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Citation for the 1999 Fred Conrad Koch Award of The Endocrine
Society to Dr. Ronald M. Evans and Dr. Michael G. Rosenfeld
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Ron Evans was born and educated in Los Angeles. As an undergraduate at UCLA, Ron majored in microbiology and published his first paper on athymic mice that were created using the technology of the day, which was to do a neonatal thymectomy. He received his Ph.D. from UCLA, carrying out his thesis work with Marcel Baluda. Ron began his career as a retrovirologist, studying how avian myeloblastosis virus induces myeloid leukemia in chickens. This work characterized the nature of the integrated provirus and was important in the burgeoning field of RT whereby RNA viruses were integrated into the DNA genome. Ron carried out postdoctoral training in Jim Darnell’s laboratory where the focus was on transcription, initiation, and processing of adenoviral RNA, the best available system at that time. Working with Ed Ziff, he was able to show that the promoter and the capped 5' terminus of RNA were coincident. This identification of a Pol II promoter represented an important early landmark in gene transcription. With the advent of restriction enzymes Ron decided that cellular genes were amenable to analysis, cloning the steroid and T3-inducible rat GH gene in collaboration with Carter Bancroft and Michael Harpold. With this gene in hand, he moved to The Salk Institute in 1978, dedicated to understanding hormonal control of gene transcription.
After the initial cloning of the glucocorticoid receptor, Ron and his
co-workers cloned the human thyroid hormone, mineralocorticoid, and
retinoic acid and retinoid X receptors, which represented seminal
advances in endocrinology and in hormone action. Having these receptors
in hand, he proceeded to analyze in detail the molecular mechanisms
underlying transcriptional control. Important discoveries include the
observation that the retinoid X receptor was a common dimeric partner
for the receptors for thyroid hormone, vitamin D, retinoids, and
certain prostaglandins. His work defined the DNA code for recognition
of specific heterodimeric pairs and structural features necessary for
heterodimer formation and for integration into larger transcriptional
complexes involving coactivators and corepressors. His work resulted in
the isolation of the first orphan ligands, 9-cis, retinoic
acid, prostaglandin J2, and more recently, oxidized products of low
density lipoprotein that are endogenous ligands for the PPAR
receptor. The importance of his work stems not simply from the cloning
of this diverse family of receptors and the identification of new
ligands, but from elucidating hormone action by systematic dissection
of receptor structure and functional properties. From his work on
transcriptional control by this class of proteins, he is pointing to
the importance of these in disease processes such as cancer (the
PML-RAR receptor), atherosclerosis (oxidized low density
lipoprotein-PPAR), and metabolic regulation (PGJ2-PPAR adipocyte
differentiation). In his work, Ron Evans has been able to bring unity
out of diversity, to illuminate pathways that are fundamental in
hormonal control of transcription, and to apply and extend these to
important human disease processes.
Ron is a professor in the gene expression laboratory at The Salk Institute, where he has spent his entire independent career, and is an investigator of the Howard Hughes Medical Institute. Ron married Dr. Ellen Potter in 1982 and has a daughter, Lena. He holds the March of Dimes Chair in Molecular and Developmental Biology.
Geof Rosenfeld was born and spent his early life in Aberdeen, MD, where his father worked as a chemist. Only later did Geof’s father confess that he had tried medical school for a year, but withdrew when he found he much preferred science. Geof’s father thus provided a role model for his subsequent career as a scientist, but not for his subsequent career as a physician. Geof attended The Johns Hopkins University, which has been ranked as the second least-fun university in the country. There he began his studies in chemistry and did research in histochemistry with Arnold Seligman at Johns Hopkins Medical School. He entered medical school at the University of Rochester at age 19 and was much influenced by externships in the laboratory of A. G. Everson Pierce at the Hammersmith in London. Geof carried out residency in internal medicine at Washington University in St. Louis, interrupting his residency for a fellowship at the National Institutes of Health where he worked with Bert O’Malley and Ira Pastan. After a chief residency in medicine at Barnes Hospital, Geof completed his postdoctoral fellowship at UCSD with Leonard Garren. Geof is, in the best sense, an autodiadact, having been put on his own when O’Malley left the NIH and again when Len Garren died soon after Geof’s arrival at UCSD. His abiding interest in hormonal control of gene transcription began through interactions with his mentors, but the remarkable discoveries and methodologies were his.
Through his early studies on hormonal control of pituitary hormone gene transcription, begun in cell culture models provided by Gordon Sato, Geof developed an interest in the mechanisms through which the hypothalamic/pituitary/neuroendocrine system develops. He discovered the PIT-1 gene and recognized it as a member of a new class of conserved homeodomain transcription factors termed POU domain proteins. This led to the cloning and characterization of many members of the family, which were shown to be essential for a variety of developmental processes, including development of the hypothalamus, auditory system, and skin. A systematic analysis of the pathway of pituitary development led to the discovery of the Prophet of PIT-1 homeodomain gene that functions upstream of PIT-1. These developmentally important transcription factors were integrated with a variety of other transcription control proteins including LIM homeodomain and OTX proteins to define an integrated picture of the steps in organogenesis within the anterior pituitary that lead to the progressive differentiation of at least seven distinct cell types. These studies on the ontogeny of the anterior pituitary provided solutions to genetic models of growth defects in mice and established a paradigm in the field. Not surprisingly, mutations in these genes have proven etiologically important in inherited human combined pituitary hormone deficiency syndromes. These studies have not only identified new classes of transcriptional factors that are necessary for the development of the anterior pituitary cell types, but have provided a coherent and integrated picture of the steps in the progressive development of each of the cell types of the anterior pituitary.
In collaboration with Dr. Christopher Glass, he defined many of the mechanistic principles through which members of the steroid/thyroid hormone superfamily of nuclear receptors work. Recently, his laboratory has discovered corepressors and coactivators of these receptors and demonstrated mechanisms through which these interact to mediate ligand control of gene transcription. Not surprisingly, the principles of corepressor and coactivator complexes worked out in hormone response systems have been shown to be equally important in the action of a number of other transcription families. Excitingly, these have been linked to enzymatic regulation of acetylation and deacetylation, providing a mechanism for control in the context of the chromatin template in which genes exist. With his collaborators, he has pointed to the importance of the large P300/CBP proteins as integrators of multiple signals arising from nuclear receptors, coactivators, CREB, and the JAK/stats system. In his work, Geof Rosenfeld has brought together thinking in the fields of endocrinology with those of developmental and molecular biology.
Geof is a professor in the Department of Medicine at the UCSD School of Medicine, where he has spent his entire independent career and is an Investigator of the Howard Hughes Medical Institute. He married Kathy Lewis in 1983. At 15, their daughter Susan is becoming quite a scholar.
Many investigators have trained in the laboratories of Ron Evans and Geof Rosenfeld. In each laboratory, the high levels of scientific rigor and the dedication to fundamental questions have proven outstanding training venues. The Koch award of The Endocrine Society is a well deserved tribute to Ronald Evans and Geoffrey Rosenfeld.
Gordon N. Gill
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Citation for the 1999 Ernst Oppenheimer Award of The Endocrine
Society to Dr. David W. Russell
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As an Assistant Professor with Brown and Goldstein, he cloned the gene that encodes the low density lipoprotein receptor, and in so doing characterized the first clear example of exon shuffling. His dissection of the mutations of the gene in subjects with familial hypercholesterolemia made it possible to perform a structure-function analysis of a receptor that mediates endocytosis, revealing the role of cysteine-rich repeats in ligand binding and tyrosines in internalization. For his work on the low density lipoprotein receptor, he was awarded the Louis N. Katz award of the American Heart Association.
As an independent investigator, he turned his interest to rare
autosomal recessive mutations that cause male pseudohermaphroditism. He
and his co-workers showed initially that two genes encode isoenzymes of
human steroid 5
-reductase, a duplication that is present in all
species examined to date, including plants. They showed that
5-reductase deficiency in humans is due to mutations in
isoenzyme 2, and using a combination of naturally occurring mutations
and site-directed mutagenesis they deduced the enzymatic mechanism used
by an enzyme so hydrophobic that it has been possible to clone the
complementary DNA but not to solubilize the protein. More importantly,
the development in his laboratory of knockout mice in which isoenzyme
1, isoenzyme 2, and then both isoenzymes were made deficient made it
possible to dissect the roles of testosterone and dihydrotestosterone
in male physiology and to demonstrate that isoenzyme 1 plays a critical
role in parturition. The molecular biology of 17ß-hydroxysteroid
dehydrogenase proved to be even more complex, and the Russell group
cloned two critical isoenzymes that perform this function, the type 6
isoenzyme that has an oxidative function, and together with Steffan
Andersson’s group, the type 3 isoenzyme, which is responsible for the
conversion of androstenedione to testosterone in testes. They showed
that autosomal recessive mutations in the 17ß-hydroxysteroid
dehydrogenase 3 gene also cause male pseudohermaphroditism and provided
a preliminary structure-function analysis of this enzyme.
Russell has also done pioneering work in cerebrotendinous xanthomatosis
and in neonatal cirrhosis. He showed that deficiency of mitochondrial
cholesterol 27-hydroxylase in cerebrotendinous xanthomatosis leads to
accumulation of cholesterol in the brain and other tissues, implicating
a role for this enzyme in the exit of sterols from cells. In neonatal
cirrhosis, he traced the defect to the oxysterol 7-hydroxylase gene,
which he had earlier isolated. As a result of studies of a rare patient
with the disorder and of knockout mice, he discovered the presence of
an alternate pathway of bile acid synthesis that may be quantitatively
more important that the classic pathway involving 7-hydroxylation.
The entire body of work is distinguished by the creative approaches,
including expression cloning techniques, used for cloning the relevant
genes and the methodical way in which the metabolic consequences of
each block have been explored, thus elucidating normal as well as
deranged physiology.
In addition, David is a conscientious member of the faculty, so that his advice and his service on committees are highly prized. He has served on editorial boards for the Journal of Lipid Research, Biochemistry, Molecular Endocrinology, the Annual Review of Biochemistry, and The Journal of Biological Chemistry (where he now is Associate Editor). He is a renowned mentor for graduate students and postdoctoral fellows, and it is a pleasure to serve on the same faculty with him.
David Russell has clearly established himself as one of the most imaginative and productive scientists of his generation, and The Endocrine Society is proud to acknowledge his accomplishments with the expectation that he will make even greater advances in our field in the future.
Jean D. Wilson
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Citation for the 1999 Robert H. Williams Distinguished
Leadership Award of The Endocrine Society to Dr. Joel F. Habener
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Joel showed an early interest in molecular biology as exemplified by his studies of DNA secondary structure in the late 1960s at the National Institutes of Health. In 1969, he joined the research group of Dr. John Potts and moved to the Massachusetts General Hospital, where he has spent the remainder of his career. As a member of this dynamic group of investigators, Joel contributed to an impressive series of studies that focused on the development of immunoassays for calcitonin and PTH. These assays were then used to elucidate pathways of synthesis, processing, secretion, and metabolism of these hormones.
In a bold move early in his career, Joel joined a cadre of MGH scientists who worked in Alex Rich’s laboratory at the Massachusetts Institute of Technology. In this environment, he was able to combine his interests in endocrine physiology with the emerging field of recombinant DNA technology. In addition, his newly acquired skills in recombinant DNA technology gave Joel an excuse to take advantage of his hobby, fishing, to procure islets from anglerfish. In this way, Joel made excursions to Cape Cod, and also found an excellent source for the isolation of islet mRNAs because of the separation of the islets and exocrine pancreas in this species.
Joel’s exciting research interests soon attracted a talented group of young physician-scientists including William Chin, Joseph Majzoub, Jack Jacobs, Kay Lund, Richard Goodman, and Gerhard Heinrich. Together, they tackled the cloning of a dazzling array of endocrine genes, and this was when it was done the hard way! Bill Chin cloned several of the glyco-protein hormone genes and performed classic studies of their hormonal regulation. Joseph Majzoub initiated studies of vasopressin and oxytocin gene regulation. Richard Goodman, Kay Lund, Jack Jacobs, and Gerhard Heinrich led a major transition in Joel’s lab from studies of PTH and calcitonin to investigation of gene expression in the pancreatic islets, which is his most enduring area of research. These studies extend beyond gene regulation and also include the processing of polypeptides, leading to the discovery of new hormones such as glucagon-like peptide-1, which functions as a potent insulin secretagogue. This first generation of trainees, in turn, assisted in the development of a second generation, which I was fortunate to join, along with Marc Montminy, Hans Zingg, Eliot Spindel, Daniel Drucker, Jacques Philippe, and many others. There have been many groups of trainees since then, and each has thrived under Joel’s mentorship.
As a nearly perpetual member of NIH study sections, one of the founding editors of Molecular Endocrinology, an Associate Editor for the Journal of Clinical Investigation, and as a member of numerous editorial boards, Joel has been very active in the peer review process. His infectious enthusiasm is most evident when he reviews a good manuscript. He is ecstatic when he can recommend a paper for acceptance without the need for revisions. He knows that authors appreciate positive feedback, and he is eager to quickly share the results with others in the research community. It is typical of Joel to see the positive attributes in a grant, a fellowship candidate, or a research presentation. He keeps reservations to himself or delivers them in a constructive manner.
What are the intangible elements that have led to the recurring success of Joel’s research group? Certainly, the brilliance of the laboratory director is a key feature. Joel has a special style of interacting with his trainees, and it is arguably unique. He seeks to stimulate innovation and creativity, which are difficult concepts to teach. He does this by constant, almost incessant brainstorming with his laboratory group. By example, he teaches that it is acceptable to have "bad" ideas as long as they are flanked by good ones. The key is to maintain a continuous flow of ideas. He also rewards bold experimental strokes. Joel has retained, as a senior scientist, the unbridled enthusiasm for experimental questions that one often sees in undergraduate students before they have been seasoned by the anguish of failed experiments. The excitement with which Joel awaits the results of an experiment is contagious. When interesting results were in hand, he is the first to share them with every member of the lab.
Joel is an ardent supporter of bringing new technology to research problems. He has generated a strong underpinning of research support that stabilizes and enhances this vibrant research environment. He has been an Investigator of the Howard Hughes Medical Institute since 1976. In addition, he has held three RO1 grants for more than 25 yr, along with others that were targeted to rapidly breaking areas of research. This outstanding track record of support is testimony to his creativity and productivity. It also speaks to the question of how to foster innovative research.
Joel has supported many societies through service on committees and editorial boards. He has also received many awards, including the Astwood award from The Endocrine Society and a MERIT award from NIH, among others. His research advances have stimulated scientists around the world. In addition to these activities, Joel’s most lasting impact may be his mentorship of young investigators and, in particular, his ability to stimulate creativity and to instill enthusiasm for research. For all of these reasons, Joel Habener richly deserves the 1999 Williams Distinguished Leadership Award.
J. Larry Jameson
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Citation for the 1999 Edwin B. Astwood Lecture Award of
The Endocrine Society to Dr. David D. Moore
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David and his colleagues also isolated a number of orphan nuclear receptors and proved or ruled out a variety of creative candidate ligands (even cyclopamine!). Perhaps the most revealing story is that of CAR, the constitutive androstane receptor. Dr. Moore and colleagues, in collaboration with Barry Forman and Ron Evans, showed that this orphan receptor is active in the absence of added ligand, but inactivated by binding of androgen-related ligand. This remarkable reversal of the usual nuclear hormone receptor paradigm was reported in Nature in 1998. But CAR was first reported 4 yr earlier under the name of MB67, based upon the initials of Miriam Baes, who initially isolated it in Dr. Moore’s lab. At that time Dr. Moore had already wanted to name it CAR, for constitutively active receptor, but reviewers would not allow that because of the remote possibility of an activating ligand that was present in all species and extracts in which the nuclear receptor was expressed. Yet in the end Dr. Moore persevered, and creatively arrived at his first choice of acronym for this groundbreaking receptor. Since another exciting orphan he discovered is named SHP (short heterodimer partner), we should probably be looking for JET and TRAIN in high profile journals sometime soon.
That’s not all. Dr. Moore was also first to apply the powerful yeast two-hybrid screening technique to nuclear hormone receptors. The list of RIPs (RXR-interacting proteins) and TRIPs (TR-interacting proteins), including numerous orphan receptors and coregulators, was considerably larger than was expected at the time. David’s prediction that the many classes of proteins he identified reflected the pleotropic functions of nuclear receptors has turned out to be right on the money. A good number of the RIPs and TRIPs have now been identified as coregulators by Dr. Moore and others.
It should be noted that Dr. Moore contributed the sequences of the RIPs and TRIPs to public databases before publishing the vast majority. This was extremely useful information for other investigators who later identified the same molecules as corepressors and coactivators. This type of service to the scientific community, and especially to molecular endocrinology, is standard for David Moore. Other major contributions include co-authoring Current Protocols in Molecular Biology, organizing the Thyroid Hormone Receptor Resource on the Internet, organizing a Hormone Action Gordon Conference, and founding the Boston Area Receptor Society (BARS). He resisted this author’s suggestion to convert this organization into a Foundation, even after leaving Boston for Houston in 1997. Not surprisingly this transition has been seamless, and the Baylor nuclear receptor mafia, already quite powerful, now looms as a dominant force for many years to come.
All of these accomplishments not withstanding, David Moore has remained a great colleague and mentor, baseball fan, husband to Judy Lin, and father to Alexander Lin-Moore. It is very fitting that David Moore be recognized by The Endocrine Society as the 1999 recipient of the Edwin B. Astwood lecture award.
Mitchell A. Lazar
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Citation for the 1999 Monsanto Clinical Investigator Lecture Award
of The Endocrine Society to Dr. Stephen J. Marx
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Steve’s work exemplifies the very best that a physician-scientist can accomplish when studying disease at levels ranging from the molecular to the whole patient. He has collaborated in this work with a wide range of colleagues at NIH and elsewhere, but his unique contributions have been vital to the success of the research. He has succeeded in elucidating the pathogenesis of three different hereditary disorders: vitamin D-dependent rickets type II (VDDR), familial hypocalciuric hypercalcemia (FHH), and multiple endocrine neoplasia type I (MEN I).
Beginning with his recognition of a familial syndrome of resistance to vitamin D, Steve and his colleagues went on to show that fibroblasts from affected subjects with VDDR have a defect in nuclear uptake of 1,25-dihydroxyvitamin D. They were able to define distinct defects in 1,25-dihydroxyvitamin D binding in different kindreds, providing evidence for molecular heterogeneity in VDDR. In collaboration with Mark Haussler’s group, Steve was able to show that fibroblasts from some subjects with VDDR possess immunoreactive vitamin D receptor. Subsequent to the cloning of the vitamin D receptor gene, several groups independently succeeded in identifying loss of function mutations in the gene from affected subjects with VDDR. Thus, the careful clinical observations and cell biology studies of the Marx group set the stage for eventual identification of specific mutations in the receptor gene.
A distinct disorder termed familial benign hypercalcemia had first been recognized by Thomas Foley, but it was the Marx group that first delineated the pathophysiology of this disorder. Emphasizing the importance of the relative hypocalcuria he observed in affected subjects, Steve renamed the disorder FHH. Importantly, he recognized that a rare syndrome of neonatal severe primary hyperparathyroidism could be the manifestation of mutations in both alleles of the gene responsible for FHH, itself an autosomal dominantly inherited disease. His study with the late Maurice Attie of urinary calcium excretion in subjects with FHH who had been rendered surgically aparathyroid proved that not only the parathyroids but also the kidneys must harbor an intrinsic defect in "calcium sensing." The implications of this study were not fully realized until the cloning of a calcium-sensing receptor by Ed Brown and colleagues in 1993, and the recognition that it is expressed abundantly and plays a key role in regulating responses to extracellular calcium in both parathyroid and kidney. Cloning of the receptor gene was rapidly followed by identification of mutations in this receptor in FHH and in neonatal severe primary hyperparathyroidism.
During his fellowship at NIH in 1971, Steve published his observations on a large kindred with MEN I. His interest in this disease led to careful clinical studies on tests useful in screening for the disorder, and confirmation of linkage to chromosome 11q13, first reported in 1988 by a group at the Karolinska Institute. By demonstrating loss of heterozygosity for loci at 11q13 in parathyroid tumors from subjects with MEN I, Marx and colleagues provided evidence that such tumors represent clonal neoplasms rather than polyclonal hyperplasia. A collaboration between the Marx group and several other groups at NIH culminated within 3 yr in identification of the MEN I tumor suppressor gene on 11q13. This permitted rapid identification by the NIH groups not only of numerous germline mutations in the gene in kindreds with MEN I, but also identification of somatic mutations in the gene in a significant number of sporadic parathyroid as well as islet cell and carcinoid tumors. Other investigators around the world have very quickly been able to apply these findings to mutation identification. This work has had immediate implications for early disease diagnosis and offers the possibility for novel treatments. At a basic level, the Marx group in collaboration with other NIH colleagues has shown that the MEN I gene product, menin, which shows no sequence similarity to other known proteins, resides primarily in the nucleus and plays a role in gene regulation by interacting with the transcription factor, junD.
These three major accomplishments and many others in both basic and clinical areas of endocrinology that I omit here due to limitations of space have led to Steve’s election to the American Society for Clinical Investigation and the Association of American Physicians. He has received the Fuller Albright Award of the American Society for Bone and Mineral Research and the Meritorious Service Award of the U.S. Public Health Service. The Endocrine Society now recognizes his many accomplishments with its 1999 Monsanto Clinical Investigator Lecture Award.
Allen M. Spiegel
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Citation for the 1999 Gerald D. Aurbach Lecture Award of
The Endocrine Society to Dr. James E. Darnell
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Highlights of Jim’s scientific contributions include his early studies on viral infection of mammalian cells in culture, followed by an extensive series of studies on RNA synthesis in the late 1960s and 1970s. During this time, he studied the roles of polyadenylation in mRNA biogenesis and then was the first to show that high molecular weight nuclear RNA was a precursor for mature messenger RNA. During the late 1970s Jim’s lab turned its attention to the regulation of transcription in mammalian cells. Perhaps the most far reaching results from Darnell’s laboratory began with research in the 1980s that culminated in 1992 with the discovery of a direct signaling pathway from the cell surface to genes in the nucleus. Darnell’ s group discovered that a set of dual function proteins they named Stats (Signal Transducers and Activators of Transcription) remain quiescent in the cell until circulating polypeptides bind to their specific cell surface receptors.
During the 1980s, a thread of research on interferon (IFN) signaling developed in Darnell’s lab, alongside studies on RNA processing and viral gene expression. The lab began to consider how nuclear genes were regulated by extracellular signals. Having carefully mapped the regulatory elements in the promoters of several IFN-inducible genes, Jim’s lab took a biochemical approach toward identifying the factors that mediate IFN-induced gene expression. In 1990 they began to publish a series of papers that characterized these factors, and, perhaps most importantly, they showed that the IFN-regulated factors preexisted in latent form before hormonal stimulation, becoming active after the cell was stimulated by the hormone. In 1992, Jim’s lab published sequences of the first two examples of the Stat protein family and showed that these proteins were activated by tyrosine phosphorylation. The biochemical approach taken by Jim’s lab was complemented by a series of collaborative studies undertaken with George Stark and Ian Kerr’s lab. Sandra Pelligrini, working with Kerr and Stark, had developed a genetic approach using cells in which IFN response genes were mutated. The collaborations between these groups provided genetic, as well as biochemical, proofs of the centrality of Stat tyrosine phosphorylation for IFN signaling. Following closely on the discovery of IFN-induced Stat signaling, many labs have discovered that this general pathway was used by numerous hematopoietic cytokines and by the pituitary hormones PRL and GH. Thus, between 1992 and the end of 1994, the fundamental properties of signal transduction for a host of previously enigmatic hormones were brought into clear focus. While many questions remain to be answered, the observations from Jim’s lab broke through a longstanding logjam that prevented progress on understanding hormonal signaling.
Jim Darnell has received numerous honors and awards; notable among them, he is a member of the National Academy of Sciences, a foreign member of the British Royal Society, and a Fellow of the American Association for the Advancement of Science. His accomplishments as an educator and mentor are as noteworthy as his particular scientific contributions. Jim’s trainees include 50 professors and lab directors, as well as 15 junior faculty. Counted among them are one Nobel Laureate (David Baltimore) and one recipient of the Society’s Edwin B. Astwood Lecture Award (Ron Evans). He has co-written the fundamental textbooks in both Virology (with Salvadore Luria) and Molecular Cell Biology (with Harvey Lodish and David Baltimore). The Society is most pleased to hear Dr. Jim Darnell’s Gerald D. Aurbach Lecture at its 1999 Annual Meeting.
Nelson D. Horseman
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Citation for the 1999 Sidney H. Ingbar Distinguished
Service Award of The Endocrine Society to Dr. M. Susan Smith
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As President of the Society, Susan instituted a permanent long-range planning process, including strategic financial planning, to chart the Society’s future. She continued, even after completing her presidency, to lead the long-range planning activity of the Society, playing a major role in changing the schedule of committee and Council meetings to improve the rational development of new programs and the annual budget. Susan implemented programs to increase Society membership diversity and participation in Society activities. She has also served as member or Chair of a number of other Society committees (Executive, Finance, Long-Range Planning, Nominations, Research Affairs, and Awards) and and on the Editorial Board of Endocrinology.
In addition to her record of outstanding service to The Endocrine Society, Susan has filled leadership roles on the Board of Directors of the Society for the Study of Reproduction, the Research Advisory Committee of the Federation of American Societies in Experimental Biology, and as Program Chair for the Endocrinology and Metabolism Section of the American Physiological Society. She currently serves on the Program Committees of the International Congress of Endocrinology and the International Society of Neuroendocrinology. Among her other professional activities have been service on the NIH Biochemical Endocrinology Study Section and the NICHD Population Research Committee and as a consultant to the Population Research Centers of four major medical centers. She recently chaired the review panel for a new NICHD program, the Specialized Cooperative Centers Program in Reproductive Biology. She has also served as Associate Editor of Current Opinion in Endocrinology and Diabetes, on the editorial boards of Biology of Reproduction, Frontiers in Neuroendocrinology, and Neuroendocrinology, and as a reviewer for many journals.
As Director of the Oregon Regional Primate Research Center at OHSU, Susan leads a research institute that includes a large number of major research programs. Simultaneously, she led the development of the new Center for Women’s Health at OHSU, itself a full-time job. During the Center’s first year in existence, she led the development of programs in clinical care, research, and education in women’s health and the planning of an innovative clinical care facility for health care programs at the Center.
Susan has a great gift for leadership and an unusual willingness to commit her energies to the cause of endocrinology in The Endocrine Society or wherever else she is needed. When she accepts a challenge, she completes it and always does it well. As a result, she has been asked and continues to be asked to lead again and again. It is for her ability and generosity in taking one leadership role after another that The Endocrine Society has selected M. Susan Smith, Ph.D., to receive the 1999 Sidney H. Ingbar Distinguished Service Award.
David N. Orth
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Citation for the 1999 Roy O. Greep Lecture Award of The
Endocrine Society to Dr. Ernst Knobil
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As described in the citation for the Koch Award, Ernst was born in Berlin and came to the USA with his parents in 1940. His undergraduate and graduate years were spent at Cornell University, where he received the B.S. and Ph.D. degrees. Cornell, and in particular the laboratory of Samuel Leonard, became the nidus that launched Ernst on five most remarkable decades of active physiological endocrine research. After completing his Ph.D. with Sam Leonard, Ernst joined Greep’s laboratory at the Harvard School of Dental Medicine, as a Milton Research Fellow. Shortly thereafter, Ernst was called upon by Greep to help Greep with his endocrine lectures at the Medical School. After Knobil had delivered his first lecture, he was offered the position of Instructor by the Chairman of the Department of Physiology. After consulting with Greep and receiving his blessing, Ernst accepted his first faculty position. Although Ernst’s fascination by control systems and integrative biology was nurtured at Harvard, the opportunity in 1961 to build his own Department of Physiology at the University of Pittsburgh Medical School was irresistible. As the Richard Beatty Mellon Professor of Physiology at Pittsburgh, Ernst embarked on a systematic investigation of the control of ovulation in the monkey, which produced a classic series of linear experiments that led to the view that menstrual cyclicity is controlled by the negative and positive feedback actions of ovarian estradiol on pituitary gonadotropin secretion. It was also in Pittsburgh that Knobil and his colleagues, while monitoring circulating LH concentrations at frequent intervals, discovered the phenomenon of episodic hormone secretion. They speculated in 1970, a year before GnRH was isolated from the hypothalamus, that episodes of LH secretion "may be due to intermittent signals from the central nervous system, unrelated to circulating LH levels, which, in turn, result in an increased production of LH releasing factor and the discharge of LH." Subsequent findings that only intermittent GnRH stimulation is able to sustain pituitary gonadotropin secretion and that pulsatile LH release is robustly correlated with volleys of electrophysiological activity in the hypothalamus were equally critical, and together these three signal observations led to the notion of the hypothalamic GnRH pulse generator, which now comprises the cornerstone of all models describing the control of gonadal function.
Ernst left the University of Pittsburgh for Houston in 1981 after founding an NIH Center for Research in Primate Reproduction that this writer and his colleagues were fortunate enough to inherit. Remarkably, Ernst was able to maintain his laboratory during his 3 yr tenure as Dean of the Medical School at the University of Texas Houston, where he has remained as The H. Wayne Hightower Professor in the Medical Sciences and Ashbel Smith Professor. Over the years, findings from the "Knobilab" have had major impacts in the clinical arena. The discovery of species specificity of GH prompted the founding of the National Hormone and Pituitary Program, and the principle of GnRH pulsatility forms the basis of treatments for prostate and breast cancer and central sexual precocity and is used extensively in Assisted Reproductive Technologies.
As previously recognized by our Society, Dr. Knobil’s contribution to endocrinology extends way beyond the impact of the results of his research. The exemplary standards that he set for every aspect of his research were applied to his other endeavors: there were no exceptions. Thus, the course in Mammalian Physiology that he and his faculty developed at Pittsburgh became a model of the Medical School Curriculum and is remembered by generations of physicians for its rigor and its relevance to the practice of medicine. Ernst was also a superb mentor who, by working, debating, and writing with his fellows, provided them an opportunity to share the logical force that guided his beautiful work.
For these fundamental contributions to reproductive endocrinology and related fields, for his role as a mentor of generations of reproductive endocrinologists, for his unquestionable candor, sincerity, and integrity, and for his friendship and leadership, The Endocrine Society is pleased to present the Roy O. Greep Lecture Award for 1999 to Dr. Ernst Knobil.
Tony M. Plant
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Citation for the 1999 Distinguished Educator Award of The
Endocrine Society to Dr. Daniel D. Federman
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Dan’s depth as a clinician and his skill as a communicator have proven invaluable to promoting high standards of medical education and ethical practice as well as implementing innovative changes in medical curriculum. At Harvard Medical School, he played a critical role in implementing the conversion of the curriculum to the active teaching mode characteristic of the Harvard Medical School "New Pathway." Dan has been active in improving standards of education for medical residents at the national level through his work with the American Board of Internal Medicine on which he served for 8 yr, becoming its Chairman in 1977. He has also been a leader in postgraduate education for physicians contributing effectively to the educational programs of American College of Physicians, and he became its President in 1982. Dan has written thoughtful articles about the need for changes in medical education, analyzing changing demands and new approaches for medical student teaching arising from the shift from in-patient to out-patient teaching. Despite his many administrative duties as Dean for Education at Harvard, Dan manages to delight new generations of medical students and house officers by continuing to serve as an inspiring teacher year after year as Attending Physician and Endocrine Attending at the Massachusetts General Hospital and the Brigham and Women’s Hospital.
Dan’s remarkable contributions at Harvard were recognized by his selection in 1992 as the first Carl W. Walter Professor of Medicine and Medical Education. His national leadership, recognized here today by his Endocrine colleagues, has been celebrated by other national organizations including the American College of Physicians, who awarded him its Distinguished Teacher Award and named him to the coveted post of Master of the College. He was elected to the Institute of Medicine in 1980. I suspect, however, that no award gives Dan Federman greater pleasure than does the receipt of The Endocrine Society’s Distinguished Educator Award.
John T. Potts, Jr.
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Citation for the 1999 Distinguished Physician Award of
The Endocrine Society to Dr. Henry G. Burger
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His interest in reproductive endocrinology emerged from the application of RIAs for FSH and LH to the menstrual cycle and in the recognition of the important role of estrogen in inducing the mid-cycle LH surge associated with ovulation. These observations were applied to the study of the fertile period in normal regularly cycling women leading to clear definition and recognition of the fertile period of the cycle. This work was recognized by his invitation to participate in World Health Organization’s task force on methods for the natural regulation of fertility.
The application of assays for FSH and LH in male reproductive disorders led him, together with a group in Melbourne, to explore the isolation of inhibin. This ultimately led to the isolation of inhibin for the first time and the subsequent establishment of RIAs for this hormone that have assisted in the unravelling of the complex physiology of this gonadal protein hormone. In particular, Henry Burger concentrated on the development of clinical applications of the measurement of inhibin and established its use in the detection and monitoring of certain types of ovarian malignancy. This work laid the scientific basis for the use of inhibin measurements in the screening of granulosa cell tumors of the ovary and ovarian mucinious cystadenomata.
His interest in defining the physiology of inhibin during puberty, the menstrual cycle, the menopausal transition, and the postmenopausal state led to a very significant interest in the clinical aspects of the menopause. This work, which has included the management of menopausal symptoms with estrogen and the use of testosterone by implants in certain patients, has been recognized by numerous awards and most recently by his election as President of the International Menopause Society.
As a practicing clinical endocrinologist, Henry Burger interfaced with undergraduate students and fellows and his clinical acumen and encyclopedic knowledge of endocrinology stimulated these colleagues, many of whom undertook doctoral studies under his guidance. Numerous Fellows have enjoyed his counsel during periods of clinical or research training and hold key appointments throughout the world. His contributions to endocrinology will endure through these former fellows and through Prince Henry’s Institute of Medical Research, which he has built up to be a major medical research institution.
His contributions have been recognized in numerous awards such as the Susman Prize of the Royal Australasian College of Physicians, the Organon award of The Endocrine Society of Australia, the Sims Travelling Fellowship awarded by Colleges of Physicians of Commonwealth Countries, and by numerous lectureships awarded by national and international organizations. Among these, he was the Dale Medallist for 1997 of the British Endocrine Society. He has served on numerous editorial boards and acts as a Senior Editor of DeGroot’s Textbook of Endocrinology. His services to endocrinology and medical research in Australia have been recognized by his appointment as an Officer of the Order of Australia and his election to the Fellowship of the Australian Academy of Science.
It is clear that Henry Burger has made unique and significant contributions to the science and practice of medicine in the field of endocrinology on the International scene. He represents a superb model of a caring physician and dedicated research scientist whose contributions have led in numerous ways to significant changes in the practice of endocrinology. The Endocrine Society’s Distinguished Physician Award is a fitting tribute for a career spanning decades of significant contributions to the field of endocrinology.
David M. de Kretser
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Citation for the 1999 Richard E. Weitzman Award of The
Endocrine Society to Dr. Jacques Simard
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The general focus of his research program is the molecular mechanisms
controlling the intracellular bioavailability of sex steroids. This
process is of major importance, especially in human and other primates,
since their adrenals secrete large amounts of the inactive steroid
precursors dehydroepiandrosterone (DHEA) and its sulfate
(DHEA-S), which are converted into potent androgens and
estrogens in normal peripheral tissues as well as in tumoral
hormone-sensitive tissues, such as breast and prostate cancers. Among
the enzymes involved in this process, the 3ß-hydroxysteroid
dehydrogenase/
5-4 isomerase (3ß-HSD)
catalyzes a step essential for the formation of all classes of
steroids, namely, progesterone, mineralocorticoids, glucocorticoids,
androgens, and estrogens. In support of this hypothesis, his group has
demonstrated that 3ß-HSD expression and/or activity is not only
present in classical steroidogenic tissues, namely, the adrenals,
gonads and placenta, but also in numerous peripheral tissues in humans,
monkeys, and rats. Jacques’ research project, conducted within the
scope of the MRC group, was mainly focused on the characterization of
the structure and function of the 3ß-HSD gene family and its
evolution as well as the elucidation of the molecular basis of human
3ß-HSD deficiency.
Following the initial characterization of the human placental 3ß-HSD in 1989 by this MRC group, Jacques’ team cloned three distinct types of 3ß-HSD in the rat in 1990, thus providing the first evidence of the existence of multiple members of this gene family. This multiplicity of enzymes suggests that such a tissue-specific expression and regulation of 3ß-HSD may play an important role in steroid formation and catabolism, a notion that he subsequently verified. Thereafter, his team characterized the rat type IV 3ß-HSD, which is predominantly expressed in the placenta and the skin in contrast to the type I and II enzymes, which are expressed in the adrenals and gonads, and type III, which is exclusively expressed in the male rat liver.
The isolation of multiple 3ß-HSDs in the rat and the heterogeneous clinical picture observed in classic 3ß-HSD-deficient patients also suggested the existence of multiple 3ß-HSDs in the human. In 1991, Jacques’ group characterized the structure and function of a second human 3ß-HSD type, whose expression is restricted to the adrenals and gonads, in contrast to type I 3ß-HSD, which is predominantly expressed in the placenta and peripheral tissues, such as the breast, prostate, and skin. He mapped the 3ß-HSD gene cluster to the p13.1 region of chromosome 1 at 1–2 cM of the centromeric marker D1Z5 by genetic linkage analysis.
In 1992, he demonstrated for the first time that mutations in the type II 3ß-HSD gene are responsible for classic 3ß-HSD deficiency, a form of congenital adrenal hyperplasia that impairs steroidogenesis in both the adrenals and gonads. However, the absence of mutations in the type I gene provided the long-awaited molecular explanation for the persistence of peripheral steroidogenesis in these patients. These studies yielded unique information on the structure function-relationship of the 3ß-HSD superfamily and provided an explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically nonapparent salt-wasting form of this autosomal recessive disorder. His group identified and characterized the functional significance of the majority of point mutations detected in the type II gene and performed the functional analysis of 3ß-HSD missense mutations.
More recently, Jacques’ team made the remarkable observation that interleukin 4 (IL-4) and IL-13 dramatically induce 3ß-HSD expression in ZR-75–1 and T-47D human breast cancer cells, HaCaT immortalized keratinocytes, HT-29 colon cancer cells, and ME-180 cervix cancer cells as well as in normal human mammary epithelial cells and human prostatic epithelial cells. The biological relevance of this finding pertains to the presence of infiltrating stromal/immune cells in solid breast tumors. These cells can account for up to 50% of the tumor and secrete a wide spectra of cytokines. This work was a direct continuation of his project on the biological action of cytokines in human breast cancer cells and indicates a mechanism whereby circulating precursors such as DHEA can be converted to potent androgens and estrogens within a developing tumor. In parallel, his group was involved in the characterization of the structure of the human type II 17ß-HSD gene, which is responsible for the inactivation of active androgens and estrogens in peripheral tissues, and mapped this gene to q24.1-q24.2 region of chromosome 16. In fact, he demonstrated in ZR-75–1 cells that exposure to DHT regulates the oxidative 17ß-HSD activity, thus favoring the degradation of 17ß-estradiol into estrone.
The type I 17ß-HSD gene, which plays a crucial role in estrogen formation and degradation, became a prime candidate gene for the hereditary breast-ovarian cancer BRCA1 gene in 1992–1993. Direct sequencing of the entire type I 17ß-HSD (EDH17B2) gene in several unrelated affected women did not uncover any sequence variations, other than the 11 polymorphisms that they had previously characterized. These data thus excluded that mutant type 17ß-HSD enzyme is responsible for breast/ovarian cancer syndrome. However, Jacques’ collaborative work led to the localization of the BRCA1 gene to a 600-kb region, a finding that was critical to the cloning of BRCA1 by Dr. Mark Skolnick’s group. His team was the first to screen BRCA1 mutations in Canadian breast/ovary cancer families and the first to identify recurrent BRCA1 mutations and to relate these mutations to specific haplotypes. In particular, the 185delAG mutation is specific to Ashkenazi Jewish women and represents the majority of BRCA1 mutations in this ethnic group. He also had an important role in the characterization of polymorphisms and rare sequence variants in the BRCA1 gene.
As a consequence of this work, he established a fruitful collaboration with Mark Skolnick’s laboratory. This led to the construction of an integrated transcription map of the BRCA2 region and, more importantly, the elucidation of the complete structure of this second breast cancer susceptibility gene. The human BRCA2 coding sequence is very large, composed of 26 exons that span 10443 bp and encodes a protein of 3418 amino acids with no sequence similarity with BRCA1.
Jacques is now in charge of the Reference Center for Hereditary Breast and Ovarian Cancers for French-Canadians in Québec province. The major goals of his research project entitled "Genetics and epidemiology of familial breast and ovarian cancers in French-Canadians" were to establish a network of molecular geneticists, genetic counselors, and clinicians to 1) identify and recruit high risk families; 2) identify the prevalence of germline mutations in breast/ovarian and prostate susceptibility genes in French-Canadians; 3) determine the penetrance of these germline mutations in French-Canadians; 4) identify potential phenotype-genotype relationships; 5) establish a network of information on the hereditary cancers in Québec; and 6) optimize the health care for both affected and unaffected carriers.
Jacques’ remarkable organizational skills are best exemplified by the success of the Xth International Congress of Hormonal Steroids that he was largely responsible for organizing last year in Québec City. This was certainly the best meeting of this Congress in recent years.
Jacques’ work is characterized by an excitement and enthusiasm for science that he readily transmits to others. This is in turn a reflection of his personality, which literally bubbles over with a sense of enthusiasm for life, breaking through the laconic genre portrayed by his French accent. It is this capacity to organize, to think new thoughts, and to communicate them to others, that marks Jacques as one of the true young leaders of his field. The Endocrine Society is proud to present the 1999 Richard E. Weitzman award to Dr. Jacques Simard in recognition of a burgeoning career.
Evan R. Simpson
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