Philip Hench, Edward Kendall, and Tadeus Reichstein received the Nobel Prize in medicine and physiology in 1950 for their “investigations of the hormones of the adrenal cortex.” Hench and Kendall took compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. This article examines the paths that led to the day when the first rheumatoid arthritis patient received cortisone, and from there to the 1950 Nobel Prize ceremony. The aftermath of this achievement is also discussed. Although there have been significant advances in corticosteroid preparations and use since 1950, the side effects remain daunting.
Key points
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Hench, Kendall, and Reichstein won the Nobel Prize in Medicine 65 years ago for their “investigations of the hormones of the adrenal cortex.”
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The discovery of cortisone is a fascinating tale of good science, perseverance, and luck that might not be possible in today’s regulatory environment.
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Although advances in corticosteroid preparations and their use have occurred since 1950, the side effects observed by Hench and his colleagues within weeks after the first patient’s dosing still haunt us today.
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Despite these issues, corticosteroids remain a critical and often life-saving component of treatment of many inflammatory diseases.
Introduction
Most rheumatologists are aware of the discovery of cortisone by Philip Hench and Edward Kendall for which they, along with the Polish chemist Tadeus Riechstein, received the Nobel Prize in medicine and physiology in 1950. Hench, the gregarious, consummate clinician in the new field of rheumatology, and Kendall, the dedicated, sometimes stubborn hormone chemist, formed the nucleus of a team that produced this remarkable breakthrough ( Fig. 1 ). In a fashion that is inconceivable today, they took the newly purified compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. The reader is referred to the recent book by Rooke for a revealing page-turner on the subject. This article examines the paths that led Hench and Kendall to that fateful day, September 21, 1948, when “Mrs G.” became the first patient with rheumatoid arthritis (RA) to receive cortisone, and from there to the 1950 Nobel Prize. We also look at the aftermath of this achievement for our heroes and their patients, a bittersweet legacy that we still live with today. The article also provides glimpses of others who played cameo roles in this poignant story, inseparable from the time of global upheaval in which it occurred.
Introduction
Most rheumatologists are aware of the discovery of cortisone by Philip Hench and Edward Kendall for which they, along with the Polish chemist Tadeus Riechstein, received the Nobel Prize in medicine and physiology in 1950. Hench, the gregarious, consummate clinician in the new field of rheumatology, and Kendall, the dedicated, sometimes stubborn hormone chemist, formed the nucleus of a team that produced this remarkable breakthrough ( Fig. 1 ). In a fashion that is inconceivable today, they took the newly purified compound E from the laboratory to the clinic to the Nobel Prize in a span of 2 years. The reader is referred to the recent book by Rooke for a revealing page-turner on the subject. This article examines the paths that led Hench and Kendall to that fateful day, September 21, 1948, when “Mrs G.” became the first patient with rheumatoid arthritis (RA) to receive cortisone, and from there to the 1950 Nobel Prize. We also look at the aftermath of this achievement for our heroes and their patients, a bittersweet legacy that we still live with today. The article also provides glimpses of others who played cameo roles in this poignant story, inseparable from the time of global upheaval in which it occurred.
Philip Showalter Hench
Philip Hench was born in Pittsburgh, Pennsylvania on February 2, 1896 with a severe cleft palate, but overcame his speech impediment to become a fine speaker. He attended Lafayette College, to which he remained loyal for life, and enlisted in the US Army Medical Corps after graduation in 1916. He graduated from Pittsburgh University Medical School in 1920, and from there began an uncanny string of firsts in medicine and rheumatology. In 1922, he became the first medical resident to train at St. Mary’s Hospital in Rochester, Minnesota, a hospital that rose from the ashes of the city after a devastating tornado in 1883. Through the dedicated efforts of Mother Alfred Moes of the Sisters of Saint Francis and Dr William W. Mayo, the 27-bed St. Mary’s opened in 1889. By the time Hench arrived, with William Mayo’s sons, Will and Charlie, as driving forces, St. Mary’s and the Mayo Clinic were becoming world leaders in medicine by adhering to the principles of patient care, research, and education. Hench subsequently became the first rheumatology fellow and then the head of the new rheumatic disease service at Mayo, established in 1926 ( Fig. 2 ).
In April of 1929, Hench observed that a 65-year-old doctor experienced relief from his inflammatory arthritis with the onset of jaundice. That quiescence lasted for months after the jaundice had resolved. In 1933, he published on seven such cases. By 1938, he had collected more than 30 cases, noting that the severity of the jaundice correlated with the benefit on inflammation. Pregnancy, infection, and surgery could have similar effects. He postulated that a “substance X” was naturally produced under these conditions, the source unclear. Deliberate induction of jaundice in some patients had benefit. The reasons for Hench’s leap to considering the adrenal glands as the potential source of substance X are speculative, but it was already well-known that surgery led to an adrenal hormone response, and in some ways, Hench believed the profound fatigue of RA to be similar to that of Addison disease.
In 1935 he began collaborating with Edward Kendall, a professor of physiologic chemistry at Mayo, and already an accomplished scientist. Kendall was involved in the highly competitive area of isolation of physiologically active adrenal hormones, of which he had identified four by 1940: compounds A (11-dehydorcoticosterone), B (corticosterone), E (dehydrocorticosterone), and F (17-hydroxycorticosterone). In an animal model, adrenal extracts could rescue adrenalectomized subjects from death. The putative life-saving hormone therein was generically known as cortin. Compound E seemed to be the most potent in this capacity, and therefore a lead candidate. But Kendall’s biggest competitor, Reichstein, working in Switzerland, had also identified the same hormone, designating it compound Fa. By 1941, Hench and Kendall were considering the possibility that compound E might not just be cortin, but in fact “substance X,” the mysterious humor that improved RA. The entrance of the United States into World War II was about to give their work an unexpected boost.
Edward Charles Kendall
Edward Kendall was born on March 8, 1886 in South Norwalk, Connecticut. He graduated from Columbia University in 1908, and remained for his doctorate in chemistry in 1910. He briefly worked on the isolation of thyroid hormones at Parke-Davis, before moving onto St. Luke’s Hospital in New York, a Columbia affiliate, in 1911. Feeling unappreciated, he left St. Luke’s in 1914 for the Mayo Clinic Medical School, becoming director of biochemistry in 1915, and subsequently professor of physiologic chemistry. There, at the age of 28, on Christmas Day, 1914, he became the first to crystallize the hormone thyroxine, starting from 6500 pounds of hog thyroids. A great disappointment of his career was his inability to then synthesize thyroxine. He also successfully studied glutathione and oxidative stress, but his biggest achievement was yet to come.
Kendall began studying adrenal hormones in 1930. By 1940, a total of 28 compounds had been identified by several laboratories. In those times, success in the tedious purification processes hung on a reliable supply of glands with which to work. Kendall, using 3000 pounds of animal adrenal glands, was only able to produce 1 g of compound A. Subsequently, with help from Merck & Company and Reichstein’s modified technique, hundreds of pounds of ox bile were used to produce 100 g of compound A. Unfortunately, once adequate material was available, it was found to be ineffective in the adrenalectomy bioassay. Compound A was clearly not cortin. Compound E differed from A by only one oxygen atom. Despite that, Hench and Kendall remained optimistic that compound E was the elusive cortin and substance X.
World War II
With America’s entry into World War II on the horizon, rumors were rampant that the Nazis were secretly importing bovine adrenal glands from Argentina via submarine to produce extracts for military use. It was long known that adrenalectomized animals would quickly succumb when exposed to even minimal stress, based on the work of Addison and Brown-Sequard in the 1880s. It seemed natural to postulate that adrenal extracts could protect against stress. The fear surfaced that Luftwaffe pilots were being given such a drug to allow them to tolerate hypoxia and fly at altitudes of 40,000 feet or more. Although these rumors were undoubtedly untrue, the specter of a steroid-enhanced enemy grabbed the attention of the US government. In 1941, the National Research Council set three major priorities for government-funded research, all influenced by impending war. Number three was the development of antimalarials for potential tropical warfare. Number two was the development of penicillin, whose utility for battlefield infections was obvious. Remarkably, the number one priority was the isolation and production of cortin! A committee of 14 chemists was assembled, including Kendall. From a practical perspective, the most important outcomes were the flow of money into adrenal hormone research and the resultant partnering with industry. Kendall now had a consistent supply (900 pounds per week) of adrenal glands from Parke-Davis and Wilson Laboratories. But the process of purification of compound E, by this point the lead candidate for the elusive cortin, remained laborious and low-yield.
Enter Lewis Sarett. Born in Champlain, Illinois in 1917, he received his bachelors of science degree in chemistry from Northwestern in 1939 and continued his work at Princeton, where his focus turned toward steroid synthesis. After graduation, Sarett moved to Merck Pharmaceuticals, principally because of their involvement in the government-sponsored cortin project. In early 1942, Sarett went to Kendall’s laboratory at Mayo for a 3-month sabbatical and discovered a key intermediary in the synthesis of compound E. He also became a close friend of Kendall before moving back to Merck headquarters in Rahway, New Jersey. By December 1944, Sarett, at the age of 26, was able to synthesize compound E from ox bile. By November of 1948, with help from Kendall, he had perfected a complex, but commercially practical, 37-step process for synthesizing compound E. The stage was now set.
Mrs G
Despite successes in the synthetic process, by 1948 Merck had invested more than $13 million in compound E without a clinical indication and with none on the horizon. At an investigator’s meeting in New York on April 29, Kendall sensed waning interest and feared the plug would soon be pulled on the project. In the meantime, Hench was continuing to induce jaundice, now using lactophenin as his preferred hepatotoxin. Two patients with severe RA arrived at Mayo in July of 1948 for trials of lactophenin. One patient, Mrs G., a 29-year-old woman from Kokomo, Indiana did not respond. In a fortuitous comingling of chutzpah and serendipity, she refused to leave until she felt better. Hench consulted Kendall about using compound E, and he agreed. On September 4, 1948, after an initially lukewarm response, the Mayo team sent a painstakingly written letter to Merck outlining their rationale. Merck acquiesced and sent 5 g of compound E.
On September 21, 1948, Mrs G. received her first of twice daily intramuscular injections of 50 mg of compound E at the hands of Dr Charles H. Slocumb, the hospital service junior rheumatologist. The next day, she felt no better. But throughout Day 3, she had progressive improvement, and by Day 4, her pain and stiffness were gone and she was visiting other patients to show off her progress. By September 28, she was pain-free and went shopping in downtown Rochester. “I have never felt better in my life.” Apparently, a miracle was happening at Mayo. We have all seen this miracle since, and we all know what usually happens next, but at the dawn of the cortisone era, all was well in Rochester, Minnesota.
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