In Memoriam: Ernst Knobil (1926–2000)

In Memoriam: Ernst Knobil (1926–2000)

P515401_FM Vol-1 10/22/05 2:05 PM Page xxi In Memoriam: Ernst Knobil (1926–2000) Ernst Knobil died on April 13, 2000, in his 73rd year of life, t...

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In Memoriam: Ernst Knobil (1926–2000)

Ernst Knobil died on April 13, 2000, in his 73rd year of life, thus ending a remarkable career of outstanding scientific accomplishments, of leadership positions in physiology and endocrinology, and of mentorship to numerous students and fellows. He was noted for his clarity of thought, his endless pursuit of excellence, and his abiding interest in integrative biology. Dr. Knobil was a visionary leader and a pioneer in many areas of endocrinology, including growth and reproduction. Dr. Knobil’s now classic contributions include the species-specific effects of GH, a model for positive and negative estrogen feedback control of the menstrual cycle, and elucidation of the hypothalamic GnRH pulse generator. His discovery that pulsatile GnRH stimulates LH, whereas continuous GnRH desensitizes pituitary LH secretion, has forever altered the field of reproductive endocrinology. This remarkable experimental observation unmasked a pivotal role for pulsatile secretion as a mechanism of hormonal control. The elder son of an Austrian father (Jakob Knobil) and a German mother (Regina Seidmann), Ernst was born in Berlin, Germany, on September 20, 1926. When Ernst was about six years old, the Knobil family moved to Paris due to the deteriorating political conditions in Germany. Then, in 1940, when the Germans invaded Paris and Ernst was 13, the family emigrated to New York City. Ernst entered the New York State College of Agriculture at Cornell in 1942, at the age of 15. He chose Animal Science as his major due to interests developed from time spent on farms in France during the summers, and from attending the Kinderhook Farm Camp, after moving to New York. Upon graduating from Cornell in 1948 (including a two-year interruption for service in the U.S. Army), he entered graduate school in zoology upon recommendation of the late Sidney Asdell, author of the well-known reference work, Patterns of Mammalian Reproduction. He worked in the laboratory of Professor Samuel L. Leonard, who, as a member of Hisaw’s laboratory at the University of Wisconsin, had participated in the initial identification of LH. After completing his Ph.D., Ernst accepted a postdoctoral position with Roy O. Greep at the Harvard School of Dental Medicine from 1951 to 1953. In Greep’s laboratory, he was introduced to the

Endocrine Reviews 22(6):721–723 Copyright © 2001 by The Endocrine Society

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xxii / IN MEMORIAM: ERNST KNOBIL (1926–2000) rhesus monkey as an experimental animal, and he performed studies on adrenal cortical function and on fetal–maternal interrelationships. While a fellow, he assumed Greep’s teaching duties in endocrinology and rapidly gained recognition as a gifted and scholarly teacher. Because of this, in 1953, he was appointed Instructor in the Physiology Department of the Harvard Medical School. In 1957, he was promoted to Assistant Professor after having been selected by Harvard Medical School for the prestigious Markle Scholar in Academic Medicine for the years 1956–1961. Ernst’s research first gained international recognition for his discovery of the “species specificity” of GH during his research in 1954–1959. His initial studies in hypophysectomized monkeys confirmed that bovine and porcine GH preparations were inert in the monkey, as had been reported for humans. However, he found that GH extracted from monkey pituitary glands was fully effective in stimulating various parameters of growth (1). These findings were quickly confirmed in humans and gave birth to the program of the National Pituitary Agency to collect human pituitary glands from which GH was purified for treatment of GH deficiency. This program was later discontinued when human GH became the first protein to be produced for clinical use using recombinant DNA technology. In 1961, Ernst was appointed Chairman of the Department of Physiology at the University of Pittsburgh School of Medicine, a position he held for 20 years. There he initiated studies on regulation of reproductive cycles in rhesus monkeys because primates had been little studied in this regard, and because new methodologies for measuring hormones in blood were becoming available. First, he established the Center for Research in Primate Reproduction and built the Pittsburgh Primate Center to supply animals and to train postdoctoral fellows. Next, he developed RIAs for progesterone, LH, FSH, and E2 “after long and arduous methodological studies” (2) to permit description of the time courses of circulating hormones during the menstrual cycle of the rhesus monkey. These and subsequent studies revealed that E2, rather than progesterone, was the ovarian hormone that stimulated the mid-cycle LH surge. Moreover, he observed that low tonic levels of E2 were inhibitory to LH secretion, whereas prolonged elevations of E2 were stimulatory to LH secretion. Progesterone was shown to be primarily inhibitory, synergizing with low levels of E2 and at higher levels, antagonizing the stimulatory effect of estradiol (2). These studies were monumentally important because they established for the first time the exact roles of E2 and progesterone in regulating gonadotropin secretion and, hence, the reproductive cycle. Another crucial discovery was the episodic nature of the interaction between the hypothalamus and pituitary. Pulses of LH secretion were observed at about hourly intervals and, hence, were denominated “circhoral oscillations.” The LH pulses were correctly assumed to be the consequence of pulsatile GnRH secretion by the hypothalamus into the pituitary portal circulation which, in turn, gave rise to the notion of an oscillator or signal generator in the central nervous system (“GnRH pulse generator”) (2,3). A decade or more of study revealed that pulsatile LH secretion was a crucial regulator of the menstrual cycle. For prolonged LH secretion, GnRH had to be administered in a pulsatile fashion; continuous administration resulted in desensitization of LH secretion (3), an observation that forms the basis of a currently popular treatment of prostate cancer in humans. Knobil further observed that the hourly pulsatile infusions into monkeys deprived of endogenous GnRH by lesioning of the arcuate nucleus reinitiated menstrual cycles. These cycles were characterized by normal LH and FSH levels and were accompanied by normal follicular growth, ovulation, and corpus luteum function as signified by normal patterns of E2 and progesterone secretion. From these studies, he argued that the ovary rather than the hypothalamus was the “zeitgeber” of the menstrual cycle; an extension of this notion was that, unlike the rat, the monkey did not require a midcycle surge of GnRH secretion to stimulate LH secretion, the heightened responsiveness of the pituitary to GnRH occasioned by E2 being sufficient (3,4). Extension of these studies to normal prepubertal monkeys led to the initiation of menstrual cycles characterized by normal gonadotropin and E2 and progesterone levels. From these studies he concluded “that neither adenohypophysial nor ovarian competence is limiting in the initiation of puberty in the rhesus monkey.” Rather, “puberty is normally initiated by the activation of hypothalamic mechanisms that control the circhoral pulsatile release of GnRH into the pituitary portal circulation” (3).

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IN MEMORIAM: ERNST KNOBIL (1926–2000) / xxiii A final breakthrough in the understanding of the primate menstrual cycle was the multiunit recording in the medial basal hypothalamus of electrical activity associated with each pulse of LH secretion. Initially, these studies were confined to ovariectomized animals because restraint in the apparatus necessary for electrical recordings from the hypothalamus suppressed menstrual cycles in intact monkeys. This problem was circumvented by adopting telemetry that permitted electrical recordings of hypothalamic activity in unrestrained monkeys exhibiting normal menstrual cycles (4,5). This very brief description of his studies hardly conveys the transforming nature of the findings. To understand their impact, it is only sufficient to note that we understand the regulation of reproductive cycles in rhesus monkeys better than for any other species. This monumental result can be attributed to several personal characteristics: 1) the logical force that is evident throughout his research career; 2) a level of clear and incisive thought that makes Occam’s razor seem dull by comparison; 3) insistence on the development of methods appropriate to the experimental question being asked, no matter how arduous or time consuming; and 4) a high level of scholarship in all matters, at all times, and in all places. In 1981, Ernst accepted the Deanship of the University of Texas Medical School at Houston. There he continued to explore regulation of the reproductive cycles in macaques; indeed, most of the studies described above on electrical recordings of the hypothalamus were conducted in Houston. After his tenure as Dean ended in 1984, he continued as Director of the Laboratory of Neuroendocrinology until 1997 when he closed his laboratory. More than 80 fellows and students studied in his laboratories in Boston, Pittsburgh, and Houston, and contributed to the studies described earlier. Ernst received many awards, including the highest ones awarded by the Society for the Study of Reproduction (Carl G. Hartman Award, 1983), The Endocrine Society (Fred Conrad Koch Award, 1982), and the American Physiological Society (Walter B. Cannon Memorial Lecture, 1997). He was elected to numerous positions of leadership including the Presidencies of The Endocrine Society (1976), the American Physiological Society (1979), and the International Society of Endocrinology (1984–1988). A noteworthy achievement of his Endocrine Society presidency was the establishment of Endocrine Reviews. He was a member of many other U.S. and foreign scientific societies’ review boards, NIH study sections, and the editorial boards of numerous scientific journals. Dr. Knobil was a member of the U.S. National Academy of Science (1986), the American Academy of Arts and Sciences, a foreign associate of the French Academy of Science, the Italian National Academy of Science and the Belgian Royal Academy of Medicine. He received several honorary degrees, including the University of Bordeaux (1980), the Medical College of Wisconsin (1983), the University of Liege (1994), and the University of Milan (2000). In addition to being the author of 217 scientific papers, he was the editor of several reference books in endocrinology and reproduction, including The Handbook of Physiology (1974), The Physiology of Reproduction (1988, 1994), and The Encyclopedia of Reproduction (1998). In addition to his numerous scientific contributions, Ernst was a visionary leader in the field of endocrinology and a wonderful mentor and friend to the many people who were privileged to work closely with him. He is survived by his wife, Julane Hotchkiss, four children, and three grandchildren. ACKNOWLEDGMENTS The editorial assistance of Dr. Adolph Friedman, Staff Consultant for the History Project of The Endocrine Society, is gratefully acknowledged. Jimmy D. Neill Distinguished Professor Department of Physiology and Biophysics University of Alabama School of Medicine Birmingham, Alabama 35294 Address all correspondence and requests for reprints to: Jimmy D. Neill, Department of Physiology and Biophysics, University of Alabama School of Medicine, Birmingham, Alabama 35294.

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REFERENCES 1. Knobil E, Greep RO 1959 The physiology of growth hormone with particular reference to its action in the rhesus monkey and the “species specificity” problem. Recent Prog Horm Res 15:1–69 2. Knobil E 1974 On the control of gonadotropin secretion in the rhesus monkey. Recent Prog Horm Res 30:1–46 3. Knobil E 1980 The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53–88 4. Hotchkiss J, Knobil E 1994 The menstrual cycle and its neuroendocrine control. In: Knobil E, Neill JD, eds. The Physiology of Reproduction. Vol. 2, ed. 2 New York: Raven Press; 711–749 5. Knobil E 1997 The wisdom of the body revisited (1997 Walter B. Cannon Memorial Lecture). News Physiol Sci 14:1–11