The Isolation of Thyroxine and Cortisone: the Work of Edward C. Kendall (2002)

Isolation of the Iodine Compound Which Occurs in the Thyroid (Kendall, E. C. (1919) J. Biol. Chem. 39, 125–147) Edward C. Kendall isolated thyroxine from the thyroid gland, he crystallized glutathione and determined its structure, and he isolated and characterized several steroid hormones from the adrenal cortex, including cortisone. He was awarded the Nobel Prize, with P. S. Hench and T. Reichstein, in 1950 (1Ingle D.J. Biographical Memoir of Edward C. Kendall. 47. National Academy of Sciences, Washington, D. C.1975Google Scholar). 1All of the information for this Classic Introduction was taken from this biography. 1All of the information for this Classic Introduction was taken from this biography. After receiving his Bachelor, Master, and Ph.D. degrees from Columbia University, Kendall started his research career at St. Luke's Hospital in New York City. His work focused on the hormones of the thyroid, following an earlier report from Professor Eugen Baumann that extracts of thyroid gland were effective in treating human hypothyroidism. By 1913 Kendall had purified the thyroid factor using a bioassay that measured changes in the urinary nitrogen of dogs. In a biography of Kendall (1Ingle D.J. Biographical Memoir of Edward C. Kendall. 47. National Academy of Sciences, Washington, D. C.1975Google Scholar), Dwight J. Ingle relates that at about this time, the hospital administrator at St. Luke's sent Kendall a box of breakfast cereal with a letter directing him to analyze the cereal.“ The letter and cereal were summarily thrown into the wastebasket,” and Kendall quit. In 1914 Kendall was invited to join the staff of the Mayo Clinic where there was special interest in diseases of the thyroid. The work reported in this Journal of Biological Chemistry (JBC) Classic paper describes the isolation and crystallization of thyroxine from 6500 pounds of hog thyroid glands. Kendall and his associates spent the next 10 years trying to determine the structure of thyroxine but failed. Kendall incorrectly concluded that the structure was triiodohexahydroxy-indole propionic acid (2Kendall E.C. Osterberg A.E. The chemical identification of thyroxin.J. Biol. Chem. 1919; 40 (232): 265Abstract Full Text PDF Google Scholar). In 1926, Dr. C. R. Harrington of University College London showed that thyroxine is the tetraiodo derivative of thyronine, and he was able to synthesize the active compound. Despite the error in determining the structure, Kendall's feat of isolation was impressive. Kendall initiated his study of adrenal glands in the early 1930s when it became clear that gland extracts would prolong the lives of adrenalectomized animals. This work occupied him and his associates for more than 20 years. The search for the active factor of the adrenal gland was an internationally competitive effort. It eventually became clear that the gland extracts contained several factors, which were given letter names by different groups leading to much confusion. Once the compounds were recognized as steroids and the structures were established, it became possible to name them properly. Kendall's Compound A was 11-dehydrocorticosterone; Compound B, corticosterone; Compound E, 17-hydroxy-11-dehydrocorticosterone (cortisone); Compound F, 17-hydroxycorticosterone (cortisol or hydrocortisone). As World War II began in Europe, research efforts in the United States were focused on supporting the war effort. In 1941, a group of leading chemists, including Kendall, was charged with an effort to synthesize adrenal steroid hormones. According to Ingle, it was rumored “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 by the Germans to counteract hypoxia of Luftwaffe pilots to permit them to fly at higher altitudes (1Ingle D.J. Biographical Memoir of Edward C. Kendall. 47. National Academy of Sciences, Washington, D. C.1975Google Scholar). After several years, the efforts to synthesize these compounds waned as their effectiveness for various war-related uses became doubtful. Eventually, only Kendall's group at Mayo and a collaborative effort at Merck continued. The first large scale synthesis of cortisone was completed in 1948. At the Mayo Clinic, Dr. Philip S. Hench convinced Kendall to do a small clinical trial of cortisone on a patient suffering from rheumatoid arthritis. It was a dramatic success, and subsequent tests on several patients were equally successful in reducing inflammation. Kendall's conviction that the steroid hormones of the adrenal gland would be therapeutically useful was borne out. It is now known that treatment of arthritis patients with steroid anti-inflammatory drugs is fraught with deleterious side effects, but at the time, this was a major discovery and probably the one for which Kendall is most recognized.