Melvin M. Grumbach, MD, widely regarded as the world’s foremost pediatric endocrinologist, died October 4, 2016, at the age of 90 (Figure 1). Beloved by all and affectionately known as Mel, he was the Edward B. Shaw Professor of Pediatrics, Emeritus, former Chairman of the Department of Pediatrics (1966–1986) at the University of California, San Francisco (UCSF), and a former President of The Endocrine Society. Mel was born December 21, 1925, in Brooklyn. He excelled academically and was the first in his family to attend college, receiving his MD from Columbia University in 1948, at age 22. Following an internship at Mount Sinai Hospital in New York (1948–1949), he studied pediatrics at Columbia (1949–1951) and served 2 years as a Captain in the United States Air Force (1951–1953). Assigned to the Institute of Nuclear Studies at Oak Ridge, Tennessee and then to the Air Force’s Biological Laboratories at Fort Detrick, Maryland, military medical service exposed Mel to exciting new areas of biology and biochemistry. Supported by a fellowship from The National Foundation for Infantile Paralysis (now known as The March of Dimes), he spent two years in Lawson Wilkins’ legendary pediatric endocrine program at Johns Hopkins University (1953–1955). He learned clinical research from Wilkins and steroid chemistry from Alfred Bongiovanni and Claude Migeon, published nine papers, and established a life-long friendship with Judson Van Wyk, who had joined Wilkins at the same time. These early papers concerned sex chromatin, adrenal steroids and congenital adrenal hyperplasia, and the classification of “hermaphroditism” (now referred to as Disorders of Sexual Development, or DSD).
Melvin M. Grumbach, MD 1925–2016.
Mel returned to New York in 1955 to establish Columbia’s first pediatric endocrine unit, rising to Associate Professor. At Columbia, he recruited his first fellows, including Selna L. Kaplan, Akira Morishima, and Felix A. Conte. A major observation from this time, reported with Jud Van Wyk, was the first description of “hormonal overlap,” in which very high TSH concentrations stimulated gonadotropin receptors. With few nonresearch responsibilities, these were highly productive times; his group published 60 papers from his 11 years at Columbia, covering many areas, of which two stand out.
First, Mel continued his studies of sex chromatin, or “Barr body,” which was used to establish chromosomal sex via buccal smear cytology. Mary Lyon in Britain and Mel at Columbia independently showed that the Barr body was an inactivated X chromosome. Mel contributed his work to the proceedings of a Symposium on Sex Chromatin in October 1960, but publication was delayed for over a year, giving Lyon precedence. Morishima, Grumbach, and Taylor then showed that the inactivated X chromosome replicated after the active one; inactivation of an X chromosome became known as “lyonization” (no one could say “Grumbachianization”). They then used tritiated thymidine labeling of DNA to show that one X chromosome replicates at the same time as the autosomes, while inactivated X chromosome(s) replicate later.
Second, Mel and Selna Kaplan initiated their long-term studies of growth and GH. Selna pursued immunologic approaches to studying protein hormones and mastered the new techniques of RIA. Following on the work of Josimovich and MacLaren, they confirmed that the early-gestation human placental syncytiotrophoblast produces a protein immunologically related to GH but showed that this protein had both prolactin-like and growth-promoting activities. Then termed “chorionic GH-prolactin” and sometimes termed “placental lactogen,” this protein is now known as “human chorionic somatomammotropin”; later work showed it is structurally and genetically much more closely related to GH than it is to prolactin.
In 1966, Mel was appointed Chairman of the Department of Pediatrics at UCSF, where he morphed a regional clinical program into one of the preeminent academic departments in the country. Mel brought his whole program from Columbia to San Francisco, including Selna, two laboratory technicians, his secretary, and a huge pile of junk on his desk (but Mel knew where everything was). Selna brought the immunoassay laboratory, and Felix rejoined them in 1970 and took over the karyotyping. They developed a robust population of patients with all manner of endocrine disorders and investigated the relevant hormonal axes in detail. By finding 46,XY karyotypes in some lymphocytes of pregnant women, they showed that fetal cells and DNA entered the maternal circulation; this study from nearly 50 years ago is still widely cited today. By asking incisive questions (backed up by sensitive hormonal assays), they delineated the pathophysiology and diagnostic criteria for GH deficiency, the ontogeny of fetal hormones, and the kinetics of gonadotropins and sex steroids across puberty. The availability of synthetic hypothalamic peptides permitted the demonstration that most patients with idiopathic hypopituitarism had hypothalamic rather than pituitary disease, facilitating provocative hormonal testing to diagnose hypothalamic/pituitary disorders. Studies of patients with gonadal dysgenesis revealed basal and GnRH-stimulated diphasic patterns of gonadotropin secretion across development. They defined the syndromes in which: congenital hypopituitarism is accompanied by hypoglycemia and microphallus; cranial irradiation or head trauma cause hypopituitarism; and “familial testotoxicosis” (male-limited, gonadotropin-independent, familial sexual precocity), later found to be activating mutations of the LH receptor. They described the endocrine sequelae of craniopharyngioma and of pediatric Cushing’s disease, separated adrenarche from puberty, and proffered the rational use of GH for short stature.
From 1979 to 1993, Mel and Selna published 27 papers termed “Hormone ontogeny in the ovine fetus.” This work was initiated by Peter Gluckman in collaboration with UCSF pediatric cardiologist Abraham Rudolph, who had developed the chronically catheterized fetal sheep system. Mel’s last great scientific contribution began with Felix Conte’s studies of a female patient with progressive neonatal virilization, hypogonadotropic hypogonadism, and delayed bone age despite elevated androgens. Felix and Mel concluded that she had a new disease, aromatase deficiency, and in collaboration with Evan Simpson, proved this genetically. By studying an affected male, Mel showed that estrogens, but not androgens, advance epiphyseal maturation, revolutionizing our understanding of the roles of estrogens in bone health. In all, Mel published 389 research papers, reviews, and chapters.
Mel stepped down as Chairman of Pediatrics in 1986, became an active Distinguished Professor, Emeritus in 1994, and hung up his white lab coat in his office for the last time in December 2014. Mel made a lasting impact on pediatric endocrinology. From 1956 to 1990, he supervised the training 82 fellows from 15 countries on five continents. Of these, 42 became professors, 40 division chiefs, 14 department chairs, and two deans. No single individual trained as many leaders or had a broader impact on pediatric endocrinology. Mel was a ubiquitous force in academic leadership. He protected the time of young faculty, encouraged them to write papers and grants, and fought for laboratory space. He was elected President of The Association of Medical School Department Chairs (1973), The Lawson Wilkins Pediatric Endocrine Society (1975), the Western Society for Pediatric Research (1978), The Endocrine Society (1981), and the American Pediatric Society (1989). Mel’s research, teaching, and leadership were widely recognized: he received The Endocrine Society’s Fred Conrad Koch Lifetime Achievement Award (with Selna Kaplan) in 1992, the Lifetime Achievement Award from the American Academy of Pediatrics (1996), the John Howland Award from the American Pediatric Society (1997), and was the first recipient of the Judson J. Van Wyk Prize for career achievement from the Lawson Wilkins Pediatric Endocrine Society (2006). He was elected to the Institute of Medicine (1983), the American Academy of Arts and Sciences (1995), and the National Academy of Sciences (1995). He received honorary doctorates from the University of Geneva (1991), the University of Paris 5 (René Descartes) (2000), and the University of Athens (2008) and was awarded the UCSF Medal in 2010.
Mel always believed that his legacy was not in the papers he wrote or awards he received but in the people he taught. He created a vibrant, dynamic Pediatric Endocrine Program and Department of Pediatrics at UCSF. The staying power of this program speaks volumes for Mel. Beyond UCSF, his training of deans, chairs, and chiefs is unequalled, his influence unmatched, his impact all-pervasive. One cannot write the history of endocrinology or of UCSF without writing of Mel. Mel was an avid fan of the San Francisco 49ers and enjoyed weekend retreats to the solitude of Sea Ranch on the Sonoma Coast. He was predeceased in 2007 by Madeline, his wife of 55 years; he is survived by his brother Lee, his three sons, and five grandchildren.
Acknowledgments
I thank Felix Conte, Kevin Grumbach, Stephen Rosenthal, Stephen Gitelman, and Robert Lustig for reviewing drafts of this manuscript, but any errors are mine.
