The Nobel Prize in Chemistry 2004
How my love of biology evolved to become a career
Towards graduation from high school I had to make a decision. The regular track would have taken me, like most Israelis, to national compulsory service in the Israeli Defense Forces, IDF, a duty we were all eager to fulfill. In addition to the regular service, the army encourages certain high school graduates to postpone their service and first obtain a university education, particularly in areas that are relevant to the military, such as medicine and different disciplines in engineering and sciences. Lacking any financial support, I thought it would be better to acquire a practical profession I could make a living from as soon as I could. As I mentioned, medicine emerged as a compromise between the complexity and mysteries of biological mechanisms to what I thought are the already well founded physics and chemistry. Not less important, medicine has traditionally been the ultimate in “Jewish” professions, the dream of every Jewish mother and family. What also attracted me to medicine is that I was under the impression that diseases can be cured: as children, we may have been influenced by short, self-limiting diseases that affected us, like influenza and measles, and were not directly aware of the major killers that left physicians and scientists alike helpless (much like these days), such as malignancies, vascular diseases and neuro-degenerative disorders: I had not appreciated at the time how far more descriptive medicine is, much more than biology. Practically and not less important (which helped solve my dilemma), was the fact that biology was not an option in this military-supported service postponement program. Last but not least, it was a practical choice, a profession one can make a living on. So, after a fierce competition I was accepted into the only medical school in Israel at that time, that of the Hebrew University and “Hadassah” in Jerusalem (1965). The first four years (1965-1969) were exciting. We studied basic and clinical sciences, and I started to seriously entertain the idea of broadening my knowledge base in biochemistry or pharmacology. Towards the end of the 4th year, once we started to examine patients, serious doubts had begun to arise whether I made the right choice and truly want to become a practicing physician. The imbalance between phenomenology and pathogenetic mechanisms of diseases on one hand, and the lack of any mechanism-based treatment for most of the major killers on the other hand, made me seriously think that I was on the wrong trail. I felt restless and started to realize how little we know, how descriptive is our understanding of disease mechanisms and pathology, and as a consequence how most treatments are symptomatic in nature rather then causative. The statement “with God’s help” that I heard so frequently from patients that were praying for cure and health, took on a real meaning. I had a feeling clinical medicine was going to bore me, and decided to take one year off in order to “taste” true and “wet” basic research. The Faculty of Medicine had a special, one year program for the few who elected to broaden their knowledge in basic research, and I decided to major in biochemistry. I had to convince my brother that this was the right thing to do, as I needed his help to further postpone my military service by one year. This was not easy, as he too had a “dream” – to see me independent with a profession from which I could make a living, and which in the traditional Jewish spirit was nothing else but practical medicine. Following our parents’ death, he felt he was responsible for my future and well being, and wanted to see me professionally and financially independent as soon as he could. I nevertheless managed to convince him, and during that year (1969-1970), under the guidance of excellent biochemists, Jacob Bar-Tana and Benjamin Shapira, I investigated mechanisms of CCl4-induced fatty liver in a rat model, and discovered that it may be caused, at least partially, by an increased activity of phosphatidic acid phosphatase, a key enzyme involved in di- and triglycerides biosynthesis. Completing this research year (and obtaining a M.Sc. degree), I knew I had found a new love – biochemistry. Jacob and Benjamin walked me through the exciting maze of biochemical pathways, and I was mystified. Yet, the consummation was still far away. Being loyal to the promise I made to my brother, and also to my commitment to the Israeli army, I completed the clinical years (1970-1972) and graduated from Medical School.
To obtain my medical license, I still had to complete one additional year of rotating internship. At that time, colleagues told me that a young talented biochemist, Dr. Avram Hershko, had just completed his post-doctoral training with Gordon Tomkins at the University of California in San Francisco (UCSF) and was recruited by the Dean and founder of the newly established Faculty of Medicine at the Technion in Haifa, the late Professor David Ehrlich, to establish a Unit of Biochemistry. I wrote to Avram, with the intention to relocate to Haifa, to carry out my rotating internship there, and to use this year to complete my M.D. research thesis under his supervision. This was a small thesis I had to submit to the Medical School in partial fulfillment of the requirements for graduation. Typically for this thesis, most medical students are evaluating statistically on-going treatments/procedures, but I decided to return to the laboratory and touch on yet another research project in biochemistry. Avram agreed to accept me as an M.D. research student, and in October 1972 we started our more than three decades voyage. Avram was still not certain about his own main research direction, and we discussed two possibilities for my M.D. thesis. One was obviously to further dissect the tyrosine aminotransferase (TAT) ATP-dependent proteolytic pathway: Avram started his own trip into the world of intracellular proteolysis with Gordon and discovered that the degradation of the gluconeogenetic enzyme TAT in cells requires energy. This was a corroboration of earlier findings of Simpson who demonstrated in the early 1950s that the degradation of the entire population of cellular proteins in liver slices requires energy. Yet, the mechanism(s) of this thermodynamically paradoxical requirement had remained elusive. The other possibility was to study the mechanism(s) involved in the cell’s “pleiotropic response” – the immediate response of serum-starved, G0 synchronized cells to the addition of serum. During his post-doctoral studies with Gordon, Avram found that among the many stimulated processes that follow the addition of serum, are rapid uptake of nucleotides, amino acids, and phosphate. As during my studies on fatty liver I acquired experience in analyzing lipids, and since Avram felt the elucidation of the TAT proteolytic mechanism may be a too difficult undertaking for a limited-in-scope M.D. thesis, we decided to add one additional layer to the study on the “pleiotropic response” and to analyze the effect of serum on synthesis of phospholipids. We assumed that following serum addition, cell membranes undergo major changes that will be reflected in phospholipid metabolism. Indeed, a few minutes after serum addition, we were able to detect a dramatic increase in the turnover of the phospho-inositol moiety on the diglycerol skeleton. A review of the literature revealed a similar effect in different target cells in response to a broad array of stimuli, including parasympathetic secretory cells responding to acetylcholine and thyroid gland cells to their cognate hormones, thyrotropin (TSH). The year (1972-1973) I spent in the laboratory (it was not a real year but rather moon lighting, as a significant part of the time I was busy in the hospital, rotating among the different clinical departments, completing my internship and duties towards graduation. I worked in the laboratory in my free evenings, nights, weekends and holidays) finally convinced me to pursue a career in Biochemistry. But I still had three years of military service ahead of me (1973-1976)