in the nature of a dietary
deficiency disease. Indeed, Fenwick, about 1880, suggested the
primary role of the stomach, but it remained for Castle, in 1928,
to demonstrate the part this organ plays in the causation of the
disease. . . . [W. B. Castle showed that meat digested with
normal gastric juice was almost as effective as liver, but found that
meat by itself, or when digested with the aid of a synthetic gastric
juice, failed to give any good effect. Normal gastric juice seems to
contain an "intrinsic factor/' which together with an "extrinsic
factor" in meat forms the active substance causing red blood cells
to mature. This active substance, called "erythrocyte maturing fac-
tor," or "EMF," is stored, among other places, in the liver. This

* From G. R. Minot, "The Development of Liver Therapy in Pernicious Anemia,"
Les Prix Nobel en 1934-

176 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

explanation was not forthcoming until Minot and Murphy had
shown the value of liver therapy.]

"Although Pepper in 1875 anc * Cohnheim in 1876 recognized
that the bone marrow was abnormal, there was a prevailing opinion
in the early part of this century that abnormal blood-destruction
played an important or primary role in the production of the
disease. Nevertheless it was believed by many physicians, as I was
taught, that the production of blood by the bone marrow was also
deeply implicated. . . . [This] led me to believe firmly that some-
thing was needed to make the primitive red cells that crowd the
bone marrow in relapse grow to normal cells. . . . In 1922 Whip-
pie suggested that in pernicious anemia there might be a scarcity
of material from which the stroma of the red blood cells was
formed, or that there existed a disease of the stroma-f orming cells
of the bone marrow. This concept fitted with the idea that there
was a deficiency of something in the body, and that dysfunction of
pigment metabolism was resultant. . . .

"For centuries the concept that food bore a relationship to
anemia had been vaguely expressed in the literature. It had been
shown that liver and kidneys, rich in complete proteins, promoted
the growth of animals, and that substances in liver could enhance
cell-division. It was likewise recognized that liver-feeding could
benefit patients with sprue (Manson 1883) and pellagra. These
were among the reasons that led to the choice of liver as a substance
likely to enhance blood-formation. Of invaluable importance was
Whipple's fundamental and classical work on hemoglobin regen-
eration by means of liver and other foods in anemia due to blood-
loss in dogs. . . .

"A few patients were fed relatively small amounts of liver dur-
ing 1924 and early 1925. Although these patients did better than
expected, the results permitted no more than speculations. Then
Dr. Murphy joined in the work and we pursued the study of these
and subsequent cases. Liver had been fed by Gibson and Howard
and other individuals to pernicious anemia patients but without
persistence or definite results. It seemed to us that to accomplish
our object a large weighed amount of liver should be fed daily
with regularity. Likewise to determine the effect it was considered
essential that data should be obtained in a large number of cases

1934 : WHIPPLE, MINOT AND MURPHY 177

to be appropriately compared with controls. By May, 1926, we had
fed liver intensively and daily to 45 patients. In many of these
patients symptomatic improvement was obvious within about a
week. Soon they craved food and color appeared in their faces.
Tongue and digestive symptoms rapidly lessened. Within about 60
days the red blood cell counts had risen on the average from low
levels to approximately normal. . . . An objective measure of the
effects upon blood-production was the chief basis of our conclusions
that by feeding liver significant Improvement had been obtained.
I refer especially to counts of new adult and young blood cells
(reticulocytes) appearing, as Peabody's studies demonstrated later,
as a result of the maturation of the immature cells crowding the
bone marrow.

"The next step naturally was to attempt to determine the nature
of the constituent in liver responsible for the effects and to learn
if an extract for therapeutic use could be obtained. Dr. Edwin J.
Cohn, ... of the Harvard Medical School, soon made a potent
extract suitable for oral use. ... It remained for Gansslen in
Germany to produce the first practical extract for parenteral [injec-
tion} therapy."

"Since the earliest use of liver in the treatment of pernicious
anemia . . . new fields of observation have been made available
both in the clinic and in the laboratory. We have been allowed the
thrill of watching the patient through a few days of depression fol-
lowing the institution of liver therapy until remission occurs with
its often sudden and almost unbelievable sense of well-being simul-
taneously with the maximum increase of the reticulocytes or new
red blood cells. Then we have followed this remission through to
completion, until the blood becomes normal. . . . Perhaps even
more dramatic has been the Improvement in the disturbances of
locomotion resulting from nerve damage. . . .

"Observation of the patients at Intervals In the office or hospital
blood clinic and attention to the Important details of treatment
have made it possible for us to maintain our patients In a state of

* From W. P. Murphy, "Pernicious Anemia," Les Prix Nobel en 1934.

178 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

economic efficiency and with reasonably good health. Forty-two of
the forty-five patients originally treated and discussed in our
first paper {Minot and Murphy] in 1926 have been kept under
observation. Of this number thirty-one, or approximately three
fourths, are living and well [1934} after almost ten years of treat-
ment. Eleven have died from various causes other than pernicious
anemia."

CONSEQUENCES IN THEORY
AND PRACTICE

The practical results of liver therapy in the treatment of perni-
cious anemia have already been indicated in quotations from the
Nobel lectures of Dr. Minot and Dr. Murphy. Other agents have
been introduced for the same purpose. "Ventriculin" is made from
the stomach wall of the hog desiccated, defatted, and powdered.
Its effect is similar to that of liver. Of more recent innovations,
vitamin Bi 2 appears to be the most important. Folic acid, isolated
from green leaves and from liver, and also synthesized, has a cer-
tain curative value in that it brings about the production of mature
red blood cells; it is not satisfactory in the treatment of pernicious
anemia because it does not stop the changes in the nervous system
which often accompany this disease. Although obtainable from
liver, it is quite distinct from the hematinic principle in liver ex-
tracts. Nothing has yet been introduced which has been capable of
supplanting liver extracts in practice. In an insidious, chronic,
debilitating disease, ultimately fatal before the introduction of liver
therapy, it has become possible to suppress the symptoms and pro-
long life. Liver is not a "cure" but rather a symptomatic remedy;
its use must be indefinitely continued. The initial effects of treat-
ment are remarkable. Within a few days the number of reticulocytes
(immature blood corpuscles) goes up, showing that the bone mar-
row, where the cells are formed, is increasingly active. The number
of normal cells in the blood gradually increases, and the abnormal
ones begin to disappear. Concurrently the patient feels better, looks
better, and becomes stronger. Liver treatment is able to prevent the
neurological symptoms which may otherwise appear, and can even
cause a recession in established symptoms.

I934 : WHIPPLE, MINOT AND MURPHY 179

The two great innovations in the treatment of noninfectious
disease during the first quarter of the present century were insulin
for diabetes and liver for pernicious anemia. Both discoveries stimu-
lated further research. Knowledge of the effect of liver gave a new
direction to the study of hematopoiesis (the formation of blood)
under both normal and pathological conditions. (For another
aspect of research on pernicious anemia, see above, pp. 66-67.)

1935

HANS SPEMANN

(1869-1941)

"For Ms discovery of the organizer effect in em-
bryonic development"

BIOGRAPHICAL SKETCH

HANS SPEMANN WAS BORN ON JUNE 27, 1869, IN STUTTGART,
Germany, where he attended the humanistic Eberhard-Ludwig
Gymnasium. After leaving school he spent a few years in his
father's business and in the performance of his military service
before beginning the study of medicine at the Universities of
Heidelberg, Munich, and Wikzburg. At Heidelberg he worked
with the anatomist Carl Gegenbaur; at Munich, with August Pauly.
He was graduated in 1895 in zoology, botany, and physics, under
Theodor Bovery, Julius Sachs, and Wilhelm Rontgen, respectively.
The years 1894-1908 were spent in the Zoological Institute at
Wurzburg. In the latter year he accepted the chair of zoology and
comparative anatomy at Rostock. In 1914 he became director of
the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem. Fi-
nally, in 1919, he was called to the professorship at Freiburg-im-
Breisgau, which he held until his retirement in 1935, the year in
which he was awarded the Nobel Prize. He died at the end of
1941, in his seventy-third year.

180

1935 : HANS SPEMANN 1

DESCRIPTION OF THE PRIZE- WINNING
WORK*

experiments] were all carried out on young amphibian
embryos, mostly on those of the ordinary . . . Triton teaeniatus
[species of newt}. In order to make the experiments understand-
able to nonspecialists, too, it becomes necessary first of all to picture
the highlights of the normal development of these eggs.

"The development begins, in direct response to fertilization,
with long-continued cell division . . . known as the segmentation
process. Through the formation of a hollow space inside the seg-
mentation cavity there arises the germinal vesicle or blastula. Its
lower, vegetative half, the thick floor of the germinal vesicle, is
composed of large, yolk-rich cells, whereas the upper, animal half,
the thin roof, is composed of numerous small cells, poor in yolk
substance. The junction between them is formed by the marginal
zone, a ring of cells of medium size.

"There now sets in a very complicated process, in many respects
mysterious, the so-called gastrulation. Its final result is that the
whole material of the marginal zone and the vegetative half of
the embryo are doubled into the interior, and are thus covered by the
animal material. It is along the line of invagination, at the primitive
orifice or blastopore, that the outer germinal layer, the ectoderm,
changes to the two layers brought into the interior, the mesoderai,
(originating in the marginal zone) and the entoderm (correspond-
ing to the yolk-rich vegetative half of the embryo). . . .

"The anlage of the central nervous system [i.e., the primordial
part in the embryo from which the adult structure is formed] arises
in the ectoderm of the back ... as a thickened, shield-shaped
plate, broader in its anterior than in its posterior half. It is the
medullary plate, the edges of which are thrust up into ridges, the
medullary ridges. By the drawing together of the ridges, the plate
is closed to form a tube, the medullary tube. This detaches itself
from the epidermis and sinks deeper. Its thick anterior end, arising
from the broad anterior part of the medullary plate, becomes the

* Translated from "Nobel- Vortrag von Hans Spemann," Les Prix Nobel en

182 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

brain; its thin posterior half the spinal cord. [Spemann then de-
scribes briefly the fate of the mesoderm, which forms the anlage of
the vertebral column, etc., and the entoderm, which forms a
groove, changing into the intestinal tube.]

"All these events ... are essentially dependent not on a new
formation of embryonic substance but on rearrangement of that
already present. It is therefore to some extent possible ... to
mark out a topography of the later anlages of the organs in the
blastula or early gastrula.

"In considering such a topographical map, the question recurs
whether an actual difference in these parts corresponds to this pat-
tern of presumptive anlages in the gastrula at the beginning;
whether they are already more or less firmly ordained for their
later fate, predestined \determmierf}, or whether they are still
indifferent and their destiny is first stamped upon them later.

"The first answer to this question was given by isolation experi-
ments. That is to say, if one undertakes a division through the mid-
die, not between the first two segmentation cells, but later, even in
the stage of the blastula or the quite young gastrula, twins can
still be produced by this means. This becomes especially clear if
the division be made in such a way that the ventral half of the
embryo is cut off from the dorsal. Then the latter also develops into
an embryo of smaller size [but] of normal proportions. Here the
new partition of materials is quite plain. The dorsal half, accord-
ing to the topographical map, possesses almost all the material for
the medullary plate, therefore much too much for a half -size em-
bryo; on the other hand it lacks the whole presumptive epidermis.
This latter must be made good from the material of the former.

"But now if presumptive medullary plate and presumptive epi-
dermis can substitute for each other, then also they must allow
themselves to be interchanged, one for the other, without prejudice
to further normal development. Embryonal transplantation must
thus in this early stage have another result than in the later
stages. , , .

"The success of the new experiments rests on these ideas, and
on the development of a method making it possible to manage the
extraordinarily fragile young embryos and to operate on them.

"The first experiment now consists in the interchange of a piece

1935 : HANS SPEMANN 183

of presumptive epidermis and medullary plate between two em-
bryos of the same age, in the beginning of gastralation. Healing
results so smoothly, and the further development goes on so nor-
mally, that the margins disappear without a trace, if the implant is
not kept visible for a time by natural pigmentation or artificial vital
staining. In this case it appears, as expected, that the pieces can
interchange mutually, so that presumptive epidermis can become
medullary plate, presumptive medullary plate epidermis.

"But from this follows not only the profound indifference of the
cells in this early stage of development; rather, the result permits
the much more important conclusion that in the new location in-
fluences of some sort must govern, which coerce the foreign piece
to its fate. . ."

CONSEQUENCES IN THEORY
AND PRACTICE

"In order [as Spemann wrote} to make the experiments under-
standable to nonspecialists," he felt it necessary to devote a large
part of his Nobel lecture "to picture the highlights of the normal
development of these eggs." The quotation given above terminates
with the first indication of the general principle which was
Spemann's chief contribution.

Spemann's most important forerunners were Roux and Driesch.
W. Roux had obtained half-formations, etc. by destroying some
of the cleavage cells in the frog's egg. His experiments led him to
the view that up to a certain point something within each part of
the embryo determines its fate; thereafter the general requirements
of the organism and the need for certain cells determine their
appearance and growth.

To illustrate the inductive effect which one embryonal area can
exert on another, Spemann performed experiments on the develop-
ing eye. The retina grows out from the brain as a vesicle, later
changed into a cuplike structure; the lens of the eye, on the other
hand, is derived from the near-by epidermis. Spemann showed that
the eyeball is able to bring about the formation of a lens from
distant epidermis which does not normally develop in this way, in
an area having nothing to do, under ordinary circumstances, with

184 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

lens production. The covering epidermis then begins to clear, as
in the formation of the transparent cornea, despite its "foreign/*
noncorneal location.

Then came the experiments in division of the embryo described
in the quotation above, and the transplants of pieces of presumptive
medullary plate, showing how rearranged cells develop according
to their new local environment. Spemann was also able to show
that if a piece of the dorsal blastopore lip is implanted in another
embryo, in an area of presumptive skin, the development of a sec-
ond embryo is thereby induced. This upper blastopore lip he later
showed to be the source of influences which determine the fate
and cause the structural and functional differentiation of various
parts, the medullary plate in particular; he therefore called the
upper blastopore lip an "organization center." Other, secondary
organization centers were also demonstrated, of which the eyecup
may be considered one.

"[Spemann's] great achievement was to bring into fruitful co-
ordination the two, in themselves inconclusive, lines of attack which
had been opened up in the casual investigation of development.
On one hand, the studies of Roux and Driesch on the develop-
mental potentialities of the first-formed blastomeres of the egg,
although they tackled the major problems of the formation of the
animal as a whole, seemed to lead only to a sterile paradox. On
the other hand, Roux's notion of dependent differentiation ap-
peared to suggest a plausible causal mechanism for development,
but the one known example of it, and that a somewhat doubtful
one, was concerned with the development of a single organ, the
lens of the eye. Spemann entered both these fields, with his famous
constriction experiments on the early cleavage states of Triton, and
his early grafting experiments on the optic rudiments of the same
form. By 1918 he was able to bring forward his concept of the
^organization-centre* and demonstrate that the morphogenesis of
the embryo, in its main outlines as well as in its details, is the result
of the interactions between different regions of tissue. For the next
fourteen years, Spemann was the leader of a school, which rapidly
filled in the outlines of what had come to be called 'embryonic in-
duction/ ... In 1932 he participated in the next major step for-

1935 : HANS SPEMANN 185

ward, the beginning of the physico-chemical investigation of the
process.

"Although his work was one of the most important influences
in the final discredit of vitalism, Spemann was never one of those
who hoped that the discovery of the organizer would rapidly enable
us to reduce the problem of biological form to a few simple chem-
ical statements. His attitude was, in fact, much more a biological
than a physico-chemical one. The extreme caution with which he
formed his conclusions, joined with intense concentration on a
narrow field favourable for an attack on fundamental problems,
enabled him to lay a foundation on which the science of experi-
mental morphogenesis can be securely based/* *

* Quoted from the obituary by C. H. Waddington in Nature (London), Vol. 149
(1942), p. 296.

1936

HENRY DALE

(1875- )

OTTO LOEWI

(1873- )

"For their discoveries relating to the chemical
transmission of nerve impulses."

BIOGRAPHICAL SKETCHES

DALE

HENRY HALLETT DALE WAS BORN IN LONDON, ON JUNE 9,
1875. From Leys School, Cambridge, he proceeded to Trinity Col-
lege, Cambridge, in 1894. This step in his education, like every
subsequent stage, was marked by the winning of a scholarship. He
was graduated through the Natural Science Tripos, Part II (Physi-
ology and Zoology.) From 1898-1900 he worked in physiology at
Cambridge under J. N. Langley. In the latter year he turned to
clinical work at St. Bartholomew's Hospital. Cambridge granted
him the B.Ch. in 1903 and the M.D. in 1909. For a time he worked
in University College, London, with E. H. Starling; here he first
met Otto Loewi. There followed four months with Paul Ehrlich
at Frankfort on the Main. Dale then returned for a brief period to
University College, but soon entered the Wellcome Physiological
Research Laboratories as pharmacologist (1904). From 1906 to
1914 he was director of the Laboratories. It was during this period

186

1936: DALE AND LOEWI 187

that he undertook the work on the pharmacology of ergot which
led to his later studies on tyramine, hlstamine, and acetylcholine. In
1914 he was elected Fellow of the Royal Society and in the same
year was appointed director of the Department of Biochemistry
and Physiology in the newly constituted National Institute for
Medical Research. In 1928 he became director of the Institute. Dale
has been the recipient of a very large number of honors and awards,
has served on many official commissions, and has traveled widely.
He is well known, also, through his graduate students in many
parts of the world.

LOEWI

OTTO LOEWI WAS BORN IN FRANKFORT ON THE MAIN, ON JUNE
3, 1873. He studied in the Gymnasium there until 1891, when he
undertook the study of medicine at Strasbourg. Later he took a part
of his course in Munich but returned to Strasbourg for the degree
Dr. med., which was granted in 1896. In 1896-1897 he studied
chemistry In Frankfort with Martin Freund, then physiological
chemistry with Franz Hofmeister in Strasbourg. In 1897-1898 he
was assistant to Karl von Noordens in the City Hospital In Frank-
fort. He was then appointed assistant at the Pharmacological In-
stitute in Marburg and became Prhatdozent in 1900. He worked
for some months in 1901-1902 with E. H. Starling In London,
but remained at Marburg until 1905, when he was named associate
professor in Vienna. For nearly thirty years (1909-1938) he was
professor of pharmacology In Graz. He then went to England and
later to the United States. Since 1940 he has been research profes-
sor at the College of Medicine of New York University.

DESCRIPTION OF THE PRIZE- WINNING

WORK

DALE *

"My chemical collaborator [in 1914], Dr. Ewins, had isolated
the substance responsible for a characteristic activity which I had

* H. H. Dale, "Some Recent Extensions of the Chemical Transmission of the
Effects of Nerve Impulses," Les Prix Nobel en 1936.

188 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

detected in certain ergot extracts, and it had proved to be acetyl-
choline, the very intense activity of which had been observed by
Reid Hunt already in 1906. Since we had found this substance in
nature, and it was no longer a synthetic curiosity, it seemed to me
of interest to explore its activity in greater detail. I was thus able
to describe it as having two apparently distinct types of action,
Through what I termed its 'muscarine' action, it reproduced at the
periphery all the effects of parasympathetic nerves, with a fidelity
which, as I indicated, was comparable to that with which adrenaline
had been shown, some ten years earlier, to reproduce those of true
sympathetic nerves. All these peripheral muscarine actions, these
parasympathomimetic effects of acetylcholine, were very readily
abolished by atropine. When they were thus suppressed, another
type of action was revealed, which I termed the 'nicotine* action,
because it closely resembled the action of that alkaloid in its intense
stimulant effect on all autonomic ganglion cells, and, as later ap-
peared, on voluntary muscle fibres. . . .

"Effects of acetylcholine, directly analogous to those which Loewi
discovered in relation to the heart vagus, were covered by what I
had termed the 'muscarine' action of acetylcholine, and were all
very readily suppressed by atropine. But there remained, as yet
without any corresponding physiological significance, the other type
of action of acetylcholine, so similar in distribution to that of
nicotine, which had come to my notice nearly twenty years
earlier. . . .

"Although from the time when it first became clear that Loewi's
Vagusstoif [see below, p. 192] was acetylcholine, I had begun to
consider the possible significance of its 'nicotine' actions, it was
long before the possibility of its intervention as transmitter at
ganglionic synapses, or at voluntary motor nerve endings, seemed
to be accessible to investigation. Experiments on the ganglion came
first in order. Chang and Gaddum had found, confirming an earlier
observation by Witanowski, that sympathetic ganglia were rich in
acetylcholine. Feldberg . . . had observed . . . that the effects
of splanchnic [visceral] nerve stimulation are transmitted to the
cells of the suprarenal medulla by the release of acetylcholine in
that tissue. Now these medullary cells are morphological analogues
of sympathetic ganglion cells, and Feldberg, continuing this study

1936: DALE AND LOEWI 189

in my laboratory, found that this stimulating action of acetylcholine
on the suprarenal medulla belonged to the 'nicotine' side of its
actions. Clearly we had to extend these observations to the ganglion;
and a method of perfusing the superior cervical ganglion of the
cat, then recently described by Kibjakow, made the experiment pos-
sible. Feldberg and Gaddum . . . found that, when eserine [see
below, p. 192] was added to the fluid perfusing the ganglion,
stimulation of the preganglionic fibres regularly caused the appear-
ance of acetylcholine in the venous effluent. It could be identified
by its characteristic instability, and by the fact that its activity
matched the same known concentration of acetylcholine in a series
of different physiological tests, covering both 'muscarine' and 'nico-
tine' actions. It appeared in the venous fluid in relatively high con-
centrations, so strong indeed, that reinjection of the fluid into the
arterial side of the perfusion caused, on occasion, a direct stimula-
tion of the ganglion-cells. It was clear that, if the liberation took
place actually at the synapses, the acetylcholine liberated by each
preganglionic impulse, in small dose, indeed, but in much higher
concentration than that in which it reached the venous effluent,
must act as a stimulus to the corresponding ganglion cells. Feldberg
and Vartiainen then showed that it was, in fact, only the arrival of
preganglionic impulses at synapses which caused the acetylcholine
to appear. They showed, further, that the ganglion cells might be
paralysed by nicotine or curarine [the active principle of the arrow-
poison, curare], so that they would no longer respond to pre-
ganglionic stimulation or to the injection of acetylcholine, but
that such treatment did not, in the least, diminish the output of
acetylcholine caused by the arrival of preganglionic impulses at the
synapses. There was, in this respect, a complete analogy with the
paralysing effect of atropine on the action of the heart vagus, which,
as Loewi and Navratil had shown many years before, stops the
action of acetylcholine on the heart, but does not affect its liberation
by the vagus impulses.

"The difficulty facing us in the case of the voluntary muscle was
largely a quantitative one. In a sympathetic ganglion, the synaptic
junctions, at which the acetylcholine is released . - . , form a large
part of the small amount of tissue perfused. In a voluntary muscle
the bulk of tissue, supplied by a rich network of capillary blood

190 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

vessels, is enormous in relation to the motor nerve endings, of
which only one is present in each muscle fibre. The volume of per-
fusion fluid necessary to maintain functional activity is, therefore,
very large in relation to the amount of acetylcholine which the scat-
tered motor nerve endings can be expected to yield when impulses
reach them. With the skilled and patient cooperation of Dr. Feld-
berg and Miss Vogt, however, it was possible to overcome these
difficulties, and to demonstrate that, when only the voluntary motor
fibres to a muscle are stimulated, to the complete exclusion of the
autonomic and sensory components of the mixed nerve, acetyl-
choline passes into the Locke's solution [chlorides of sodium, cal-
cium, and potassium, with sodium bicarbonate, dextrose, and dis-
tilled water], containing a small proportion of eserine, with which
the muscle is perfused. If, by calculation, we estimate the amount
of acetylcholine thus obtained from the effect of a single motor
impulse arriving at a single nerve ending, the quantity is of the
same order as that similarly estimated for a single preganglionic
impulse and a single ganglion cell. . . . We found that, if the
muscle was denervated . . . , direct stimulation, although evoking
vigorous contractions, produced no trace of acetylcholine. If, on the
other hand, the muscle was completely paralysed to the effects of
nerve impulses by curarine, stimulation of its motor nerve fibres
caused the usual output of acetylcholine, although the muscle re-
mained completely passive. Again there is a complete analogy with
Loewi's observations on the heart vagus and atropine. . . ."

LOEWI

"Natural or artificial stimulation of nerves induces in them an
occurrence known as progressive excitation, which leads to a re-
sponse in the organ activated by the nerves concerned.

"Up to the year 1921 it was unknown how excitation of a nerve
influences its responsive organ to function in other words, in
what way the impulse of the nerve is transferred from the nerve
ending to the responsive organ. For the most part it was sup-
posed that there was a direct encroachment of the wave of excita-

* Translated from Otto Loewl, "Die chemisette Ubertragung der Nerven*
wirkung," Les Prix Nobel en 1936.

1936* DALE AND LOEWI 191

tlon of the nerve fiber on the organ of response. But as a matter of
fact, there were also those who had already formed the opinion that
the transference takes place by chemical means, and had commu-
nicated [the results of their] researches. Thus W. H. Howeli had
formed the view on the ground of his own research that vagus
stimulation liberates potassium in the heart, and that this occasions
the result of stimulation. . . . {The vagus nerve has an inhibitory
Influence on the heart. In 1908, Howeli, with W. W. Duke, re-
ported an increase in the concentration of potassium in the fluid
perfusing an isolated mammalian heart during vagal stimulation.
Howell's work In this connection dates from 1906. Loewi also
mentions the name of W. M. Bayliss, who had written in his
famous textbook of physiology (ed. 1902, p. 344) that "the nerve
may act by the production of the same chemical substance which
excites directly, or the chemical excitant may act on the same
terminal mechanism as the excitatory process in the nerve fibre
does."]

"Although these data were known to me, I was first made aware
a year after my discovery that earlier i.e., in 1904 {T. R.}
Elliott, at the conclusion of a short note, had already intimated the
possibility that stimulation of sympathetic nerves works through
the liberation of adrenalin, and that {W. E.] DIxon had already
[1907], in a place difficult of access, brought out researches aimed
at elucidation of the question whether a substance Is set free on
stimulating the vagus which Induces the result. [Emll Du Bois-
Reymond (1818-1896) hinted a similar explanation. It appears
that none of these suggestions was supported by satisfactory proof.}

"In the year 1921 I succeeded for the first time In furnishing to
this end the proof capable of only one interpretation, [by show-
ing] that through stimulation of the nerves of a frog's heart [sus-
pended in a glass vessel containing saline] substances are set free,
part of which enter the perfusion fluid of the heart, and being
transferred with this to [another] test heart, here work exactly like
the stimulation of the corresponding nerves. It was thereby proved
that the nerves do not act directly on the heart, but that the imme-
diate result of nerve stimulation is the freeing of chemical sub-
stances, and that these first act directly in bringing about the

192 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

functional change in the heart which is characteristic of nerve
action. . . .

[The autonomic, or involuntary, nervous system, controlling
those functions that are largely independent of the will and of
direct outside influences, has two divisions, called the sympathetic
and the parasympathetic The vagus nerve contains parasympathetic
fibers; Loewi and his co-workers investigated the nature of the sub-
stance, which he called "Vagusstoff," released by their stimula-
tion.} "We were able to establish that its action is suspended by
atropine, and [in any case] disappears very quickly. In the search
for a substance sharing both these peculiarities, I found that out of
the series of known vagomimetic substances [i.e., chemicals with
the physiological effects of "Vagusstoff"}, muscarine, pilocarpine,
choline, and acetykholine, this held true only for the latter. It
could then be directly established further, that the rapid cessation
of the action of Vagusstoff and acetykholine depends on the de-
composition of these substances through the action of an esterase in
the heart, already duly postulated by Dale. [An esterase is an en-
zyme, or ferment, which acts specifically on a certain ester; acetyl-
choline is numbered chemically among the esters.} I was able to
show further that the action of this esterase is specifically retarded
"by minimal concentrations of eserine. [Eserine is a vegetable sub-
stance derived from the Calabar bean of western Africa; chemically
it is an alkaloid and is known also as physostigmine. By showing
that the breakdown of his "Vagusstoff" could be prevented in this
way, Loewi made it relatively easy to enhance its eif ect and to
detect its presence.} . . .

tc Not only as regards its reaction with atropine and its de-
structibility by esterase, but also in respect of all other attributes,
Vagusstoff behaves identically with acetykholine. When, over and
above this, acetykholine could be directly demonstrated in the
organs by Dale and Dudley, no doubt remained that Vagusstoff
is acetykholine. "

1936- DALE AND LOEWI 193

CONSEQUENCES IN THEORY
AND PRACTICE

For well over a century the study of the electric changes during
nerve activity was the sole path toward knowledge of the mecha-
nism of nervous function. Sherrington and Adrian, Erlanger and
Gasser all of them Nobel laureates were electrophysiologists.
But all cells, including nerve cells, require energy for their activity;
in a living cell, chemical reactions form the source of energy. Only
in the last thirty years, however, has evidence accumulated respect-
ing the chemical side of nerve activity.

Loewi performed his perfusion experiments in 1921. In 1926
A. V. Hill and his associates were able to measure the heat produc-
tion of the resting nerve and the increased heat production follow-
ing stimulation. As in the case of Hill's studies of heat production
in muscle, this biophysical approach pointed to chemical change
from which the thermal change resulted. Gerard and Meyerhof,
and at the same time (1927) Fenn, could confirm this by measure-
ment of the extra oxygen uptake.

Loewf s work was limited to the autonomic nervous system.
Dale and his associates, following the lead of Kibjakow, tried to
extend this concept, suggesting that acetykholine might transmit
impulses across ganglionic synapses and at neuromuscular junctions.
(It may be noted that an important part of Nobel Prize scientific
study has centered in the nerve-muscle relationship.) The evidence,
of which only an early indication is given in the excerpt from
Sir Henry Dale's lecture, was chiefly based on ( i ) liberation of
acetykholine after stimulation of preganglionic fibers on motor
nerves; (2) stimulation of the sympathetic ganglion and the
striated muscle by injection of small amounts of acetykholine; and
(3) "potentiation" of the effects of nerve stimulation by the use
of eserine. Dale and his group worked out ingenious techniques
and contributed very extensively to the piling up of the evidence.

There were two principal difficulties. Neurons and striated mus-
cle fibers act with lightning speed. Any chemical reaction involved
must occur with the same speed. The question was whether or not
the rate of acetylcholine metabolism was high enough to fit the

194 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

timetable of nervous mechanism. The second difficulty was the
question whether the modes of conduction along nerve fiber and
across synapses are fundamentally different. There seems to be
reason to think that no basic difference exists.

In the last twenty-five years enzyme chemistry has assumed
greater and greater importance. It seems probable that all "trace
substances" compounds active in minute amounts are correlated
to enzyme systems. Because of the high concentration of choline
esterase it has been suggested that the rate of acetylcholine metab-
olism is high enough to parallel electrical events during nerve
activity. It has also been pointed out that the choline esterase is
localized at the neuron surface and that a parallel exists between
the voltage associated with nerve impulse and the concentration
of the enzyme. These findings in connection with other known facts
have suggested that the release of acetylcholine is not limited to the
nerve endings but occurs everywhere at the neuron surface. Acetyl-
choline appears to be an essential factor in generating the nerve
action potential by its effect on the surface membrane of the nerve.
Furthermore, although Loewi and Dale were once of the opinion
that there is no acetylcholine present in sensory nerves, it has been
detected more recently not only in the motor nerves but also in the
sensory nerves, including the optic nerves. The range of action and
the fundamental importance of the substance which began life, so
to speak, as "Vagusstoff," have been shown to be vastly greater
than was perceived some twenty to thirty years ago, when the
pioneer experiments were performed.

Discoveries of this kind are contributions to basic knowledge.
One should hardly expect any immediate practical results. (Wil-
liam Harvey's discovery of the circulation of the blood, announced
in 1628, had little effect on practice for many years, yet this dis-
covery is the foundation of all modern medicine.) In the case of
Dale and Loewi, however, a sort of "premium" in the way of
practical consequences was not long in appearing. The eserine
which played so large a part in their experiments is also known as
physostigmine. To put it briefly, this substance inhibits the esterase
which inhibits acetylcholine, and therefore it "potentiates" the
acetylcholine action. A disease called myasthenia gravis is known
as a chronic and progressive muscular weakness, usually beginning

1936: DALE AND LOEWI 195

in the face and throat. On the assumption that physostigmine,
exerting an inhibitory action on cholinesterase, might be of benefit
in this disease, it was introduced as a new treatment by Mary
Broadfoot Walker in 1934. Together with prostigmine, which is
closely similar in action and which was introduced for the same
purpose by L. Remen in 1932, physostigmine continues to hold a
place in the management of myasthenia gravis.

REFERENCES

NACHMANSOHN, D. "The Role of Acetylcholine in the Mechanism of
Nerve Activity," in R. S. Harris and K. V. Thimann, eds., Vitamins
and Hormones, Vol. 3 (New York: Academic Press, 1945).

. "Biochemical Approach," a symposium, in D. Nachmansohn,

ed., Nerve Impulse: Transactions of the First Conference, March 2-3*
(New York: Josiah Macy, Jr. Foundation, 1951).

1937

ALBERT VON SZENT-GYORGYI

(1893- )

"For bis discoveries in connection with the biolog-
ical combustion processes, with especial reference
to vitamin C and the catalysis of fumaric acid."

BIOGRAPHICAL SKETCH

ALBERT VON SZENT-GYORGYI [APPROXIMATE PRONUNCIATION,
Saint Georgie} was bora in Budapest, on September 16, 1893.
Receiving his preliminary education in Budapest, he also studied
medicine there, beginning in 1911. The professor of anatomy was
Szent-Gyorgyfs uncle, in whose laboratory he began to do research
as a first-year student; thereafter he published a series of histologi-
cal studies. His education was interrupted by the First World War,
in which he served on the Russian and Italian fronts. Having been
wounded, he returned to the university and completed his course
in 1917 He then went to Pozsony as assistant to the pharmacolo-
gist G. Mansfeld. Next he studied electrophysiology for a short
time with A. von Tschermak in Prague. He also worked with L.
Michaelis in Berlin. He spent two years in Hamburg in the study
of physical chemistry, and two years in Leyden, Holland, as as-
sistant in the Pharmacological Institute. After this he was assistant
to H. J. Hamburger in the Physiological Institute of Groningen,
Holland, where he discovered "hexuronic acid'* in the adrenal
cortex. At this time he was teaching biochemistry as Privatdozent.
In 1927 he went to Cambridge as a Rockefeller Fellow. The fol-

196

1937 : ALBERT VON SZENT-GYORGYI 197

lowing year he was in Rochester, Minnesota, at the Mayo Founda-
tion, with E. C. Kendall. In 1929 he was back at Cambridge. Finally,
in 1930, he returned to Hungary, as professor of medical chemistry
at the University of Szeged.

World War II brought further changes, leading to the establish-
ment, under Szent-Gyorgyi' s direction, of the Institute for Muscle
Research at Woods Hole, Massachusetts, financed by Armour and
Company, the American Heart Association, the Association for the
Aid of Crippled Children, and the Muscular Dystrophy Associa-
tion. For approximately twelve years past, Szent-Gyorgyi has con-
centrated his energies on the study of the biochemistry of muscle.

A brilliant and original investigator, Szent-Gyorgyi is also an
able writer, and the author of a number of books, some of which
have appeared in English translation.

DESCRIPTION OF THE PRIZE -WINNING
WORK*

"I was led into the field of oxidations ... by a false assump-
tion. I was interested in the function of the adrenal cortex. If the
function of this organ is suppressed, life, too, is suppressed ( Addi-
son's disease). But before life is extinguished, there appears in
man a brown pigmentation, similar to that of certain fruits: apples,
pears, bananas, etc., which, in withering, likewise assume a brown
color. Through the investigations of the great Russian botanist,
Palladin, it was known that this brown coloring of plants is con-
nected with the damaged oxidation mechanism. Since I myself was
convinced (and am still convinced) that in the basic functions, as
represented, too, by oxidation, there exist no differences in prin-
ciple between animal and plant, I undertook the study of the
oxidation system of potatoes, browning of the plants depending on
its damage. I did this in the hope of finding through these studies
the key to the understanding of adrenal function.

"It was already known that those plants which turn brown as
the result of damage about half of all plants contain a poly-
phenol, . . . besides this a ferment, the polyphenoloxidase, which,

* Translated from ''Nobel-Vortrag von Albert Szent-Gyorgyi; ' Les Prix Nobel
en 1937.

198 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

with the help of oxygen, oxidizes the polyphenol. There was a
complicated interpretation of the working mechanism of this
oxidase. It fell to me to show that it is simply a question of the
oxidase, along with oxygen, oxidizing the polyphenol to quinone
[compound which results when two opposite hydrogen atoms are
replaced by oxygen]. In the intact plant the quinone is again
reduced by the hydrogen mobilized from foodstuff. The phenol
thus works as a hydrogen-transporter between oxygen and H-
donator, and we are here confronted . . . with a system of succes-
sive hydrogen combustion. ... In the damaged plant the reduc-
tion of the quinone cannot keep pace with the mounting oxidation
of the phenol, and the quinones remain unreduced and form pig-
ments.

"But the system gave rne no information about adrenal func-
tion. So I turned to the plants which do not assume a brown color
on withering, and which therefore must contain an oxidation sys-
tem differently organized. As regards these plants, this much was
known, that they contain a very active peroxidase. This peroxidase
has the power to activate peroxide. In the presence of this ferment,
peroxide is able to oxidize various aromatic substances to colored
pigments. Without peroxidase this reaction does not take place. If,
for example, benzidine is added to a peroxide in the presence of
peroxidase, a deep blue color appears at once, produced by the
oxidation of the benzidine. Without peroxidase this reaction, which
also serves as a test for the ferment, does not occur.

"But when, in this reaction, I substituted for a purified per-
oxidase simply the juice squeezed from these plants, and added
benzidine and peroxide, then the blue pigment appeared, but only
after a slight delay of about a second. The analysis of this retarda-
tion showed that it was occasioned by the presence of a strong re-
ducing substance, which again reduced the oxidized benzidine,
until it was itself exhausted.

"It was a moment of great excitement, when, in my little cellar
room in Groningen, I found that the adrenal cortex contains an
analogous reducing substance in relatively large amount.

"My means and my chemical knowledge were both inadequate to
investigate this substance more closely. But thanks to the invitation

1937 : ALBERT VON SZENT-GYORGYI 199

of F. G. Hopkins and the help of the Rockefeller Foundation I
was able ten years ago [i.e., in 1927] to transfer my laboratory to
Cambridge, where for the first time I could devote myself to chem-
istry in earnest. Soon I was successful in isolating this fragile sub-
stance from adrenal glands and various plants and showing that it
corresponded to the formula C 6 H 8 O 6 and was related to the car-
bohydrates. This latter circumstance induced me to turn to Prof.
W. N. Haworth, who at once perceived the chemical interest of
the substance and asked me for a larger amount for constitutional
analysis. But unfortunately it turned out that adrenal glands were
the only material suitable for large-scale preparation. AH my efforts
to find suitable vegetable material for a starting point remained
ineffectual, and adrenal glands in large quantity were not available
in England.

"Professor Krogh tried to help me by generously sending me
adrenal glands by air from Copenhagen. But unfortunately the
substance was spoiled in transit. The Mayo Foundation and Profes-
sor Kendall now came to my aid in a magnificent way and made it
possible for me, regardless of expense, to work on the material
from the great American slaughterhouses. The result of a year's
work was 25 g. of a crystalline substance which received the name
'hexuronic acid.* This quantity of the substance I divided with
Professor Haworth. He undertook to investigate the exact struc-
tural formula. I used the other half of my preparation to obtain a
closer insight into the function of the substance. [It} could not
take the place of the adrenal glands, but it overcame the pigmenta-
tion of Addison's disease to the point of disappearance.

"Unfortunately the amount of the substance proved insufficient
for ascertaining the chemical constitution. The preparation could
not be repeated for lack of means, and no cheaper material was
found permitting extraction of the acid in larger amount.

"From the beginning I suspected the substance to be identical
with vitamin C [discovered in 1907 by A. Hoist and T. FrSlich}.
But my wandering life was unsuited for vitamin research, in which,
also, I had no experience. In the year 1930, however, I gave up
my nomad life, in that I settled down in my fatherland, at the
University of Szeged. Also fortune soon sent me an excellent
young American co-worker, J, L. Svirbely, who had experience

200 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

with vitamin research. ... In the autumn of 1931 our first in-
vestigations were concluded and showed clearly that hexuronic
acid has an antiscorbutic effect [preventing and counteracting
scurvy} and that the antiscorbutic activity of the juices of plants
corresponds with their hexuronic acid content. . . . [Szent-
Gyorgyi here mentions related work of Tillman, King, and
Waugh.]

"All at once the hexuronic acid that had been so long disre-
garded pressed into the foreground, and there was urgent need of
larger amounts of this substance, in order on the one hand to
continue the analysis of its constitution, and on the other to make
sure of its vitamin nature. But we used the last remnant of our
substance in our vitamin researches; it was impossible for us to
undertake its preparation from adrenal glands; and, as I men-
tioned, every other material was inadequate for large-scale work.
"My city, Szeged, is the center of the Hungarian paprika indus-
try. As this fruit is not transportable in good condition, I had had
no earlier opportunity to test it. One evening the sight of this
wholesome fruit inspired me with a last hope, and the same night
investigation showed that this fruit offers an incredibly rich source
of hexuronic acid, which Haworth and I rechristened ascorbic
acid. Taking advantage of the last of the paprika season, which
was nearing its end, it was possible, through the support given on
a generous scale by the American Josiah Macy Jr. Foundation, to
prepare more than half a kilogram, in the following year more
than 3 kilograms, of crystalline ascorbic acid. I divided this sub-
stance among all the investigators who wished to work on it. I also
had the privilege of furnishing both my fellow laureates, P. Kar-
rer and W. N. Haworth, with plentiful material, and making pos-
sible their analysis of its constitution. I myself, together with Varga,
prepared the mono-acetone derivative of ascorbic acid, forming
splendid crystals, from which, after repeated recrystallizations,
ascorbic acid, undiminished in activity, may again be split off.
This was the first proof that ascorbic acid is identical with vitamin
C and that the activity of the substance is not dependent on im-
purities. . . .

"To return to the oxidation processes, I now attempted further

1937 : ALBERT VON SZENT-GYORGYI 201

analysis of the respiratory system of plants in which ascorbic acid
and peroxidase play important roles. I had already found out,
while in Rochester, that the peroxidase plants contain a ferment
which reversibly oxidizes ascorbic acid, with two valences, in the
presence of oxygen. Further analysis showed that here there was
a respiratory system in which hydrogen is oxidized step by step. I
should like to sum up briefly the result of this research carried out
with St. Huszak.

"The ascorbic acid oxidase, with oxygen, reversibly oxidizes the
acid to dehydroascorbic acid. The oxygen thereby combines with
two labile H-atoms of the acid to form hydrogen peroxide. This
peroxide reacts with peroxidase and oxidizes a second molecule
of ascorbic acid. Both those molecules of dehydroascorbic acid, pos-
sibly by the mediation of SH-groups, now take up hydrogen again
from foodstuffs.

"But the peroxidase does not oxidize the ascorbic acid directly.
I succeeded in showing that between the two still another sub-
stance is inserted, which belongs to the large group of yellow,
vegetable, water-soluble phenol-benzol- y-pyran-dyestuffs (flavone,
flavonole, flavanone). The peroxidase here oxidizes the phenol
group to quinone, which then oxidizes the ascorbic acid directly by
accepting both its H-atoms/*

CONSEQUENCES IN THEORY
AND PRACTICE*

Many scientists have contributed to present knowledge of the
chemical events which are known in sum as "respiration." The
contributions of Warburg and Keilin have been discussed in part
above (see pp. 149-152). Cytochrome, however, is not a very
powerful oxidizing agent and It was realized that what Szent-
Gyorgyi calls the WK system (Warburg-Keilin) "could not
oxidize such stable formations as the foodstuff molecules'* without
help. H. Wieland then showed that foodstuff is activated, and made

* The brief quotations in this section are from Albert von Szeat-Gyorgyi, "Oxida-
tion and Fermentation," in J. Needham and D. E. Green, cds., Perspectives in
Biochemistry (Cambridge: The University Press, 1937), PP- 165-174.

202 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

ready for oxidation, by catalysts called dehydrogenases. These make
the molecule give up its hydrogen more readily. The WK system
then takes over.

This version of the story of respiration was further modified and
supplemented by the work of Szent-Gyorgyi, who wrote:

"The theory is this: the Q dicarboxylic acids are a link in the
respiratory chain between foodstuff and the WK system. Their
function is to transfer the hydrogen of the foodstuff to cytochrome
and to reduce by this hydrogen its trivalent iron again to the
divalent form. Speaking more precisely, the cytochrome oxidizes
off two hydrogen atoms from the succinic acid molecule. By the
loss of two hydrogen atoms, the succinic acid is converted to
fumaric acid. These two lost H atoms are replaced again by H com-
ing from the foodstuff. The foodstuff, however, does not give its
H immediately to fumaric acid. It gives its two H atoms to oxalo-
acetic acid, which is also a C 4 dicarboxylic acid. By taking up 2H,
oxaloacetic turns into malic acid. Malic acid then gives its 2H to
fumaric, and thus fumaric is converted to succinic acid. This can
again be oxidized by cytochrome, while malic acid, after giving
off its 2H, becomes oxaloacetic, which can take up H from the
foodstuff again, and so the play goes on, H being transmitted all
the time from the foodstuff via oxaloacetic-malic-fumaric-succinic
to the WK system."

A catalytic system was demonstrated between the Wieland de-
hydrogenase system, on the one hand, and the WK system of
ferrous enzymes, on the other.

Szent-Gyorgyi also described a respiratory system in which the
hydrogen is oxidized by degrees through the agency of ascorbic
acid. This discovery is the subject of the principal quotation given
above. Although ascorbic acid, or rather the antiscorbutic substance,
vitamin C, had been identified in the first decade of the century by
Hoist and Frolich, and had been shown to be the missing necessity
in cases of scurvy and Barlow's disease (or infantile scurvy), it
was through Szent-Gyorgyi and Svirbely that it could be proven
identical with the highly reducing ascorbic acid obtained from
adrenal glands and from certain vegetable materials. Thus the
way was opened for clarifying the chemical composition of the

1937 : ALBERT VON SZENT-GYORGYI 203

substance. Within two years of the Szent-Gyorgyi-Svirbely work,
it became possible to produce a synthetic vitamin C. This result may
be considered a by-product of basic research which had as its chief,
although not its most directly useful, consequence added under-
standing of the mystery of respiration.

1938

CORNEILLE HEYMANS

(1892- )

"For his discovery of the role played by the sinus
and aortic mechanisms in the regulation of respi-
ration/ 9

BIOGRAPHICAL SKETCH

CORNEILLE HEYMANS WAS BORN AT GAND, BELGIUM, ON MARCH
1 8, 1892. He is the son of Dr. J. F. Heymans, onetime professor
of pharmacology and rector of the University of Gand, as well as
founder of the J. F. Heymans Institute of Pharmacodynamics and
Therapeutics at the same university. Heymans' father was his first
and principal teacher and it was with him that the original experi-
ments, leading to the award of the Nobel Prize, were begun.
Corneille Heymans was educated at the local university, studied
later in the laboratories of E. Gley in Paris, N. M. Arthus in
Lausanne, H. H. Meyer in Vienna and E. H. Starling in London.
In 1927-1928 he worked in the United States, chiefly in the labora-
tory of C. F. Wiggers at Western Reserve University, Cleveland.
In 1922 he began to teach the course in pharmacodynamics at
Gand, and in 1930 he succeeded his father there. He has traveled
and lectured extensively and has been awarded many prizes and
honorary degrees. He is probably the best known of Belgian
workers in the biological sciences. Professor Heymans is now asso-
ciated with the University of Ghent.

204

1938: CORNEILLE HEYMANS 205

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"It has long been known that . . . elevation of arterial pressure
Inhibits respiration; sudden and severe hypertension can even pro-
voke [cessation of breathing]. It is equally well known that hypo-
tension [low blood pressure] leads to [abnormally deep and rapid
breathing]. These interactions . . . have generally been attributed
to a direct action ... on the activity of the respiratory center [the
part of the brain which controls respiratory movements].

[Experiments to test this theory and to reveal the actual mecha-
nism of these events were begun in 1924 by J. F. and C. Heymans,
using crossed circulation in dogs. Two dogs, A and B, are anesthe-
tized. The head of dog B is separated from its body, except for the
vagus-aortic nerves, connecting with the respiratory center; these
are left intact. Life is maintained in the body section by artificial
respiration; circulation in the body continues. The isolated head is
then linked to the body circulation of the other dog, A, by attach-
ing from the latter the principal arteries for blood supply to the
head, the two common carotids; these are anastomosed i.e., joined
end to end with the corresponding parts of the nearly severed
head of B. In the same way the external jugular veins of the two
dogs are anastomosed. The severed head is thus completely isolated
from its own body as regards circulation, but is connected by the
aortic nerves. The effects which this head shows from whatever is
done to its own body are mediated by the nerves; whatever is done
to the body of the other dog can influence it only through the blood
stream. Breathing movements due to the activity of the respiratory
center may be seen in the head. A method is thus available for
showing whether high and low pressure affect this center directly
or by means of a nervous reflex.]

"We observed right away that arterial hypotension limited solely
to the body circulation of the dog B brings about a stimulation of
the activity of the respiratory center of the perfused head of B;

* Translated and paraphrased from Cornellle Heymans, "Sur le r6!e des presso
et des chimio recepteurs vasculaires dans la regulation de la respiration,"
Les Prix Nobel en 1940-44.

206 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

augmentation of the arterial pressure in the trunk B, on the con-
trary, causes an inhibition of the activity of [this] respiratory
center. . . . When one injects a hypertensive dose of adrenaline
into the trunk B, one observes a total inhibition of the respiratory
movements of the isolated and perfused head of B. . . ."

[This showed (i) that the effects once thought due to direct
action of the blood pressure on the respiratory center are really
brought about by a nervous reflex; and (2) that the path of this
reflex lies through the aortic nerves. But what sense organ responds
to the changes in pressure and starts the reflex? The carotid sinus
(a slight enlargement of the common carotid artery at the point
where it divides into the external and internal carotids) had pre-
viously been shown to play an important role in the regulation of
heart rate and arterial blood pressure. Heymans was able to show
that respiratory reflexes, as described in the quotation above, can
also originate there. There exist in the wall of the sinus sensory
organs which are called presso-receptors, because they are sensitive
to pressure changes. Cross-circulation experiments of a rather dif-
ferent kind from those detailed above helped to show how they
work. The sinus of one dog, B, was isolated from the general cir-
culation and perfused with the blood of another animal, A, while
the nerve supply of the sinus was left intact. With sinus B isolated,
the arterial pressure of dog A was raised, whereupon that of dog
B fell. Conversely, a reduction in blood pressure of dog A caused a
rise in the blood pressure of dog B. Obviously the effect of a
change in blood pressure upon these presso-receptors is to initiate
reflexes which tend to reverse the pressure change. The effects of
pressure on respiration are also mediated through reflexes begin-
ning in presso-receptors.

[Close to the carotid sinus is a small structure looking like a gland,
called the carotid body, or glomus caroticum. Heymans and his
associates found this to be chemo-receptive, responding to changes
in the chemical composition of the blood as the presso-receptors
answer to changes in blood pressure. Variations in oxygen and car-
bon dioxide affect breathing by this means, although the increased
respiration caused by an accumulation of carbon dioxide is partly
the result of direct stimulation of the respiratory center. The aortic
body (glomus aorticttm) at the base of the aorta is also chemo-

1938: CORNEILLE HEYMANS 207

receptive. It was found that certain drugs which stimulate respira-
tion act directly on the respiratory center, but that others work
only through the carotid and aortic bodies; still others have both a
direct and a reflex action. Most of this information was worked
out over a period of many years, with the help of many co-workers;
it was accomplished in large part by means of ingenious isolation
and cross-circulation experiments such as those described above.}

CONSEQUENCES IN THEORY
AND PRACTICE

In an earlier section (see above, pp. 162-163) some account was
given of the work of Sir Charles Sherrington on the integrative
action of the nervous system. Sherrington revealed the role of the
muscle spindle in initiating reflexes which have to do with posture.
Other receptors were also studied by him as the initiators of special
reflex action. It was the important contribution of Professor Hey-
mans and his co-workers to show the part played by the sinus and
aortic mechanisms in the regulation of respiration and blood pres-
sure. The carotid sinus was demonstrated to be presso-receptive,
the carotid and aortic bodies to be chemo-receptive. A later Nobel
laureate, W. R. Hess (see below, pp. 260-264) has contributed to
the proof that central control of blood pressure lies in groups of
cells in the medulla and diencephalon; the peripheral mechanism
is the set of reflexes described by Heymans. Hormonal factors, re-
lating especially to the adrenal gland, are also involved. The heart,
the kidneys, and the vascular system in general are primarily or
secondarily concerned. Clinicians and laboratory scientists are there-
fore advancing from many directions in their assault on the still
unsolved problems of blood-pressure abnormality. It is obvious
that the Heymans contribution forms an essential part of the bask
knowledge required.

There are, however, more immediate applications of this knowl-
edge. The carotid sinus has nervous connections with the vagus.
Among other effects which the latter nerve produces is inhibition
of heart action. The sinus is also connected with the cervical sym-
pathetic and the medulla. Now occasionally the sinus becomes
hypersensitive and the consequence is a distinctive set of symptoms.

208 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Patients have been observed who suffer from spontaneous attacks
of dizziness, weakness, and unconsciousness, with or without con-
vulsions, in whom mechanical stimulation over the division of one
or the other carotid artery i.e., pressure on the carotid sinus
will at once induce an attack. Three forms of this disturbance ap-
pear, corresponding to the threefold nervous communication men-
tioned above. In some cases cardiac inhibition, due to a vagal
reflex, is marked; this can be abolished by the use of atropine. In
others, vasodilatation, with a consequent fall in arterial blood pres-
sure, is observed; this lowering of pressure and the symptoms
which attend it can be prevented by ephedrine. The third, or cere-
bral variety, is associated with convulsions. Apparently it is best
treated by denervation of the sinus i.e., by cutting the nerve con-
nections involved. Patients with spontaneous epileptic seizures
induced by slight pressure on an irritable sinus have been relieved
by this operation. Stripping of the nerve plexus from the carotid
artery at the bifurcation (division into two parts) may affect a cure,
or may give only temporary relief; division of the carotid sinus
nerve is considered to give the best results.

It has long been known that pressure exerted on the carotid sinus
area will often slow the heart and put a stop to attacks of the dis-
turbance called "auricular paroxysmal tachycardia/' a very rapid
heartbeat which occurs in sudden paroxysms. This is a dangerous
procedure which may stop the heart altogether. It should be per-
formed only by a physician familiar with the proper technique and
equipped with the drugs to meet an emergency. The effect was
formerly attributed to pressure on the vagus; it is now known to
be due to carotid sinus pressure.

1939

GERHARD DOMAGK

(1895- )

ff For Ms discovery of the antibacterial effects of
prontosil"

BIOGRAPHICAL SKETCH

GERHARD DOMAGK WAS BORN ON OCTOBER 30, 1895, IN LAGOW,
Brunswick, Germany. He had just entered the University of Kiel
when the First "World War broke out, and in October 1914, he
volunteered for the army, in which he served four years. At first
he was in a grenadier regiment, but after being wounded in 1915
he was transferred to the medical corps for the remainder of the
war. Returning to Kiel, he was graduated in medicine in 1921. In
1924 Domagk became Prhatdozent at the University of Grief s-
wald. The following year he received an appointment in the
Pathological Institute at Miinster, where in 1928 he became Ex-
traordinary Professor of General Pathology and Pathological
Anatomy. He then accepted a position with the I. G. Farbenindus-
trie and became director of the Laboratory for Experimental
Pathology and Bacteriology at Wuppertal-Elberfeld. In a precon-
ceived and systematic program, combining a search for new dyes
with a search for new drugs, the I. G. Farbenindustrie postulated
the preparation of a substance later to be called "prontosiT as
early as 1920, but apparently nothing further was done about it
until 1932. The synthesis of azo compounds had been entrusted to
Drs. Fritz Mietzsch and Joseph Klarer, and it was one of Domagk's

209

210 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

duties to test the chemotherapeutic effects of the substances pro-
duced. It was in this way that the extraordinary powers of the sul-
fonamide drugs were first revealed in the trials of prontosil.

When notified in October 1939 that he had won the Nobel
Prize, Domagk sent a letter of thanks to the rector of the Caroline
Institute, but toward the end of November a second letter reached
Stockholm in which Domagk declined the prize in accordance with
Nazi law. In the interval he had been arrested by the Gestapo. The
second letter was prepared by the Ministry of Education and
Domagk signed it under duress. The year of grace permitted by the
Nobel regulations had long expired, and the prize money had
reverted to Nobel Foundation funds, before Domagk was able to
speak freely. In 1947 he visited Stockholm, delivered his Nobel
lecture, and received the gold medal and diploma; but it was then
too late for the award of the prize money.

DESCRIPTION OF THE PRIZE- WINNIN G
WORK*

"Up to the present time 1935} it has been the general opinion
that only protozoal infections were susceptible to chemotherapy.
In the sphere of the protozoal infections we possess remedies which
are operative against the cause e.g., against trypanosome infec-
tions [sleeping sickness}, suramin; against kala-azar, neostibosan;
against malaria, plasmochin and atabrin; against spirochete infec-
tions, especially syphilis, salvarsan and its modifications.

"Chemotherapeutic agents operative to any extent against infec-
tions with cocci have been unknown up to the present. . . . [Cocci
are bacteria of spherical shape, including the gonococci, which pro-
duce gonorrhea, the meningococci, of a kind of meningitis, the
pneumococci, of pneumonia, and the staphylococci and streptococci,
which cause a wide variety of infections. Domagk next reviews
earlier attempts to find effective drugs for such diseases. These
efforts had centered chiefly on a number of compounds of the

* Translated from Gerhard Domagk, "Ein Beltrag zur Chemotherapie der bak-
teriellen Infektlonen," Deutsche medizinische Wochenschrijt, Vol. 61 (1935),
pp. 250-253.

1939: GERHARD DOMAGK 211

metals, particularly gold. All had proved failures for one reason or
another, many of the substances being too toxic for use.}

"Because of the disadvantages described, we turned our particu-
lar attention toward chemical compounds of other types, on a purely
organic, metal-free basis, which in experiments with mice gave
perceptible indication of being effective against streptococcal sepsis.
Among azo and acridine compounds * we had become acquainted
with a series of substances which showed a relatively good effect
against streptococci in disinfection research in vitro [i.e., in the
test tube} . But this effect, in part even an excellent one in vitro, was
almost always completely lost on the injection of these substances
into the animal body. . . . [Here follows an account of this re-
search. One of the substances tested was an azo compound called
chrysoidine. It was the addition to this compound (itself ineffective
against streptococci) of a sulfonamide group (SO 2 NH 2 ) which
produced prontosil.}

"In the course of our investigations, however, we later hit upon
a group of very innocuous azo compounds, which, to be sure,
showed no substantial disinfective value against streptococci in
vtiro, but now in experiments with mice gave a clear and per-
ceptible effect. To this group belongs prontosil, synthesized in 1932
by Mietzsch and Klarer. With prontosil we were able to establish
the best chemotherapeutic effects observed at any time in streptococ-
cal infections in animal research. It is the hydrochloride of 4'-sul-
fonamide-2, 4-diaminoazobenzene. . . .

"The harmlessness of the preparation is shown by the toxi-
cological data. . . . [Large amounts, at least 500 mg. per kilo of
body weight, were tolerated by mice and rabbits; larger doses were
vomited. Similar data are given regarding subcutaneous and in-
travenous injections. So far as these tests showed, the drag ap-
peared to be nontoxic.}

"Prontosil is ... an extraordinarily inert compound phar-
macologically . . . [i.e., it appeared to have little or no effect on
the various functions of the healthy animal body}.

"Cbemotherapeutically, prontosil shows an elective effect in

* Azo compound: a substance derived from a hydrocarbon by replacement of part
of the hydrogen by nitrogen. Acridine compound: a substance obtained from coal
tar; usually a yellow or brown dye.

212 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

streptococcal sepsis in the mouse [i.e.. It appears to act specifically
on streptococci, as if by choke]. ... All the animals alike were
infected with 0.3 c.c. of a 24-hour streptococcal bouillon culture.
Of the untreated control animals, none lived after 48 hours, so
that no [further] comparisons could be made. . . . When the
organs of untreated control animals are investigated, typical signs
of severe general infection are found in the liver, spleen, kidneys,
heart, and numerous other organs. . . .

"In the animals successfully treated with prontosil all these
pathological tissue changes are lacking, when treatment is started
promptly with adequate doses. In other cases one hinders the fur-
ther extension of tissue damage already existing. . . .

"It is worth notice . . . that in research in vitro, [prontosil]
shows no particular effect against either streptococci or staphylo-
cocci. It works like a true chemotherapeutic agent only in the liv-
ing organism. . . /*

CONSEQUENCES IN THEORY
AND PRACTICE

Accompanying this first report were three microphotographs of
the blood of infected mice. The first, picturing blood from an un-
treated animal, showed innumerable cocci; the second, taken 24
hours after subcutaneous injection of prontosil, revealed active
phagocytosis (the eating up of bacteria by white cells); and the
third, taken 48 hours after the injection, displayed a later stage of
the same healing process, with no free cocci whatever! These pic-
tures demonstrated how prontosil "works like a true chemothera-
peutic agent in the living organism," although not in the test tube.

The original protocol on the value of prontosil in the control of
experimental streptococcal infections in mice is dated December
20, 1932. Experimental work on animals was continued. Mean-
while Domagk's young daughter developed a serious streptococcal
infection following a needle prick. Ordinary treatment failed to
check the spread of the infection. Domagk treated her with large
doses of prontosil. She recovered.

Long before Domagk's original paper was published, reports
appeared in the German medical literature. The drug was dis-

1939: GERHARD DOMAGK 213

tributed for clinical trial early in 1933, and on May 17 Foerster
read the first report before the Diisseldorf Dermatalogical Society.

Since chrysoidine was powerless to check streptococci, and since
the only difference between chrysoidine and prontosil consisted in
the sulfonamide group attached to the latter, it appeared that this
group must be responsible for the chemotherapeutic effect. Assum-
ing that prontosil is split up in the organism, releasing sulfanila-
mide (para-amino-benzene-sulfonamide), Mr. and Mrs. J. Tre-
fouel, J. Nitti, and D. Bovet introduced the latter, which was given
its clinical trials by P. H. Long and L. Colebrook. In the next, few
years a very large number of "sulfa drugs" appeared, with special
advantages claimed for each, in reduced toxicity or in the type of
organisms affected. Sulfapyridine, for example, introduced in 1937
by L. Whitby, was particularly effective in cases of pneumonia.

"In 1935," writes Professor Spink,* "there was no specific
therapy for hemolytic streptococdc infections. Every clinician feared
streptococcic bacteremia [the presence of living bacteria in the
circulating blood}, with its mortality rate approximating 75 per
cent. Only a rare patient recovered from streptococcic meningitis.
In midwinter, hospital beds were occupied with cases of erysipelas
and mastoiditis, all caused by hemolytic streptococci. Sulfanilamide
took the sting out of these debilitating and fatal streptococcic
diseases. {The operation for mastoiditis has almost become a thing
of the past since the advent of sulfatherapy.} The mortality rate
of untreated pneumococcic meningitis was 100 per cent, but patients
recovered following the use of sulfapyridine. Chronic cases of
gonorrhea clogged up the out-patient services of hospitals, and its
devastating complication, gonococcal arthritis, was the frequent
cause of prolonged hospitalization. The sulfonamides soon offered
a more hopeful outlook for these individuals. The sulfonamides
proved to be highly effective in meningococcic bacteremia and
meningitis. A new chapter, and a dramatic one, had been written
in the therapy of human disease/*

There were certain drawbacks. The "sulfa drags" often pro-
voked serious side effects, especially kidney failure. Many patients
showed hypersensitivity to the drags after one or more courses of

* Wesley W. Spink, "Present Status of Sulfonamide Therapy," The Merck
Report, Apr. 1951, pp. i7-*9

214 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

treatment, in the form of skin eruptions and fever. Secondly, strains
of bacteria, notably gonococd, soon appeared which were resistant
to the self onamides. Thirdly, the sulfonamides had a relatively nar-
row range of activity; many of the causative agents of infectious
disease were not susceptible to their action. The first of these diffi-
culties, the toxicity of the "sulfas," was in part overcome by the
development of newer and safer variants, such as sulf adiazine and
sulfamerazine.

Although antibiotics, such as penicillin, streptomycin, and aureo-
mydn, now occupy a more prominent place in the treatment of
infectious diseases, because they are generally more efficient and
less toxic and have a wider range, the sulfonamides, especially sul-
fadiazine and sulfamerazine, continue to be widely used. This is
particularly true in parts of the world where the newer antibiotics
are as yet unavailable. Ease of administration and low cost con-
tribute to the enduring popularity of the sulfonamides. Moreover,
they are undoubtedly effective, and in meningococcic infections
they probably work as well as any of the antibiotics. There are like-
wise a number of diseases in which they have been given simul-
taneously with an antibiotic, although it is considered difficult to
assess the merit of this practice. These drugs not only find a wide
application in the treatment of disease but have also been used
successfully in the prevention of such diseases as epidemic menin-
gococcic meningitis.

The sulfonamides revolutionized the management of a con-
siderable number of important infectious diseases. The knowledge
acquired through the study of these drugs in laboratory and clinic
has been put to further use in more recent work on the antibiotics.

REFERENCES

LONG, PERRIN H. "Award of the Nobel Prize in Physiology and Medi-
cine to Dr. Gerhard Domagk," Scientific Monthly, Vol. 50 (1940),
pp. 83-84.

1940-1942

No Award

1943

HENRIK DAM

(1895- )
"For bis discovery of vitamin K."

EDWARD A. DOISY

(1893- )

ef For Ms discovery of the chemical nature of vitamin

K."

BIOGRAPHICAL SKETCHES
DAM

(CARL PETER) HENRIK DAM WAS BORN IN COPENHAGEN, ON
February 21, 1895. He wa s graduated in chemistry from the Poly-
technic Institute there in 1920, and was awarded the degree Sc. Dr.
in biochemistry by the University of Copenhagen in 1934. Mean-
while he had studied microchemistry with F. Pregl in Graz, Austria,
in 1925, and metabolism of sterols in Rudolph Schoenheimer's
laboratory in Freiburg, Germany, as a Rockefeller Fellow, in 1932-
1933. He also worked with P. Karrer, in Zurich, in 1935 and later.
Dam was appointed instructor in chemistry at the School of Agri-
culture and Veterinary Medicine in Copenhagen in 1920; instruc-
tor in biochemistry at the Physiological Laboratory, University of

216

1943 : DAM AND EOISY 217

Copenhagen, in 1923; and assistant professor at the Institute of
Biochemistry of the same institution in 1928. He served as asso-
ciate professor at the University from 1929 to 1941, and lectured
in the United States and Canada in 1940-1941. This tour was
planned before Denmark was occupied by German troops (April
1940). Dr. Dam carried out research in Woods Hole Marine
Biological Laboratories in 1941; at the University of Rochester,
New York, 1942-1945, as a senior research associate; and at the
Rockefeller Institute for Medical Research, 1945, as an associate
member. Despite his absence from Denmark he had meanwhile
been appointed professor of biochemistry at the Polytechnic Insti-
tute, Copenhagen. His many papers, some published jointly and
others alone, deal mainly with the biochemistry of sterols, fats, and
the vitamins K and E.

DOISY

EDWARD A. DOISY WAS BORN IN HUME, ILLINOIS, ON NOVEMBER
13, 1893. From the University of Illinois he received his A.B. in
1914 and his M.S. in 1916; he was awarded a Harvard Ph.D. in
1920 and has since been granted honorary degrees by several uni-
versities, in addition to a large number of medals and prizes. He
was assistant in biochemistry, Harvard Medical School, 1915-1917.
From 1917 to 1919 he served in the U. S. Army. He then became,
successively, instructor, associate, and associate professor in bio-
chemistry, Washington University School of Medicine, 1919-1923;
was appointed professor of biochemistry at the St. Louis University
School of Medicine, in 1923; and was appointed director of the
Department of Biochemistry, St. Mary's Hospital, in 1924. Dr.
Doisy has been active in professional associations and has served
on the League of Nations Committee on the Standardization of the
Sex Hormones. His publications have dealt with various aspects of
metabolism; insulin; blood buffers; isolation and chemical charac-
terization of theilin, theelol, and dihydrotheelin; ovarian hormones
and estrogenic substances; gonadotropic and thyrotropic principles,
as well as various other aspects of endocrinology; isolation of vita-
mins KI and K 2 ; determination of constitution and synthesis of
vitamin K x ; and antibiotic compounds.

218 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE- WINNING

WORK

BAM *

"The discovery of vitamin K arose from some studies on the
cholesterol metabolism of chicks carried out during the years 1928-
30 in the biochemical institute of the University of Copenhagen.
[Cholesterol, which chemists classify as an alcohol, is found in bile,
brain, blood cells, egg yolk, etc., and in varying amounts in animal
tissues. It belongs among the sterols, solid alcohols closely related
to steroids; the latter include a number of important hormones.
Another sterol is ergosterol, which, when irradiated, forms vitamin
D 2 .} It was then already known that rats, mice and dogs can
synthesize cholesterol but some experiments had been published
which seemed to show that chicks could not thrive on a diet from
which the sterols had been removed by extraction. When these
experiments were published ... in 1914, the role of fat-soluble
vitamins was not very well recognized, and I therefore found it
interesting to repeat them using artificial, practically sterolfree
diets to which vitamins A and D were added in the form of sterol-
free concentrates made from cod-liver oil, or of small amounts of
cod-liver oil of known cholesterol content. Chicks were reared on
such diets for different lengths of time from the day of hatching
and the amount of cholesterol in their excretions and their body
was determined and compared with the cholesterol content in newly
hatched chicks from the same litter. It was thereby found that a
considerable part of the cholesterol which the newly hatched chick
has taken over from the egg yolk disappears during the first 2 or
3 weeks, whereafter cholesterol is formed in increasing amount as
the body weight increases. Chicks therefore are able to synthesize
cholesterol, just as well as are rats, mice and dogs, and they are also
able to break it down.

"More interesting than this finding was, however, an unexpected
symptom which showed up in some of the chicks which were kept

* From Henrik Dam, "The Discovery of Vitamin K, Its Biological Functions and
Therapeutical Applications," Les Prix Nobel en 1946, pp. 205-220.

1943 : DAM AND DOISY 219

on the diet for more than 2 or 3 weeks. They got hemorrhages
under the skin, in muscles or other organs, and blood occasionally
taken out for examination showed delayed coagulation.

"The lack or low content of cholesterol in the diet could not be
the cause of the hemorrhages, since the experiments showed that
chicks can synthesize cholesterol. Further, the hemorrhages also
appeared in chicks which received a daily supplement of cholesterol.

"The low amount of fat in the diet would, apparently, also be
ruled out as a cause of the symptom since it was found that linseed
oil and triolein could not prevent its appearance. . . . Other au-
thors had already reported that chicks do not require vitamin C,
and daily ingestion of lemon juice . . . also proved to be ineffec-
tive. . . . [When] pure vitamin C became available ... I could
easily show that . . . injections of ascorbic acid failed to prevent
the disease. . . .

"The salt mixture could be varied considerably without influence
on the disease, and wheat germ oil was without protective effect,
whereas a high content of cereals and seeds in the diet prevented
the symptom. It was therefore safe to announce that the new experi-
mental disease was due to the lack of a hitherto unrecognized factor
in the diet. This was done in 1934.

"Then a number of animal organs and plant material were ex-
amined for their ability to protect against the disease and it was
found that green leaves and hog liver were among the most potent
sources. It was also found that the factor was fat-soluble, and in
1935 it was characterized as a new fat-soluble vitamin and given
the designation vitamin K. The letter K was the first one in the
alphabet which had not, with more or less justification, been used
to designate other vitamins, and it also happened to be the first
letter in the word "koagulation" according to the Scandinavian and
German spelling. . . .

"The hemorrhages in vitamin K deficiency develop in this way,
that minute vascular lesions caused by minor mechanical trauma
are not closed by rapid clotting, as is the case in normal animals.
This causes oozing of blood from the impaired region.

"According to the accepted theory the process of blood coagula-
tion may be separated into two stages.

220 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"(i) Protlirombin ~f- Thrombopiastin + Ca ~ Thrombin

"(2) Fibrinogen -f- Thrombin -~ Fibrin . . .

"It is easy to show that it is protbrombin and no other component
which is lacking when vitamin K has been withdrawn from the
diet. . . .

"Vitamin K from green plants is called KI. Chemically it differs
slightly from vitamin K formed by putrefaction, which is called K 2
[discovered by Almquist and Stokstad, University of California}.

. . The preparation of pure vitamin K from green leaves was
first reported by Dam, Karrer and co-workers, 1939. . . . The
elucidation of its composition was accomplished by Doisy and co-
workers, and by Fieser and co-workers. Doisy and co-workers also
prepared pure vitamin K 2 from putrefied fishmeal [and established
its chemical difference from KI.} . . .

"Andrus, Lord and Moore, 1939, excised the liver in normal
dogs and studied the prothrombin level with and without ingestion
of vitamin K and bile salts. They found that the blood prothrombin
decreased in both instances, indicating that the liver is necessary for
the action of vitamin K. Several other observations also show that
the liver is the organ concerned with prothrombin formation.'*

DOISY

[Doisy and his co-workers in the St. Louis University School of
Medicine isolated vitamin KI from alfalfa (Journal of Biological
Chemistry, Vol. 130 [1939}, pp. 219-234). Partition among vari-
ous solvents and crystallization from solvents proved unsuccessful,
and the large amount of impurities in crude preparations made low-
pressure distillations difficult and impractical; at the same time the
inactivity of the vitamin toward many chemical reagents and its
instability toward others eliminated chemical reactions as a means
of isolation. After extraction, therefore, repeated adsorptions were
used to obtain the vitamin. In a similar manner vitamin K 2 was
isolated from purified fish meal (Journal of Biological Chemistry,
Vol. 131 [1939}, pp* 327-344). The constitution of vitamin KI
was worked out and its synthesis accomplished by the same group in
St. Louis. Almost simultaneously three other groups, Almquist and
Kiose, Fieser et aL, and Karrer et aL, reached the same goal. Doisy

1943 : DAM AND DOISY 221

and his co-workers summarized their findings on vitamin K* as
follows.*]

"Vitamin KI was found to be a 2, 3-disubstituted a-naphtho-
quinone having an unsaturated side chain. By oxidation of the vita-
min with chromic acid phthalk acid was formed, which demon-
strated that the benzenoid ring of the vitamin carries no side chain.
A second acid isolated from the oxidation products was identified
as 2-methyl-i, 4-naphthoquinone-3-acetic acid, which showed that
the quinone nucleus has a methyl group at the 2 position and that
the side chain in the 3 position has an ethylenic linkage between the
and and 3rd carbon atoms from the quinone ring. These con-
clusions were confirmed by the products obtained by degradation of
the diacetyl dihydro derivative of the vitamin. Oxidation with
chromic acid formed the diacetyl dihydro derivative of the quinone
acid, and a ketone Ci 8 H 36 O. This ketone was also formed by
ozonolysis of the diacetyl dihydro vitamin and was identified as
2, 6, io-trimethylpentadecanone-i4 which proved the arrange-
ment of the remaining carbon atoms of the unsaturated side chain.

"The constitution of vitamin KI as 2-methyl-3-phytyl-i, 4-naph-
thoquinone was confirmed by synthesis. Phytyl bromide was con-
densed with the monosodium salt of 2-rnethyl-i, 4-naphthohydro-
quinone, the vitamin being isolated in the pure condition as the
diacetyl dihydro derivative. The synthetic compound was degraded
by the same procedure as that used for the natural vitamin deriva-
tive and shown to give the same degradation products."

CONSEQUENCES IN THEORY
AND PRACTICE

The first hemorrhagic disease in man to be recognized as due to a
deficiency of vitamin K was the bleeding which accompanies ob-
structive jaundice. Bile is important for the proper absorption of
vitamin K from the intestine, f and when the bile duct is blocked
by gallstones or tumor a bleeding tendency is one of the conse-
quences. This formerly constituted a real danger in operations for

* Journal of Biological Chemistry, Vol. 131 (i939) P- 3^9-

f Vitamin K is insoluble in water and its absorption and transportation depend

on the presence of desoxycholic acid.

222 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

the relief of obstruction. But in 1938 three different groups, Dam
and a colleague among them, independently reported that the bleed-
ing tendency is due to vitamin K deficiency. As Dam observes:
"Since then, the practical utilization of vitamin K in surgery has
been tried by a large number of surgeons and its value has been
fully established. It is possible by suitable vitamin K treatment, to
eliminate completely the risk of bleeding in such patients, provided
of course, that the case is not complicated by severe damage of the
liver so that vitamin K cannot act."

Furthermore, "a bleeding tendency due to reduced absorption
of vitamin K from the intestine can ... be observed in certain
intestinal diseases, where profuse diarrhoea occurs and the intes-
tinal mucosa is damaged. This has been found in cases of sprue, for
instance, where the absorption of fat is greatly diminished, or in
ulcerative colitis." Here again vitamin K is useful in treatment.

Vitamin K deficiency is also seen in the newborn infant. The low
prothrombin level which occurs in the first week after birth may
be raised by treatment with vitamin K. Where bleeding actually is
noted this is essential; the prothrombin may be raised to approxi-
mately normal values in 24 hours. Bleeding almost certainly occurs,
however, in many cases where it is not easily detectable, and the
administration of vitamin K to parturient women before delivery
has reduced the death rate among the newborn.

Vitamin K is a napthoquinone compound having a phytyl side
chain; vitamin K 2 contains a naphthoquinone ring with a much
longer and more unsaturated side chain. It Is now known that a
number of synthetic 2 -methyl- 1, 4-naphthoquktone compounds
possess vitamin K activity, as do several water-soluble substances
e.g., 4~amino-2-methyl-i-naphthol hydrochloride.

1944

JOSEPH ERLANGER

(1874- )

HERBERT SPENCER GASSER

(1888- )

"For their discoveries regarding the highly differ-
entiated junctions of single nerve fibers."

BIOGRAPHICAL SKETCHES
ERLANGER

JOSEPH ERLANGER WAS BORN IN SAN FRANCISCO, ON JANUARY
5, 1874. He received the B.S. degree in chemistry from the Univer-
sity of California, and in 1899 tne M.D. degree from the Johns
Hopkins University. After serving for one year as interne In the
Johns Hopkins Hospital he was appointed assistant in the Depart-
ment of Physiology at the Johns Hopkins University Medical School
under Dr, William H. Howell, then served successively as instruc-
tor, associate, and associate professor at that school. He then went
to the University of Wisconsin as the first professor of physiology
in the newly organized medical school there, where one of his
pupils was Herbert S. Gasser. In 1910 he was appointed professor
of physiology and head of the department in the reorganized medi-
cal school of Washington University, St. Louis. Gasser later re-
joined him there and their work together was carried out in St.
Louis. Dr. Erlanger became emeritus professor In 1944.

223

224 NOBEL PEIZE WINNERS IN MEDICINE AND PHYSIOLOGY

GASSER

HERBERT SPENCER GASSER WAS BORN IN PLATTEVILLE, A SMALL
town in Wisconsin, on July 5, 1888. He was educated in the State
Normal School there, and afterward in the State University. He
records that "the preciinical years of the Medical School had just
started and classes were so small that the faculty became not only
teachers but friends." His first course in physiology was with Dr.
Joseph Erlanger. The clinical years were completed at the Johns
Hopkins Medical School in 1915. Next there followed a year in
pharmacology at Wisconsin. He then rejoined Dr. Erlanger, who
had meantime become professor of physiology at Washington Uni-
versity, St Louis. In 1921 Dr. Gasser was made professor of
pharmacology at Washington University. Two years later, at the
instigation of Dr. Abraham Flexner, of the Rockefeller Founda-
tion, Gasser was granted leave of absence for two years of study
in Europe. After his return to the United States he remained at
Washington University until 1931, when he left to become profes-
sor of physiology at the Cornell Medical School in New York City.
In 1935 he was appointed director of the Rockefeller Institute for
Medical Research.

DESCRIPTION OF THE PRIZE-WINNING
WORK*

{It has been mentioned earlier (p. 160) that Gasser was one of
the pioneers in the use of amplifiers in physiology. Whereas Adrian
combined the amplifier with the capillary electrometer, Erlanger
and Gasser combined it with the cathode-ray oscillograph, invented
by F. Braun in 1897. (Braun received the Nobel Prize in Physics
in 1909.) A stream of electrons is given off from the negative
electrode (cathode) in a Crookes tube; in Braun's cathode-ray tube,
otherwise the same, these rays are narrowed into a threadlike beam
which is subjected to the influence of external electric currents. It

* Joseph Erlanger and Herbert S. Gasser, "The Compound Nature of the Action
Current of Nerve as Disclosed by the Cathode Ray Oscillograph," American
Journal of Physiology, Vol. 70 (1924), p. 624.

I944 : ERLANGER AND GASSER 225

is then focused on a screen so that the oscillations caused by these
outside potentials may be recorded. Erlanger and Gasser, in their
first publication on this subject (1922), pictured and discussed
the changes which the action current in nerve was sometimes found
to undergo in its course. The record of this potential close to its
source was a triangular wave with a rounded peak. Later it ex-
hibited one or more humps on the descending lirnb. In a subse-
quent paper, quoted below, Erlanger and Gasser presented a partial
explanation, afterward greatly elaborated, of the nature of these
waves.]

'Tight upon the fundamental nature of the waves which the
cathode ray oscillograph has disclosed in the amplified action cur-
rent was first obtained in experiments designed to ascertain whether
altering the distance the action current is propagated along the
nerve affects the relative positions of the waves. In these experi-
ments the nerve is mounted in a moist chamber and kept at a con-
stant temperature, . . . The stimulus is delivered through pairs of
platinum electrodes of which several, 3 to 5, range along the nerve
at measured distances from the proximal lead into the oscillograph.
By means of ... switches situated outside the moist chamber any
desired pair of electrodes can be connected with the inductorium.
... At the longer conducting distances [in the sciatic nerve of
the bullfrog} the action current is composed of three waves, though
the third in some instances is not very distinct. These waves may be
designated alpha, beta and gamma from before backwards in the
action current. . . . [Figures derived from an analysis of the
waves] give the very definite impression that the shift in the rela-
tive positions of the waves that occurs with the change in the con-
ducting distance, is due to differences in the rates with which the
waves move along the nerve. . . .

* 'Every observation we have made indicates that each wave repre-
sents a discrete action current started by the one stimulus, but
travelling in different groups of nerve fibers. Thus each wave, or
better, perhaps, each group of fibers ... has its own conduction
rate. . . . The positions of the starts of the slower waves can not
be ascertained with even a reasonable degree of accuracy. We,
therefore, have taken the times elapsing between the crests of
alpha and of beta . . . [etc.] as the lags between these waves. This

226 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

is justifiable because . . . these crests at fairly long conducting
distances are not materially displaced by summation and because
the times to maximum of all the waves are essentially alike.
[Each wave, or each group of fibers, was concluded to have
not only its own conduction rate but also} its own threshold of
stimulation and its own refractory period. . . . ["Threshold of
stimulation" refers to the strength of stimulation required to pro-
duce an effect. It was found that different stimulation strengths
produced different patterns; in one case, for instance, a completely
developed action current appeared, while in another there was only
an alpha wave, etc. Analysis of the patterns produced by graded
action currents therefore contributed to the view that not one but
several discrete action currents were being recorded. The "refrac-
tory period" is the time that must elapse after delivering an effec-
tive stimulus before another response to a second stimulus is
obtainable from the same point. By applying stimulation at differ-
ent intervals and studying the resultant wave patterns, the varying
refractory periods of alpha, beta, etc. were revealed.}

"Of even greater . . . interest, however, is the experimental
dissociation of the action current into the several processes of which
it is composed, that is made possible through the fact that the alpha
and beta (and gamma) processes have different stimulation thresh-
olds as well as different refractory phases. If by properly selecting
the strength of stimulation, an action current consisting solely of
a maximal alpha process is started in a nerve, and if while the nerve
still is absolutely refractory to this alpha process it is stimulated a
second time through the same electrodes with a strong shock, one
that ordinarily would elicit all of the processes, the action current
started by the second stimulus will be without an alpha process/'

CONSEQUENCES IN THEORY
AND PRACTICE

The work described above, developed in further detail, led to
the establishment of a theory of differentiated function. The evi-
dence presented in the last paragraph above was a strong indication
that the alpha process resulted from a separate action current in a
separate division of the nerve i.e., in a particular group of fibers.

1944 : ERLANGER AND GASSER 227

It was concluded as the result of later studies that the thickest, or
A-fibers, have the highest conduction velocity; that those of Inter-
mediate size, the B-fibers, have a lower rate; and that the lowest
rate of all is in the slenderest, the Ofibers. Individual fibers, run-
ning in the same nerve, were thought to serve different purposes;
for example, the lowest rate of conduction was found In fibers
carrying pain impulses. A part of the work, pursued chiefly by
Gasser, was concerned with the changes of excitability that occur
at a nerve cross section at which impulses arrive. The arrival of
one or several impulses to such a region was found to be followed
by slow changes of excitability associated with slow changes of
electrical potential. These changes of excitability enhance or depress
succeeding impulses. It was shown that such "after-potentials" be-
haved in a different manner in the three main types of fiber, con-
firming the concept of a high degree of differentiation of the nerve
fibers for their various tasks. Gasser, however, In his Nobel lecture,
delivered in December 1945, observed in regard to pain, touch,
temperature, etc., that "attempts to identify modalities with definite
segments of the velocity spectrum have not been very successful.
We are left faced with evidence for conduction of single modalities
at very different velocities, and inclusion of a number of modalities
within a narrow band of fibers. What then is the significance of the
wide velocity range? Is it timing? Reflection on this, the most ob-
vious Interpretation of all, causes It to loom progressively larger.
One need but consider the speed with which posture Is controlled
in preparation for the reception of oncoming detailed Information
and adjustment of fine movement; or again the mode of transmis-
sion of excitation through any central ganglion. . . . Differential
axonal velocities must play their part in the mechanism. Be this
their only contribution to integration, it Is still a large one."

Adrian and others had studied responses from a single nerve
fiber after teasing a nerve until only one fiber remained Intact. In
the work of Erlanger and Gasser, and especially in the later work
of Erlanger and Blair, an intact nerve was selected, such as the
frog's phalangeal nerve, likely to contain a fiber of particular ex-
citability so that a threshold stimulus would excite that fiber only.
Thus the investigation of a more nearly physiological condition be-
came possible with the refined apparatus used. These studies have

228 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

been pursued, as Erlanger stated in his Nobel lecture, delivered in
1947, "because it is felt . . . that in the investigation of this com-
paratively simple structure, the nerve fiber, lies the hope of finding
clues to an understanding of the much more complicated mecha-
nisms that determine the activities of peripheral and central nervous
mechanisms."

1945

ALEXANDER FLEMING

(1881- )

ERNST BORIS CHAIN

(1906- )

HOWARD WALTER FLORET

(1898- )

"For the discovery of penicillin and its therapeutic
effect for the cure of different infectious maladies"

BIOGRAPHICAL SKETCHES

FLEMING

ALEXANDER FLEMING WAS BORN ON AUGUST 6, 1881, AT LOCH-
field, in Ayrshire, Scotland. He obtained Ms general education at
Loudoun Moor School, Darvel School, Kilmarnock Academy, and
the London Polytechnic. Before beginning the study of medicine
he worked for four years in a shipping office. He then began his
medical education at St. Mary's Hospital Medical School, Univer-
sity of London. He qualified in 1906 and immediately commenced
work in Sir Almroth Wright's laboratory in St. Mary's Hospital.
He has worked at St. Mary's ever since, latterly in the Wright-
Fleming Institute. He has been professor of bacteriology since

229

230 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

1929. Fleming has published many articles on immunology, gen-
eral bacteriology, and chemotherapy. His most important papers
have dealt with antiseptics, lysozyme (an antibacterial substance
discovered in 1922), and penicillin. He has consistently made use
of variations of Wright's technique of the teat and the capillary
tube (see lecture below) in his studies of human blood. He has
Been the recipient of many honorary degrees and prizes and was
jmade Knight Bachelor in 1944.

CHAIN

SON OF DR. MICHAEL CHAIN, A CHEMIST AND INDUSTRIALIST,
Ernst Boris Chain was born on June 19, 1906, in Berlin. Educated
at the Luisengymnasium, Berlin, he early became interested In
chemistry and In 1930 was graduated as a chemist from the Fried-
rich- Wilhelm University. After several years of research work on
enzymes at the Pathological Institute of the Charite Hospital in
Berlin he emigrated to England; this was early in 1933, soon after
the access to power of the Nazi regime in Germany. He spent two
years In the Cambridge School of Biochemistry, the domain of Sir
Frederick Gowland Hopkins, whom he greatly admired. In 1935
he was invited to Oxford by H. W. Florey to develop a chemical
section In the Department of Pathology. In 1938 he initiated jointly
with Florey a systematic Investigation of antibacterial substances
produced by microorganisms. This work led to the reinvestigation
of penicillin, described nine years earlier by Fleming, and to the
discovery of its chemotherapeutk action.

FLOREY

HOWARD WALTER FLOREY WAS BORN ON SEPTEMBER 24, 1898,
at Adelaide, South Australia. After attending local schools and
Adelaide University (1916-1921), he went to Magdalen College,
Oxford, In 1922, as a Rhodes Scholar. He later studied at Cam-
bridge and at the London Hospital, and was Rockefeller Travelling
Fellow in the United States, 1925-1926. He became Huddersfield
Lecturer in Special Pathology, Cambridge, 1927; professor of
pathology, University of Sheffield, 1931; and professor of pathol-

1945 : FLEMING, CHAIN AND FLOREY 231

ogy, Oxford, 1935. In 1935 he Invited Chain to join him at Ox-
ford. In 1941 he was elected Fellow of the Royal Society and in
1944 was made Knight Bachelor. He has received many prizes and
honorary degrees. In 1944 he was Nuffield Visiting Professor to
Australia and New Zealand. The subjects of his research have In-
cluded inflammation, capillary blood circulation, and the functions
of the lymphocyte. His work on lysozyme led to a general study of
antibiotics, in association with Chain; this in turn led to the dis-
covery of the chemotherapeutlc value of penicillin.

DESCRIPTION OF THE PRIZE-WINNING

WORK

FLEMING *

'The origin of penicillin was the contamination of a culture plate
of staphylococci by a mould. [Staphylococci are among the com-
mon pus-forming bacteria. A culture plate is a flat, shallow glass
dish containing a gelatinous solid, commonly agar, on the surface
of which the bacteria are grown.} It was noticed that for some
distance around the mould colony the staphylococcal colonies had
become translucent and evidently lysis [solvent action] was going
on. This was an extraordinary appearance and seemed to demand
investigation so the mould was isolated in pure culture and some
of its properties were determined.

"The mould was found to belong to the genus penlcllllum and
it was eventually identified as penicillium notatum. . . .

"Having got the mould in pure culture I planted It on another
culture plate and after it had grown at room temperature for 4 or
5 days I streaked different microbes radially across the plate. Some
of them grew right up to the mould others were inhibited for a
distance of several centimetres. This showed that the mould pro-
duced an antibacterial substance which affected some microbes and
not others. . . .

"Then the mould was grown on fluid medium to see whether the
antiseptic substance occurred in the fluid. After some days the

* From Alexander Fleming, "Nobel Lecture on Penicillin/' Les Prix Nobel en
> PP- 155-1^4.

232 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

fluid on which the mould had grown was tested ... by placing
it in a gutter in a culture plate and then streaking different microbes
across the plate. The result [indicated] that the microbes which
were most powerfully inhibited were some of those responsible for
our most common infections. . . .

"All the experiments I have cited showed that [penicillin] was
bacteriostatic, that is, it inhibits the growth of microbes. But I
showed also that it was bactericidal that it actually killed them.
Then the very first observation . . . showed that it induced lytic
changes in the bacteria. Thus it was bacteriostatic, bactericidal and
bacteriolytic. . . .

ft l had since the war of 1914/18 been interested in antiseptics
and in 1924 I described what I think is probably the best experi-
ment I ever did. This showed up in a dramatic fashion the relative
activity of a chemical on bacteria and on human leucocytes [white
blood cells].

"Normal human blood has a strong bactericidal power on the
ordinary cocci ... but this power is completely lost if the leuco-
cytes are removed from the blood. If defibrinated blood is infected
with a small number of staphylococci . . . and incubated in a
capillary space [e.g., a fine glass tube with a hairlike bore] the
cocci which survive grow out into colonies which can easily be
enumerated. But only about 5 per cent grow out. If however, phenol
[carbolic acid] is added to a concentration of i in 600 all the cocci
grow out freely. Here the phenol in a concentration which does
not interfere with bacterial growth has destroyed the leucocytes
which constitute one of our most powerful defenses against infec-
tion.

"I had tested all the chemicals which were used as antibacterial
agents and they all behaved in the same way in some concentra-
tion they destroyed leucocytes and allowed bacteria to grow. When
I tested penicillin in the same way on staphylococcus it was quite a
different story. The crude penicillin would completely inhibit the
growth of staphylococci in a dilution of up to i in 1000 when
tested in human blood [phenol loses its inhibitory power when
diluted more than 300 times] but it had no more toxic effect on the
leucocytes than the original culture medium in which the mould

1945 : FLEMING, CHAIN AND FLOREY 233

had been grown. I also injected it into animals and it had appar-
ently no toxicity.

"A few tentative trials [on hospital patients] gave favourable
results but nothing miraculous and I was convinced that ... it
would have to be concentrated. . . .

"We tried to concentrate penicillin but we discovered . . . that
penicillin is easily destroyed . . . and our relatively simple pro-
cedures were unavailing. . . .

"In 1929 I published the results which I have briefly given/'

CHAIN AND FLOREY *

"It was first established that penicillin was an acid . . . [which,
extracted from the culture fluid with ether and shaken up with
dilute aqueous alkali, formed stable salts]. In addition to ether, a
number of organic solvents . . . could be used to extract the free
acid form of penicillin. The salts of penicillin were much more
soluble in water than in the organic solvents, and therefore penicil-
lin was removed from the organic solvent by about 1/5 to i/io
the volume of alkali solution. A concentration of penicillin was
thereby achieved, and by repeating the extraction several times with
different solvents and at a suitable pH, a considerable purification
of penicillin and simultaneous reduction of the bulk of liquid was
obtained. . . . [By drying at low temperature and pressure] a
preparation of a salt of penicillin was obtained, in powder form,
which kept its antibacterial activity unchanged for a long time.

"Chemically, however, the preparation was far from pure, con-
taining, as is now known, not more than a small percentage of pure
penicillin. The isolation of penicillin in the pure state from this
mixture proved a difficult problem because of its instability to-
wards many reagents and the unfavourable solubilities of the free
acid and its salts. . . . [By distribution between different solvents
and water, by adsorption methods, and by a variety of other means,
later much elaborated, it became possible] to produce penicillin
preparations from which crystalline salts could be made. The purest
material obtained at Oxford [1945] has an activity of about i ? ooo

* From Ernst Chain and H. W. Florey, "The Discovery of the Chemotherapeutic
Properties of Penicillin," Caribbean Medical Journal, Vol. 7 (i945>, PP- *5i-*55-

234 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Oxford units per mg., and is capable of inhibiting the growth of
certain bacteria at a dilution of about 1:50,000,000. . . . [The
Oxford unit, also called Florey unit, was an arbitrary amount de-
termined by comparison with a standard preparation.]

"For the first biological experiments very crude preparations
were used. ... So great was the antibacterial power of even the
crudest extracts that at that time not realizing the extraordinary
potency of penicillin we believed them to be fairly pure. In actual
fact we know now that they contained about i per cent of pure
penicillin. . . .

"It was shown that the extracts were remarkably non-toxic to
mice. . . . Not only were the extracts relatively innocuous to the
whole animal, but leucocytes and tissue cultures withstood many
hundreds of times the concentration needed to inhibit such organ-
isms as the streptococcus. In light of present knowledge of the gross
impurity of the original extracts, one can only be thankful that the
mass of impurities, as well as the penicillin, were so little toxic.

"Penicillin was readily absorbed in animals after intramuscular
or subcutaneous injection, and from the small intestine. It could not
of course be given by mouth because the acid of the gastric juice
destroyed it, nor by rectum as the bacteria there inactivated it. It
was largely excreted, still in an active form, in the urine . . . and
to a certain extent in the bile and saliva. . . . Though penicillin
was readily soluble and diffusible, it did not pass in detectable
quantities from the blood into the cerebro-spinal fluid.

"In agreement with Fleming's observations it was found that the
action of penicillin was bacteriostatic, in that it merely inhibited
the growth of organisms and did not kill them quickly, as did
poisonous antiseptics. . . . Most antibacterial substances such as
ordinary antiseptics and the sulphonamides are . . . not active in
the presence of pus, and hence their therapeutic efficacy is severely
limited. It was therefore a particularly fortunate property of
penicillin that pus, tissue autolysates [products of the self-digestion
of cells, called autolysis}, blood and serum had no inhibitory effect
on its activity. It was found too that the number of organisms
present had little effect on its inhibitory power again a contrast
with the sulphonamides. . . .

1945 : FLEMING, CHAIN AND FLOREY 235

"In terms of the labour involved It was ... a big step from
experiments on mice to making observations on the human subject,
for the mould produces very little of the active substance. Months
elapsed before enough material could be accumulated to try the
first injection on man.

"Injection in the human subject disclosed that some substance
was present in the crude penicillin preparations which caused a
rigor and sharp rise of temperature. This had not been suspected
from observations on animals. By good fortune the pyrogenic effect
was not due to the penicillin but to an impurity which could be
removed.

"Insufficient material had been accumulated for the first 2 cases
treated, and although both patients, who were seriously ill, did
well for a time, they relapsed and further treatment could not be
carried out for lack of material. In the course of some months
enough was accumulated ... to treat by parenteral injection a
further 18 patients. . . . Toxic reactions, apart from pyrogen,
were not observed and some striking recoveries of patients Infected
with staphylococci were obtained. Suitable dosage was worked out
and the principles of treatment were formulated. At the same time
penicillin was shown to be valuable for local application in various
septic conditions. . . /'

CONSEQUENCES IN THEORY
AND PRACTICE

Chain and his colleagues at Oxford began the long and difficult
task of elucidating the structure of penicillin; this problem was sub-
sequently taken up elsewhere, chiefly in the United States. Mean-
while the job of producing penicillin In quantity from the mold
was undertaken by a number of American pharmaceutical houses,
at first independently, later under the aegis of the War Production
Board. The manifold production problems were solved in a surpris-
ingly short time.

Penicillin could be used on many cases in which sulf onamldes
would be ruled out, as on patients with kidney damage and those
reacting allergically to the "sulf a" drags. Its effectiveness was at
first hard to evaluate, for insufficient supplies and Insufficient ex-

236 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

perience often resulted in inadequate dosage. It proved effective
against pneumonia and other diseases due to staphylococci and
largely beyond the reach of the "sulfas" or any other form of treat-
ment. It showed itself a powerful weapon against streptococci and
the bacilli of gas gangrene. It cured gonorrhea rapidly and without
the sometimes unpleasant reactions due to "sulfa" therapy. It trans-
formed the treatment of syphilis. It cured a large percentage of
cases of bacterial endocarditis, a disease previously regarded as
almost 100 per cent fatal. Although powerless against tuberculosis,
typhoid fever, and such nonbacterial diseases as malaria and infan-
tile paralysis, it was shown to have a wide * 'bacterial spectrum"
and to be the most powerful microbe-killer yet discovered.

Penicillin nevertheless has its limitations. It is primarily active
against gram-positive organisms those which take a blue or deep
violet stain when treated by Gram's differential staining method.
It has little activity against the gram-negatives the red-staining
organisms which cause cholera, typhoid, dysentery, and other dis-
eases. Many of these have since proved susceptible to streptomycin
and other new agents. Penicillin has acted as a spur to the search
for these newer antibiotics, of which about half a dozen are now
in fairly general use, most of them the products of soil bacteria. It
is now quite common, although still expensive, to give penicillin
orally, means having been found to prevent its destruction before
it can act. It was at first supposed that penicillin was quite innocu-
ous and that all bad effects would vanish as soon as a pure product
had been obtained. Although it is true that penicillin is remarkably
nontoxic for a drug of such potency, it is nevertheless not entirely
free of noxious side effects; these are seldom so serious, however,
as those which sometimes complicate the use of the sulfonamides.
A not uncommon, and certainly highly unpleasant, allergic symp-
tom is a severe urticaria (a reaction in the nature of hives) which
may persist for days, or even for weeks, after the discontinuance of
penicillin therapy. Bad reactions to penicillin are annoying, and
sometimes dangerous, but they are neither frequent enough nor
serious enough to constitute any considerable limitation on the use
of the drug. As in the case of the sulfonamides, bacterial genera-
tions may arise which are penicillin-resistant.

I945 : FLEMING, CHAIN AND FLOJUEY 237

Despite its various limitations and drawbacks, penicillin remains
the most important of antibiotic drugs.

REFERENCES

RATCLIFF, J. D. Yellow Magic: The Story of Penicillin (New York:
Random House, 1945).

1946

HERMANN JOSEPH MULLER

(1890- )

'For his discovery of the production of mutations
by means of X-ray irradiation"

BIOGRAPHICAL SKETCH

HERMANN JOSEPH MULLER WAS BORN IN NEW YORK CITY, ON
December 21, 1890. He attended a public primary school in Har-
lem and the Morris High School in the Bronx. In 1907 he won a
scholarship for entry into Columbia College, where he became in-
terested in biology. He attributes his particular interest in genetics
to reading a book on this subject by R. H. Lock. In 1909 he
founded a students* biology club, in which Altenburg, Bridges, and
Sturtevant participated, all destined to be distinguished geneticists.
After graduation he held first a scholarship, then a teaching fellow-
ship, in physiology, the latter at Cornell Medical College; he then
taught zoology at Columbia, 1912-1915. From 1910 on he was a
member of Morgan's research group (see above, p. 165) and in
1912 he began to do original research in genetics. From 1915 to
1918 he was an instructor in the Rice Institute, Houston, under
Julian Huxley. During this time and the two years following, when
he instructed at Columbia, he elaborated methods for quantitative
mutation study. In 1920 he went to the University of Texas as
associate professor, becoming professor in 1925. His first evidence
of mutations produced by X rays was obtained in 1926 and pub-
lished in 1927. In 1932 he was awarded a Guggenheim Fellowship

238

1946: HERMANN JOSEPH MULLER 239

for a year in Oscar Vogt's Institute in Berlin, in Timofeeff's De-
partment of Genetics. He then spent more than three years as
Senior Geneticist at the Institute of Genetics of the Academy of
Sciences of the U.S.S.R., first in Leningrad, later in Moscow. Then
followed work in the Institute of Animal Genetics, University of
Edinburgh (1937-1940), Amherst College (1940-1945) and
Indiana University, where he accepted a professorship in the
Zoology Department in 1945.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"If ... mutations were really non-teleological, with no rela-
tion between type of environment and type of change, and above
all no adaptive relation, and if they were of as numerous types as
the theory of natural selection would demand, then the great
majority of the changes should be harmful in their effects, just as
any alterations made blindly in a complicated apparatus are usually
detrimental to its proper functioning, and many of the larger
changes should even be totally incompatible with the functioning
of the whole, or, as we say, lethal. . . .

"To get exact evidence . . . required the elaboration of special
genetic methods, adapted to the recognition of mutations that ordi-
narily escape detection (i) lethals, (2) changes with but small
visible effects, and (3) changes without any externally visible
effects but influencing the viability more or less unfavourably, * .

"It was possible in the first mutation experiments, which [Ed-
gar] Altenburg and the writer conducted, partly in collaboration,
in 1918-19, to get definite evidence in Drosophila that the lethal
mutations greatly outnumbered those with visible effects, and that
among the latter the types having an obscure manifestation were
more numerous than the definite conspicuous ones used in ordinary
genetic work. Visible or not, the great majority had lowered via-
bility. Tests of their genetic basis . . . showed them to be most
varied in their locus in the chromosomes, and it could be calcu-
lated . . . that there must be at least hundreds, and probably

* From H. J. Muller, "The Production of Mutatioas," Les Prix Nobel en 1946,
pp. 257-274.

240 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

thousands, of different kinds arising in the course of spontaneous
mutation. . .

"Objectivity of recognition, combined with [their greater num-
ber] . . . made it feasible for lethals to be used as an index of
mutation frequency. ... In the earliest published work, we ...
attempted not only to find a quantitative value for the 'normal'
mutation frequency, but also to determine whether [temperature}
. . . affected the mutation frequency. . . . The results ... in-
dicated that a rise of temperature, within limits normal to the
organism, produced an increase of mutation frequency of about the
amount to be expected if mutations were, in essentials, orthodox
chemical reactions.

". . . Mutations, when taken collectively, should be subject to
the statistical laws applying to mass reactions, but the individual
mutation . . . should be subject to the vicissitudes of ultrami-
croscopic or atomic events. . . . This is a principle which gives
the clue to the fact . . . that differences in external conditions
... do not appear to affect the occurrence of mutations, while on
the other hand, even in a normal and sensibly constant environ-
ment, mutations of varied kinds do occur. It is also in harmony
with our finding, of about the same time, that when a mutation
takes place in a given gene, the other gene of identical type present
nearby in the same cell usually remains unaffected, though it must
of course have been subjected to the same macroscopic physico-
chemical conditions. On this conception, then, the mutations ordi-
narily result from submicroscopic accidents, that is, from caprices
of thermal agitation, that occur on a molecular and submolecular
scale. . . .

"Now this inference ... led naturally to the expectation that
some of the 'point effects' brought about by high-energy radiation
like X-rays would also work to produce alterations in the hereditary
material. For if even the relatively mild events of thermal agita-
tion can . . . have such consequences, surely the energetically far
more potent point changes caused by powerful radiation should
succeed. And, as a matter of fact, our trials of X-rays . . . proved
that such radiation is extremely effective, and inordinately more so
than a mere temperature rise, since by this method it was possible
to obtain, by a half hour's treatment, over a hundred times as many

1946 : HERMANN JOSEPH MULLER 241

mutations ... as would have occurred . . . spontaneously in
the course of a whole generation. These mutations too were found
ordinarily to occur pointwise and randomly, in one gene at a time,
without affecting an identical gene that might be present nearby
in a homologous chromosome.

"In addition to the individual gene changes, radiation also pro-
duced rearrangements of parts of chromosomes. As our later work
... has shown, these latter were caused in the first place by
breakages of the chromosomes, followed afterwards by attach-
ments occurring between the adhesive broken ends, that joined
them in a different order than before. The two or more breaks in-
volved . . . may be far apart, caused by independent hits, and
thus result in what we call gross structural change. ... By the
rejoining, in a new order, of broken ends resulting from two . . .
nearby breaks, a minute change of sequence of the genes is brought
about."

CONSEQUENCES IN THEORY
AND PRACTICE

Possibly the most obvious lesson of Mullens important discovery
is that "the great majority of mutations being undesirable . . .
their further random production in ourselves should so far as pos-
sible be rigorously avoided." It thus "becomes an obligation for
radiologists ... to insist that the simple precautions are taken
which are necessary for shielding the gonads. . . . And, with the
coming increasing use of atomic energy, even for peacetime pur-
poses, the problem will become very important of insuring that the
human germ plasm ... is effectively protected from this addi-
tional and potent source of permanent contamination."

Other agents were soon found to produce mutations alpha rays,
neutrons, ultraviolet and infrared light, mustard gas and related
chemical compounds. The latter were investigated by J. M. Robson
and C. Auerbach, because Robson had noticed a similarity between
the effects of mustard gas on the body and those produced by X ray
and radium. Muller had already inferred that "a large proportion
... of the somatic effects of irradiation . . . arise secondarily as
consequences of genetic effects produced in the somatic cells. The

242 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

usefulness of this interpretation has been shown in recent studies
dealing with improved methods of irradiation of mammalian
carcinoma." Dr. Muller is also of the opinion that studies in this
field are "helping to clear the way for an understanding of the
mechanism by which radiation acts in inhibiting growth, in causing
sterilization, in producing necrosis [local death of tissue} and
burns, in causing recession of malignant tissue, and perhaps also,
on occasion at least, in inducing the initiation of such tissue."

The importance of the discovery in aiding scientists to under-
stand the mechanism of evolution has been hinted in the principal
quotation. Its importance for further studies in genetics is sug-
gested by MuUer's assertion that "every natural mutation, when
searched for long enough, is found to be producible also by radia-
tion." The abundant, if random, production of mutations has
enormously extended the materials of the geneticist's work. For
instance, "position effect" (implying that the function of a gene
is to a certain extent dependent upon what other genes are near
by) had been observed previously, but it was not known to what
extent the effect might be a special one until numerous rearrange-
ments could be studied; this was made possible by irradiation, and
there is now evidence that "position effect" is a general principle.
This is one instance only of the way in which Muller's discovery
has affected genetics. Analysis of the properties of the chromosomes
and their parts has gained a great deal from studies in which parts
have been removed, added, or rearranged. Mutations are produced
at random, but they are so numerous that it is possible to pick out
those best suited for successive steps in analysis, and the method
has been applied not only to "pure" genetics but also to studies in
the biochemical synthesis of amino acids, vitamins, purines, etc.
By means of induced mutations it has been possible to develop
strains of fungi which have lost the power to synthesize certain
substances. Such studies promise to shed more light on synthetic
processes in the organism and to improve our understanding of
certain hereditary metabolic disturbances. Hereditary diseases in
general are ultimately due to mutations. Mutations also determine
the development of new properties in bacteria, such as resistance
to particular drags.

1946; HERMANN JOSEPH MULLER 243

The possibility of applying any influence which will change in-
dividual genes to order seems very remote, but there has been
evidence that induced mutations may at times be used for selection
in artificial breeding.

1947

BERNARDO ALBERTO HOUSSAY

(1887- )

ff For his discovery of the part played by the hor-
mone of the anterior pituitary lobe in the metabo-
lism of sugar"

(The award for 1947 was shared with C, P. and G. T. Con;
see below, pp. 248-254.}

BIOGRAPHICAL SKETCH

BERNARDO ALBERTO HOUSSAY WAS BORN IN BUENOS AIRES, ON
April 10, 1887. His early studies were in a private academy. In
1901 he was admitted to the School of Pharmacy of the University
of Buenos Aires, where he was graduated in 1904. He had already
commenced his work at the medical school, from which he obtained
his M.D. in 1911 for his thesis on the hypophysis, or pituitary
body. Before he had completed his medical studies he was ap-
pointed professor of physiology in the University of Buenos Aires
School of Veterinary Medicine. In 1919 he resigned this position
to occupy the chair of physiology in the medical school, as the first
full-time professor in an Argentine university; he remained as
professor and director of the Institute of Physiology until 1943.
Since 1944 Professor Houssay has carried on his research at the
Institute of Experimental Biology and Medicine, organized with
the support of private funds. He has worked in almost every field
of physiology, but has given particular attention to problems of
endocrinology. From first to last he has never ceased to study the
functions of the hypophysis.

244

I947 : HOUSSAY, CORI AND CORI 245

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The production and consumption of glucose and hence the
blood sugar level are controlled by a functional endocrine equilib-
rium. [The endocrine glands are ductless glands secreting hor-
mones into the bloodstream.} This mechanism acts on the liver
the organ which produces and stores glucose and on the tissues
which are the consumers of glucose, by means of hormones which
play a part in the chemical processes of carbohydrate metabolism.

"The secretion of each endocrine organ is controlled by a physi-
ological mechanism. For instance, the pancreas secretes insulin in
adequate quantities so as to maintain a normal blood sugar level
and the blood sugar level regulates the amount of insulin secreted.
Thus hyperglycemia [high blood sugar} increases the secretion of
insulin [which lowers the blood sugar}, and hypoglycemia [low
blood sugar} diminishes or completely inhibits it. ... The ex-
trinsic innervation of the pancreas is not necessary for the regula-
tion of insulin secretion [i.e., cutting the nerves has little effect on
the control of the endocrine part of the gland}.

"Not only is the secretion of each gland regulated according to
the organic needs of each moment, but there is also an equilibrium
between the secretions of the different glands [e.g., those which
raise blood sugar and those which lower it}. . . ,

"In 1907, when I was a medical student, I was attracted to the
study of the hypophysis because the microscopic picture showed
glandular activity and its lesions were accompanied by serious
organic disturbances, such as acromegaly, dwarfism, etc. [The
hypophysis, or pituitary body, is a small two-lobed body at the base
of the brain. Both parts produce hormones. Those of the anterior
lobe control the thyroid, the sex glands and cortex of the suprarenal
glands, regulate the , formation of milk and the growth of the
whole body; Houssay has shown that this anterior lobe also has a
part in the conversion of sugar. Disordered function in the secre-
tion of the growth hormone causes acromegaly, a disease described

* B. A. Houssay, "The Role of the Hypophysis in Carbohydrate Metabolism and
in Diabetes," Les Prix Nobel en 1947* PP- 129-136.

246 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

by Pierre Marie in 1886, In which there is progressive enlarge-
ment of the head and face, the hands, feet, and thorax.]

"The frequency of glycosuria [sugar in the urine] or diabetes in
acromegaly has been reported many times. . , . Moreover extracts
of the posterior lobe of the hyphosis produce ... a transitory
hyperglycemia. Therefore it was commonly accepted that if the
hypophysis played a part in carbohydrate metabolism, it would
be due to the activity of its posterior lobe.

"One year after the discovery of insulin a systematic study of
the influence of endocrine glands on its activity was organized in
my laboratory. [When the hypophysis had been removed from
dogs, a difficult surgical procedure, they were found to be exces-
sively sensitive to the action of insulin; this was also found in a
large kind of toad, plentiful in Argentina, which Houssay used in
many of his experiments. Later he found that administration of
extract of anterior lobe prevented or corrected this hypersensitive-
ness to insulin.] The next step consisted in the removal of the
pancreas in hypophysectomized dogs and toads, ... [A dog
without a pancreas is diabetic; but removal of the hypophysis or its
anterior lobe] produced a considerable attenuation of the severity
of pancreatic diabetes. The injection or implantation of anterior
hypophyseal lobe reestablished or even increased the usual severity
of diabetes. , . .

"Later the diabetogenic [diabetes-producing] effect was also
demonstrated in dogs with a surgically reduced pancreas or [by
other workers] with an intact pancreas. A permanent diabetes was
produced by prolonged treatment with the extract of anterior lobe.
. . . [This was shown to be due to the damage caused to the /J
cells, or insulin-secreting cells, of the pancreas.] If after a few
days the anterohypophyseal treatment is discontinued the diabetic
condition disappears, the blood sugar returns to a normal level,
and later the p cells regain their normal aspect. If daily injections
. are continued for several weeks ... the animals remain
permanently diabetic."

1947 : HOUSSAY, CORI AND CORI 247

CONSEQUENCES IN THEORY
AND PRACTICE

The far-reaching importance in animal metabolism of the tiny
hypophysis has been realized only in the present century. Its rela-
tion to body growth was first clearly appreciated during the first
decade of the century, but not until 1944 did H. M. Evans and
C. H. Li produce the growth hormone in pure form. In the same
way the influence of the pituitary body on sex functions, although
perceived about fifty years ago, was not worked out in detail until
much later. The effect of the hypophysis on the pancreas, although
surmised, was little investigated or understood before the work
of Houssay. Beginning in 1924, Houssay demonstrated that an
animal deprived of its pituitary is abnormally sensitive to insulin;
that a pituitary extract will offset this effect, showing an anti-
insulin property; that this influence emanates from the anterior
lobe of the pituitary; that diabetes caused by removal of the pan-
creas is distinctly relieved by removal of the pituitary body too;
and that the diabetogenic (diabetes-producing) capacity of the
anterior lobe is so great that sufficient quantities of extract in-
jected into a test animal will evoke the symptoms of diabetes.

In 1930 P. E. Smith discovered that the anterior lobe of this
vital organ also has an adrenocorticotropic function i.e., that it
produces a hormone which stimulates the functional activity of the
adrenal cortex. This hormone was later isolated and Is known as
ACTH (see below, p. 282). One of its effects, and doubtless the
principal one, is to cause the adrenal cortex to secrete cortisone. A
number of workers investigating the latter substance have reported
that it possesses a diabetogenic capacity. One might therefore sup-
pose that the ability of a pituitary extract to influence carbohydrate
metabolism is actually nothing more than its ability to enlist the
force of the adrenal cortex. There seems to be evidence, however,
that this is not the whole story; and among other points it is par-
ticularly relevant to note here that C. F. and G. T. Cori, who
received the other half of the 1947 Prize, could show a direct in-
fluence of pituitary extract on an important step in the body chem-
istry of carbohydrate an influence reinforced by an extract of the

248 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

adrenal cortex and blocked by insulin. (See below, p. 254.) Hous-
say had already shown that, whatever the mechanism concerned,
the diabetes which results from pituitary injections is due to de-
struction of the insulin-producing cells of the pancreas.

Carbohydrate metabolism is of such enormous importance to the
body's economy that whatever serves to throw light upon it is a
useful contribution. Hope of determining the basic cause of dia-
betes must depend upon increasing knowledge of this exceedingly
complex mechanism. Houssay has demonstrated a link in the cycle.
He has also helped to attract further attention to the importance
of the anterior pituitary, a subject of ever-increasing interest.

CARL R CORI

(1896- )

GERTY T. CORI

(1896- )

*Tor their discovery of how glycogen is catalyti-
cally converted"

(The award for 1947 was shared with B. A. Houssay; see
above, pp. 244-248.)

BIOGRAPHICAL SKETCHES
CARL F, CORI

CARL FERDINAND CORI WAS BORN IN PRAGUE, THEN PART OF
Austria-Hungary, on December 5, 1896. His father was director
of the Marine Biological Station in Trieste, and his maternal

1947 : HOUSSAY, CORI AND CORI 249

grandfather, Ferdinand Lippich, professor of theoretical physics
at the German University of Prague, so that he was early subjected
to influences deriving from both the physical and the biological
sciences. He attended the Gymnasium at Trieste and studied medi-
cine at Prague, where he was graduated in 1920. His wartime
studies were interrupted by service as a lieutenant in the Sanitary
Corps of the Austrian Army on the Italian front. His collaborative
scientific work with Gerty Theresa Cori (nee Radnitz) began
when they were classmates, with a publication on the complement
of human serum. They were married in 1920. At the Universities
of Vienna and Graz, Cori devoted the next two years chiefly to
pharmacology. In 1922 he moved to the United States, becoming
an American citizen in 1928. From 1922 to 1931 he served as
biochemist at the State Institute for the Study of Malignant Dis-
eases in Buffalo, New York. He then joined the faculty of Wash-
ington University Medical School in St. Louis, first as professor of
pharmacology and later as professor of biochemistry. His work has
been centered on enzymes and hormones, particularly in relation
to carbohydrate metabolism.

GERTY T, CORI

GERTY THERESA CORI (NEE RADNITZ) WAS BORN IN PRAGUE,
on August 15, 1896. She was privately tutored until the age of ten,
when she entered a school for girls. In 1914 she enrolled in the
medical school of the German University of Prague, and in 1920
she received her doctorate. In the same year she married her class-
mate, Carl F. Cori, with whom she had already published an
immunological study. After two years at the Carolinen Children's
Hospital in Vienna she joined her husband at the State Institute
for the Study of Malignant Diseases in Buffalo, New York; in
1931 she accompanied him to the Washington University School
of Medicine as research associate, and in 1947 she was appointed
professor of biochemistry. Their joint work has dealt with the
catalytic and hormonal metabolism of the carbohydrates.

250 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE -WINNING
WORK*

"The discovery of polysaccharide phosphorylase and glucose-
i -phosphate [Cori ester] can be traced to systematic work on the
formation of hexose-6-phosphate in muscle. Of particular impor-
tance was the fact that the method used for the determination of
hexose-6-phosphate consisted of two independent measurements,
one based on the reducing power of the compound and the other
on its phosphate content, and that there was generally good agree-
ment between these two measurements. In this manner it was found
that a number of procedures led to an increase In the hexose-6-
phosphate content of muscle, among which may be listed anaerobio-
sis, Injection of epinephrine in intact animals, incubation of
isolated frog muscle in Ringer's solution containing epinephrine,
and gastric stimulation of mammalian or frog muscle.

"Balance experiments during aerobic recovery of previously
stimulated and isolated frog muscle Indicated that the hexose-6-
phosphate which disappeared was in large part reconverted to
glycogen; hence it was made probable that the reaction, glyco-
gen - glucose-6-phosphate, was reversible. The next step was the
finding that the increase in hexose-6-phosphate in Isolated frog
muscle incubated anaerobicaUy with epinephrine was accompa-
nied by a corresponding decrease in inorganic phosphate. . . .
Phosphocreatine and adenosine triphosphate (ATP) remained un-
changed, suggesting that they were not involved In the formation
of iiexose-6-phosphate, but since their regeneration through lactic
acid formation was not excluded, the experiments were repeated
with muscles poisoned with iodoacetate. The results were the same
as with unpoisoned muscle and it was therefore concluded that
hexose-6-phosphate was formed from glycogen by esterification
with inorganic phosphate. . . .

"The following experiments led to the detection and isolation
of glucose- 1 -phosphate. Minced frog muscle was extracted 3 times

* From Carl F. Cori and Gerty T. Cori, "Polysaccharide Phosphorylase," Les Prix
Nobel en 1947, pp. 216-235. The first quotation is from Part I, by Carl F. Cori;
the second is from Part II, by Gerty T. Cori.

1947 : HOUSSAY, CORI AND CORI 251

with 20 volumes of cold distilled water, a procedure which re-
moved most of the acid-soluble phosphates normally present la
muscle, but did not remove glycogen. When the washed residue
was incubated anaerobically at 20 in isotonic phosphate buffer
at pH 7.2, some hexosemonophosphate was formed. On addition
of a catalytic amount of muscle adenylic acid, the formation of
hexosemonophosphate was very markedly increased. When phos-
phate was replaced by isotonic KC1, no ester formation occurred.
The glucose part of the ester could have come only from glycogen,
and the phosphate part only from the added inorganic phosphate,
thus confirming the reaction postulated for intact muscle.

"After short periods of incubation there was much more organic
phosphate present in the hexosemonophosphate fraction than cor-
responded to the reducing power of hexose-6-phosphate. Such a
discrepancy had not been encountered before in analyses of the
hexosemonophosphate fraction, and since the discrepancy became
smaller or disappeared completely after longer periods of incuba-
tion, the formation of a precursor of glucose-6-phosphate was sus-
pected. Short hydrolysis in NH 2 SO 4 at 100 (conditions under
which hexose-6-phosphate is not hydrolyzed) revealed the presence
of a compound which yielded equivalent amounts of fermentable
sugar and inorganic phosphate. . . .

'The new phosphate ester was isolated as the crystalline bracine
salt in a large-scale experiment . . . and identified as glucose- 1-
phosphate.

"When glucose- 1 -phosphate was added to a cell-free frog or
rabbit muscle extract, It was converted rapidly to glucose-6-phos-
phate by an enzyme which was named phosphoglucomutase. It was
due to the leaching out of the mutase that glucose- 1 -phosphate
accumulated in minced frog muscle. Mutase is greatly enhanced
in its activity by magnesium ions. In order to demonstrate the
formation of glucose- 1 -phosphate from glycogen and inorganic
phosphate in muscle extract, it was necessary to remove magnesium
Ions by dialysis. . . . [The chemical properties of the isolated
ester were determined and it was later synthesized.}

"The first clue for a possible reversibility of the reaction, glyco-
gen -f- phosphate -> glucose-i -phosphate, came from the observa-
tion that addition of glucose- 1 -phosphate to a reaction mixture con-

252 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

taining enzyme, glycogen and phosphate was strongly inhibitory,
while glucose-6-phosphate had only a weak inhibitory effect on the
formation of glucose- 1 -phosphate. Further investigation showed
that conditions for reversibility were unfavourable because the con-
centration of glucose- 1 -phosphate could not be maintained, owing
to the activity of phosphoglucomutase. ... It became clear that
a separation of the two enzymes was necessary in order to investi-
gate reversibility. A partial separation was first achieved by adsorp-
tion of phosphorylase on aluminium hydroxide, followed by elu-
tion with disodium phosphate and dialysis to remove inorganic
phosphate. When glucose- 1 -phosphate was added to this enzyme
preparation, inorganic phosphate was set free and a polysaccharide
was formed in equivalent amounts, showing the reversibility of the
reaction. . . . Reversibility could also be demonstrated with phos-
phorylase preparations of heart and brain [and liver}. . . ."

'The protein fraction of a muscle extract, precipitated by less
than 0.5 saturation with (NH 4 ) 2 SO 4 , showed a marked rise in
phosphorylase activity per unit of protein over the unfractionated
starting material. This was however the case only when the enzyme
was catalyzing the reaction toward the right:

Glycogen -j- inorganic phosphate ^ glucose- 1 -phosphate

"When enzyme activity was tested in the opposite direction a
puzzling difficulty was encountered. Activity set in only after a lag
period; refractionation of the enzyme increased this lag period from
minutes to hours and in some preparations completely abolished
the activity toward polysaccharide formation. . . .

"Liver phosphorylase, upon salt fractionation, was found to re-
tain activity toward polysaccharide synthesis. Such preparations
always contained traces of glycogen, while the purified muscle
enzyme was free of glycogen. This observation offered a clue. Addi-
tion of glycogen to the reaction mixture in as low a concentration
as 10 mg. per cent led to immediate activity of muscle phos-
phorylase preparations, seemingly inactive when tested without
glycogen addition. . . . From these observations it followed that
glycogen was needed for the activity of the enzyme in both direc-
tions. . . /'

1947 : HOUSSAY, CORI AND CORI 253

CONSEQUENCES IN THEORY
AND PRACTICE

The chemical changes involved in the contraction and relaxa-
tion of muscle have long been subjected to careful study (cf. the
work of Meyerhof, pp. 106-108 above). It seemed probable that
cyclical changes also occur during periods of rest, a conversion of
energy taking place in the same way but with less intensity. Ever
since the discovery of glycogen, or animal starch, by Claude Ber-
nard, much effort has also been devoted to the study of carbohydrate
metabolism. In the work of the Coris these two avenues of research,
already merging, were brought together. The discoveries of these
workers helped to elucidate specific details of what happens when
glycogen is changed into sugar and vice versa. Tissues such as
muscle and liver contain enzyme systems which bring about the
phosphorylation of both glycogen and glucose. To an understand-
ing of the phosphorylation of glucose, Meyerhof (1927) was the
pioneer contributor with his discovery of "hexokinase," which
later turned out to consist of two enzymes, both present in muscle.
The phosphorylation of glycogen was explained by the Coris on the
basis of a somewhat different mechanism.

As indicated above, they were able to produce from muscle an
ester of hexose-phosphoric acid in which the phosphoric acid was
linked to the sugar near carbon atom i. In the presence of muscle
extract this changed to the 6-ester, the process requiting the pres-
ence of magnesium and of a special enzyme, phosphoglucomutase.
When the latter had been destroyed in the presence of phosphor-
ylase, which causes phosphoric acid to be split off, they were able
to build up glycogen from Cori ester, thus reversing the process;
but, as shown in the brief quotation from Gerty T. Cori's Nobel
lecture, small quantities of glycogen had to be present in order to
bring about the synthesis. The reaction between the Cori ester and
the 6-ester was also shown to be reversible. Two of the Coris*
associates succeeded in converting glucose into a glucose-6-phos-
phoric acid.

The Coris further showed that addition of pituitary gland extract
retarded the synthesis of hexose-6-phospfaate ester, an action

254 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

strengthened by an extract of the adrenal cortex but blocked by
insulin. In this way they were able to throw light on the chemical
mechanism by which the hormones concerned in carbohydrate
metabolism do their work.

1948

PAUL MULLER

(1899- )

f Tor Ms discovery of the high efficacy of DDT as a
contact poison against several arthropods!'

BIOGRAPHICAL SKETCH

PAUL MULLER WAS BORN IN OLTEN, SOLOTHURN CANTON,
Switzerland 5 on January 12, 1899, but lived from the age of four
or five in Basel. There he went to school and, during 1916-1917,
worked in industrial chemical laboratories, an experience which he
considers to have been of great practical value. In 1918 he re-
turned to secondary school, completing the course in 1919. He
then began the academic study of chemistry at the University, ob-
taining his doctorate in 1925, with chemistry as major and physical
chemistry and botany as minors. In the same year he accepted a
position as managing chemist with the dye works of the J. R. Geigy
Company of Basel. There he has worked not only on dyes and
insecticides but also on disinfectants and tanning agents. DDT was
synthesized and its effects discovered in the autumn of 1939, but
the first commercial DDT insecticides did not appear until 1942.
During the Second World War and since, such insecticides have
found world-wide use for a broad range of agricultural and
hygienic purposes.

255

256 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"The composition of important vitamins and hormones, as well
as bacteriostatic substances such as penicillin, streptomycin, etc.,
... has been made clear, and some have since been synthesized.
But despite all these successes, we are still far from knowing how
to predict, with any degree of reliability, what physiological effect
to anticipate from a given composition. . . .

"The relationships are still more difficult in the field of artificial,
and particularly synthetic, insecticides. . . .

"When I began, about 1935, on behalf of my firm, the J. R.
Geigy Company of Basel, to work in the field of insecticides and
especially the insecticides important for agriculture, the situation
looked hopeless. There already existed an immense literature in this
field, and a flood of patents had been taken out. But of the many
patent insecticides there were practically none on the market, and
special experiments indicated that they were not equal in value to
. . . arsenicals, pyrethrum [etc.].

"That gave me the courage to work on. But just the same the
chances were very bad, for only an exceptionally cheap or unusually
effective insecticide could have any prospect of finding applica-
tion in agriculture, yet the demands which must be made on an
insecticide for agriculture are especially severe. ... I reflected
about what my ideal insecticide must be like and what character-
istics it should have. I soon perceived that a contact insecticide
would have a far better chance than a food poison. The character-
istics of this ideal insecticide must be as follows:

"i. Great toxiclty for insects,

"2. Rapid commencement of toxic effect,

"3. Little or no toxicity for warm-blooded animals and plants,

"4. No irritant effect and no smell, or a faint and at any rate not
unpleasant one,

"5. The range of effectiveness should be the greatest possible,
and extend to the largest possible number of arthropods [joint-

* Translated from Paul Miiller, "Dichlordiphenyltrichlorathan. und neuere In-
sektizide," Les Prix Nobel en 1948, pp. 122-132,

I94 8: PAUL MULLER 257

footed invertebrate animals, including crustaceans, insects, centi-
pedes, and arachnoids spiders, scorpions, mites, and ticks],

"6. Long duration of effect i.e., great chemical stability,

"7. Low price = economic use. . . .

"To begin with, at all events, it was a question of finding a sub-
stance with great effect as a contact insecticide. . . . My bio-
logical tests were carried out in a large glass case . . . into which
I shot a fine spray of the substance to be tested in a nonpoisonous
solvent. . . .

"After the fruitless testing of hundreds of different substances,
I realized that it is not easy to find a good contact insecticide. In the
field of science one attains something only through obstinacy and
steadfast work. . . .

"It was known to me from earlier research that compounds with
the group CH 2 C1 . . . often show definite effectiveness. From
work on moth repellents carried out in our firm at this time by
Dr. H. Martin and his co-workers, in which I myself had no share,
it was known to me that compounds with the general formula:

Cl X Cl, X = SO 2 , SO, S, O, etc.

often showed quite considerable effect as food poison for moths.

"In studying the literature I came across an article by Chattaway
and Muir ... in which the formation of diphenyltrichloroethane
is described :

/ \-CH~

CC1 3

I recollected my old research with substances containing the
CH 2 C1 group . . . and I was curious as to what possible influ-
ence the =CC1 3 group would have on the contact-insecticide effect.
"The substance was produced in September 1939 and the test
gave a very considerable contact-insecticide effect on flies. I began
to make derivatives of this basic formula, and, influenced I dare-
say by the results of the work on moth repellents, I synthesized the
pjp'-dichlor-compound :

[DDT]
CC1 3

258 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"This compound, which had already been brought forward by an
Austrian student in the course of his dissertation in 1873, had now
such a strong contact-insecticide effect as I had never observed in
any substance thus far. After a short time my fly chamber was so
much poisoned that after it had apparently been carefully cleansed,
new flies perished from contact with the walls without spraying of
the substance. . . . [This effect persisted for about a month.]

"Other insects were tested later. . . . The new compound was
everywhere effective, although often death first occurred after some
hours or even days. . . . [DDT was found to fulfill all but the
second of Muller's seven desiderata of the ideal insecticide: its
action, although very powerful, is not immediate, and it is therefore
often combined with a "knockdown" such as pyrethrum.}

"Finally the laboratory results were confirmed by field research
. . . and it was found that the effect against Colorado beetles lasts
four to six weeks. . . .

"The DDT insecticides have now been introduced into all pos-
sible spheres of insect control, for example in hygiene, in the safe-
guarding of textiles and provisions, and in the protection of
plants."

CONSEQUENCES IN THEORY
AND PRACTICE

It is hardly necessary to expatiate on the significance of Dr.
Muller's discovery. As shown above, the primary aim was to find a
good agricultural insecticide; this aspect of the success attained is
not without importance, from the nutritional point of view, for
world health. Effectual control of flies has had a more direct bear-
ing on medicine in the reduction of fly-borne diseases. Most dra-
matic of the triumphs of DDT has been its success against typhus.
In October 1943 a typhus epidemic broke out in Naples under
conditions which made control seem impossible. In January 1944,
when sixty new cases were appearing daily, use of DDT was begun
on a large scale for delousing the population. In three weeks
1,300,000 persons were deloused and the outbreak was stopped.
Never before in history had it been possible to check a winter
epidemic of typhus. This experience was repeated in Japan three

1948: PAUL MULLER 259

months after the occupation. Miiller thus provided a corollary of
the greatest importance to the work of the 1928 Nobel laureate,
Charles Nicolle, who discovered that typhus is conveyed by lice
(see above, pp. 130-133). DDT has similarly proved of great
value in preventing malaria and other diseases spread by arthro-
pods. The discovery has also been a stimulus for further work in
synthesizing chemical compounds to control plant and animal
parasites and to destroy the vectors of disease.

REFERENCES

WEST, T. F., AND CAMPBELL, G. A. D.D.T. and Newer Persistent In-
secticides (London, 2nd ed., 1950).

1949

WALTER RUDOLF HESS

(1881- )

ff For Ms discovery of the functional organization

of the interbrain as a coordinator of the activities

of the internal organs."

{The award for 1949 was shared with Egas Moniz; see be-
low, pp. 264-271.)

BIOGRAPHICAL SKETCH

WALTER RUDOLF HESS WAS BORN ON MARCH 17, 1881, IN
Frauenfeld, a town in eastern Switzerland. He was fortunate in his
early training, which combined expeditions into the woods and
fields with elementary instruction in physical science by his father,
who permitted him great freedom in the use of scientific apparatus.
He matriculated in 1900 at the Gymnasium of his native town,
thereupon beginning the study of medicine, which he pursued in
Lausanne, Berne, Berlin, Kiel, and Zurich; his medical doctorate
was granted by the latter university in 1906. Although attracted
to physiology early in his medical course, he turned to ophthalmol-
ogy on graduation and practiced his specialty until 1912. In that
year, although already the father of a family, he gave up a success-
ful practice to devote himself to the study of physiology, principally
in Bonn. In 1917 he was appointed director of the Physiological
Institute in Zurich. Further advanced study, postponed by the First
World War, took him to England, where he came under the in-
fluence of Langley, the great pioneer in the study of the autonomic

260

1949 : HESS AND MONIZ 261

nervous system, Sherrington, Starling, Hopkins, and Dale. His
research was at first directed to hemodynamics (study of the blood
pressure), then to the regulation of breathing, and finally to the
central control of the internal organs in general through the vegeta-
tive, or autonomic, nervous system. He worked out a technique for
applying pin-point electrical stimulation to specific areas in the
brain, using fine electrodes (0.2 mm. in diameter), insulated ex-
cept at their very tips. He could thus produce strictly localized
stimulation and also localized destruction of brain tissue. His in-
vestigations in this field were rewarded by the discoveries for
which he was given the Nobel Prize. In addition to the work under
review, Hess made early contributions to the study of blood
viscosity (1907-1920) and squint (Hess screen, 1911).

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"In contrast with the very extensive . . investigation of the
vegetative [i.e., involuntary or autonomic] nervous system, there
existed relatively limited knowledge of the central organization of
the whole regulating apparatus. ... It had nevertheless become
clear that ... the parts of the brain joined from above directly
to the spinal marrow the medulla oblongata and the portion lying
immediately under the cerebrum, the so-catted interbrain exert a
decisive influence on the vegetative regulations. . . . [Something
was known in this connection of the function of a group of nuclei
at the base of the brain referred to collectively as the hypothala-
mus.} But up to the time the special investigations were started,
what still lay in the dark was the relation of particular functions
to definite morphological substrata. ... To achieve clarity on
this point, so far as possible, was the problem I duly set my-
self. . . .

"The autonomic nervous system is divided into two parts: the
sympathetic, arising from cells in the thoracic and upper lumbar
region of the spinal cord; and the parasympathetic, arising from
cells in the midbrain, the medulla oblongata, and the lower, or

* Translated from W. R. Hess, "Die zentrale Regulation der tatlgkelt innerer
Organe," Les Prix Nobel en 1949* PP- 115-123.

262 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

sacral, region of the spinal cord. There is also evidence that the
sympathetic has a control center in the hypothalamus. The two
divisions of the system have different, and usually opposite, effects
on the organs and vessels they innervate.] Those functions which
are mediated by the sympathetic division of the vegetative nervous
system are related to a part, extending from posterior to middle
... of the hypothalamus. This is therefore to be considered the
central 'source/ so to speak, of the sympathetic. To give complete
physiological meaning to this discovery calls for further explana-
tion. . . . The question has ... arisen whether a circumscribed
effect is associated with the classical sympathetic, denned primarily
by the limitation of its root zone to the thoracic spinal marrow.
.... Where the sympathetic takes effect, it sustains the efficiency
of the body and helps the organism to better success through com-
ing to terms with its environment. It is functional insofar as it
comprises an ergotropic or dynamogenic [i.e., energizing or work-
producing} system. But with this knowledge further experiences
fit in, of particular interest to the psychiatrist, but also to anyone
who is aware that behind the diversity of phenomena stands the
unity of the organism. Stimulations in a circumscribed area of the
ergotropic (dynamogenic) zone regularly induce a distinct change
of mood. Thus a previously good-natured cat becomes angry; she
begins to mew and spit, and on someone's approach she turns to
a well-directed attack. While the pupils widen markedly, and at
the same time the hair stands on end, a picture develops such as the
cat shows when she is attacked by a dog and is unable to elude him.
The widening of the pupils and bristling of the hair are quite com-
prehensible as sympathetic effects; but the same does not hold good
for the change in psychic attitude. . . .

[Space does not permit listing all the various effects produced
by the pin-point electrical stimulation of different centers. When
the electrode is placed a little farther forward than in the experi-
ment just described, a general relaxation of skeletal muscles ensues.
Not far away is another center which when stimulated soon brings
on what appears to be a perfectly natural sleep. From various
sharply limited areas it is possible to influence blood circulation and
breathing, salivation and heat regulation, etc.}

"In each case collective symptoms appear. [Several activities are

1949 : HESS AND MONIZ 263

initiated at the same time, as in the case of the angry cat, to bring
about a coordinated response.] Groups of organs are called into
action, and in such a way that the separate effects are com-
bined. . . ."

CONSEQUENCES IN THEORY
AND PRACTICE

Professor Hess is one of the group of modern investigators (stu-
dents of the nervous system and the endocrine glands) who have
contributed to present knowledge of the integrated action of the
body of the way in which the organism mobilizes its force and
reacts, as a whole, to routine demands made upon it, and especially
to emergencies. The mechanism of the body's reactions, both nerv-
ous and hormonal, to unusual stress is today one of the most actively
cultivated and most promising fields of research.

Since the internal organs, such as the blood vessels, heart, lungs,
and digestive tract, are chiefly controlled by the autonomic nerv-
ous system, it is obviously of prime importance to know as much
about this system as possible. Dr. Hess has greatly extended the
knowledge of the subject contributed by W. H. Gaskell, J. N.
Langley, and others. It is such knowledge which underlies modern
surgery in this field. Sympathectomies (eradications of parts of the
system) have been used in the treatment of angina pectoris, essen-
tial hypertension, certain forms of disease in the blood vessels of
the extremities, and a variety of other conditions. The regulation
of blood pressure to meet the varying demands of the body occa-
sioned by changes in external and internal environment is depend-
ent in large part on sympathetic regulation, and it is known that
injuries, encephalitis, and tumors which damage the central control
areas occasionally cause profound blood-pressure changes. Other
sympathetic effects have also been attributed to such causes.

Current teaching of the functions of the hypothalamus is based
largely on American and British work. The distinctive feature of
Hess's approach to the problem is his use of the intact, unnarcotized
animal. His method is to place steel-needle electrodes in the brain
tinder anesthesia, and to fasten them in place by fixing them to a
frame, which in turn is attached to the skull itself. The actual ex-

264 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

periments in stimulation of brain centers are performed later with-
out anesthesia. In this way the effects both of anesthesia and of
operative trauma are eliminated and the experiments approach
more nearly the ideal physiological condition.

It is likely that these experiments, constituting basic research in
physiology, will assume greater significance as more is learned of
further nerve communications, especially with the higher brain
centers, and as the mechanism of integrated action and the response
to stress are made clearer. Hess himself looks to electroencephalog-
raphy (the study of "brain waves") and to biochemistry to answer
the "where" and "how/' remarking that it is characteristic of
work of this kind to raise new questions.

REFERENCES

MCDONALD, D. A. "W. R. Hess: The Control of the Autonomic
Nervous System by the Hypothalamus," The Lancet, Mar. 17, 1951,
pp. 627-629.

EGAS MONIZ

(1874- )

"For Ms discovery of the therapeutic value of pre-

frontal leucotomy in certain psychoses"

(The award for 1949 -was shared with W. R. Hess; see

above, pp. 260-264.)

BIOGRAPHICAL SKETCH

EGAS MONIZ (ANTONIO CAETANO DE ABREU FREIRE) WAS BORN
at Avanga, Portugal, on November 29, 1874. A student of the
medical faculty of Coimbra, he continued his work there, becom-

HESS ANr> MONIZ 265

ing professor in 1902. In 1911 he became the first occupant of the
new chair of neurology in Lisbon. For many years, partly in col-
laboration with Almeida Lima, he devoted himself to angiography,
the visualization of blood vessels, especially those of the brain,
after the injection into an artery of a substance opaque to X rays.
In this field he was a pioneer, for he obtained the first "arterio-
graph" in man. In 1931 he published a large volume on the diag-
nosis of cerebral tumors by this method. In 1936 appeared the
first memoir on prefrontal leucotomy. He is also the author of
several other volumes on various aspects of medicine, including
clinical neurology, sexual physiology and pathology, and medical
history, and has produced literary and political writings. Dr. Moniz
has taken an active part in the political life of Portugal. He was
deputy in several legislatures from 1903 to 1917, Portuguese Min-
ister in Madrid in 1917, Minister of Foreign Affairs, 1917-1918,
and president of the Portuguese delegation to the Paris Peace
Conference, 1918.

DESCRIPTION OF THE PRIZE- WINNING
WORK*

"It was no sudden inspiration which caused me to work out the
surgical operation which I named 'prefrontal leucotomy.' I already
laid stress on this fact in my first publication in 1936 and also
in my first monograph, which I published in Turin in 1937.

"As an adherent of the doctrine of Ramon y Cajal [see above,
pp. 36-37] and on the basis of the theory regarding the con-
nections of the nerve cells, I turned my attention to the origin of
normal and pathological psychic activity and its dependence on
the neurons. The impulses course along the fibrils through the
neurons. Changes are brought about at the synapses which influ-
ence many other cells.

"I pondered, along with the activity of the brain in normal
psychic life, the changes which are displayed in most psychoses and
which heretofore still had no anatomico-pathological explanation.
I was particularly struck by the fact that the psychic life in some

* Translated from Egas Moniz, "Mela Weg zur Leukotomie," Deutsche medi-
zmhche Wockenscbrift, Vol. 73 (*948), PP- 581-583.

266 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

mental diseases here I thought especially of the compulsive psy-
choses and melancholia is constricted to a very small circle of
thoughts, which master all others, recurring again and again in the
sick brain, and I sought to find an explanation for this.

"JTA section on the general anatomy of the nervous system fol-
lows.] Starting from [the] anatomical facts I came to the conclu-
sion that synapses, which are found in millions of instances, are
the organic foundations of thought. [A synapse is the close ap-
proximation or contact of processes of different nerve cells; it is the
point of functional linkage between one nerve cell and another.]
"The normal psychic life depends on good synaptic function,
and psychic disturbances arise as consequences of synaptic dis-
turbances. . . .

"If the fibrils become sick or the in-between substance suffers a
change . . . the passage of the impulses is more difficult as a
result of the more or less complete interruption of coherence. In
other cases the [terminations] adhere to the cells with abnormal
firmness and the impulses then always take their course along the
same paths and always find their expression in the same psychic
manifestations. I explain in this way the perseverance of the
same morbid thoughts, which constantly reinvade the diseased
psyche. ..."

[The author next discusses the nature of the nerve impulse and
the factors determining the course it takes. He gives a brief ac-
count of Pavlov's work on the conditioned reflex to indicate that
new association pathways may be set up. He also discusses the
anatomy of the pref rontal lobe, defining it for his own purposes as
the region lying in front of the motor area. He points out that its
functions are not definitely localized, as are those of the motor
area.]

"The pref rontal region is closely associated with the psychic
phenomena and has a less autonomous function than the so-called
brain centers. Its activity depends on the enormous number of
synapses of innumerable neurons which are concerned in the forma-
tion of the psychic phenomena.

"The functions of the prefrontal lobe can be established in the
higher mammals experimentally and in man through clinical find-
ings.

1949 : HESS AND MONIZ 267

"The classical experiments of Bechterew and Luzaro are worthy
of mention. They found that after removal of the pref rontal lobe
in dogs the dogs became aggressive, irritable, and impulsive. Their
capacity for adaptation was diminished. These findings were con-
firmed by the experiments of other authors.

"Very valuable are the experiments of Fulton and Jacobsen with
chimpanzees previously trained. They found that a unilateral exci-
sion of the pref rontal areas produced no important change. Bilateral
removal of this region, however, always produced an alteration
in the behavior of the animal. After extensive destruction it be-
came impossible to elicit from the animals the performances of
their old training. . . .

"These facts are in accord with what has been established in
humans. Clinical experience has yielded valuable results for the
solution of this important problem. . . . {Evidence is derived
from injuries, tumors, and surgical removals.}

"A whole frontal lobe, as is well known, can be removed with-
out considerable consequences for the psychic life. This can at
most bring about for the first few days a disorientation for space
and time, which, however, gradually disappears again (Penfield).

"Richard Brickner's case is extremely important. This author
made a detailed psychiatric investigation in a patient from whom
Dandy had to take out important parts of both anterior lobes in
order to remove an extensive meningeoma [a tumor of the mem-
branous envelope of the brain}.

"At first there occurred a loss of knowledge earlier acquired.
But the patient little by little adapted himself again to his environ-
ment, despite clearly existing difficulties: character changes, dimin-
ished intelligence, etc. According to Brickner the patient later
recovered the same personality as before the operation and retained
his 'personality type/

"Prefrontal leucotomy gave still more exact findings regarding
the function of the frontal brain. But that is already history and I
should like to speak now of the time before the operation which
concerns us here was carried out. I should like, so to speak, stand-
ing on this side of the bank, to give an account of the reasons
which induced me to cross the river.

268 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"People who suffer from melancholia and are tormented by un-
happy compulsive ideas, and for whom a medical treatment, a shock
treatment or psychotherapy, is of no use, live in everlasting anguish
on account of a thought, perpetually present, which overtops all
the cares of daily life.

". . . These morbid ideas are deeply rooted in the synaptic
complex which regulates matters of knowledge in the conscious-
ness, stirs these up, and keeps them in constant activity.

"All these considerations led me to the following conclusion:
It is necessary to alter the synaptic arrangements and thus the paths
which are selected by the impulses in their continual course; there-
by the corresponding thoughts are altered and forced into other
channels.

"On these grounds, after two years' deliberation, I determined
to sever the connecting fibers of the neurons in question. In the
conviction that the prefrontal lobes are very important for the
psychic life, I chose this region for my experiment. . . . Through
complete alteration of the existing fiber arrangements, and organ-
ization of other synaptic fiber groups, I believed that I could
transform the synaptic reactions and thereby cure the patient,

"Since my plan was to do away with a large number of associa-
tions, I preferred to attack the cell-connecting fibers of the anterior
parts of both lobes of the frontal brain *en masse/ in order to
obtain positive results. At first alcohol injections were used for the
destruction, later I performed incisions with the leucotome, a
small apparatus designed for this purpose. The white matter of
the brain has only a limited blood supply and the operation ought
on that account to be free from danger. Everything was done with
the greatest care in order to protect the patient's life.

"Permit me to reproduce here a short paragraph from my book
Tentatzves operatoires, which is a cornerstone of my work.

" 'On the eve of my first experiment I had to begin with a justi-
fied anxiety. But all fears were put aside by the hope of obtaining
favorable results. If we were able to do away with certain psychic
symptom-complexes through destruction of the cell-connecting
groups, then we would demonstrate conclusively that the psychic
functions and the regions of the brain which contribute to their

I949 : HESS AND MONIZ 269

manifestation are in close relation to one another. That would be
a great step forward and a fundamental fact for building the
investigation of the psychic functions on an organic basis/

"And this page concluded thus:

" 'We are sure that this operation will produce a strong discus-
sion in medical, psychiatric, philosophic, and other fields. We
expect that, but at the same time we hope that this discussion will
serve the progress of science, and above all that it will be of use to
mentally ill patients/

"So we went to work with our outstanding co-worker, Almeida
Lima, whom we are obliged to thank for a large part of the pioneer
work. The first alcohol injection into the white matter of the pre-
frontal lobe was made on November 12, 1935, and the first opera-
tion with the leucotome was carried out on December 27 of the
same year. We obtained cure and improvement, but no mischance
which would have compelled us to give up our work."

CONSEQUENCES IN THEORY
AND PRACTICE

As the founder of modern psychosurgery, Egas Moniz opened
a new chapter in the surgery of the brain. Sir Victor Horsley
(1857-1916), famous for his work on cerebral localization, had
devised an operation for resecting an area of brain cortex to relieve
convulsive movements of the arm. There had been other operations
of like nature, but concerned, as was Horsley's, with the motor part
of the brain. Aside from these, the great brain surgeons, such as
Harvey Gushing, had been chiefly occupied in operations to mini-
mize the damage of brain injuries, or to remove brain tumors.
Interference with the parts of the brain controlling psychic func-
tions had never been attempted in a rational manner before 1935,
except when these parts were affected by injury or tumor.

Psychosurgery has since undergone great technical evolution.
There are at least six types of operation on the frontal lobe cur-
rently in use for the treatment of mental disorders. These are all,
however, variations on the basic method of Egas Moniz, for the
common feature in all such procedures is the interruption of frontal
lobe fibers.

270 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Dr. Walter Freeman and Dr. James Watts, having performed
a large number of these operations by the lateral approach through
the temple, devised a somewhat simpler procedure, the transorbital
lobotomy, so called because the instrument is inserted through the
eye socket. "Open" operations have also been worked out, involv-
ing greater exposure and aiming at better control through a direct
view of the field; these require removal of a piece of the skull
rather than the mere drilling of a hole. "Selective cortical under-
cutting/* developed by Dr. William B. Scoville, of Yale, implies
a selective local cut where the grey matter of the brain joins the
major white fibers. This is supposed to work as well as the more
radical division of the latter, but to cause fewer side effects.

When psychosurgery is used in a long-standing and badly de-
generated case of schizophrenia, the side effects may hardly be
noticed. In less severe cases they are of great importance and con-
stitute psychosurgery' s principal drawback. Compulsive worries,
morbid thoughts, and terrible anxieties may be abolished or greatly
weakened. It appears that the inevitable price for this relief, at
least when the more radical measures are used, is a certain blunt-
ing of personality. This effect, as Dr. Edward K. Wilk observes,
"reveals itself in the higher realms of creative imagination, fore-
sight, ambition and social sensitivity/* It is for this reason that
psychosurgery remains a last resort in mental cases, to be employed
only when all other treatments have failed.

The results reported for the different operations vary consider-
ably; results also vary in different examples of the same operation.
Broadly speaking it may be said that about one third of psycho-
surgery patients improve sufficiently to go home, one third are
improved but have to be kept in a hospital, and one third show no
improvement

1949 : HESS AND MONIZ 271

REFERENCES

FULTON, J. F. Frontal Lobotomy and Affective Behaviour, A Neuro-
fbysiological Analysis (New York; Norton, 1951).

- , "Surgery of Mental Disorder," McGill Medical Journal, Vol.

17 (1948), pp. 1-13-

GREENBLATT, M., R. ARNOT, AND H. C. SOLOMON, eds. Studies in
Lobotomy (New York: Grune and Stratton, 1950).

"Symposium: A Psychiatric Evaluation of Psychosurgery," Surgery,
Gynecology and Obstetrics, Vol. 92 (1951), pp. 601-617. (A popu-
lar abstract appeared in Time, May 28, 1951, pp. 38-40.)

1950

EDWARD CALVIN KENDALL

(1886- )

PHILIP SHO WALTER HENCH

(1896- )

TADEUS REICHSTEIN

(1897- )

ff For their discoveries concerning the suprarenal
cortex hormones, their structure and biological

effects."

BIOGRAPHICAL SKETCHES

KENDALL

EDWARD CALVIN KENDALL WAS BORN IN SOUTH NORWALK,
Connecticut, on March 8, 1886. His advanced education was pur-
sued at Columbia University, where he received the B.S. degree
in 1908 and the M.S. the following year. He was Goldschmidt
Fellow in 1909-1910, and obtained his Ph.D. in chemistry in
1910. For a short time (1910-1911) he was research chemist with
Parke, Davis and Company in Detroit. From 1911 to 1914 he
worked in St. Luke's Hospital, New York City. Since 1914 he has
been professor of physiological chemistry and head of the Section

272

1950- KENDALL, HENCH AND REICHSTEIN 273

of Biochemistry in the Graduate School at the Mayo Foundation,
Rochester, Minnesota.

In 1914 Kendall was able to isolate the active constituent of
the thyroid hormone, a substance he called thyroxin. Its structure
was determined partly by Kendall, partly by C. R. Harrington;
Harrington and G. Barger were responsible for its definitive syn-
thesis in 1926. Apart from his work in this field, Kendall has
been occupied chiefly with studies of oxidation in the animal
organism, glutathione,* and the isolation and synthesis of hor-
mones of the adrenal cortex.

HENCH

PHILIP SHOWALTER HENCH WAS BORN IN PITTSBURGH,
February 28, 1896. He was graduated (A.B.) from Lafayette Col-
lege in 1916 and took the M.D. in 1920. From 1921 to 1924 he
was fellow at the University of Minnesota. He received the M.S.
degree in 1931. In 1928-1929 he worked in Freiburg and in von
Miiller's Clinic in Munich. At the Mayo Clinic he was first assist-
ant in medicine from 1923 to 1925, associate from 1925 to 1926,
consultant and head of the Section for Rheumatic Diseases from
1926 on. At the Graduate School of the Mayo Foundation he was
instructor in medicine from 1928 to 1932, assistant professor from
1932 to 1935, and associate professor from 1935 to 1947. He has
been professor since 1947. Dr. Hench has devoted the greater part
of his career to the study of rheumatic diseases,

REICHSTEIN

TADEUS REICHSTEIN WAS BORN ON JULY 20, 1897, IN WLOOLA-
wek, Poland. He passed most of his early childhood at Kiev, where
his father worked as an engineer. In 1905 the family moved to
Berlin and later to Zurich, where they settled permanently and
acquired Swiss citizenship in 1914. After private tutoring, Reich-
stein entered the Zurich Oberrealschule (technical school of
junior college grade) and then the Eidgenossische Tedmischc

* An important substance in oxidatioa-reduction, discovered by another Nobel
laureate, F. G. Hopkins. See above, p. 136.

274 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Hochschule (state technical college), where he obtained his first
degree, in chemical engineering, in 1920. After a year in industry
he returned to E.T.H., receiving the doctor's degree in organic
chemistry in 1922. He then worked for some years on an industrial
project, a study of the aromatic substances of roasted coffee. In
1930 he became a part-time instructor at E.T.H., and in 1931 was
appointed Leopold Ruzicka's assistant. His later appointments in
the Department of Organic Chemistry at E.T.H. assistant profes-
sor, 1934, and associate professor, 1937 were followed by his
selection in 1938 as head of the Department of Pharmacology and
director of the Pharmaceutical Institute, University of Basel. Since
1946 he has been head of the Organic Division in the same univer-
sity and director of its organic laboratories. Independently of Sir
Norman Haworth and his associates in Birmingham, Reichstein
succeeded in synthesizing ascorbic acid (vitamin C) in 1933. This
was his best-known work prior to his Nobel Prize investigations
in the chemistry of adrenal cortical hormones.

DESCRIPTION OF THE PRIZE -WINNING

WORK

KENDALL *

"Of the several ductless glands, the adrenal cortex is the last to
yield its secrets to the investigator. The essential work on the pan-
creas was done in a matter of months, and insulin was made avail-
able to clinical medicine within less than a year. It required only
a few years to complete the work on the parathyroid, adrenal
medulla, and the male and female sex hormones, but eighteen years
passed from the time the physiologic activity of the adrenal cortex
was first demonstrated until cortisone was available for use in
clinical medicine. This is a measure of the unprecedented difficul-
ties which had to be surmounted.

"Investigations of the adrenal cortex carried out during the
decade 1930-1940 by Wintersteiner and Pfiffner, Reichstein and

* E. C, Kendall, "Cortisone Its Historic Development and Certain Chemical
and Biochemical Aspects," The Merck Report, Vol. 59, No. 4 (Oct. 1950),
pp. 4-8.

1950: KENDALL, HENCH AND REICHSTEIN 275

his associates, and in my laboratory, resulted in the isolation of no
less than 28 crystalline compounds. Of these only four showed
significant physiologic activity when tested in small animals. These
compounds were designated in my laboratory by the letters A, B,
E, and F. . . .

"No sharp qualitative difference was found between the physi-
ologic activity of these four compounds on adrenalectomized ani-
mals [animals with the adrenal glands removed}, and it was
assumed that any one of them could be used in substitution therapy
for patients with Addison's disease {adrenal insufficiency, usually
due to tuberculosis of the glands}. Unfortunately, the supply of
these four hormones was so limited that it was impossible to carry
out an investigation on the human being. For example, the amount
of compound A which could be isolated from half a ton of adrenal
glands of cattle was equivalent to only one small tablet. The supply
of adrenal glands was necessarily limited to the number of cattle
slaughtered, and the amounts of compounds A, B, E, and F which
could be obtained in the laboratory were, therefore, insignificantly
small.

"The most significant physiologic properties of these compounds
were their strong effect on the metabolism of carbohydrate and
protein, and their rather mild influence on the metabolism of water
and electrolytes. These two types of physiologic activity were clearly
recognized, and were associated with the chemical structure of
these hormones some time before 1940.

"There was speculation that compounds A, B, E> and F would
be of value for substitution or replacement therapy in Addison's
disease, and there was hope that they would be useful in the treat-
ment of shock, traumatic injuries, burns, and some types of infec-
tion; but beyond this there was no projected place for any product
of the adrenal cortex in clinical medicine. The prospect that the
hormones of the adrenal cortex would have but limited application
against disease offered no encouragement toward making these
compounds available in quantity for study in clinical medicine.

"However, World War II provided a great impetus to efforts to
synthesize and produce these hormones on a krge scale. Shortly
before the entry of the United States into World War II, it was
thought that adrenal cortical hormones might be valuable in avia-

276 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

tion medicine and in the treatment of shock and battle fatigue.
There were rumors that Germany was buying the adrenal gland
output of Argentine slaughterhouses, extracting these glands, and
administering the extracts to Luftwaffe pilots. According to these
rumors, the adrenal extracts enabled the pilots to fly and fight at
altitudes of forty thousand feet without difficulty. Though untrue,
the rumors persisted and provided a real stimulus to attempts to
synthesize adrenal cortical hormones.

"In 1941, the National Research Council placed three subjects
at the top of its war agenda, in this order: (i) hormones of the
adrenal cortex, (2) penicillin, and (3) antimalarial agents. And
on December 20, 1941, the National Research Council called a
conference in Washington, D. C, inviting scientific representatives
of the Mayo Clinic, certain universities, and a few industrial organ-
izations * . . to survey possible production of adrenal cortical
hormones.

"It was decided first to attempt to make compound A, n-dehy-
drocorticosterone. This was accomplished in my laboratory in 1944,
and in 1945 Merck & Co., Inc., prepared a large sample by our
method.

"In the first months of 1946 the synthesized product was tested
on laboratory animals and was found to behave exactly as did com-
pound A isolated from the adrenal cortex. It was found to be of
value in protecting them against certain poisons and exposure to
cold, but when given to patients who had Addison's disease it was
found to be of little value. This was a great disappointment and
interest in the hormones of the adrenal cortex sank to a very low
level.

"There was no conclusive evidence that compound E (which we
later named corf is one to avoid confusion with vitamin E) would
be qualitatively different from compound A, and there was, there-
fore, no assurance that large-scale production of compound E, or
cortisone, would be worth while. Nevertheless, Merck & Co., Inc.,
had in the meantime decided to go ahead in an attempt to syn-
thesize this compound. This was ultimately accomplished by Dr. L.
H. Sarett, who, working in the research laboratory of Merck & Co.,
Inc., succeeded in preparing a few milligrams of the compound.

1950: KENDALL, HENCH AND REICHSTEIN 277

The yield was so small, however, that the method used by Dr.
Sarett could not be applied to large-scale production.

"During the following eighteen months important improve-
ments of some of the steps in the preparation of compound A were
devised in my laboratory, and Dr. Sarett discovered an entirely new
procedure to convert a product closely related to compound A, to
compound E, or cortisone. . . . The final yield of cortisone was
thereby raised almost a hundredfold. Further important practical
improvements were introduced, and several new, more productive
steps were devised through the continuing work in my laboratory
and by the staff of development chemists at Merck, under the
leadership of Drs. Max Tishler and Jacob van de Kamp. . . .
[But in April, 1948, when a group of clinicians met to consider the
question} it was feared that compound E would take a place among
discarded drugs, right beside compound A."

HENCH AND KENDALL *

"Since 1929 one of us (P. S. H.) has studied the beneficial
effects of pregnancy and Jaundice on rheumatoid arthritis. Results
of these and other studies led us to the following conclusions. Even
though the pathologic anatomy of rheumatoid arthritis is more or
less irreversible, the pathologic physiology of the disease is poten-
tially reversible, sometimes dramatically so. Within every rheuma-
toid patient corrective forces lie dormant, awaiting proper stimula-
tion. Therefore, the disease is not necessarily a relentless condition
for which no satisfactory method of control should be expected.
The inherent reversibility of rheumatoid arthritis is activated more
effectively by the intercurrence of jaundice or pregnancy than by
any other condition or agent thus known. Regardless of the sup-
posed Validity* of the microbic theory [i.e., the theory that arthritis
is caused by microbes} rheumatoid arthritis can be profoundly in-
fluenced by phenomena which are primarily biochemical.

* Philip S. Hench, Edward C. Kendall, Charles H. Slocumb, and Howard F.
Policy, "The Effect of a Hormone of the Adrenal Cortex (ly-hydroxy-n-dehydio-
cortkosterone: compound E) and of Pituitary Adrenocorticotropic Hormone on
Rheumatoid Arthritis," Proceedings of the Staff Meetings of the Mayo Clinic,
Vol. 24 (1949), pp. 181-197. This is the original "preliminary report."

278 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

"It became increasingly difficult to harmonize the microbic
theory of the origin of rheumatoid arthritis with the phenomenon
of relief of the disease by jaundice or pregnancy. It became easier,
rather, to consider that rheumatoid arthritis may represent, not
a microbic disease, but some basic biochemical disturbance which
is transiently corrected by some incidental biologic change common
to a number of apparently unrelated events. It seemed logical to
suppose that what causes relief of rheumatoid arthritis in preg-
nancy is closely related to, if not identical with, that which relieves
the same disease in jaundice; if so, it could be neither hyperbili-
rubinemia [the presence in the blood of an excessive amount of
bilirubin, a reddish bile pigment found in large amount during
jaundice] nor a unisexual (female) hormone since neither of these
is common to both pregnancy and jaundice. It was believed that
the discovery of some biochemical denominator common to vari-
ous agents or states beneficial in rheumatoid arthritis, but common
especially to jaundice and pregnancy, would provide us with an
improved treatment or control of the disease.

"Finally, it was conjectured that the hypothetic common de-
nominator or "antirheumatic substance X* was not a disintegration
product from a damaged liver, but probably was a biologic com-
pound specific in nature and function, a compound which was
normal to the human organism. But if this was true, we had no
certain clue as to its chemical nature or the organ of its origin.
. . . [There follows an account of the attempts to relieve arthritis
with female hormones, biliary products associated with jaundice,
etc.]

"In time we conjectured that the antirheumatic substance X
might be an adrenal hormone. This conjecture was strengthened
by the knowledge that temporary remissions of rheumatoid arthritis
are frequently induced by procedures which are now known to be
capable of stimulating the adrenal cortices, such as general anesthe-
sia or surgical operation. In 1938 we administered to several rheu-
matoid volunteers lecithin [one of a group of compounds containing
two fatty acid molecules and a molecule each of glycerophosphoric
acid and choline} separated from the adrenal gland, not as an
adrenal product per se, but in an attempt to induce hyperlipemia
[an excessive degree of lipemia, or fat droplets in the blood} such

1950'- KENDALL, HENCH AND REICHSTEIN 279

as may occur in association with pregnancy and jaundice. In Janu-
ary, 1941, we recorded our interest in adrenal cortical fractions
in general and in Kendall* s compound E in particular, and we
used briefly Kendall's cortical extract. But compound E was not
available to us until September, 1948. . . .

"Since the fall of 1948 [this report is dated April 13, 1949}
we have given compound E more or less continuously to 5 rheuma-
toid patients, and for periods of eight to sixty-one days to 9 other
patients; a total of 14 patients. None had mild or moderate disease.
All had 'moderately severe* or 'severe' chronic polyarticular rheu-
matoid arthritis of four and a half months to five years' dura-
tion. . . .

"To provide adequate controls, the intragluteal injection of
compound E [i.e., injection into the buttocks} was in some cases
preceded, and in other cases replaced, by the injection of a fine
aqueous suspension of cholesterol . . . indistinguishable in ap-
pearance from compound E. The times when the control solution
and the adrenal hormone were interchanged were unknown to the
patients and were, for five weeks, unknown even to the three
clinical authors who were evaluating the results. . . . {The dosage
was more or less guesswork at first but fortunately turned out to
be about right from the beginning. Progress was checked not only
by appearance and symptoms but by the sedimentation rate of the
red blood cells and other objective tests.]

"In each of the 14 patients the initial results were as follows.
Within a few days there was marked reduction of stiffness of
muscles and joints, lessening of articular aching or pain on motion
and tenderness, and significant improvement of articular and mus-
cular function. . . . Articular swellings generally diminished,
sometimes fairly rapidly and completely. . . . [Some flexion de-
formities disappeared.}

"Those who found the following maneuvers difficult or impos-
sible often were able within a few days to do them much more
easily or even 'normally*: getting in or out of bed unassisted, rising
from chairs or toilets, shaving, washing the hair or back of the
neck, opening doors with one hand, lifting a cup or book with one
hand, and climbing stairs.

"The appetite often was rapidly improved. Several patients

280 NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

gained weight on routine general diets. . . . Improved strength
was frequently noted. Several patients stressed the loss of the
'toxicity* of the disease and experienced a marked sense of well-
being. . . .

"[On discontinuance of injections} the arthritis returned slowly
in most cases, and rapidly in two . . . and again improved strik-
ingly after use of the hormone was resumed/'

REICHSTEIN *

"Research on the hormones of the adrenal cortex is based on
the following facts:

"a. The adrenals are vital organs; in nearly all animals com-
plete bilateral adrenalectomy leads to death in a few days. Numer-
ous post-operational insufficiency symptoms have been observed,
but there is as yet no agreement as to which constitutes the primary
cause of death.

"b. The vital function is connected with the adrenal cortex, and
appears to operate principally by delivery into the blood of a mix-
ture of substances, since by injection of suitable cortical extracts
adrenalectomized animals can be kept alive and the numerous
insufficiency symptoms prevented or cured.

* V, Investigation of active cortical extracts shows that the activity
can be concentrated in those fractions which contain principally a
mixture of relatively heavily oxygen-substituted steroids. A con-
siderable number (twenty-eight in all . . .) of such steroids have
been isolated as pure crystalline compounds; the structure and con-
figuration of most of these are known in detail, while some have
been prepared by partial synthesis. Some six or seven compounds
have been found to be more or less active according to various
methods of assay, in that they either prolong life in adrenalec-
tomized animals or are able to prevent or cure single insufficiency
symptoms. . . .

{Reichstein and Shoppee then discuss the evaluation of these
methods of assay and the chemical methods of isolation of the com-

* T, Reichstein and C. "W. Shoppee, "The Hormones of the Adrenal Cortex/' in
R. S. Harris and K. V. Thimann, eds., Vitamins and Hormones, Vol. i (New
York: Academic Press, 1943).

1950: KENDALL, HENCH AND REICHSTEIN 281

pounds. There follows a list of the steroids isolated from the
adrenal gland, with the structural formula and the physical, chem-
ical, and biological properties of each, so far as then known. Of
the twenty-eight substances mentioned, Reichstein, alone or with
his associates in Basel, isolated twenty-six, and it was one of his
colleagues who isolated the twenty-seventh. Many of these sub-
stances were also isolated by other scientists working independently
elsewhere, many of them by Kendall and his group. This is true of
the eighth substance on this list, ly-hydroxy-dehydrocorticosterone,
later to be called cortisone.]

"Isolated and described as 'Compound F' by Wintersteiner and
Pfiffner {1936}, isolated and called "Compound F by Kendall
ct al. [1936], isolated and named Substance Fa' by Reichstein
[1936], also isolated by Kuizenga and Cartland {1939}. [Then
follows an account of the physical properties of cortisone, such as
melting point, nature of the crystals, etc., and of the more impor-
tant chemical characteristics. The constitution and configuration had
by this time been worked out, chiefly by Reichstein himself.} The
compound is little active in the test with dogs. ... It also pos-
sesses only slight activity in the survival test in rats. . . . On the
other hand it possesses high activity in those methods of assay
which are related to carbohydrate metabolism. [Half a dozen
workers} demonstrated its diabetogenic [diabetes-producing} ac-
tivity ... in rats and Grattan and Jansen its anti-insulin effect in
mice. Big doses produce glycosuria [sugar in the urine} even in
normal rats. As shown by Thorn et aL, in normal dogs it increases
the excretion of sodium and chloride. . . ."

CONSEQUENCES IN THEORY
AND PRACTICE

As stated by Kendall at the beginning of the first quotation
above, the adrenal cortex long resisted all efforts to probe its
secrets. "Addison's disease/* a chronic insufficiency resulting from
any one of several adrenal lesions but chiefly from tuberculosis,
was first described by Thomas Addison in 1849. Toward the end
of the century and early in the present one, a series of investigations
resulted in the isolation of adrenaline, product of the adrenal

282 NOBEL PJOZE WINNERS IN MEDICINE AND PHYSIOLOGY

medulla; W. B. Cannon then demonstrated the "emergency func-
tion" of this hormone. But no relevance to Addison's disease was
shown and efforts to obtain active extracts from the cortex were at
first unsuccessful. The work of Hartman, Swingle, and Pfiffner
led to the production of "cortin," which was used in the treatment
of Addison patients. This was only the beginning. The extensive
work of Reichstein, Kendall, and many others had by 1943 reached
the point described by the former in his lengthy review, a brief
excerpt from which is given above. Meanwhile the clinical observa-
tions and speculations of Hench had suggested that the cortical
hormones might be of more than theoretical interest. The war-
time speed-up carried the work forward, although progress was
still relatively slow because of the complexity of the chemical prob-
lems involved.

In the preliminary report on the treatment of rheumatoid arthri-
tis, Hench and his colleagues had already recorded their experience
not only with cortisone but also with ACTH, or "adrenocortico-
tropic hormone." This is a product of the anterior lobe of the
so-called "master gland," the pituitary body or hypophysis, situated
at the base of the brain. (This important organ was the chief object
of study of the 1947 Nobel laureate in medicine, B.A. Houssay.
See above, pp. 244-248.) ACTH was found to produce effects
which are in general quite similar to those of cortisone. It acts on
the adrenal cortex, stimulating it to action, and the consequences
are therefore indirect. While Merck and Company were busy with
the production of cortisone, chemists of Armour and Company
were occupied in the extraction of ACTH, following the pioneer
work of Smith, Collip, and others, and likewise stimulated by war-
time pressure.

It is not too much to say that a revolution in medicine was in
preparation. As other scientists and clinicians took up the study of
these compounds, it was found that both agents not only influenced
a few relatively rare endocrine conditions, but might profoundly
alter many diseases which appeared to be nonhormonal and to have
no connection with the pituitary or adrenal gland. Both were shown
to be antirheumatic, first in rheumatoid arthritis and then in acute
rheumatic fever. Beyond this they possess marked anti-allergic
activity and have limited influence on certain blood dyscrasias

1950^ KENDALL, HENCH AND REICHSTEIN 283

i.e., diseased states of the blood with abnormal cells. A variety of
skin conditions, inflammatory diseases of the eye, intestinal dis-
eases such as ulcerative colitis, and even respiratory infections are
greatly improved by the use of these extraordinary drags. But al-
though the symptoms of many diseases may be partly suppressed
or temporarily abolished altogether, the diseases are not "aired."
In pneumonia and tuberculosis, for example, the causative organ-
isms persist. To describe what is known of the way in which the
hormones work, Dr. Hench has borrowed the Churchillian expres-
sion "a riddle wrapped in a mystery inside an enigma." Hench has
also remarked that these agents do not extinguish the fire, but they
provide an asbestos suit in which the patient, like Shadrach,
Meshach, and Abednego, walks unscathed in the furnace. If the
protection is not discarded until the end of the natural duration of
the "fire" the patient remains well. This may almost be taken
literally, as well as figuratively, for a severely burned patient, be-
yond the help of older methods, may sometimes by this means be
kept alive and even reasonably comfortable until the worst danger
is over.

Another comparison which has been suggested in describing the
effects of these hormones is that between disease and an iceberg,
each seven-eighths submerged. Cortisone or ACTH melts away
the visible portion, i.e., the characteristic symptoms of a given
disease which represent a specialized response to a specific form
of stress; the submerged seven-eighths is left unchanged. This con-
cept of a basic pathologic process underlying disease in general
a general response to stress as distinguished from more obvious
special responses is an attempt to explain the wide-ranging action
of these hormones and their function in the organism. It is a subject
to encourage speculation. More important, it encourages further
careful work in clinic and laboratory, and it is probable that corti-
sone and ACTH will find their greatest long-term value as tools of
research.

INDEX

Acetylcholine, 187194
ACTH, 1 8, 247, 282-283
Accommodation, extracapsular, 7172;

intracapsular, 6872
Acromegaly, 245246
Addison, T., 281
Addison's disease, 197, 199, 275, 276

281-282
Adrenal cortex, 197-200, 202, 245,

247-248, 254, 272-283. See also

Cortisone

Adrenaline, 281-282
Adrenocortkotropic hormone, see

ACTH
Adrian, E. D., 155, 159-161, 163164,

193, 224, 227
Agote, L., 146
Almquist, H. J., 220
Altenburg, ,,238
Altmann, R., 66
Anaphylaxis, 7883
Anderson, J. F., 82
Andrus, W. De W., 220
Anemia, pernicious, see Pernicious ane-
mia

Angiography, 265
Anopheles mosquitose, 11-13
Anthrax, 25

Antineuritic vitamin, see Vitamin Bi
Antitoxin, 52-55. See also Diphtheria,

Tetanus

Aortic body, 206-207
d'Arsonval, J. A., 130
Arteriography, 265
Arthritis, 172, 277-280, 282
Arthus, N. M., 81-82, 204
Ascorbic acid, see Vitamin C
Atomic energy, 241
Auerbach, C., 241
Auricular paroxysmal tachycardia, 208

Babkin,B. P., 23
Bacillus pestis, 92-93
Balfour, F. M., 154
Ballot, B., 115

Bamberger, E., 143

Banting, F. G., 109114

Banting Institute, no

Barany, R., 39, 84-87

Barany tests, 87-88

Barger, B., 60, 273

Baron, M., 1 1 1

Bassini, E., 57

Bateson, W., 166

Bayliss, W. M., 21, 191

Bechterew, V. M.V., 267

Behring, E, v., 3-9, 78, 82, 120

Beri-beri, 134, 135, 136-137, 139, 140-

141, 175

Bernard, C., 130, 253
Besredka, A., 83
Best, C. H., 109, in, 114
Bidder, F. H., 21
Bilharziasis, 124
Billroth, T., 57
Bizzozero, G-, 32
Blair, E. A., 227
Blalock, A., 77
Blood groups, 143-147
Blood pressure, regulation of, 205 208,

261, 263

Blood transfusion, 76, 146147
Blunt, T. P., 15, 1 6
Bohr, C., 96
Bolk, L., 87
Bordet, J., 56,90-95
Bordet-Gengou bacillus, 94
Borrel, A. s 124
Botkin, S. P., 20
Bovery, T., 169, i So
Bovet, D., 213

285

286

NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Braun, F., 224
Brickner, R., 267
Bridges, C B., 165,238
Bronk, D.W. 164
Brooks, W.K., 165
Bruce, D., 45, 133
Bruck, C, 95
BuIIoch, W., 52
Burian, R., no
Biirker, K., 102

Cacexia stramipriva, 58-60

Cancer, 38, 39, 60, 66, no, 120-124,

152, 172, 242, 265, 269
Cannon, W. B., 282
Capillaries, anatomy and physiology,

96-100
Capillary electrometer, 116-117, 160,

224
Carbohydrate metabolism, 109-114,

245-253, 275, 281
Carcinoma, see Cancer, Spiroptera car-
cinoma

Carotid body, 206
Carotid sinus, 206208
Carrel, A., 73-77
Carre! Foundation for the Study of

Human Problems, 74
Cartland, G. F., 281
Castle, W.B., 175
Cathode-ray oscillograph, 224-227
Chain, E. B., 230, 233-235
Chain, M., 230
Chemotherapy, 52. See also Sulfona-

mides, Prontosil, Penicillin
Cholera, 154; transmission, 26; cholera

vibrio, 91, 92
Christian, H. A., 173
Clunet, J.,. 124

Coarctatlon, of the aorta, 76-77
Cohn,E.J., 177
Cohoheim, J. F., 51, 176
Colebrook, L. r 213
Collip, J. B., 109, 113, 114, 282
Complement fixation, 90-95
Compound E., see Cortisone
Conditioned reflex, 21, 23, 24
Cori, C. F., 1 08, 248254
Cori, G. T., 1 08, 248-254

Cori ester, 250-253
Cortisone, 18, 247, 272-283
Cotton, T. F., 97
Crafoord, C., 76
Cretinism, see Thyroid gland,

Myxedema
Culex mosquitoes, n
Curling, T. B., 59
Gushing, H., 269
Cyon, E. v., 20
Cytochronie, 152, 201202

Dakin,H,D., 62, 73

Dale, H. H., 97, 186-190, 192, 193
194, 261

Dam, H., 142, 216-220, 222

Dandy, W.E., 267

Darwin, C., 168

Davis, M., 141

DDT, 13, 133, 255-259

Decastello, A.v., 146

Dehelly, G., 74

Dementia paralytica, see General paral-
ysis of the insane

Diabetes, 109-114, 246-248, 281. See
also Carbohydrate metabolism, In-
sulin

Diencephalon, 207, 261-264

Digestion physiology of, 20-24

Diphtheria, 3-9, 55, 78, 120

Dixon, W. E., 191

Doisy, E. A., 217, 220-221

Domagk, G., 209-214

Donders, F. C,, 115

Douglas, S., 49

Downes, A. H., 15, 16

Driesch, H., 183, 184

Du Bois Reymond E., 62, 191

Dudley, H.W., 192

Duke, W. W., 191

Dungern, E. v., 147

Ebbecke, V., 97

Ehriich, P,, 8, 30, 37, 51-56, 90, 94

146, 186
Eijkman C. s 134-137, 140-142
Eijkman's test, 135
Einthoven, W., 115-118
Electrocardiography, 115-118

INDEX

Electrometer, capillary, see Capillary

electrometer
Elliott, T, R., 191
Embden, G., 108
Embryology, 180-185
Epilepsy, 78

Erlanger, J., 160, 164, 193, 223-227
Erysipelas, 125, 127
Erythroblostosis foetlis, 147
Eserine, 189, 190, 192, 194-195
Evans, G. H., 45
Evans, H. M., 247
Ewins, A. J., 187

Fagge, H., 59

Feeding, sham, see Sham feeding

Feldberg, W., 188, 189, 190

Fenn,W. O., 193

Fenwick, S. } 175

Fibiger, J., 120-124

Fieser, L. F., 220

Finsen, N. R., 15-19

Fischer, E., 65, 143, 148

Fleming, A., 229-230, 231-233, 234

Fletcher, W. M., 102, 105, 107

Flexner, A., 224

Florey, H. W., 230-231, 233-235

Foerster, O.H., 213

Forbes, A., 160

Foster, M., 135, 154

Frankel, C, 4

Freeman, W., 270

Frerichs, F. T., 51

Freund, M., 187

Frolich, T. 199, 202

Frontal Lobotomy, 264-271

Fujimaki, A. Y., 124

Fulton, J. F., 267

Fumaric acid, 202

Gaddum, J. H., 188, 189
Galeb, M., 122

Galvanometer, string, 116-117
Gansslen, M., 177
Gaskell, W. H., 154, 263
Gasser, H. S., 160, 164, 193, 223-227
Gegenbaur, C., 180

General paralysis of the insane, 95,
125129

287

Genetics, 156-170, 238-243
Gengou, O., 90-94
Gerard, R.W., 193
Gley, E., 60, 204
G lorn us aortic urn, 206207
Glomus caroticunij 206
Giucose-I-phosphate, see Cori ester
Glutathione, 136, 273
Glycogen, 106, 108, 250-253
Goiter, see Thyroid gland
Goldberger, J., 141
Golgi, C, 32-39, 45, 162
Golgi apparatus, 38
Golgi cells, 33

Golgi stain, 32-33, 3<$ 37, 38, 39
Goltz, F.L., 155
Gorgas, W. C., 14
GrassiG. B., 13
Grijns, G., 140
Gross, R. E., 76

Growth hormone, 245; growth vita-
mins, see Vitamins A and B
Gruber, Max v., 143
Gull, W., 59
Gullstrand, A., 68-72
Guthrie, C. C, 74

Hagedorn, H. C, 114

Haldane, J. S., 150

Hamburger, H. J., 196

Hansen, G. H. A., 27

Harrington, C. R., 60, 273

Hartman, F. A. s 282

Hartree, W., 105

Harvey, W,, 194

Hasselbakh,K.A.,96

Haworth s W. N,, 199-200, 274

Heidenhain, R. P, H., 20, 51

Helmholtz, H. L. F. v., 62, 71

Hench, R S., 273, 277-279, 282

Henle, J., 25, 46

Hericourt, J., 78

Hess, W. R., 207, 260-264

Hexuronic acid, see Vitamin C

Heymans, C., 204-207

Heymans, J. F., 204, 205

Heynsius, A. 115

Hill, A. V., 102-105, 107-108, 193

Hill, L., no

NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

288

Hirszfeld, L., 14?

Hofmeister, K, 187

Hoist, A., 199, 202

Hooper, CW. 5 173, *74

Hopkins, F. G., 102, 105, 107, 134-
136, 138-142, 199, 230, 261

Hoppe-Seyler E. F., 62, 63

Horsley, V., 60, 154-155, 269

Houssay, B. A., 114, 244-248

Howell, W. H., 172, 191, 223

Hunt, R., 188

Huxley J., 238

Hypertension, see Blood pressure, regu-
lation of

Hypophysis, see Pituitary body

Hypotension, see Blood pressure, regu-
lation of

Hypothalamus, 261-264

Hypothyroidism, 60. See also Myx-
edema

Insecticides, see DDT
Insulin, 109-114, 245-248
Interbrain, see Diencephalon

Jacobsen, C. F., 267
Jaundice, 221-222, 277-278
Jeanbrau, E., 146
Jenner, E., 82

Kala-azar, n, 45, 210

Kamp, J. v. d., 277

Karrer, P., 200, 216,220

Keilin,D., 152, 201

Kendall E. C., 60, 197, 199, 272-282

Kibjakow, A. W., 189, 193

Kitasato, S., 7, 78

Klarer, J., 209,211

Klein, E., 10

Klose, A. A., 220

Koch, R,, 3, 25-31, 120, 125, 127, 154

Koch's postulates, 28, 30-31, 45

Kocher T., 57-61

K6lliker,R. A. v., 34,116

Kossel, A., 62-67

Koster, W., 115

Krogh, A., 96-100, 199

Krogh, M., 96

Kubowitz, F., 150
Kiihne, W., 62
Kuizenga, M. H., 281

Lactic acid metabolism, 102, 105-108

Laennec, R. T. H., 29, 130

Laguesse, E., 112

Landsteiner, K., 143-147

Langley, J. N., 102, 154, 186, 260,

263

Laveran, A., 10, 4 X ~45
Lavoisier, A. L., 151
Lea, S., 154

Leishmaniasis, 45. See also Kala-azar
Lepra bacillus, 27
Leucotomy, (pre) frontal, 264-271
Lewis, T., 97, 117
Lewisohn, R., 146
Li, C. H., 247
Light Inistitute, 15
Light treatment, see Phototherapy
Liljestrand, G., 160
Lima, A., 265, 269
Lindbergh, C A., 73, 74
Lindhard, J., 96
Lippich, F., 249
Lister, J., 58, 59

Liver treatment, in anemias, 171-178
Lobotomy, (pre) frontal, 264-271
Lock,R.H.,2 3 8
Loftier, F. A., 4
Loewi, O., 186-194
Loir, A., 130
Lombroso, C., 32
Long, P. H., 213
Lord, J. W., Jr., 220
Lucas, K., 155
Ludwig, C. F., 20
Lundsgaard, E., 108
Lunin, N., 139
Lupus vulgaris, 15-18
Lysozyme, 230, 231

MacCallum, W. G., 13
McCollum, E. V., 141
Macleod, J. J. R., 109-114
MacMunn, C A., 150, 152
Magendie, F., 130

INDEX

Malaria, 10-14, 26, 41-45, 210, 236;
parasites, io s 33, 38, 41-45; thera-
peutic inoculation 125-129

Mansfeld, G., 196

Manson, P.> 10, 13, 14, 13 3, 176

Marie, P., 246

Marine, D., 61

Martin, H., 257

Martin, H. N., 154, 165

Maxcy, K. F., 130

Mendel, J. G., 147, 166, 169

Mendel, L. B., 141

Mendeleev, D. I., 20

Mesnil, F., 45

MetchnikofF, E. 8, 46-50, 90

Meyer, H. H., 204

Meyerhof, O. F., 102-103, 106-108,
193

Miescher, F., 62, 63

Michaelis, L., 196

Mietzsch, F., 209, 211

Minot, G. R., 172-173, 175-177, 178

Moni2, E., 264271

Moore, R. A,, 220

Moreschi, C, 95

Morgan, T. H., 165-170, 238

Morgenroth, J., 56, 146

Mosquitoes, see Anopheles, Culex t
Stegomyia

Moynihan, B., 58

Muller, F. v., 273

Miiller, J., 116

Miiller, P., 133, 255-259

Muller, H. J., 165, 170, 238-243

Murphy, J. B., 74

Murphy, W. P., 173, 177-178

Murray, G. R., 60

Muscle, chemical changes in 106-108,
197, 250-253

Mutations, 1 68; X-ray, 238-243

MyasthemY gravis, 1 94-1 9 5

Myxedema, 59, 60, 126

Navratil, E. s 189

Neisser, A. L. S,, 95

Neisser, M., 95

Neuron theory, 33, 36-39, 265

Nicolle, C, 14, 130-133, 259

Nicolle, M. 3 130

289

Nitti J., 213
Noble, E.G., 113
Noordens, K. v,, 187
Nucleic acids, 62-67
Nucleoproteins, 62-67

Ophthalmology, 68-72
Optics, 68-72
Ord, W. M. t 59
Organizer effect, 180185
Oriental boil, 45
Osborne, T, B., 141

Oscillograph, cathode-ray, see Cathode-
ray oscillograph
Otology, 84-87

Paludism, see Malaria

Pancreas, 20, 21, 111-112

Paracelsus, 59

Paralysis, general, see General paralysis

of the insane
Paresis, see General paralysis of the

insane

Park, W. H,, 8
Parnas, J., 108

Paroxysmal tachycardia, auricular, 208
Paschen, E., 103
Pauly, A., 1 80
Pavlov, L P., 20-24, 15^
Payr, E., 74
Peabody, F. W., 177
Pekelharing, C. A., 1 34
Pellagra, 141, 175, 176
Penfield, W., 267
Penicillin, 229-237
Pepper, W., 176
Pernicious anemia, 67, 171-179
Peters, R. A., 105
Pfeiffer, R., 94
Pfiffner, J. J., 274, 281
Phagocytosis 9 47-50, 212
Phototherapy, 15-19
Physostigmine, see Eserine
Pituitary body, 244-248, 282
Plague, 26; serum, 93
Plasma skimming, 99
Plasmodium, see Malaria parasites
Plater, F., 58
Plaut, F., 95

290

NOBEL PRIZE WINNERS IN MEDICINE AND PHYSIOLOGY

Policy, H. F., 277
Polyneuritis, see Beri-beri
Portier, P., 79, 80
Prefronta! lobotomy, 264-271
Pregl, F., 216
Protosil, 209-213
Proprioceptive system, 156, 162
Proteosoma, 13
Psychosurgery, 264-271
Punnett, R. C., 166

Ramon, G., 8

Ram6n y Cajal, S., 32-34, 36-39, 87,
265

Reed, "W., 14

Reflex, re* Conditioned reflex, Stretch
reflex

Reichstein, T., 273-274, 280-282

Remen, L., 195

Respiration, control of, 205-207

Respiratory enzymes, 148152, 202

Reverdin, J, L,, 59

Rhesus factor, 147

Rheumatic fever, 282

Rheumatoid arthritis, see Arthritis

Richard, G., 80

Richards, A. N., 97

Richet, A., 78

Richet, C., 21, 78-83

Rickets, 1 8

Robscheit-Robbins, F., 174

Robson, J., M., 241

Rockefeller Institute for Medical Re-
search, 73, 74, 143, i?2, 217, 224

Rontgen, W., 180

Rosenau, M. J., 82

Ross, R., 10-14, 45

Ross Institute and Hospital for Tropical
Diseases, n

Roux,E., 4, 132

Roux,W., 183, 184

Ruzicka, L., 274

Sachs, H., 95
Sachs, J., i So
Salmonsen, C. J,, 120
Sarett, L. H., 276-277
Schick, B., 8; Schick test, 8

Schmidt, C, 21

Schoenheimer, R., 216

Schucht, A., 95

Scott, D. A., 114

Scoville, W. B., 270

Scurvy, 202

Sechenov, I. M,, 20

Secretin, 21

Semon, F., 59

Sham feeding, 20, 2223

Shattock, S., 146

Sherrington, C. S., 38, 154-159, 162-

164, 193, 207, 261
Shopee, C.W,, 280
Siebold,CT.E.v., 4 6
Siegfried, M., no
Siade, J. G., 97
Slit-lamp, Gullstrand's, 72
Slocumb, C. H., 277
Smallpox, 15, 19
Smith, J. I., 1 50
Smith, P. E., 247, 282
Smith, T., 14, 133
Soulier, H., 74
Spemann, H., 180-185
Spink, W.W., 213
Spiroptera carcinoma, 120124
Sprue, 175, 176, 222
Starling, E. H., 21, 186, 187, 204, 261
Stegomyia mosquitoes, n
Stevenson, T,, 135
Stewart, G. N., 74
Stretch reflex, 157-159, 163
Strieker, S., 97

String galvanometer, 1 1 6-117
Sturli,A., 146
Sturtevant, A. H., 165, 238
Sulfonamides, 50, 209-214
Sutton, W., 169
Svirbely, J. L, 3 199, 202, 203
Swingle, W.W., 282
Sympathetic nervous system, see Ca-
rotid sinus, Hypothalamus
Syphilis, 126-129, 210, 236
Szent-Gyorgyi A. v., 108, 141, 196-203

Taussig, H. G., 77
Tetanus, 78; antitoxin, 78
Thayer,W. S., 172

INDEX

Thiouracil, 61

Thorn, G. W., 281

Thyroid gland, 57-61, 245, 273

Thyroidectomy, see Thyroid gland

Thyrotoxicosis, 61

Thyroxin, 60, 273

Tishler, M., 277

Transfusion, blood, see Blood trans*

fusion

Trefouei, J., 213
Trevelyan, G. M., 155
Trypanosomiasis, 26, 45, 210
Tschermak, A. v., 196
Tubercle bacillus, 26-31, 121
Tuberculin, 30, 125, 127
Tuberculosis, 3, 25-31, 78, 236
Typhus, 130-133, 258-259

Ultraviolet light, see Phototherapy

Vassale, G. s 60

Villemin, J. A., 26, 29

Virchow, R., 29, 32, 67, 123, 154

Vitamins, 134-142; A and B, 138-140;
Bi, 136-137* *39 140-141; Bis,
178; C, 196-203, 274*, D, 140;
D 2 , 18; K, 142, 216-222

Vogt, O., 239

Vres,H.de, 168,169

291

Wagner- Jauregg, J., 125-129
Waldeyer, W. ? 36, 51
Walker, M.B., 195
Waller, A. D.,n6
Warburg, E., 148
Warburg, O., 103, 148-153, 201
Wassermann, A. v., 95
Wassermann reaction, 95
Watts, J., 270
Weichselbaum, A., 143

Welch, W. H., 172

Whipple, G. H., 171-172, 173~*75
176

Whitby, L., 213

Widmark, J., 15

Wieland, H., 201-202

Wiener, A. S., 147

Wiggers, C F., 204

Wilk, E. K., 270

Winkler, C, 134

Wintersteiner, O., 274, 281

Wright, A., 49, 229-230

Wright-Fleming Institute, 229

X-rays, 124, 238-243, 265
Yersin, A., 4

Zinsser,H., 130
Zotterman, Y., 160,164

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