Taking the Medicine: A Short History of Medicine’s Beautiful Idea, and our Difficulty Swallowing It

by Burch, Druin

  At the end of March 1931, Paine left to study puerperal fever with Leonard Colebrook in London, later returning to Sheffield to work at a women’s hospital. He never again experimented with penicillin and did not publish accounts of his few trials of it.

  Milton Wainwright and Harold Swan interviewed Paine towards the end of his life. They concluded that ‘Paine had obviously seen a therapeutic potential in penicillin, although mainly in relation to its use as an antiseptic, but he was beaten by the unstable nature and variability of the crude extract’. It seems a fair summary. Paine’s own verdict on himself was harsher, and quite different. Wainwright and Swan asked Paine where he saw himself fitting in to the story of penicillin’s discovery.

  ‘Nowhere’, he replied:

  a poor fool who didn’t see the obvious when it was stuck in front of him. I suppose that there are many things that conspired to stop me doing it. I’m sorry, but there it is. It might have come on to the world a little earlier if I’d had any luck.

  What Paine was suggesting was also, in its way, very fair. If you are going to acknowledge people who make discoveries, you also have to acknowledge those who came close but failed, those who ‘didn’t see the obvious when it was stuck in front of’ them. Paine’s sadness does not seem to have been for having missed out on fame and fortune. It was for the death and suffering that might have been avoided if he had achieved what others – including giants like Lister and Pasteur – also failed at.

  Domagk’s success with sulfonamides helped make penicillin achievable. Seeing his work, people turned to thinking about the production of other drugs with antibiotic properties. In Oxford, during the Second World War, a remarkable group of researchers took the Penicillium mould and reliably extracted pure concentrations of the molecule that gave it antibacterial activity. They were led by Howard Florey, an Australian Rhodes scholar who arrived at Magdalen College with burning intelligence, great ambition and a terror of the ways in which a man could fail in the world.

  ‘I can see myself developing into a rather nasty product,’ he wrote back to his sweetheart, herself a doctor.

  I’m that most damnably lonely I don’t know what to do, sometimes. I’m not complaining against anyone or anything . . . but the fact is I haven’t really got a friend as I conceive the term, and am quite incapable of having one.

  Florey found people to support and encourage him, however, even if others shared the view that his greatest gifts were not social ones. ‘Florey had a rather abrasive personality,’ noted a colleague. ‘He wouldn’t call a spade a spade but he’d call it a bloody shovel.’

  With Ernst Chain and Norman Heatley, Florey drove the development of penicillin as a drug. Much acclaim ended up going to Fleming, once the world began to realise the power of penicillin. Fleming was willing to give interviews, Florey was not. Fleming was well connected in London, and his supporters were quick to claim a greater share of the credit for him than he deserved. Newspaper journalists, more interested in writing quickly than writing truthfully, were happy to simplify and distort the story. Fleming himself did not go out of his way to attract extra credit, but made little effort to refuse it.

  Out of the Oxford group, only Chain seemed to possess a genuine lust for fame, and a consequent grudge over history cheating him. Florey was angry at the misrepresentation, but his desire to put people right was calmer than Chain’s. ‘Nor should anyone suppose that we have performed any great intellectual feats here,’ he wrote to Britain’s Medical Research Council, while asking them to make the drug’s history clear. ‘All we did was to do some decent experiments and have the luck to hit on a substance with astonishing properties.’ Norman Heatley agreed: ‘There wasn’t anything original in it. It was a question of: here is a product; here is a method of making something. What is the something? How do you make it? . . . It was just a question of applying already-known techniques.’

  The problem of credit could have been avoided, as Eric Lax pointed out in The Mould in Dr Florey’s Coat, if the Oxford group had simply called their drug something different from ‘penicillin’. Fleming originally used the name partly because of his own inability to figure out what substance within his mould juice was having an antibacterial effect. For him, ‘penicillin’ meant a poorly understood mix of fungal broth. The compound that Florey and his team isolated and mass-produced was something quite different, just as Aspirin was different from a piece of willow bark. Branding could – and should – have made all the difference.

  The development of penicillin was a wartime adventure. Chief among the worries of the Oxford team was what might happen to their work in the event of a successful German invasion. For some time, that seemed far more likely than not. The title of Lax’s book referred to the plan Florey and his colleagues developed during the bleakest days of the Second World War, when Britain’s defeat looked close at hand. They intended to destroy their laboratories and burn their records, in order that the potential of penicillin should not fall into the hands of Hitler’s Reich. As in the world’s previous conflicts, disease as much as weaponry could decide the ultimate outcome of war. Florey, Chain, Heatley and others planned to rub Penicillium mould into their clothes, then try to escape. Their hope was that one of them, at least, might survive and reach a free country where they could continue their work.

  The country they had in mind was America. Though they never needed to seek asylum there, American support for penicillin still proved vital. Florey’s group was supported from an early stage – 1936 – by American money, filling gaps left by a lack of British funding.

  William Osler’s Principles and Practice of Medicine, first published in 1892 and the medical world’s leading textbook for several decades after, had brought home to the medical community that their advances in understanding diseases were not matched by therapeutic breakthroughs. Osler’s famed ‘therapeutic nihilism’, the scepticism about the value of therapy that he held in common with his friend Oliver Wendell Holmes, was provocative. (It was also far from complete, as shown by Osler’s continued belief in the value of bleeding to treat pneumonia.) Principles and Practice played a key part in the influencing the aims of Rockefeller’s rich philanthropic foundation. Founded in 1913 and endowed with $100 million by the following year, the Rockefeller Foundation showed an explicit interest in responding to Osler’s proclamation that the world lacked effective medical drugs. One of the ways that interest manifested itself was in financial support for Florey’s group in Oxford.

  Penicillin, rather than the mould or its crudely gathered juice, was first used in Oxford’s Radcliffe Infirmary in January 1941. Elva Akers, dying of cancer, was asked if she was willing to submit to an experimental dose of the stuff. There was no suggestion that it might do her any good – the point was that she was dying anyway. Was she willing to help? She was, and the drug did her no obvious harm.

  Since it seemed safe, it was next given to an Oxfordshire policeman. The previous September, spending a quiet hour in his garden, he had scratched his cheek on a rose thorn. By February he was dying, his body riddled with infected abscesses, his left eye having been replaced by pus and then cut away entirely by surgeons. He responded beautifully to the penicillin, improving almost literally overnight. The drug was well on its way to saving his life when supplies, including those gathered by recrystallising it from his urine, ran out. He died.

  Producing more in their university laboratory, the British team achieved properly successful human trials, curing other patients whose infections were clearly killing them. Despite their greatest attempts, though, they only managed to make enough of the drug for a handful of people. The Penicillium mould turned out such a small amount of the active drug that even their best methods of mass-production resulted in only tiny amounts of pure penicillin. British pharmaceutical companies, stretched by the war, were unwilling and unable to take much interest. So the Rockefeller Foundation flew Florey and Heatley to the USA. Florey stayed long enough to convince people, then returned to Oxford.
Heatley, who knew most about actually growing and purifying penicillin, stayed longer.

  He was there in March 1942, when penicillin was first used successfully in America. Anne Miller, thirty-three years old, was dying of a bacterial infection following a miscarriage – effectively a form of puerperal fever. Despite sulphonamides, the disease could still kill. Anne Miller was dying, however, in Yale, and that made all the difference. A fellow patient knew of penicillin, and at her doctor’s request contacted the authorities that controlled the drug’s wartime use. The pharmaceutical company Merck released a teaspoonful of the drug. At that stage, despite the efforts and investment of Merck and other companies, that teaspoonful was roughly half of the world’s supply.

  Norman Heatley, despite being the only person in America with clinical experience of penicillin, was not medically qualified. His background was pure science, and his morals and his Englishness made him feel that it was not his place to advise doctors. His private diaries, quoted in Lax’s history of penicillin, give a flavour of the result. The Yale physician John Bumstead was amazed by Anne Miller’s marvellous response to penicillin. Wary of the drug, he wanted to reduce the dose as quickly as possible. Heatley, recalling the Oxford policeman whose disease fatally recurred when his penicillin ran out, disagreed, but could not quite bring himself to say so. Bumstead was acute enough to understand that Heatley was motivated by modesty, not ignorance. So, doggedly, he pursued the Englishman.

  Each day Bumstead asked Heatley, ‘What would you recommend? Should we carry on with the penicillin?’ And every time, Heatley answered, ‘Look, I’m not medically qualified. It would be quite unethical for me to suggest anything.’ So Bumstead would ask, ‘Well, what do you think Dr Florey would say?’ And Heatley would answer brightly, ‘Oh, I think he would say carry on. You know, you can’t stop it now.’

  Anne Miller’s therapy continued, the penicillin lasted, and she recovered completely. Later, as the power of penicillin became clear, the industrial production of it became part of the American war effort. By 1943 penicillin was America’s second highest research priority. The only thing ahead of it was the Manhattan Project.

  By D-Day the United States was manufacturing enough penicillin each month to treat 40,000 people – enough to have, as everyone had hoped, a significant effect on wartime fatalities.

  Penicillin’s success saved lives and encouraged research. It also cemented in the minds of doctors the belief that you could figure out what a drug did simply by giving it and seeing what happened. It was, after all, a genuine miracle drug, a wonder. Its good effects were of such a magnitude there was no mistaking them and, by chance, it was remarkably safe. Doctors too easily concluded that science was providing them with such new and marvellous cures, that there was no need to engage in any complicated weighing-up of risks, no requirement to think carefully about balancing harms and benefits: no need to be scientists themselves.

  Merck, one amongst many drug companies who were impressed by this experience of penicillin, immediately started looking for similar drugs. They were far from the only ones to do so, but they were certainly one of the most successful. Merck had continued to be a family firm from its inception in 1668 through to George Merck setting up an American branch in 1891. His son, George W. Merck, graduated from Harvard in 1915 – a time when his plan for returning to Germany to engage in research was particularly impractical. Instead he started straight away, working for the family company. In 1917, as a result of the war, it became a legally separate entity from its German parent. A Merck, however, was still in charge.

  During the Second World War, George W. Merck showed his patriotism and his power. He did everything he could to help America win the war through pharmaceuticals. That meant sulfonamides, penicillin and, at Camp Detrick in Maryland, germ warfare.

  One of Merck’s efforts at discovering new antibiotics lay in the company’s funding of Selman Waksman. A Russian émigré, Waksman’s academic interest at Rutgers University was in soil microbiology. Inspired by penicillin, Waksman focused on trying to extract antibacterial compounds from the microscopic life that soil was packed with. In human terms, they were part of the carbon cycle, breaking down detritus and making the earth fertile. In their own terms, they were engaged in the same sort of battle for survival as every other creature – and germ warfare was one of the ways in which they fought too.

  In 1942, Waksman took on a doctoral student named Albert Schatz. Schatz’s studies were interrupted by the war, but not for long. Within a year he was discharged from the army, a bad back making him ineligible for active duty. He returned to Waksman. The arrangements that the two men made, like other aspects of their relationship, are now subject to disagreement. Some accounts say that Schatz spent his army months watching men die from tuberculosis, arriving back at Rutgers and insisting on being allowed to look for a cure. Others describe him agreeing to work on antibiotic research only because Waksman made it a condition of his getting paid.

  The ill feeling between the two men was based on what happened in October of 1943. After studying Waksman’s soil samples for only a few months, Schatz discovered a new antibiotic. Others had been found before in soil, but they had proven too toxic for human use. This one – streptomycin – was different. Waksman, having set up the programme of soil testing but taken no part in Schatz’s day-to-day laboratory work, arranged for the new compound to be tested at the Mayo Clinic. It was given to four tuberculous guinea pigs. None were cured, but their disease was significantly subdued and the drug seemed to do them no harm. It was an impressive result, suggesting real potential. Waksman pressured Merck into calling a board meeting. He wanted the company to back further research into the drug, an expensive business. The board members were reluctant to agree. Then George W. arrived, late, to the meeting. He supported Waksman’s idea wholeheartedly.2

  In the way it affected bugs, streptomycin turned out to be very different from penicillin. It did not kill them, only stopped them from reproducing. That seemed to be enough, though, to allow the body’s immune system to get the upper hand. Waksman travelled to the Mayo Clinic to explain the story so far at first hand. ‘In September 1943,’ he told his audience, ‘my assistants and I succeeded in isolating in our laboratory an organism that produced an antibiotic.’ Thereafter he was even less charitable, often failing to mention Schatz at all. The rancour between the two men grew. Waksman continued to receive the credit and the benefits of the discovery, going on to become rich from the patent and ennobled by a Nobel prize. Schatz, in contrast, finished his life sharpening knives in Philadelphia, feeling bitter and cheated. ‘Thou shalt not take the credit for thy junior collaborators’ work,’ was the verdict of the Nobel laureate Max Perutz, who wrote about the controversy. Waksman collected the soil organisms and set up the machinery to study them, but Schatz was lucky enough to stumble across exactly the right one. The notion that an element of luck made someone ineligible for credit was ludicrous, at least to Perutz, who knew from experience how vital good fortune was for scientific discovery.

  The corporate nature of scientific research, in which credit often deserved to be shared, was sometimes difficult for scientists to acknowledge. Waksman seems to have imagined that he and Schatz belonged to a system where all credit was due to the leader who sat at the top (almost literally: while Schatz was in the basement doing his experiments, Waksman was sitting above in his office). Of more concern to patients than the priority for discovery, however, were emerging doubts over exactly what it was that the new drug offered.

  Measurements of its concentration in blood showed little correlation between how much a patient was given and the quantity that flowed around their body. That was worrying, since streptomycin was clearly dangerous, damaging nerves and kidneys and destroying people’s hearing. Yet the experiments on guinea pigs continued to be promising, and streptomycin very much seemed like the sort of thing that ought to work. On the back of the success of sulphonamides and penicillin, the blind conviction was tha
t antibiotics were good things. Without further trials, America adopted the drug enthusiastically.

  Even at the time, people should have known better. The unquestioning use of streptomycin was not rational: it was an example of the optimism with which doctors and patients had been dosing themselves for thousands of years. By the middle of the twentieth century, it should have been clear that there were more sensible ways of behaving. Even within the treatment of tuberculosis, there were recent lessons.

  Another new drug of the time was Sanocrysin, a gold-based compound. Developed in Denmark, it became popular in America from the middle of the 1920s. Gold was known to be thoroughly toxic, but then tuberculosis was dangerous and the benefits of the drug were felt to outweigh its harms. In 1925 the American Journal of Public Health managed to reserve a little judgement over the new therapy, but approved all the same of doctors using it on the basis of good reports from Europe. ‘It can be said of this alleged cure that it is being given to the public in a thoroughly professional manner,’ it decided. The Canadian Medical Journal, in 1927, held a similar opinion, suggesting that although the proper dose of the drug was not yet established, it was clearly beneficial.

  Other doctors managed to disagree, but since they focused on the patients who did badly, while the drug’s supporters dwelt on those who did well, neither side could persuade the other. Not until 1931 was the drug tested with any degree of reliability. In Detroit, an unusually thoughtful group of doctors took twenty-four tuberculous patients and tried to split them into two equally matched groups. ‘Obviously, the matching could not be precise, but it was as close as possible, each patient having previously been studied independently by two of us.’ With a flip of a coin, one group was allocated to Sanocrysin and the other to nothing. The doctors running the trial took care to hide the allocation from the patients and the other staff. They gave everyone either Sanocrysin, or similar looking injections that were actually nothing but sterile water.