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Long, Cyril Norman Hugh

LONG, CYRIL NORMAN HUGH

(b. Nettleton, Wiltshire, England, 19 June 1901; d. Pemaquid Beach, Maine, 6 July 1970)

biochemistry, endocrinology.

Long was the elder son of John Edward and Rose Fanny Langdill Long. His father, a tax surveyor, had strong interests in history, literature, collecting rare books, and a variety of handicraft hobbies. The parents encouraged their children to participate in intellectual and cultural matters. Long attended the Wigan Grammar School until 1918, and then the University of Manchester, which awarded him the B.Sc. in chemistry with first-class honors in 1921 and the M.Sc. in physiology in 1923, under the tutelage of Archibald Vivian Hill, who had received the Nobel Prize in physiology or medicine for 1922.

From 1923 to 1925 Long was demonstrator in physiology at University College, London, and from 1925 to 1932, lecturer and assistant professor of medical research at McGill University, Montreal, During this period he received the M.D., C.M. from McGill (1928) and the D.Sc. from Manchester (1932). He was director of the George S. Cox Medical Research Institute and assistant professor of medicine at the University of Pennsylvania from 1932 to 1936. In 1936 Long moved to Yale University, where he served as professor and chairman of the department of physiological chemistry until 1951, and simultaneously was chairman of the department of pharmacology (1939–1941) and dean of the medical school (1947–1952). He was chairman of the department of physiology from 1951 to 1964. From his retirement in 1969 until his death, he was a fellow of the John B. Pierce Foundation Laboratory, New Haven.

In 1928 Long married Hilda Gertrude Jarman; they had two daughters. Barbara Rosemary and Diana Elizabeth. He became a U.S. citizen in 1942.

Long was appointed Sterling professor of physiological chemistry and in physiology at Yale. He was a fellow of Calhoun College, Yale, and received many honorary degrees, including the M.A. (Yale), Sc.D. (Princeton, McGill), and M.D. (University of Venezuela). He also received the Squibb Award of the Endocrine Society, the Banting Memorial Medal of the American Diabetes Association, the Schering Scholarship of the Endocrine Society, the Modern Medicine Award, the Scientific Award of the Phar maceutical Manufacturers Association, the Medal of Hiroshima University, the Army–Navy Certificate of Appreciation, and a plaque from the Faculty of Medicine, Tokyo University. In 1966 Yale estab lished the C. N. H. Long professorship in his honor. He was a fellow of the John S. Guggenheim Memorial Foundation (1955–1956) and was elected to membership in the National Academy of Sciences and the American Philosophical Society, and to fellowship in the American Academy of Arts and Sciences.

Long was a member of the American Diabetes Association, the American Physiological Society, the American Society for Clinical Investigation (elected president, 1945), the Argentine Society of Biology, the Association of American Physicians, the Biochemical Society (Great Britain), The British Diabetic Association, the Endocrine Society (elected president, 1947), the Fulton Society, the Horseshoe Club (London), the International Brain Research Association, the Peripatetic Club, the Physiological Society (Great Britain), and the Society for Ex perimental Biology and Medicine. He also served as a member of the editorial boards of American Journal of Physiology, Endocrinology, Journal of Applied Physiology, Physiological Reviews, Proceedings of the Society for Experimental Biology and Medicine, and Yale Journal of Biology and Medicine.

In the summer of 1950. Long traveled to Japan to head an advisory group of the Atomic Bomb Casualty Commission, whose goal was the rebuilding of the medical schools there after World War II. He was consultant or member of the Armed Forces Institute of Pathology, the Atomic Energy Commission, the Armed Forces Quartermaster’s Food and Container Institute, the Department of Health, Education, and Welfare, the Institute for Defense Analyses, the National Research Council, the National Science Foundation, the Office of Scientific Research and Development, the President’s Scientific Advisory Committee for the United States Army, and the United States Public Health Service.

Several factors probably influenced Long’s de velopment into a scientist. His father’s hobby of experimenting with making jams, soaps, and per fumes induced an interest in laboratory manipulations that was encouraged by his father, who hoped young Hugh wold become a serious scholar and scientist. As a schoolboy Long was intersted in photography and in other hobbies that he followed into his adult life, such as stamp collecting. He did well in school, both scholastically and in athletics, participating actively in cricket, soccer, and camping. During his final year at Wigan School, Long was first exposed to chemistry. Under the tutelage of an enthusiastic, effective science master he rose immediately to the top of his class, and became infected with the interest he followed for the remainder of his life.

Because of the eminence of its Honors School of Chemistry. Long selected Manchester as his university. His undergraduate studies centered on organic chemistry, especially of the carbohydrates, but after graduation he volunteered or was persuaded (the recollections of Hill and Long differ) to join A. V. Hill in studies of the mechanism of muscle contraction. It was recognized at that time that during muscle activity the concentration of muscle glycogen fell and that of lactic acid increased. One hypothesis about the mechanism of contraction was that the increased intracellular acidity associated with for mation of lactic acid might somehow cause a short ening of the protein fibers that make up the active machinery of the muscle cell. Hill’s approach to studying this possibility involved following the changes in concentration of glycogen and lactic acid during the course of muscle activity in animals and of glucose and lactate in the blood plasma of exercising human subjects.

At first Long was not enthusiastic about working with biological systems. In his own words he was “used to dealing with substances that could be crystallized, whose physical constants and chemical properties were predictable. The heterogeneous, messy and unknown properties of extracts of cells or of blood which this investigation required me to analyze seemed to offer nothing but a struggle against large odds” (Smith and Hardy, 270). Yet he entered into the research, providing both the analytical ex pertise and a good deal of the exercise and blood required for the human part of the investigation. From this research Long published, alone or jointly with Hill, H. Lupton, L. N. Katz, and others, some fifteen papers concerned with lactic acid, oxygen, and hydrogen ion metabolism in resting and exer cising skeletal and heart muscle. With K. S. Hetzel he published a paper on the metabolism of a diabetic individual during and after exercise (1926), his first study in the field that was to become the major interest of his scientific life.

Long’s early researches on lactate production, first in conjuction with Hill and his colleagues and later with Jonathan Meakins (1927) and others in Montreal, involved him in a study of the mechanisms controlling glycogen synthesis, the level of glucose in the blood, and the conversion of precursors such as lactate and, more important, protein into car bohydrate. By the early 1930’s it had become apparent from the work of Carl and Gerty Cori and others that the lactate released from muscles during exercise is converted into glycogen in the liver and released into the blood as glucose to replenish the muscle glycogen. Epinephrine stimulates breakdown of liver glycogen and promotes this process, but does not produce the pattern of diabetes mellitus. It raises the blood glucose concentration and lowers the liver glycogen level, but it does not increase conversion of protein to carbohydrate (gluconeo-genesis) or cause increased production of partially oxidized fatty acids (ketone bodies), nor does chronic administration of epinephrine lead to established diabetes mellitus. Nevertheless, the idea of diabetogenic hormone(s) causing overproduction of glucose as a cause of diabetes mellitus continued to be prominent, though the exact endocrine mechanism was not known.

In 1921, at about the time Long became interested in carbohydrate metabolism. Frederick Banting, Charles Best, and John James MacLeod first isolated an extract (insulin) from pancreatic islets that corrects the metabolic abnormality of diabetic animals and human beings. At about the same time Bernardo Houssay, in Argentina, reintroduced the importance of nonpancreatic endocrine secretion in the pathogenesis of diabetes mellitus by demonstrating that removal of the pituitary gland of diabetic toads and dogs ameliorates many of the metabolic abnormalities of the disease. In Long’s words, “The diabetes was not entirely obliterated, but was transformed from a rapidly fatal condition into one of mild degree” (“Recent Advances in Carbohydrate Metabolism.” 169). In 1932 Houssay, Biasotti, and Rietti showed that administering an alkaline aqueous extract of the pituitary gland to diabetic hypophysectomized dogs restores the severity of diabetes, and that the same extract produces hyperglycemia and glycosuria in normal dogs.

At this time Long had moved from McGill to become director of the George S. Cox Medical Research Institute of the University of Pennsylvania, where a plaque on the wall instructed him that the purpose of the institute was “to find a cure for diabetes,” a task not accomplished even fifty years later! Long immediately recognized the importance of Houssay’s findings in pursuing this mission, and set about trying to discover how the pituitary gland exerts its effects on carbohydrate metabolism. He appreciated that “in the absence of these (pituitary) hormones, sugar production from protein is de creased and… a greater portion of glucose formed from protein is utilized” (“Recent Advances in Car bohydrate Metabolism,” 169). Of the target glands controlled by the anterior pituitary, the thyroid and the gonads were dismissed as unlikely candidates for a role in diabetogenesis. The adrenal cortex however, was an attractive candidate. Hypophy sectomy causes atrophy of the adrenal cortex (but not of the medulla, the source of epinephrine): ad renalectomy of normal animals results in low fasting blood glucose and liver glycogen levels; extracts of the adrenal cortex raise the blood glucose and liver glycogen concentrations. In human Addison’s dis ease, where adrenal cortical function is defective, the blood glucose is low.

Using this rationale, Long, with Francis D. W. Lukens, attempted the difficult task of removing the adrenal glands from cats with diabetes mellitus (1936). After a successful technique had been de veloped, they published a series of important papers demonstrating that adrenalectomy reduced the high blood glucose and urinary glucose excretion, reduced the loss of nitrogen into the urine (a reflection of protein breakdown), prevented accumulation of ke tone bodies and the acidosis associated with them, and extended the survival of untreated animals from four days to several weeks. Moreover, although pituitary extract restored diabetes in hypophysec tomized diabetic animals, it did not have this effect in adrenalectomized animals with diabetes mellitus.

On the other hand, adrenal corticosteroids such as corticosterone both restored the severity of the diabetes in adrenalectomized pancreatectomized animals and caused hyperglycemia and glycosuria in normal animals. Long concluded that “these experiments strongly suggest that the ketogenic (and diabetogenic) activity of anterior pituitary extracts may be mediated through the adrenal cortex” (“Recent Advances in Carbohydrate Metabolism,” 172). This judgment was somewhat premature, since it incorrectly overlooked the contribution of hypophyseal growth hormone to the control of carbohydrate metabolism. In his later work Long recognized this factor.

An important basic question remained to be answered: Where does the increased carbohydrate associated with adrenocortical activity come from? A series of elegant experiments performed after Long’s move to Yale, with B. Katzin and Edith Fry, proved that the glucose and glycogen produced by adrenal cortical hormones could be accounted for quantitatively by increased breakdown of protein to glucose (1940).

These studies stimulated Long, Jay Tepperman, and F. L. Engel to explore intensively the nature of the hormones of the pituitary and their relationship to adrenal function (1943). With Abraham White he had succeeded in purifying prolactin (1942); and with White and George and Marion Sayers a purified preparation of adrenocorticotropic homone (ACTH) was isolated (1943). The key to this isolation and purification was the development of a simple assay for corticotropic activity. This was provided first by the demonstration by the Sayerses, White, and Long that ACTH reduces the concentration of cholesterol in the adrenal of the rat (1943). Later the Sayerses provided simpler assay, measuring the ability of ACTH to reduce the content of adrenal ascorbic acid, that was widely used (1946). Studies of the effects of ACTH explained why pituitary extracts did not affect carbohydrate metabolism in adrenalectomized animals, since ACTH is ineffective unless the adrenal cortex is present. Alfred Wilhelmi, Jane Russell, and Jack Fishman, from the Yale laboratory, later prepared the first crystalline pituitary growth hormone (somatotropin). All of these hormones proved to have important direct or indirect effects on carbohydrate metabolism.

The most common form of diabetes mellitus is associated with obesity. In 1940 Long, with John R. Brobeck and Jay Tepperman, began a series of experiments to study the effects of inducing obesity in diabetic rats (published 1943). The method most deeply studied involved producing electrolytic (and later chemical) lesions in the hypothalamus. This induces uncontrolled hyperphagia, which leads to obesity and aggravation of pancreatic diabetes. With Brobeck and others, an important contribution was made to the functional anatomy of the hypothalamus. The presence and encouragement of the eminent neurophysiologist John F. Fulton, chairman of the department of physiology, was of great importance in this work.

After America’s entry into World War II in 1941, much attention was paid to research on the metabolic nature of traumatic shock. Frank L. Engel, Jay Tepperman, Helen Harrison, Jane Russell, Alfred Wilhelmi, and Long studied this problem for several years, demonstrating that reduced blood flow and oxygen supply to the liver is the most important single contributor to the metabolic derangements (1944).

Two major themes occupied Long’s research interest for the remainder of his life. With Ora K. Smith, W. W. Winternitz, and others, he pursued in detail the mechanisms controlling the metabolism of the tissue amino acids and gluconeogenesis, especially in muscle, liver, and kidneys. In addition, with A. Brodish, W. V. McDermott, H. Gershberg, and Fry he studied the regulation of ACTH secretion (1950, 1956, 1962), its effects on the adrenal cortex, and, with F. Ulrich and Denis M. Abelson, the metabolism of the corticosteroids. He and his team were leaders in working out the way in which the anterior pituitary and the adrenal cortex modulate the metabolic interrelationships of carbohydrate, protein, and fat. He also enunciated perhaps the most basic principle of endocrinology: hormones modulate existing pathways but do not engender new reactions

In 1936, when Long left the Cox Institute to become chairman of the department of physiological chemistry at Yale, he replaced the eminent bio chemical nutritionist Lafayette Mendel. At that time the department was composed almost entirely of scientists studying the chemistry of the diet and the requirements for adequate nutrition. This group continued to make contributions under the leadership of George R. Cowgill, in a separate laboratory of nutrition that was a subdivision of the department. Hubert B. Vickery, who was director of the Connecticut Agriculture Station and an adjunct professor in the department, was especially important in his studies of the chemistry of amino acids. However, the main body of the department took a new direction reflecting Long’s interests in endocrinology, intermediary metabolism, and the physiological factors controlling the mixture of metabolic substrates. He had brought with him from Philadelphia the most consistently helpful and loyal of his colleagues, Edith Fry and Gerald Evans. In addition he recruited outstanding physiologists such as Jane Russell, Clara M. Szego, and Daniel L. Kline; Ralph I. Dorfman, a steroid chemist; Philip P. Cohen, an enzymologist; and protein chemists such as Abraham White and Alfred E. Wilhelmi. A collaboration with the Sheffield Scientific School of Yale added biochemists such as Joseph S. Fruton, Sofia Simmonds. Henry D. Hoberman, and Jacob B. Fishman.

Long never forgot his roots as a physician, and welcomed many postdoctoral M.D. trainees, including Philip K. Bondy (later chairman of the department of medicine at Yale and professor of medicine at Royal Marsden Hospital, London), William V. McDermott. Jr. (who became chairman of the department of surgery at Harvard), Sheila P. V. Sherlock (later professor of medicine at the Royal Free Hospital, London, and president of the Royal College of physicians of London), James A. F. Stevenson (who became chairman of the department of physiology and dean of the Faculty of Graduate Studies, University of Western Ontario), and Jay Tepperman (later professor of experimental medicine, State University of New York Upstate Medical Center).

As a result of these changes, the department evolved into three separate but integrated groups: a team concerned mainly with endocrinology and the physiology of metabolic processes, led by Long; a separate nutrition laboratory led by Cowgill; and a team of basic biochemists and enzymologists led by Fruton. This diversity provided the wide-ranging interests essential for the ultimate evolution into a general department of biochemistry. When Long left to head the department of physiology, he took with him the group interested in physiological interactions. The nutritional group had, by this time, retired or moved elsewhere; and the residue, under Fruton, evolved into a leading department of bio chemistry.

Although he became increasingly involved in political and committee work on the national and international scene, Long was not an “absentee chairman” of his department of physiological chemistry. He was an outstanding lecturer and carried other formal teaching responsibilities, but he was most at home wandering around the research and teaching laboratories, lounging against the desk with his crooked smile, asking questions making suggestions, and providing a framework on which to hang research results. He did not hector his young colleagues, but he had little patience with bluffing or hazy comprehension. When he found soft thinking, he would probe relentlessly until the student reached a solid base of understanding. When he was pleased, he was generous in his praise. But his visits to the laboratory were not always concerned with science. He had a good sense of humor and an intense interest in the questions of the day, including sports. He was especially taken by new equipment, interesting gadgets, and unconventional ways of thought.

As an educator Long embraced the Yale system enthusiastically. This philosophy, first introduced in the 1920’s by Dean Milton W. Winternitz, assumes that medical students are adults and as capable as other graduate students of taking responsibility for their education. Thus, evidence of scholarship is required in the form of a thesis; examinations are used to test comprehension rather than to estimate class standings; and students are expected to regulate their attendance at classes, laboratories, and conferences so as to obtain the maximum benefit from the opportunities provided them. Long supported the emphasis on the unity of science and felt that the most important consideration was to teach ways of thinking about science rather than details of facts and techniques. This is especially important since, as he said, “independence of thought and a capacity to form judgments will be required of the physician all his life, while techniques and the interpretation of information are always changing.”

Long also felt that an excessive amount of time was spent in formal education for the M.D. degree. He crusaded for integrating college and medical school into a single course in the European style, to be completed within five years after graduating from high school. His sponsorship of this reform was not successful at Yale, though other universities, such as Brown and Johns Hopkins, later worked out a schedule similar to that proposed by Long.

Hugh Long was the last part-time dean at Yale. The burden of handling the administrative chores of the deanship increasingly competed with the time necessary for building and running an effective medical school department. As a result, Long and the administration at Yale became convinced that the deanship should be held by a professional educational administrator on a full-time basis. Thus Long’s experience helped to prepare the way for appointment of his successor, Vernon W. Lippard, the first full-time dean at Yale. In spite of the pressures, however, Long achieved a good deal as dean. Perhaps the most important developments during his tenure were the amalgamation of New Haven Hospital with the Grace Hospital to form Grace-New Haven Hospital (now Yale-New Haven Hospital). He was also involved in establishing the valuable affiliation with the West Haven Veterans Administration Medical Center.

Not the least of the special qualities of Long’s interaction with his department and with the medical school was the warm interest he and his wife, Hilda, had in the students and young faculty. They provided a social atmosphere that encouraged friendship, and provided help for the newcomer and support for the troubled. Long was ready to give advice and counsel that was direct, honest, and realistic.

After his retirement, Long continued to work with Ora Smith at the John b. Pierce Foundation; his last paper, on renal gluconeogenesis, was published with her (1971). He died suddenly, apparently of a heart attack, while on holiday in Maine.

BIBLIOGRAPHY

I. Original Works.“The Metabolism of the Diabetic Individual During and After Muscular Exercise,” in Proceedings of the Royal Society of London, B99 (1926), 279– 306, with K. S. Hetzel; “Oxygen Consumption, Oxygen Debt and Lactic Acid in Circulatory Failure,” in Journal of Clinical Investigation4 (1927), 273–293, with Jonathan Meakins; “Recent Advances in Carbohydrate Metabolism with Particular Reference to Diabetes Mellitus,” in Annals of Internal Medicine9 (1935), 166–174; “The Effects of Adrenalectomy and Hypophysectomy upon Experimental Diabetes in the Cat,” in Journal of Experimental Medicine, 63 (1936), 465–490, with Francis D. W. Lukens; “The Adrenal Cortex and Carbohydrate Metabolism,” in En docrinology, 26 (1940), 309–344, with B. Katzin and E. G. Fry: “Prolactin,” in Journal of Biological Chemistry, 143 (1942), 447–464, with A. White and R. W. Bonsnes; “The Effect of Experimental Obesity upon Carbohydrate Me tabolism,” in Yale Journal of Biology and Medicine, 15 (1943), 893–904, with J. R. Brobeck and J. Tepperman; “Preparation of Pituitary Adrenotropic Hormone,” in Proceedings of the Society of Experimental Biology and Medicine, 52 (1943), 199–200, with G. Sayers, M. A. Sayers, and A. White; “A Review of Adrenal Cortical Hypertrophy,” in Endocrinology32 (1943), 373–402, with J. Tepperman and F. L. Engel: “Biochemical Studies on Shock. III , The Role of the Liver and the hepatic Cir culation in the Metabolic Changes During Hemorrhagic Shock in the Rat and the Cat,” in Journal of Experimental Medicine, 79 (1944), 9–22, with F. L. Engel and H. C. Harrison; “The Effect of Pituitary Adrenotrophic Hormone on the Cholesterol and Ascorbic Acid Content of the Adrenal of the Rat and the Guinea Pig,” in Endocrinology, 39 (1946), 1–9, with G. Sayers, M. A. Sayers, and T.-Y. Liang; “Mechanism of Control of Adrenocorti cotrophic Hormone,” in Yale Journal of Biology and Medicine, 23 (1950), 52–66, with W. V. McDermott, E. G. Fry, and J. R. Brobeck; “Changes in Blood ACTH Under Various Experimental Conditions by Means of a Cross Circulation Technique,” in Endocrinology, 59 (1956), 666– 676, with A. Brodish; and “ACTH-Releasing Hypothalamic Neurohumor in Peripheral Blood,” ibid., 71 (1962), 298– 306, with A. Brodish.

II. Secondary Literature. P. K. Body, obituary, in Endocrinology, 88 (1971), 537–539; Joseph Furton “Cyril Norman Hugh Long (1901–1970),” in American Philosophical Society Year Book 1970 (1971), 143–145; and O. L. K. Smith and J. D. Hardy, “Cyril Norman Hugh Long” in Biographical Memoirs. National Academy of Sciences, 46 (1975), 265–306

Philip K. Bondy

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