The Rise and Fall of Modern Medicine (8 page)

Selman Waksman, the discoverer of streptomycin, was born in the Ukraine in 1888. He had two great passions: his mother and the land. ‘The odour of the black soil so filled my lungs I was never able to forget it. Later it would lead me to the study of the natural processes that are responsible for the aroma.'
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As indeed it did, for, having migrated to the United States, he enrolled at Rutgers Agricultural College in New York and, while pursuing his scientific interest in the soil, became enamoured of the low life that inhabited it, and one species of bacteria in particular, the actinomycetes. This culminated in the publication in his thirties of his monumental 900-page book
The Principles of Soil Microbiology
. Waksman was struck by a paradox. The soil is teeming with bacteria and fungi whose many functions include the decomposition of organic matter, yet none of the bacteria that cause disease in humans can be isolated from the soil, which is surprising, because they certainly find their way there via human excreta. Thus two years before Florey and Chain famously rediscovered penicillin, Waksman had anticipated the therapeutic possibility that chemicals produced by one species of bacteria might destroy other bacteria, for which he coined the term antibiosis – literally ‘against life'.

In 1943 Albert Schatz, a young postgraduate, joined Waksman's department and set out to work through the many species of actinomycetes, searching for the elusive chemical that might kill bacteria in humans.

The research technique Schatz used was simple enough. In the ‘streak test' he ‘streaked' a strain of the actinomycetes bacteria in a line across an agar plate and then at right-angles he ‘streaked' one or other of the bacteria that cause disease in humans. After a few days he looked to see whether its growth had been inhibited. Within a few months he had found streptomycin, which was dramatically effective in inhibiting the growth of tuberculosis germs. It did not take long to show that streptomycin cured guinea pigs experimentally infected with tuberculosis and soon afterwards a 21-year-old woman, Patricia, became the first patient to be cured with the new drug. Described as ‘a pretty dark-haired farmer's daughter', she was ‘wracked by persistent coughing, emaciated from consumption and pale, bathed in a fever of sweat and dying from widespread tuberculosis in both lungs'. Between 20 November 1944 and 7 April 1945 she received five courses of streptomycin injections, each of which lasted ten to eighteen days. Her temperature fell and the infection in her left lung melted away, implying her tuberculosis had at least been partially cured. But it had not been easy. Tuberculosis did not respond to treatment like other bacterial infections, as was only too clear from the protracted course
of her treatment. There was, however, a storybook ending. Patricia recovered fully and, after leaving the sanatorium, married and became the mother of three fine children.
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The second anti-tuberculous drug, para-amino salicylic acid or PAS, is a chemical variant of salicylic acid closely related to aspirin. In contrast to the long gestation and hard labour that led to streptomycin, PAS was the product of a single imaginative stroke of genius by a Danish doctor, Jorgen Lehmann. In 1940, while working in neutral Sweden, Lehmann received a letter from an old friend, Frederick Bernheim, containing a short article – just two paragraphs, 300 words in total – he had published in the journal
Science
. It reported the results of an experiment in which he had observed that the addition of just 1mg of aspirin to a culture of tuberculous bacilli increased the amount of oxygen they consumed by almost 100 per cent.
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There was no obvious reason why this should happen, but Lehmann, after thinking about the matter for a while, wrote to a Swedish pharmaceutical company, suggesting that were they to make a chemical variant of aspirin (or salicylic acid) to produce para-amino salicylic acid, it would be an effective treatment for tuberculosis. His reasoning was as follows: aspirin increased the amount of oxygen consumed by tubercle bacilli, so a chemical variant of aspirin might act as a ‘competitive inhibitor', blocking its consumption of oxygen so the bacteria could not survive. It was a brilliant, logical and highly original idea – which, as will be seen, would subsequently lead to the discovery of several other important drugs. But regrettably, at the time no one believed him. His medical colleagues had experienced so many false dawns in the treatment of tuberculosis that it was only natural for them to be sceptical about a suggestion that a variant of aspirin could be the answer, but Lehmann finally overcame these well-justified prejudices.
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In
a short article published in
The Lancet
on 5 June 1946 – ‘PAS and the Treatment of Tuberculosis' – Lehmann reported a couple of short case histories, describing a fall in temperature and an improvement in appetite in two patients with tuberculosis. There was, however, at the time no evidence that PAS, unlike streptomycin, could actually cure tuberculosis in the lungs.
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So when the Tuberculosis Trials Committee in Britain convened later in the same year streptomycin was at the time the only drug deemed worthy of investigation. Bradford Hill argued persuasively that the manner of that investigation should take the form of a clinical trial in which the decision about who should be given the drug and who should act as a ‘control' should be determined ‘at random'. And why was this so important?

The principle of the clinical trial could not be more straightforward: a simple experiment where the efficacy of a remedy is tested by comparing the outcome in those given it with that in a similar group who are not. If there is a measurable improvement in those receiving the remedy it can be presumed that it works. If there is not, it does not. The essence of a trial, then, is a comparison of the outcome between two groups. This is a modest enough scientific experiment and scarcely novel, having been used by the Parisian physician Pierre Charles Louis in investigating the benefits of bleeding in pneumonia (in which he found ‘no apparent difference in intensity or duration of symptoms between those bled and not bled')
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and famously by the Scottish ship's surgeon James Lind when investigating the merits of several cures, including lemons, for scurvy, whose devastating effect on British naval expeditions had become a major impediment to further expansion of the Empire.
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The method of comparison in the clinical trial requires that
the treatment be alternated, giving it to one patient but not the next, and so on, allocating patients to the ‘treatment' or ‘control' group at random. Bradford Hill explained it thus:

He then goes on to emphasise

This would all seem entirely reasonable and the lucidity of Bradford Hill's prose only makes it seem even more so. From the beginning of 1947 three London hospitals started admitting patients into the first streptomycin trial, in which fifty-five patients were to be given streptomycin for four months, the results being compared with fifty-two ‘controls' who were to be
‘treated' with bed-rest and, if necessary, the collapse treatment of the lung that Bradford Hill himself had undergone almost thirty years earlier. The allocation to ‘treatment' or ‘control' was determined by a series of random numbers devised by Bradford Hill and placed in a set of sealed envelopes.

By the end of six months, twenty-eight of those given the streptomycin were markedly improved and only four had died, compared to fourteen deaths among those unfortunate enough to have been randomly allocated to the ‘control' group. This finding, that those given streptomycin ‘did better' than those who were not, scarcely justifies the considerable time and energy devoted to the organisation of a randomised trial but, in a way that Bradford Hill could scarcely have anticipated, his insistence that streptomycin be objectively evaluated was to be completely (if tragically) vindicated. There was a fundamental limitation in the use of streptomycin to treat tuberculosis. Patients certainly improved but the requirement that treatment should last several months guaranteed that some of the tubercle bacilli would become resistant to the streptomycin and, when this happened, their condition subsequently deteriorated again.
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The streptomycin trial had been so intelligently organised that it was a straightforward matter to assess the potential seriousness of this problem of resistance, and the clear statistical presentation of the results brought home the full gravity of the problem – as revealed by an ‘update' published three years later, by when thirty-two of the fifty-five patients treated with streptomycin had died.
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The authoritative verdict of Bradford Hill's first trial was thus much more compelling than the resolution of the issue of whether or not streptomycin worked. Rather, it made it absolutely clear that streptomycin represented ‘a false dawn' where an initial impressive improvement in a patient's condition
was followed by a subsequent relapse that was closely related to the development of resistance. From this perspective there could be no greater vindication of Bradford Hill's espousal of the objective evaluation of new treatments over the subjective impression of doctors.

His methodical approach immediately pointed to the next step, which was to repeat exactly the same trial but this time, in the hope of combating the problem of resistance, combining streptomycin with Lehmann's PAS. This second trial started in December 1948 and exactly one year later, long before the study was complete, the organisers took the unprecedented step of issuing an interim communication that they had ‘demonstrated unequivocally that the combination of PAS with streptomycin considerably reduces the risk of the development of streptomycin-resistant strains of tubercle bacilli'.
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With the publication of the full results in November 1950 the benefits of the combination of the two drugs was glaringly obvious: thirty-three of the participants in the first trial had become resistant to streptomycin, compared to only five in the second trial. No longer, as happened at the first trial, did patients respond initially to treatment only to die several years later from a recrudescence caused by resistance to streptomycin. With streptomycin and PAS the survival rate soared to 80 per cent.
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This was not the end of the story. Over the next ten years tuberculosis treatment became ever more refined and successful, with the introduction of other drugs, notably isoniazid in 1952 and rifampicin in 1970.
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It soon became clear that the combination of three drugs was even better than two, and that if given continuously for a period of up to two years then virtually every patient could be cured of the disease. This happy situation persisted until the late 1980s when the difficulties of treating AIDS patients with tuberculosis led to the emergence
of tubercle bacilli that were ‘multiply resistant' to all anti-tuberculous drugs, raising the spectre that once again tuberculosis would become, as it had been prior to 1950, essentially an ‘incurable' disease.

As a final reminder of that time, it is appropriate to recall the fate of George Orwell, who died in 1950 aged forty-seven, just a few months before the results of the combination of PAS and streptomycin were published. Orwell had first been diagnosed as having tuberculosis back in 1938. His condition improved with bed-rest and lengthy convalescence in Morocco, but he suffered a relapse in 1946, soon after moving to a remote farmhouse on the island of Jura in the Hebrides, where he had gone to complete the last and greatest of his books,
Nineteen Eighty-Four
. He managed, through the influence of David Astor, the proprietor of the
Observer
, to obtain a small quantity of streptomycin. Initially all went well and a month after starting treatment he wrote to his friend Julian Symons: ‘I have been having the streptomycin and it is evidently doing its stuff. I haven't gained much weight but I am better in every way.' He was, however, one of the unlucky ones who developed a strong allergic reaction to the drug, in the form of a terrible rash and blisters such that he was no longer able to continue with treatment. His tuberculosis returned and he died in University College Hospital on 21 January 1950 from a massive haemorrhage into both his lungs. The famous literary critic Cyril Connolly wrote subsequently: