The C o v e r . . .
Edward C. Kendall HEN a man is the first t o isolate a hormone, he deserves a n honored place in t h e Book of History, hut when, he isolates two of the most important hormones, he deserves to be placed on a pedestal in the Hall of Fame. Such a man is E d w a r d Calvin Kendall, who was t h e first to isolate thyroxin, hormone of t h e thyroid glands, a n d cortisone, principal hormone of the adrenal cortex. Having obtained the B.S. i n chemistry under Marston T. Bogert a n d Henry C. Sherman at Columbia in 1908 a n d t h e M.S. in 1909, E. C. Kendall w a s granted t h e first Goldschmidt fellowship so that h e could continue his work o n enzymes. O n the day he received his Ph.D. in 1910, Kendall wired Parke, Davis & Co. a n d was invited to go to Detroit. There he was given the task of isolating the active principle of thyroid. Although, he moved twice during the next four years, first to St. Luke's Hospital in New York, where the principal inducement was a free hand with the order book, and later t o the Mayo Foundation in Rochester, Minn., each time h e took his problem with him. While at St. Luke's Kendall was able to demonstrate the stability of t h e thyroid hormone. After going to the M a y o Clinic in February 1914, where h e soon received an appointment as professor of biochemis try in t h e graduate school of t h e Univer sity of Minnesota, he w a s able t o com plete t h e problem with the isolation of thyroxin in less than a year. A n unfortu nate error occurred, however, in t h e de termination for iodine, which indicated a molecular weight of 565 instead of 777. This error deprived him of possible prior ity in t h e synthesis of thyroxin, which was first accomplished by Charles R. Harington of England. During the next several years Kendall worked on the histological conditions in duced b y physiological activity of thy roxin. Following the conclusion of this phase of his career Dr. Kendall became interested in cystine, cysteine, and gluta thione. He and his associates were suc cessful in being t h e first t o isolate gluta thione in crystalline form a n d to discover t h a t it is a tripeptide rather than a dipeptide as previously supposed. T h e third amino acid was found to be glycine. He reported these results at the International Congress of Physiologists i n Boston, Mass., in August 1929 to establish priority by only a few weeks over similar work that w a s done independently and without his knowledge in England by F. G. Hopkins. Dr. Kendall's interests b y this time, how ever, h a d turned to t h e compounds of the adrenal cortex. Two separate groups in this country h a d found t h a t extracts of the adrenal glands would prolong the life of adrenalectomized animals a n d patients with Addison's disease. On the basis of
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these reports clinicians at the Mayo Clinic asked Dr. Kendall t o prepare ex tracts of t h e adrenals for experimental use in treating Addison's disease. This led Dr. Kendall to seek to isolate the active principle of the a d r e n a l cortex, i n 1930 a n d 1931 h e thought there w a s just one compound involved. Later it b e came apparent that there were many. From 1934 to 1936 he isolated compounds A through H, all of which w e r e identified by 1938. Working independently in Switzerland, T. Reichstein isolated 28 com pounds from the adrenal cortex but did not go as extensively into tests of physiological action as did Kendall. Both laboratories contributed to the final determination of many of the structures. A puzzle to both was t h e nature and form of t h e "inactive" oxygen, a problem that w a s solved by Kendall's group, which showed that t h e oxygen was hydroxylic and would go t o a ketone. Through tests on muscle function, Kendall's compounds Ε and F were found to b e very active. During t h i s period 150 tons of adrenal glands w e r e treated in Kendall's laboratory and as much as 50 to 60 grams of compound Ε were isolated. After 1934 the laboratory w e n t on a tlireeshift basis to treat 900 pounds of glands per week. As h e obtained it, Dr. Kendall gave countless grams of compound Ε and others to investigators all o v e r t h e world. Laboratory Becomes Semipilot Plant As yet, however, it was not certain which of t h e compounds of the adrenal cortex was t h e critical or most active one. In order to find out, much larger quantities had to b e obtained. Between 1940 and 1944, a practical, partial synthesis of com p o u n d A was devised in Kendall's labo ratory. In 1945 Merck & Co., Inc., used Kendall's method to synthesize com p o u n d A in test quantities. Trials w i t h patients in 1946, however, showed it to have very little value in Addison's disease. Compound Ε was then attacked a n d a partial synthesis worked out with the co operation of L . H. Sarett, w h o devised a method for t h e introduction of the 17hydroxyl group. This synthesis required a tremendous outlay of funds b y Merck in a gamble on t h e most complicated series of reactions ever carried out o n an industrial scale, b u t the gamble w o n . Compound Ε was found to b e satis factorily active in Addison's disease. T h u s the initial objective of Kendall's investiga tions was attained. Then compound Ε was tried by Hench, Kendall, Slocumb, and Polley in 1948 on patients having rheumatoid arthritis, and t h e spectacular results, which are today p u b l i c informa tion, were obtained. T h e many years of steady devotion by Dr. Kendall to his investigations of the
CHEMICAL
compounds of the adrenal cortex have b e e n cited b y Detlev Bronk as disproving t h e accepted theory that victories are won b y quick assault. William Mansfield Clark has described Kendall as having a flair for tough problems and t h e n pursuing t h e m with bulldog tenacity. Truly, h e fulfills t h e Greek saying, "Before t h e gates of excel lence the gods have placed a moat of sweat." "All his friends know Dr. Kendall to b e an indefatigable worker, not limited t o business hours b u t prone to working even ings, Sundays, a n d holidays," writes Oliver Kamm. "It was on Christmas D a y in 1914," he continues, "that Kendall suc ceeded in isolating p u r e crystalline t h y roxin." Again on Christmas D a y 34 years later concluding clinical observations w e r e made which revealed t h e effectiveness of cortisone in rheumatoid arthritis. F r o m those w h o know him well, Dr. Kendall is u n a b l e to hide his feelings of optimism. A visitor once told him, "You impress me as a m a n w h o confidently expects something is going to h a p p e n . " This was long before, t h e usefulness of cortisone h a d been demonstrated. Born on March 8, 1886, in South Norwalk, Conn., E. C. Kendall exhibited an early interest and ability in science and mechanics. At about t h e age of 10 and without help he installed a telephone b e tween his h o m e and that of a friend. H e went on to construct motors and to become an expert on marine engines while in his early teens. As a youth Kendall enjoyed strenuous outdoor activity and once walked from Norwalk to N e w York in one day. Despite his 137 pounds h e played high school foot ball and at Columbia w e n t out for t h e freshman crew. His strong attraction to heights led him at one time during his college days to walk from New York to Brooklyn over t h e narrow, unprotected catwalk strung b e tween the towers of the Manhattan Bridge, which was then under construction. Married in 1915 to Rebecca Kennedy of Buffalo, Ν. Υ., Dr. Kendall h a d three sons and a daughter. One son studied medicine while another is an electronics engineer. For a n u m b e r of years h e shared his love of the outdoors with his sons, with w h o m he took an annual canoe trip down t h e Flambeau River in Wisconsin. Nowadays, however, h e confines his recreation to more sedentary pursuits, such as playing correspondence chess with Dr. Sarett. Dr. Kendall has b e e n t h e recipient of many honors, including t h e John Scott Award ( 1 9 2 2 ) , t h e Chandler Medal ( 1 9 2 3 ) , t h e Squibb Award ( 1 9 4 5 ) , t h e Lasker Award, jointly with Dr. Hench ( 1 9 4 9 ) , t h e award of t h e American P h a r maceutical Manufacturers' Association ( 1 9 4 0 ) , t h e Passano Award, jointly with Dr. Hench ( 1 9 4 0 ) , the presidency of t h e American Society of Biological Chemists ( 1 9 2 6 ) a n d of the Association for Study of Glands of Internal Secretion ( 1 9 3 1 ) . H e is â m e m b e r of the National Academy of Sciences.
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