The Isolation of Adrenocorticotropic Hormone by Three Pioneers inMolecular Endocrinology: Choh Hao Li, Abraham White, and Cyril Norman HughLong

Adrenocorticotropic Hormone (Li, C. H., Evans, H. M., and Simpson, M. E.(1943) J. Biol. Chem. 149,413-424) Preparation and Properties of Pituitary Adrenotropic Hormone (Sayers,G., White, A., and Long, C. N. H. (1943) J. Biol. Chem. 149,425-436) In the 1930s and 1940s, Yale Medical School was a driving force for thebeginnings of molecular endocrinology thanks to the pioneering research ofscientists like Cyril Norman Hugh Long (1901-1970) and Abraham White(1908-1980). Together, in 1937, the two isolated bovine prolactin(1White A. Catchpole H.R. Long C.N.H. A crystalline protein with high lactogenic activity.Science. 1937; 86: 82-83Crossref PubMed Scopus (5) Google Scholar), the first of the proteinpituitary hormones to be obtained in pure crystalline form. Then in 1943, Longand White along with George Sayers, who also did significant work in thebeginnings of molecular endocrinology, isolated a highly purified preparationof porcine adrenocorticotropic hormone (ACTH) by isoelectric precipitation.However, at the same time, another scientist at Berkeley, Choh Hao Li(1913-1987), reported that he had purified ACTH from sheep by saltfractionation. Both groups published their results back-to-back in one issueof the Journal of Biological Chemistry (JBC). The papers, reprintedhere as JBC Classics, show that both methods produced good yields of the sameprotein (as determined by similar isoelectric points, molecular weights, andcarbon, hydrogen, nitrogen, and sulfur contents), and both were proven activeby similar biological assays. What is so interesting about Long, White, and Li is that not only did theyisolate, characterize, and sequence most of the pituitary hormones as well asmany other hormones, but they also each contributed enormously to the heritageof biochemistry. At the time Choh Hao Li published his method for isolating ACTH, he wasworking with Herbert Evans at the University of California, Berkeley. Li, whogrew up in Guangzhou, China, came to Berkeley in 1935 from the University ofNanking to earn a Ph.D. After finishing a Ph.D. in chemical kinetics in 1938,Evans offered him a job studying the endocrinology of the pituitary gland atthe Berkeley Institute for Experimental Biology. This marked the beginning ofthe half-century that Li would spend studying peptide and protein hormones,making significant contributions to the field of endocrinology and eventuallyleading to his establishment of the Berkeley Hormone Research Laboratory in1950. 1All the biographical information on Choh Hao Li was taken from Ref.4Cole R.D. Biographical Memoir of Choh Hao Li. 70. National Academy of Sciences, Washington D. C.1996: 220-239Google Scholar. 1All the biographical information on Choh Hao Li was taken from Ref.4Cole R.D. Biographical Memoir of Choh Hao Li. 70. National Academy of Sciences, Washington D. C.1996: 220-239Google Scholar. In addition to isolating ACTH, Li contributed to the identification,purification, and molecular structure determination of many of the otheranterior pituitary hormones, including luteinizing hormone,follicle-stimulating hormone, growth hormone, lipotropin, melanotropin, andprolactin, as well as other hormones such as endorphin and insulin-like growthfactor I. By doing some of the first detailed amino acid sequence studies onmany of these hormones, Li was able to show that portions of their structureswere homologous, explaining why many of them had overlapping biologicalfunctions. Li also pioneered the idea that hormones consist of biologicallyactive fragments combined with regulatory regions, which he proved bysynthesizing peptide fragments of the hormones in the early 1950s. Throughoutthe 1960s Li's team synthesized longer and longer peptides until they wereable to synthesize the entire corticotrophin molecule in 1973(2Yamashiro D. Li C.H. Adrenocorticotropins. 44. Total synthesis of the human hormone by the solid-phase method.J. Am. Chem. Soc. 1973; 95: 1310-1315Crossref PubMed Scopus (128) Google Scholar). Li also made several editorial contributions to biochemistry, includingserving as editor of the series Hormonal Proteins and Peptides andArchives of Biochemistry and Biophysics, as well as serving asco-associate editor and then editor-in-chief of the International Journalof Peptide and Protein Research. He had a very generous spirit, and hiscollection of pure pituitary hormones, which he doled out to otherinvestigators in microgram amounts, was legendary. In honor of Li, memoriallectureships were established at Berkeley, the Academia Sinica, and theNational University of Taiwan. His family also endowed a professorship in hisname at Berkeley. Like Li, Cyril Norman Hugh Long was a chemist from abroad. He was born inWiltshire, England and was educated as an organic chemist at ManchesterUniversity. Shortly after earning an M.D. from McGill University, Long becamedirector of the newly formed George S. Cox Research Institute at theUniversity of Pennsylvania. The purpose of the institute was to find a curefor diabetes, which as Long later recalled was, “a rather overwhelmingassignment for a young man.” Despite the daunting nature of this task,Long and Francis Lukens made a significant contribution to diabetes researchby showing that diabetes could be ameliorated with the removal of the adrenalglands, causing the disease to be reconsidered in the light of knowledge ofthe parts played by the pituitary and other ductless glands. As a result ofthis research, in 1936, Long proposed what is still one of the most importantideas in endocrine research, that “the clinical condition that followshypo- or hyper-function of an endocrine organ is not merely due to the loss orplethora of that particular internal secretion but is a result of thedisturbance of the normal hormonal equilibrium of the body.” 2All the biographical information on Cyril Norman Hugh Long was taken fromRef. 5Smith O.L.K. Hardy J.D. Biographical Memoir of Cyril Norman Hugh Long. 46. National Academy of Sciences, Washington D. C.1975: 264-309Google Scholar. 2All the biographical information on Cyril Norman Hugh Long was taken fromRef. 5Smith O.L.K. Hardy J.D. Biographical Memoir of Cyril Norman Hugh Long. 46. National Academy of Sciences, Washington D. C.1975: 264-309Google Scholar. In 1936, Long moved again, this time to Yale Medical School to becomeChairman of the Department of Physiological Chemistry where he remained forthe next 33 years. His department, renamed the Department of Biochemistry in1952, was the first “Biochemistry” department to be created in theU.S. (by Russell Henry Chittenden in 1882) and to be distinguished from theparent discipline, Physiology. Later, Long became Chairman of the Departmentof Physiology and eventually Dean of the School of Medicine. While at Yale Medical School, Long participated in the overallreorganization of the teaching of biology at the university. He stronglybelieved that the most important responsibility of the school to the communitywas to provide leadership in teaching and research. His own leadership waseventually recognized by the endowment of a chair in his name at Yale devotedto endocrinology and metabolism. Long was also a great supporter of women inscience, encouraging and training a large number of women, starting with hisfirst graduate student, Eleanor Venning, who worked for Long at a time whenwomen were not accepted universally in the laboratory or as physicians. Longwas also elected to the National Academy of Sciences in 1948 and was presidentof the Endocrine Society in 1947-1948. Long's research at Yale centered around the effects of pituitary andadrenal extracts on the metabolism of carbohydrates, and he is recognized asone of the leading investigators of his generation in the field ofendocrinology. On the basis of work carried out with Edith Fry and B. Katzin,Long was able to describe quantitatively for the first time the biologicalproperties of the adrenal cortical hormones(3Long C.N.H. Katzin B. Fry E.G. The adrenal cortex and carbohydrate metabolism.Endocrinology. 1950; 26: 309-344Crossref Scopus (142) Google Scholar). This led to the eventualdevelopment of the adrenal ascorbic acid bioassay for the pituitaryadrenocortical hormones in Long's laboratory. While at Yale, Long met a young faculty member named Abraham White. White,whose postdoctoral research had focused on the metabolism of sulfur-containingcompounds and the amino acid sequence of proteins, was newly appointed to theMedical School faculty in 1933. Long convinced White to use his knowledge andexperience in protein chemistry in investigations of the protein hormones ofthe pituitary, starting a new and fruitful series of investigations intoendocrinology to which White devoted much of his subsequent researchefforts. 3All the biographical information on Abraham White was taken from Ref.6Smith E.L. Biographical Memoir of Abraham White. 55. National Academy of Sciences, Washington D. C.1985: 506-536Google Scholar. 3All the biographical information on Abraham White was taken from Ref.6Smith E.L. Biographical Memoir of Abraham White. 55. National Academy of Sciences, Washington D. C.1985: 506-536Google Scholar. White's initial work on ACTH led to his observation, with Thomas F.Dougherty, that the actions of ACTH on the adrenal glands produced aninvolution of all lymphoid tissues and a pronounced lymphocytopenia effectedby the dissolution of lymphocytes. This and other studies by White andDougherty provided the basis for the later clinical use of adrenal steroids inthe treatment of lymphoid neoplasms as well as the use of steroids on patientsprior to organ transplants to depress their immune systems. White followedthese studies with investigations of the enzymes involved in the metabolism ofadrenal steroids, on the role of lymphoid tissue in immunity, and on thenature of the pituitary control of the adrenal cortex. He also studied thethymus gland, establishing it as an endocrine gland, and purified thymosinfrom the thymus. Like Long, White was interested in innovative medical education andeventually left Yale in 1948 to chair and found the Department ofPhysiological Chemistry at the UCLA School of Medicine. Later, he helped CarlDjerassi found Syntex Research based on isolation of steroid hormones fromMexican plants. He worked at Syntex for 2 years (1951-1953) and then returnedto academia to become one of the major figures in the organization of theAlbert Einstein College of Medicine in New York. After retiring in 1972, Whitemoved to Palo Alto to work at Syntex and also enjoyed a teaching affiliationwith the biochemistry department of Stanford Medical School. White's interestin education and recognition that there was no satisfactory modern textbook ofbiochemistry also led him to join Philip Handler, DeWitt Stetten, and Emil L.Smith in writing the classic textbook Principles of Biochemistry in1954.

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