Philip Showalter Hench, 1896–1965

Heberden Historical Series-Series Editor: M. Jayson

M. Lloyd

Department of Rheumatology, Frimley Park Hospital, Frimley, Surrey GU16 5UJ, UK

Philip Hench was born in Pittsburgh, Pennsylvania on 2 February 1896 to Jacob Bixler Hench and Clara Showalter. Best known for his work in the development of cortisone, for which he shared the Nobel Prize in 1950, Hench was also a highly regarded clinician, teacher and medical historian.

Hench graduated from Lafayette College in 1916 and then enlisted in the medical corps of the US army, completing his medical training at Pittsburgh University in 1920. In 1922, ‘by an accident of fate’, he became the first medical resident at St Mary's Hospital in Rochester, Minnesota. It was here that the Mayo Clinic's first rheumatic disease service was established and by 1928 Hench had become its head, spending the following year studying in Germany. He fell in love with and married Mary Kahler, daughter of the founder of Rochester's other hospital system, John Kahler. Eventually Hench became vice-president of the Kahler Hospital and Hotel Corporation, a delicate situation of which he was well aware [1].

A large man with an imposing presence, Hench overcame a severe cleft palate to become a fine orator, captivating the audiences of the American Society of Rheumatology in 1949 (E. Bywaters, personal communication). Born into a Protestant family, Hench spent his career happily in Catholic institutions, writing ‘any single truth, no matter how impressive or useful it may be, is only an infinitesimal fragment of what is the whole truth...known to The Great Physician’. Humility tempered his success and he advised that scientists should be ‘men whose hearts keep step with their minds’. His clinical teachings, known informally as ‘Hench's axioms’, emphasized the importance of a broad clinical medical knowledge in assessing an arthritic patient. Detailed charts were kept, documenting degrees of joint pain and swelling [2]. Hench was also a student of the work of Walter Reed, whose research for the US Army in the late 19th century overturned the widely held belief that yellow fever was spread by direct contact. Hench's collection on the subject is held by the University of Virginia.

In the 1920s, rheumatoid arthritis had yet to be defined, and most acute arthritides were considered to have an infectious basis. The department of rheumatology was regarded as the ‘soft underbelly of the Mayo clinic’ [1]. From this inauspicious start, the first step in the development of cortisone was a simple clinical observation. On 1 April 1929 Hench noted that the arthritis of a 65-yr-old doctor started to improve the day after he became jaundiced. The jaundice passed in 4 weeks, but his improvement lasted 7 months. Hench recognized the phenomenon in a number of conditions, but ‘in all but one pain was due to one of the so-called rheumatic diseases: arthritis, fibrositis or sciatica’. In 1933 he was able to describe in detail seven patients with ‘chronic infectious arthritis’ who improved following jaundice of various causes. ‘It would’, he wrote, ‘be gratifying if one were able to repeat Nature's miracle’ [3].

By 1938 he had collected a further 31 cases of improvement with jaundice. He observed that the response depended more on the depth of jaundice than its origin and that other conditions, including pregnancy, infection and the postsurgical state, could also lead to temporary remission. Lastly, Hench noted that allergic phenomena were similarly improved. He postulated that an innate substance, ‘substance X’, was responsible for the effect, either by correcting a chemical deficiency or oversufficiency or by exerting an antibacterial effect. There were few clues as to its origin. Attempts to reproduce the phenomenon by the administration of bile salts, human and ox bile, and even by transfusing jaundiced blood, failed, although some benefit was seen after the artificial induction of jaundice [4].

Knowledge that the postsurgical state led to an adrenal response and the observation that the fatigue in Addison's disease was similar to that seen in rheumatoid arthritis may have led Hench to turn his attention to the adrenals as the possible source of substance X. Fortuitously, he was able to cooperate with Edward Kendall, Professor of Physiological Chemistry at the Mayo Clinic. Kendall was a prolific researcher; he was described by a contemporary as ‘the man who celebrated Christmas Day and, indeed, every day in his laboratory’. In 1914, aged 28, he had been the first to isolate thyroxine in its crystalline form; by the 1930s he had become deeply involved in adrenal research.

From 1935, Hench and Kendall became friends as well as collaborators (Fig. 1Go). Hench was to describe him as ‘the one man in the world who could have given both the advice and the materials which were required’ [1]. Over the next 15 yr, laboratories in the USA and Switzerland (under Tadeus Reichstein) leap-frogged each other in attempts to isolate and purify the adrenal hormones. By 1940, 28 compounds had been isolated, four of which appeared to have physiological effects in animal experiments: 11-dehydrocorticosterone (compound A), corticosterone (compound B), dehydrocorticosterone (compound E, known to Reichstein as compound Fa) and 17-hydroxycorticosterone (compound F). The work was laborious: 3000 pounds of animal adrenal gland was required to produce 1 g of compound A.



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FIG. 1.  Philip Hench (right) and Edward Kendall. Reprinted with permission from Mayo Clin Proc 2000;75:337–9.

 
Compound E appeared to be particularly effective in preserving the life of adrenalectomized animals and by 1941 Hench and Kendall had come to the conclusion that it might be their substance X. The idea was a paradigm shift from the infectious theories of rheumatoid arthritis. However, further work was stalled by war and the tiny amounts of material available.

During the Second World War, Hench became Chief of the Medical Service and Director of the US Army's Rheumatism Centre. At the same time, US Government interest also led to an acceleration of adrenal hormone research, albeit in a curious way. Rumours spread that Luftwaffe pilots were able to fly at altitudes of over 40 000 feet, thanks to injections of adrenal extract. In addition, US intelligence reported that Germany was buying large numbers of adrenal glands taken from cattle in Argentina [5].

After the war, Kendall collaborated with Lewis Sackett of Merck in producing larger amounts of compound E. Having invested 14 million dollars without clinical results and knowing that the wartime rumours were false, the company was becoming dubious of finding a role for the compound. In April 1948, with 9 g of compound E available, Merck called a conference of endocrinologists to discuss the possible clinical uses of the hormone [6].

Two grams was given to each of three clinical investigators in Boston, New York and Rochester (Sprague) for studies in patients with Addison's disease and diabetes and 3 g to ‘chemists for further chemical studies’. Hench asked Sprague for some of his allotment of compound E for use in rheumatoid arthritis, but all was committed. Hench persisted and, via Kendall, in September 1948 managed to obtain a further supply of 5 g from James Carlisle and Randolph Major at Merck [7].

Hench and Kendall realized this was a gamble; compound E differed from the by now discredited compound A by only one oxygen atom and the pharmaceutical company was ready to drop the project. Kendall wrote ‘we had reached the end of the road. The answer had to be yes or no’. For their first patient Hench chose a Mrs Gardner, a 29-yr-old who had had severe, erosive rheumatoid arthritis for 5 yr and was effectively chair-bound. She had been an in-patient for almost 2 months and resisted attempts to be discharged, saying that she had come to the Mayo clinic for relief and wasn't leaving until she had had it [7].

Hench's colleague, Charles Slocumb, gave the first injection of 50 mg on 21 September 1948. At the time, the dose seemed large but Hench and Kendall were anxious not to inadvertently underdose. After 4 days of a dose of 100 mg daily, the patient was able to walk out of the hospital. A week later Hench gave the Heberden oration, not mentioning this success. A further 15 patients were treated over the following months, including two with the recently isolated ACTH. Uniformly good results were obtained. Characteristically, Hench chose to present and publish these through the regular Wednesday night meeting of the scientific staff of the Mayo Clinic on 13 April 1949 [8]. The room was packed and the presentation, which included dramatic ‘before and after’ cine film, was followed by a standing ovation. A reporter from the New York Times had been tipped off and news of the ‘modern miracle’ (initially labelled ‘corsone’ by Kendall but renamed by Hench as ‘cortisone’) spread rapidly through the lay and scientific press. This was despite Hench and Kendall emphasizing that ‘use of these hormones should be considered an investigative procedure’ [9].

The following year Hench shared the Nobel Prize in Medicine or Physiology with Edward Kendall and Tadeus Reichstein. This was the 50th anniversary of the prize, and the audience included Sir Alexander Fleming. Hench and Kendall shared their prize money with their colleagues at the Mayo Clinic, and sent the nursing supervisor of the arthritis wing, Sister Mary Pantaleon, with whom Hench had worked for 20 yr, for an audience with the Pope.

It was not until 1952 that a biological method of manufacture (using Rhizopus nigricans) was found, and the 2 yr leading up to this were difficult times. Physicians were besieged by patients seeking the new ‘cure’ and a large market for dubious imitations arose. Hench's discomfort was compounded by the exclusion of rheumatologists from the Richards Committee, a US governmental body set up to oversee the rationing of cortisone [10]. In addition, the side-effects of high doses became all too apparent. However, by the time of Hench's retirement in 1957, cortisone had become a readily available standard treatment for several conditions. After retirement, Hench worked with officials from the Nobel Foundation to set up the Nobel Conferences, high-level discussion forums on the implications of scientific advance.

Perhaps appropriately for one whose deductive reasoning helped lead to a watershed in medicine, Hench was a member of the Sherlock Holmes Society; his collection of Conan Doyle early editions is housed in the University of Minnesota. He wrote, perhaps echoing the fictional detective, ‘any truth is everybody's business’ [1].

Philip Hench died in 1965 in Ocho Rios, Jamaica.Go



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FIG. 2.  Philip Hench, Reggie Lightwood (centre) and Eric Bywaters (right).

 

References

  1. Hench PS. A reminiscence of certain events before, during and after the discovery of cortisone. Minnesota Med1953;July:705–11.
  2. Paulson GS. Challenges in rheumatology. A tribute to Nobel Laureate Philip Hench. S Dakota J Med1970;November:9–21.
  3. Hench PS. Analgesia accompanying hepatitis and jaundice in cases of chronic arthritis, fibrositis and sciatic pain. Proc Staff Meet Mayo Clin1933;8:430–7.
  4. Hench PS. Effect of spontaneous jaundice on rheumatoid arthritis. Attempts to reproduce the phenomenon. Br Med J1938;20 August:394–8.
  5. Le Fanu. The rise and fall of modern medicine. Little, Brown, 1999.
  6. Hetenyi G, Karsh J. Cortisone therapy: a challenge to academic medicine in 1949–52. Perspect Biol Med1997;40:426–39.[ISI][Medline]
  7. www.mayo.edu/pmts/mc4400-mc4499.
  8. Hench PS, Kendall E, Slocumb CH et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: Compound E) and the pituitary adrenocorticotropic hormone on rheumatoid arthritis. Preliminary report. Proc Staff Meet Mayo Clin1949;24:181–97.[ISI]
  9. Hench PS, Kendal EC, Slocumb CH et al. Effects of cortisone acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med1950;85:545–666.[ISI]
  10. Marks HM. Cortisone, 1949: a year in the political life of a drug. Bull Hist Med1992;66:419–39.[ISI][Medline]




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