0888-8809/92/l 346-l 354$03.00/O Molecular Endocrinology Copyright 0 1992 by The Endocrine
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THE
ENDOCRINE SOCIETY 1992 ANNUAL AWARDS
Citation for the Ernst Oppenheimer Award of The Endocrine Society to James Larry Jameson The Endocrine Society honors Dr. J. Larry Jameson, who is 37 yr old, for his outstanding contributions to the understanding of the regulation of glycoprotein hormone gene expression. Larry embodies the spirit of this award because of his remarkable accomplishments in both basic and clinical research. His work has provided important new concepts with regard to mechanisms of gene regulation that have direct relevance to the fundamental aspects of the defective regulation of endocrine glands. Larry received his B.S., M.D., and Ph.D. degrees, all with honors, from the University of North Carolina, He subsequently trained in internal medicine and endocrinology at the Massachusetts General Hospital. After his clinical fellowship, he worked with Dr. Joel Habener in the Molecular Endocrinology Unit at Massachusetts General. During his endocrine research training, Larry’s brilliance and unending energies led to the identification and characterization of the CAMP-responsive enhancer sequence in the gonadotropin a-subunit gene, one of the first such elements to be characterized. These studies culminated in the cloning of CAMP response element binding protein, the CAMP-responsive transcription factor responsible for the activation of CAMP-stimulated gene transcription, He also succeeded in cloning genes encoding the P-subunits for the gonadotropins LH, FSH, and CG, providing a full complement of gene sequences for the gonadotropins with which to embark on a detailed investigation of how the expression of these genes is regulated. In 1987, at the age of 32, Larry became the chief of the prestigious and historic Thyroid Unit at the Massachusetts General Hospital. Taking over the reins of the Thyroid Unit honed Larry’s leadership instincts, resulting in the assembly of a talented group of young research associates and the beginning of a series of important discoveries that have had a major impact in the field of the hormonal regulation of gene expression. During the past 5 yr, Larry’s research has been directed toward an understanding of the mechanisms involved in the hormonal control of the expression of the pituitary hormone genes, and how alterations of specific control points occur in conjunction with pituitary neoplasia and in inherited endocrine diseases. He and his colleagues have used molecular technique to demonstrate that 15-20% of clinically nonfunctioning tumors arise from glycoprotein hormone cell types. Larry has also demonstrated that muta-
tions in glycoprotein hormone cells can give rise to a previously unrecognized form of infertility. Most important are the conceptual contributions that Larry has made regarding two intriguing questions existent in the field of the regulation of pituitary hormone gene expression: 1) how are the expression of the LY- and P-subunit genes of the pituitary glycoprotein hormones coordinately regulated?; and 2) how do glucocorticoids and thyroid hormones upregulate some genes and down-regulate others? Larry demonstrated that the flanking region of the CGPsubunit gene conferred transcriptional responsivity to CAMP in a manner different from that of the a-subunit gene. The CAMP-mediated time-dependent induction curves for the transcription of the (Y- and P-subunit genes were different; these studies demonstrated that during its evolution from the LHP gene, the CG@ gene had acquired a novel promoter region and that the regulatory region of the CGP gene does not contain a typical CAMP-responsive enhancer but rather contains a G-rich sequence that mediates regulation by CAMP. The implication is that CAMP-responsive transcription of the (Y and @ genes occurs by different mechanisms and involves different trans-activator proteins. These impor1346
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tant findings provided for the first time an explanation for the coordinate expression of the two genes, mediated by CAMP-dependent mechanisms and also accommodated the observations of the disassociationof (Y- and P-subunit gene expression that occurs in the later stagesof placental development and also in pituitary tumors. A major conceptual contribution made by Larry has been the elucidation of a mechanism to explain the bidirectional regulation of the expressionof genesby glucocorticoid receptor and by thyroid hormone receptors. The mechanism involves interactions of the glucocorticoid and thyroid hormone receptors with other transcription factors that bind to the promoter. For example, thyroid hormone, acting via its nuclear receptor, causes transcriptional repression of the TSHa gene promoter. Larry demonstrated that the thyroid hormone receptor interacts with this gene adjacent to the TATA box. The exciting notion is that thyroid hormone suppression of a-subunit gene transcription is in part a consequence of interference with TATA box binding proteins, the vital components of the basal transcriptional machinery. His further evaluation of an extensive set of linker scanning mutants throughout the promoter and enhancer region of the a-gene showed that there are multiple thyroid hormone receptor binding sites throughout the region of the basal promoter. These issuesof protein-protein interactions involved in the regulation of gene expression by specific transcriptional DNA-binding proteins are of paramount importance to understanding of the molecular endocrinology of gene expression, and Larry has made important contributions in the elucidation of such mechanisms. In patients with resistance to thyroid hormone action, he has shown that the mutant receptors, which lack hormone binding, are unable to suppressthe TSH gene. Moreover, the mutant receptors were shown to inhibit the suppressive capability of normal receptors, providing a likely explanation for the autosomal dominant inheritance of the disorder. Larry’s research activities have been recognized internationally, as evidenced by his being invited to give keynote lectures at many international conferences, including the Serono Gonadotropin Symposium, the Keystone symposia on molecular approaches to the study of thyroid hormone action in 1991 and 1992, and as a plenary lecturer for the German, Austrian, and Italian Endocrine Societies on the genetic basis of endocrine disease. Becauseof his research accomplishments and international recognition as a leader and important figure in the field of biomedical research, Larry richly deserves the recognition brought by the Ernst Oppenheimer Memorial Award of the Endocrine Society. Citation
for the Richard E. Weitzman to Fred E. Cohen
Memorial
Award
Fred E. Cohen has been awarded the Richard E. Weitzman Memorial Award for his contributions to the understanding of protein structure and its use for pharmaceutical design. He is currently Associate Professor of Medicine, Pharmaceutical Chemistry, and Biochemistry and Biophysics at the University of California, San Francisco (UCSF). He received
undergraduate education at Yale, where he graduated magna cum laude in 1978 with distinction in biochemistry and biophysics and where as a senior he was tapped as a Scholar of the House and began research in structural biology under Frederic M. Richards. He received a Rhodes Scholarship in 1978 to pursue graduate work in molecular biophysics at Oxford under Sir David Phillips. During this time, he built on early work that had begun to predict secondary protein structures from amino acid sequencesand demonstrated that secondary structure knowledge could be used to predict the folding of these structures into proteins. Accurate tertiary structure predictions were made for several proteins, including myoglobin, cytokines, immunoglobulins, and glycolytic enzymes. He completed his doctoral work in 2 yr and in 1980 received a specialpostdoctoral fellowship from the American Cancer Society to enter Stanford Medical School and complete postdoctoral training at UCSF under I. D. Kuntz. By that time it was apparent that the rules for predicting protein secondary structures from amino acid sequences needed improvement, and Cohen and Kuntz made major refinements in predicting the formation of strands, helices, and turns using advanced computational approaches. These revised rules have been verified by protein structural analyses. The two also developed models to understand the order of folding of secondary structures into proteins and applied these computational methods to several pharmaceutically relevant systems. Fred completed medical school in 1984 and began a residency at UCSF in internal medicine and a clinical fellowship in endocrinology at UCSF in 1987. He joined the UCSF faculty in 1985. During this time, he developed models for the three-dimensional structures of interleukin-2, human
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GH, and interleukin-4 based on primary structures that were subsequently verified and that catalyzed experimental manipulations of these proteins to identify second generation pharmaceuticals rationally. Upon completion of his clinical training in 1988, Fred began full-time faculty work at UCSF and received a Searle junior faculty scholarship. He has continued to apply advanced computational methods to develop means to predict how amino acid chains fold in proteins. He has also collaborated with Gordon Strewler and Robert Nissenson at UCSF in studies of PTH and the PTH-related peptide. His group developed models for the three-dimensional structures of the receptor-binding portions of these molecules that gave insight into how these two molecules could bind to the same receptor in spite of a significant lack of homology in important portions of the molecules. Aspects of the models were confirmed by spectroscopic analyses. The group has used these models to design novel antagonists and agonists with potential pharmacological usefulness. More recently, Cohen and McKerrow have demonstrated further the power of structural biology methods for designing novel pharmaceuticals in their studies of an elastase which the water-borne cercariae of schistosomes secrete to bore through the foot pad of the host and enter the lymphatic system and ultimately the liver. They constructed a threedimensional model of the elastase and designed mechanismbased inhibitors that block both elastase activity and infectivity of the organism in vim. Fred has been a member of The Endocrine Society since 1989. Additional indications of his impact are reflected by his numerous invitations to speak at major meetings such as the American Chemical Society, American Physical Society, ICN/UCLA Symposia, and the National Academy of Sciences, service on the NIH Biophysics and Biochemical Chemistry Study Section, service on the editorial boards of the Journal of Molecular Biology and Protein Engineering, and receipt of NIH grants and a program grant from the Defense Advanced Research Project Agency. He currently supervises eight postdoctoral fellows and graduate students and is widely sought after by biotechnology and pharmaceutical companies as a consultant on drug design. While developing a program in research with international impact, Fred has also developed into one of UCSF’s most sought-after teachers who is equally comfortable on the medical wards reviewing problems in endocrinology or general internal medicine, or in the basic departments. He is respected by his colleagues as an excellent clinical endocrinologist and internist and as such defies the trend of the disappearing triple threat. Fred thus represents an unusual combination of clinical endocrinologist and structural biochemist who is at the forefront of a technology that is likely to have even greater impact on endocrinology in the future. The Endocrine Society is proud to award him the Richard E. Weitzman Award. Citation for the Fred Conrad Koch Award Endocrine Society to Melvin M. Grumbach Selna L. Kaplan
of The and
The Endocrine Society is pleased to bestow its most prestigious honor, the Fred Conrad Koch award, on that dynamic
duo of pediatric endocrinology, Melvin M. Grumbach and Selna L. Kaplan. Mel and Selna have collaborated for 35 yr, influencing much of our understanding of pituitary physiology, growth, puberty and neuroendocrinology, and virtually every aspect of pediatric endocrinology. Mel got off to a quick start, with an M.D. from Columbia University in 1948 at the tender age of 22, and he completed his fellowship with the legendary Lawson Wilkins in 1955. Like many of us, Mel was always interested in sex. While with Wilkins he began his studies of sex chromatin and its various disorders in hermaphroditism and of the disorders of adrenal steroid synthesis causingpseudohermaphroditism. Upon moving back to Columbia University to head the newly formed division of Pediatric Endocrinology, Mel continued his landmark studies of sex chromatin, showing that all human X chromosomesin excessof one replicated late and proving that late replication caused heterochromatinization and formation of sex chromatin (the Barr body). He advanced the fixed differentiation hypothesis of X chromosomebehavior independently of Mary Lyon (but somehow the term “Grumbachianization” of sex chromatin never caught on). He showed that the second X chromosome was not completely inactive, and that geneson the secondX chromosome were necessaryfor normal ovarian development. He and his colleaguescorrelated karyotypes and phenotypes in sex chromosomeabnormalities, leading to his independent discovery of the discordance between phenotype and sex chromatin pattern in Turner and Klinefelter syndromes. Obviously things were going well for Mel, but his research effort made a quantum leap forward in 1958 when Selna Kaplan joined Mel as one of his first postdoctoral fellows. Selna was also a native New Yorker but had taken a longer course before returning home. Crowded with returning veterans on the GI bill, the medical schools of the late 1940s did not welcome women with open arms. Selna outfoxed them by first going to graduate school, earning her Ph.D. in
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Anatomy from Washington University (St. Louis) in 1953 and her M.D. from the same institution in 1955. When Selna joined Mel’s lab, two really hot fields were just beginning to make their mark in endocrinology. First, Berson and Yalow were developing immunoassay technology uptown at the Bronx VA Hospital. Second, new techniques in protein purification, pioneered by the late C. H. Li, led to the isolation of most of the pituitary hormones in pure form. Mel and Selna quickly mastered these new technologies. They were among the first to use human GH (hGH) RIA to delineate the roles of hGH in various disorders of growth, and they were the first to show that the whole hGH molecule was needed for activity, when most thought a small core peptide sequence would suffice. They developed RIAs for other hormones, including LH, FSH, TSH, and PRL. Not content just to measure hormones, they codiscovered one of their own-human chorionic somatomammotropin (sometimes termed placental lactogen)-and described its GH-like activity and its first RIA. In 1966 Mel and Selna followed Horace Greeley’s advice and headed west. Mel had been appointed Chairman of Pediatrics at the University of California, San Francisco, and Selna took over the operation of the pediatric endocrine research laboratory. Their new environment proved even more productive than the old. Based on incisive analysis of TRH-induced changes in PRL concentrations, Mel and Selna were the first to show that the overwhelming majority of children with idiopathic hypopituitarism or isolated GH deficiency had a hypothalamic, rather than a pituitary disease. They have always been leaders in the scientific investigation of disorders of growth and the use and effects of GH, publishing dozens of widely cited papers in this field. They defined the syndromes of neonatal hypopituitarism with hypoglycemia, of septo-optic dysplasia, and of hypopituitarism as a consequence of central nervous system (CNS) irradiation. When the mini-epidemic of Creutzfeld-Jacob disease
in recipients of pituitary-derived GH was discovered, the pediatric endocrine community turned to Selna Kaplan for guidance. As chairman of the Growth Hormone Subcommittee and president of the Lawson Wilkins Pediatric Endocrine Society, she worked with NIH officials to gather data and inform patients and provided a perspective and a firm, logical hand in the face of exaggerated fears, claims, and counterclaims. As principal investigator of the first national trial of hGH made by recombinant DNA technology she greatly facilitated the expeditious approval of biosynthetic hGH to replace pituitary hGH. Using exquisitely sensitive RIAs for gonadotropins and sex steroids, Mel and Selna painstakingly described the hormonal changes in normal infants and in children in puberty. They described the striking rise of LH in response to GnRH that precedes clinical signs of puberty and demonstrated the increasing insensitivity of sex-steroid feedback on the hypothalamus as puberty advances. They discovered that puberty is restrained in normal children by the CNS rather than by sex steroids and showed that it was the waning of this CNS inhibition that initiates puberty. They showed that the onset of adrenarche is independent of puberty and were among the first to describe the use of GnRH agonists in the treatment of precocious puberty. Beginning in the late 1970s they initiated work with the chronically catheterized sheep fetus, a technically demanding but powerful physiological system for delineating the developmental endocrinology of the third trimester mammalian fetus. This led to their continuing series of papers, “Hormone ontogeny in the ovine fetus,” published largely in Endocrinology; number 26 in this series appeared in December, 199 1. Beyond these and a great number of other achievements in clinical endocrinology and whole animal physiology, perhaps Mel and Selna’s greatest impact has been through the people they trained. Over 80 postdoctoral fellows and visiting scientists learned from and worked with Mel and Selna. Over 35 of these now head their own laboratories, 26 are professors, and 10 chair departments of pediatrics. Both have vigorously championed the rights of children, stringent review of clinical experimentation, and careful consideration of the social impact of medical technology. In an era of premature enthusiasm and media hype, they have been the voice of restraint in the use of biosynthetic hGH for treating short healthy non-GH deficient children. This unmatched record of achievement in endocrinology and pediatrics has not gone unnoticed. Although a detailed list of all their awards and honors would take many pages, a few highlights include the following. Both have served as president of the Lawson Wilkins Pediatric Endocrine Society, Selna has served as president of the Western Society for Pediatric Research, and Mel served as president of The Endocrine Society in 1984. They have served on NIH study sections and councils and on innumerable national advisory boards in endocrinology and pediatrics, served on about a dozen editorial boards of journals, and have been elected to dozens of national and international societies. Our society previously honored Mel with the Robert H. Williams Leadership Award in 1980 and honored Selna with the Ayerst Service Award in 1987. Mel is also a member of the Institute of Medicine of the National Academy of Sciences and re-
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ceived an honorary doctorate from the University of Geneva in 1991. Thus, in view of this long record of outstanding achievement in basic and clinical research, of service to science, medicine, and society, and in training the next generation of endocrinologists, The Endocrine Society bestows the 1992 Fred Conrad Koch Award on Melvin M. Grumbach and Selna L. Kaplan. Citation
for the Edwin B. Astwood Lectureship Endocrine Society to Michael 0. Thorner
of The
The Endocrine Society has selected Michael 0. Thorner, M.B., B.S., D.Sc., Professor of Medicine, Chief of the Division of Endocrinology, and Director of the General Clinical Research Center at the University of Virginia, as the recipient of the 1992 Edwin B. Astwood Lectureship for Scientific Achievement. This selection recognizes his outstanding contributions to clinical and basic research in neuroendocrinol%Y. Dr. Thorner was born in Beaconsfield, west of London, UK, and received his M.B., B.S. with honors, in 1970 from the Middlesex Hospital at the University of London. Clinical training followed the English pattern with internship and residency in a wide spectrum of subspecialties at several London hospitals. A long-standing interest in endocrinology was pursued by fellowship with Michael Besser and subsequent appointment as Lecturer in Medicine at St. Bartholomew’s, one of the major endocrine training centers in the UK. During this time, Dr. Thorner developed his interest in neuroendocrinology, and he played a major role in establishing the basic physiology and clinical applications of somatostatin. This work established the clinical effects of somatostatin in the gastrointestinal tract and on GH secretion, and was the forerunner of the current use of long-acting somatostatin analogs in the treatment of acromegaly. This interest in GH physiology and acromegaly led to studies on the role of dopamine agonists and established their place in the treatment of acromegaly. Parallel work established the principals of human PRL physiology and laid the groundwork for the use of bromocriptine in the management of hyperprolactinemia. In this latter area Dr. Thorner was the major proponent of medical therapy of PRL-secreting pitutiary tumors. He established the efficacy of bromocriptine in restoring pituitary-gonadal function and in the long-term management of prolactinomas. Of real import was the demonstration that pituitary tumor size rapidly regressed during bromocriptine treatment, which allayed doubts that medical therapy did not address the mass effects of PRL-secreting pituitary tumors. In 1977, Dr. Thorner accepted a position as Associate Professor of Medicine at the University of Virginia and together with Drs. MacLeod, Rogol, and Evans among others, began elucidating the neuroregulation of PRL secretion. He also pursued basic investigation of the mechanisms of hypothalamic hormone action on GH, ACTH, and gonadotropin secretion from isolated pituitary cells. This active involvement in both laboratory and clinical research allowed problems in clinical endocrinology to be directly investigated at the bench. A superb example is seen in events which led to
the isolation and structural identification of GH-releasing hormone (GHRH). A patient with acromegaly was referred for pituitary surgery which failed to restore normal GH secretion. Joint work with Dr. Kalman Kovacs (University of Toronto) indicated that the pituitary showed somatotroph hyperplasia, suggesting the presence of a GH-stimulating substance. Logical thinking led to investigations which revealed the presence of a pancreatic tumor, removal of which restored plasma GH and somatomedin to normal. Realizing the opportunity presented by these events, Dr. Thorner provided the tumor to scientists at the Salk Institute which led to characterization of GHRH. This concluded a long search for GHRH which had been hampered by the coexistence of somatostatin in hypothalamic extracts. It also typifies Dr. Thorner’s innovative approach to endocrinology and refusal to accept superficial explanations for failure of therapy-the true hallmark of a physician-scientist. Subsequent synthesis of GHRH allowed studies of the mechanisms of GHRH action, and development of in vitro systems furthered our knowledge of the roles of the GHRH, somatostatin, and somatomedins in the physiological control of GH secretion. In parallel with these basic studies, Dr. Thorner played a lead role in establishing the application of GHRH to the treatment of GH deficiency. He first demonstrated the efficacy of GHRH in stimulating GH, somatomedin-C, and subsequent growth in GH-deficient patients. This work established effective therapeutic protocols but also provided important insight into the roles of somatostatin and GHRH in regulating GH secretion, Recognition of the intermittent nature of GH secretion during continuous infusion of GHRH led to the proposal that intermittent hypothalamic somatostatin secretion occurs in humans, thus establishing the dual roles of GHRH and somatostatin in regulating normal pulsatile GH secretion.
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Dr. Thorner’s accomplishments have been recognized by many invitations to present his work at national and international meetings, and by his election to the American Society of Clinical Investigation and the Association of American Physicians. He was awarded the Albion 0. Bernstein Award in 1984 and voted Virginia’s Outstanding Scientist in 1985. He has played leadership roles in endocrinology, having served on the council of The Endocrine Society, NIH Study Section, and the editorial boards of the Journal of Clinical Endocrinology and Metabolism and Neuroendocrinology. He is President of the General Clinical ResearchCenter Program Directors’ Association. Dr. Thorner’s career has been characterized by an innovative approach to clinical endocrinology and by a healthy scepsisscientifica where the facts were discrepant to prevailing opinion. He has achieved worldwide renown as a clinical endocrinologist, is a highly regarded lecturer and teacher, and his enthusiasm for endocrinology, both basic and clinical, inspires a highly productive cadre of endocrinologists at the University of Virginia. Dr. Thorner has truly bridged the fields of basic and clinical investigation. He is a superb example of a physican-scientist whose innovative achievements are truly embodied in the honor of the Edwin B. Astwood Lectureship. Citation for the Sidney H. Ingbar Distinguished Service Award to Nettie Karpin This year, Nettie Karpin is to receive the Distinguished Service Award which will carry the name of Sidney H. Ingbar for the first time. Those who knew Nettie and knew Sid will be especially pleasedand will appreciate the appropriateness of this conjunction. They will be pleased not only because Nettie and Sid had worked closely and tirelessly together for many years, but because both of them shared an intense affection for The Endocrine Society and for their colleagues and respected and appreciated one another. Many elementshave contributed to the successand growth of The Endocrine Society: exciting and expanding science, enthusiastic and participatory members, and collegiality and innovative leadership by devoted officers and committee members. To function optimally, these elements require an organizational structure that maintains continuity over time, and that interacts with the larger community. And, in turn, the successof the organizational structure depends on the creativity, integrity, intelligence, and charisma of its executive director. Nettie Karpin is honored this year because she exemplifies all of those qualities. In the 14 yr between 1974 and 1988 Nettie indoctrinated and gently directed presidents, vice-presidents, secretary-treasurers, council members, and committee chairpersons. She sat in on all of the important committee meetings and in her own quiet but forceful way was able to ensure that the necessary documentation was available, that the objectives of the meetings were met, and that the human consequencesof the decision process were not overlooked. Eminently practical, hardheaded but also empathetic, she saw to it that committee actions were prudent, objective, and humane. During her 14-yr tenure, Nettie worked with many committees to choose a convention center and worked out pro-
grams for both scientific and social events at the annual meeting, the postgraduate assembly, and other events. The meetings, which attract thousands of participants, ran extraordinarily smoothly, due in good measure to Nettie’s attention to detail, intimate knowledge and long experience in the hotel and catering business,and her talents for persuasion and compromise. I doubt if there has ever been an equal in the art of the gentle reminder. Under Nettie’s stewardship, the offices of The Endocrine Society were moved to Rockville, MD, and there she developed the staff and systems to handle the increasing membership of the society, the vast growth of publication activities, and the management of the society’s investments. Contracts with publishers were negotiated, new publications initiated, and liaison maintained with officers and staff of other scientific organizations. During her tenure also came the revolution in patterns of grant funding by the NIH. The Endocrine Society recognized the importance of educating the public and its representatives to the practical values of abstruse endocrine research and organized a committee for dealing with political affairs headed by Claude Migeon. Nettie was in the midst of the effort, working with lobbyists, activists from the society, arranging meetingswith congress,and congressionalstaffers, dealing with emergency political problems. Again and again, her practical intelligence and intuition enabled her to enlist personal help from the membership and to inspire and support their activities. Surely, this activity was not in the job description originally proposed by Mort Lipsitt when he recruited her, but shewas prepared to help by her knowledge of the way in which Washington worked and her special
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skills in dealing with people. Perhaps her bachelor’s degree in early childhood education, her teaching experience in a Methodist nursery school in East Harlem, and her career as a mother of two daughters, Carolyn and Rita, prepared her for that job. When Nettie retired as Executive Director in 1988, Nick Christy, then Secretary-Treasurer, published a tribute in the Newsletter of The Endocrine Society acknowledging how Nettie had managed to cope with the long debilitating illness and then death of her husband Fred and with other personal crises. He wrote, “None of these impaired her function or interfered in the slightest with the work of the society. Through them all she maintained her good humor. She unfailingly had time, made time, to help the officers, councilors and members of the society, a society which she had taken on not as a job but a vocation, Nettie was quite literally on duty 24 hr a day. Indeed she became the mother of us all.” Citation
for the Robert Service Award
H. Williams Distinguished to Claude J. Migeon
The Robert H. Williams Distinguished Service Award honors a member of The Endocrine Society who, in the image of Dr. Williams, has served the field of endocrinology and has nutured generations of endocrinological scholars. The 1992 recipient is Claude J. Migeon, M.D. Claude was born in Lievin (Pas-De-Calais) France and received his baccalaureate degree from Lycee de Reims and his medical degree from the University of Paris. The times were uneasy-it was World War II in occupied France. Occasionally Claude can be persuaded to share with fellows and colleagueshis epic adventures as a young student working with the French resistance.And he will alsorelate medical adventures describing how, along with a nun, an elderly physician, and meager medical equipment and medication, he cared for a displaced Ukranian woman in need of a Cesarean section. This unusual trio also provided medical care for badly wounded soldiers, including four Americans from Patton’s army. An early turning point in his career came in 1946, when, confronted with a ward full of children with tuberculous meningitis for whom he could provide no meaningful treatment, he vividly recognized the importance of research to the progressof medicine. Having completed his pediatric training at the Hopital des Enfants Malades in Paris and postdoctoral training in biochemistry at the University of Paris, young Claude Migeon, speaking virtually no English, ventured forth to Baltimore and The Johns Hopkins Medical Institutions to study with the Father of Pediatric Endocrinology, Lawson Wilkins. Lawson’sinfluence on Claude was profound and inspirationalasit was on every one of Wilkins’ fellows. Claude developed a life-long interest in steroid metabolism. To further expand his horizons and his training, he spent three years as a research instructor in biochemistry with Leo Samuels at the University of Utah. This was a heady atmosphere for the young French physician. The group, which included Don Nelson, Chris Eik Ness, Gene
Bliss,Avery Sandberg, and others, was involved in the study of the physiology of cortisol secretion and its relationship to stress, It was in Salt Lake City that Claude reported the isolation of the first androgen from human blood-dehydroepiandrosterone sulfate. In 1955, Claude made a decision that profoundly influenced the course of his career. When Wilkins invited him to return to Hopkins, he accepted with alacrity. Thirty-seven years later he is still there carrying on the remarkable tradition of pediatric endocrinological training that has become one of the hallmarks of this great institution. There are many tales about Claude’s elopement with Barbara Ruben, a Harriet Lane pediatric resident. The most accurate, of course, comes from Barbara and Claude themselves. Accompanied by Bill and Marty Cleveland and by the inimitable Lawson Wilkins, they went off to Arlington, VA. Wilkins provided the joie de vivre as well as the wines, champagnes,and liquors. Wilkins loved this senseof participation in his fellows’ lives, a wonderful trait that Barbara and Claude have perpetuated in their relationships with succeedinggenerations of endocrine fellows. In 1961, Wilkins retired. From then until 1973, Claude shared responsibility for the Division of Pediatric Endocrinology with Dr. Robert M. Blizzard. When Blizzard left Hopkins to become chairman of the department of pediatrics at Charlottesville, Claude took over the leadership of the Hopkins division. Lawson Wilkins was a great clinician and dearly enjoyed teaching his young fellows who, in those days, were known as “the boys,” even though the group included a few girls. Migeon carried on the tradition, obtaining an NIH training grant in 1961 which provided stipends for six fellows. It was the threat by the Nixon administration in 1974 to eliminate NIH training grants that drove Claude into public affairs.
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I ne tnaocnne society
Helping to galvanize the scientific community to defend the training grant programs, Claude becamea zealot on this issue and so many other public policy issuesaffecting academic science.In recognition of his many contributions in this area, he received the Ayerst Award from The Endocrine society in 1982. During his 40-yr career, Claude Migeon has contributed to the instruction of 65 American fellows and 37 fellows from abroad. Among them, 10 have been or are chairmen of pediatric departments, 3 are assistant or associatedeans of medical schools,and 5 are associatedwith major pharmaceutical companies. Almost all the others are directors of pediatric endocrine clinics and training programs in the United States, Europe, or South America. Thus, Claude’s influence on successivegenerations of pediatric endocrinologists has been profound and certainly worthy of the Williams Award. Claude’s contributions to the body of knowledge of steroid metabolism are legend. Since 1950 he has authored 350 scientific papers and numerous book chapters. Early in his careerhe studied the transplacental passageof steroids. Later, the establishment of the double isotope derivative methods allowed him to extend his studies to plasma androgens in man. Collaborating on these projects were Jean Bertrand, Carl Gemzell, Inese Beitins, Marco Rivarola, Jose Saez, Bernadette Loras, Maguelone Forest, and Roland Tremblay. In the sixties, Claude established the norms of adrenal function in infancy and childhood. Studies of cortisol secretion were carried out with Fritz Kenny, Paul Malvaux, Orville Green, Wellington Hung, and others. In 1970, with Francis Bayard, Inese Beitins, and Ave Kowarski, he published the first description of an RIA method for plasma and urinary aldosterone. Additional aldosterone studies with Bob Blizzard, Grant Liddle, Ave Kowarski, and Virginia Weldon showed that aldosterone secretion was increased in nonsalt-losing congenital adrenal hyperplasia. Additionally, his studies showed that although cortisol secretion is related to body size during growth and development, aldosterone secretion is constant from infancy to adulthood. With the help of Perrin White and in collaboration with Pat Donohoue, Neil Van Dop, Nick Jospe, and Romolo Sandrini, the Migeon-led group contributed to the study of the molecular basis of congenital adrenal hyperplasia. Because of Claude’s early involvement with this disorder, he along with John Rock, Georgeanna Klingensmith, Rose Mulaikal, and Maria Urban, was also able to report on the longterm follow-up of male and female patients. Another important contribution has been the study of androgen receptors in human skin fibroblasts and the investigation of the androgen insensitivity syndrome. Early studies were carried out with Bruce Keenan, Walter Meyer, Barbara Migeon, James Amrhein, Marc Maes, and Charles Sultan. Later the work of Terry Brown provided the molecular basis for the earlier research. Claude has had a long-standing interest in sex differentiation. Recently, he has participated with Gary Berkovitz, Patricia Fechner and collaborators in Peter Goodfellow’s laboratory investigating the role of the sex determining region of Y in testis determination. How does one measure such a remarkable career? By the
number of fellows trained? By the number of scientific reports? By the number of patients cared for? Obviously, there are no simple answers. Rather, the answer lies in the marvelous ability to combine all three and to include compassion and sensitivity for one’s colleagues and patients along the way. Claude Migeon embodies these qualities along with those of the great researcher, teacher, and physician. He is an international scholar in the finest sense of the word, having attracted these and many other young endocrinologists from the world over to study with him at Hopkins. He is truly deserving of the Williams Award. Citation Clinical
for the Rhbe-Poulene Rorer Pharmaceutical Investigator Award of The Endocrine Society to Samuel S. C. Yen
Samuel S. C. Yen is currently a Professor of Reproductive Medicine at the University of California, San Diego, where for at least the last 20 yr he has added to our knowledge of the neuroendocrine regulation of the reproductive system, the endocrinology of the menstrual cycle, and the effects of reproductive hormones on metabolism. He has offered provocative theories on the genesisand/or treatment of polycystic ovary syndrome, premenstrual tension, menopause, hypothalamic causesof amenorrhea, pseudocyesis,and anorexia nervosa. He has studied feedback mechanismsas they relate to normal function and disease. Sam was born in Beijing, China, in 1927 and grew up during the Japaneseoccupation of China and the hostilities of World War II. He flew with the Flying Tigers asa teenager. His father was a physician who remained in China, but Sam entered the Medical School of the University of Hong Kong from which he graduated in 1954 followed by an internship in medicine at Queen Mary Hospital. He met Nicholson Eastman, Professor of Obstetrics from Johns Hopkins at this time in Hong Kong and obtained a coveted appointment to
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the Johns Hopkins obstetrical and gynecological residency from which he graduated in 1960. Sam next obtained a 2-yr fellowship as Chief of the Department of Obstetrics and Gynecology at the Guam Memorial Hospital, which qualified him to reenter the United States for citizenship. In his short tenure at Guam, he developed two interesting papers, one on the rupture of the liver during pregnancy and the other on the high incidence of diabetes and abnormal glucose tolerance during pregnancy in the native women of Guam. On reentering the United States in 1962, Sam migrated quickly from a fellowship at Harvard to a teaching post at the Case Western University Department of Obstetrics and Gynecology run by a friend from residency days, Kenneth J. Ryan. Under the tutelage of Olaf Pearson, Sam became interested in growth hormone and placental lactogen in pregnancy. For the next 10 yr there was a flow of studies from his laboratory on hormonal profiles during puberty and the menstrual cycle, studies of hormonal half-life in blood, the effects of clomiphene and wedge resection on polycystic ovary syndrome, and the effects of hormones on carbohydrate metabolism. All during this period he engaged in the practice and teaching of obstetrics and gynecology. In 1970, Sam moved to UCSD as a professor in a department that included Benirschke, Naftolin, Judd and Ryan. He quickly established himself as a true physiologist of the
reproductive system with elegant studies on neuroendocrine control of the cycle. This included an 11-yr period as chairman of the department. Roger Guillemin was at the Salk Institute in La Jolla at the time, and with his discovery of LH-releasing hormone a working collaboration with Sam evolved on the biological effects of LH-releasing hormone in patients. This was followed by studies with somatostatin and corticotropin-releasing hormone. Sam’s laboratory has also studied the effects of RU486 on the menstrual cycle and endometriosis. In 1978, Yen authored and edited with Bob Jaffe their classic text on reproductive endocrinology that has gone through its third successive edition by 199 1. An extraordinary number of fellows have worked in Sam’s laboratory and gone on to academic and research positions throughout the world. It is altogether fitting that he should be recognized by the Rorer award for his influential and pioneering work on the endocrinology of the reproductive system. Along with this award, Yen has been honored with numerous awards, lectureships, and services; among them are the Reproductive Biology Study Section, NIH; the National Advisory Council, NICHD; Member, Institute of Medicine, National Academy of Science, Society for Gynecological Investigation (past president), and the Johns Hopkins Society of Scholars. Also, Yen has been honored by the University of California San Diego as the first recipient of the Wallace R. Parsons Endowed Chair in Reproductive Endocrinology.
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Society
THE
ENDOCRINE SOCIETY 1992 ANNUAL AWARDS
Citation for the Ernst Oppenheimer Award of The Endocrine Society to James Larry Jameson The Endocrine Society honors Dr. J. Larry Jameson, who is 37 yr old, for his outstanding contributions to the understanding of the regulation of glycoprotein hormone gene expression. Larry embodies the spirit of this award because of his remarkable accomplishments in both basic and clinical research. His work has provided important new concepts with regard to mechanisms of gene regulation that have direct relevance to the fundamental aspects of the defective regulation of endocrine glands. Larry received his B.S., M.D., and Ph.D. degrees, all with honors, from the University of North Carolina, He subsequently trained in internal medicine and endocrinology at the Massachusetts General Hospital. After his clinical fellowship, he worked with Dr. Joel Habener in the Molecular Endocrinology Unit at Massachusetts General. During his endocrine research training, Larry’s brilliance and unending energies led to the identification and characterization of the CAMP-responsive enhancer sequence in the gonadotropin a-subunit gene, one of the first such elements to be characterized. These studies culminated in the cloning of CAMP response element binding protein, the CAMP-responsive transcription factor responsible for the activation of CAMP-stimulated gene transcription, He also succeeded in cloning genes encoding the P-subunits for the gonadotropins LH, FSH, and CG, providing a full complement of gene sequences for the gonadotropins with which to embark on a detailed investigation of how the expression of these genes is regulated. In 1987, at the age of 32, Larry became the chief of the prestigious and historic Thyroid Unit at the Massachusetts General Hospital. Taking over the reins of the Thyroid Unit honed Larry’s leadership instincts, resulting in the assembly of a talented group of young research associates and the beginning of a series of important discoveries that have had a major impact in the field of the hormonal regulation of gene expression. During the past 5 yr, Larry’s research has been directed toward an understanding of the mechanisms involved in the hormonal control of the expression of the pituitary hormone genes, and how alterations of specific control points occur in conjunction with pituitary neoplasia and in inherited endocrine diseases. He and his colleagues have used molecular technique to demonstrate that 15-20% of clinically nonfunctioning tumors arise from glycoprotein hormone cell types. Larry has also demonstrated that muta-
tions in glycoprotein hormone cells can give rise to a previously unrecognized form of infertility. Most important are the conceptual contributions that Larry has made regarding two intriguing questions existent in the field of the regulation of pituitary hormone gene expression: 1) how are the expression of the LY- and P-subunit genes of the pituitary glycoprotein hormones coordinately regulated?; and 2) how do glucocorticoids and thyroid hormones upregulate some genes and down-regulate others? Larry demonstrated that the flanking region of the CGPsubunit gene conferred transcriptional responsivity to CAMP in a manner different from that of the a-subunit gene. The CAMP-mediated time-dependent induction curves for the transcription of the (Y- and P-subunit genes were different; these studies demonstrated that during its evolution from the LHP gene, the CG@ gene had acquired a novel promoter region and that the regulatory region of the CGP gene does not contain a typical CAMP-responsive enhancer but rather contains a G-rich sequence that mediates regulation by CAMP. The implication is that CAMP-responsive transcription of the (Y and @ genes occurs by different mechanisms and involves different trans-activator proteins. These impor1346
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The Endocrine Society
tant findings provided for the first time an explanation for the coordinate expression of the two genes, mediated by CAMP-dependent mechanisms and also accommodated the observations of the disassociationof (Y- and P-subunit gene expression that occurs in the later stagesof placental development and also in pituitary tumors. A major conceptual contribution made by Larry has been the elucidation of a mechanism to explain the bidirectional regulation of the expressionof genesby glucocorticoid receptor and by thyroid hormone receptors. The mechanism involves interactions of the glucocorticoid and thyroid hormone receptors with other transcription factors that bind to the promoter. For example, thyroid hormone, acting via its nuclear receptor, causes transcriptional repression of the TSHa gene promoter. Larry demonstrated that the thyroid hormone receptor interacts with this gene adjacent to the TATA box. The exciting notion is that thyroid hormone suppression of a-subunit gene transcription is in part a consequence of interference with TATA box binding proteins, the vital components of the basal transcriptional machinery. His further evaluation of an extensive set of linker scanning mutants throughout the promoter and enhancer region of the a-gene showed that there are multiple thyroid hormone receptor binding sites throughout the region of the basal promoter. These issuesof protein-protein interactions involved in the regulation of gene expression by specific transcriptional DNA-binding proteins are of paramount importance to understanding of the molecular endocrinology of gene expression, and Larry has made important contributions in the elucidation of such mechanisms. In patients with resistance to thyroid hormone action, he has shown that the mutant receptors, which lack hormone binding, are unable to suppressthe TSH gene. Moreover, the mutant receptors were shown to inhibit the suppressive capability of normal receptors, providing a likely explanation for the autosomal dominant inheritance of the disorder. Larry’s research activities have been recognized internationally, as evidenced by his being invited to give keynote lectures at many international conferences, including the Serono Gonadotropin Symposium, the Keystone symposia on molecular approaches to the study of thyroid hormone action in 1991 and 1992, and as a plenary lecturer for the German, Austrian, and Italian Endocrine Societies on the genetic basis of endocrine disease. Becauseof his research accomplishments and international recognition as a leader and important figure in the field of biomedical research, Larry richly deserves the recognition brought by the Ernst Oppenheimer Memorial Award of the Endocrine Society. Citation
for the Richard E. Weitzman to Fred E. Cohen
Memorial
Award
Fred E. Cohen has been awarded the Richard E. Weitzman Memorial Award for his contributions to the understanding of protein structure and its use for pharmaceutical design. He is currently Associate Professor of Medicine, Pharmaceutical Chemistry, and Biochemistry and Biophysics at the University of California, San Francisco (UCSF). He received
undergraduate education at Yale, where he graduated magna cum laude in 1978 with distinction in biochemistry and biophysics and where as a senior he was tapped as a Scholar of the House and began research in structural biology under Frederic M. Richards. He received a Rhodes Scholarship in 1978 to pursue graduate work in molecular biophysics at Oxford under Sir David Phillips. During this time, he built on early work that had begun to predict secondary protein structures from amino acid sequencesand demonstrated that secondary structure knowledge could be used to predict the folding of these structures into proteins. Accurate tertiary structure predictions were made for several proteins, including myoglobin, cytokines, immunoglobulins, and glycolytic enzymes. He completed his doctoral work in 2 yr and in 1980 received a specialpostdoctoral fellowship from the American Cancer Society to enter Stanford Medical School and complete postdoctoral training at UCSF under I. D. Kuntz. By that time it was apparent that the rules for predicting protein secondary structures from amino acid sequences needed improvement, and Cohen and Kuntz made major refinements in predicting the formation of strands, helices, and turns using advanced computational approaches. These revised rules have been verified by protein structural analyses. The two also developed models to understand the order of folding of secondary structures into proteins and applied these computational methods to several pharmaceutically relevant systems. Fred completed medical school in 1984 and began a residency at UCSF in internal medicine and a clinical fellowship in endocrinology at UCSF in 1987. He joined the UCSF faculty in 1985. During this time, he developed models for the three-dimensional structures of interleukin-2, human
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GH, and interleukin-4 based on primary structures that were subsequently verified and that catalyzed experimental manipulations of these proteins to identify second generation pharmaceuticals rationally. Upon completion of his clinical training in 1988, Fred began full-time faculty work at UCSF and received a Searle junior faculty scholarship. He has continued to apply advanced computational methods to develop means to predict how amino acid chains fold in proteins. He has also collaborated with Gordon Strewler and Robert Nissenson at UCSF in studies of PTH and the PTH-related peptide. His group developed models for the three-dimensional structures of the receptor-binding portions of these molecules that gave insight into how these two molecules could bind to the same receptor in spite of a significant lack of homology in important portions of the molecules. Aspects of the models were confirmed by spectroscopic analyses. The group has used these models to design novel antagonists and agonists with potential pharmacological usefulness. More recently, Cohen and McKerrow have demonstrated further the power of structural biology methods for designing novel pharmaceuticals in their studies of an elastase which the water-borne cercariae of schistosomes secrete to bore through the foot pad of the host and enter the lymphatic system and ultimately the liver. They constructed a threedimensional model of the elastase and designed mechanismbased inhibitors that block both elastase activity and infectivity of the organism in vim. Fred has been a member of The Endocrine Society since 1989. Additional indications of his impact are reflected by his numerous invitations to speak at major meetings such as the American Chemical Society, American Physical Society, ICN/UCLA Symposia, and the National Academy of Sciences, service on the NIH Biophysics and Biochemical Chemistry Study Section, service on the editorial boards of the Journal of Molecular Biology and Protein Engineering, and receipt of NIH grants and a program grant from the Defense Advanced Research Project Agency. He currently supervises eight postdoctoral fellows and graduate students and is widely sought after by biotechnology and pharmaceutical companies as a consultant on drug design. While developing a program in research with international impact, Fred has also developed into one of UCSF’s most sought-after teachers who is equally comfortable on the medical wards reviewing problems in endocrinology or general internal medicine, or in the basic departments. He is respected by his colleagues as an excellent clinical endocrinologist and internist and as such defies the trend of the disappearing triple threat. Fred thus represents an unusual combination of clinical endocrinologist and structural biochemist who is at the forefront of a technology that is likely to have even greater impact on endocrinology in the future. The Endocrine Society is proud to award him the Richard E. Weitzman Award. Citation for the Fred Conrad Koch Award Endocrine Society to Melvin M. Grumbach Selna L. Kaplan
of The and
The Endocrine Society is pleased to bestow its most prestigious honor, the Fred Conrad Koch award, on that dynamic
duo of pediatric endocrinology, Melvin M. Grumbach and Selna L. Kaplan. Mel and Selna have collaborated for 35 yr, influencing much of our understanding of pituitary physiology, growth, puberty and neuroendocrinology, and virtually every aspect of pediatric endocrinology. Mel got off to a quick start, with an M.D. from Columbia University in 1948 at the tender age of 22, and he completed his fellowship with the legendary Lawson Wilkins in 1955. Like many of us, Mel was always interested in sex. While with Wilkins he began his studies of sex chromatin and its various disorders in hermaphroditism and of the disorders of adrenal steroid synthesis causingpseudohermaphroditism. Upon moving back to Columbia University to head the newly formed division of Pediatric Endocrinology, Mel continued his landmark studies of sex chromatin, showing that all human X chromosomesin excessof one replicated late and proving that late replication caused heterochromatinization and formation of sex chromatin (the Barr body). He advanced the fixed differentiation hypothesis of X chromosomebehavior independently of Mary Lyon (but somehow the term “Grumbachianization” of sex chromatin never caught on). He showed that the second X chromosome was not completely inactive, and that geneson the secondX chromosome were necessaryfor normal ovarian development. He and his colleaguescorrelated karyotypes and phenotypes in sex chromosomeabnormalities, leading to his independent discovery of the discordance between phenotype and sex chromatin pattern in Turner and Klinefelter syndromes. Obviously things were going well for Mel, but his research effort made a quantum leap forward in 1958 when Selna Kaplan joined Mel as one of his first postdoctoral fellows. Selna was also a native New Yorker but had taken a longer course before returning home. Crowded with returning veterans on the GI bill, the medical schools of the late 1940s did not welcome women with open arms. Selna outfoxed them by first going to graduate school, earning her Ph.D. in
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The Endocrine
Society
Anatomy from Washington University (St. Louis) in 1953 and her M.D. from the same institution in 1955. When Selna joined Mel’s lab, two really hot fields were just beginning to make their mark in endocrinology. First, Berson and Yalow were developing immunoassay technology uptown at the Bronx VA Hospital. Second, new techniques in protein purification, pioneered by the late C. H. Li, led to the isolation of most of the pituitary hormones in pure form. Mel and Selna quickly mastered these new technologies. They were among the first to use human GH (hGH) RIA to delineate the roles of hGH in various disorders of growth, and they were the first to show that the whole hGH molecule was needed for activity, when most thought a small core peptide sequence would suffice. They developed RIAs for other hormones, including LH, FSH, TSH, and PRL. Not content just to measure hormones, they codiscovered one of their own-human chorionic somatomammotropin (sometimes termed placental lactogen)-and described its GH-like activity and its first RIA. In 1966 Mel and Selna followed Horace Greeley’s advice and headed west. Mel had been appointed Chairman of Pediatrics at the University of California, San Francisco, and Selna took over the operation of the pediatric endocrine research laboratory. Their new environment proved even more productive than the old. Based on incisive analysis of TRH-induced changes in PRL concentrations, Mel and Selna were the first to show that the overwhelming majority of children with idiopathic hypopituitarism or isolated GH deficiency had a hypothalamic, rather than a pituitary disease. They have always been leaders in the scientific investigation of disorders of growth and the use and effects of GH, publishing dozens of widely cited papers in this field. They defined the syndromes of neonatal hypopituitarism with hypoglycemia, of septo-optic dysplasia, and of hypopituitarism as a consequence of central nervous system (CNS) irradiation. When the mini-epidemic of Creutzfeld-Jacob disease
in recipients of pituitary-derived GH was discovered, the pediatric endocrine community turned to Selna Kaplan for guidance. As chairman of the Growth Hormone Subcommittee and president of the Lawson Wilkins Pediatric Endocrine Society, she worked with NIH officials to gather data and inform patients and provided a perspective and a firm, logical hand in the face of exaggerated fears, claims, and counterclaims. As principal investigator of the first national trial of hGH made by recombinant DNA technology she greatly facilitated the expeditious approval of biosynthetic hGH to replace pituitary hGH. Using exquisitely sensitive RIAs for gonadotropins and sex steroids, Mel and Selna painstakingly described the hormonal changes in normal infants and in children in puberty. They described the striking rise of LH in response to GnRH that precedes clinical signs of puberty and demonstrated the increasing insensitivity of sex-steroid feedback on the hypothalamus as puberty advances. They discovered that puberty is restrained in normal children by the CNS rather than by sex steroids and showed that it was the waning of this CNS inhibition that initiates puberty. They showed that the onset of adrenarche is independent of puberty and were among the first to describe the use of GnRH agonists in the treatment of precocious puberty. Beginning in the late 1970s they initiated work with the chronically catheterized sheep fetus, a technically demanding but powerful physiological system for delineating the developmental endocrinology of the third trimester mammalian fetus. This led to their continuing series of papers, “Hormone ontogeny in the ovine fetus,” published largely in Endocrinology; number 26 in this series appeared in December, 199 1. Beyond these and a great number of other achievements in clinical endocrinology and whole animal physiology, perhaps Mel and Selna’s greatest impact has been through the people they trained. Over 80 postdoctoral fellows and visiting scientists learned from and worked with Mel and Selna. Over 35 of these now head their own laboratories, 26 are professors, and 10 chair departments of pediatrics. Both have vigorously championed the rights of children, stringent review of clinical experimentation, and careful consideration of the social impact of medical technology. In an era of premature enthusiasm and media hype, they have been the voice of restraint in the use of biosynthetic hGH for treating short healthy non-GH deficient children. This unmatched record of achievement in endocrinology and pediatrics has not gone unnoticed. Although a detailed list of all their awards and honors would take many pages, a few highlights include the following. Both have served as president of the Lawson Wilkins Pediatric Endocrine Society, Selna has served as president of the Western Society for Pediatric Research, and Mel served as president of The Endocrine Society in 1984. They have served on NIH study sections and councils and on innumerable national advisory boards in endocrinology and pediatrics, served on about a dozen editorial boards of journals, and have been elected to dozens of national and international societies. Our society previously honored Mel with the Robert H. Williams Leadership Award in 1980 and honored Selna with the Ayerst Service Award in 1987. Mel is also a member of the Institute of Medicine of the National Academy of Sciences and re-
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ceived an honorary doctorate from the University of Geneva in 1991. Thus, in view of this long record of outstanding achievement in basic and clinical research, of service to science, medicine, and society, and in training the next generation of endocrinologists, The Endocrine Society bestows the 1992 Fred Conrad Koch Award on Melvin M. Grumbach and Selna L. Kaplan. Citation
for the Edwin B. Astwood Lectureship Endocrine Society to Michael 0. Thorner
of The
The Endocrine Society has selected Michael 0. Thorner, M.B., B.S., D.Sc., Professor of Medicine, Chief of the Division of Endocrinology, and Director of the General Clinical Research Center at the University of Virginia, as the recipient of the 1992 Edwin B. Astwood Lectureship for Scientific Achievement. This selection recognizes his outstanding contributions to clinical and basic research in neuroendocrinol%Y. Dr. Thorner was born in Beaconsfield, west of London, UK, and received his M.B., B.S. with honors, in 1970 from the Middlesex Hospital at the University of London. Clinical training followed the English pattern with internship and residency in a wide spectrum of subspecialties at several London hospitals. A long-standing interest in endocrinology was pursued by fellowship with Michael Besser and subsequent appointment as Lecturer in Medicine at St. Bartholomew’s, one of the major endocrine training centers in the UK. During this time, Dr. Thorner developed his interest in neuroendocrinology, and he played a major role in establishing the basic physiology and clinical applications of somatostatin. This work established the clinical effects of somatostatin in the gastrointestinal tract and on GH secretion, and was the forerunner of the current use of long-acting somatostatin analogs in the treatment of acromegaly. This interest in GH physiology and acromegaly led to studies on the role of dopamine agonists and established their place in the treatment of acromegaly. Parallel work established the principals of human PRL physiology and laid the groundwork for the use of bromocriptine in the management of hyperprolactinemia. In this latter area Dr. Thorner was the major proponent of medical therapy of PRL-secreting pitutiary tumors. He established the efficacy of bromocriptine in restoring pituitary-gonadal function and in the long-term management of prolactinomas. Of real import was the demonstration that pituitary tumor size rapidly regressed during bromocriptine treatment, which allayed doubts that medical therapy did not address the mass effects of PRL-secreting pituitary tumors. In 1977, Dr. Thorner accepted a position as Associate Professor of Medicine at the University of Virginia and together with Drs. MacLeod, Rogol, and Evans among others, began elucidating the neuroregulation of PRL secretion. He also pursued basic investigation of the mechanisms of hypothalamic hormone action on GH, ACTH, and gonadotropin secretion from isolated pituitary cells. This active involvement in both laboratory and clinical research allowed problems in clinical endocrinology to be directly investigated at the bench. A superb example is seen in events which led to
the isolation and structural identification of GH-releasing hormone (GHRH). A patient with acromegaly was referred for pituitary surgery which failed to restore normal GH secretion. Joint work with Dr. Kalman Kovacs (University of Toronto) indicated that the pituitary showed somatotroph hyperplasia, suggesting the presence of a GH-stimulating substance. Logical thinking led to investigations which revealed the presence of a pancreatic tumor, removal of which restored plasma GH and somatomedin to normal. Realizing the opportunity presented by these events, Dr. Thorner provided the tumor to scientists at the Salk Institute which led to characterization of GHRH. This concluded a long search for GHRH which had been hampered by the coexistence of somatostatin in hypothalamic extracts. It also typifies Dr. Thorner’s innovative approach to endocrinology and refusal to accept superficial explanations for failure of therapy-the true hallmark of a physician-scientist. Subsequent synthesis of GHRH allowed studies of the mechanisms of GHRH action, and development of in vitro systems furthered our knowledge of the roles of the GHRH, somatostatin, and somatomedins in the physiological control of GH secretion. In parallel with these basic studies, Dr. Thorner played a lead role in establishing the application of GHRH to the treatment of GH deficiency. He first demonstrated the efficacy of GHRH in stimulating GH, somatomedin-C, and subsequent growth in GH-deficient patients. This work established effective therapeutic protocols but also provided important insight into the roles of somatostatin and GHRH in regulating GH secretion, Recognition of the intermittent nature of GH secretion during continuous infusion of GHRH led to the proposal that intermittent hypothalamic somatostatin secretion occurs in humans, thus establishing the dual roles of GHRH and somatostatin in regulating normal pulsatile GH secretion.
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The Endocrine Society
Dr. Thorner’s accomplishments have been recognized by many invitations to present his work at national and international meetings, and by his election to the American Society of Clinical Investigation and the Association of American Physicians. He was awarded the Albion 0. Bernstein Award in 1984 and voted Virginia’s Outstanding Scientist in 1985. He has played leadership roles in endocrinology, having served on the council of The Endocrine Society, NIH Study Section, and the editorial boards of the Journal of Clinical Endocrinology and Metabolism and Neuroendocrinology. He is President of the General Clinical ResearchCenter Program Directors’ Association. Dr. Thorner’s career has been characterized by an innovative approach to clinical endocrinology and by a healthy scepsisscientifica where the facts were discrepant to prevailing opinion. He has achieved worldwide renown as a clinical endocrinologist, is a highly regarded lecturer and teacher, and his enthusiasm for endocrinology, both basic and clinical, inspires a highly productive cadre of endocrinologists at the University of Virginia. Dr. Thorner has truly bridged the fields of basic and clinical investigation. He is a superb example of a physican-scientist whose innovative achievements are truly embodied in the honor of the Edwin B. Astwood Lectureship. Citation for the Sidney H. Ingbar Distinguished Service Award to Nettie Karpin This year, Nettie Karpin is to receive the Distinguished Service Award which will carry the name of Sidney H. Ingbar for the first time. Those who knew Nettie and knew Sid will be especially pleasedand will appreciate the appropriateness of this conjunction. They will be pleased not only because Nettie and Sid had worked closely and tirelessly together for many years, but because both of them shared an intense affection for The Endocrine Society and for their colleagues and respected and appreciated one another. Many elementshave contributed to the successand growth of The Endocrine Society: exciting and expanding science, enthusiastic and participatory members, and collegiality and innovative leadership by devoted officers and committee members. To function optimally, these elements require an organizational structure that maintains continuity over time, and that interacts with the larger community. And, in turn, the successof the organizational structure depends on the creativity, integrity, intelligence, and charisma of its executive director. Nettie Karpin is honored this year because she exemplifies all of those qualities. In the 14 yr between 1974 and 1988 Nettie indoctrinated and gently directed presidents, vice-presidents, secretary-treasurers, council members, and committee chairpersons. She sat in on all of the important committee meetings and in her own quiet but forceful way was able to ensure that the necessary documentation was available, that the objectives of the meetings were met, and that the human consequencesof the decision process were not overlooked. Eminently practical, hardheaded but also empathetic, she saw to it that committee actions were prudent, objective, and humane. During her 14-yr tenure, Nettie worked with many committees to choose a convention center and worked out pro-
grams for both scientific and social events at the annual meeting, the postgraduate assembly, and other events. The meetings, which attract thousands of participants, ran extraordinarily smoothly, due in good measure to Nettie’s attention to detail, intimate knowledge and long experience in the hotel and catering business,and her talents for persuasion and compromise. I doubt if there has ever been an equal in the art of the gentle reminder. Under Nettie’s stewardship, the offices of The Endocrine Society were moved to Rockville, MD, and there she developed the staff and systems to handle the increasing membership of the society, the vast growth of publication activities, and the management of the society’s investments. Contracts with publishers were negotiated, new publications initiated, and liaison maintained with officers and staff of other scientific organizations. During her tenure also came the revolution in patterns of grant funding by the NIH. The Endocrine Society recognized the importance of educating the public and its representatives to the practical values of abstruse endocrine research and organized a committee for dealing with political affairs headed by Claude Migeon. Nettie was in the midst of the effort, working with lobbyists, activists from the society, arranging meetingswith congress,and congressionalstaffers, dealing with emergency political problems. Again and again, her practical intelligence and intuition enabled her to enlist personal help from the membership and to inspire and support their activities. Surely, this activity was not in the job description originally proposed by Mort Lipsitt when he recruited her, but shewas prepared to help by her knowledge of the way in which Washington worked and her special
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No 8
skills in dealing with people. Perhaps her bachelor’s degree in early childhood education, her teaching experience in a Methodist nursery school in East Harlem, and her career as a mother of two daughters, Carolyn and Rita, prepared her for that job. When Nettie retired as Executive Director in 1988, Nick Christy, then Secretary-Treasurer, published a tribute in the Newsletter of The Endocrine Society acknowledging how Nettie had managed to cope with the long debilitating illness and then death of her husband Fred and with other personal crises. He wrote, “None of these impaired her function or interfered in the slightest with the work of the society. Through them all she maintained her good humor. She unfailingly had time, made time, to help the officers, councilors and members of the society, a society which she had taken on not as a job but a vocation, Nettie was quite literally on duty 24 hr a day. Indeed she became the mother of us all.” Citation
for the Robert Service Award
H. Williams Distinguished to Claude J. Migeon
The Robert H. Williams Distinguished Service Award honors a member of The Endocrine Society who, in the image of Dr. Williams, has served the field of endocrinology and has nutured generations of endocrinological scholars. The 1992 recipient is Claude J. Migeon, M.D. Claude was born in Lievin (Pas-De-Calais) France and received his baccalaureate degree from Lycee de Reims and his medical degree from the University of Paris. The times were uneasy-it was World War II in occupied France. Occasionally Claude can be persuaded to share with fellows and colleagueshis epic adventures as a young student working with the French resistance.And he will alsorelate medical adventures describing how, along with a nun, an elderly physician, and meager medical equipment and medication, he cared for a displaced Ukranian woman in need of a Cesarean section. This unusual trio also provided medical care for badly wounded soldiers, including four Americans from Patton’s army. An early turning point in his career came in 1946, when, confronted with a ward full of children with tuberculous meningitis for whom he could provide no meaningful treatment, he vividly recognized the importance of research to the progressof medicine. Having completed his pediatric training at the Hopital des Enfants Malades in Paris and postdoctoral training in biochemistry at the University of Paris, young Claude Migeon, speaking virtually no English, ventured forth to Baltimore and The Johns Hopkins Medical Institutions to study with the Father of Pediatric Endocrinology, Lawson Wilkins. Lawson’sinfluence on Claude was profound and inspirationalasit was on every one of Wilkins’ fellows. Claude developed a life-long interest in steroid metabolism. To further expand his horizons and his training, he spent three years as a research instructor in biochemistry with Leo Samuels at the University of Utah. This was a heady atmosphere for the young French physician. The group, which included Don Nelson, Chris Eik Ness, Gene
Bliss,Avery Sandberg, and others, was involved in the study of the physiology of cortisol secretion and its relationship to stress, It was in Salt Lake City that Claude reported the isolation of the first androgen from human blood-dehydroepiandrosterone sulfate. In 1955, Claude made a decision that profoundly influenced the course of his career. When Wilkins invited him to return to Hopkins, he accepted with alacrity. Thirty-seven years later he is still there carrying on the remarkable tradition of pediatric endocrinological training that has become one of the hallmarks of this great institution. There are many tales about Claude’s elopement with Barbara Ruben, a Harriet Lane pediatric resident. The most accurate, of course, comes from Barbara and Claude themselves. Accompanied by Bill and Marty Cleveland and by the inimitable Lawson Wilkins, they went off to Arlington, VA. Wilkins provided the joie de vivre as well as the wines, champagnes,and liquors. Wilkins loved this senseof participation in his fellows’ lives, a wonderful trait that Barbara and Claude have perpetuated in their relationships with succeedinggenerations of endocrine fellows. In 1961, Wilkins retired. From then until 1973, Claude shared responsibility for the Division of Pediatric Endocrinology with Dr. Robert M. Blizzard. When Blizzard left Hopkins to become chairman of the department of pediatrics at Charlottesville, Claude took over the leadership of the Hopkins division. Lawson Wilkins was a great clinician and dearly enjoyed teaching his young fellows who, in those days, were known as “the boys,” even though the group included a few girls. Migeon carried on the tradition, obtaining an NIH training grant in 1961 which provided stipends for six fellows. It was the threat by the Nixon administration in 1974 to eliminate NIH training grants that drove Claude into public affairs.
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I ne tnaocnne society
Helping to galvanize the scientific community to defend the training grant programs, Claude becamea zealot on this issue and so many other public policy issuesaffecting academic science.In recognition of his many contributions in this area, he received the Ayerst Award from The Endocrine society in 1982. During his 40-yr career, Claude Migeon has contributed to the instruction of 65 American fellows and 37 fellows from abroad. Among them, 10 have been or are chairmen of pediatric departments, 3 are assistant or associatedeans of medical schools,and 5 are associatedwith major pharmaceutical companies. Almost all the others are directors of pediatric endocrine clinics and training programs in the United States, Europe, or South America. Thus, Claude’s influence on successivegenerations of pediatric endocrinologists has been profound and certainly worthy of the Williams Award. Claude’s contributions to the body of knowledge of steroid metabolism are legend. Since 1950 he has authored 350 scientific papers and numerous book chapters. Early in his careerhe studied the transplacental passageof steroids. Later, the establishment of the double isotope derivative methods allowed him to extend his studies to plasma androgens in man. Collaborating on these projects were Jean Bertrand, Carl Gemzell, Inese Beitins, Marco Rivarola, Jose Saez, Bernadette Loras, Maguelone Forest, and Roland Tremblay. In the sixties, Claude established the norms of adrenal function in infancy and childhood. Studies of cortisol secretion were carried out with Fritz Kenny, Paul Malvaux, Orville Green, Wellington Hung, and others. In 1970, with Francis Bayard, Inese Beitins, and Ave Kowarski, he published the first description of an RIA method for plasma and urinary aldosterone. Additional aldosterone studies with Bob Blizzard, Grant Liddle, Ave Kowarski, and Virginia Weldon showed that aldosterone secretion was increased in nonsalt-losing congenital adrenal hyperplasia. Additionally, his studies showed that although cortisol secretion is related to body size during growth and development, aldosterone secretion is constant from infancy to adulthood. With the help of Perrin White and in collaboration with Pat Donohoue, Neil Van Dop, Nick Jospe, and Romolo Sandrini, the Migeon-led group contributed to the study of the molecular basis of congenital adrenal hyperplasia. Because of Claude’s early involvement with this disorder, he along with John Rock, Georgeanna Klingensmith, Rose Mulaikal, and Maria Urban, was also able to report on the longterm follow-up of male and female patients. Another important contribution has been the study of androgen receptors in human skin fibroblasts and the investigation of the androgen insensitivity syndrome. Early studies were carried out with Bruce Keenan, Walter Meyer, Barbara Migeon, James Amrhein, Marc Maes, and Charles Sultan. Later the work of Terry Brown provided the molecular basis for the earlier research. Claude has had a long-standing interest in sex differentiation. Recently, he has participated with Gary Berkovitz, Patricia Fechner and collaborators in Peter Goodfellow’s laboratory investigating the role of the sex determining region of Y in testis determination. How does one measure such a remarkable career? By the
number of fellows trained? By the number of scientific reports? By the number of patients cared for? Obviously, there are no simple answers. Rather, the answer lies in the marvelous ability to combine all three and to include compassion and sensitivity for one’s colleagues and patients along the way. Claude Migeon embodies these qualities along with those of the great researcher, teacher, and physician. He is an international scholar in the finest sense of the word, having attracted these and many other young endocrinologists from the world over to study with him at Hopkins. He is truly deserving of the Williams Award. Citation Clinical
for the Rhbe-Poulene Rorer Pharmaceutical Investigator Award of The Endocrine Society to Samuel S. C. Yen
Samuel S. C. Yen is currently a Professor of Reproductive Medicine at the University of California, San Diego, where for at least the last 20 yr he has added to our knowledge of the neuroendocrine regulation of the reproductive system, the endocrinology of the menstrual cycle, and the effects of reproductive hormones on metabolism. He has offered provocative theories on the genesisand/or treatment of polycystic ovary syndrome, premenstrual tension, menopause, hypothalamic causesof amenorrhea, pseudocyesis,and anorexia nervosa. He has studied feedback mechanismsas they relate to normal function and disease. Sam was born in Beijing, China, in 1927 and grew up during the Japaneseoccupation of China and the hostilities of World War II. He flew with the Flying Tigers asa teenager. His father was a physician who remained in China, but Sam entered the Medical School of the University of Hong Kong from which he graduated in 1954 followed by an internship in medicine at Queen Mary Hospital. He met Nicholson Eastman, Professor of Obstetrics from Johns Hopkins at this time in Hong Kong and obtained a coveted appointment to
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* 1992
the Johns Hopkins obstetrical and gynecological residency from which he graduated in 1960. Sam next obtained a 2-yr fellowship as Chief of the Department of Obstetrics and Gynecology at the Guam Memorial Hospital, which qualified him to reenter the United States for citizenship. In his short tenure at Guam, he developed two interesting papers, one on the rupture of the liver during pregnancy and the other on the high incidence of diabetes and abnormal glucose tolerance during pregnancy in the native women of Guam. On reentering the United States in 1962, Sam migrated quickly from a fellowship at Harvard to a teaching post at the Case Western University Department of Obstetrics and Gynecology run by a friend from residency days, Kenneth J. Ryan. Under the tutelage of Olaf Pearson, Sam became interested in growth hormone and placental lactogen in pregnancy. For the next 10 yr there was a flow of studies from his laboratory on hormonal profiles during puberty and the menstrual cycle, studies of hormonal half-life in blood, the effects of clomiphene and wedge resection on polycystic ovary syndrome, and the effects of hormones on carbohydrate metabolism. All during this period he engaged in the practice and teaching of obstetrics and gynecology. In 1970, Sam moved to UCSD as a professor in a department that included Benirschke, Naftolin, Judd and Ryan. He quickly established himself as a true physiologist of the
reproductive system with elegant studies on neuroendocrine control of the cycle. This included an 11-yr period as chairman of the department. Roger Guillemin was at the Salk Institute in La Jolla at the time, and with his discovery of LH-releasing hormone a working collaboration with Sam evolved on the biological effects of LH-releasing hormone in patients. This was followed by studies with somatostatin and corticotropin-releasing hormone. Sam’s laboratory has also studied the effects of RU486 on the menstrual cycle and endometriosis. In 1978, Yen authored and edited with Bob Jaffe their classic text on reproductive endocrinology that has gone through its third successive edition by 199 1. An extraordinary number of fellows have worked in Sam’s laboratory and gone on to academic and research positions throughout the world. It is altogether fitting that he should be recognized by the Rorer award for his influential and pioneering work on the endocrinology of the reproductive system. Along with this award, Yen has been honored with numerous awards, lectureships, and services; among them are the Reproductive Biology Study Section, NIH; the National Advisory Council, NICHD; Member, Institute of Medicine, National Academy of Science, Society for Gynecological Investigation (past president), and the Johns Hopkins Society of Scholars. Also, Yen has been honored by the University of California San Diego as the first recipient of the Wallace R. Parsons Endowed Chair in Reproductive Endocrinology.
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