The Nobel Prize in Physiology or Medicine 1994
Alfred G. Gilman, Martin Rodbell
I was born on December 1, 1925 in
Baltimore, Maryland where I attended public schools and graduated
from the accelerated course at Baltimore City
College, a public high school of special note because it took
selected students from around the city. An all boys school, it
resembled a private college preparatory school in both its
scholastic standards and by giving sufficient college courses to
qualify after graduation to enter the second year of a
university. Special attention was given to languages (Latin,
Greek, German, French); the sciences were understated. In fact,
the only class in chemistry was given by a teacher who seemed to
know Lavoisier personally since he was given the highest status
in that course. As a result, my interests tended toward
languages, especially French, which greatly influenced my
direction when I entered Johns Hopkins University in 1943. On the other hand,
I had acquired a great interest in chemistry despite the high
school teacher. That interest was acquired through a special
boyhood friendship with two individuals from my neighborhood. We
were gifted students, highly competitive, and interested in math
and chemistry. The three of us shared these interests throughout
our boyhood and were together from elementary school to Johns
Hopkins. We separated during the war when each of us went into
different wartime situations. I was drafted into the Navy, the
other two stayed at universities under the auspices of Uncle Sam,
the expression used for those taken in the armed services.
I happily went into the armed services from Hopkins. I was bored with the courses given during wartime; most of the young, enthusiastic teachers had left for the services. More importantly for me, most of my friends had gone to war. As a Jew, fighting Hitler was the highest priority. However, in the Navy I spent most of the time in the South Pacific where the fighting was with the Japanese. I was a radio operator attached to the Marine Corps until I contracted malaria in the jungles of the Philippines. After recovering, I practiced my profession on several ships and traveled, as a result, to Korea and China. I mention this aspect of my life because my interactions with so many different types of people under trying conditions provided me with a healthy respect for the human condition. In fact, this experience buttressed the wonderful childhood atmosphere that I experienced in my home and in my neighborhood where my father's grocery store served as a focal point for contact between people in the area. I believe all of these experiences conditioned me for the life I have led as a scientist.
When I returned from the war and re-entered Johns Hopkins, I was again attracted to French literature and became an avid reader of contemporary French writers, particularly Gide and those promoting the existentialist philosophy. My father was interested in my going to medical school. Pre-medical school was not at all interesting to me in part because of the intense competition among students for obtaining the highest grades, so necessary at the time to enter medical school. The turning point for me was a small class given by James Ebert, then a graduate student in the Biology department. Lengthy discourses on science philosophy and his deep interest and knowledge of embryology along with his enthusiasm for biology in general probably were the principal inducements for me to consider a career in the biological sciences. Moreover, the Biology department was filled with great professors like Bentley Glass and Vincent Dethier. When graduation time came, I went to Dr. Glass for advice. He told me to enter the field of Biochemistry. Not having taken advanced chemistry courses, I spent an extra year taking every advanced course in chemistry available at Hopkins. I knew at the end of that year that science was my forte.
I met my future wife, Barbara Ledermann, in 1949. She had come to America from Holland where she survived the war in the Dutch underground. Her sister and parents disappeared in the ovens of Auschwitz. During the war she learned photography and maintained her training as a ballet dancer. She had come to Baltimore and by chance was given a part in Moliere's "School for Wives" in a production by the Johns Hopkins "Barnstormers". In a short time she had acquired a number of friends interested in theater, art, and music. I had never met so many interesting people. Given my proclivity for literature and my somewhat limited experience in classical piano, the scene that unfolded was overwhelming. I knew she would be the perfect companion. We married in 1950. Not only had I entered the world of Science, my life now became intensely immersed in the Arts.
Having disappointed my father with my choice to become a scientist I gave him another shock by departing with Barbara for the U. of Washington in Seattle. Hans Neurath had just taken the chair of Biochemistry. The department was young with only a few graduate students and youthful professors (Ed Krebs, Don Hanahan, Frank Huennekens, among others). I chose Hanahan as my thesis advisor and became immersed in lipid chemistry, particularly in the metabolism of phospholipids. I learned from Hanahan how to assay for the actions of phospholipases in ether solution. Not realized at the time, my life as a biochemist was to be immersed in membranes. My thesis concerned the biosynthesis of lecithin in the rat liver. Unfortunately for me, Eugene Kennedy was working on the same subject and succeeded in demonstrating that CTP rather than ATP is responsible for the biosynthetic pathway. That experience taught me a good lesson; never rely on the purity of biological chemicals, as I had done. That lesson helped greatly in the later discovery of the role of GTP in signal transduction.
I received my Ph.D. in Biochemistry in 1954. We immediately left Seattle for Urbana, Illinois where I became a post-doctoral fellow under Dr. Herbert E. Carter, then chairman of the department of Chemistry at the U. of Illinois. It was a wonderful place to be at that time, not only because of the great chemists in the department but also because the department of Microbiology had such notables as Gunsalus, Luria and Spiegelman who enlivened seminars with their egocentric views and vivid arguments about everything. I took on the research problem of the biosynthesis of chloramphenicol, an antibiotic of note that interested Dr. Carter. The molecule contained a nitro group appended to its benzene ring and two chlorides in the aliphatic side chain. My interest was how inorganic chloride was taken up into the side chain. I had some good ideas toward the second and final year after spending a great deal of effort trying to crush the mycelia into cell-free extracts. Finally it came down to the understanding that chloride was taken up into an activated (radical?) carbon at the two position of acetylacetate derived from the metabolism of phenylalanine! That problem was ultimately solved. The challenge was exciting, it was time to move on. Dr. Carter asked me at what university would I wish to teach. I replied: none. I had experienced teaching his lecture courses for the first year students: few of the students passed my exams. Devastated I decided never to teach. I chose research as my metier. Dr. Anfinsen at the National Heart Institute accepted me for a position in his laboratory to work on "clearing factor". By the time I arrived, Dr. Edward Korn (an old and dear friend at NIH) had established clearing factor as lipoprotein lipase, an enzyme that hydrolyzed the triglycerides in chylomicrons, the principle form of fat circulating in the bloodstream. Using emulsions of coconut oil as substrate, the enzyme required the presence of serum lipoproteins. My interest was to discern the nature of the lipoproteins on the surface of chylomicrons. Fortunately for me, Dr. Donald Frederickson and other scientists in the Heart Institute had extensive experience with serum lipoproteins; he and scientists at the Rockefeller Institute in New York supplied me with copious quantities of human chylomicrons. Using a newly developed "fingerprinting" method I established that at least five different proteins (designated alphabetically as A,B,C..etc) were present. Years later these five proteins proved to have very significant roles in diseases involving lipoproteins. For me, this was a fine exercise in protein chemistry that I had gained from Neurath's department combined with my invaluable experience with phospholipids.
In 1960 I reached the conclusion that I wanted to return to my initial interest in cell biology: embryology. Fortunately I was granted a fellowship in Professor Jean Brachet's department at the Free University of Brussels. A delightful man of great erudition and wit, Brachet was my perfect opening into the culture of Europe. I learned many new techniques; especially useful was an ultrathin x-ray film process to record localization of tritium-labeled molecules in cells. My family, meanwhile, lived in the Hague, enjoying the remaining family of Barbara: the Citroens of which Paul Citroen was a great Dutch painter. Traveling to and fro by train between Brussels and the Hague proved too much after 6 months. Luckily I found a suitable laboratory in Leiden, headed by Dr. Peter Gaillard, a pioneer in the techniques of cell culturing. In that lab I acquired expert training in the use of cultured heart cells for discerning the uptake of tritium-labeled chylomicrons. The year in Belgium and Holland, however, proved to be most important because of the cultural impact of European civilization on my life. I have been wedded to Europe since then.
On returning to the States I found myself in the Institute of Arthritis and Metabolic Diseases headed by DeWitt Stetten who gave me a position in the Laboratory of Nutrition and Endocrinology. With my experience in cell culturing, I became interested in discerning whether lipoprotein lipase was synthesized and released from fat cells. Korn had already established that the enzyme was present in adipose tissue. After months of trying several means of disrupting adipose tissue, I discovered that collagenase (actually an impure preparation containing many proteases) rapidly digested the tissue matrix, releasing the fat cells. Since fat cells floated to the surface of the incubation medium, it proved a simple matter to separate and purify these cells from the mostly vascular cells in adipose tissue. Little did I realize that this simple procedure was to change the course of research and the rest of my scientific career!
Dr. Bernardo Houssay, the great physiologist and Nobelist from Argentina was visiting the laboratory (one of his post-doctoral students was Robert Scow, section head of my lab) and learned of my feat. However, he questioned whether the cells were metabolically viable and said I must demonstrate to him that the cells were susceptible to insulin action. A few days later I showed him the results of insulin action on glucose utilization. He was ecstatic and proclaimed that this would be a landmark in the history of endocrinology. I was nonplussed but heartened by his enthusiasm. Insulin action, particularly its site of action on the cell, became a driving force. Testing the effects of my old favorites, phospholipases, I found that they mimicked the effects of the hormone on glucose utilization and protein synthesis. I had considered their actions to be restricted to the surface membrane. These results suggested that insulin may act by stimulating phospholipases thereby altering the structure of the surface membrane. As importantly, these data provided indirect evidence that the insulin receptor is located on the surface of fat cells. Prompted by teachings of Dr. Robert Williams of the department of Medicine at the U. of Washington, I decided to pursue this research by gently removing the fat from the cell while retaining many of the structural and metabolic aspects of the cell. This preparation I termed fat cell "ghosts". Importantly, they were responsive to a variety of hormones in terms of their actions on glucose utilization.
In the mid-sixties, Earl Sutherland gave a lecture on his "second-messenger" theory of hormone action in which cyclic AMP was demonstrated to be a product of the actions of a variety of hormones on adenyl (adenylate, adenylyl) cyclase. I believe his lecture had a great impact on a number of us at NIH. Certainly, it caused me to turn to the "cyclic AMP" paradigm. Until that time I worked in the lab with Ann Butler Jones as technician. In 1967, just prior to embarking on a sabbatical in Geneva, we were joined by Lutz Birnbaumer. He proved to be a prime source for the next two years of the important information that led ultimately to the concept of transducers and the principles of signal transduction that I projected in lectures and in writings. News of our investigations rapidly spread. When I returned from Geneva, Michiel Krans and Stephen L. Pohl joined in our efforts with fat cell ghosts and later with rat liver membranes.
Meanwhile I had been asked by Albert E. Renold, a great endocrinologist and a noble man, to take over his Institut de Biochimie Clinique in Geneva while he was going on sabbatical in the laboratory of Robert Williams. That was the beginning of my long love affair with the city of Geneva and my many friends and colleagues there. Later I was to be Professor in the Laboratory of Biochemistry at the University (1981-83) where I carried out research on the structure/function of glucagon. During the period 1967-68, I carried out very interesting research on the effects of hormones on ion and amino acid translocations in fat cell ghosts with Torben Clausen who was serving a post-doctoral period from the U. of Aarhus in Denmark. We both learned from that experience that hormones originally thought to act monotheistically actually are pleiotropic agents; i.e., they can do many different things by separate routes. Certainly in my mind, endocrinology was no longer just a science; it was imbued with existentialism!
There is no point in recounting the story of the discovery of the role of GTP and magnesium ions in hormone action. That story evolved in our lab with many contributors over the past two decades of harmonious and exciting times. Looking back it was a period in which my life experiences had kaleidoscoped into a wonderful sense of creativity shared with not only my immediate colleagues but with scientists from all over the world. My life as a scientist has been joyful in large part because of my wife and our four children (Paul, Suzanne, Andrew, and Phillip) who succored me during those long days and nights of intense thought and often of frustration when ideas were scarce. In many respects, my career and my experiences with people and events have been seamless in that I cannot separate one from another. Without doubt, the thread of one's life should be within the matrix of the total human experience.
From Les Prix Nobel. The Nobel Prizes 1994, Editor Tore Frängsmyr, [Nobel Foundation], Stockholm, 1995
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.
Martin Rodbell died on December 7, 1998.
Copyright © The Nobel Foundation 1994
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