The Rise and Fall of Modern Medicine (5 page)

Finally, despite the complexity and diverse mechanisms by which antibiotics work, the process of their discovery turned out to be astonishingly simple. All that was required, as Florey pointed out in his Nobel Prize speech, was the screening of micro-organisms to identify the handful that could destroy other bacteria, and then identification of the active antibiotic ingredient. Thus, though antibiotics are commonly perceived as a triumph of modern science, scientists alone could never have invented or created them from first principles. They are, rather, ‘a gift from nature', which raises the question of what their role in nature might be.

The most obvious and commonly accepted explanation is that antibiotics are ‘chemical weapons' produced by bacteria to maximise their own chances of survival against other organisms in the atmosphere and the soil. This was certainly the view of Selman Waksman, the discoverer of streptomycin for the treatment of tuberculosis. Waksman was, by training, a soil microbiologist and knew more about the ways in which bacteria in the soil interacted with each other than anyone else in the world. His reason for studying bacteria in the soil as a potentially potent source of antibiotics was as follows:

Waksman received the Nobel Prize in 1952 for his discovery of streptomycin, and yet in the following years he came to realise that his original perception of antibiotics as ‘chemical-warfare' weapons deployed by bacteria in the soil must be mistaken. He noted the ability to make antibiotics was limited to a very few species and so could not play an important role in the ecology of microbial life. Further, the ability of microorganisms to produce antibiotics turned out to be highly dependent on the quality of the soil, and indeed they were only reliably produced in the artificial environment of the laboratory. And so, if antibiotics did not act as bacterial ‘chemical weapons' in the struggle for survival in the soil, what did Selman Waksman believe their role to be? They are, he observed, a ‘purely fortuitous phenomenon . . . there is no purposeness behind them . . . the only conclusion that can be drawn from these facts is that these microbiological products are accidental.'
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This is a very difficult concept to accept. It seems inconceivable that bacteria, the simplest of organisms, should have the ability to produce such complex molecules which then serve no purpose in their survival, but as Leo Vining, a biologist from Dalhousie in Canada, observed at a conference in London in 1992, ‘Even accepting these products [antibiotics] have a role, does not mean that we can readily agree upon or perceive what that role might be'.
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The story of penicillin and the other antibiotics that followed is thus very different from that so often presented – and usually perceived – as the triumph of science and rationalism in the conquest of illness. The unusual climatic circumstances that led to Fleming's discovery of the antibacterial properties of the penicillium mould were quite staggeringly fortuitous. The crucial decision that led to its mass production – Florey's resolve to turn his university laboratory into a penicillin factory when a
German invasion was imminent – was a triumph of will over reason. Lastly the question of how, and more particularly why, a handful of the simplest of micro-organisms should have the ability to create these complex chemicals, or why they should exist at all, is simply not known. This, ‘the mystery of mysteries' of modern medicine, will be revisited.

C
ortisone – commonly known as ‘steroids' – is the second of the two drug discoveries that created the modern therapeutic revolution. Whereas the first, antibiotics, defeated an external enemy – the bacteria that caused infectious disease – cortisone mobilised the body's capacity to heal itself. This concept requires some elaboration. The human body as a robust and self-sufficient organism must be able to heal itself. This is seen most obviously in the recovery after a wound to the skin or a fracture to the bone but it is, of course, a generalised phenomenon much exploited by doctors over the centuries. Given time, rest, warmth and adequate nutrition, many illnesses will simply get better. These self-healing properties of the body are so pervasive that it was natural to infer there must be some physical or spiritual force to guide them. For the anatomist John Hunter it was a ‘vital spirit', for the French physiologist Claude Bernard ‘homeostasis' and for the physician William Osler the ‘vis medicatrix naturae'
.

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'.
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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 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.'
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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.'
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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.
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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.
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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.
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Soon after, US military intelligence agents reported that Germany was buying up large quantities of adrenal glands taken from cattle in Argentina.