Cortisone is not by itself the ‘vis medicatrix naturae’; yet, through its influence on the body’s response to stress and inflammation, this naturally occurring hormone cures or ameliorates upwards of 200 different illnesses and so can probably be described as its main component. As with antibiotics, cortisone’s discovery was entirely unanticipated, based on a series of fortuitous and coincidental events that stretched back nearly two decades.
The story of cortisone is synonymous with Dr Philip Showalter Hench, head of the Division of Medicine at the Mayo Clinic in Rochester, Minnesota, a large, powerful man of relentless determination. His speech was very loud, and, because of a severe cleft palate, difficult to understand, but nonetheless he spoke incessantly and in time became a magnificent lecturer.
On 26 July 1948 a young woman of twenty-nine, Mrs Gardner, was admitted under Dr Hench’s care. Her rheumatoid arthritis – from which she had suffered for more than five years – had proved to be relentlessly progressive despite every form of available treatment. ‘Many joints were stiff, swollen, tender and painful on motion,’ Dr Hench observed. ‘Her right hip joint had been eroded away so she could only walk with the utmost difficulty and was essentially confined to a wheelchair.’ Two months later she was no better and Dr Hench turned to a biochemist colleague, Edward Kendall, who informed him that the pharmaceutical company Merck had just synthesised a quantity of Compound E – now known as cortisone – which is secreted by the adrenal gland. The following morning a small amount of Compound E arrived by airmail in a special-delivery package. ‘We began with daily injections of 100mg,’ Dr Hench recalls. ‘During that day no change was apparent, the patient ventured only once out of her room as walking was so painful.’ But two days later, on 23 September, ‘when she awoke, she rolled over in her bed with ease and noticed much less muscular soreness’. The following day ‘her painful muscular stiffness was entirely gone’. Scarcely able to walk three days previously, she now walked with only a slight limp. Four days later ‘she shopped down town for three hours, feeling tired thereafter – but not sore or stiff’.1
Over the following three months Philip Hench treated a further thirteen patients, each as severely afflicted as Mrs Gardner, and presented the results to his fellow physicians at a meeting in April 1949.
The lights were turned down and a colour film began flickering on the screen. First came the ‘before treatment’ pictures in which patients with characteristically deformed joints struggled to take a few steps. Suddenly an electrifying gasp swept through the audience as the ‘after treatment’ scenes appeared and the doctors saw the very same patients jauntily climbing steps, swinging their arms and legs and even doing little jigs as if they had never been crippled at all. Even before the film ended, the watching physicians had filled the hall with wave after wave of resounding applause. When the lights went up and Dr Hench approached the lectern, he was greeted with a standing ovation.2
The origins of this momentous occasion go back twenty years to 1928, to a chance discussion between Hench and one of his patients, a 65-year-old doctor with rheumatoid arthritis, ‘one of the most intractable, obstinate and crippling diseases that can befall the human body’. The doctor, on being admitted to hospital for investigation of an episode of jaundice associated with inflammation of the liver, recounted to Hench how the day after his symptoms had appeared, the pain and swelling in his joints ‘had begun to diminish’, and that he found he could walk painlessly a distance of one mile. Altogether his jaundice lasted four weeks, but his arthritic feet and hands remained free of pain for a further seven months.
Hench realised this transient remission of rheumatoid arthritis was no mere coincidence when, over the following few years, he came across several other patients who described the same experience. As he noted: ‘The therapeutic implications are obvious. It would be gratifying to repeat nature’s miracle – to provide at will a similar beneficial effect by the use of some nontoxic accompaniment of jaundice.’3
Hench certainly had no grounds for believing this chance observation might be put to some practical use as he had no way of knowing what vital agent – which he designated ‘Substance X’ – might be responsible. Was it a constituent of the bile, or an abnormal chemical produced when the liver was damaged? Or was it something outside the liver altogether that was ‘activated’ by the jaundice? Hench had no alternative other than to seek to replicate nature’s ‘miracle’ by trial and error. He tried everything. He gave his arthritic patients bile salts, diluted bile, liver extracts, even transfused them with blood taken from jaundiced patients – all to no avail. Nonetheless he concluded his dismal litany of therapeutic failure in an article in the British Medical Journal in 1938 on an optimistic note: ‘It is important for us to identify nature’s dramatic, if accidental, antidotes . . . [but] the next step belongs to the future.’4
Meanwhile he had made two further very important observations. Firstly, he noted the symptoms of rheumatoid arthritis also improved in pregnancy, which made it much more likely that his Substance X was not specifically related to jaundice but was rather a hormone whose concentration in the blood increased both during pregnancy and when the liver was damaged. Further, jaundice and pregnancy produced a remission not only of rheumatoid arthritis but also of hayfever, asthma and the neurological disorder myasthenia gravis. So, whatever Substance X might turn out to be, it should, in theory, have been able to improve not just the symptoms of rheumatoid arthritis but these other illnesses as well.5
The most significant of all the many fortuitous events on the long road leading to the identification of Substance X as ‘cortisone’ was that while Hench was trying to treat his rheumatoid patients with bile and liver extracts, the completely unrelated research programme of another scientist working in the same hospital – Edward Kendall – would finally provide the answer.
Edward Kendall was the Professor of Physiological Chemistry at the Mayo Clinic. Back in 1914, when still only twenty-eight, he had isolated the hormone secreted by the thyroid gland – thyroxine. Since then another hormone – insulin, secreted by the pancreas – had been found to cure diabetes and there was naturally enormous interest in other similar diseases related to hormonal deficiency. These included Addison’s disease of the adrenal glands, which sit on top of the kidneys, whose destruction causes a progressive illness of weakness and debility leading to death within six months. Patients with Addison’s could be treated with a porridgey compound made from adrenal glands taken from cats, but the precise nature of the hormones they secreted was not known. In 1929, the same year as Hench’s conversation with his jaundiced patient alerting him to the possibility of Substance X, Professor Kendall set out to identify what these adrenal hormones might be. By 1936 he, along with researchers from other institutes, had isolated several different chemicals, which would be known as Compounds A, B, E and F.6,7
Hench and Kendall became close friends and ‘on innumerable occasions’ they conjectured together whether one or other of these compounds might be the mysterious Substance X. There was, however, no incentive for any pharmaceutical company to undertake, on such a shaky hypothesis, the laborious task of synthesising these new compounds in sufficient quantities to investigate their therapeutic potential. So Hench recorded ‘in my pocket notebook’ the possibility that they might relieve the symptoms of rheumatoid arthritis – but that, for the moment, was the end of the matter.
Then, just as with the development of penicillin, the exigencies of war created the incentive to carry the research further when Dr Hans Selye of Montreal’s McGill University, investigating the precise functions of the adrenal gland hormones, found they increased the resistance of laboratory animals to the stress of oxygen deprivation.8 Soon after, US military intelligence agents reported that Germany was buying up large quantities of adrenal glands taken from cattle in Argentina.
This was enough to balloon the rumour that Luftwaffe pilots (boosted with injections of adrenal cortex hormones) were able to fly at heights of o
ver 40,000 feet. The US Air Force promptly instituted a major research programme in every laboratory in the United States and Canada where work had been done on the adrenal extract.9
The rumour about Luftwaffe ‘super-pilots’ was soon scotched, but by then the research programme had developed a momentum of its own, which was a good thing because, as expected, synthesising the hormones proved to be a long and laborious task. It was not until 1948 that Dr Lewis Sarett, working for the drug company Merck, managed, by a complex chemical process, to obtain a few grams of pure Compound E. That would prove to be the mysterious Substance X.
There are two final important details, without which the remarkable potency of Compound E, soon to be renamed cortisone, would never have been realised:
For reasons that are not at all clear Dr Hench chose to use a dosage of 100mg a day. In 1948 this would have been considered a vastly excessive dose in relation to hormone requirement for other conditions. Had they used a smaller dose we now know there probably would not have been any result, and the discovery of cortisone might have been delayed for many years. Secondly, the size of the crystals in the preparations [of cortisone] happened to be dissolved at approximately the right speed. Had they been larger absorption would have been slower and the clinical remissions far less dramatic.10
When the news of the 1949 meeting where Hench provided the flickering images of patients ‘before and after’ treatment leaked out to the press, cortisone was presented as a genuine ‘miracle cure’. As the medical correspondent of The Times reported: ‘Within a few days of administration, patients were able to get out of bed and walk about, and the pain and swelling of the affected joints disappeared.’11 No Nobel Prize has ever been awarded more rapidly. The following year Hench and Kendall travelled to Stockholm to receive their award and Hench donated part of his prize money to Sister Pantaleon – the nun who had run his rheumatology ward for twenty-three years – so she could travel to Rome to see the Pope.12
Hench, however, was only too aware that cortisone was not a ‘miracle cure’ but merely controlled the symptoms and inevitably, once the treatment was discontinued, the arthritis would relapse. And then there was the problem of side-effects. When the British rheumatologist Dr Oswald Savage visited Hench at the Mayo Clinic in 1950, he found him ‘depressed by the increasingly numerous reports of side-effects . . . My generation will never forget the severe complications they produced – the moon face, the perforated and bleeding ulcers, the bruising and crushed vertebrae. It was clear this drug was so powerful it was imperative to use it safely.’ What an irony to have spent a lifetime discovering a cure for an untreatable illness only to find it was so powerful as to be virtually unusable!13
Soon the enthusiasm for treating rheumatoid arthritis with cortisone started to wane. The temporary – albeit apparently miraculous – improvement was being bought, it seemed, at too high a price.14 And yet, just as cortisone’s reputation for treating rheumatoid arthritis began to decline, so its absolutely central role in modern therapeutics began to emerge. Choose virtually any illness of unknown cause for which there is no effective treatment, however unpleasant or even life-threatening, give cortisone and see what happens.15 In 1950, a single issue of the Bulletin of the Johns Hopkins Hospital featured four separate papers describing the effects of cortisone in treating chronic intractable asthma; hypersensitivity reaction to drugs; the serious disorders of connective tissue, systemic lupus erythematosis and polyarteritis nodosa; and eye diseases including iritis, conjunctivitis and uveitis.16 The results were so uniformly good as to seem repetitive, and differed from those obtained in the treatment of rheumatoid arthritis in two important ways. Firstly, the benefits could be achieved at much lower doses, or by applying the cortisone externally to the skin or eyes, thus minimising the problem of side-effects. Secondly, it emerged that cortisone could in many circumstances carry a patient through a ‘crisis’, an acute medical problem of relatively short duration – such as an acute attack of asthma – after which the drug could be discontinued.
Cortisone and its derivatives, now collectively known as ‘steroids’, were (as shown on page 36) to completely transform the treatment of six medical specialties – rheumatology, ophthalmology, gastroenterology, respiratory medicine, dermatology and nephrology (kidney disorders), as well as facilitating the two most remarkable therapeutic developments of the postwar years – organ transplantation and the cure of childhood cancer. Two general points deserve emphasis.
Firstly, as Hench had originally predicted, steroids are effective in a wide variety of different pathological processes, including allergy (anaphylactic shock, asthma, rhinitis, conjunctivitis and eczema); autoimmune disorders (the connective tissue disorders, haemolytic anaemia, chronic active hepatitis and myasthenia gravis); life-threatening infectious disease (septic shock, tuberculosis and meningitis); acute inflammatory disorders (polymyalgia, optic neuritis, psoriasis); and potentially lethal swelling of the brain and spinal cord following injury.
Secondly, the precise causes of many of these diseases remain unknown and herein lies the truly revolutionary significance of steroids, in that they subverted the common understanding of how medicine should progress. It would seem obvious that a proper understanding of disease would be indispensable to developing an effective treatment, but the discovery of steroids permitted doctors to pole-vault the hurdles of their own ignorance, or, mixing metaphors, the inscrutable complexity of disease was dissolved away in the acid bath of steroid therapy where, in practical terms (at least for the patient), the only really important question – ‘What will make this better?’ – was resolved by the simple expedient of writing a prescription for cortisone. And yet this ‘panacea’ – which, despite their limitations, steroids certainly are – is a naturally occurring hormone, which brings us back to a necessary reconsideration of the functions of cortisone in the body and why it proved to be therapeutically so beneficial in so many different illnesses.
Diseases responsive to steroid therapy
(From Martindale, The Extra Pharmacopoeia, 31st edition, Royal Pharmaceutical Society, 1996. Readers are referred to this source for relevant references.)
Cortisone plays a crucial role in the body’s ability to heal itself – the vis medicatrix naturae – through its effects on the process of inflammation. Consider an infected joint, which is painful and swollen because of the damage caused by invading bacteria. The white blood cells secrete powerful enzymes to destroy the bacteria and remove the damaged tissue – this is the ‘inflammatory’ phase of healing, which is followed by ‘resolution’, when the debris is removed and new tissue laid down. Thus, during the ‘inflammatory’ phase, the symptoms of pain and swelling in an infected joint are as much the result of the powerful enzymes secreted by the white blood cells as part of the process of healing as of the infecting bacteria themselves. When, as happens with rheumatoid arthritis, the healing process cannot eliminate the ‘cause’ (which is not known), the inflammation persists along with its symptoms of pain, redness and swelling, which further damages the tissues of the joint.
Cortisone in several different ways orchestrates and controls this inflammatory response and, as the fundamental pathological feature of rheumatoid arthritis is the persistence of inflammation, so cortisone will, by suppressing it, result in an improvement in symptoms. Thus Hench’s real achievement was much greater than demonstrating cortisone’s effectiveness in improving the symptoms of rheumatoid arthritis. He opened the way to the understanding that many illnesses share the unifying feature of being caused by uncontrolled or excessive inflammation. Put another way, prior to Hench there was no sense that this vast range of diseases were connected at all and it was certainly inconceivable they might all be ameliorated by a naturally occurring hormone.
This therapeutic potency of cortisone could never have been anticipated, and so it could never have been created from first principles. It is thus, just like antibiotics, best conceived of as ‘a gift from nature’ whose discovery was qu
ite fortuitous. Retracing Hench’s odyssey one is struck by the extraordinary improbability that the therapeutic use of steroids was ever discovered at all. It all started with a chance conversation with a patient whose symptoms had improved during an attack of jaundice, a striking phenomenon perhaps, but, as at the time rheumatoid arthritis was thought to be an infectious illness, there were no theoretical grounds for Hench to follow through the implications that some substance produced by the body would have therapeutic properties – but he did.
Hench would never have been able to fruitfully pursue his hunch that there must be a ‘Substance X’ had it not been for the coincidence that Edward Kendall, whose brilliant skills as a biochemist were at the time centred on an apparently unrelated area of research – the nature of the hormones secreted by the adrenal cortex – was working in the same hospital.
The quantities of hormones produced by the adrenal glands were far too small to allow their therapeutic potential to be investigated, so there the matter would have rested had it not been for the rumour about Luftwaffe ‘super-pilots’ that stimulated the research programme that would eventually lead to the discovery that Substance X was, in fact, Compound E. When it came to treating his first patients with rheumatoid arthritis it was fortuitous that Hench chose a dose large enough and prepared in such a way as to give the dramatic results that generated the interest of fellow physicians to investigate the functions of the drug further. Finally, as has been noted, Hench got it right for the wrong reasons, since steroids, as it turned out, are not a particularly good treatment for rheumatoid arthritis but are very effective for many other illnesses.*
The Rise and Fall of Modern Medicine Page 4
