|
I
was born in Wilno, Poland on November 30, 1926, being of Polish, Austro-Hungarian,
French and Swedish ancestry. My father, a professional soldier trained
in the military academies of Vienna, Austria and St. Cyr, France, had
to leave his family when the Second World War broke out to fight with
the Allied Forces. My life and outlook were influenced by the harsh childhood
which I spent in the Nazi-occupied Eastern Europe, but I was fortunate
to survive the holocaust while living among the Jewish-Polish Community
in Roumania. I used to speak Polish, Roumanian, Yiddish, Italian and some
German and Russian, but I have almost completely forgotten them, and my
French in which I used to excel is also now far from fluent. In 1945,
I moved via Italy and France to England and Scotland. In spite of post-war
economic and nutritional austerity, the United Kingdom seemed like a paradise
to me because of the respect for human rights. Since that time, I have
always had a profound friendship for the British. I received my high school
diploma in Scotland in 1946 and afterwards studied chemistry in London.
I adored English and Scottish association football and I even tried out
as an inside forward for some English and Scottish football clubs, but
since I could not devote enough time to training I never made regular
First Division teams. However, since 1946 I have always stayed in excellent
physical shape by swimming daily and practicing other sports. "Mens sana
in corpore sano" has always truly been my motto. In England I also developed
a great liking for classical music, especially
Beethoven,
Brahms and
Liszt.
My interest in medical research started at the age of 23, when I joined
the National Institute of Medical Research (NIMR, MRC) Mill Hill, London,
England. I was fortunate to work with and be exposed to the stimulating
influences of such scientists as Dr. D. F. Elliott, Sir Charles Harington,
Dr. R.R. Porter, Dr. A.J.P. Martin, Dr. R. Pitt-Rivers, Dr. J. Gross,
Dr. T. S. Work, Dr. H. Fraenkel-Conrat, and Dr. W. Cornforth, several
of whom later won Nobel Prizes for chemistry or physiology and medicine.
Although my position was very junior at Mill Hill, my work was appreciated
and this was a source of tremendous satisfaction for me, inasmuch as this
recognition came from scientists of such caliber. I learned much in those
2 1/2 years, not only technical expertise but also the philosophy of research
and a systematic approach to scientific investigations. These years of
instruction (1950-1952) were decisive in providing inspiration, training,
and laboratory discipline and profoundly influenced the course of my career.
In fact, it was at NIMR, Mill Hill where I endured my "baptism of fire"
in medical research and became addicted to it. In May, 1952, I moved to
Montreal, Canada where I was given the opportunity to work and study at
McGill University. There I learned endocrinology from the brilliant lectures
by Professor D. L. Thomson and from my work with Dr. M. Saffran in the
laboratory of experimental therapeutics of the Allan Memorial Institute
of Psychiatry headed by Dr. R. A. Cleghorn. The work at this laboratory
was devoted to ACTH and adrenal cortical steroids. That period marked
the beginning of my interest in the relationship between brain function
and endocrine activity, and it was there in 1954 that my involvement in
the hypothalamic field began.
In 1955, using in vitro systems, Dr. M. Saffran and I demonstrated the
presence of corticotropin releasing factor (CRF) in hypothalamic and neurohypophysial
tissue. This was the first experimental proof of the existence of hypothalamic
hormones regulating pituitary function postulated with prophetic insight
by Dr. G. W. Harris. I obtained my doctorate at McGill University in May,
1957, and in September of the same year I was able to secure a position
which enabled me to continue my work on CRF at Baylor University College
of Medicine in Houston, Texas, where I was associated with Dr. R. Guillemin.
My years in Houston (1957-1962) where I was Assistant Professor of Physiology
and a Senior Research Fellow of the U.S. Public Health Service were discouraging
and frustrating because of problems with the isolation of CRF. Our failure
to obtain enough CRF to determine its structure tended to cast doubt on
the initial findings. We encountered much skepticism, but I remained unshaken
in my confidence in the correctness of the observations on CRF and in
the postulation of other hypothalamic hormones regulating anterior pituitary
function.
In 1961 I spent about one month at the Institute of Biochemistry in Uppsala
with Dr. J. Porath where I gained useful experience in the use of Sephadex
and column electrophoresis. I also visited Dr. V. Mutt and the late Professor
E. Jorpes in Stockholm, in connection with our collaboration on gastrointestinal
hormones, and I was encouraged that they and other astute scientists had
confidence in our work and the foresight to appreciate the possible scientific
and medical importance of hypothalamic hormones.
I was grateful for the opportunities I was given in the United States,
for which I felt a complete allegiance, and in 1962 became a naturalized
citizen. When Dr. Joe Meyer, then head of the Veterans Administration
(VA) basic research, offered in June, 1962, to set up a VA laboratory
devoted to research on the hypothalamus and make me its chief, I accepted
since this gave me a clear opportunity to be in complete command of such
an effort. The support of a number of individuals, including Dr. E. H.
Bresler, then Associate Chief of Staff for Research of the New Orleans
VA Hospital, Dr. C. Y. Bowers and Dr. G. Burch of the Department of Medicine
of Tulane University School of Medicine, and Dr. W. Locke of the Ochsner
Foundation Hospital, was instrumental in helping me establish the laboratory
in New Orleans. In December of 1962, I was appointed Chief of the Endocrine
and Polypeptide Laboratories at the VA Hospital in New Orleans and Associate
Professor of Medicine at Tulane University, and, in 1966, Professor. The
earliest members of our 1962 VA-Tulane team were T. W. Redding, W. H.
Carter, and M. Tanaka. They have stayed with me all these years, and without
their devoted help we could not have resolved the many problems associated
with our work on TRH in 1969, LH-RH in 1971, and porcine somatostatin
in 1975. Working in a clinical environment, I became more aware of the
need for better diagnosis and treatment of patients than I had been before.
It occurred to me early that problems with infertility on the one hand
and the necessity for population control on the other would make a breakthrough
in the control of reproduction particularly desirable from the standpoint
of society, and therefore I became especially interested in reproductive
endocrinology. To broaden our knowledge of reproductive processes at the
brain level, we studied the central effects of contraceptive steroids
and clomiphene. In some of the early studies on LH-RH, before its isolation,
we collaborated with one of the pioneers of the hypothalamus and the man
I always admired deeply, Professor C. H. (Tom) Sawyer and also with Drs.
J. Hilliard, D. Holtkamp, A. Parlow and W. F. White.
It was my good fortune that in 1964 Dr. A. J. Kastin and in 1965 Dr. A.
Arimura came to join our laboratory. Dr. Abba Kastin was mainly interested
in continuing his work on control of release of MSH and in helping us
in clinical work on hypothalamic hormones. He quickly became my best friend
and a most efficient collaborator. Dr. Akira Arimura was an experienced
physiologist and endocrinologist. Because of his great knowledge, enthusiasm
and very hard work, he made great contributions in all phases of our program,
and also broadened it with many independent ideas, especially in immunology.
Other excellent collaborators at that time included Drs. I. Ishida, A.
Kuroshima, T. Saito, and S. Sawano from Japan, and Dr. E. E. Muller from
Italy.
All during the period
since 1962, I had been hard at work on TRH with Cy Bowers and Tom Redding.
In 1966, we reported for the first time the isolation of porcine TRH and
determined that it contained three amino acids (glutamic acid, histidine,
and proline) in equimolar ratio, but did not take full advantage of this
original early finding, as we were preoccupied with parallel studies on
reproduction and growth hormone-releasing hormone (GH-RH). However, when
R. Burgus and R. Guillemin announced at the 1969 Tucson, Arizona, conference
that they also found the same three amino acids in ovine TRH, I realized
that we had the right substance. The same year I established the correct
amino acid sequence of porcine TRH with Dr. R. M. G. Nair in New Orleans.
Subsequently, with help from Drs. F. Enzmann and J. Boler working in K.
Folkers laboratory in Austin, Texas, we were able to determine the structure
of porcine TRH and synthesize it. We have shared the credit with R. Burgus,
W. Vale and R. Guillemin, who elucidated the structure of ovine TRH at
about the same time.
The identification of TRH removed the skepticism surrounding the work
on the hypothalamus and I realized that many workers would now be attracted
to the field. We therefore redoubled our efforts on LH-RH.
In 1965, in Mexico City, I met Dr. C. Gual of the National Institute of
Nutrition who invited me to collaborate with him in the clinical testing
of hypothalamic hormones in Mexico. We took advantage of this invitation
and in 1968 demonstrated, with Cy Bowers, that preparations of natural
TRH are active in humans. Subsequently, again in collaboration with Carlos
Gual, Abba Kastin and I established that highly purified porcine LH-RH
unequivocally released LH and FSH in men and women under a variety of
conditions. It was clear that LH-RH might be useful clinically and this
encouraged us to continue the agonizing effort involved in the isolation
of this hormone. Although I consider myself an endocrinologist or neuroendocrinologist,
with considerable interest in clinical endocrine research and not a biochemist,
I personally carried out the isolation work on TRH, LH-RH, somatostatin,
and other hormones. Only a person such as myself with strong faith in
the presence of these materials would have the patience to go through
the many fastidious steps of the isolation procedure, since the effort
required in isolating exceedingly small quantities of gradually purer
and purer materials from a crude hypothalamic exctract is so enormous.
I was able to isolate a small amount (800 µg) of LH-RH from 160,000 hypothalami
and proved it to be a polypeptide. This tiny amount of material was passed
to our chemists, Dr. H. Matsuo and Dr. Y. Baba, with suggestions for a
structural approach. Since I did not think that amounts of LH-RH on hand
would be enough to complete our structural work, I decided to isolate
additional amounts of LH-RH. Drs. Matsuo and Baba worked hard and efficiently,
and we were able to determine the complete structure of LH-RH with the
800 µg material. After confirming the structure by synthesis, we were
in a position to present our findings at the Endocrine Society meeting
in San Francisco, California, in June 1971. It was one of the high points
in my life to be able to report for the first time the solution to the
problem which had preoccupied me and others for so long.
Physiological and subsequently immunological studies with natural and
synthetic LH-RH in our laboratory by Drs. A. Arimura, L. Debeljuk, J.
Reeves and M. Saito, and with others demonstrated that LH-RH was indeed
the physiological hormone. With the synthetic LH-RH readily available,
Dr. Kastin and I continued to carry out a variety of clinical studies
in Mexico in association with Dr. Gual and later with Drs. A. Zarate and
D. Gonzalez-Barcena. I also did parallel clinical tests with Dr. J. Zanartu
in Chile and in Argentina with Drs. L. Schwarzstein, N. Aparicio, and
the late R. Mancini.
The importance of analogs, particularly with respect to the possibility
of developing a new birth control method was uppermost in my mind. I was
very fortunate in being able to induce Dr. D. H. Coy, a superb peptide
chemist and his wife Esther, also a researcher, to join our laboratory
in 1972. More than 300 analogs of LH-RH were synthesized by the Coys with
the help of Drs. Y. Hirotsu, K. Nikolics and J. Seprodi in our laboratory
between 1972 and 1977. We were particularly interested in stimulatory
long-acting superactive analogs for clinical use and in inhibitory analogs
which would block LH and FSH release. We were joined in this important
work by researchers from many countries. The work of Drs. J. Vilchez from
Venezuela, A. de la Cruz from Peru, E. Pedroza from Colombia, and N. Nishi
from Japan established in 1976 that the antagonists of LH-RH can indeed
completely block ovulation in animals. Very recently with Dr. D. Gonzalez-Barcena
in Mexico we showed that these analogs are also active in humans. This
of course raises the possibility that such analogs could eventually form
the basis of a new birth control method. However, much work is still needed
to make my dream of being able to control reproduction at the central
level come true.
In 1971, immediately after solving the LH-RH problem, I decided to reinforce
our attacks on PIF and GH-RF next, but six years of hard work with Dr.
A. Arimura and Drs. J. Sandow from Germany, A. Dupont from Canada and
J. Takahara from Japan resulted only in a demonstration that hypothalamic
catecholamines and gamma-amino butyric acid (GABA) may be involved in
the control of release of prolactin, but did not yet lead to the development
of any clinical agents. In our preoccupation with PIF and GH-RH, we did
not work on factors inhibiting growth hormone release but after P. Brazeau
and collaborators in 1973 announced the isolation and structure of ovine
somatostatin, we purified this hormone from porcine hypothalami, determined
its structure and synthesized it. We also carried out much physiological
and immunological work (some in collaboration with Dr. F. Labrie in Quebec,
Canada), as well as clinical work which convinced us of its importance.
Particularly important was the establishment of a radioimmunoassay for
somatostatin by Dr. Arimura. The clinical work on somatostatin was carried
out mainly in England. Brilliant clinicians Professor R. Hall from the
Royal Victoria Infirmary in Newcastle-upon-Tyne and Professor G. M. Besser
of St. Bartholomew's Hospital in London were our leaders of two clinical
teams which also included excellent collaborators such as Drs. A. Gomez-Pan,
D. Evered, C. Mortimer, S. R. Bloom, and others. These clinical studies
in England (based in part on some of our suggestions) showed that somatostatin
inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Basic
studies carried out in England in collaboration Dr. A. Gomez-Pan and in
Poland with Professor S. Konturek showed that somatostatin also inhibits
gastric acid and pepsin secretion, and the release of duodenal hormones,
secretin and cholecystokinin. Since the immunological work of Dr. Arimura
showed the presence of somatostatin in the pancreas, stomach and intestine,
we then suggested that this substance may be involved in the control of
secretion not only of the pituitary, but also of the pancreas, stomach
and duodenum. Since somatostatin has multiple short-lived effects, Drs.
D. H. Coy and C. Meyers are achieving considerable success in the synthesis
of long-acting and selective analogs of somatostatin, some of which could
be more practical clinical agents.
Also among our present
projects is the isolation of all the compounds with PIF activity, of PRH,
GH-RH, CRF, and other hypothalamic substances. In addition to authoring
or co-authoring many publications, I take satisfaction from the fact that
I helped Dr. W. Locke write a book for clinical endocrinologists.
Since much work with hypothalamic hormones and their analogs is being
carried out in Latin America and Spain, my ability to communicate in Spanish
and Portuguese has aided me greatly, and resulted in the formation of
many beautiful friendships. However, the greatest reward for learning
Spanish and Portuguese came when, in 1974, in the course of my work in
Brazil I met a very charming endocrinologist, Ana Maria de Medeiros-Comaru
(M.D.). Our friendship soon deepened into love and led to our marriage.
I have had the satisfaction
that my work in the hypothalamus was honored by top U.S., Canadian and
Spanish awards: Van Meter Prize of the American Thyroid Association; Ayerst-Squibb
Award of the U.S. Endocrine Society; William S. Middleton Award, the highest
award of the VA; Charles Mickle Award of the University of Toronto; Gairdner
Foundation International Award, Canada; Edward T. Tyler Award; Borden
Award of the Association of American Medical Colleges; Albert Lasker Basic
Medical Research Award, and the Laude Award, Spain. In 1973 I was made
a Senior Medical Investigator by the Veterans Administration, an honor
reserved for only a few. When I learned about my Nobel Prize, I was too
grateful and too moved to be overcome with joy, but that came a few hours
later when my friends from all over the world began to phone or wire.
However, I do not feel that these prizes will have an adverse effect on
my future productivity. I am still as keen as ever to make new discoveries
and useful contributions to endocrinology.
From Les Prix Nobel
1977.
|