Vol. 73, No. 2 Printed in U.S.A
0021-972X/9l/7302-0447$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
THE ENDOCRINE SOCIETY 1991 ANNUAL AWARDS
Citation for the Rorer Pharmaceutical Clinical Investigator Award of The Endocrine Society to Lawrence A. Frohman Lawrence A. Frohman is one of these rare bioscientists whose creative energy and drive have led him to explore and illuminate a dazzling variety of important topics in neuroendocrinology, metabolism, and cancer. His career has moved seamlessly from basic science to clinical investigation to clinical medicine, and his numerous review articles and textbook chapters have made him a major teacher of students throughout the world. Larry was born in Detroit in 1935. He took his undergraduate and medical schooling at the University of Michigan, house staff training in internal medicine at Yale-New Haven Medical Center, and spent two years as a fellow in endocrinology at Duke University where his career as an endocrinologist finally took off. He was an Associate Professor at State University of New York at Buffalo, Chief of Endocrinology at Michael Reese Hospital in Chicago, and is now the Professor of Medicine and Chief of Endocrinology at the University of Cincinnati. He has made countless contributions to the endocrine community, including service on the council of The Endocrine Society, national and international committees, advisory boards, and journal editorial boards. Several themes run through all of Larry's research activity, and he has returned to them time and again since his first studies on insulin, carbohydrate, and lipid metabolism in 1965. These areas include neural control of glucoregulatory hormones, neural control of GH secretion, pathogenesis of obesity, and clinical neuroendocrinology. In each of these areas he has made bold innovations. Larry and his collaborators showed that obesity after ventromedial nuclear lesions in the rat was largely due to intense hyperinsulinism induced via the vagus nerves. He was the first to identify regions of the hypothalamus electrically excitable for GH regulation, one of the most important proofs of neural control of this hormone, and he convincingly showed that a purified hypothalamic extract stimulated GH release. This was an important forerunner of his later work on GHRH isolation. He later showed that both GH and somatomedin C exerted feedback effects on somatostatin release from the isolated hypothalamus. His work has clarified many aspects of regulation of secretion of GH and of GHRH, using state-of-the-art recombinant techniques including the use of transgenic mice bearing the gene for GHRH. In this latter work he has had as collaborator Michael A. Frohman, his son.
Perhaps Larry's most important clinical contribution was the classical description of the syndrome of acromegaly due to ectopic GHRH secretion, and the first demonstration that tumors from such patients contained GHRH activity. These observations made possible the later work by others that led to isolation of GHRH from pancreatic tumors. Other important clinical contributions include the outstanding studies of epidemiology of thyroid cancer after head and neck irradiation and the use of GHRH in clinical medicine. Those who know Larry are never surprised by his creative thinking that goes on constantly. He has an uncanny ability to identify important new areas and to pursue them with elegance. He excels in his ability to simplify and clarify complex problems. A generation of medical students have benefited from his comprehensive analytical chapters in textbooks such as Harri447
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son's and Cecil's textbooks of medicine; and nearly a generation of his fellows have benefited from his guidance and supervision. Larry is the consummate endocrinologist, at home both in the laboratory and in the clinic.
Citation for the Richard E. Weitzman Memorial Award of The Endocrine Society to Synthia H. Mellon Dr. Mellon represents a unique combination of molecular biologist, endocrinologist, teacher, and mother. She received her undergraduate education at Rutgers where she was elected to Phi Beta Kappa and graduated cum laude in 1975 with distinction in Biochemistry. She then went to Columbia University where she worked with a previous President of The Endocrine Society, Seymour Leiberman, and his associate, Richard Hochberg, receiving her Ph.D. degree in 1979. In her studies she characterized a new series of adrenal steroids, fatty acid esters of pregnenolone. She demonstrated the biosynthesis of these compounds in adrenal mitochondria and then extended this work to lipoidal derivatives of estradiol in the bovine uterus, showing that these derivatives were different from the adrenal derivatives of pregnenolone. These compounds are now known as naturally occurring, long-acting estrogens that are synthesized and stored in estrogen target tissues. This seminal discovery has led to the possibility of a new class of estrogenic therapeutic compounds. In 1980, Dr. Mellon joined John Baxter's laboratory at the University of California, San Francisco (UCSF) to learn the then new science of molecular endocrinology. She brought to fruition the new RNA polymerase run-on assays. This work provided the first direct demonstration that glucocorticoid and thyroid hormones stimulate GH synthesis and messenger (m) RNA accumulation directly at the level of GH gene transcription. Dr. Mellon then taught herself in situ hybridization histochemistry and collaborated with C. F. Deschepper to show that renin is a paracrine factor made at its site of action in the adrenal as well as in numerous other previously unsuspected sites, in addition to its traditional site of synthesis in renal juxtaglomerular cells. Working with T. Reudelhuber and others, she performed an extensive series of gene transfer experiments that led to the identification of a tissue-specific proteinDNA interaction that is essential for rat GH gene expression. This factor, first termed GC-2, and now known as Pit-1, was the first tissue-specific trans-acting transcriptional regulatory protein identified in the pituitary. At the same time, Dr. Mellon and A. Gutierrez-Hartmann showed that one of three RNA polymerase III genes contained within the rat GH gene, called TR or truncated repeat, is expressed in rat brain and in transfected neuronal cells but not in glial and other nonneuronal cells, thus demonstrating that certain members of the TR family can function as neural-specific identifier elements. In 1987, Dr. Mellon was appointed Assistant Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at UCSF. She combined molecular endocrinology with work in steroid hormone biosynthesis to study the regulation of genes for the steroidogenic enzymes. She showed that the tropic hormone- or cAMP-mediated increase in the mRNA for
the cholesterol side-chain cleavage enzyme, P450scc, in mouse Leydig MA-10 cells is due to a direct effect on the transcription of the P450scc gene. She showed that the cAMP-mediated increase in P450scc mRNA in MA-10 cells, unlike bovine adrenal cells, is direct, cycloheximide-insensitive, and does not require the synthesis of an additional protein. This key observation has necessitated reexamination of the role of protein synthesis in the induction of steroidogenesis. She also cloned and sequenced the complementary (c) DNAs for rat P450cl7 and adrenodoxin, and demonstrated that MA-10 cells do not express P450cl7 mRNA and that the regulation of adrenodoxin mRNA is similar to the regulation of P450scc mRNA in these cells. At the same time, Dr. Mellon collaborated with Dr. Walter Miller to determine if the extra-adrenal 21-hydroxylase activity found in pregnant women and in human fetal tissues is due to the adrenal 21-hydroxylating enzyme, P450c21. She used RNase protection assays to analyze RNA from the human fetal tissues shown by others to contain 21-hydroxylase activity, and demonstrated that P450c21 mRNA is found only in human fetal adrenals, thus explaining the persistence of 21-hydroxylated steroids in patients with P450c21 mutations causing congenital adrenal hyperplasia. In these experiments, Dr. Mellon was the first to show that RNA probes from heterologous species could be used for RNase protection assays, thus extending this powerful technique to circumstances in which homologous cDNAs are unavailable. Extending these studies of extra-endocrine steroidogenesis,
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THE ENDOCRINE SOCIETY Dr. Mellon used polymerase chain reaction amplification rat brain cDNA to show that the cholesterol side-chain cleavage enzyme activity reported in rat brains (hence the synthesis of neurosteroids) is not due to P450scc, thus answering an important question in endocrinology through her combined training as a steroid biochemist and molecular endocrinologist. Dr. Mellon has used RNase protection and in situ hybridization assays to study the cell-specific regulation of the steroidogenic enzyme mRNAs in vivo in rats. She showed that only the P450scc mRNA in the adrenal, but not in testis or ovary, is increased by a low-salt diet and decreased by dexamethasone. Furthermore, the P450scc mRNA increased by low salt is confined to the outer zone of the adrenal, whereas only P450scc mRNA in the inner zones is decreased by dexamethasone. Perhaps Dr. Mellon's most exciting discovery concerns the zone-specific regulation of rat P450cll mRNA. Using RNase protection and in situ hybridization assays, she demonstrated that rats have two forms of P450cll mRNA, one found exclusively in the zona glomerulosa, the second throughout the adrenal cortex. These two mRNAs are regulated independently in a zone-specific fashion; the glomerulosa form is regulated by dietary salt, and the other form is regulated by glucocorticoids. Dr. Mellon also found that the regulation of P450cll mRNAs is different in the adrenal of the pregnant rat from that in the nonpregnant rat. The P450cll mRNA found throughout the adrenal is no longer regulated by glucocorticoids in pregnancy, and the P450cll mRNA found in the glomerulosa is now even more sensitive to dietary sodium. Finally, Dr. Mellon has collaborated with S. Mesiano and R. Jaffe to study the effect of ACTH on basic fibroblast growth factor (FGF) mRNA. RNase protection and in situ hybridization assays showed that bovine (b) FGF mRNA expression is enhanced in human fetal adrenocortical cells by ACTH. This first demonstration of bFGF synthesis in the human fetal adrenal points the way to an important means of regulating adrenal growth during gestation. Dr. Mellon has been a committed member of The Endocrine Society. With the exception of the 1989 meeting (during which she delivered her second child), she has attended every meeting of the Society since 1978. She is often seen pushing a baby carriage through the poster sessions at the meetings with one or both of her small children. In an era when many women feel forced to choose between family and career, Dr. Mellon has achieved a remarkable balance that includes both, offering an outstanding role model to young women entering science.
Citation for the Edwin B. Astwood Lectureship of The Endocrine Society to Marc E. Lippman The Endocrine Society has selected Marc Estes Lippman, M.D., Professor of Medicine and Pharmacology and Director of the Vincent T. Lombardi Cancer Center, Georgetown University School of Medicine, Washington, D.C., as the recipient of the 1991 Edwin B. Astwood Lectureship for scientific achievement for his outstanding basic and clinical contributions to the understanding and treatment of breast cancer. Dr. Lippman was born in Brooklyn, New York, received his B.A. magna cum laude from Cornell University and his M.D. in 1968 from Yale Medical School. He then carefully developed
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his skills and training in several relevant areas. After an internship and residency in internal medicine at Johns Hopkins, he moved to the NIH, where he was a Clinical Associate in the Leukemia Service of the NCI. After that, he moved to the Laboratory of Biochemistry of the NCI, where he took training in basic cell biology and steroid hormone action in E. B. Thompson's laboratory. There, Dr. Lippman carried out an important study showing a correlation in human leukemia between glucocorticoid receptor and response to therapy that included glucocorticoids. At the same time, he pursued basic research on glucocorticoid receptors in cultured leukemic cells. These studies provoked a widespread interest in the predictive role of glucocorticoid receptors in lymphomas and leukemias, a subject still under active investigation in a number of labs today. Returning to clinical medicine, Dr. Lippman took a fellowship in endocrinology at Yale and then was recruited back to the NIH to be a Senior Investigator in the Medicine Branch of the NCI. Shortly thereafter he became head of the Medical Breast Cancer Section. In this position he developed a program extending from fundamental biological research to clinical treatment of breast cancer. He supervised and led studies at NIH on correlations between steroid hormone receptors and prognosis for breast cancer. He carried out successful trials of new treatments for breast cancer, including aggressive chemotherapy for advanced breast cancer. In his laboratory he employed cell lines of human breast cancer to study mechanisms of development of resistance to hormonal therapy and
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the role of steroid hormone receptors in these cells. His work led to the findings that these cells make various growth factors and oncogene products, which themselves are often under steroid hormone control. Thus, the burgeoning understanding of the autocrine/paracrine growth control of cancer has benefited significantly by the studies from Dr. Lippman's group. The concept that steroid hormones are part of the important regulatory system that control the paracrine and autocrine factors driving malignant and normal breast epithelial growth has been a breakthrough in understanding this and other types of hormone-dependent malignancies and malignancies arising from hormone-dependent tissues. Dr. Lippman's group has specifically contributed to or originated discoveries that in breast cancer cells estrogen is involved in the regulation of transforming growth factor-a, transforming growth factor-/3, insulin-like growth factor-1-like protein, insulin-like growth factor-2, and platelet-derived growth factor. These findings are leading directly to the construction and testing of entirely new modes of therapy based on the interactions of the growth factors and their receptors. Dr. Lippman's research has not only involved breast cancer but also has included studies in renal malignancies, leukemias, Kaposi's sarcoma, cancer of the colon, and the uterus. In 1988 Dr. Lippman left the NIH to assume his current duties as Director of the Vincent T. Lombardi Cancer Center and Professor of Medicine and Pharmacology at Georgetown University. He has continued in his role as Clinical Professor of Medicine and Pharmacology at the Uniformed Services University of the Health Sciences. At the Lombardi Cancer Center Dr. Lippman and a large group of scientists he has attracted there continue to pursue their studies of breast cancer and other malignancies and their control by traditional and nontraditional hormonal systems. They are also deeply involved in the interactions of drugs with these growth regulatory systems and the trials of new therapies for breast cancer. Dr. Lippman's accomplishments have been recognized by invitations to present his work at numerous international and national locations. He has won a leadership role in both the endocrine and the cancer communities, having been chairman of the Gordon Conference on Hormone Action and an organizer of The Endocrine Society Course on Hormones and Cancer, as well as serving on a large number of important scientific and financial groups pertaining to oncology. Dr. Lippman serves on a large number of editorial boards for both hormone- and cancer-related subjects. These include Molecular Endocrinology, Journal of Steroid Biochemistry, Cancer Research, Journal of Clinical Oncology, and many others. At the Lombardi Center Dr. Lippman has quickly established a forceful and well funded outstanding group of investigators engaged in an important spectrum of work, pursuing his lifetime emphasis on bridging basic science to clinical science. He is an outstanding example of a member of The Endocrine Society who has first prepared himself well in both arenas and then used the findings of basic endocrine and biochemical sciences to extend the limits of the definitions and applications of endocrinology into areas both clinical and basic. He is a scientist and clinician who we can all be proud to have as a member of our Society and a fine example of the achievement meant to be honored by the Edwin B. Astwood Lectureship.
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Citation for the Robert H. Williams Distinguished Leadership Award to William D. Odell The Robert H. Williams Distinguished Leadership Award honors a member of The Endocrine Society who, in the image of Dr. Williams, has served the field of endocrinology and has nurtured generations of endocrinological scholars. The 1991 recipient is William D. Odell, M.D., Ph.D. Bill is appreciated worldwide for his remarkable range of abilities and accomplishments, covering research, education and training, patient care, and administrative leadership. Most of all, he is the perfect role model, esteemed as a clinician, as a physiological scientist, and as a person. Bill received his B.A. from the University of California at Berkeley, his M.D. from the University of Chicago, and his Ph.D. from George Washington University, the latter while he was working extremely productively at the NIH. His residency had been at the University of Washington, culminating with the Chief Residency. How fitting that Bill should receive the award that perpetuates the memory of his Chief, Robert Williams, a mentor he related to as a son to a father. He then spent the early sixties at the NIH, first as a fellow, then as a senior investigator. He learned endocrinology and science from Mort Lipsett, Griff Ross, and Roy Hertz, and he also honed his natural instinct for leadership. He then moved back to the West Coast as Chief of Endocrinology at Harbor-UCLA Medical Center (then Harbor General Hospital), where he developed, from scratch, one of the finest endocrine training programs in the country. Bill was the organizer, the recruiter (Stan Korenman, Del Fisher, Ron Swerdloff, and George Bray, to name a few), the driver, the model, and the inspiration. Since 1960 at the NIH, he has never stopped doing research with his own hands, no matter what administrative burdens he was carrying. In the 1960s at Harbor, he was always in the lab, always available to advise, stimulate, nurture, encourage, and comfort a growing group of fellows. One way to recount the story of Bill Odell's distinguished leadership in endocrinology is to list fellows who worked directly under his tutelage and who became household names in our field: at the NIH, Jack Wilber, Peter Kohler, and Phil Rayford; at Harbor, Ron Swerdloff, Pat Walsh (Urology), Jerald Nelson, Glenn Howard Jacobs (the U.K.), Glen Braunstein, Mark Molitch, John Marshall, Bob Rubin, David Heber, and many others. Even while chairing a large and growing Department of Medicine at Salt Lake City, he has continued to work directly with fellows. Reviewing this list, one concludes that a single super-motivator has given a crucial boost to at least 8 of the leading contemporary figures in academic, clinical, and physiological endocrinology. In all, he has been directly responsible for the postdoctoral development of 52 research fellows, of whom only 9 are not in academic work. He became chairman of the Department of Medicine at Harbor in 1972 and the University of Utah in 1980. In these posts he has brought his leadership qualities to the parent field, internal medicine. Each of his departments has grown and prospered. Bill's ability to inspire is not limited to endocrinology. His research has been original, courageous, at the forefront, often surprising, and always well buttressed by findings. With
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that question, but one can list some of his qualities that may have contributed: extraordinary energy, unflagging enthusiasm, indestructible optimism, solid dedication to his art and science, sincere concern with the welfare of his faculty and trainees, constant warmth and friendliness, unquestionable integrity, considerable generosity, sparkling creativity, and, despite all of this, a willingness to listen. Perhaps even more impressive is his equanimity, good humor, and the Odell smile. A leader in endocrinology, a leader in internal medicine, a personal leader among colleagues and students, Dr. William Odell richly deserves the Robert H. Williams Award.
Citation for the Ernst Oppenheimer Award of The Endocrine Society to Perrin C. White
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Bob Utiger and Jack Wilber he developed the first RIA for TSH and, with others, the first RIAs for LH, FSH, and human (h) CG. Later he added MSH and gastrin to his list. He used these RIAs (and, more recently, immunoradiometric assays) to expand our knowledge greatly—the MCR of the pituitary glycoproteins, their production rates, the hormonal correlates of the normal menstrual cycle, the signal system for the ovulatory surge of LH, the effect of oral contraceptives on the pituitarygonadal axis, and the hormonal basis for the onset of puberty— all of these were elucidated by Bill Odell and his colleagues. His RIA for TSH remained the standard method worldwide for well over 20 yr. His other area of continuous study has been the phenomenon of ectopic hormone production by cancers. An impressive body of his work now has established that several hormones {e.g. hCG, an ACTH precursor, vasopressin, and calcitonin) are present in normal cells of many tissues and has led to the inference that hormone production by cancers is not ectopic but rather is an exaggeration of a property possessed by normal cells. Wherever he has been, Bill has shown that the quadruple threat is still alive. He is a splendid teacher at all levels, starting with endocrine physiology for first-yr medical students at UCLA and University of Utah, which he has taught continuously for 25 yr. He is a superb clinical endocrinologist and, just as he is unwavering in research and teaching, he has never stopped being the doctor for a significant number of patients. How does this man do it all? No one can accurately answer
Dr. Perrin C. White, who is 40 years old, received his A.B. and M.D. degrees from Harvard University. He spent his first 2 yr of pediatrics training at Johns Hopkins Hospital, completed a 2-yr postdoctoral fellowship in developmental and molecular biology with Dr. Gerald Edelman at Rockefeller University, and finished his pediatrics training at the New York Hospital. He was appointed Assistant Professor of Pediatrics at Cornell University Medical College in 1981 after completion of his residency, was promoted to Associate Professor in 1987, and was granted tenure in 1989. Dr. White's research for the past 9 yr has concentrated on the molecular genetic analysis of inherited disorders of steroid metabolism, particularly the disorders of cortisol biosynthesis collectively termed congenital adrenal hyperplasia. One of these disorders, 21-hydroxylase deficiency, is one of the most common autosomal recessive diseases in man. At the time that Dr. White began his work, it was known that 21-hydroxylase deficiency was inherited as an autosomal recessive trait closely linked to the human leukocyte antigen major histocompatibility complex on chromosome 6. However, the identity of the defective gene was unknown. Dr. White purified the 21-hydroxylase enzyme from bovine adrenal glands, produced an antiserum to the protein, and used the antiserum to isolate a cDNA clone encoding the enzyme from a bovine adrenal cDNA library that he had constructed. He demonstrated that the corresponding gene was located in the major histocompatibility complex in both mouse and man, and that certain patients with 21-hydroxylase deficiency had a deletion encompassing the gene. Subsequently, he precisely mapped two 21-hydroxylase genes in the human genome, and showed that the second gene was a nonfunctional pseudogene. This work was carried out in the laboratory of Dr. Bo Dupont at Sloan-Kettering Institute, pending construction of Dr. White's own laboratory at Cornell, which opened in 1985. Since that time, Dr. White has completely analyzed the nucleotide sequences of the 21-hydroxylase genes, identifying several deleterious mutations in the nonfunctional pseudogene. His laboratory cloned and characterized mutant 21-hydroxylase genes from patients with 21-hydroxylase deficiency, demonstrating that transfers of deleterious sequences from the pseudogene to the normally active gene—a process termed gene conversion— account for most mutations causing 21-hydroxylase deficiency. This is the only human genetic disease where most defective alleles result from recombinations between the normally active
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ber of other physiologically important enzymes using molecular genetic techniques, most notably 110-hydroxysteroid dehydrogenase, the enzyme required for interconversion of cortisol and cortisone. This activity apparently confers ligand specificity on the type I (mineralocorticoid) receptor and is thus a crucial component of renal sodium homeostasis. Because 21- and ll/?-hydroxylase deficiencies account for about 98% of cases of congenital adrenal hyperplasia, Dr. White's work has almost completely defined the molecular genetic basis of this common inherited disease. This outstanding work makes him a most deserving recipient of the Ernst Oppenheimer Award.
Citation for the Fred Conrad Koch Award of The Endocrine Society to John T. Potts, Jr.
gene and a pseudogene. Dr. White also precisely mapped deletions of the 21-hydroxylase gene that constitute about onefourth of 21-hydroxylase deficiency alleles, showing that the unequal crossovers causing these deletions occur at characteristic points within the gene. In recent work, Dr. White and his associates expressed several mutant 21-hydroxylase enzymes in cultured cells using recombinant vaccinia virus, finding that the clinical severity of the disease correlates relatively well with the degree of enzymatic compromise. Deficiency of 11/3-hydroxylase is the second most common defect of cortisol biosynthesis after 21-hydroxylase deficiency. Dr. White cloned and characterized bovine and human cDNAs encoding 11/3-hydroxylase and found that there are two related genes on human chromosome 8. He determined the nucleotide sequences of both genes, and found that only one gene is expressed at high levels in the human adrenal cortex, although there are no obviously deleterious mutations in the second. He identified a mutation in the highly expressed gene associated with 11/3-hydroxylase deficiency in Jews of Moroccan origin; in contrast to the findings in 21-hydroxylase deficiency, this is a de novo point mutation and not a gene conversion. He recently found that the second 110-hydroxylase gene is expressed at high levels in aldosterone-secreting tumors and that it encodes a protein with enzymatic activities required for aldosterone synthesis. Consistent with this idea, Dr. White has shown that a mutation in or near one of the ll^-hydroxylase genes results in a defect in aldosterone biosynthesis termed corticosterone methyloxidase II deficiency. Dr. White and his colleagues have also characterized a num-
Our current understanding of calcium metabolism rests in large part on a series of discoveries made by John Potts. In a continually productive career spanning three decades, Potts has applied the rigor of biochemistry to difficult problems in physiology and medicine. John Potts went to medical school at the University of Pennsylvania (M.D. in 1957), at first solely because of interest in clinical medicine. His excitement about science, kindled during his clinical clerkship in internal medicine, began to focus on calcium metabolism during an elective with an inspiring parathyroid surgeon, Dr. Brooke Roberts. House officer training at the Massachusetts General Hospital introduced him to the traditions in parathyroid research established by Fuller Albright and Joseph Aub. He went then to Christian B. Anfinsen's laboratory in the National Heart Institute with the plan to receive broad training in protein chemistry in order to tackle, subsequently, the problem of characterizing the parathyroid hormone molecule. This decision to apply rigorous biochemical tools to approach physiological and clinical problems characterizes much of Potts's subsequent career. After studying ribonuclease with Anfinsen, Potts established his own laboratory in the National Heart Institute and initiated, in collaboration with G. D. Aurbach, who had also just established a laboratory at NIH, a series of studies on PTH; Potts and Aurbach combined their skills in protein chemistry and the biology of calcium metabolism to work on PTH and related issues for 7 yr. The purification of the hormone led Potts and Aurbach, in collaboration with S. A. Berson and R. S. Yalow, to the development in 1963 of a sensitive RIA that provided, for the first time, an accurate and precise method for the measurement of PTH levels in blood. This advance permitted systematic studies of the control of secretion of the hormone in animals. These landmark experiments established the basic features of the feedback regulation of PTH secretion by calcium. By applying several new strategies for protein sequencing, Dr. Potts and colleagues determined over a 5-yr period, the complete amino acid sequence of bPTH. During the time that the work on PTH progressed, Potts and his colleagues began work on the chemical properties of calcitonin, discovered in 1962 by Harold Copp and Paul Munson. Potts and colleagues, working with Munson, reported the isolation and complete amino acid sequence of porcine calcitonin. Potts and coworkers then deduced the complete amino acid sequence of salmon calcitonin in a collaborative study with
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Harold Copp. Salmon calcitonin has subsequently been introduced worldwide in the therapy of Paget's disease of bone and other disorders. In 1968 Dr. Potts assumed the position of Chief of the Endocrine Unit at the Massachusetts General Hospital. His group there deduced the complete amino acid sequences of porcine and human PTH. The latter achievement was especially important, since nonhuman PTH was too immunogenic for diagnostic or therapeutic use in humans. Potts and colleagues achieved the complete synthesis of the biologically active portion of the bovine hormone in 1970. Later, as work on the human hormone progressed, the active portion of the human hormone was synthesized. The availability of a chemically defined form of the human hormone permitted Potts and colleagues to introduce the hormone into clinical investigation. Potts and colleagues have continued to the present time their work with the synthesis of PTH; over 100 fragments and analogs have been made of the bovine, porcine, rat, and human hormones. These have been applied to systematic evaluation of structure/activity studies of the hormone using a variety of biological test systems in vivo and in vitro. Most recently, Potts and colleagues have used site-directed mutageneis of recombinant DNA expression vectors to generate and characterize hundreds of PTH analogs. Further, bacterial expression vector has been used to synthesize large amounts of full-length hPTH. The group's recent cloning of cDNA encoding PTH receptors from cultured bone and kidney cell lines will further the analysis of PTH action. Dr. Potts and colleagues have been able to define the minimum structure necessary for expression of hormone action and
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the contributions of individual residues. In related studies, they established that the deletion of specific portions of the amino terminus of the molecule produced peptides which bound to receptors but did not activate subsequent biological responses in the test tissue. This work has led to the development of a competitive inhibitor of PTH action that is active in vivo. Potts and colleagues initiated a wide ranging series of investigations in the biosynthesis of the hormone in collaboration with Dr. Alexander Rich at MIT. The group was the first to identify the initial gene product of a polypeptide hormone. They isolated and sequenced preproPTH, the initial product of translation of the mRNA for the hormone, in work using mRNA translation in cell-free systems. The group has subsequently characterized DNA complementary in sequence to the mRNA for bovine, human, and chicken PTH, as well as human and rat PTH genomic DNA. Throughout his investigative career, Potts has been interested in the clinical applications of these basic research advances. Beginning with the early development of the RIA for PTH Potts and colleagues have applied this technique to the study of abnormalities in PTH production that occur in hyperparathyroidism. Guided by the extensive structure-function analysis of PTH and by their characterization of PTH's metabolism, Potts and colleagues recently developed a two-site immunoradiometric assay for PTH. This assay, and equivalents subsequently developed by others, measures only intact, biologically active hormone and has unprecedented sensitivity. Most importantly, the assay can separate completely those hypercalcemic patients with hyperparathyroidism from patients with malignant hypercalcemia. Potts and colleagues have introduced a variety of diagnostic tests employing infusions and injections of the synthetic PTH into patients with hypoparathyroidism. Therapeutic trials are
also being undertaken with the PTH in small doses in combination with other agents such as vitamin D3 in an attempt to reverse the severe bone mineral loss seen in patients with osteoporosis. Potts and colleagues were the first to introduce calcitonin into the therapy of Paget's disease. Although Dr. Potts's research accomplishments form the primary basis for his designation as Koch Awardee, he also has served endocrinology well in other ways. Dr. Potts has been and continues to be an outstanding mentor of younger colleagues in the endocrine field. He has unselfishly guided the careers of many endocrinologists in his roles as Director of the Endocrine Fellowship Training Program (1968-1981), Chief of Medicine (1981 to present), and Director of the PhysicianScientist Training Program (1984 to present) at the Massachusetts General Hospital. Dr. Potts has played an active role in the leadership of several organizations that further endocrinology. He has served on the Council of the NIDDK (1982-1987), has had a variety of leadership roles in the organization of the International Conferences on Calcium Regulating Hormones (1968-1986), has been a member of the Institute of Medicine (1986 to present), and served as President of The Endocrine Society (1987 and 1988). Dr. Potts's impressive accomplishments have been recognized by a series of honors over the years, including the Ernst Oppenheimer Award of The Endocrine Society and the Prize Andre Lichwitz. In 1987, he received the William F. Neumann
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Award, the highest award of the American Society of Bone and Mineral Research. Dr. Potts moves back and forth between his research, teaching, and administrative interests with tremendous energy and enthusiasm. He brings to these activities authentic concern for the lives and careers of his colleagues. The Endocrine Society thus honors with the Koch Award an innovative investigator and an inspiring leader.
Citation for the Distinguished Service Award of The Endocrine Society to Francine L. Trull The Distinguished Service Award of The Endocrine Society for 1991 is presented to Francine L. Trull, known to all as Frankie. Because Frankie and the National Association for Biomedical Research (NABR) are only one institution, we must first state what is the NABR. It is a nonprofit organization which was established in 1979 and was consolidated in 1985 with the National Society for Medical Research. NABR supports the responsible use and humane care and treatment of laboratory animals in research, education, and product safety testing. Further, NABR believes that only as many animals as necessary should be used; that any pain or distress animals may experience should be minimized; and that alternatives to the use of live animals should be developed and employed, wherever feasible. Still, NABR recognizes that now and in the foreseeable future it is not possible to completely replace the use of animals and that the study of whole, living organisms is an indispensable element of biomedical and veterinary research. NABR membership includes more than 350 institutions: universities, medical and veterinary schools, teaching hospitals, voluntary health agencies, academic and professional societies, as well as pharmaceutical and laboratory animal breeder companies. It is satisfying to report that The Endocrine Society, upon recommendation of its Public Affairs Committee, became an early member of NABR, in 1982. At the beginning, NABR was Frankie Trull. To a large extent, this remains true. So, let us now consider Frankie the individual. She started her academic life at Randolph Macon Woman's College in Virginia where she could also pursue her life-long interest in horses. However, after a short while, she returned home to Massachusetts to earn a B.A. degree in history, cum laude, in 1972. During the next 5-6 yr, Frankie combined a career of Administrator at the School of Dentistry of Tufts University and of student for an M.A. degree in Sociology, specializing in the field of organizational behavior. During those years in Boston, her work in planning Tufts' School of Veterinary Medicine brought her to the halls of state legislatures, governors' offices, and Congress. Her dedication to animal science, her organizational skill, and her ability to communicate brought her to the attention of Tufts President Jean Mayer. At that time, the animal rights movement, the modern-day heir to victorian antivivisection, was becoming more active in the United States. A group of academic and industry leaders approached Frankie to ask whether she would help the biomedical research community to respond to the challenge. Because of Frankie's talents and
despite her consideration of a doctoral degree, President Jean Mayer counseled her: "It is a shame to interrupt your present educational process for a Ph.D. degree." Frankie Trull listened to the advice and in 1980, as its lone staff member, she founded the Association for Biomedical Research, devoted solely to animal research issues. Given its tiny budget, mailing to members originated on the Executive Director's living room floor. By 1983, with a small but growing membership and income barely above $100,000, NABR had taken its place among existing scientific groups active in the nation's public policy arena. It was also recognized that, to address the general public more effectively about the importance of animal research for continued medical progress, a broader effort was required. A sister organization, the Foundation for Biomedical Research, was founded for the sole purpose of public education. With Frankie Trull at the helm of both NABR and the Foundation, guided by two boards of directors made up of distinguished scientists from academia and industry, a unified voice began to be heard advocating the vital role of laboratory animals in the search to relieve suffering and save lives. To respond to increased congressional and public interest in these issues, NABR and the Foundation moved to Washington, D.C. in 1984. Presently, NABR plays a central role in working with Congress and federal agencies on legislation and regulation which furthers the goal of continued responsible animal research.
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THE ENDOCRINE SOCIETY Meanwhile, the Foundation has made enormous strides in public education, producing much needed resources for the scientific community's use, including videotapes, brochures, press kits, public service announcements, and a poster series. Working with a network of state-level organizations, the Foundation has offered spokespersons and background information for all forms of media. Without Frankie's talent, dedication, and sustained efforts
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over the years, biomedical research and educational programs could not have survived the unrelenting attacks of the misguided animal rights movement. For the essential leadership she has provided as President of the National Association and Foundation for Biomedical Research, The Endocrine Society is very pleased to honor Frankie Trull with the Distinguished Service Award for 1991.
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0021-972X/9l/7302-0447$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
THE ENDOCRINE SOCIETY 1991 ANNUAL AWARDS
Citation for the Rorer Pharmaceutical Clinical Investigator Award of The Endocrine Society to Lawrence A. Frohman Lawrence A. Frohman is one of these rare bioscientists whose creative energy and drive have led him to explore and illuminate a dazzling variety of important topics in neuroendocrinology, metabolism, and cancer. His career has moved seamlessly from basic science to clinical investigation to clinical medicine, and his numerous review articles and textbook chapters have made him a major teacher of students throughout the world. Larry was born in Detroit in 1935. He took his undergraduate and medical schooling at the University of Michigan, house staff training in internal medicine at Yale-New Haven Medical Center, and spent two years as a fellow in endocrinology at Duke University where his career as an endocrinologist finally took off. He was an Associate Professor at State University of New York at Buffalo, Chief of Endocrinology at Michael Reese Hospital in Chicago, and is now the Professor of Medicine and Chief of Endocrinology at the University of Cincinnati. He has made countless contributions to the endocrine community, including service on the council of The Endocrine Society, national and international committees, advisory boards, and journal editorial boards. Several themes run through all of Larry's research activity, and he has returned to them time and again since his first studies on insulin, carbohydrate, and lipid metabolism in 1965. These areas include neural control of glucoregulatory hormones, neural control of GH secretion, pathogenesis of obesity, and clinical neuroendocrinology. In each of these areas he has made bold innovations. Larry and his collaborators showed that obesity after ventromedial nuclear lesions in the rat was largely due to intense hyperinsulinism induced via the vagus nerves. He was the first to identify regions of the hypothalamus electrically excitable for GH regulation, one of the most important proofs of neural control of this hormone, and he convincingly showed that a purified hypothalamic extract stimulated GH release. This was an important forerunner of his later work on GHRH isolation. He later showed that both GH and somatomedin C exerted feedback effects on somatostatin release from the isolated hypothalamus. His work has clarified many aspects of regulation of secretion of GH and of GHRH, using state-of-the-art recombinant techniques including the use of transgenic mice bearing the gene for GHRH. In this latter work he has had as collaborator Michael A. Frohman, his son.
Perhaps Larry's most important clinical contribution was the classical description of the syndrome of acromegaly due to ectopic GHRH secretion, and the first demonstration that tumors from such patients contained GHRH activity. These observations made possible the later work by others that led to isolation of GHRH from pancreatic tumors. Other important clinical contributions include the outstanding studies of epidemiology of thyroid cancer after head and neck irradiation and the use of GHRH in clinical medicine. Those who know Larry are never surprised by his creative thinking that goes on constantly. He has an uncanny ability to identify important new areas and to pursue them with elegance. He excels in his ability to simplify and clarify complex problems. A generation of medical students have benefited from his comprehensive analytical chapters in textbooks such as Harri447
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son's and Cecil's textbooks of medicine; and nearly a generation of his fellows have benefited from his guidance and supervision. Larry is the consummate endocrinologist, at home both in the laboratory and in the clinic.
Citation for the Richard E. Weitzman Memorial Award of The Endocrine Society to Synthia H. Mellon Dr. Mellon represents a unique combination of molecular biologist, endocrinologist, teacher, and mother. She received her undergraduate education at Rutgers where she was elected to Phi Beta Kappa and graduated cum laude in 1975 with distinction in Biochemistry. She then went to Columbia University where she worked with a previous President of The Endocrine Society, Seymour Leiberman, and his associate, Richard Hochberg, receiving her Ph.D. degree in 1979. In her studies she characterized a new series of adrenal steroids, fatty acid esters of pregnenolone. She demonstrated the biosynthesis of these compounds in adrenal mitochondria and then extended this work to lipoidal derivatives of estradiol in the bovine uterus, showing that these derivatives were different from the adrenal derivatives of pregnenolone. These compounds are now known as naturally occurring, long-acting estrogens that are synthesized and stored in estrogen target tissues. This seminal discovery has led to the possibility of a new class of estrogenic therapeutic compounds. In 1980, Dr. Mellon joined John Baxter's laboratory at the University of California, San Francisco (UCSF) to learn the then new science of molecular endocrinology. She brought to fruition the new RNA polymerase run-on assays. This work provided the first direct demonstration that glucocorticoid and thyroid hormones stimulate GH synthesis and messenger (m) RNA accumulation directly at the level of GH gene transcription. Dr. Mellon then taught herself in situ hybridization histochemistry and collaborated with C. F. Deschepper to show that renin is a paracrine factor made at its site of action in the adrenal as well as in numerous other previously unsuspected sites, in addition to its traditional site of synthesis in renal juxtaglomerular cells. Working with T. Reudelhuber and others, she performed an extensive series of gene transfer experiments that led to the identification of a tissue-specific proteinDNA interaction that is essential for rat GH gene expression. This factor, first termed GC-2, and now known as Pit-1, was the first tissue-specific trans-acting transcriptional regulatory protein identified in the pituitary. At the same time, Dr. Mellon and A. Gutierrez-Hartmann showed that one of three RNA polymerase III genes contained within the rat GH gene, called TR or truncated repeat, is expressed in rat brain and in transfected neuronal cells but not in glial and other nonneuronal cells, thus demonstrating that certain members of the TR family can function as neural-specific identifier elements. In 1987, Dr. Mellon was appointed Assistant Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at UCSF. She combined molecular endocrinology with work in steroid hormone biosynthesis to study the regulation of genes for the steroidogenic enzymes. She showed that the tropic hormone- or cAMP-mediated increase in the mRNA for
the cholesterol side-chain cleavage enzyme, P450scc, in mouse Leydig MA-10 cells is due to a direct effect on the transcription of the P450scc gene. She showed that the cAMP-mediated increase in P450scc mRNA in MA-10 cells, unlike bovine adrenal cells, is direct, cycloheximide-insensitive, and does not require the synthesis of an additional protein. This key observation has necessitated reexamination of the role of protein synthesis in the induction of steroidogenesis. She also cloned and sequenced the complementary (c) DNAs for rat P450cl7 and adrenodoxin, and demonstrated that MA-10 cells do not express P450cl7 mRNA and that the regulation of adrenodoxin mRNA is similar to the regulation of P450scc mRNA in these cells. At the same time, Dr. Mellon collaborated with Dr. Walter Miller to determine if the extra-adrenal 21-hydroxylase activity found in pregnant women and in human fetal tissues is due to the adrenal 21-hydroxylating enzyme, P450c21. She used RNase protection assays to analyze RNA from the human fetal tissues shown by others to contain 21-hydroxylase activity, and demonstrated that P450c21 mRNA is found only in human fetal adrenals, thus explaining the persistence of 21-hydroxylated steroids in patients with P450c21 mutations causing congenital adrenal hyperplasia. In these experiments, Dr. Mellon was the first to show that RNA probes from heterologous species could be used for RNase protection assays, thus extending this powerful technique to circumstances in which homologous cDNAs are unavailable. Extending these studies of extra-endocrine steroidogenesis,
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THE ENDOCRINE SOCIETY Dr. Mellon used polymerase chain reaction amplification rat brain cDNA to show that the cholesterol side-chain cleavage enzyme activity reported in rat brains (hence the synthesis of neurosteroids) is not due to P450scc, thus answering an important question in endocrinology through her combined training as a steroid biochemist and molecular endocrinologist. Dr. Mellon has used RNase protection and in situ hybridization assays to study the cell-specific regulation of the steroidogenic enzyme mRNAs in vivo in rats. She showed that only the P450scc mRNA in the adrenal, but not in testis or ovary, is increased by a low-salt diet and decreased by dexamethasone. Furthermore, the P450scc mRNA increased by low salt is confined to the outer zone of the adrenal, whereas only P450scc mRNA in the inner zones is decreased by dexamethasone. Perhaps Dr. Mellon's most exciting discovery concerns the zone-specific regulation of rat P450cll mRNA. Using RNase protection and in situ hybridization assays, she demonstrated that rats have two forms of P450cll mRNA, one found exclusively in the zona glomerulosa, the second throughout the adrenal cortex. These two mRNAs are regulated independently in a zone-specific fashion; the glomerulosa form is regulated by dietary salt, and the other form is regulated by glucocorticoids. Dr. Mellon also found that the regulation of P450cll mRNAs is different in the adrenal of the pregnant rat from that in the nonpregnant rat. The P450cll mRNA found throughout the adrenal is no longer regulated by glucocorticoids in pregnancy, and the P450cll mRNA found in the glomerulosa is now even more sensitive to dietary sodium. Finally, Dr. Mellon has collaborated with S. Mesiano and R. Jaffe to study the effect of ACTH on basic fibroblast growth factor (FGF) mRNA. RNase protection and in situ hybridization assays showed that bovine (b) FGF mRNA expression is enhanced in human fetal adrenocortical cells by ACTH. This first demonstration of bFGF synthesis in the human fetal adrenal points the way to an important means of regulating adrenal growth during gestation. Dr. Mellon has been a committed member of The Endocrine Society. With the exception of the 1989 meeting (during which she delivered her second child), she has attended every meeting of the Society since 1978. She is often seen pushing a baby carriage through the poster sessions at the meetings with one or both of her small children. In an era when many women feel forced to choose between family and career, Dr. Mellon has achieved a remarkable balance that includes both, offering an outstanding role model to young women entering science.
Citation for the Edwin B. Astwood Lectureship of The Endocrine Society to Marc E. Lippman The Endocrine Society has selected Marc Estes Lippman, M.D., Professor of Medicine and Pharmacology and Director of the Vincent T. Lombardi Cancer Center, Georgetown University School of Medicine, Washington, D.C., as the recipient of the 1991 Edwin B. Astwood Lectureship for scientific achievement for his outstanding basic and clinical contributions to the understanding and treatment of breast cancer. Dr. Lippman was born in Brooklyn, New York, received his B.A. magna cum laude from Cornell University and his M.D. in 1968 from Yale Medical School. He then carefully developed
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his skills and training in several relevant areas. After an internship and residency in internal medicine at Johns Hopkins, he moved to the NIH, where he was a Clinical Associate in the Leukemia Service of the NCI. After that, he moved to the Laboratory of Biochemistry of the NCI, where he took training in basic cell biology and steroid hormone action in E. B. Thompson's laboratory. There, Dr. Lippman carried out an important study showing a correlation in human leukemia between glucocorticoid receptor and response to therapy that included glucocorticoids. At the same time, he pursued basic research on glucocorticoid receptors in cultured leukemic cells. These studies provoked a widespread interest in the predictive role of glucocorticoid receptors in lymphomas and leukemias, a subject still under active investigation in a number of labs today. Returning to clinical medicine, Dr. Lippman took a fellowship in endocrinology at Yale and then was recruited back to the NIH to be a Senior Investigator in the Medicine Branch of the NCI. Shortly thereafter he became head of the Medical Breast Cancer Section. In this position he developed a program extending from fundamental biological research to clinical treatment of breast cancer. He supervised and led studies at NIH on correlations between steroid hormone receptors and prognosis for breast cancer. He carried out successful trials of new treatments for breast cancer, including aggressive chemotherapy for advanced breast cancer. In his laboratory he employed cell lines of human breast cancer to study mechanisms of development of resistance to hormonal therapy and
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the role of steroid hormone receptors in these cells. His work led to the findings that these cells make various growth factors and oncogene products, which themselves are often under steroid hormone control. Thus, the burgeoning understanding of the autocrine/paracrine growth control of cancer has benefited significantly by the studies from Dr. Lippman's group. The concept that steroid hormones are part of the important regulatory system that control the paracrine and autocrine factors driving malignant and normal breast epithelial growth has been a breakthrough in understanding this and other types of hormone-dependent malignancies and malignancies arising from hormone-dependent tissues. Dr. Lippman's group has specifically contributed to or originated discoveries that in breast cancer cells estrogen is involved in the regulation of transforming growth factor-a, transforming growth factor-/3, insulin-like growth factor-1-like protein, insulin-like growth factor-2, and platelet-derived growth factor. These findings are leading directly to the construction and testing of entirely new modes of therapy based on the interactions of the growth factors and their receptors. Dr. Lippman's research has not only involved breast cancer but also has included studies in renal malignancies, leukemias, Kaposi's sarcoma, cancer of the colon, and the uterus. In 1988 Dr. Lippman left the NIH to assume his current duties as Director of the Vincent T. Lombardi Cancer Center and Professor of Medicine and Pharmacology at Georgetown University. He has continued in his role as Clinical Professor of Medicine and Pharmacology at the Uniformed Services University of the Health Sciences. At the Lombardi Cancer Center Dr. Lippman and a large group of scientists he has attracted there continue to pursue their studies of breast cancer and other malignancies and their control by traditional and nontraditional hormonal systems. They are also deeply involved in the interactions of drugs with these growth regulatory systems and the trials of new therapies for breast cancer. Dr. Lippman's accomplishments have been recognized by invitations to present his work at numerous international and national locations. He has won a leadership role in both the endocrine and the cancer communities, having been chairman of the Gordon Conference on Hormone Action and an organizer of The Endocrine Society Course on Hormones and Cancer, as well as serving on a large number of important scientific and financial groups pertaining to oncology. Dr. Lippman serves on a large number of editorial boards for both hormone- and cancer-related subjects. These include Molecular Endocrinology, Journal of Steroid Biochemistry, Cancer Research, Journal of Clinical Oncology, and many others. At the Lombardi Center Dr. Lippman has quickly established a forceful and well funded outstanding group of investigators engaged in an important spectrum of work, pursuing his lifetime emphasis on bridging basic science to clinical science. He is an outstanding example of a member of The Endocrine Society who has first prepared himself well in both arenas and then used the findings of basic endocrine and biochemical sciences to extend the limits of the definitions and applications of endocrinology into areas both clinical and basic. He is a scientist and clinician who we can all be proud to have as a member of our Society and a fine example of the achievement meant to be honored by the Edwin B. Astwood Lectureship.
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Citation for the Robert H. Williams Distinguished Leadership Award to William D. Odell The Robert H. Williams Distinguished Leadership Award honors a member of The Endocrine Society who, in the image of Dr. Williams, has served the field of endocrinology and has nurtured generations of endocrinological scholars. The 1991 recipient is William D. Odell, M.D., Ph.D. Bill is appreciated worldwide for his remarkable range of abilities and accomplishments, covering research, education and training, patient care, and administrative leadership. Most of all, he is the perfect role model, esteemed as a clinician, as a physiological scientist, and as a person. Bill received his B.A. from the University of California at Berkeley, his M.D. from the University of Chicago, and his Ph.D. from George Washington University, the latter while he was working extremely productively at the NIH. His residency had been at the University of Washington, culminating with the Chief Residency. How fitting that Bill should receive the award that perpetuates the memory of his Chief, Robert Williams, a mentor he related to as a son to a father. He then spent the early sixties at the NIH, first as a fellow, then as a senior investigator. He learned endocrinology and science from Mort Lipsett, Griff Ross, and Roy Hertz, and he also honed his natural instinct for leadership. He then moved back to the West Coast as Chief of Endocrinology at Harbor-UCLA Medical Center (then Harbor General Hospital), where he developed, from scratch, one of the finest endocrine training programs in the country. Bill was the organizer, the recruiter (Stan Korenman, Del Fisher, Ron Swerdloff, and George Bray, to name a few), the driver, the model, and the inspiration. Since 1960 at the NIH, he has never stopped doing research with his own hands, no matter what administrative burdens he was carrying. In the 1960s at Harbor, he was always in the lab, always available to advise, stimulate, nurture, encourage, and comfort a growing group of fellows. One way to recount the story of Bill Odell's distinguished leadership in endocrinology is to list fellows who worked directly under his tutelage and who became household names in our field: at the NIH, Jack Wilber, Peter Kohler, and Phil Rayford; at Harbor, Ron Swerdloff, Pat Walsh (Urology), Jerald Nelson, Glenn Howard Jacobs (the U.K.), Glen Braunstein, Mark Molitch, John Marshall, Bob Rubin, David Heber, and many others. Even while chairing a large and growing Department of Medicine at Salt Lake City, he has continued to work directly with fellows. Reviewing this list, one concludes that a single super-motivator has given a crucial boost to at least 8 of the leading contemporary figures in academic, clinical, and physiological endocrinology. In all, he has been directly responsible for the postdoctoral development of 52 research fellows, of whom only 9 are not in academic work. He became chairman of the Department of Medicine at Harbor in 1972 and the University of Utah in 1980. In these posts he has brought his leadership qualities to the parent field, internal medicine. Each of his departments has grown and prospered. Bill's ability to inspire is not limited to endocrinology. His research has been original, courageous, at the forefront, often surprising, and always well buttressed by findings. With
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that question, but one can list some of his qualities that may have contributed: extraordinary energy, unflagging enthusiasm, indestructible optimism, solid dedication to his art and science, sincere concern with the welfare of his faculty and trainees, constant warmth and friendliness, unquestionable integrity, considerable generosity, sparkling creativity, and, despite all of this, a willingness to listen. Perhaps even more impressive is his equanimity, good humor, and the Odell smile. A leader in endocrinology, a leader in internal medicine, a personal leader among colleagues and students, Dr. William Odell richly deserves the Robert H. Williams Award.
Citation for the Ernst Oppenheimer Award of The Endocrine Society to Perrin C. White
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Bob Utiger and Jack Wilber he developed the first RIA for TSH and, with others, the first RIAs for LH, FSH, and human (h) CG. Later he added MSH and gastrin to his list. He used these RIAs (and, more recently, immunoradiometric assays) to expand our knowledge greatly—the MCR of the pituitary glycoproteins, their production rates, the hormonal correlates of the normal menstrual cycle, the signal system for the ovulatory surge of LH, the effect of oral contraceptives on the pituitarygonadal axis, and the hormonal basis for the onset of puberty— all of these were elucidated by Bill Odell and his colleagues. His RIA for TSH remained the standard method worldwide for well over 20 yr. His other area of continuous study has been the phenomenon of ectopic hormone production by cancers. An impressive body of his work now has established that several hormones {e.g. hCG, an ACTH precursor, vasopressin, and calcitonin) are present in normal cells of many tissues and has led to the inference that hormone production by cancers is not ectopic but rather is an exaggeration of a property possessed by normal cells. Wherever he has been, Bill has shown that the quadruple threat is still alive. He is a splendid teacher at all levels, starting with endocrine physiology for first-yr medical students at UCLA and University of Utah, which he has taught continuously for 25 yr. He is a superb clinical endocrinologist and, just as he is unwavering in research and teaching, he has never stopped being the doctor for a significant number of patients. How does this man do it all? No one can accurately answer
Dr. Perrin C. White, who is 40 years old, received his A.B. and M.D. degrees from Harvard University. He spent his first 2 yr of pediatrics training at Johns Hopkins Hospital, completed a 2-yr postdoctoral fellowship in developmental and molecular biology with Dr. Gerald Edelman at Rockefeller University, and finished his pediatrics training at the New York Hospital. He was appointed Assistant Professor of Pediatrics at Cornell University Medical College in 1981 after completion of his residency, was promoted to Associate Professor in 1987, and was granted tenure in 1989. Dr. White's research for the past 9 yr has concentrated on the molecular genetic analysis of inherited disorders of steroid metabolism, particularly the disorders of cortisol biosynthesis collectively termed congenital adrenal hyperplasia. One of these disorders, 21-hydroxylase deficiency, is one of the most common autosomal recessive diseases in man. At the time that Dr. White began his work, it was known that 21-hydroxylase deficiency was inherited as an autosomal recessive trait closely linked to the human leukocyte antigen major histocompatibility complex on chromosome 6. However, the identity of the defective gene was unknown. Dr. White purified the 21-hydroxylase enzyme from bovine adrenal glands, produced an antiserum to the protein, and used the antiserum to isolate a cDNA clone encoding the enzyme from a bovine adrenal cDNA library that he had constructed. He demonstrated that the corresponding gene was located in the major histocompatibility complex in both mouse and man, and that certain patients with 21-hydroxylase deficiency had a deletion encompassing the gene. Subsequently, he precisely mapped two 21-hydroxylase genes in the human genome, and showed that the second gene was a nonfunctional pseudogene. This work was carried out in the laboratory of Dr. Bo Dupont at Sloan-Kettering Institute, pending construction of Dr. White's own laboratory at Cornell, which opened in 1985. Since that time, Dr. White has completely analyzed the nucleotide sequences of the 21-hydroxylase genes, identifying several deleterious mutations in the nonfunctional pseudogene. His laboratory cloned and characterized mutant 21-hydroxylase genes from patients with 21-hydroxylase deficiency, demonstrating that transfers of deleterious sequences from the pseudogene to the normally active gene—a process termed gene conversion— account for most mutations causing 21-hydroxylase deficiency. This is the only human genetic disease where most defective alleles result from recombinations between the normally active
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ber of other physiologically important enzymes using molecular genetic techniques, most notably 110-hydroxysteroid dehydrogenase, the enzyme required for interconversion of cortisol and cortisone. This activity apparently confers ligand specificity on the type I (mineralocorticoid) receptor and is thus a crucial component of renal sodium homeostasis. Because 21- and ll/?-hydroxylase deficiencies account for about 98% of cases of congenital adrenal hyperplasia, Dr. White's work has almost completely defined the molecular genetic basis of this common inherited disease. This outstanding work makes him a most deserving recipient of the Ernst Oppenheimer Award.
Citation for the Fred Conrad Koch Award of The Endocrine Society to John T. Potts, Jr.
gene and a pseudogene. Dr. White also precisely mapped deletions of the 21-hydroxylase gene that constitute about onefourth of 21-hydroxylase deficiency alleles, showing that the unequal crossovers causing these deletions occur at characteristic points within the gene. In recent work, Dr. White and his associates expressed several mutant 21-hydroxylase enzymes in cultured cells using recombinant vaccinia virus, finding that the clinical severity of the disease correlates relatively well with the degree of enzymatic compromise. Deficiency of 11/3-hydroxylase is the second most common defect of cortisol biosynthesis after 21-hydroxylase deficiency. Dr. White cloned and characterized bovine and human cDNAs encoding 11/3-hydroxylase and found that there are two related genes on human chromosome 8. He determined the nucleotide sequences of both genes, and found that only one gene is expressed at high levels in the human adrenal cortex, although there are no obviously deleterious mutations in the second. He identified a mutation in the highly expressed gene associated with 11/3-hydroxylase deficiency in Jews of Moroccan origin; in contrast to the findings in 21-hydroxylase deficiency, this is a de novo point mutation and not a gene conversion. He recently found that the second 110-hydroxylase gene is expressed at high levels in aldosterone-secreting tumors and that it encodes a protein with enzymatic activities required for aldosterone synthesis. Consistent with this idea, Dr. White has shown that a mutation in or near one of the ll^-hydroxylase genes results in a defect in aldosterone biosynthesis termed corticosterone methyloxidase II deficiency. Dr. White and his colleagues have also characterized a num-
Our current understanding of calcium metabolism rests in large part on a series of discoveries made by John Potts. In a continually productive career spanning three decades, Potts has applied the rigor of biochemistry to difficult problems in physiology and medicine. John Potts went to medical school at the University of Pennsylvania (M.D. in 1957), at first solely because of interest in clinical medicine. His excitement about science, kindled during his clinical clerkship in internal medicine, began to focus on calcium metabolism during an elective with an inspiring parathyroid surgeon, Dr. Brooke Roberts. House officer training at the Massachusetts General Hospital introduced him to the traditions in parathyroid research established by Fuller Albright and Joseph Aub. He went then to Christian B. Anfinsen's laboratory in the National Heart Institute with the plan to receive broad training in protein chemistry in order to tackle, subsequently, the problem of characterizing the parathyroid hormone molecule. This decision to apply rigorous biochemical tools to approach physiological and clinical problems characterizes much of Potts's subsequent career. After studying ribonuclease with Anfinsen, Potts established his own laboratory in the National Heart Institute and initiated, in collaboration with G. D. Aurbach, who had also just established a laboratory at NIH, a series of studies on PTH; Potts and Aurbach combined their skills in protein chemistry and the biology of calcium metabolism to work on PTH and related issues for 7 yr. The purification of the hormone led Potts and Aurbach, in collaboration with S. A. Berson and R. S. Yalow, to the development in 1963 of a sensitive RIA that provided, for the first time, an accurate and precise method for the measurement of PTH levels in blood. This advance permitted systematic studies of the control of secretion of the hormone in animals. These landmark experiments established the basic features of the feedback regulation of PTH secretion by calcium. By applying several new strategies for protein sequencing, Dr. Potts and colleagues determined over a 5-yr period, the complete amino acid sequence of bPTH. During the time that the work on PTH progressed, Potts and his colleagues began work on the chemical properties of calcitonin, discovered in 1962 by Harold Copp and Paul Munson. Potts and colleagues, working with Munson, reported the isolation and complete amino acid sequence of porcine calcitonin. Potts and coworkers then deduced the complete amino acid sequence of salmon calcitonin in a collaborative study with
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Harold Copp. Salmon calcitonin has subsequently been introduced worldwide in the therapy of Paget's disease of bone and other disorders. In 1968 Dr. Potts assumed the position of Chief of the Endocrine Unit at the Massachusetts General Hospital. His group there deduced the complete amino acid sequences of porcine and human PTH. The latter achievement was especially important, since nonhuman PTH was too immunogenic for diagnostic or therapeutic use in humans. Potts and colleagues achieved the complete synthesis of the biologically active portion of the bovine hormone in 1970. Later, as work on the human hormone progressed, the active portion of the human hormone was synthesized. The availability of a chemically defined form of the human hormone permitted Potts and colleagues to introduce the hormone into clinical investigation. Potts and colleagues have continued to the present time their work with the synthesis of PTH; over 100 fragments and analogs have been made of the bovine, porcine, rat, and human hormones. These have been applied to systematic evaluation of structure/activity studies of the hormone using a variety of biological test systems in vivo and in vitro. Most recently, Potts and colleagues have used site-directed mutageneis of recombinant DNA expression vectors to generate and characterize hundreds of PTH analogs. Further, bacterial expression vector has been used to synthesize large amounts of full-length hPTH. The group's recent cloning of cDNA encoding PTH receptors from cultured bone and kidney cell lines will further the analysis of PTH action. Dr. Potts and colleagues have been able to define the minimum structure necessary for expression of hormone action and
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the contributions of individual residues. In related studies, they established that the deletion of specific portions of the amino terminus of the molecule produced peptides which bound to receptors but did not activate subsequent biological responses in the test tissue. This work has led to the development of a competitive inhibitor of PTH action that is active in vivo. Potts and colleagues initiated a wide ranging series of investigations in the biosynthesis of the hormone in collaboration with Dr. Alexander Rich at MIT. The group was the first to identify the initial gene product of a polypeptide hormone. They isolated and sequenced preproPTH, the initial product of translation of the mRNA for the hormone, in work using mRNA translation in cell-free systems. The group has subsequently characterized DNA complementary in sequence to the mRNA for bovine, human, and chicken PTH, as well as human and rat PTH genomic DNA. Throughout his investigative career, Potts has been interested in the clinical applications of these basic research advances. Beginning with the early development of the RIA for PTH Potts and colleagues have applied this technique to the study of abnormalities in PTH production that occur in hyperparathyroidism. Guided by the extensive structure-function analysis of PTH and by their characterization of PTH's metabolism, Potts and colleagues recently developed a two-site immunoradiometric assay for PTH. This assay, and equivalents subsequently developed by others, measures only intact, biologically active hormone and has unprecedented sensitivity. Most importantly, the assay can separate completely those hypercalcemic patients with hyperparathyroidism from patients with malignant hypercalcemia. Potts and colleagues have introduced a variety of diagnostic tests employing infusions and injections of the synthetic PTH into patients with hypoparathyroidism. Therapeutic trials are
also being undertaken with the PTH in small doses in combination with other agents such as vitamin D3 in an attempt to reverse the severe bone mineral loss seen in patients with osteoporosis. Potts and colleagues were the first to introduce calcitonin into the therapy of Paget's disease. Although Dr. Potts's research accomplishments form the primary basis for his designation as Koch Awardee, he also has served endocrinology well in other ways. Dr. Potts has been and continues to be an outstanding mentor of younger colleagues in the endocrine field. He has unselfishly guided the careers of many endocrinologists in his roles as Director of the Endocrine Fellowship Training Program (1968-1981), Chief of Medicine (1981 to present), and Director of the PhysicianScientist Training Program (1984 to present) at the Massachusetts General Hospital. Dr. Potts has played an active role in the leadership of several organizations that further endocrinology. He has served on the Council of the NIDDK (1982-1987), has had a variety of leadership roles in the organization of the International Conferences on Calcium Regulating Hormones (1968-1986), has been a member of the Institute of Medicine (1986 to present), and served as President of The Endocrine Society (1987 and 1988). Dr. Potts's impressive accomplishments have been recognized by a series of honors over the years, including the Ernst Oppenheimer Award of The Endocrine Society and the Prize Andre Lichwitz. In 1987, he received the William F. Neumann
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THE ENDOCRINE SOCIETY
JCE & M • 1991 Vol 73 • No 2
Award, the highest award of the American Society of Bone and Mineral Research. Dr. Potts moves back and forth between his research, teaching, and administrative interests with tremendous energy and enthusiasm. He brings to these activities authentic concern for the lives and careers of his colleagues. The Endocrine Society thus honors with the Koch Award an innovative investigator and an inspiring leader.
Citation for the Distinguished Service Award of The Endocrine Society to Francine L. Trull The Distinguished Service Award of The Endocrine Society for 1991 is presented to Francine L. Trull, known to all as Frankie. Because Frankie and the National Association for Biomedical Research (NABR) are only one institution, we must first state what is the NABR. It is a nonprofit organization which was established in 1979 and was consolidated in 1985 with the National Society for Medical Research. NABR supports the responsible use and humane care and treatment of laboratory animals in research, education, and product safety testing. Further, NABR believes that only as many animals as necessary should be used; that any pain or distress animals may experience should be minimized; and that alternatives to the use of live animals should be developed and employed, wherever feasible. Still, NABR recognizes that now and in the foreseeable future it is not possible to completely replace the use of animals and that the study of whole, living organisms is an indispensable element of biomedical and veterinary research. NABR membership includes more than 350 institutions: universities, medical and veterinary schools, teaching hospitals, voluntary health agencies, academic and professional societies, as well as pharmaceutical and laboratory animal breeder companies. It is satisfying to report that The Endocrine Society, upon recommendation of its Public Affairs Committee, became an early member of NABR, in 1982. At the beginning, NABR was Frankie Trull. To a large extent, this remains true. So, let us now consider Frankie the individual. She started her academic life at Randolph Macon Woman's College in Virginia where she could also pursue her life-long interest in horses. However, after a short while, she returned home to Massachusetts to earn a B.A. degree in history, cum laude, in 1972. During the next 5-6 yr, Frankie combined a career of Administrator at the School of Dentistry of Tufts University and of student for an M.A. degree in Sociology, specializing in the field of organizational behavior. During those years in Boston, her work in planning Tufts' School of Veterinary Medicine brought her to the halls of state legislatures, governors' offices, and Congress. Her dedication to animal science, her organizational skill, and her ability to communicate brought her to the attention of Tufts President Jean Mayer. At that time, the animal rights movement, the modern-day heir to victorian antivivisection, was becoming more active in the United States. A group of academic and industry leaders approached Frankie to ask whether she would help the biomedical research community to respond to the challenge. Because of Frankie's talents and
despite her consideration of a doctoral degree, President Jean Mayer counseled her: "It is a shame to interrupt your present educational process for a Ph.D. degree." Frankie Trull listened to the advice and in 1980, as its lone staff member, she founded the Association for Biomedical Research, devoted solely to animal research issues. Given its tiny budget, mailing to members originated on the Executive Director's living room floor. By 1983, with a small but growing membership and income barely above $100,000, NABR had taken its place among existing scientific groups active in the nation's public policy arena. It was also recognized that, to address the general public more effectively about the importance of animal research for continued medical progress, a broader effort was required. A sister organization, the Foundation for Biomedical Research, was founded for the sole purpose of public education. With Frankie Trull at the helm of both NABR and the Foundation, guided by two boards of directors made up of distinguished scientists from academia and industry, a unified voice began to be heard advocating the vital role of laboratory animals in the search to relieve suffering and save lives. To respond to increased congressional and public interest in these issues, NABR and the Foundation moved to Washington, D.C. in 1984. Presently, NABR plays a central role in working with Congress and federal agencies on legislation and regulation which furthers the goal of continued responsible animal research.
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THE ENDOCRINE SOCIETY Meanwhile, the Foundation has made enormous strides in public education, producing much needed resources for the scientific community's use, including videotapes, brochures, press kits, public service announcements, and a poster series. Working with a network of state-level organizations, the Foundation has offered spokespersons and background information for all forms of media. Without Frankie's talent, dedication, and sustained efforts
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over the years, biomedical research and educational programs could not have survived the unrelenting attacks of the misguided animal rights movement. For the essential leadership she has provided as President of the National Association and Foundation for Biomedical Research, The Endocrine Society is very pleased to honor Frankie Trull with the Distinguished Service Award for 1991.
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