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GH-IGF Journal


The Nineth International Congress of the GRS and IGF Society

September 14-17, 2018 Seattle, Washington


 Honorary Members of the GRS

Raymond Hintz Zvi Laron Hans Ørskov Peter Sönksen Minoru Irie MichaelO.Thorner MichaelO.Thorner MichaelO.Thorner


Raymond Hintz

   The Growth Hormone Research Society honors one of its founders and former president, Professor Emeritus Raymond Hintz with an honorary membership.

   Ray has been instrumental in unraveling the GH-IGF axis and has been a leader in the field for 4 decades. He trained in the University of North Carolina during the initial days of the formation of our understanding of the biology of GH and has been the co-discoverer of the IGF-binding proteins. Soon afterwards, he settled in Stanford University where he created a leading research and training program in the field. His career spanned the spectrum of basic research, clinical research, teaching and patient care. He trained dozens of fellows, received scores of grants, was bestowed many honors and awards, and authored hundreds of papers.His lab developed important novel assays for GH-IGF axis components including, for example, the first ALS assay. Arguably, Ray's greatest contribution to the field has been his leadership in advancing GH therapy to new indications beyond GHD, most notably, ISS, with his classic paper in NEJM, paving the way to the approval of GH for this condition. Dr. Hintz retired from Stanford University in 2006 and lives in Palo Alto with his wife Carol. He continues to attend academic meetings. His work continues to influence and inspire all of us in the field.


   It is with great sadness that we share that Dr. Raymond L. Hintz, among the group of Founders and former secretary and president of the Growth Hormone Research Society passed away on September 12, 2014. He was an internationally recognized force in growth hormone science, and an extraordinary clinician, prolific investigator, and dedicated teacher, mentor, and leader. Hintz was born and raised in the small town of Clyde, Ohio. He received his undergraduate education at California Institute of Technology and The Ohio State University, and his M.D. from Western Reserve University. He was a pediatric intern at the University of Wisconsin, and was a pediatric resident and chief resident at Columbus Children’s Hospital at The Ohio State University. During his year as chief resident in 1968, Hintz authored one of the first descriptions in the literature of familial holoprosencephaly complicated by endocrine dysgenesis, putting him firmly on his path to a career in pediatric endocrinology. After two years of military service in the Air Force, he moved to the University of North Carolina for fellowship training under the mentorship of Judson J. Van Wyk. Hintz took his first faculty position in 1972 at the University of Connecticut, before being recruited to Stanford University in 1975 as Chief of the Division of Pediatric Endocrinology. He built pediatric endocrinology and metabolism at Stanford from essentially a one-person unit to a large, diverse, academically robust, and thriving division. Hintz retired as Professor Emeritus in 2005.

   Hintz was a pioneer and one of the giants in the field of growth and growth hormones. He was responsible for much of the seminal work that served as a critical catalyst for the future of the field, including purification and characterization of what was then called “sulfation factor” (later somatomedin C, then IGF-1), and investigation of its cellular mechanisms. His successes in characterizing what were referred to as “the family of somatomedins,” IGF receptor sites and binding proteins were innovative advances and led to an enhanced understanding of insulin receptors and insulin resistance. Hintz’s influential contributions encompassed both basic and clinical research, including creation of diagnosis and treatment algorithms for growth failure, and recognition of derangements of growth hormone and insulin-like growth factors in a range of clinical conditions and patient populations. Hintz’s body of work includes more than 350 scientific publications in journals including The New England Journal of Medicine, PNAS, Science, and Nature, as well as books, book chapters, and editorials. In addition to numerous major invited lectureships and presentations, Hintz was honored for his outstanding work by awards including the Alexander von Humboldt Prize (1989), the Human Growth Foundation Award (2007), and the Judson J. Van Wyk Prize (2013). His expertise, productivity, and ability in team building led to his many national and international leadership roles, including as chair of numerous symposia and meeting organizing committees, editorial boards including the Journal of Pediatric Endocrinology and Growth Hormone and IGF Research, chairman for the sub-board of Pediatric Endocrinology, and advisor to the NIH and US Food and Drug Administration. Hintz served both as president (1991-92) and secretary (1998-2004) of the Pediatric Endocrine Society, president of the Growth Hormone Research Society (1998-2000), and was a member of the board of directors for the Genentech Foundation for Growth and Development (1993-2001).

   Hintz was deeply dedicated to the care of his patients and they were devoted to him, maintaining connections with him even after they transitioned out of pediatric care or treatment ended. His guiding principle was always to provide extraordinary care to his patients and families, which often meant tenaciously pursuing multiple lines of inquiry to ascertain the best diagnostic and therapeutic approach. It was this determination that led Hintz to recognize connections between the unusual and rapidly progressing symptoms of ataxia in a former patient, and treatment with human growth hormone. This would lead to a challenging chapter in pediatric endocrinology, during which Hintz and others quickly alerted the community to the risks for a rare degenerative neurologic disease, Creutzfeldt-Jakob disease. Hintz’s dedicated work to protecting patients led to his being awarded a Commissioner's Special Citation, by the US Food and Drug Administration, in 1988.

   Hintz trained countless medical students and residents, and mentored more than 30 fellows and post-doctoral fellows in his laboratory throughout the many years of his career. He shared his own excitement in the discovery of new scientific knowledge with his students and fellows, infusing them with the momentum and energy to sustain them through their careers. The majority of his trainees went on to academic careers, many continuing to develop leading-edge research, becoming division chiefs, department chairs, and achieving other leadership positions. But it was equally important to Hintz to instill in his trainees a deep understanding of their responsibility to the patient and family while caring for the disease. He is remembered by his mentees as a role model, not only for his passion for research, but for his kindness, gentleness, and compassion. His own journey of expanding scholarship and thirst for learning led him to visiting professorships, including at the Karolinska Institute in Stockholm in 1983, and in Munich in 1989 and 1990. He also developed and led comprehensive courses focusing on comparative international medicine, clinical research, and research design for the Stanford University Overseas Studies Programs in Berlin in 1996, and in Oxford in 2005.

   Although Hintz is recognized for his enormous contributions to pediatric endocrinology, he considered his roles as husband and father as his most important. He is survived by the partner of his life and wife for 53 years, Carol, his four children, and six grandchildren. Memorial contributions in honor of Dr. Raymond L. Hintz may be directed to the Clyde Public Library (222 W Buckeye St, Clyde, OH 43410 (419) 547-7174), where his pursuit of learning and intellectual excellence was first sparked and encouraged.

   GRS thanks Dr. Susan R. Hintz, daughter of Dr. Raymond Hintz, for preparing this obituary.

Zvi Laron

   Dr. Zvi Laron was born on February 6, 1927 in Cernauti, Romania. During WWII he was deported to the Ukraine (1941–1943). He began his medical education in Timisoara, Romania but immigrated to Israel in 1948. He graduated from Hadassah Hebrew University Medical School in Jerusalem, Israel in 1952. He was a Fellow in Pediatrics at the Massachusetts General Hospital in Boston from 1956–1957. In 1958, he was appointed Director of the Institute of Pediatric and Adolescent Endocrinology, Beilinson Medical Center, Petah Tikva, Sackler Faculty ofMedicine, Tel Aviv University, and continued as Director until 1992.

   In 1966 in Israel, Laron and coworkers reported a genetic form of dwarfism in three Yemenite Jewish siblings with clinical and biochemical features of growth hormone deficiency, but with ‘‘abnormally high concentrations of immunoreactive serum growth hormone.’’ This syndrome is usually referred to as ‘‘Laron Syndrome’’ and has led to important insights into the actions of growth hormone. Since then, some 250 patients have been identified with Laron Syndrome worldwide. Professor Laron has been a founding member of the ISPAD (International Society for Pediatric and Adolescent Diabetes), the ESPE (European Society for Pediatric Endocrinology),COPES (CoordinationOffice for Pediatric Endocrine Societies), and the GRS (Growth Hormone Research Society). He was a council member of the GRS from 1992 to 1998. He has received many awards for his contributions, and has been the editor of several influential journals. Dr. Laron is now Professor Emeritus of Pediatric Endocrinology, Tel Aviv University and Director of Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center of Israel.

Hans Ørskov

   Hans Ørskov is the story of a young man, who descended a staircase to a dark cellar underneath Aarhus Kommunehospital. He has stayed there for over 40 years spending the time developing one of the most productive research laboratories in endocrinology and diabetes. In his spare time, he graduated from Medical School at Aarhus University in 1960 and completed his thesis for which he was awarded his DMSc in 1975. He became a full Professor in 1983. In the beginning Hans worked with Professor Knud Lundbæk on the hypothesis of a causal relationship between growth hormone hypersecretion and the evolution of late diabetic complications. In the slipstream of this theory Hans fathered a series of immunoassays, which formed the backbone of investigations carried out by a large number of co-workers. The list is long and ranges from iodothyronines to insulin. The spine of his own favourite research, however, remains the growth hormone axis. In collaboration with a host of young colleagues assays have been developed for ghrelin, growth hormone, pegvisomant (a growth hormone antagonist), growth hormone binding protein, total and free IGF-I, bioactive IGF-I, and some others.

   Over the years this has ramified into research in areas such as IGF-I and experimental diabetic nephropathy, the impact of growth hormone on substrate metabolism, pharmacological and clinical aspects of growth hormone therapy, medical treatment of acromegaly, free IGF-II and tumor-induced hypoglycemia. Hans was also Vice Dean of the Faculty of Health Sciences at Aarhus University with a thoroughbred, albeit understated, talent for the politics of Academia. He has received several awards including the Hagedorn Price and the Lundbæk Medal, and he is honorary member of the Danish Endocrine Society. It is often stated that power is a matter of conquering space and money. To Hans power means two things. First, to create space for young investigators. Second, to send money after ideas, and not the other way around. That is why his cellar continues with vintage productions.

Peter Sönksen

   Professor Peter Sonksen was born 29th March 1936 in Germany to an English mother and German father. In 1939 he and his family left Germany to live in England. He graduated from Middlesex Hospital Medical School, London UK in 1960. He worked with Professor Sir John Nabarro at the Middlesex Hospital Medical School as a Leverhulme research fellow (1963–1964) where he developed a sensitive insulin bioassay. This research formed the basis of his MD which was awarded in 1967. He was awarded a Harkness Fellowship and studied at Havard Medical School, Boston, Massachusetts, USA from 1967 to 1969 where he investigated the in vivo distribution, binding and metabolism of insulin and growth hormone. In 1971 he was appointed Senior Lecturer to Professor Bill Cranston at St. Thomas_ Hospital and became a fellow of the Royal College of Physicians in 1976. In 1979 he accepted a Chair in Endocrinology at St. Thomas Hospital Medical School. He was appointed clinical director of Endocrinology and Diabetes, Guys and St. Thomas_ NHS Trust in 1989 and became Chairman of the Division of Endocrinology and Chemical Pathology from 1988 to 1993 and Chairman of the Division of Medicine from 1996 to 1998. It is rare for a clinician to make one important discovery leading to a change in clinical practise but Peter was responsible for at least three.

   In the 1970s through research into insulin metabolism he discovered the efficacy of parenteral insulin infusions and pioneered the use of continuous low dose insulin infusion for the treatment of diabetic ketoacidosis. Together with Dr. Clara Lowy he was the first to pioneer home blood glucose monitoring for diabetic patients. In the 1980s his life-long interest in growth hormone led his demonstration of the vital importance of this hormone in normal adult life. He has campaigned tirelessly for the recognition of GH replacement for growth hormone deficient adults. He was a member of the International Olympic Committee and its Medical Sub-Commission on ‘‘Doping and Biochemistry in Sport’’ (1993–2003) and has in recent years been developing a test for the detection of GH abuse in sport. He has been the editor of many scientific journals including Clinical Endocrinology (1975–1979) and GH and IGF-I research. Peter was a founding member of the GRS and first President.

Minoru Irie

   Dr. Minoru Irie was born on March 10, 1928 in Tokyo, Japan. He graduated from Faculty of Medicine, University of Tokyo in 1952, and commenced his clinical and research career at the Third Department of Internal Medicine, University of Tokyo. His main research interest has been the clinical and basic endocrinology, especially of the pituitary and thyroid gland.

   He was awarded a Fulbright Fellowship allowing him to undertake studies in Boston from 1959 to 1962. After one year of clinical experience, he worked in the Department of Endocrinology, New England Medical Center with Drs. E.B. Astwood and M.S. Raben. With Dr. Raben, he undertook pioneering work in extracting GH to treat children and adult with hypopituitarism. With the courtesy of Dr. Raben, he provided GH for the first treatment of pituitary dwarfism in Japan. He also undertook basic immunological studies on human GH and a number of pituitary peptides in collaboration with H. Friesen and colleagues (Endocrinology and J.Exp. Med, 1962). He also has done a preliminary work on GH assay at the Mass. General Hospital in 1962.

   On return to the University of Tokyo in 1963, he established radioimmunoassays of insulin and GH. Together with Drs. Toshio Tsushima and Maki Sakuma, he provided some of the most important research findings in the GH field including (i) The effect of changes in plasma free fatty acids level on the secretion of human GH (Proc.Soc.Exp.Biol.&Med. 1967, 1970 and Endocrinol. Japon.1970),(ii) GH secretion during nocturnal sleep in normal subjects (with Honda et al., JCEM 1969) and (iii) increase of serum GH concentration following thyrotropin-releasing hormone injection in patients with acromegaly or gigantism (JCEM 1972).

   In 1971, he took up an appointment as Professor of Medicine, School of Medicine, Toho University, and he continued to work on GH with his colleagues. Their studies included clinical trials of recombinant GH in various diseases and in hypopituitary adults, work on the direct effect of GH on lipolysis (Endocrinol. Metab. 1997), and standardization of GH assays (Horm.Res.2005).

   In 1998, he initiated a body of work on 20KDa GH when it became available with the advent of recombinant technology. The study group of 20KDa GH worked on basic and clinical aspects of this GH isoform, established a highly sensitive and specific assay which led to the characterization of its secretion in various conditions (JCEM 1999). The group also undertook the first clinical trial of 20KDa GH (JCEM 2004) and demonstrated the existence of negative feedback of 22KDa GH and 20KDa GH on endogenous GH secretion (JCEM and Endocrine J, 2000). This finding led him to study the possibility of using serum 20KDa GH level as a marker of exogenous 22KDa GH administration. He worked with Drs. Makoto Ueki and Takashi Kawahara to develop this approach as a GH doping test. They are working now as investigators in an Australia-Japan Consortium on a project supported by the WADA.

   Dr. Irie has been a leading member on a number of the national and international medical societies in his field. He was the chairman of the Study Group of Hypothalamo-Pituitary Disorders, Ministry of Health and Welfare from 1990 to 1996. Since 1999, Dr. Irie has been the Chairman, Board of Directors of the Foundation for Growth Science, which promotes the clinical and research development in growth science. The Foundation co-organized “The 3rd International Congress of the GRS and IGF Society” and organized its Satellite Meeting on “Use and Abuse of GH”, “The 6th Meeting of the International Society for Neonatal Screening” in 2006, and“XI International Congress of Auxology”in 2007.

   In addition, Dr. Irie with Dr. Hiroshi Naruse initiated neonatal hypothyroid screening in 1975 using blood spot on filter paper (Lancet 1975). This program covers almost 100% of newborn babies in Japan, and has identified approximately 10,000 cases for early treatment. This experience has broadened his interest to iodine deficient disorders (IDD). He has been an active members of the ICCIDD (International Council for Control of IDD) since 1985.

   Dr. Irie is still active and enthusiastic for the promotion of the field of growth science.

Michael O. Thorner

The description below is taken, in part, from the 2013 Fred Conrad Koch Award of The Endocrine Society by Robert Carey

   Dr. Michael O. Thorner graduated in medicine with honors in Therapeutics and Applied Pharmacology from the Middlesex Hospital School of Medicine, University of London in 1970. There he came under the spell of Sir John Nabarro, the senior endocrinologist. He completed fellowship training in Endocrinology and Metabolism at St Bartholomew’s Hospital (Barts) under the mentorship of G. Michael Besser, Phil Lowry, John Landon, Tim Chard, and Lesley Rees. He was at Barts from 1972 to 1977, the time of the discovery, sequencing, and synthesis of the hypothalamic hormones, and introduction of immunoassays. The Barts group together with Dr Reginald Hall’s group in Newcastle-upon-Tyne, were collaborators with Dr Andrew Schally, who provided the new synthetic hypothalamic hormones for the initial studies in humans. Thorner’s project was directed toward prolactin. The Barts group was working with a specific inhibitor of prolactin secretion developed by Edward Flueckiger at Sandoz (now Novartis) in Basel. At that time it was not known how bromocriptine inhibits prolactin secretion (before the identification of dopamine receptors). At the University of Virginia, Dr Robert MacLeod’s pioneering observations that dopamine is the hypothalamic factor inhibiting prolactin release led to Thorner visiting the University of Virginia. Soon after, Thorner was recruited to the University of Virginia (in 1977). At Virginia, Thorner developed as one of the world’s foremost clinical neuroendocrinologists and a renowned basic and clinical investigator of neurohormonal mechanisms of disease. Thorner pioneered the use of dopamine agonist drugs in patients with prolactin-secreting pituitary tumors to restore normal prolactin levels, normal gonadal function, cessation of galactorrhea, and reduction of the size of the tumor, obviating the need for pituitary surgery. As a result of Thorner’s work, medical treatment, instead of surgery, is now the standard of care for prolactin-secreting tumors. An astute clinical observation led to the discovery of growth hormone-releasing hormone (GHRH). A patient with acromegaly unexpectedly had hyperplasia rather than an adenoma of the somatotrophs of the pituitary. Thorner identified a tumor in the tail of the pancreas; removal of this tumor led to cessation of the excessive growth hormone (GH) secretion within 1 hour. The tumor contained GHRH, and he provided the tumor to Drs Wylie Vale and Roger Guillemin to study. GHRH was isolated, sequenced and ultimately cloned from the tumor. Thorner rapidly cloned the GHRH receptor. Thorner demonstrated that GHRH selectively stimulates GH secretion and that idiopathic GH deficiency is most commonly due to GHRH deficiency. Chronic administration of GHRH restored normal growth in children with GH deficiency. Together with Dr Cyril Bowers, Thorner demonstrated that the GH-releasing peptide, a synthetic hexapeptide, which acts through a novel and distinct receptor, acts synergistically with GHRH to stimulate pulsatile GH secretion. His studies were the basis for Merck Research Laboratories’ choice of a long-acting spiropiperidine analog for human studies. Thorner then led a team who demonstrated that GH secretion in the elderly can be stimulated in a physiologic, pulsatile fashion with a single daily oral dose of this GH secretagogue (MK-677). After a two-year, double-blind, placebo-controlled study of 65 healthy older men and women was completed and Thorner successfully obtained a use patent for growth hormone secretatogues in the treatment of sarcopenia in the elderly, which he is now developing into a venture company. Thus, Thorner is striving to translate his life’s work into a therapy to enable the elderly to remain independent for as long as possible. Additionally, Thorner’s laboratory has developed specific two-site assays for measurement of the two forms of ghrelin, the natural ligand for the GH secretagogue receptor and a ligand for an as-yet unknown receptor. Thorner’s work could have only succeeded with the close collaborations with investigators around the world including 33 postdoctoral fellows. Finally, Thorner developed the Pituitary Program at the University of Virginia, which is widely recognized as a leading center for the treatment of patients with pituitary and hypothalamic disease. He successfully chaired the Department of Medicine at University of Virginia for nine years and currently holds an endowed professorship in endocrinology. He has received continuous funding from the NIH and the pharmaceutical industry throughout his career. He has received numerous national and international awards for his contributions to the understanding of pituitary disease. He is an elected member of the American Society for Clinical Investigation, the Association of American Physicians, and the American Clinical and Climatological Association and was elected Fellow of the American Academy of Arts and Sciences in 2000. In summary, Dr Michael O. Thorner is an extraordinary basic and clinical research scientist in the field of endocrinology with landmark contributions to the treatment of pituitary tumors, the discovery of GHRH and its receptor, and the actions and potential uses of GHRH and ghrelin mimetics in the treatment of sarcopenia of aging.

Ron G. Rosenfeld

   Dr. Rosenfeld received his B.A. from Columbia and his M.D. from Stanford. He served on the faculty at Stanford from 1980-93. From 1993-2002, he was Chairman of Pediatrics at OHSU, returning to Stanford as Senior VP for Medical Affairs of the Lucile Packard Foundation. In 2008, he established STAT5, LLC, to provide specialized consultation services in endocrinology and pharmacogenomics, while maintaining his research laboratory at OHSU. Dr. Rosenfeld is an internationally renowned authority on the endocrine basis of growth and development and has been at the forefront of understanding the biology of growth hormone and growth factors. His work has elucidated physiological, pathological, cellular and molecular aspects of mammalian growth. The author of over 600 publications, Dr. Rosenfeld has received numerous awards, including a Mellon Foundation Fellowship, Basil O’Connor Award from the March of Dimes, an NIH Career Development Award, and 30 years of continuous NIH grant support. He is the recipient of the Kaiser Award for Excellence in Teaching at Stanford, the Joseph St. Geme, Jr. Award from the Society for Pediatric Research for pediatric education, the Ross Award for Research from the Society for Pediatric Research, The Clinical Endocrinology Trust Medal from the Royal Society of Medicine, the Maureen Andrew Mentor Award from the Society for Pediatric Research, the 2008 Transatlantic Medal as the outstanding North American endocrinologist from the Society for Endocrinology, the 2008 Robert H. Williams Distinguished Leadership Award from the Endocrine Society, and the 2013 Lifetime Achievement Award from Stanford University. He has been active on many editorial boards and study sections, and served as Chair of the Endocrinology Study Section of the NIH and as Chair of the Clinical Research Advisory Board of the March of Dimes. In 1997, he served as President of the Lawson Wilkins Pediatric Endocrine Society.

Michael J. Waters

   Professor Waters has been involved in the study of Growth Hormone action for nearly fifty years. He was the first to purify and characterize the GH receptor in Henry Friesen’s laboratory, and to create a panel of monoclonal antibodies to the GH receptor (marketed worldwide). He used these to show that the serum GH binding protein is derived from the GH receptor extracellular region by cleavage, and later verified cleavage by sequencing with Genentech. This has resulted in the use of serum GH binding protein assays as a clinical diagnostic for GH resistance due to receptor mutation. His MAbs were also used to comprehensively define the cell and tissue distribution of the GH receptor throughout the body. He collaborated with Genentech in the cloning and expression of the GH receptor, the first cytokine receptor to be cloned. Over 50 different clinical mutations have now been identified in the GH receptor coding sequence which result in dwarfism, and the cloning led to the creation of a GH antagonist (Trovert, Pegvisomant) which is superior for the treatment of acromegaly and is being trialed in the treatment of cancers and diabetic retinopathy. Since then he has been involved in structure-function studies on the GH receptor, as well as identifying signalling pathways and elements used by GH to regulate gene expression. In the last decade he published the first in vivo gene array study for a protein/peptide hormone, and reported the first targeted knockin mice with mutations to GH receptor signalling domains. These mice were used to identify transcription factor candidates responsible for postnatal growth, together with over 300 genes regulated by GH which were related to the signalling pathways initiated from different parts of the receptor cytoplasmic domain. He recently described in a Science Article the mechanism of GH receptor activation of JAK2 tyrosine kinase, superseding the Genentech hormone-dependent dimerization model. In Nature Cell Biology he developed the concept of tandem tyrosine kinase usage by this receptor by showing that the GH receptor does not signal exclusively through JAK kinases. He has identified a new signaling pathway from receptor associated Src to ras/ERK via PLCg which is needed for liver regeneration and identified gene transcripts altered by its action in vivo. He has made novel observations of nuclear localized GH and nuclear receptor in relation to cancer etiology, and shown that cell proliferation and nuclear localization of the receptor correlate. He identified a key co-activator and splicing protein, CoAA as associating with the receptor extracellular domain in a GH-dependent manner. Recently he has defined an essential role for GH in exercise-dependent neural stem cell activation, and characterized GH receptor expressing neural stem cells. He has developed a new in vitro micro- bioassay for quantifying hGH in serum and other matrices, which is now recommended by US Pharmacopoeia to replace animal testing for quality control of hGH manufacturing batches worldwide by Pharma. Recently he has shown that a constitutively active GHR is more effective than GH and GH receptor transgenes in promoting somatic growth in fish, with important implications for aquaculture production. Prof Waters has published over 260 manuscripts, and his work has been cited over 10,000 times (H factor 52). He has served on the editorial board of Molecular Endocrinology and Endocrinology (2 terms each), IGF- & GH Research, and was Scientific Editor of the Journal of Endocrinology for a decade. He is a Society for Endocrinology Asia and Oceania Medalist. He is an NHMRC Senior Principal Research Fellow and a Fellow of the Australian Academy of Science.







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