00019616-200203000-00001ArticleThe EndocrinologistThe Endocrinologist© 2002 Lippincott Williams & Wilkins, Inc.12March 2002
p 73-76Maurice S. Raben and the Treatment of Growth Hormone DeficiencyFeatures: Historical NoteSawin, Clark T. M.D.Office of the Medical Inspector, Veterans Health Administration, Washington, DCAddress correspondence to: Clark T. Sawin, M.D., Office of the Medical Inspector (10MI), VHAQ, 810 Vermont Avenue NW, Washington, DC 20420.In late February 1957, Maurice S. Raben (1915–1977) saw a boy (G.H.) who was much shorter than he should have been. Even though he was 17 years old, he was only approximately 4 feet and 2 inches tall and had never shown signs of puberty. Raben had seen the boy over the course of the previous year and one-half, and he had grown only three-quarters of an inch during that time. The boy, who should have been a man, had the diagnosis of “pituitary dwarf” (also then called “pituitary infantilism”), and there was no apparent reason for why his pituitary hormones had been absent. That February, Raben began to administer injections of a preparation to the boy. The preparation was made from human pituitary glands that contained growth hormone (GH). The hope was that it would cause the boy to grow taller. It was clearly an experiment, as previous attempts to bring about growth in these patients with pituitary extracts had either failed or provided false hope. To Raben’s great satisfaction, the boy did in fact grow. At the end of 10 months of treatment, the boy had grown more than 2 inches in height [1]. The treatment had worked and a new era had begun for these patients.Raben sent a short letter describing these results to the editor of the principle endocrine clinical journal, the Journal of Clinical Endocrinology and Metabolism, and it was printed in the August 1958 issue. The contrast to the July 1958 issue of the same journal was striking. Lawson Wilkins, the premier pediatric endocrinologist of the time, reported his work with 26 such patients. Six had been administered some sort of pituitary GH preparation over the course of the years “without discernible effect,” and Wilkins noted that he had to manage his patients “in the absence of an effective GH preparation” [2]. Incidentally, modern endocrinologists need to remember that when Raben performed his work, there was no assay for GH in humans and all were based on clinical observation and judgment. In essence, today’s current management of children who are short and who grow better with injections of human GH flows directly from Raben’s studies more than 40 years ago.How did Raben’s achievement come to pass? And why was it he who achieved his goal when the fact that the pituitary gland contained a GH had been known since the 1920s? Part of the answer, of course, lies in the character of Raben himself. Another part derives from where he was working at the time. And a third part arises from the conjunction of his work with the issue of the “species-specificity” of some hormones.Maurice Raben, “Maury” to all who knew him, was a smart and quiet man who seemed to know almost everything. He was not one to break into a conversation so that his view would be known early. Others would finish what they had to say and then he would speak. He spoke hesitatingly but thought clearly and poignantly. And he did not hesitate to express his views whether they differed from whomever had just spoken; he would carefully explain why he thought the way he did. He was that seemingly outmoded term, a “gentleman.”Maury was born in 1915 in Port Chester, New York. After Yale and medical school at New York University, he finished an internship and a year of residency and then joined the United States army (it was the time of World War II). After the military, he trained as a resident at Goldwater Memorial Hospital in New York—then a hotbed of training for academic medicine and the National Institutes of Health—and at Boston City Hospital, which was his first year of exposure to Boston medicine. He returned to New York as a junior staff physician in cardiology at Bellevue Hospital, but in 1948, he decided to go back to Boston as a research fellow in endocrinology as a postdoctoral trainee. He chose for this training to join the laboratory—and clinic—of Edwin B. “Ted” Astwood, who at that time was only 6 years Maury’s senior but had already become world-famous because of his discovery of the antithyroid drug treatment of hyperthyroidism. Maury had stepped into a world highly focussed on the thyroid gland and remained there for the rest of his career.Maury’s initial ventures were, unremarkably, in the physiology and clinical aspects of the thyroid gland. By the end of 1950, he had published three articles on the effects of antithyroid agents on thyroid function in animals and on the use of radioiodine in man. Characteristically, as was always the case in Astwood’s laboratory, Raben was either the sole author or co-author with another fellow on any publication that did not directly involve Ted in the actual work (the result is that Ted’s input is not always evident in what was discovered in his laboratory).But 1949 and 1950 were also years of the adrenal gland in endocrinology. In 1949, the biochemist Edward C. Kendall (1886–1972), working with his clinical colleague Phillip S. Hench (1896–1965) at the Mayo Clinic in Rochester, Minnesota, told of the remarkable success in “curing” rheumatoid arthritis with injections of cortisone or the pituitary hormone, adrenocorticotropin (ACTH). These results so struck the world of science that both Kendall and Hench won the Nobel Prize in 1950.Ted and Maury, the latter now a senior fellow, became involved with the issue of ACTH as well in 1950 and aimed for its purification and identification in addition to examining its role in the treatment of human disease. As it happened, this was not really an entirely new venture for Ted. He had already worked on the assay and effects of ACTH during the War as a result of the United States government’s interest in adrenal function (this interest itself was the result of rumors that German aviators experienced less fatigue and could fly for more hours if administered adrenal extracts; funds for adrenal research flowed almost instantly). In 1942, Ted found that a low pH level enhanced the extraction of ACTH from pituitary powder (mostly from pigs or cows). But adrenal research in Ted’s laboratory lapsed after 1943 when he worked out the use of antithyroid drugs.When Maury arrived and they examined ACTH again, they applied what was an almost heretical extraction medium to porcine pituitary powder, namely glacial acetic acid. Most expected that this would be so destructive that no ACTH would be retrieved. In fact, this turned out to be an ideal extractant. Almost all of the ACTH was extracted into the strong acetic acid. With a few more steps, including the adsorption of ACTH onto oxycellulose, by the end of 1950, they had a reasonably pure preparation of ACTH suitable for clinical use that was essentially uncontaminated by other pituitary hormones [3,4]. Thus, pure porcine ACTH was clinically effective in man.With this purer preparation of ACTH they thought that they were on the way to its chemical identification. They were confident enough that they placed their names on the program of the Laurentian Hormone Conference (which was co-chaired by Ted in the first place), expecting to announce the structure of ACTH [5]. It was not to be. The structure was not elucidated by the summer of 1951 and the molecular weight of ACTH was still uncertain.That same year, 1951, Raben performed another experiment with the glacial acetic acid extract, apparently out of curiosity. When extracting ACTH, reasonable assurance that the ACTH preparation administered to patients contained little or none of the other pituitary hormones was needed. The bioassays were reassuring: there were almost no thyroid-stimulating hormones or gonadotropins after the initial extraction steps, and the oxycellulose step took the ACTH out of whatever was left in solution. But where was the GH? Somewhat to their surprise, they found that the fractions of porcine pituitary extract used to derive the porcine ACTH, and from which the oxycellulose finally extracted the ACTH, contained a large amount of GH, as assayed in hypophysectomized rats. Fortuitously, ACTH was adsorbed by the oxycellulose but GH was not. What Maury and his fellow, Westermeyer, had serendipitously found was a method for the extraction of GH itself (perhaps appropriately, Maury’s fellow was funded by the Arthritis and Rheumatism Foundation). It turned out that, though far from planned, this article was the critical one for the future treatment of hypopituitarism with GH [6,7].Maury was nothing if not versatile. The end of the 1940s and the early 1950s were times of the increasing use of radioisotopes in science. Ted and Maury were familiar with various radioiodine isotopes, but the newly available carbon-14 was not easy to measure with the then-available techniques. Perhaps there was a way to magnify the relatively weak β radiation. Indeed, there was: expose the material containing the carbon-14 to something that flashed when radiation hit it, i.e., a scintillator, and then detect the flash with a photomultiplier. Maury reasoned that this idea would work best if the carbon-14 material were actually dissolved in the scintillator. So, working with a colleague at the Nuclear Laboratory at Harvard University, Maury went ahead and invented liquid scintillation counting of radioisotopes with the addition of coincidence counting using two photomultipliers so that what was counted was likely to be a true flash from a radioisotope and not random noise [7]. This was a truly remarkable feat that was the basis for a great deal of the research performed worldwide over the course of the next decades. Today, of course, it would have been patented with royalties flowing to Maury (and perhaps his colleagues and the New England Medical Center where he worked), but I can testify that that was not his way nor was it the ethic of the time. Physicians—including Ted—simply did not believe one should patent their discoveries made for the benefit of patients, and they did not (foolish or honorable?).By the early 1950s, Maury was established on the staff of the New England Medical Center and Tufts Medical School. He functioned, in essence, as Ted’s major research “arm” (if one could describe anyone in Ted’s loosely-run laboratory in such terms). While he and Ted attended to patients, most of the clinical work was performed by others.During the 1950s, Maury pursued the problems of GH and ACTH and published one or two articles per year on these topics. During this time, GH became even more confusing. Whereas ACTH from pigs worked well in man, GH from pigs or cows did not. Many thought it was just a matter of purity. The idea was that impure preparations of GH from cows did not work in man, even though they did in rats, because the preparations were too impure to work in man. So the thrust of much work was to purify GH. However, that did not seem to do the trick. The lead to the answer came from comparative endocrinology, a field, as pointed out by Friesen [8], much neglected in the overall world of endocrinology. Data from 1954 showed that fish GH worked well in fish but did not in rats. This raised the idea that perhaps some hormones had a degree, larger or smaller, of species-specificity; that is, a hormone, even when pure, might work in one species but not in another. This would be, of course, in contrast to the case of ACTH in which purification did, in fact, make it more effective and there was little species-specificity. Maury knew of the concept of species-specificity in 1954, although he hoped it did not apply to GH [9].In Boston in 1955 at Harvard Medical School’s department of physiology, Ernst Knobil (1926–2000) was also puzzled by the inability of either porcine or bovine GH to act in monkeys. He, too, learned of the fish experiments and decided that the answer might be that GH was species-specific in its actions. Knobil arranged for Raben to prepare monkey GH from Knobil’s collection of monkey pituitary glands. Maury did so, gave the monkey GH to Knobil, and Knobil then showed in 1956 that he was right: monkey GH did, in fact, work in monkeys [10]. The idea of species-specificity likely applied to man as well as monkey, so Maury gave some of his human GH to colleagues in Canada, one of whom had previously worked with Ted Astwood, to see if this GH had physiologic effects in man. It did, although the study was not designed to show an effect on growth [11]. Note that Maury still had not published his method for making primate GH, yet he had provided it to other investigators, another characteristic of the man.Maury finally published his method for preparing biologically active human GH in a 2-page paper printed in the same issue of Science as the article documenting the effects of human GH in man [12]. Because the two articles were printed on sequential pages, it seems likely that there was an editorial arrangement.A few months before his article describing the method of preparing human GH appeared in Science, Maury had started his therapy of the short boy noted at the beginning of this note. The culmination was Maury’s article in the Journal of Clinical Endocrinology and Metabolism that documented that the boy grew [1]. The first patient treated for short stature with human GH was a success; GH therapy in man was a reality.Once he had started, it was difficult for Maury to stop. His laboratory became a place of production of human GH on an industrial scale. Each year, he collected thousands of human pituitaries that had been gathered during autopsy from all over the United States. Stored in acetone until the magical days in the spring when they were converted to human GH, these pituitaries were legendary. Initially, with the help of others in the laboratory and after a few years with the collaboration of Fukashi Matsuzaki from Japan, the odor of glacial acetic acid permeated the air. There were no doors on others’ laboratories to block the fumes; therefore, many would find other activities to perform on those days. Even more pungent was the next day when Maury used large quantities of ether as a precipitant; nothing ever blew up, but no one today could (or would want to) use that procedure. The product was human GH in such quantities that others all over the country had their supply for experimental use in GH-deficient children. Maury’s superb review says it all, and it is still worth a look by modern clinicians [13].After a few years, it was clear that Maury could not handle production and distribution alone. The Endocrine Study Section of the National Institutes of Health stepped in, and in 1962, with Maury’s strong support, devised the National Pituitary Agency that not only supplied human GH to those in need but also made other human pituitary hormones available to researchers. Maury was the stimu-lus for it all. He had managed to do what most physician–endocrinologists would want to do: combine laboratory investigation with clinical therapy for the direct benefit of patients.Maury continued to study GH and its actions over the course of the next decade and a half. His responsibilities shifted, however, in the 1960s when he was asked to direct cardiovascular research at the hospital. He focussed on metabolic changes in the heart in various experimental models. He took up a few byways as well: the curious growth factor in the Spirometra parasite that interacts with GH receptors and the hypoglycemic effect of the Jamaican akee bean. By the early 1970s, his mentor, Ted Astwood, had retired to work in general practice in Bermuda where he was born. Maury worked in cardiovascular research, and a new chief of endocrinology (Seymour Reichlin) was recruited to replace Ted. Many will remember the tight funding for research in the 1970s (if one was not studying cancer). But Maury, as always, continued on and published three or four articles each year. Most will recall him, however, as the master of GH.For his real contributions, his colleagues in the Endocrine Society awarded him one of its high honors, the Ayerst Award, in 1975.Maury died suddenly on September 19, 1977, when he was only 62 years old. All who knew him then felt the loss; I suspect he would not mind being remembered as the one who made short persons grow.FIGUREJOURNAL/endst/04.03/00019616-200203000-00001/figure1-1/v/2021-02-17T201642Z/r/image-pngNo caption available.References1. Raben MS: Treatment of a pituitary dwarf with human growth hormone. J Clin Endocrinol Metab 1958; 18: 901.[Context Link][CrossRef][Medline Link]2. Martin MM, Wilkins L: Pituitary dwarfism: diagnosis and treatment. J Clin Endocrinol Metab 1958; 18: 679.[Context Link][CrossRef][Medline Link]3. Payne RW, Raben MS, Astwood EB: Extraction and purification of corticotropin. J Biol Chem 1950; 187: 719.[Context Link][Medline Link]4. Astwood EB, Raben MS, Payne RW, et al.: Purification of corticotropin with oxycellulose. J Am Chem Soc 1951; 73: 2969.[Context Link][CrossRef]5. Astwood EB, Raben MS, Payne RW: Chemistry of corticotrophin. Recent Prog Horm Res 1952; 7: 1.[Context Link]6. Raben MS, Westermeyer VW: Recovery of growth hormone in purification of corticotropin. Proc Soc Exp Biol Med 1951; 78: 550.[Context Link][Full Text][CrossRef][Medline Link]7. Raben MS, Bloembergen N: Determination of radioactivity by solution in a liquid scintillator. Science 1951; 114: 363.[Context Link][CrossRef][Medline Link]8. Friesen HG: Raben lecture 1980: A tale of stature. Endocr Rev 1980; 1: 309.[Context Link][CrossRef][Medline Link]9. Raben MS: Discussion. In Hypophyseal Growth Hormone, edited by Smith RW, Gaebler OH, Long CNH, p. 98. New York, McGraw-Hill 1955.[Context Link]10. Knobil E, Wolf RC, Greep RO: Some physiological effects of primate growth hormone preparations in hypophysectomized rhesus monkeys. J Clin Endocrinol Metab 1956; 16: 916.[Context Link]11. Beck JC, McGarry EE, Dyrenfurth I, et al.: Metabolic effects of human and monkey growth hormone in man. Science 1957; 125: 884.[Context Link][CrossRef][Medline Link]12. Raben MS: Preparation of growth hormone from pituitaries of man and monkey. Science 1957; 125: 883.[Context Link][CrossRef][Medline Link]13. Raben MS: Human growth hormone. 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Raben and the Treatment of Growth Hormone DeficiencySawin Clark T. M.D.Features: Historical NoteFeatures: Historical Note212p 73-76
