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Our New President: Kurt Julius Isselbacher
KURT
J.
!SSELBACHER,
2
M .D .
GASTROENTEROLOGY® Official Publication of the American Gastroenterological Association @CoPYRIGHT 1974 THE WILLIAMS
Vol. 67
&
WILKINS Co.
July 1974
Number 1
OUR NEW PRESIDENT: KURT JULIUS ISSELBACHER It is a distinct pleasure for me to describe to the membership of the American Gastroenterological Association the milestones in the professional career of Dr. Kurt Isselbacher. I do so, however, with some trepidation for it is difficult to chronicle the prodigious accomplishments of this man adequately, and also to characterize fully his stellar intellectual qualities, continuous pursuit of excellence, outstanding leadership abilities, and humor. Kurt Isselbacher was born in Wirges, Germany, on September 12, 1925. He attended Harvard College from 1944 to 1946 and was elected to Phi Beta Kappa. He received his medical degree cum laude from Harvard Medical School in 1950, and, in addition, was elected to Alpha Omega Alpha. From 1950 to 1953, he served on the Department of Medicine house staff at the Massachusetts General Hospital. Kurt then worked for 3 years (1953 to 1956) at the National Institutes of Health where he received excellent basic training in biochemistry, working primarily with Dr. Herman Kalckar. While an embryonic investigator at the National Institutes of Health, Kurt made two outstanding contributions. First, he helped elucidate and describe the biochemical reactions whereby the important corticosteroids, such as cortisone, are metabolized in the liver. Second, Kurt, along with Dr. Kalckar , recognized and described the specific enzyme defect in the heredity disorder, galactosemia. These observations resulted in the development of an enzymatic assay for detecting the disease in newborns . In 1957, at the age of 32, Kurt was appointed Chief of the Gastrointestinal Unit at the Massachusetts General Hospi-
tal, although he had little formal training in gastroenterology. This was an appointment that understandably surprised a lot of people. However, Dr. Walter Bauer, then Chairman of the Department of Medicine at the Massachusetts General Hospital , clearly recognized that Kurt Isselbacher had that unique talent to translate basic biochemical techniques to relevant clinical problems, and that he would also develop into an outstanding clinical gastroenterologist as a result of "on the job training." What follows is a resume of the events of the next 17 years. Hopefully, some of the flavor and excitement of the activities of the Massachusetts General Hospital Gastrointestinal Unit will be evident. From 1958 to approximately 1962, Kurt carried out additional studies on the glucuronide conjugating system and partially purified the important enzyme, glucuronyl transferase. His prior researc h on steroids led him to discover and isolate another bilirubin derivative, namely bilirubin sulfate. He observed that this metabolite is normally excreted in bile, and the enzymatic synthesis of bilirubin sulfate was achieved in his laboratory. It is not generally recognized that Kurt's laboratory was one of the first to provide evidence that the interesting disorder, Whipple's disease, may well be an infectious disease. In work done with Alan Cohen and published in 1960, electron-microscopic studies were carried out on intestinal mucosal biopsy specimens obtairied . from a patient with Whipple's disease. These studies revealed macrophages in the intestinal mucosa which contained numberous "bacillary bodies" with a structure similar to that of bacteria . This finding has s ubsequently 3
4
KURTJ. ISSELBACHER: NEW PRESIDENT
been confirmed in several other laboratones. In the early 1960's, along with Dr. Senior, Kurt made major contributions in elucidating the biochemical steps involved in the intestinal absorption of fat. These investigators demonstrated that lipid esterification is a required step in the transport of fatty acids across the intestinal mucosa. Furthermore, the important role of monoglycerides in fat absorption and the major enzymatic steps involved in the formation of mono- and diglycerides were identified and characterized. In the middle to late 1960's, a number of additional fundamental studies on the mechanisms involved in intestinal transport of lipids and lipoproteins were carried out in association with Drs. Sabesin, Greenberger, and Ockner. First, it was demonstrated that agents which inhibit protein synthesis , such as puromycin and cycloheximide, result in impaired lipid transport. These studies had important clinical implications, and, in addition, served as a model to study the interesting hereditary disorder, abetalipoproteinemia . Second, a series of studies compared the transport of short and medium chain fatty acids and of long chain fatty acids across the intestinal mucosa. These studies provided a sound physiological basis upon which medium chain triglycerides became established therapy in the treatment of malabsorptive disorders. Subsequent studies with Dr. Ockner provided new insights into the role of the intestine in synthesis of very low density lipoproteins. Also during the mid 1960's the structure and function of the intestinal brush border and microvillous membrane was further defined in collaboration with Drs. Forstner, Sabesin, and Alpers . In the middle 1960's, fundamental observations were made which have clarified the pathogenesis of two hereditary disorders, namely, abetalipoproteinemia and isovaleric acidemia. After the initial observation that compounds which inhibit protein synthesis result in impaired fat absorption, Kurt formulated the key concept that a basic defect in abetalipoproteinemia is defective lipid transport, which, in turn, is
Vol. 67, No . I
the result of impaired synthesis of I)-lipoproteins in the liver and gut. This concept explained many of the metabolic abnormalities in this disorder, namely, accumulation of lipid within the gut, fatty infiltration of the liver, and low values for both serum cholesterol and serum triglycerides. Another example of his unique ability to ask the important questions is reflected in the discovery of the metabolic disorder, isovaleric acidemia. I recall vividly the day Kurt called me to the emergency ward to see two children who presented with the puzzling history of recurrent episodes of acidosis, coma, and a peculiar odor. The odor was that of a "sweaty foot smell," and imparted to the examining room the odor of a locker room . The children were then seen in consultation by some industrial chemists who indicated that the odor was typical of short chain fatty acids. Kurt intuitively concluded that there must be a defect in amino acid metabolism with accumulation of an unnatural precursor. This latter compound was thought to be responsible for the clinical syndrome. With characteristic thoroughness, the putative compound, isovaleric acid, was identified by gas-liquid chromatography and found to be an intermediate product in the metabolism of leucine. Next, the missing enzyme, isovaleryl CoA dehydrogenase, which catalyzes the decarboxylation of isovaleric acid, was identified by an assay using white blood cells. Finally, loading studies with leucine caused a marked increase in blood levels of isovaleric acid and reproduced the clinical syndrome. Thus, in relatively short order, the complete story on a new inborn error of leucine metabolism was unfolded. Important studies in the early to mid1960's also included work on the pathogenesis of the alcohol-induced fatty liver, pathogenesis of alcohol-induced hyperlipidemia, and metabolic aspects of liver injury . Working with Dr. Alpers, the mechanism of carbon tetrachloride-induced liver injury was further defined. In the late 1960's and 1970's, working with Dr. Walker, fundamental studies were carried out concerning the uptake of macromolecules by the neonatal and adult
July 1974
KURT J. ISSELBACHER: NEW PRESIDENT
intestine. These studies demonstrated that significant uptake of macromolecules does occur in the neonatal period, and that such uptake may result in immunological responses. These studies have shed some light on the effect of physiological mac romolecules, such as enterotoxin, on the gut mucosa. From 1970 to 1971, Kurt took a long overdue sabbatical leave. Working in the laboratories of M. G. P. Stoker, at the Imperial Cancer Research Fund Laboratories in Lincoln Inn Field, London, as an American Cancer Society and Eleanor Roosevelt Fellow, he completed a very important study. Animal cells were virally transformed in tissue culture into malignant cells, and it was demonstrated that these malignant cells transport sugar and amino acids at a greater rate than comparable nontransformed cells. This observation has immense potential for additional inquiry into the nature of malignancy. More recently, Kurt has produced similar results with cells of rat liver and chick embryo, while other investigators have made comparable observations. Although the obvious question posed by these studies, as to "which is' cart and which is horse ," has not been settled, the important implication is that there may be an oncogenic mechanism that changes the characteristics of the cell membrane to permit inordinate influx of nutrients. The key question as to whether this influx sets off the cycle of cell division and unregulated growth remains to be answered. To recapitulate briefly, Kurt Isselbacher has made outstanding contributions in several areas including steroid metabolism , galactose metabolism, bilirubin metabolism, alcohol-induced fatty liver, intestinal lipid transport, gut structure and function, metabolic disorders , such as abetalipoproteinemia and isovaleric acidemia, and growth characteristics of neoplastic cells. Mastery of these many fields has resulted in a truly prodigious research output of some 210 publications. Kurt 's outstanding research accomplishments have resulted in his election to membership in a large number of learned
5
societies. These include: The National Academy of Sciences, The American Academy of Arts and Sciences, The American Society for Clinical Investigation (in which he served as Vice-President in 1967) , The American Gastroenterological Association, The Interurban Clinical Club, The Society for Experimental Biology and Medicine, The American Society of Biological Chemists, The Association of American Physicians, and The Biophysical Society. He has been a member of the editorial boards of several journals including Medicine, Gastroenterology, The Journal of Clinical Investigation, Disease-a-Month, and is a co-editor of Harrison's Principles of Internal Medicine. He has been a member of the Council of the American Society for Clinical Investigation, The Association of American Physicians, and President of The American Association for the Study of Liver Diseases. In addition to all of these assignments, he has served as Chairman of the Committee on Research at the Massachusetts General Hospital, Chairman of the Harvard University Cancer Committee, and Chairman of the Executive Committee of the Departments of Medicine at Harvard Medical School since 1968. He is currently Mallinckrodt Professor of Medicine at the Harvard Medical School. Another index of Kurt Isselbacher's important contribution to American gastroenterology is the large number of his trainees that have remained in academic medicine. Limitations of space will not permit a complete listing of the trainees, but the following list is representative: Holt, Senior, Scheig, Forstner, Greenberger, Rodgers, Plotkin, Budd, Sabesin, Alpers, Ockner, Franks, Tanaka, Koff, Alpert, Walker, Grand, Heizer, Glickman, and Goldfinger. In addition, several outstanding gastroenterologists have returned to academic careers outside the United States, and a partial list would include Dawson, Saunders, Datta , M<:Manus , Douglas, Thompson, and Mcintyre . If my calculations are correct, Kurt has trained eight individuals who are now, or have been, directors of a division of gastroenterology, and two individuals who are
6
KURT J. ISSELBACHER: NEW PRESIDENT
chairmen of departments of medicine. Kurt 's outstanding accomplishments in research have obscured the fact that he is a fine clinical gastroenterologist as well as a superb teacher. One is continually impressed with his ability to dissect complex clinical problems into readily soluble components. His keen diagnostic insights and sympathy to his patient's problems are obvious. His spontaneous discussions of clinical problems are characterized by a lucid and incisive flow of information that reflect his broad fund of biomedical information. His formal presentations are a model of clarity and brilliant exposition. That Kurt Isselbacher has accomplished so much is due, in large part, to a number of very special personal qualities. His calm exterior belies a quiet intensity and a compulsiveness for excellence, as well as an insistence that all his publications and presentations, both formal and informal, bear the stamp of excellence and quality.
Vol. 67, No . 1
He is a meticulously organized individual who spends an inordinate amount of time immersed in his work. He can do this because he has a seemingly unlimited capacity for continuous hard work. Anyone who has had much contact with Kurt also appreciates that he has a wry sense of humor and that he is a scholar both inside and outside the sphere of medicine. He takes great pride in the nonmedical accomplishments of his wife Rhoda and their four children. In summary, the new President of the American Gastroenterological Association is a truly outstanding individual. He has been a prodigious investigator mastering many fields, an accomplished teacher, a fihe clinical gastroenterologist, and a highly effective administrator and organizer. The American Gastroenterological Association is indeed fortunate to have Kurt J. Isselbacher as its new President. NORTON J. GREENBERGER, M.D.
J.
!SSELBACHER,
2
M .D .
GASTROENTEROLOGY® Official Publication of the American Gastroenterological Association @CoPYRIGHT 1974 THE WILLIAMS
Vol. 67
&
WILKINS Co.
July 1974
Number 1
OUR NEW PRESIDENT: KURT JULIUS ISSELBACHER It is a distinct pleasure for me to describe to the membership of the American Gastroenterological Association the milestones in the professional career of Dr. Kurt Isselbacher. I do so, however, with some trepidation for it is difficult to chronicle the prodigious accomplishments of this man adequately, and also to characterize fully his stellar intellectual qualities, continuous pursuit of excellence, outstanding leadership abilities, and humor. Kurt Isselbacher was born in Wirges, Germany, on September 12, 1925. He attended Harvard College from 1944 to 1946 and was elected to Phi Beta Kappa. He received his medical degree cum laude from Harvard Medical School in 1950, and, in addition, was elected to Alpha Omega Alpha. From 1950 to 1953, he served on the Department of Medicine house staff at the Massachusetts General Hospital. Kurt then worked for 3 years (1953 to 1956) at the National Institutes of Health where he received excellent basic training in biochemistry, working primarily with Dr. Herman Kalckar. While an embryonic investigator at the National Institutes of Health, Kurt made two outstanding contributions. First, he helped elucidate and describe the biochemical reactions whereby the important corticosteroids, such as cortisone, are metabolized in the liver. Second, Kurt, along with Dr. Kalckar , recognized and described the specific enzyme defect in the heredity disorder, galactosemia. These observations resulted in the development of an enzymatic assay for detecting the disease in newborns . In 1957, at the age of 32, Kurt was appointed Chief of the Gastrointestinal Unit at the Massachusetts General Hospi-
tal, although he had little formal training in gastroenterology. This was an appointment that understandably surprised a lot of people. However, Dr. Walter Bauer, then Chairman of the Department of Medicine at the Massachusetts General Hospital , clearly recognized that Kurt Isselbacher had that unique talent to translate basic biochemical techniques to relevant clinical problems, and that he would also develop into an outstanding clinical gastroenterologist as a result of "on the job training." What follows is a resume of the events of the next 17 years. Hopefully, some of the flavor and excitement of the activities of the Massachusetts General Hospital Gastrointestinal Unit will be evident. From 1958 to approximately 1962, Kurt carried out additional studies on the glucuronide conjugating system and partially purified the important enzyme, glucuronyl transferase. His prior researc h on steroids led him to discover and isolate another bilirubin derivative, namely bilirubin sulfate. He observed that this metabolite is normally excreted in bile, and the enzymatic synthesis of bilirubin sulfate was achieved in his laboratory. It is not generally recognized that Kurt's laboratory was one of the first to provide evidence that the interesting disorder, Whipple's disease, may well be an infectious disease. In work done with Alan Cohen and published in 1960, electron-microscopic studies were carried out on intestinal mucosal biopsy specimens obtairied . from a patient with Whipple's disease. These studies revealed macrophages in the intestinal mucosa which contained numberous "bacillary bodies" with a structure similar to that of bacteria . This finding has s ubsequently 3
4
KURTJ. ISSELBACHER: NEW PRESIDENT
been confirmed in several other laboratones. In the early 1960's, along with Dr. Senior, Kurt made major contributions in elucidating the biochemical steps involved in the intestinal absorption of fat. These investigators demonstrated that lipid esterification is a required step in the transport of fatty acids across the intestinal mucosa. Furthermore, the important role of monoglycerides in fat absorption and the major enzymatic steps involved in the formation of mono- and diglycerides were identified and characterized. In the middle to late 1960's, a number of additional fundamental studies on the mechanisms involved in intestinal transport of lipids and lipoproteins were carried out in association with Drs. Sabesin, Greenberger, and Ockner. First, it was demonstrated that agents which inhibit protein synthesis , such as puromycin and cycloheximide, result in impaired lipid transport. These studies had important clinical implications, and, in addition, served as a model to study the interesting hereditary disorder, abetalipoproteinemia . Second, a series of studies compared the transport of short and medium chain fatty acids and of long chain fatty acids across the intestinal mucosa. These studies provided a sound physiological basis upon which medium chain triglycerides became established therapy in the treatment of malabsorptive disorders. Subsequent studies with Dr. Ockner provided new insights into the role of the intestine in synthesis of very low density lipoproteins. Also during the mid 1960's the structure and function of the intestinal brush border and microvillous membrane was further defined in collaboration with Drs. Forstner, Sabesin, and Alpers . In the middle 1960's, fundamental observations were made which have clarified the pathogenesis of two hereditary disorders, namely, abetalipoproteinemia and isovaleric acidemia. After the initial observation that compounds which inhibit protein synthesis result in impaired fat absorption, Kurt formulated the key concept that a basic defect in abetalipoproteinemia is defective lipid transport, which, in turn, is
Vol. 67, No . I
the result of impaired synthesis of I)-lipoproteins in the liver and gut. This concept explained many of the metabolic abnormalities in this disorder, namely, accumulation of lipid within the gut, fatty infiltration of the liver, and low values for both serum cholesterol and serum triglycerides. Another example of his unique ability to ask the important questions is reflected in the discovery of the metabolic disorder, isovaleric acidemia. I recall vividly the day Kurt called me to the emergency ward to see two children who presented with the puzzling history of recurrent episodes of acidosis, coma, and a peculiar odor. The odor was that of a "sweaty foot smell," and imparted to the examining room the odor of a locker room . The children were then seen in consultation by some industrial chemists who indicated that the odor was typical of short chain fatty acids. Kurt intuitively concluded that there must be a defect in amino acid metabolism with accumulation of an unnatural precursor. This latter compound was thought to be responsible for the clinical syndrome. With characteristic thoroughness, the putative compound, isovaleric acid, was identified by gas-liquid chromatography and found to be an intermediate product in the metabolism of leucine. Next, the missing enzyme, isovaleryl CoA dehydrogenase, which catalyzes the decarboxylation of isovaleric acid, was identified by an assay using white blood cells. Finally, loading studies with leucine caused a marked increase in blood levels of isovaleric acid and reproduced the clinical syndrome. Thus, in relatively short order, the complete story on a new inborn error of leucine metabolism was unfolded. Important studies in the early to mid1960's also included work on the pathogenesis of the alcohol-induced fatty liver, pathogenesis of alcohol-induced hyperlipidemia, and metabolic aspects of liver injury . Working with Dr. Alpers, the mechanism of carbon tetrachloride-induced liver injury was further defined. In the late 1960's and 1970's, working with Dr. Walker, fundamental studies were carried out concerning the uptake of macromolecules by the neonatal and adult
July 1974
KURT J. ISSELBACHER: NEW PRESIDENT
intestine. These studies demonstrated that significant uptake of macromolecules does occur in the neonatal period, and that such uptake may result in immunological responses. These studies have shed some light on the effect of physiological mac romolecules, such as enterotoxin, on the gut mucosa. From 1970 to 1971, Kurt took a long overdue sabbatical leave. Working in the laboratories of M. G. P. Stoker, at the Imperial Cancer Research Fund Laboratories in Lincoln Inn Field, London, as an American Cancer Society and Eleanor Roosevelt Fellow, he completed a very important study. Animal cells were virally transformed in tissue culture into malignant cells, and it was demonstrated that these malignant cells transport sugar and amino acids at a greater rate than comparable nontransformed cells. This observation has immense potential for additional inquiry into the nature of malignancy. More recently, Kurt has produced similar results with cells of rat liver and chick embryo, while other investigators have made comparable observations. Although the obvious question posed by these studies, as to "which is' cart and which is horse ," has not been settled, the important implication is that there may be an oncogenic mechanism that changes the characteristics of the cell membrane to permit inordinate influx of nutrients. The key question as to whether this influx sets off the cycle of cell division and unregulated growth remains to be answered. To recapitulate briefly, Kurt Isselbacher has made outstanding contributions in several areas including steroid metabolism , galactose metabolism, bilirubin metabolism, alcohol-induced fatty liver, intestinal lipid transport, gut structure and function, metabolic disorders , such as abetalipoproteinemia and isovaleric acidemia, and growth characteristics of neoplastic cells. Mastery of these many fields has resulted in a truly prodigious research output of some 210 publications. Kurt 's outstanding research accomplishments have resulted in his election to membership in a large number of learned
5
societies. These include: The National Academy of Sciences, The American Academy of Arts and Sciences, The American Society for Clinical Investigation (in which he served as Vice-President in 1967) , The American Gastroenterological Association, The Interurban Clinical Club, The Society for Experimental Biology and Medicine, The American Society of Biological Chemists, The Association of American Physicians, and The Biophysical Society. He has been a member of the editorial boards of several journals including Medicine, Gastroenterology, The Journal of Clinical Investigation, Disease-a-Month, and is a co-editor of Harrison's Principles of Internal Medicine. He has been a member of the Council of the American Society for Clinical Investigation, The Association of American Physicians, and President of The American Association for the Study of Liver Diseases. In addition to all of these assignments, he has served as Chairman of the Committee on Research at the Massachusetts General Hospital, Chairman of the Harvard University Cancer Committee, and Chairman of the Executive Committee of the Departments of Medicine at Harvard Medical School since 1968. He is currently Mallinckrodt Professor of Medicine at the Harvard Medical School. Another index of Kurt Isselbacher's important contribution to American gastroenterology is the large number of his trainees that have remained in academic medicine. Limitations of space will not permit a complete listing of the trainees, but the following list is representative: Holt, Senior, Scheig, Forstner, Greenberger, Rodgers, Plotkin, Budd, Sabesin, Alpers, Ockner, Franks, Tanaka, Koff, Alpert, Walker, Grand, Heizer, Glickman, and Goldfinger. In addition, several outstanding gastroenterologists have returned to academic careers outside the United States, and a partial list would include Dawson, Saunders, Datta , M<:Manus , Douglas, Thompson, and Mcintyre . If my calculations are correct, Kurt has trained eight individuals who are now, or have been, directors of a division of gastroenterology, and two individuals who are
6
KURT J. ISSELBACHER: NEW PRESIDENT
chairmen of departments of medicine. Kurt 's outstanding accomplishments in research have obscured the fact that he is a fine clinical gastroenterologist as well as a superb teacher. One is continually impressed with his ability to dissect complex clinical problems into readily soluble components. His keen diagnostic insights and sympathy to his patient's problems are obvious. His spontaneous discussions of clinical problems are characterized by a lucid and incisive flow of information that reflect his broad fund of biomedical information. His formal presentations are a model of clarity and brilliant exposition. That Kurt Isselbacher has accomplished so much is due, in large part, to a number of very special personal qualities. His calm exterior belies a quiet intensity and a compulsiveness for excellence, as well as an insistence that all his publications and presentations, both formal and informal, bear the stamp of excellence and quality.
Vol. 67, No . 1
He is a meticulously organized individual who spends an inordinate amount of time immersed in his work. He can do this because he has a seemingly unlimited capacity for continuous hard work. Anyone who has had much contact with Kurt also appreciates that he has a wry sense of humor and that he is a scholar both inside and outside the sphere of medicine. He takes great pride in the nonmedical accomplishments of his wife Rhoda and their four children. In summary, the new President of the American Gastroenterological Association is a truly outstanding individual. He has been a prodigious investigator mastering many fields, an accomplished teacher, a fihe clinical gastroenterologist, and a highly effective administrator and organizer. The American Gastroenterological Association is indeed fortunate to have Kurt J. Isselbacher as its new President. NORTON J. GREENBERGER, M.D.