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Biographical Memoirs: Volume 47 (1975)

Chapter: 7 Edward C. Kendall

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Suggested Citation:"7 Edward C. Kendall." National Academy of Sciences. 1975. Biographical Memoirs: Volume 47. Washington, DC: The National Academies Press. doi: 10.17226/570.
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EDWARD C. KE N DALL March 8, 1886_May 4,1972 BY DWIGHT J. INGLE . . . ~ EDWARD CALVIN KENDALL isolated thyroxine from the thyroid gland; he and associates crystallized glutathione and estab- lished its chemical structure; and he and associates isolated a series of steroid compounds from the adrenal cortex and con- tributed importantly to the determination of the structure and synthesis of several of them. With Philip S. Hench, he con- ceived the idea that cortisone might be useful in treating rheumatoid arthritis, and they planned clinical studies that confirmed the hypothesis. Kendall also initiated and partici- pated in a number of related studies. During his professional life he was called "Nick" by close friends and by his wife. He was referred to as "The Chief" by some of his laboratory associates, but commonly he was ad- dressed with deference, as "Doctor Kendall." Edward C. Kendall, the third child of George S. and Eva F. Kendall, was born March 8, 1886, at South Norwalk, Connecti- cut. The home was a citadel for religious teachings. The father, a dentist by profession, took an active interest in com- munity affairs. Edward attended the Franklin Elementary School and, for two years, South Norwalk High School. He spent a year at Stamford High School preparing for college. During these years he excelled in mathematics and became interested in the work of a foundry and a machine shop. In his 249

250 BIOGRAPHICAL MEMOIRS teens, he set up a shop in the attic of his home; there he built electrical apparatus and did machine work. At Stamford High School Kendall developed an interest in chemistry. It was enhanced by his brother-in-law's stories of an amateur chemist who developed a secret process for making high-quality writing paper. This much admired brother-in- law graduated from Columbia University in 1900, and this in- fluenced Edward to enter there four years later. Edward concentrated his attention on chemistry and, as a college senior, he wrote a thesis under the guidance of Professor H. C. Sherman. During the summer of 1908, he served as a laboratory instructor in the department of biochemistry. He was awarded a scholarship for post-graduate work in biochem- istry and received an M.S. degree in tune 1909. He then became the first recipient of the Goldschmidt Fel- lowship and began research on amylase, an enzyme of the pan- creas. Kendall observed that the amount of reducing sugar produced by given amounts of amylase varied considerably, and he identified sodium chloride as the factor causing the vari- ability; the presence of the salt enhanced the activity of amy- lase severalfold. His first paper reported this research in the Journal of the American Chemical Society; Professor Sherman was co-author. He received the Ph.D. from Columbia in June 1910. (Hereafter, I shall refer to my subject as Dr. Kendall, for I addressed him thus for forty years.) In his memoirs, Dr. Kendall tells of departing from the sheltered, restricted life of his boyhood; but he cites specifically only that he played cards on Sundays and that he once tested the consequences of saying "God damn" out loud. As an adult, he was not overly religious, but he was more puritanical than many who practice religion loudly. These early years must have been important in the development of his quiet, scholarly demeanor and self-discipline. He continued to keep physically

EDWARD C. KENDALL 251 fit throughout his adult life. He had participated in high school sports and, in college, he was a bow oar in a four-man shell. On September 1, 1910, Dr. Kendall began working in the chemical laboratory of Parke Davis and Company; his assign- ment was to isolate the hormone of the thyroid gland. He stayed five months. He found that punching a time clock was annoying, and he was disappointed by the intellectual isola- tion. There were no seminars, and he found himself working, in competition with another chemist who was assigned the same problem. After returning to New Yorl; City, he accepted an invitation to occupy and equip a new laboratory in St. Luke's Hospital. In the beginning, he worked without salary but was given funds for supplies and equipment. Eventually a salary of $1200 a year was provided, but it was never increased. Dr. Kendall continued research on the thyroid gland. Near the end of the nineteenth century, Professor Eugen Baumann, a physiological chemist at the University of Freiburg, had pre- pared iodine-containing extracts of thyroid glands that were useful in treating clinical hypothyroidism. Baumann's partially purified principle was named iodothyrin. The findings of Baumann served as a starting, point for Dr. Kendall. By 1913 he had purified the active principle about a hundredfold. The method of bioassay was to measure changes in the urinary nitro- gen of dogs. The biologic activity of the partially purified preparations was also demonstrated in hypothyroid patients. The research was not appreciated by the clinical staff of the hospital, whose attitude toward the partial purification of the iodine-containing compound seems to have been "So what?" At about tins time the hospital administrator sent Dr. Ken- dall a box of cereal with a letter directing him to analyze the contents. The letter and the cereal were thrown summarily into the wastebasket. Not then or ever would the young chemist

252 BIOGRAPHICAL MEMOIRS take orders of this sort or accept distraction from his own goals. This and similar incidents formed the basis of his determina- tion to move to a research-oriented institution. It was Professor Clarence M. Jackson, soon to become a great teacher of anatomy at the UniversitY of Minnesota. who ~ ~11 ~~ Ir ~~ ~_11 _ ~ 1 _ ~ cola Or. Kendall ot ctevelopments at the Mayo Clinic and sug- gested that he apply to Dr. Louis B. Wilson, Director of Labora- tories, for a position. Dr. Henry S. Plummer, a many-sided genius, was involved in the treatment of diseases of the thyroid and in studies of its pathologic physiology. Drs. Will and Charlie Mayo were interested in diseases of the thyroid. Dr. Kendall was invited to join the staff of the Mayo Clinic and he began his research there on February 1, 1914. He was con- cerned with two projects: first, the isolation of the hormone of the thyroid gland, and second, the determination of the amount of the acid-insoluble fraction of thyroid glands re- moved surgically from patients so these data could be corre- lated with other clinical and laboratory findings. Baumann had prepared iodothyrin by boiling thyroid tis- sue with 10 percent sulfuric acid to hydrolyze the proteins; Dr. Kendall came to use repeated treatment with hot dilute sodium and barium hydroxides followed by separation of the acid-insoluble material. Near the end of 1914, an acid-in- soluble fraction that contained 47 percent iodine had been prepared. At this point, ethanol was used as a solvent. On December 23, a sample was dissolved in a small amount of ethanol and evaporation started. The young chemist was tired and fell asleep. When he awakened, the ethanol had evapo- rated, leaving on the bottom of the beaker a white crust sur- rounded by a ring of yellow waxy material. When more ethanol was added, the latter material dissolved but the white crust did not. When the residue was analyzed the following, morning, it was found to contain 60 percent iodine. During the day, more of the crust alas prepared. On Christmas morn-

EDWARD C. KENDALL 253 ing, some of the white crust was dissolved in ethanol that con- tained a small amount of sodium hydroxide. The addition of a few drops of acetic acid precipitated crystals. This pure com- pound was later named "thyroxin" and, still later, when it was found to be an amino acid with an amine group, an "e" was added to make the name "thyroxine" (The ending "ine" indi- cates the chemical class to which the compound belongs.) Some hypothyroid patients were treated with the crystalline hor- mone; it was fully active in relieving the symptoms of thyroid deficiency. A year later, Edward C. Kendall married Rebecca Kennedy of Buffalo, New York. To Dr. Kendall and "Becky," four chil- dren were born—Hugh, Roy, Norman, and Elizabeth. Before coming to the Mayo Clinic, Dr. Kendall had applied for a position at the Rockefeller Institute and was bluntly turned down by its director, Dr. Simon Flexner. This rankled the younger man and, in 1916, he took special satisfaction in reading a paper, "Isolation ill Crystalline Form of the Iodine- Containing Compound of the Thyroid Gland," at a session of the Federation of American Societies for Experimental Biology, chaired by Dr. Flexner. Efforts to identify the structure of thyroxine and to synthe- size the compound extended over the next ten years; they re- sulted in failure. Dr. Kendall described thyroxine incorrectly as triiodo-hexahydro-oxindolepropionic acid. In 1926, Dr. C. R. Harington of University College, London, identified the nu- cleus of thyroxine as the tetra-iodo derivative of thyronine and he synthesized thyroxine. At that point, the Mayo Clinic closed its research on the chemistry of the thyroid hormone. Dr. Kendall was already an important scientist and was to accomplish goals more significant than the isolation of thy- roxine; but he was not then, nor was he to become, a great chemist. His formal training in chemistry had been brief, and from the time he had received his Ph.D., he no longer worked

254 BIOGRAPHICAL MEMOIRS with a master. A stubborn man, throughout his life he held that his intuitive beliefs were valid until the evidence against them became overwhelming. Other chemists had advised him over and over that his proposed structural formula for thy- roxine was incorrect. Usually, when confronted with proof that a belief was incorrect, he would accept it with good grace; but undue faith in his own ideas and resistance to the sug- gestions of others characterized his whole life as a scientist. Yet, in another sense, these foibles may have been necessary for his noble aims, his tenacity, and, hence, his great achievements. As Albert Szent-Gyorgyi said, "Discovery consists of seeing what everybody has seen, and thinking what nobody has thought." The research interests of Dr. Kendall shifted to studying the specific compounds involved in the effect of thyroxine on oxi- dation in the body. Attention was focused on cysteine and gluta- thione. Since the latter compound could not be purchased, the Mayo group became involved in a program to crystallize it and prepare it by synthesis. The compound was first isolated, ana- lyzed, and named by Professor F. Gowland Hopkins of Cam- bridge Universi ty in 1921. Bernard F. McKenzie and Dr. Harold L. Mason were collaborators of Dr. Kendall in isolating glutathione in crystalline form and in identifying it as a tri- peptide of glutamic acid, cysteine, and glycine. This was ac- complished independently of the isolation of crystals of gluta- thione and determination of structure by Professor Hopkins. The two groups agreed that the compound is glutamyl-cys- teinyl-glycine. It was first synthesized by Dr. C. R. Harington. The Section of Biochemistry at the Mayo Clinic was in- volved in basic research, graduate education, and performing clinical biochemistry. The last-named function was directed by Dr. Arnold E. Osterberg, first research associate of Dr. Kendall at the Mayo Clinic. It was Osterberg who suggested the name "thyroxin." Although Dr. Kendall participated in graduate

EDWARD C. KENDALL 255 education to a small extent—he held the rank of professor since 1921—he would permit few distractions to his research. He was never to become a sitting scientist; he was almost always at the bench. In the fall of 1929, Albert Szent-Gyorgyi, who, throughout his life made discoveries and stimulated the research of others, be- came a visiting scientist in Biochemistry at the Mayo Clinic. Szent-Gyorgyi had isolated small amounts of a substance that he first named "hexuronic acid." It is widely distributed in plants and animals and relatively large amounts are in the adrenal cor- tex. Fresh beef adrenal glands were made available to Dr. Szent- Gyorgyi, and he isolated substantial amounts of the compound during the eight months he spent in Dr. Kendall's laboratories. Hexuronic acid was later identified as vitamin C and given the name "ascorbic acid." The initiation of research on adrenal glands in Dr. Ken- dall's laboratories coincided with the publication of convincing evidence that an extract of beef adrenal glands would sustain life in adrenalectomized animals and would reverse the symp- toms of Addison's disease in human patients. Several investi- gators claimed to have achieved this during the 1920s, but the first to publish statistically reliable evidence (1927) for the pro- longation of life in adrenalectomized animals was Professor Frank A. Hartman at the University of Buffalo. In 1930, Hart- man and Katherine A. Brownell at Buffalo and J. J. Pfiffner and W. W. Swingle at Princeton University prepared extracts of the adrenal cortex that would sustain adrenalectomized ani- mals indefinitely, would revive them from a state of adrenal crisis, and would relieve the symptoms of patients with Addi- son's disease. The efficacy of the Pfiffner-Swingle extract was demonstrated on patients with Addison's disease by Dr. Leonard G. Rowntree of the Mayo Clinic. Dr. Rowntree came to Dr. Kendall with a plea to prepare adrenal cortical extract. The challenge was accepted, but Dr. Kendall looked beyond the

256 BIOGRAPHICAL MEMOIRS immediate clinical need toward the isolation and chemical identification of the hormone of the adrenal cortex. During the early 1930s, Dr. Giles A. Koelsche, a Fellow in Biochemistry, carried out an important study of the effects of thyroxine and of adrenal cortical hormones on nitrogen bal- ance in dogs. It is generally believed that the hormones of each gland are catabolic. This is true when they are given in excess, but Koelsche demonstrated experimental conditions in which physiological doses of adrenal cortical hormones favor a posi- tive nitrogen balance and anabolism. Dr..Joseph L. Svirbely came to the Mayo Clinic for one year, did sophisticated bio- logical studies, then returned for several summers. Svirbely had contributed importantly to the identification of hexuronic acid as vitamin C during his association with Dr. Szent-Gyorgyi at Szeged, Hungary. Dr. Frank C. Mann supported the research of Dr. Kendall in two important respects. First, he was director of the Insti- tute of Experimental Medicine of the Mayo Clinic, which car- ried out all animal experimentation. Dr. Mann performed all of the adrenalectomies on dogs used by the Kendall group in bioassay procedures and research. Second, Dr. Mann was a member of Mayo's Board of Governors for a number of years. He was one of the effective spokesmen for the Clinic's labora- ~ , ~ - . ~ . . · ~ · , . tory investigations. He was a great experimental surgeon and physiologist, and a pathologist of broad interests, who had im- portant Insights Into the complexities of life and disease. Dr. Kendall and Dr. Mann were, in unique ways, strong personali- ties. Each had a warm personal regard for the other, but Dr. Mann was well aware of Dr. Kendall's foibles as a scientist. Dr. Kendall's knowledge of physiology was shallow; he did not appreciate the complexity of cause-and-effect relationships, and he did not fully appreciate the extent of biological variability. He was also given to making premature announcements of laboratory results. All of this exasperated Dr. Mann. On one

EDWARD C. KENDALL 257 occasion, a brash young biochemist who came to the Institute to do research and bioassays on adrenalectomized dogs was questioned by Dr. Mann about his knowledge of physiology. The new Fellow replied that, since he was trained in biochem- istry, he had good basic knowledge of physiological processes. Dr. Mann replied, "I know more than two hundred biochemists and not a damn one of them knows any physiology." When the remark was repeated to Dr. Kendall, he said, "I know more than two hundred physiologists and not one of them knows any bio- chemistry." Some members of the Clinic staff and some members of the Board of Governors questioned the wisdom of supporting basic research in the Section of Biochemistry. So long as Drs. Will and Charlie Mayo ran the clinic, they supported lair. Kendall's programs. Dr. Charlie especially would come frequently to Dr. Kendall's laboratory bench to chat and keep in touch with progress. When the Mayo brothers began to turn over more and more administrative responsibilities to committees, the re- search program of Dr. Kendall was in some danger. He had to appear before the Board each year and resell the program. These were depression days and the Mayo Clinic did not accept any outside support for any of its functions. Dr. Kendall could plead a cause with quiet optimism, always promising early progress. But there were years in which there was little progress to report. Dr. Mann was in a position to scuttle Dr. Kendall's program but did not. He would express misgivings, then sup- port the continuation of the research. There was no true in- consistency in this, for Dr. Mann understood better than most physicians the necessity for basic research, that it is errant, and that years of effort may go by without discovery. In 1928, when I was an undergraduate student, a physician friend gave me a publication containing "before and after" pictures of a ten-vear-old girl in whom treatment with thy- roxine at the Mayo Clinic had corrected cretinism within a few

258 BIOGRAPHICAL MEMOIRS months. There was a remarkable spurt in growth. I wrote a letter to Dr. Kendall. I received a reply to each of my questions about this patient. In 1932, I heard him speak on thyroxine at the University of Minnesota School of Medicine. After the lecture I wrote to him and was again treated with kind con- sideration. I was told that he note aimed to isolate the hormone of the adrenal cortex. I was studying the work performance of adrenalectomized rats: The general technique was to anesthe- ~ze one rat warn sodium phenobarbital, weight the gastrocne- m~us muscle won ~~u grams, and stimulate it electrically to lift the weight three times per second. Normal rats could continue work of the stimulated muscle for more than fourteen days. When the adrenal glands were removed, the amount of work accomplished began to fall below that of sham-operated animals within two hours, and muscular responsiveness was lost within a day. I had shown that ability to work was lost because of ~ ~ _ _ _ . , 1 1 · 1 · . 1 ~ off 1 circulatory failure and that the state of shock was due to absence of the adrenal cortex rather than of the adrenal medulla. When I asked Dr. Kendall for a sample of adrenal cortical extract, he suggested that I first test lactyl epinephrine. He had an intuitive guess that since the adrenal glands contain both lactic acid and epinephrine, the two compounds might be linked together to form the hormone of the adrenal cortex. He be- lieved that he had extracted this compound from adrenal glands, but the evidence was tenuous. A final ether extract contained lactic acid and gave a positive test for the catechol grouping. He believed that synthetic lactyl epinephrine was prepared in his laboratory, again basing chic concl',sion an th`> finding that an ether-soluble product contained lactic acid and gave a positive test for the catechol grouping. There was no proof that lactic acid and epinephrine were chemically bonded. Dr. Kendall had injected this latter product into dying adrenal- ectomized dogs and had observed temporary improvement in some of them; I found the product to have an epinephrine-like = . ~ _ ~ ~ ~ ~ ., - ^ ~ _

EDWARD C. KENDALL 259 effect on my "fatigued" adrenalectomized rats and to cause a small temporary recovery in muscle work. The benefit to both the dogs and rats was due to the presence of free catecholamine and represented only a pharmacologic effect. When I treated "fatigued" adrenalectomized rats with adrenal cortical extract supplied by Dr. Kenclall, there was an almost complete recovery of work output. It was simpler to treat the animals with extract from the time of adrenalectomy and the beginning of muscle stimulation. I developed a twenty- four-hour assay test of adrenal cortical extract that was sensitive, fast, and reliable. Bioassays done on adrenalectomized cats and dogs required several days and large amounts of extract, and were not very sensitive. I was invited by Dr. Kendall to join his group as a Mayo Foundation Fellow, and I did so in September of 1934. In December, 1933, a crystalline organic substance was iso- lated from adrenal cortical extract. Dr. Kendall announced the isolation in crystalline form of the hormone of the adrenal cortex. It was then assumed that the adrenal cortex secretes but one hormone and that any crystals formed during fractiona- tion of the extract were likely to represent that hormone. The crystalline material was tested in adrenalectomized dogs, and it was concluded that it sustained the lives of these animals. After I established the muscle-work test at the Mayo Institute, my first assignment was to test this crystalline material. It did not have demonstrable activity. It was then retested in adrenal- ectomized dogs with negative results. During the first series of tests on adrenalectomized dogs, a high dietary intake of sodium chloride was used; this prevented symptoms of adrenal cortical insufficiency. It is possible that the crystalline material con- tained some biologically active compounds, but the data did not prove the presence of a hormone, nor were the crystals shown to be a single compound. Dr. Kendall never fully explained these facts in any subsequent publication, so his claim to have

260 BIOGRAPHICAL MEMOIRS isolated the hormone of the adrenal cortex in 1933 has been regarded by some reviewers as a report of the first isolation of cortisone. At about the same time, Dr. Arthur Grollman at Johns Hopkins Medical School reported the isolation of crystalline material from adrenal cortical extracts and that the crystals sustained the life of adrenalectomized rats. These claims were not independently confirmed and the chemical nature of his crystalline material was not fully determined. Dr. Mann was deeply concerned, first, when Dr. Kendall reported verbally on the apparent activity of lactyl epinephrine —he did not publish a claim for activity—and, again, when his published claim (1934) to have isolated the hormone of the adrenal cortex was not confirmed. At this time, Dr. Kendall was asked by the Board of Governors to give Dr. Harold L. Mason increased responsibility for the purification of crystalline material and chemical characterization. Mason was well trained in organic chemistry and had learned the then new methods of microanalysis. He was a perfectionist, who did elegant work at the bench. Dr. Kendall was not a master of the principles of research nor of all the methods needed in this program; his intuitive judgments as to what should be done were a source of frustration to his young colleagues. He did not follow the advice of Dr. Mann to give Mason greater responsibility. About this time, Mason and Charlie Myers went to Dr. Kendall to air their complaints. At their suggestion, a weekly conference was set up and this proved an important means of advancing the project. Happily, the muscle-work test was of use in following bio- logical activity during fractionation and purification. By the fall of 1935, Dr. Hugo W. Nilson and Mr. Donald Krockow joined the group to conduct bioassays and research on adrenal- ectomized dogs. Each did his work superbly. The Kendall group was at this time processing large quan- tities of beef adrenal glands supplied by Parke Davis and Com-

EDWARD C. KENDALL 261 pany. Dr. Kendall was at his best as an extractionist. In ex- change for the glands, epinephrine was separated, purified, and returned to Parke Davis. The Wilson Laboratories also sup- plied beef adrenal glands in exchange for bioassays on the adrenal cortical extract prepared for clinical use by this com- pany. For at least five years, the laboratory processed 900 pounds of beef adrenal glands every week. Bernard McKenzie had an important part in the success of this program. Dr. Kendall supplied adrenal cortical extract to Mayo Clinic physicians to treat patients with Addison's disease. It was now generally available from commercial sources, but large amounts were required to restore a patient with Addison's disease to normal vigor; no patient could afford to purchase all of the cortical extract needed. Dr. Robert F. Loeb of Columbia Uni- versity demonstrated that animals and patients with insufficient amounts of adrenal cortical hormones will survive for a long time under nonstress conditions if given a high sodium chloride diet or saline to drink. Dr. George Harrop of Johns Hopkins Hospital called attention to the elevated blood serum potas- sium of animals and patients during adrenal cortical insu~i- ciency. Under the direction of Dr. Kendall, William D. Allers, a Mayo Foundation Fellow, prepared high sodium-low potas- sium diets and demonstrated that adrenalectomized dogs could survive nonstress conditions for indefinite periods and could even reproduce—but did not lactate—when fed these diets. These findings were promptly applied in the treatment of patients with Addison's disease at the Mayo Clinic; some patients were stabilized for months on the high sodium-low potassium diet. Adrenal cortical extract was used only if the patient got into trouble when subjected to some form of stress or if he failed to continue the special diet. Dr. Hugo Nilson continued and ad- vanced the studies on adrenalectomized dogs. All phases of the program were significantly advanced dur- ing 1935-1936. The research led to the isolation of five crystal- line compounds. It was an uneasy time, for two rival groups

262 BIOGRAPHICAL MEMOIRS were in the field. Dr. i. J. Pfiffner had moved from the Prince- ton University laboratories of Professor W. W. Swingle to col- laborate with Dr. Oskar Wintersteiner at Columbia University. Wintersteiner was a superb organic chemist, who had mastered the methods of microanalysis: The Wintersteiner group began to isolate crystalline compounds at about the same time as the Kendall group. In Switzerland, Professor Tadeus Reichstein and his students were progressing, rapidly toward the same On~ectlve. Compound E of the Kendall group was found to be active in the muscle-work test in late 1935. Wintersteiner and Pfiffner were the first to report the isolation of a few milligrams of this compound, but they did not recognize it as being biologically active. The same substance, later to be called cortisone, was isolated by the Reichstein group; they too failed to recognize it as biologically active. The Kendall group converted their Compound E (cortisone) into a diketone, which had andro- genic activity, as demonstrated by Professor F. C. Koch of the University of Chicago. It was correctly deduced from this find- ing that Compound E is a steroid. Independently, the com- peting groups recognized that the compounds isolated from the adrenal cortex are steroids. Prior to the chemical identification of compounds, each of the three competing groups referred to a compound by letter, as A, B. C, or the like. Each group happened to assign a dif- ferent letter to its compound. This led to some confusion among those who read the original research reports and among, interested persons who had only secondhand information about the researches. Noncrystalline preparations from the adrenal cortex were far more potent than was Kendall's Compound E in sustaining, the life of adrenalectomized animals. This was first shown by Wintersteiner and Pfifiner. The search for the hormone of the adrenal cortex continued. In 1936 we heard a rumor that

EDWARD C. KENDALL 263 Reichstein had isolated the life maintenance hormone and had named it corticosterone. There was some dismay in the Mayo group; but, when Reichstein published (1937) the chemical characteristics of the new compound, it was recognized as being identical with Kendall's Compound B. which had been isolated earlier. It, too, was much less potent than noncrystalline frac- tions in sustaining life in adrenalectomized animals. As the structure of these compounds was worked out, it be- came possible to name them. In the Kendall series, Compound B was corticosterone, Compound A alas 11-dehydrocortico- sterone, Compound E was 17-hydroxy-11-dehydrocorticosterone (cortisone), and the soon-to-be-isolated Compound F was 17- hydroxy-corticosterone (cortisol or hydrocortisone). Each of these compounds was active in the muscle-work test, cortisol being the most potent. By 1938 Professor C. N. H. Long and his students at Yale Medical School had shown that each of these compounds affects carbohydrate metabolism and can be bioassayed by measuring the level of liver glycogen in fasting young adrenalectomized rats or mice. In 1937 M. Steiger and T. Reichstein prepared 11-desoxy- corticosterone by partial synthesis. Dr. George W. dehorn of Johns Hopkins Hospital found this steroid to be highly potent in sustaining the life of adrenalectomized animals and of pa- tients with Addison's disease. Only minute amounts were found in adrenal cortical extracts. It seemed unlikely that this steroid was the naturally occurring life-maintaining hormone of the adrenal cortex, but the urgency to isolate an adrenal cortical hormone of clinical importance seemed to be over. I interrupt the account of research to describe more of Dr. Kendall's personal life. He was a quiet man but did not conceal his enthusiasms. His treatment of others was usually kind, but he would sometimes become sharply inpatient and sarcastic. I once caused him to lose his temper. I refused to do an experi-

264 BIOGRAPHICAL MEMOIRS ment according to his research plan and proceeded to tell him of his weaknesses in biologic research. This was well inten- tioned, but unwise, and I soon regretted it. He did not raise his voice but his face flushed, then paled, and his lips and hands trembled. I lost the argument and did the experiment as he directed, but I added controls. When my data showed the controls to be necessary, he accepted the findings in good humor. I learned to do my own experiments first and to bring the data to Dr. Kendall after the studies were completed. To be more precise, I re Ported results only if they seemed signifi- cant. Dr. Kendall neither tested ideas in private nor concealed his mistakes, as many of us do. He would announce what he expected to find "just around the corner." During the holidays Dr. and Mrs. Kendall hosted members of the laboratory 'group. Mrs. Kendall was an unassuming, gracious, and generous lady. Summers, the whole family lived at their cottage on Lake Zumbro where each child became a fine swimmer. On weekends, a nap after lunch was routine. Dr. Kendall would plan research strategy then and some nights. One of his few diversions was playing chess, and he kept a few games going by mail. Each Fourth of July, the members of his laboratory group would gather at the Kendall cottage for a picnic. For years, Dr. Kendall offered a prize to any guest who could cross Lake Zumbro in a tub. There were some who made the attempt, but I am not aware that anyone won the prize. Several summers, Dr. Kendall took his three sons on long canoe trips. Dr. Kendall was a man of scholarly demeanor, yet he was not a scholar. He excluded from his life many activities that others enjoy. He focused attention on long-range research ob- jectives and relaxed his attention and effort only to the extent needed to maintain physical and mental fitness. I have mentioned that Dr. Arnold E. Osterberg directed the laboratories of clinical biochemistry. Dr. Marschelle H. Power

EDWARD C. KENDALL 265 was an important member of this group and was to become head of the section when Dr. Kendall retired. In 1936 Dr. Willard Hoehn, a well-trained organic chemist, came to Mayo's to replace Dr. Charles S. Myers. Warren F. McGuckin and Bernard F. McKenzie were productive members of the team doing research on steroids. Miss Eva Hartzler joined the group to work with Dr. Hugo Nilson in studies of changes in electrolyte metabolism caused by adrenal cortical insuffi- . · . clency In Dogs. Before the end of the decade, Drs. Pfiffner and Winter- steiner dropped research on the adrenal hormones. Both Hugo Nilson and I left the Kendall group. Harold Mason and Wil- lard Hoehn were soon to drop out of the program. Dr. Frank Stodola came to work with Dr. Kendall for a time. Before shifting his interests to other problems, Mason prepared a non- crystalline residue of adrenal cortical extract that was far more potent than 11-desoxycorticosterone in sustaining the life of adrenalectomized animals. There was something important in the adrenal cortex that remained to be isolated in pure form and chemically identified. In 1934 Dr. Kendall had suggested that the adrenal cortex may secrete more than one hormone; other investigators ad- vanced the same hypothesis, but I believe that Dr. Kendall was the first. He then dropped the idea for several years. By 1939 Dr. George W. Thorn and I, working with steroids supplied by the Mayo group, demonstrated a qualitative dissociation of the biological properties of 11-desoxycorticosterone and 17- hydroxy-1 1-dehydrocorticosterone (cortisone). Our findings were supported by the studies of Professor C. N. H. Long and his associates at Yale, with whom eve regularly exchanged data. Our general conclusions were confirmed independently by Dr. Benjamin B. Wells and Dr. Kendall. Dr. Roger Reinecke joined the Kendall group and did important studies of the ,~lycogenic effects of the adrenal steroids. It became clear that Kendall's compounds A, B. E, and F. each of which is oxygenated at posi-

266 BIOGRAPHICAL MEMOIRS tion 11 of the steroid nucleus, affect organic metabolism and that 11-desoxycorticosterone, and an as yet unidentified prin- ciple in the amorphous residue, affected the metabolism of electrolytes and water. Professor Hans Selye called the 11-oxy compounds "glucocorticoids" and the latter "mineralcorticoids." These characterizations were too simple and not entirely accu- rate, but nevertheless useful. Animal experimentation by the Mayo group ended in 1942. Meanwhile, events in other parts of the world had begun to affect the lives of all of us: Europe was at war. Prior to the direct involvement of the United States, our armed services and the National Research Council began to organize and set priorities for research to support military medicine. Attention focused on a rumor that Germany was buying beef adrenal glands in South America for the purpose of making adrenal cortical extract. It was said that the extract was being used to counteract the hypoxia of Luftwaffe pilots to permit them to fly at higher altitudes. It was being claimed, especially by American pharmaceutical houses, that adrenal cortical extract would counteract traumatic shock and surgical shock. There were other claims that it would raise resistance of laboratory animals to hypoxia. It was well established that adrenally insufficient animals and patients are abnormally sensitive to all forms of stress. It seemed reasonable to expect that the cortical steroids would raise the resistance of combatants to the kinds of stressors encountered in war. The medical research division of the Office of Scientific Research and Development gave top priority to the synthesis of Kendall's Compound A. In late 1941 a committee of outstanding chemists, most of them experienced in steroid chemistry, was appointed to plan and direct the research. Dr. Kendall was one of them. The committee decided to first prepare Kendall's Compound A as a step toward the more difficult job of preparing Com- pound E. Research toward this objective was carried out in a

EDWARD C. KENDALL 267 number of laboratories including those of Merck and Com- pany. In the fall of 1943, Compound A was synthesized in very small yields by Professor T. Reichstein. Research continued, especially in Dr. Kendall's laboratories. To this laboratory came a series of brilliant young chemists, several of them from Merck and Company, including Lewis H. Sarett. Dr. Vernon Mattox joined the Kendall group to stay; he has played an important role in the Section of Biochemistry since that time. The steps toward the synthesis of Compound A were improved. A small amount of the substance was pre- pared in Dr. Kenda]l's laboratories. By the middle of 1944 all members of the collaborating groups, except those of Mayo's and Merck, stopped research on the synthesis of Compound A. By then the biological studies on the usefulness of adrenal cortical extract and adrenal steroids in raising resistance to hypoxia, surgical and traumatic shock, and other stressors had yielded largely negative results. Collaboration between the Mayo group and the Merck group—the exchange of scientists was continued—plus informa- tion from Professor Reichstein, made it possible for Merck and Company to prepare nearly 100 grams of Compound A by the end of 1945. Tests of Compound A were begun with high hopes by sev- eral groups of clinical scientists. All the results were in agree- ment: The compound had little therapeutic value in patients with Addison's disease. Most of the once interested chemists dropped research on the synthesis of Compound E; Dr. Kendall wanted to keep at the original objective and the Merck group agreed to continue the collaboration. The officers and scientists of this company deserve great credit for farsighted policies of research in this and other areas. The early years of the 1940s brought personal sadness to Dr. Kendall. Near the beginning of the decade, Mrs. Kendall

268 BIOGRAPHICAL MEMOIRS experienced the first of a series of periodic mental illnesses. Also, their son, Roy, developed a malignancy during his medi- cal internship, and he died after about eighteen months. Hugo Nilson and I there with Dr. Kendall in Atlantic City when this happened. I had just left the two of them ashen Dr. Kendall received word that his son was dead. Hugo was stunned and unable to find words to express his feelings; Dr. Kendall was a father figure to each of us, and site had affection for each mem- ber of the family. It alas the older man who placed his hand on Hugo's shoulder and spoke quietly of the cruelty of disease and that man must work toward the reduction of it. Nothing short of his own death should prevent his striving toward that goal. Dr. Kendall's son, Norman, took his own life soon after he was discharged from militar-y service, adding to the tragedies of these years. In December of 1944, Dr. Lewis H. Sarett of Merck and Company prepared a few milligrams of Compound E. During the collaboration aimed to improve the yields, several impor- tant contributions came from the Kendall group, most of them from the young men. Dr. Kendall had learned a great deal of steroid chemistry by this time and alas the source of some fruit- ful ideas. Still, his major role was to keep the program going and to focus the efforts of a number of gifted collaborators on the problem. The first large-scale synthesis of Compound E was com- pleted at Merck and Company in 1948. Most clinical endocri- nologists had lost interest in the possible clinical usefulness of this and other glucocorticoids. Another phase of research on the hormones of the adrenal cortex seemed to be over. Dr. Philip S. Hench of the Mayo Clinic had observed that patients with rheumatoid arthritis sometimes go into remission when they become jaundiced and that some women have relief from arthritis when they become pregnant. He postulated that some humoral substance formed during jaundice and during

EDWARD C. KENDALL 269 pregnancy is responsible for the remission. I heard him talk about this theory and the relevant evidence in the middle 1930s. One of the young physicians working with him came to me to learn how to ligate the common bile duct of the rat so as to induce jaundice; he then studied the joints of the jaundiced animals, but there were no significant changes. Drs. Hench and Kendall discussed the problem on a number of occasions. It was decided in 1941 to test Compound E for a possible effect on rheumatoid arthritis, when a sufficient amount became available . . . . . for clinical Investigation. In September of 1948 some synthetic Compound E was in- jected into a female patient. It came from a supply that had been prepared at the Mayo Clinic by Vernon Mattox from a precursor (4,5-,8-dihydrocortisone acetate ~ supplied by Merck and Co. There was dramatic improvement in the patient. The clinical study was continued and expanded by the use of Com- pound E supplied by Merck; almost all arthritic patients treated with the steroid went into a remission that lasted as long as the hormone was given. There was great excitement at the Mayo Clinic, but it was tempered with caution against making a pre- mature announcement. The results were kept confidential for several months. At that time I was a research scientist at the Upjohn Com- pany. In February of 1949, Dr. Gifford Upjohn told me of a rumor that a great medical discovery had been made at the Mayo Clinic. I made a trip to the Mayo Clinic and was taken by Dr. Hench to see arthritic patients in remission; I was shown the recently completed film of the effects of treatment. This was quite exciting, and I was especially pleased to hear the story from Dr. Kendall. He had never lost faith that Compound E would be of use in clinical medicine. Dr. Randall G. Sprague talked faith me about the possible o~erdosage effects of Compound E; doses required to suppress the symptoms of rheumatoid arthritis are large. Was it not

270 BIOGRAPHICAL MEMOIRS likely that continued high dosage would induce Cushing's syndrome in the patients? I knew that normal animals could be brought to death by overdosa3e with Compound E; it seemed plausible that unwanted effects would occur in humans as well. Would the adrenal cortices of these patients undergo compensa- tory atrophy? It seemed probable. Would continued high dosage of the steroid damage the capacity of the anterior pitui- tary to again secrete corticotropin when the administration of steroid was stopped? I was almost certain this would not occur, but I was wrong. When Dr. Sprague and I met in At- lantic City in April of the same year, he told me that Cushing's syndrome had begun to appear in some arthritic patients treated with Compound E. Did Dr. Kendall have some special foresight that Compound E and related steroids would suppress inflammation and there- fore the symptoms of arthritis? He never claimed to have. Dr. Kendall had suggested the testing of Compound E in mental diseases, in cancer, and in other diseases. It is my belief that he and Dr. Hench were playing a hunch without much evi- dence or logic to support it. In 1941 a strange, brilliant man named Valey Menkin demonstrated that adrenal cortical extract and Compound E would suppress inflammation in laboratory animals. Most of us ignored the research of Menkin. There is no evidence that Dr. Kendall attached special significance to it, although he supplied the Compound E for the studies. Compound E could have been tested in arthritic patients years before it actually was, for several grams that had been isolated from natural sources were at hand, and more could have been extracted and purified at any time. The first test came about as follows: In the latter half of 1948, Dr. Hench had a female arthritic patient who had not responded to treat- ment; she begged him to try any possible sort of new therapy. Dr. Hench came to Dr. Vernon NIattox—Dr. Kendall was on a trip—and inquired into the possibility of obtaining, some Com-

EDWARD C. KENDALL 271 pound E to test. Dr. Mattox replied that he could not supply the steroid unless instructed to do so by Dr. Kendall. When Dr. Kendall returned, Dr. Hench raised the question with him and the two agreed to the clinical trial. In May of 1949 Drs. Kendall and Hench discussed the nam- ing of Compound E; they coined the word "cortisone." In the days, weeks, and months that followed announcement of the therapeutic value of cortisone in inflammatory diseases, there was wide acclaim, which surely brought satisfaction to each of the two men. On October 25, 1950, a newspaper cor- respondent with an inkling that Dr. Kendall would receive the Nobel Prize called the scientist's daughter, Elizabeth, in New York State, and she passed the news on to her father. In the early afternoon on the following day, it was officially announced that Edward C. Kendall, Philip S. Hench, and Tadeus Reich- stein would receive the Nobel Prize in Medicine and Physi- ology for their investigations of the adrenal cortex. Replying to my telegram of congratulations, Dr. Kendall thanked me and addecl, "That was the day!" Dr. Kendall shared his financial award with several of his associates who had contributed importantly to the isolation, identification, and synthesis of cortisone; Harold Mason and Vernon Mattox were among them. Other honors and awards followed, including election to the National Academy of Sciences in 1950. Dr. Kendall retired from the Mayo Clinic in 1951, but he did not retire from the bench. He moved to Princeton, New Jersey, became a visiting professor of chemistry at the university, and set up a research program at the James Forrestal Research Center just north of the city. By then it had become apparent that cortisone does not cure rheumatoid arthritis or other inflammatory diseases. These diseases are not caused by a deficiency of adrenal cortical hor" manes and prolonged treatment with the amounts of corticoids

272 BIOGRAPHICAL MEMOIRS required to suppress inflammation causes unwanted side effects in a significant number of patients. A better form of treatment was needed and Dr. Kendall set out to find it. He postulated, first in 1945, that an unidentified steroid is secreted by the adrenal cortex and that this steroid is linked with ascorbic acid. His quest included the extracting of adrenal glands and the attempted synthesis of postulated formulae. He worked to- ward this general objective for almost all of his remaining life. He focused on the aim to synthesize a ketal representing a con- jugate of ascorbic acid and hydrocortisone. As a step in this direction, he prepared furandiones—somewhat simplified ana- logs of ascorbic acid. He published two communications to the editor of the Journal of the American Chemical Society, con- cerning the preparation and properties of tetrahydro-3,4-furan- dione and its dioxolane and dioxane derivatives. He did not achieve his objective of creating a new therapeutic agent, al- though each letter and each Christmas message implied that success was near. On one occasion when I visited Dr. Kendall at his Princeton laboratories, he talked with me about a fable that I had written for reading at a dinner meeting of the Endocrine Society. It was about a great scientist who was destroyed by administrative duties. Dr. Kendall guessed correctly that I was frustrated by distractions from research; he proposed that we take a walk. Within the woods adjoining his laboratory was an abandoned circular building almost hidden by vines, brush, and untrimmed trees. Dr. Kendall called it "The \Vitches Nest." "I need a biologist with me," said The Chief. "If you want isolation, I will find salary money, research funds, and fix up 'The Witches Nest' for you. And you can have it with no telephone." (I dated the beginning of my troubles from the day I first acquired a telephone.) It was a high compliment from Dr. Kendall: He wanted me to work with him again. But I could not. Dr. Kendall called our home a few weeks before he died.

EDWARD C. KENDALL 273 I was away and he talked with my wife, Geneva. She said that he seemed tired and lonely and she was sad because this was completely unlike him. But he kept working. While having lunch with several scientists on a consulting trip to the Merck Company, May 1, 1972, he went to the blackboard to write a formula. He was suddenly taken ill, was hospitalized, and died from a coronary failure three days later. Mrs. Kendall died February 14, 1973. I have argued that a man should be remembered for his best personal qualities and his achievements rather than for his foibles and failures, but I cannot write of Dr. Kendall without describing his weaknesses as well as his stren~rh.s. To r1o .~o . ~ . c, _ ~ would create an image of a person who never existed. His greatness lay in his ability to select imnort~nt ~1~ that TAT~tf~ 1 ' ~ . -' ~ --rot <KIEV ~ vamp acn~evao~e, to persevere toward them during periods of ad- versity and disappointment, and to select gifted associates. Once when a younger associate asked permission to spend some time at another problem, Dr. Kendall replied, "I arrant to grow a great big oak tree; I am not interested in a bunch of black- berry bushes." In his autobiography he writes of the driving force that keeps a scientist at an important goal, and he adds, "But two components of the drive can be understood and are appreciated by almost everyone. These are a love of whatever things are true and a desire to create something." There was, I think, another quality of the man, which is suggested in this closing quotation by the French anthropologist C. Levi-Strauss: A grain of slightly mad recklessness, Might, in this domain as in others, Be the price you have to pay for great and noble findings. -r ~ To ~

274 AWARDS BIOGRAPHICAL MEMOIRS HONORS AND AWARDS John Scott Prize, City of Philadelphia Chandler Medal, Columbia University Squibb Award, Endocrine Society Lasker Award (with P. S. Hench), Lasker Foundation Research Corporation Award, Research Corporation of New York 1950 Page One Award (with P. S. Hench), New York Newspaper Guild 1950 John Phillips Memorial Award, American College of Phy- . . slclans 1950 Remsen Award, American Chemical Society, Maryland Section 1950 Edgar F. Smith Award, American Chemical Society, Phila- delphia Section 1950 Research Award, American Pharmaceutical Manufacturers Association 1950 Passano Award (with P. S. Hench), Passano Foundation 1950 Medal of Honour, Canadian Pharmaceutical Manufacturers Association 1950 Nobel Prize (with P. S. Hench and T. Reichstein), Nobel Foundation 1951 Dr. C. C. Criss Award (with P. S. Hench), Omaha Mutual Insurance Association 1951 Award of Merit (with P. S. Hench), Masonic Foundation 1951 Cameron Award (with T. Reichstein), University of Edin- burgh 1951 Heberden Award, Heberden Society of London 1952 Kober Award, Association of American Physicians 1961 Alexander Hamilton Medal, Alumni of Columbia College 1965 Scientific Achievement Award, American Medical Association HONORARY DEGREES (DOCTOR OF SCIENCE) 1922 University of Cincinnati 1950 Western Reserve University 1950 Williams College 1950 Yale University 1951 Columbia University

EDWARD C. KENDALL 1951 National University of Ireland 1964 Gustavus Adolphus College MEMBER American Academy of Arts and Sciences American Chemical Society American Philosophical Society American Physiological Society American Society of Biological Chemists (President, 1925-1926) American Society of Experimental Biology and Medicine American Society of Experimental Pathology Association of American Physicians Endocrine Society (President, 1930-1931) National Academy of Sciences Sigma Xi HONORARY MEMBER Columbian Society of Endocrinology Heberden Society, London Royal Society of Medicine of England Swedish Society of Endocrinology 275

276 KEY TO ABBREVIATIONS BIOGRAPHICAL MEMOIRS BIBLIOGRAPHY Am. J. Physiol. American Journal of Physiology Arch. Intern. Med. - Archives of Internal Medicine Biochem. i. Biochemical Journal Collect. Pap. Mayo Clin. Collected Papers of the Mayo Clinic and the Mayo Foundation Fed. Proc. Federation Proceedings I. Am. Chem. Soc. journal of the American Chemical Society J. Am. Med. Assoc. journal of the American Medical Association .l Biol. Chem. Journal of Biological Chemistry i.-Lancet- iournal-Lancet J. Org. Chem. Journal of Organic Chemistry Med. Clin. North Am. Medical Clinics of North America Minn. Med.- Minnesota Medicine Proc. Soc. Exp. Dial. Med. Proceedings of the Society for Experimental Biology and Medicine Proc. Staff Meet. Mayo Clin. Proceedings of the Staff Meetings of the Mayo Clinic Trans. Assoc. Am. Physicians Transactions of the Association of Amer- ican Physicians 1908 With H. C. Sherman. The detection and identification of certain reducing sugars by condensation with p-brombenzylhydrazide. T. Am. Chem. Soc., 30: 1451-55. 1910 With H. C. Sherman and E. D. Clark. Studies on amylases. I. An examination of methods for the determination of diastatic power. J. Am. Chem. Soc., 32:1073-86. With H. C. Sherman. Studies on amylases. II. A study of the action of pancreatic amylases. l. Am. Chem. Soc., 32:1087-1105. A Quantitative Study of the Action of Pancreatic ilmylases. New York: Wynkoop Hallenbeck Crawford Co. 83 pp. 1911 - The determination of copper—a modification of the iodid method. J. Am. Chem. Soc., 33:1947-52.

EDWARD C. KENDALL 1912 277 A new method for the determination of the reducing sugars. J. Am. Chem. Soc., 34: 317~1. The determination of iodin in the presence of other halogens and organic matter. l. Am. Chem. Soc., 34: 894-909. 1913 Evidence of the specific physiologic activity of certain constituents of the thyroid. Journal of the Pathology Society (1913-1914~. 1914 The determination of iodin in connection with studies in thyroid activity. i. Biol. Chem., 19:241-56. The isolation in crystalline form of the compound containing iodin which occurs in the thyroid: its chemical nature and physiological activity. Trans. Assoc. Am. Physicians, 30:420-49, 1914; also in J. Am. Med. Assoc., 64:2042-43, 1915. 1915 A method of decomposition of the protein of the thyroid with a description of certain constituents. I. Biol. Chem., 20:500-509. 1916 With L. B. Wilson. The relationship of the pathological histology and iodin compounds of the human thyroid. American journal of Medical Sciences, 151: 79-91. The function of the thyroid-parathyroid apparatus. i. Am. Med. Assoc., 66:811-913. Studies of the active constituent, in crystalline form, of the thyroid. Trans. Assoc. Am. Physicians, 31: 134~5. Recent advances in our knowledge of the active constituent in the thyroid: its chemical nature and function. Boston Medical and Surgical Journal, 175: 557-62. 1917 The fate of phenolsulphonphthalein when injected into the animal organism; factors other than the kidney influencing its "reten-

278 BIOGRAPHICAL MEMOIRS lion." Preliminary report. J. Am. Med. Assoc., 68:343-45. The active constituent of the thyroid. Its isolation, chemical proper- ties and physiologic activity. Proceedings of the American Society of Biological Chemists, 11:29. The thyroid hormone. Collect. Pap. Mayo Clin., 9: 309-36. Experimental hyperthyroidism. J. Am. Med. Assoc., 69:612-14. On the crystalline compound containing iodin which occurs in the thyroid. Endocrinology, 1: 153-69. Recent advances in our knowledge of the active constituent of the thyroid: its chemical nature and function. .~.-Lancet, 37:366-67. The relation of the thyroid to the other ductless glands. ~.-Lancet, 37:768-71. With A. E. Osterberg. The preparation of cyanamid. J. Biol. Chem., 32:297-98. 1918 The thyroid hormone and its relation to the other ductless glands. Endocrinology, 2: 81-93. The active constituent of the thyroid: chemical groups that are re- sponsible for its physiologic activity. J. Am. Med. Assoc., 71: 871-73. The isolation and identification of the thyroid hormone; the physio- logical action of the thyroid. Am. I. Physiol., 45: 540-41. 1919 The physiological action of thyroxin. Endocrinology, 3:156-63. The use of turpentine resin in turpentine as a foam breaker. I. Biol. Chem., 38:529. The use of coal as a substitute for talcum to induce rapid boiling. i. Am. Chem. Soc., 41:1189-90. The isolation of the iodin compound which occurs in the thyroid. First paper. l. Biol. Chem., 39: 125-47. With A. E. Osterberg. The chemical identification of thyroxin. Second paper. J. Biol. Chem., 40:266-334. The chemical and physiologic nature of the active constituents of the thyroid. Med. Clin. North Am., 3:583-602. 1920 Determination of iodin in connection with studies in thyroid activity. Third paper. J. Biol. Chem., 43:149-59.

EDWARD C. KENDALL 279 With A. E. Osterberg. The preparation of certain derivatives of cyclohexane. J. Am. Chem. Soc., 42:2616-26. With F. S. Richardson. Determination of iodin in blood and in animal tissue. Fourth paper. I. Biol. Chem., 43:161-70. The chemistry of the thyroid secretion. In: The Harvey Society Lectures, 1920-1921, ser. 15, pp. 40-57. Philadelphia: J. B. Lippincott Co. 1921 The chemical nature of the thyroid secretion. In: Keen's Surgery, vol. 8, pp. 47-50. Philadelphia: W. B. Saunders Co. The chemical influence of the active constituents of the ductless glands. Surgery, Gynecology and Obstetrics, 32: 205-9. With A. E. Osterberg. The ortho-diethylamine-cyclohexanol ester of para-aminobenzoic acid. l. Am. Chem. Soc., 43: 1370-71. Some physical and chemical properties of thyroxin. Collect. Pap. Mayo Clin., 13:484-87. 1923 The chemistry and the pharmacologic action of thyroxin. Annals of Clinical Medicine, 1:256-58. 1924 Chemistry of the thyroid gland. i. Am. Med. Assoc., 83:1166-67. 1925 The quantitative study of the physiologic action of thyroxin. I. Biol. Chem., 63:x)-xii; also in Proc. Soc. Exp. Biol. Med., 22:307-8. The influence of ductless glands on biologic reaction. Wisconsin Medical Journal, 24:303-5. The function of thyroxin. Trans. Assoc. Am. Physicians, 40: 162-69. The influence of the thyroid gland on oxidation in the animal organism. journal of Industrial and Engineering Chemistry, 17: 525-34. 1926 With J. W. Ort. The oxidation-reduction potentials of 2-oxy- dihydroindole-3-propionic acid and some of its halogen deriva- tives. J. Biol. Chem., 68:611-30.

280 BIOGRAPHICAL MEMOIRS With F. F. Nord. Reversible oxidation—reduction systems of cysteine-cystine and reduced and oxidized glutathione. l. Biol. Chem., 69:295-357. With A. E. Osterberg and B. F. McKenzie. The preparation of 2-oxo-dihydro and 2-oxo-hexahydroindol-3-propionic acid, and some of their halogen derivatives. Studies on thyroid activity. Fifth paper. i. Am. Chem. Soc., 48:1384-1401. Progress in the study of thyroxin. Minn. Med., 9:230-31. 1927 Isolation of thyroxin. i. Biol. Chem., 72:213-21. Oxidation catalysts. New York: Columbia Univ. Press. 20 pp. The physiology of the thyroid gland. Atlantic Medical Journal 30:602, 612. With B. R. Kirklin. A new iodine compound for cholecystography. Radiology, 9:205-8. With A. E. Osterberg. Some halogen and hydroxyl derivatives of 2-oxo-dihydro-2-oxo-hexahydro-indole-3-propionic acid, and of 2-oxo-hexahydrobenzofuran-3-propionic acid. I. Am. Chem. Soc., 49:2047-50. 1928 Contributions of the chemist to our knowledge of biological oxida- tions. Science, 67: 379-85. With D. F. Loewen. The reducing power of cysteine. Biochem. i-, 22: 649-68. With D. F. Loewen. The mechanism of oxidation-reduction poten- tial. I. The oxidation-reduction potential of cysteine and cystine. Biochem. i-, 22:669-82. The oxidizing and reducing power of cysteine and glutathione. J. Biol. Chem., 78:xl. Seasonal and geographic variations in the iodine and thyroxine con- tent of the thyroid gland. Trans. Assoc. Am. Physicians, 43: 142~45. With Daisy C. Simonsen. The seasonal variations in the iodine and thyroxine content of the thyroid gland. J. Biol. Chem., 80: 357 377. ' 1929 With B. F. McKenzie and H. L. Mason. A study of glutathione. I. Its preparation in crystalline form and its identification. l. Biol. Chem., 84:657-74.

EDWARD C. KENDALL 1930 281 Function of the suprarenal gland. Introduction. Proc. Staff Meet. Mayo Clin., 5: 133-35. With H. L. Mason and B. F. McKenzie. Crystalline glutathione. l. Biol. Chem., 87:xli. A study of glutathione. III. The structure of glutathione. l. Biol. Chem., 87: 55-79. With H. L. Mason and B. F. McKenzie. A study of glutathione. IV. Determination of the structure of glutathione. I. Biol. Chem., 88:409-23. 1931 With I. E. Holst. The oxidation of cobaltous cysteine. I. Biol. Chem., 91 :435-74. Chemical study of active constituents of suprarenal gland. I. Biol. Chem., 92:1vi; also in Proc. Staff Meet. Mayo Clin., 6:296 (A). The removal of traces of oxygen from nitrogen; a convenient appa- ratus for studies in oxidation-reduction potentials. Science, 73: 394-97; also in Proc. Staff Meet. Mayo Clin., 5: 199-200~1930) (A). The consideration of some of the glands of internal secretion from a chemical viewpoint. Endocrinology, 15: 357-64. With J. E. Holst. Oxidation of cobaltous cysteine. Proc. Soc. Exp. Biol. Med., 28:674-75. 1932 Chemical studies of the suprarenal gland. l. Biol. Chem., 97:iv-v; also in Proc. Staff Meet. Mayo Clin., 7:135-36 (A). Studies on experimental suprarenal deficiency. Proc. Staff Meet. Mayo Clin., 7:595-96. Further studies on experimental suprarenal deficiency. Proc. Staff Fleet. Mayo Clin., 7: 664-65. 1933 With B. F. McKenzie. Separation of the active principle essential to life from the suprarenal gland. Proc. Staff Meet, Mayo Clin., 8: 90-92. With H. L. Mason, B. F. McKenzie, and C. S. Myers. The physio- logic action and chemical nature of the active principle in the suprarenal gland essential to life. J. Biol. Chem., 100: 1ix-lx.

282 BIOGRAPHICAL MEMOIRS Chemical nature of the hormone of the suprarenal cortex essential to life. Proc. Staff Meet. Mayo Clin., 8:392-95. 1934 With H. L. Mason, B. F. McKenzie, C. S. Myers, and A. G. Koelsche. The chemical nature and physiologic activity of the hormone of the suprarenal cortex. l. Biol. Chem., 105:xlv-xlvi. With H. L. Mason, B. F. McKenzie, C. S. Myers and G. A. Koelsche. Isolation in crystalline form of the hormone essential to life from the suprarenal cortex: its chemical nature and physiologic properties. Trans. Assoc. Am. Physicians, 48: 147-52; also in Proc. Staff Meet. Mayo Clin., 9:245-49 (A). 1935 Suprarenal cortical hormone. Minn. Med., 18:71-73. With H. L. Mason, B. F. McKenzie, C. S. Myers, and W. D. Allers. Recent developments in the investigation of the hormone of the suprarenal cortex. Proc. Staff Meet. Mayo Clin., 10:245~6. Vitamins from a chemical viewpoint. Med. Clin. North Am., 19: 447-86. With G. A. Koelsche. The relation of the suprarenal cortical hor- mone to nitrogen metabolism in experimental hyperthyroidism. Am. J. Physiol., 113:335~9. Adrenal cortex extract. i. Am. Med. Assoc., 105: 1486-89. Glutathione. In: Cycloped ia of Med icine, ed. by G. M. Piersol. Philadelphia: F. A. Davis Co. 1936 With R. M. Wilder, A. M. Snell, E. J. Kepler, E. H. Rynearson, and Mildred Adams. Control of Addison's disease with a diet re- stricted in potassium: a clinical study. Proc. Staff Meet. Mayo Clin., 11: 273-83. With W. D. Allers and H. W. Nilson. Studies on adrenalectomized dogs: the toxic action of potassium. Proc. Staff Meet. Mayo Clin., 11 :283-87. With H. L. Mason and C. S. Myers. Concerning the chemical nature of the hormones of the adrenal cortex. Proc. Staff iMeet. Mayo Clin., 11:351-52. With H. L. Mason, C. S. Myers, and W. D. Allers. A physiologic and

EDWARD C. KENDALL 283 chemical investigation of the suprarenal cortex. .T- Biol. Chem., 114:1vii-lviii. With i. L. Svirbely. Vitamin C and the adrenal cortical hormone. Am. J. Physiol., 116: 187-93. With H. L. Mason and C. S. Myers. The chemistry of crystalline substances isolated from the suprarenal gland. If- Biol. Chem., 114:613-31. With D. i. Ingle. Survival of the adrenalectomized nephrectomized rat. Am. .T- Physiol., 117: 200-203. With H. L. Mason and C. S. Myers. Chemical studies of the supra- renal cortex. II. The identification of a substance which pos- sesses the qualitative action of cortin: its conversion into a dike- tone closely related to androstenedione. .T Biol. Chem., 116: 267-76. 1937 With W. D. Alters. Maintenance of adrenalectomized dogs without cortin through control of the mineral constituents of the diet. Am. I. Physiol., 118: 87. With D. J. Ingle and H. W. Nilson. The effect of cortin on the concentrations of some constituents of the blood of adrenalecto- mized rats. Am. l. Physiol., 118:302. With R. M. Wilder, A. M. Snell, E. J. Kepler, E. H. Rynearson, and Mildred Adams. The intake of potassium, an important con- sideration in Addison's disease. A metabolic study. Arch. Intern. Med., 59:367-93. With H. L. Mason, W. M. Hoehn and B. F. McKenzie. Studies in the chemistry of the suprarenal cortex. The structure and physio- logic activity of compound B: its relation to compound A and Reichstein's corticosterone. Proc. Staff Meet. Mayo Clin., 12:136. With H. L. Mason, W. M. Hoehn, and B. F. McKenzie. Studies in the chemistry of the suprarenal cortex. The probable position of the undetermined atom of oxygen. Proc. Staff Meet. Mayo Clin., 12:270. With H. L. Mason, W. M. Hoehn, and B. F. McKenzie. Chemical studies of the suprarenal cortex. III. The structures of com- pounds A, B and H. J. Biol. Chem., 120:719. The chemical constitution and physiologic activity of crystalline products separated from the suprarenal cortex. Trans. Assoc. Am. Physicians, 42: 123.

284 BIOGRAPHICAL MEMOIRS A chemical and physiologic investigation of the suprarenal cortex. Cold Spring Harbor Symposium on Quantitative Biology, 5:299. With D. J. Ingle. The significance of the adrenals for adaptation to mineral metabolism. Science, 86: 18. With D. I- Ingle. Atrophy of the adrenal cortex of the rat produced by the administration of large amounts of cortin. Science, 86: 245. 1938 Metabolic processes influenced by certain ductless glands. Proc. Staff Meet. Mayo Clin., 13:379; also in Endocrinology, 24:798-805. The influence of cortin, insulin and glucose on the metabolism of potassium. Proc. Staff Meet. Mayo Clin., 13:519. With H. L. Mason and W. M. Hoehn. Chemical studies of the supra- renal cortex. IV. Structures of compounds C, D, E, F and G. i. Biol. Chant., 124:459. With E. V. Flock, ]. L. Bollman, and F. C. Mann. The effect of the intravenous injection of glucose and other substances on the concentration of potassium in the serum of the dog. J. Biol. Chem., 125:57. With E. V. Flock, J. L. Bollman, and F. C. Mann. The influence of cortin and sodium chloride on carbohydrate and mineral me- tabolism in adrenalectomized dogs. l. Biol. Chem., 126:679. With D. l. Ingle. \Veights of adrenal glands in rats fed different amounts of sodium and potassium. Am. i. Physiol., 122:585. With D. l. Ingle and G. W. Higgins. Atrophy of the adrenal cortex in the rat produced by administration of large amounts of cortin. Anatomical Record, 71:363-72. 1 939 Influence of some of the ductless glands on metabolic processes. Endocrinology, 24:798. Report of the International Congress of Physiologists at Zurich. Proc. Staff Meet. Mayo Clin., 14:78. 1940 Glutathione. In: Cyclopedia of Medicine, p. 791. Philadelphia: F. A. Davis Co.

EDWARD C. KENDALL 285 With B. B. Wells. A qualitative difference in the effect of com- pounds separated from the adrenal cortex on distribution of electrolytes and on atrophy of the adrenal and thymus glands of rats. Proc. Staff Meet. Mayo Clin., 15: 133-39. The function of the adrenal cortex. Proc. Staff Meet. Mayo Clin., 15:207-304. With B. B. Wells. The influence of corticosterone and C~7-hydroxy- dehydrocorticosterone (compound E) on somatic growth. Proc. Staff Meet. Mayo Clin., 15: 324-28. The influence of the adrenal and thyroid on gluconeogenesis in phlorhizin diabetes. Proc. Staff Meet. Mayo Clin., 15:493-96. With B. B. Wells. The influence of the adrenal cortex in phlorhizin diabetes. Proc. Staff Meet. Mayo Clin., 15: 565-73. With D. l. Ingle. Influence of amorphous fraction from adrenal cortex on efficiency of muscle. Proc. Soc. Exp. Biol. Med., 45: 602-6. Some observations of the physiologic activity of the thyroid. Trans- actions of the American Association for the Study of Goiter, pp. 265-71. 1941 With B. B. Wells. The influence of the hormones of the adrenal cortex on ketonuria in rats treated with phlorhizing. Proc. Staff Meet. Mayo Clin., 16: 113-16. Hormones. Annual Review of Biochemistry, 10: 285-336. The function of the adrenal cortex. J. Am. Med. Assoc., 116:3294-98. The adrenal cortex. Archives of Pathology, 32:464-501. With F. H. Stodola. Studies on steroid ,8-ketols. I. The partial syn- thesis of 16-keto-sterone acetate. I. Org. Chem., 6: 837~40. With F. H. Stodola and B. F. McKenzie. Studies on steroid p-ketols. II. A new partial synthesis of 5-androstene-3,16,17-triol: an intermediate in the preparation of 16-hydroxytestosterone. Org. Chem., 6:841-44. 1942 With W. J. Eversole and Robert Gaunt. The effect of adrenal steroids in water intoxication. Am. l. Physiol., 1 3~: 378. Hormones of the adrenal cortex. Endocrinology, 30:853.

286 BIOGRAPHICAL MEMOIRS With Robert Gaunt and W. I. Eversole. Influence of some steroid hormones on lactation in adrenalectomized rats. Endocrinology, 31 :84-88. With Frank H. Stodola. Studies on steroid ,8-ketols. III. A partial synthesis of 3,17-diacetoxy-5-androstene-16-one. I. Org. Chem., 7:336. With R. M. Reinecke. Method of bioassay of hormones of the adrenal cortex which influence deposition of glycogen in the liver. Endocrinology, 31 :573. 1943 With R. M. Reinecke. A comparison of the influence of some crystal- line hormones of the adrenal cortex on the deposition of glycogen in the liver. Endocrinology, 32:505-8. With R. D. Williams. Influence of thiamine on induced hyperthy- roidism. Arch. Intern. Med., 72: 185-95. 1944 With F. R. Heilman. The influence of 11-dehydro-17-hydroxycorti- costerone (compound E) on the growth of a malignant tumor in the mouse. Endocrinology, 34:416-20. 1946 With B. F. McKenzie and W. F. McGuckin. Steroids derived from bile acids. I. The preparation of 3~-hydroxy-~ 11-choleric acid from desoxycholic acid. .t Biol. Chem., 162:555-63. With L. L. Engel, V. R. Mattox, B. F. McKenzie, and W. F. Mc- Guckin. Steroids derived from bile acids. II. 3~-hydroxy-11, 12-dibromo-cholenic acid and related compounds. l. Biol. Chem., 162:565-70. With R. B. Turner, V. R. Mattox, L. L. Engel, and B. F. McKenzie. Steroids derived from bile acid. III. Derivatives of ~9 -choleric acid with substituents at C3 and Cat. J. Biol. Chem., 162:571-84. With V. R. Mattox, R. B. Turner, L. L. Engel, B. F. McKenzie, and W. F. McGuckin. Steroids derived from bile acids. IV. 3,9-Epoxy- ~-cholenic acid and closely related compounds. J. Biol. Chem., 164:569-86. With R. B. Turner, V. R. Mattox, L. L. Engel, and B. F. McKenzie.

EDWARD C. KENDALL 287 Steroids derived from bile acids. V. Introduction of oxygen at Car, . J. Biol. Chem., 166: 345-65. 1947 Steroids derived from bile acids. IV. 3,9-Epoxy-~-cholenic acid, as an intermediate in the partial synthesis of dehydrocorticosterone. Recent Progress in Hormone Research, 1:65-81. 1948 With V. R. Mattox. The preparation of 3-keto-~4-steroids. l. Am. Chem. Sac., 70:882-83. With B. F. McKenzie, V. R. Mattox, and L. L. Engel. Steroids de- rived from bile acids. VI. An improved synthesis of methyl 3,9-epoxy-~-cholenate from desoxycholic acid. I. Biol. Chem., 173:271-81. \\lith V. R. Mattox, R. B. Turner, B. F. McKenzie, and L. L. Engel. Steroids derived from bile acids. VII. The probable stereochemical configuration of some derivatives of the bile acids. .l Biol. Chem., 173: 283-94. With B. F. McKenzie and V. R. Mattox. Steroids derived from bile acids. VIII. Catalytic hydrogenation of methyl 3~-hydroxy-12- keto-~9 ~~-cholenate and related compounds. J. Biol. Chem., 175:248-63. With V. R. Mattox and B. F. McKenzie. Hemibydrohalides of 3(cz)- hydroxy steroids. l. Am. Chem. Soc., 70:2662. The influence of the adrenal cortex on the metabolism of water and electrolytes. Vitamins and Hormones, 6: 277-327. 1949 The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehy- drocorticosterone: compound E) and of pituitary adreno-cortico- tropin hormone arthritis: preliminary report. Proc. Staff Meet. Mayo Clin., 24: 181-97. With P. S. Hench, C. H. Slocumb, A. R. Barnes, H. I,. Smith, and H. F. Polley. The effects of the adrenal cortical hormone 17- hydroxy-l l-dehydrocorticosterone (compound E) on the acute phase of rheumatic fever: preliminary report. Proc. Staff Meet. Mayo Clin., 24:277-97.

288 BIOGRAPHICAL MEMOIRS Some observations on the hormone of the adrenal cortex designated compound E. Proc. Staff Meet. Mayo Clin., 24:298-301. The chemistry and partial synthesis of adrenal steroids. In: The Adrenal Cortex. Annals of the New York Academy of Sciences, 50: 540~7. With P. S. Hench, C. H. Slocumb, and H. F. Polley. Effects of en- docrine secretions: the effect of cortisone and of ACTH on rheu- matoid arthritis and acute rheumatic fever. Seventh Interna- tional Congress on Rheumatic Diseases, May 31, 1949. Reprinted from Rheumatic Diseases. 1950 Studies related to the adrenal cortex. Fed. Proc., 9:501-5. With R. G. Sprague, M. H. Power, H. L. Mason, A. Albert, D. R. lMathieson, P. S. Hench, C. H. Slocumb, and H. F. Polley. Ob- servations on the physiologic effects of cortisone and ACTH in man. Arch. Intern. Med., 85:199-258. With P. S. Hench, C. H. Slocumb, and H. F. Polley. Effects of corti- sone acetate and pituitary ACTH on rheumatoid arthritis, rheu- matic fever and certain other conditions. Arch. Intern. Med., 85: 545-666. Cortisone. Chemical and Engineering News, 28:2074-77. With V. R. Mattox. The mechanism of elimination of hydrogen bromide from a-bromo keto-steroids through formation of hydra- zones. l. Am. Chem. Soc., 72:2290. With C. H. Slocumb, H. F. Polley, and P. S. Hench. Effects of corti- sone and ACTH on patients with rheumatoid arthritis. Proc. Staff Meet. Mayo Clin., 25:476. With V. R. Mattox. Steroids derived from bile acids. IX. Diphenyl- carbinol and diphenylethylene derivatives. i. Biol. Chem., 185: 589-92. With V. R. Mattox. Steroids derived from bile acids. X. Preparation of bromo derivatives of some 3-keto steroids. J. Biol. Chem., 185: 593-99. With V. R. Mattox. Steroids derived from bile acids. XI. Prepara- tion of 3-keto-~4-steroids. l. Biol. Chem., 185: 601-14. Cortisone. Annals of Internal Medicine, 33:787-96; also in Neue Medizinische Welt, No. 35/36, pp. 1-19. With P. S. Hench, C. H. Slocumb, and F. H. Polley. Effects of corti-

EDWARD C. KENDALL 289 sone and pituitary adrenocorticotropic hormone (ACTH) on rheumatic diseases. I. Am. Med. Assoc., 144: 1327-35. The story of cortisone. Hospital Management. With P. S. Hench, C. H. Slocumb, and H. F. Polley. The anti-rheu- matic effects of cortisone and pituitary ACTH. Transactions and Studies of the College of Physicians of Philadelphia, 18 (4 ser.~: 95-102. 1951 With V. R. Mattox. Steroids derived from bile acids. XII. Adrenal cortical hormones: introduction of a double bond. i. Biol. Chem., 188:287-97. Cortisone. Quarterly of Phi Beta Pi, 47:187-98. With G. M. Higgins and Kathryn A. Woods. Some observations on the physiologic activity of 6-dehydrocortisone (diene). Endocri- nology, 48: 175-88. The development of cortisone as a therapeutic agent. Antibiotics and Chemotherapy, 1: 7-15. With G. A. Fleisher. Preparation and absorption spectra of steroids with 2,4-dinitrophenylhydrazone groups at C-20 and C-21. l. Org. Chem., 16: 556-72. With G. A. Fleisher. Steroids with a glyoxal side chain at C-17 and related compounds. J. Org. Chem., 16: 573-85. The development of cortisone and hydrocortisone as therapeutic agents. American Academy of Orthopedic Surgeons: Instructional Course Lectures, vol. 8, pp. 60-67. The development of cortisone as a therapeutic agent. (Nobel lecture, Dec. 11, 1950) Stockholm: Kungl. Bokthyckeriet P. A. Norstedt and Soner. Alfred Nobel: the man and his prizes. Proc. Staff Meet. Mayo Clin., 26:417-37. The adrenal cortex and rheumatoid arthritis. British Medical iour- nal, pp. 1295-99. 1952 Title F. B. Colton, W. R. Nes, D. VanDorp, H. L. Mason, and A. {. L.aVine. Steroids derived from bile acids. XIII. Introduction of the 17-hydroxyl group in the partial synthesis of cortisone. I. Biol. Chem., 194:235-45.

290 BIOGRAPHICAL MEMOIRS With F. B. Colton. Steroids derived from bile acids. XIV. Halogen and other derivatives of a -pregnant. i. Biol. Chem., 194: 247-60. With V. R. Mattox, G. Woroch, and G. A. Fleisher. Steroids derived from bile acids. XVI. Preparation of 6-dehydrocortisone. i. Biol. Chem., 197:261-70. With W. F. NIcGuckin. Steroids derived from bile acids. XVII. Dehydrobromination of 3-keto-4-bromosteroids with 2,4-dini- trophenylhydrazine. i. Am. Chem. Soc., 74:3951. Hormones of the adrenal cortex in clinical medicine. (Cameron Prize Lecture) Edinburgh Medical journal, 59:1. With W. F. McGuskin. Steroids derived from bile acids. XVIII. Introduction of the 4,5-double-bond of cortisone. I. Am. Chem. Soc., 74:5811. With R. B. Turner, V. R. Mattox and W. F. McGuckin. Steroids de- rived from bile acids. XIX. Barbier-Wieland degradation of the 11-keto series. i. Am. Chem. Soc., 74:5814. With V. R. Mattox, R. B. Turner, W. F. McGuckin, and E. I. H. Chu. Steroids derived from bile acids. XX. Degradation of 3a!, 9~-epoxy-11-ketonorcholanic acid to A, 9,`-epoxy-11-ketoetio- cholanic acid. I. Am. Chem. Soc., 74:5818. Acceptance of Kober Medal for 1952. 'Trans. Assoc. Am. Physicians, 65:52. 1953 Hormones of the adrenal cortex in health and disease. Proceedings of the American Philosophical Society, 97:8-11. Hormones of the adrenal cortex. Bulletin of the New York Academy of Medicine, 29:91-99. 1960 With Zolton G. Hajos. Tetrahydro-3,4-furandione. I. Preparation and properties. I. Am. Chem. Soc., 82:3219. With Zolton G. Hajos. Tetrahydro-3,4-furandione. I. Dioxolane and dioxane derivatives. J. Am. Chem. Soc., 82:3220.

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Biographic Memoirs: Volume 47 contains the biographies of deceased members of the National Academy of Sciences and bibliographies of their published works. Each biographical essay was written by a member of the Academy familiar with the professional career of the deceased. For historical and bibliographical purposes, these volumes are worth returning to time and again.

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