The Endocrine Society 1990 annual awards.

0021-972X/90/7102-0536$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society

Vol. 71, No. 2 Printed in U.S.A.

THE ENDOCRINE SOCIETY 1990 ANNUAL AWARDS Citation for the Fred Conrad Koch Award of The Endocrine Society to Donald F. Steiner The Endocrine Society has chosen Donald F. Steiner as the recipient of the Fred Conrad Koch Award for 1990. Steiner pioneered and established the field of protein precursor biosynthesis and processing and has remained a key figure in this area for 20 yr. He is widely considered one of the most outstanding scientists involved in diabetes research and has made numerous important discoveries which have had a profound influence on this field as well as on many other areas of endocrinology. Steiner was born in Lima, OH in 1930. He attended the University of Cincinnati (BS, 1952) and the University of Chicago [MS in Biochemistry; MD in 1956 (AOA)]. During medical school he undertook a research project on in vitro antibody production with Professor Herbert Anker. Its success was a major influence in his decision to pursue a research oriented career. After completing medical school, he did an internship followed by several years of fellowship in Endocrinology and Metabolism at the University of Washington in Seattle under the guidance of Robert H. Williams. In this setting, Steiner's interests in endocrine mechanisms in general and insulin in particular were stimulated. After four very productive years in Seattle, Steiner was offered a position as an Assistant Professor in the Department of Biochemistry at the University of Chicago. The atmosphere in the Department which was chaired by Earl A. Evans, Jr., was most supportive, of the continued development of Steiner's independent intellectual and scientific growth. This setting, with its intimate contact between basic and clinical departments, provided Steiner with a special opportunity to look into the challenging question as to how the two constituent chains of insulin were linked together and this enquiry led to the seminal discovery of the first hormone precursor, proinsulin, in 1967. In the several years after the identification of proinsulin, Steiner made a series of fundamental observations of great importance. He characterized proinsulin from normal islets of Langerhans and human islet cell tumors in a series of careful and incisive experiments that unequivocally demonstrated its precursor role and defined its covalent structural organization. He was also the first to demonstrate that proinsulin is present as a contaminant in crystalline insulin prepared for commercial use, and subsequently he and his co-workers purified bovine proinsulin to homogeneity from bovine insulin and determined its complete covalent structure. Steiner also demonstrated that reduced and unfolded proinsulin regenerated the native oxidized structure of insulin in much higher yields than isolated A and B chains. Further research on the biosynthetic processes

of the islets then led to the discovery that proinsulin is converted to insulin within the (S-cells during secretion granule maturation by a proteolytic mechanism which he and his colleagues defined and are continuing to study in detail. A related finding was that the C-peptide fragment derived from the intracellular conversion of proinsulin to insulin is retained in the islet secretion granules and released in equimolar amounts with insulin. Steiner and co-workers then developed methods for purification and microsequencing of C-peptides from many species including humans, enabling them to correctly predict the structure of human proinsulin in 1971. In collaboration with Arthur H. Rubenstein, Steiner established that both proinsulin as well as the C-peptide circulate in the plasma in man. Appropriate RIAs were then developed to measure these peptides and Rubenstein and Steiner and their co-workers have used these to define the metabolic parameters of proinsulin and C-peptide in man and to effectively characterize many aspects of normal and abnormal islet physiology in humans, including the progressive decline of islet function in juvenile diabetes and the disordered processing of precursors by islet cell tumors. In later studies Steiner and co-workers demonstrated the 536

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THE ENDOCRINE SOCIETY existence of a larger precursor of proinsulin which they designated preproinsulin. In addition to thoroughly exploring the production, cleavage, and kinetic behavior of preproinsulin, Steiner and co-workers used radiochemical microsequencing techniques (developed earlier in his laboratory for studies of Cpeptide processing and secretion) to define the amino sequence of the N-terminal extensions of rat preproinsulin. Later he and his co-workers developed the first full-length cDNA clones of both rat preproinsulin mRNAs (and later of human preproinsulin). These studies along with others on the initial translation products of insulin mRNA in vitro taken altogether led to the complete elucidation of the primary structures of the translation products of the insulin genes in rats (and later on in such evolutionary remote species as the Atlantic hagfish (Myxine glutinosa) and divergent New World species, such as the guinea Pig)In collaboration with workers at Cetus Corporation, Steiner's laboratory was the first to produce and characterize biosynthetic human proinsulin (in Escherichia coli). Human proinsulin is now produced commercially by several companies. In the early 1970s, Steiner and his co-workers began to extend the precursor concept to other systems, first to glucagon with the discovery of a larger form in 1973, and later with the successful identification and characterization of both proglucagon and prosomatostatin from rat islets. This body of work, and especially the pioneering studies on proinsulin and preproinsulin, have provided a paradigm for biosynthetic protein processing which is now widely recognized as universal in its relevance in eukaryotic organisms. In addition, in more recent studies, Steiner with his co-workers and Tager and Rubenstein have been the first to identify mutations in the human insulin gene in several patients. These abnormal insulins were associated with impaired carbohydrate metabolism, or in some instances, overt diabetes. Steiner has also made significant contributions to studies on the mechanism by which insulin produces its metabolic effects. His earlier studies concentrated on the role of insulin in the liver, supporting the idea of a direct metabolic as well as trophic effect on this organ. He identified increased synthesis of RNA, proteins, and glycogen as very rapid effects of insulin, providing some of the earliest evidence for effects of insulin on gene expression, in addition to its well known effects on sugar and amino acid transport. Studies on insulin degradation by isolated hepatocytes with Susan Terris provided the first evidence linking receptor binding to the metabolic handling of the hormone. The discovery that receptor-bound insulin is taken up and degraded by liver cells contributed importantly to the development of the concept of receptor-mediated endocytosis and has been confirmed in parallel studies in other laboratories on such diverse substances as low density lipoprotein, epidermal growth factor, and bacterial toxins. The recognition of internalization and recycling as aspects of insulin receptor function has influenced views regarding both insulin action and metabolic clearance. Studies are currently in progress in Steiner's laboratory on aspects of the cell biology of insulin biosynthesis, intracellular transport, and processing, the identification of islet cell surface antibodies in diabetes, the identification of mutations that

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affect the proteolytic processing of the insulin proreceptor, and the identification of new secretory products of the /3-cells that may play a role in diabetes. His work has had major impact on methods of production of insulin, on theories of the pathogenesis and treatment of diabetes, on concepts regarding the mechanisms of production and action of insulin and on fundamental concepts of the cell biology of neural and endocrine peptide production. In addition to his research accomplishments, Steiner has had a major influence on the scientific milieu at the University of Chicago, where he was appointed the A. N. Pritzker Distinguished Service Professor of Biochemistry a,nd Molecular Biology and Medicine in 1984. He served at Chairman of the Department of Biochemistry (1973-1979), Director of the Diabetes Research and Training Center (1974-78), and President of the University of Chicago Medical Alumni Association (19881989). He is currently a Senior Investigator in the Howard Hughes Medical Institute. He has also been a member of numerous advisory committees to other institutions and was a member of the Diabetes, Endocrinology, Digestive and Kidney Diseases Institute Advisory Council of the NIH. Steiners's accomplishments have been recognized by numerous named lectures, awards, and honors. Among these are The Lilly Award and Banting Medal of the American Diabetes Association, The Ernst Oppenheimer Award of The Endocrine Society, The Gairdner Award, The Passano Foundation Award, The Borden Award of the AAMC, the David Rumbough Award of the Juvenile Diabetes Foundation, and the Wolf Foundation Prize in Medicine. He received Honorary Degrees from the University of Umea in 1973 and the University of Illinois in 1984. He is a member of the National Academy of Sciences. Despite Steiner's great success he remains a modest and unassuming individual. He is the most wonderful example of a dedicated scientist, who continues to work in the laboratory with obvious enthusiasm and enjoyment. His brilliant and vigorous analysis of experimental data, his creative instincts about new directions in research, his exemplary personal scientific standards, and his generosity and kindness to numerous students, postdoctoral fellows, and colleagues are greatly admired. By recognizing Steiner with the Koch Award, The Endocrine Society is honoring a dedicated and innovative investigator whose approach to science has and will continue to inspire all who are fortunate enough to interact with him. Citation for the Edwin B. Astwood Lectureship of the Endocrine Society to Stephen B. Baylin The Endocrine Society has selected Stephen B. Baylin, MD, Professor of Oncology at the Johns Hopkins University School of Medicine to receive the 1990 Edwin B. Astwood Lectureship for scientific achievement for his outstanding basic and clinical contributions to our understanding of the biology and oncology of the neuroendocrine system. Dr. Baylin was born in Durham, NC and received both his BA (1964) and MD (1967) degrees from Duke University. After spending a year each of internship and residency in Internal Medicine at the Duke University Medical Center, he spent 2 yr as a Research Investigator and Staff Associate in the Experimental Therapeutics Section of the National Heart and Lung


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Institute at the NIH. He then moved to Baltimore and the Johns Hopkins University School of Medicine where he spent an additional year as an Assistant Resident in Internal Medicine followed by two years of Fellowship in Physiology and Endocrinology. In 1974, Dr. Baylin was appointed Assistant Professor of Medicine at the Johns Hopkins University School of Medicine and in 1979, he was appointed Associate Professor of Medicine. In 1986 he was appointed Professor of Oncology. Dr. Baylin's work has focused on the constituent endocrine cell populations that make up human tumors, both those that arise directly from endocrine cells (medullary thyroid carcinoma) and those that arise within complex epithelial systems, but have endocrine features (small cell carcinoma of the lung). In medullary thyroid carcinoma (MTC), Dr. Baylin and his collaborators have defined the evolution of cell populations in the tumor and how the biochemistry of MTC cells reflects progression and virulence of the disease. They have described how the changing cell populations reflect the endocrine differentiation status of the neoplastic C-cells, what molecular functions regulate differentiation, and how the regulation of normal differentiation may be disrupted during tumor progression. Dr. Baylin's group early showed that medullary thyroid carcinoma is a clonally derived neoplasm which develops, during tumor progression and with increasing virulence of the disease, heterogeneous cell populations with regard to calcitonin (CT) and other markers, dopa decarboxylase (DDC), and diamine oxidase (DO). Furthermore, the demonstration of an inverse relationship between CT and DDC in virulent tumors suggested that a progressive maturation block to endocrine differentiation was a hallmark of tumor progression in MTC. For the past several years Dr. Baylin and his associates have attempted to understand the molecular parameters of the differentiation block in MTC with the hope that elucidating these might explain the origins of the tumor, the determinants of its progression, and the determinants of endocrine cell differentiation in general. For this purpose, Dr. Baylin's group used a culture line of human medullary thyroid carcinoma (the TT cells) to derive an in vitro model system of endocrine cell differentiation. They focused on manipulating calcitonin production in these cells as a measure of C-cell differentiation. As a direct result of this work, his group cloned the human CT gene for purposes of monitoring its expression at a molecular level and determining its chromosomal location. They also demonstrated that expression of the CT gene, including its

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mRNA splicing patterns, is carefully regulated during simple growth of MTC cells. Dr. Baylin's group also showed that the differentiation status of the MTC cells is controlled by alterations in the protein kinase C and protein kinase A pathways. Most importantly, the coordination of differentiation control is achieved with insertion of the mutated Harvey ras oncogene which stops cell growth, increases CT gene transcription and mRNA splicing to CT and induces the cells to form mature neurosecretory granules. These observations formed the basis for further understanding of how the ras gene differentiates the C-cells, what signal transduction events ensue, and most importantly what genes for transcription factors play the crucial role in maintaining differentiation of C-cells. In recent studies, Dr. Baylin and his collaborators have investigated the genetic events which underlie development of inherited and spontaneous MTC. Their results suggested how an initial inherited germ line event may contribute to preceding C-cell hyperplasia in familial forms of the disease, while subsequent somatic genetic alterations underlie clonal evolution of the MTC. The study of small cell lung cancer by Dr. Baylin's group has followed a somewhat similar course to that described for medullary thyroid carcinoma. The work has contributed some of the early concepts regarding the presence of cellular heterogeneity in human tumors and has helped to clarify the origin and cell differentiation relationships of endocrine cells derived in complex epithelial systems. The biochemical study of his group 10 yr ago suggested two things: small cell carcinoma like MTC (but even more dramatically) had a very heterogeneous cell constituency for expression of endocrine features and loss of these seemed to accompany tumor progression. Furthermore, there was a spectrum of nonsmall cell lung carcinomas with a distinct neuroendocrine profile. It was hypothesized that small cell lung carcinomas might arise from an endocrine oriented cell that was endodermally derived in the bronchus and related along a differentiation spectrum to the other epithelial cells that gave rise to squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated lung carcinoma. During the last several years, Dr. Baylin's group has attempted to follow the above hypothesis by modeling in tissue culture the transition of small cell carcinoma to nonsmall cell carcinoma. His group has demonstrated that the transition from small cell to large cell carcinoma with an accompanying loss or decrease of endocrine features can be accomplished by insertion of the mutated ras oncogene into small cell tumors which have an amplified C-myc oncogene. In their latest work involving cotransfection studies, Dr. Baylin's group has gained direct evidence that both myc and ras are absolutely required to make this change. The change is accompanied by the switching on of growth factor genes such as the epidermal growth factor receptor gene, transforming growth factor a and plateletderived growth factor, which are not expressed in small cell tumors. In small cell tumors which have unusually well developed endocrine features, such as very high transcription and expression of the CT gene, expression of the mutated ras gene has a distinctly separate effect. Rather than causing a transition to the large cell phenotype, the oncogene causes a similar


THE ENDOCRINE SOCIETY increase in endocrine cell differentiation to that seen with MTC cells. The above work in small cell lung cancer strongly suggests that pulmonary endocrine cells are linked along a differentiation spectrum to the other epithelial cells of the bronchial mucosa which are endodermally derived. A model system has resulted to further understand this process, to determine the molecular control mechanisms, and to understand how position and cell lineage determine complex cellular responses of endocrine cells to the ras family of genes. In addition to the substantial accomplishments mentioned above, it should be mentioned that Dr. Baylin exemplifies the best attributes of the physician scientist. He has served as an excellent role model for investigators both in this country and abroad and his laboratory has been a training ground for many young and maturing scientists. In addition to The Endocrine Society, he is member of several other major societies, including the American Society for Clinical Investigation, the American Federation for Clinical Research, and the American Association of Cancer Research. He has served on several study sections, advisory groups, and councils for the National Institutes of Health and American Cancer Society and he has been elected to aQa. He is a respected leader in the fields of oncology and endocrinology and his many important contributions make him an ideal investigator to be awarded the Edwin B. Astwood Lectureship of The Endocrine Society.

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University honored Dr. Avioli in 1972 with an endowed professorship. His growing interest in metabolic bone disease and calciotropic hormones culminated in the University's decision to develop a new Division of Bone and Mineral Diseases in 1979 under his direction. He is currently in his 16th year as Director of an NIH postdoctoral training grant which has been pivotal to the education of 119 trainees. Dr. Avioli has also provided organizational leadership and service to endocrinology and related fields. He was coeditor of The Journal of Clinical Endocrinology and Metabolism from 1973-1977, and Editor 1977-1978. He served on the Council of The Endocrine Society from 1984-1987 and is currently a representative of the United States Endocrine Society to the Central Committee of the International Society for Endocrinology. As an endocrine consultant to the NASA Space Science Board from 1973-1978, he chaired the endocrine panel which was enjoined by the National Academy of Sciences to evaluate the effects of prolonged space flight on bone and endocrine systems. He is a reviewer in endocrinology for the Accreditation Council for Graduate Medical Education, and also serves currently as a member of the Advisory Panel on Endocrinology for the US Pharmacopeial and the National Formulary. Dr. Avioli has served as a member (and chairman) of both the NIHAMD General Medicine B and Metabolic Disease Program Project Study Section Committees; he has been Chairman of the Gordon Conference of Bones in 1982, and has served as a consultant to the Public Health Services of China, Finland, Australia, and Canada. Dr. Avioli was also the founder and

Citation for the Robert H. Williams Distinguished Leadership Award of The Endocrine Society to Louis V. Avioli The Robert H. Williams Distinguished Leadership Award

traditionally honors a member of The Endocrine Society for distinguished service in the field of endocrinology. The 1990 recipient is Louis V. Avioli, currently Shoenberg Professor of Medicine and Professor of Cell Biology and Physiology of the Washington University School of Medicine, Director of the Division of Bone and Mineral Diseases at the University, and Director of Endocrinology at the Jewish Hospital of St. Louis. Considered as one of the country's leading medical authorities on osteoporosis and metabolic bone disease, Dr. Avioli has not only achieved great distinction as an investigator in bone cell metabolism and the biological actions of the calciotropic hormones, but also for his continued service as an educator in academic endocrinology. Lou received his BA at Princeton University, magna cum laude, and his MD from Yale University where he won the class award for his graduate thesis detailing studies performed with Dr. Joseph Fruton, Chairman of Biochemistry. He subsequently completed a medical residency at the North Carolina Memorial Hospital and then served as a research fellow at the National Cancer Institute under Drs. Mortimer Lipsett and Roy Hertz. He joined the nascent faculty at the New Jersey College of Medicine in 1960, where he progressed academically to Director of Endocrinology. He transferred his activities in 1965 to the Endocrine Division of Washington University School of Medicine where he successfully established a satellite division of endocrinology at The Jewish Hospital of St. Louis. Washington


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past president of the American Society for Bone and Mineral Research and has been Editor-in-Chief of Calcified Tissue International for the last 12 yr. Lou's many contributions have achieved global recognition by the academic community. In 1979 the French government bestowed upon him the coveted Andre Lichwitz International Prize for research in bone and mineral metabolism, in 1987 the American College of Nutrition honored him with the Physician Teacher Investigator Award, and in 1988 his "distinguished achievement in the field of bone and mineral research" merited him the prized William F. Neuman Award of the American Society for Bone and Mineral Research. The Japanese honored him with a life-long appointment to the Japanese Endocrine Society, and the Spanish named him Professor of Medicine and Endocrinology at the University of Madrid, a distinction awarded only three times since Spain became a democracy. In 1967 Dr. Avioli was one of the first to document the biological activation of vitamin D in humans and the pivotal

role of hepatic fnction in this regard. In 1968, he and his collaborators were also first to define the essential role of the human kidney in the bioactivation scheme, reporting alterations in vitamin D metabolism in patients with chronic renal failure. In the subsequent years, he, together with his many trainees, reported on acquired alteration in vitamin D metabolism in humans induced by anticonvulsants, glucocorticoids, metabolic acidotic syndromes, and in patients with familial hypophosphatemic rickets. Dr. Avioli was also instrumental in designing studies to define the acquired alterations in calciotropic hormone metabolism in growing children with diabetes mellitus and the specific biological alterations in end organ responsivity to calciotropic hormones in diabetic models of diabetes mellitus. He has devoted his most recent research activities to studies designed both to characterize and to interpret signal-transduction pathways in the osteoblast and their modulation by the family of calciotropic hormones. He also has and continues to publish extensively about the diagnoses and therapies of osteoporotic syndromes and other metabolic bone diseases. His second edition of The Osteoporotic Syndrome: Detection, Prevention and Treatment proved to be a "best seller," and the 2nd edition of Metabolic Bone Disease and Related Clinical Disorders, which Lou recently coedited with Dr. Stephen Krane, will become available in the summer of 1990. Lou Avioli's career is studded with examples of leadership and academic achievements. His constant pursuits to inspire research fellows and younger academic peers alike with a relentless enthusiasm and an untiring energy has and continues to represent an enviable model of service for our discipline.

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Indiana University, and his PhD in Zoology /Endocrinology at Indiana University. In the period immediately after receipt of his doctorate he held a succession of positions, until he went to the University of Louisville School of Medicine as an Assistant Professor of Physiology and Biophysics. He remained in Louisville for 9 yr where he pursued a career in teaching and research on contractility of the heart. In 1967 Dr. Tolman began the journey which was to result in 20 yr of involvement with, and service to, endocrinology and endocrinologists. He was selected for the Grants Associate Program of the NIH, an individually tailored program for training bench scientists to become health science administrators. In 1969 he was appointed as the Endocrinology Research Program Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Disease, NIH. Although research in endocrinology is supported in some manner by all of the Institutes of the NIH, the major portion of it is supported through NIDDK. In 1969, when Dr. Tolman started, the Institute was called the National Institute for Arthritis and Metabolic Disease and its hormonal arm was responsible for grants and contract valued at roughly $13,000,000. Over the next 20 yr, investigative endocrinology flourished, and its administrative support at NIDDK, under Dr. Tolman's aegis, grew apace. The program currently supports over 300 grants and contracts with an annual budget in excess of $50,000,000. The essence of what Dr. Tolman has done over the years is to act as a crucial conduit between the endocrinologist, the study sections, and Council. To accomplish this, he assiduously

Citation for the Distinguished Service Award of The Endocrine Society to Robert A. Tolman The Distinguished Service Award, in recognition of outstanding service in the field of endocrinology, is given to Robert A. Tolman. Dr. Tolman's contributions to endocrinology, in his role at the NIH, have served almost every individual who has any kind of interest in endocrine investigation. Dr. Tolman was born and raised in Springfield, MA. He received his BS at the University of Massachusetts, his MA at



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attended every study section meeting that considered grants in endocrinology, so that the ultimate "pink sheet" was not passed to the investigator in a vacuum. It is hard to overestimate the importance of this aspect of Dr. Tolman's activity. Within days, sometimes minutes, of completion of the Study Section's deliberations, the phone at Dr. Tolman's office began an almost uninterrupted clamor— anxious endocrinologists seeking news. Borderline or downright poor scores were transmitted thoughtfully, and always with hope. "Fix this, change that, recast your thought," always said with kindness and optimism, helped many frustrated investigators to renew their efforts, and to be funded another day. He was the perfect, compassionate person to help endocrinologists, at their most vulnerable moment, to piece their egos back together for another try. Only they and he knew who might be pursuing other careers but for his encouragement and support. In addition to the time and spirit-consuming efforts of being a confessor and guide to applicants for grants, Dr. Tolman advised Council about what appeared to be "hot" in endocrinology. In this role, he was influential in planting the seeds for many RFPs which helped give shape to modern clinical and basic endocrinology. Robert Tolman's tenure at the NIH has exemplified the synergy that results from the selfless, thoughtful, intelligent, and caring administration of science. For that, we are in his debt. Citation for the Rorer Pharmaceutical Clinical Investigator Award of The Endocrine Society to J. Maxwell McKenzie The third recipient of the William H. Rorer Clinical Investigator Award of the Endocrine Society is John Maxwell "Max" McKenzie. Dr. McKenzie has for the past 9 yr been Kathleen and Stanley Glaser Professor and Chairman of the Department of Medicine at the University of Miami School of Medicine. A Scot by birth, born in Glasgow, Dr. McKenzie received his MB, ChB degree from St. Andrews. After his clinical training and early reserach experience, he crossed the Atlantic for two years at the New England Center Hospital with E. B. Astwood, returning to Scotland to receive his MD degree with honors from St. Andrews in 1958. He settled at McGill University in 1959, rose to the rank of Professor in 1968, became Director of the Endocrine-Metabolic Division in 1974, and contributed greatly to the Department of Medicine at McGill and the Royal Victoria Hospital until 1980 when he returned to the United States to assume his present position. In his travels, Dr. McKenzie became a Fellow of the Royal College of Physicians of Edinburgh, the Royal college of Physicians and Surgeons of Canada, and the American College of Physicians, a rare troika of fellowships. Dr. McKenzie's contributions are distinct, individual, original, and well known. The first was the development in 19571958 of a practical, sensitive, precise, and reliable bioassay for thyrotropin using mice. This became the standard assay for TSH in tissues and body fluids until RIA for TSH came along in 1963 and remained in use long after that. Second, and most notably, he applied this bioassay to the detection and rough quantification of the long-acting thyroid stimulator (LATS) of

Graves' disease, described 2 yr earlier by Adams and Purves. McKenzie's unique contribution here was to develop a practical method that allowed research to proceed rapidly. McKenzie's assay for LATS became known quickly all over the world and led to an explosion of studies that very soon transduced Graves' disease from a disorder of unknown etiology to the first example of an autoimmune endocrine hyperfunctioning state due to a stimulatory antibody. McKenzie contributed prominently to this transduction. He showed that LATS was not TSH bound to a plasma protein and later that it had all the characteristics of a 7-globulin and that its active portion was the antigen-combining Fab fraction. Further, he was the first to suggest that neonatal thyrotoxicosis was explained by placental transmission of this thyroid-stimulating immunoglobulin (TSI) from mother to fetus. He gave a Laurentian Hormone Conference on this whole topic in 1967. Other studies of Graves' disease poured out, energized by the availability of an assay for TSI, even though it was clear that the results using the mouse bioassay were not explaining all the phenomena of Graves' disease in man. With Liddle and Heyssel, he showed that at least some cases of the puzzling entity, euthyroid Graves' ophthalmopathy, could be explained by the coexistence of two autoimmune thyroid disorders, Graves' disease and Hashimoto's thyroiditis. With McCullagh, he presented evidence, later confirmed with more specific methods for assaying TSI, that LATS in serum could not explain Graves' ophthalmopathy. McKenzie and Zakarija then adopted a method of measuring the Graves' immunoglobulin by the ability of sera to increase cAMP generation in human thyroid tissue and showed that such activity is present in almost all Graves' sera. They also distinguished this thyroid-stimulating antibody from the thy-


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rotropin-binding-inhibiting immunoglobulin (TBII) demonstrated by others. They concluded that the TSI is the cause of Graves' hyperthyroidism, that LATS activity simply illustrates that species nonspecificity of the antibody is rather frequent, and that TBII and TSAb are not necessarily the same, and do not necessarily coexist. They renamed LATS/TSI as TSAb and summarized the evidence that TSAb is the cause of Graves' hyperthyroidism in a second Laurentian Hormone Conference. Next, by identifying both stimulatory and inhibitory immunoglobulins in mother's and child's sera in neonatal thyrotoxicosis, they showed that the time of onset of hyperthyroidism is determined by the relative concentrations of stimulary and inhibitory thryoid-directed immunoglobulins. During these studies, his groups identified at least three thyroid-membranedirected antibodies affecting the binding of TSH to its receptor. Finally, in recent work, Zakarija and McKenzie have presented strong evidence that there is no need to postulate the presence of a thyroid growth promoting immunoglobulin (TGI) in Graves' disease. They showed that cAMP (known to be increased in thyroid cells after stimulation with either TSH or TSAb) can itself explain thyroid cell hypertrophy. While creating this valuable body of research, Dr. McKenzie has also spent a great deal of time and energy providing leadership in academic medicine in North America. He received the Ayerst Award of The Endocrine Society; served as a Director, First Vice-President, and President of the American Thyroid Association; was a member of the editorial boards of The Journal of Clinical Endocrinology and Metabolism, Endocrine Research, and the Journal of Endocrinologic Investigation; was a member and chairman of the Endocrinology Grants Committee of the MRC of Canada; and was a career investigator of the MRC. His awards also include the Parke-Davis Distinguished Lectureship of the American Thyroid Association. He is a member of the American Society for Clinical Investigation and the Association of American Physicians. In recognition of his distinguished career in endocrinology and his unique contributions to our understanding of Graves' disease and neonatal thyrotoxicosis, The Endocrine Society is proud to present the Rorer Pharmaceutical Clinical Investigator Award to Max McKenzie.

Citation for the Richard E. Weitzman Memorial Award of The Endocrine Society to Marc R. Montminy

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nase-A) for activation. He showed that transfected kinase-A deficient cell lines were unable to support somatostatin transcription in response to forskolin. The observation that CRE sequences are highly conserved led him to propose that these elements would recognize a common nuclear factor. After moving to The Clayton Foundation Laboratories for Peptide Biology at The Salk Institute, he was able to detect CRE-binding activity in nuclear extracts of PC12 cells using a DNAse I protection assay. By employing DNA sequence-specific affinity chromatography he purified a 43 kDa protein (which he named CREB) to apparent homogeneity from PC12 cells and brain tissue. He discovered that purified CREB bound to DNA as a homodimer. When added to nuclear extracts, purified CREB specifically stimulated transcription of CRE-containing genes like somatostatin and this activity was markedly enhanced by kinase A phosphorylation, suggesting that CREB was an inducible transcription factor as well as a DNA-binding protein. Using partial amino acid sequence information on his purified proteins Marc went on to isolate a cDNA clone for CREB. When expressed in Escherichia coli, the protein encoded by this cDNA possesses CRE-binding activity which is identical to that of purified CREB. The predicted CREB sequence included a cluster of protein kinase-A, protein kinase-C, and casein kinase II consensus recognition sites near the N-terminus of the protein. The close proximity of these sites to one another suggests that they may interact to regulate CREB activity. With in vitro mutagenesis studies he has defined a single site which is phosphorylated and thereby activates CREB-mediated transcription. In agreement with his hypothesis, Marc has demonstrated that cAMP regulated transcription of cAMP responsive genes by phosphorylation of CREB at a defined site. CREB is, in fact, the first transcription factor whose regulation has been shown to be completely dependent upon phosphorylation. Thus, Marc established that the cDNA he obtained was actually a functional CREB based on a comparison of various properties (including protein sequence, dimerization, phosphorylation, and transcriptional activity in vitro) of the expressed and isolated proteins. A related but not identical cDNA was independently characterized by Joel Habener's laboratory which used a molecular screening approach. More recently, Marc's group has characterized a second trans-activating region, termed a, in the CREB protein, which is encoded by an alternate exon which is absent

Marc Montminy has made major contributions to the understanding of how hormones working through cAMP control gene transciption. Marc, who is 33 yr old, received MD and PhD degrees from Tufts University School of Medicine, working jointly with Richard Goodman and Joel Habener on the structure and regulation of the somatostatin gene. After cloning the gene, he discovered a promoter sequence conferring cAMP inducibility. This sequence included a palindromic core motif which was highly conserved among numerous cAMP inducible genes including VIP, a-chorionic gonadotropin, proenkephalin, CRF, tyrosine hydroxylase, and c-fos. The cAMP response element (CRE) displayed properties of a classical enhancer sequence, and was dependent upon cAMP-dependent protein kinase (ki-



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in the CREB-related cDNA reported by Joel Habener's group. The a-region interacts cooperatively with the kinase-A phosphorylation site to activate CREB, suggesting that phosphorylation may ultimately regulate CREB through an allosteric mechanism. Thus the alternative splicing of the CREB gene may reflect a means of regulating transcription factor activity. Marc has employed an impressive array of biochemical, molecular, and cell biological methods to solve a difficult and important problem that is fundamental to the understanding of how hormones control gene expression. The actions of many hormones are mediated by cAMP and it appears that CREB may be the major, if not exclusive, mediator of the transcriptional effects of cAMP. Marc is an outstanding independent investigator who has already made a major impact on Endocrinology and Cell Biology. There is no doubt that Marc will become one of the preeminent leaders of our field.

Citation for the Ernst Oppenheimer Memorial Award of The Endocrine Society to Michael Karin Dr. Michael Karin was born in Tel Aviv, Israel in 1951 where he grew up and received his BSc degree in biology from Tel Aviv University. He moved to the United States to enroll as a graduate student at the Molecular Biology Institute at the University of California, Los Angeles to broaden his horizons and receive more training in molecular biology. His doctorate studies concerned the regulation of human metallothionein gene expression and were under the guidance of Dr. Harvey Herschman. During these graduate studies, Dr. Karin first demonstrated that metallothionein synthesis is induced by glucocorticoids and proposed that this induction explains how glucocorticoids exert their known effect on zinc uptake. After further characterizing this system, he then first demonstrated that glucocorticoids are primary inducers of metallothionein mRNA accumulation. After receiving his PhD in 1979, Dr. Karin spent 1 yr as a postdoctoral trainee with Dr. Beatrice Mintz at the Institute for Cancer Research in Fox Chase, PA. During that time, he was the first to characterize the pathway for transferrin uptake and demonstrated that both transferrin and its receptor are recycled after endocytosis, while the bound iron was released within a lysosome-like compartment. His paper published in the Journal of Biological Chemistry paved the way to a series of observations on this unique endocytosis pathway, made in other laboratories. With the intention of acquiring first-hand expertise in the emerging technology of recombinant DNA, Dr. Karin moved to San Francisco to join the laboratory of Dr. John Baxter at UCSF. There he got involved in studies on the regulation of GH gene expression and was among the first to demonstrate that a transfected GH gene can still be regulated by glucocorticoids, thus indicating that the cloned gene contains sequences required for regulation. However, not forgetting the use of the metallothionein system for studies on gene regulation, Dr. Karin has dedicated a large proportion of his time to the isolation and characterization of the human metallothionein Ha gene. In 1982 in an article published in Nature, he was the first to demonstrate that the human genome contains a processed pseudogene derived from a perfect reverse

transcript (cDNA) of metallothionein Ha mRNA. Soon after that similarly generated pseudogenes were found in other laboratories. In 1982 Dr. Karin took the position of Assistant Professor at the Department of Microbiology at the University of Southern California in Los Angeles and in the beginning of 1988 left USC to become an Associate Professor of Pharmacology at the University of California at San Diego, where he became a full professor in 1989. Dr. Michael Karin has made numerous contributions to the fields of eukaryotic gene regulation and molecular endocrinology. He is best known for studies that originated with the characterization of the human metallothionein Ha promoter. In a series of papers published in Cell and Nature his group was the first to show that a promoter of a eukaryotic gene is composed of multiple regulatory elements each of which is dedicated to a different signal transduction pathway. In collaboration with Dr. Miguel Beato in Marburg, Germany, he was the first to identify binding sites for the glucocorticoid receptor on a cellular gene and identified the consensus sequence of the glucocorticoid response element. His group has also shown that different metallothionein genes are differentially regulated because of basic differences in their promoter structures. These studies together with those done in the laboratory of Dr. Richard Palmiter at Seattle on the mouse metallotionein I gene have paved the way for the wide spread use of the metallothionein promoter system for inducible expression of foreign genes by both academia and industry. After studying the cis elements of the hMTIIa promoter, Dr. Karin's group has begun to identify the transacting factors that recognize these elements. These studies have resulted in the identification of two novel transcription factors AP-1 and AP-2 that are regulated by two of the major signal transduction pathways involving protein


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kinases A and C. In fact, the work on AP-1, published in Cell, showed that this factor mediates many of the effects that phorboles ester tumor promoters exert on gene expression. This important discovery has led to many others, culminating in the identification of AP-2 as a protein complex composed of the products of the c-jun and c-fos protooncogenes. This seminal finding has bridged the fields of oncogene research, signal transduction, and transcriptional control. Dr. Karin's group is continuing to study these important transcriptional factors and recently demonstrated that some members of the jun gene family encode proteins that act as negative regulators of the cjun gene. In collaboration with Dr. Tony Hunter's group it was shown that the activity of c-jun is regulated posttranslationally by phosphorylation and dephosphorylation of a specific residue near the DNA-binding domain of that molecule. This is probably the first example of how protein phosphorylation affects DNA-binding activity. Dr. Karin's group has also made important contributions to the understanding of cell type specific gene expression in higher

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eukaryotes. They have identified, purified, sequenced, and isolated a cognate cDNA for a putuitary specific transcription factor, GHF-1, that binds and activates the GH promoter. GHF-1 has turned out to be a homeodomain protein-another breakthrough discovery that helped to bridge the fields of developmental biology and transcriptional control by providing proof that homeodomain proteins are sequence specific transcription factors. Dr. Karin and his collaborators have recently shown that GHF-1 is specifically expressed during embryonic development in the cells that will give rise to the somatrotrophs in the mature pituitary. They were also the first to demonstrate that the transcription of a cell-type specific transcription factor is subject to hormonal regulation, in this case by GRF and cAMP. Dr. Karin has been serving on the editorial board of the Society's journal Molecular Endocrinology since its inception. He is also a member of several other editorial boards including those of DNA, Molecular Carcinogenesis and Genes, and Chromosomes and Cancer. Several years ago, Dr. Karin was chosen as a Searle scholar.


Endocrine Society Laureate Awards.

95th annual meeting of the Endocrine Society.

Pfizer awards 1990.

ISBER annual awards.

Countdown begins to seventh annual BMJ Awards.

Proceedings of the British Medical Ultrasound Society. 22nd annual meeting. Harrogate, December 4-6, 1990. Abstracts.

Quantitative approaches to neuroscience research. 1990 annual meeting of the Neuroscience Society.

69th annual general meeting of the British Cardiac Society. Torquay, 22-25 May 1990. Abstracts.

The Teratology Society, thirtieth annual meeting. June 8-12, 1990, Victoria, BC, Canada. Program, abstracts.

2014 American Society of Naturalists awards.

Environmental Mutagen Society of Japan. 19th annual meeting. 29-31 October 1990, Fukuoka, Japan. Selected abstracts.

Teratology Society members, 1989-1990.

[Prizes and awards by the German Radiology Society 2015].

Presidential address: the Endocrine Society.

Crafting a conference: Endocrine Society of India Annual Conference Bhopal 2013.

The second annual meeting of the International Society for Environmental Epidemiology. August 13-15, 1990, Berkeley, CA.

1990 program & abstracts. Twelfth annual meeting of the American Society for Bone and Mineral Research. Atlanta, Georgia, August 28-31, 1990.

55th annual teratology society meeting.

Growth of the Endocrine Society journals.

American Society for Bone and Mineral Research awards.

ESPAS: The Endocrine Society Presidential Address Syndrome.

Neurobehavioral Teratology Society, fourteenth annual meeting. June 7-10, 1990, Victoria, British Columbia, Canada. Program and abstracts.

Canadian spine society 15th annual scientific conference.

Irish thoracic society annual scientific meeting 2014.