Chain reaction

Armed with a microphone, I stopped strangers on a London thoroughfare to ask: ‘Do you recall your first penicillin treatment?’. A remarkable proportion were happy to share stories of treatment and cure. The very first patient to be treated for an infection with penicillin was injected 82 years ago, early in 1941, during World War II. There was not enough available to save the dying policeman, whose scratch from a rose had become infected. Yet its effect was so remarkable that a new drug was recognised as a game-changer.

Within a very few years of that first treatment, penicillin had become world-famous. In the immediate aftermath of the war, Ernst Chain, Howard Florey and Alexander Fleming were awarded the Nobel Prize for Physiology or Medicine for the drug’s development – indeed, Chain’s medal, citation and the text of his acceptance speech is offered at Bonhams’ Fine Books and Manuscripts sale in London in June.

As the first antibiotic, followed soon by many more, penicillin demonstrated how a natural product could be discovered, mass-produced and safely prescribed to prevent or cure bacterial infection. Today, we know antibiotics are not ‘wonder drugs’, with their abuse having now helped resistant strains of bacteria to evolve. Yet, while the early propaganda raised excessive expectations, penicillin really did transform medicine and, indeed, society. Getting infected with gonorrhoea or, worse, with pneumonia had formerly been regarded as the sign of some kind of moral failing, but in the years after the Second World War such infections came to be widely regarded as just technical problems; meanwhile, in hospitals, procedures that had hitherto been impossibly dangerous because they compromised the body’s immune system became common and useful. At a time when the development of nuclear weapons threw the consequences of science into doubt, penicillin was the icon of its benefits.

Penicillin emerged as a drug during the Second World War and, at the same time, the story of its discovery by Alexander Fleming, working at London’s St Mary’s Hospital in 1928, became folklore. But what Alexander Fleming called penicillin was a yellow liquid with weak antibacterial effects, not the white crystalline wonder drug of two decades later. He discovered that the ‘mould-juice’ exuded by the Penicillium fungus could kill certain kinds of dangerous bacteria but, despite the support of colleagues at St Mary’s and at the nearby School of Hygiene and Tropical Medicine, the responsible constituent could not be isolated. It was both fragile and dilute: its concentration was comparable to that of gold in sea water. It was only a decade later that a new attempt made at Oxford proved successful.

Ultimately history-making, the work at Oxford began with serendipity and the contribution of an insecure Jewish refugee from Nazi Germany. In 1933, after the election of Hitler, the young chemist Ernst Chain fled to Britain. He went first to University College, London and then Cambridge. Moving on to a new group at Oxford, established by the dynamic Australian Howard Florey in the 1930s, he studied a variety of proteins. To chemists at the time, learning about this class of huge molecules was a top priority, and to many it seemed that they would be the key to understanding reproduction, even life itself – and, of course, lead to fame and financial security as well. Chain studied lysozyme, a germ-killing protein that Alexander Fleming had discovered a few years earlier. Seeking a new protein-related problem, Chain searched the scientific literature and turned up penicillin. Since Fleming’s lysozyme could kill bacteria, it was reasonable to expect that the apparently similar penicillin was also a protein. By luck, Chain found a sample of the penicillin liquid in his Oxford laboratory and then began work to purify it – for scientific, not medical, reasons.

New technology was available in the late 1930s. In Cambridge, already preparing for another war, work had begun on preserving blood plasma through freeze-drying. Familiar with this process, Chain imported it to his Oxford laboratory and managed to obtain samples of solid, albeit highly impure, extract of the active principle of Fleming’s penicillin. In March 1940, a preparation of this solid, now itself interpreted as ‘penicillin’, was injected into mice – which responded without the immune response that would have been expected when a protein was injected. Though others have suggested that the non-protein nature of penicillin had already been proven, Chain would accord great significance to this experiment. It marked a shift of emphasis from penicillin’s scientific interest to its medical importance.

Penicillin attracted the attention of other members of the enlarging Oxford team. Norman Heatley and Edward Abraham suggested additional new ways of purifying the penicillin and, in May, there was enough to test on eight sick mice. Those that were untreated died, but the four treated with penicillin survived. Early the next year, there was enough to test on a few sick people and, while not all the patients survived, it was clear that here was a potentially remarkable way to treat bacterial infections. In July, Florey and Norman Heatley flew to the United States in the hope that American industry could make much more penicillin than wartime Britain. There they found laboratories at the Department of Agriculture and the Pfizer Corporation, which had much more experience and expertise than the British in the industrial-scale exploitation of such moulds as Penicillium. Back in Oxford, by the end of 1942, Abraham and Chain had achieved 50% purity, a far cry from the 0.2% with which they had worked 30 months earlier. Chain’s role in penicillin’s development to post-war success now diminished, and the Oxford achievement had been the product of a large team – not of a single man. Nonetheless, his creative energy and determination had made possible the transformation from Fleming’s enigmatic yellow liquid to a potential bacteria-beating medicine.

As British and American teams worked on producing, purifying and testing the drug, the public came to learn of it. Lord Beaverbrook, the leading newspaper proprietor, was close friends with, and a patient, of the dean of the impoverished St Mary’s Medical School where Fleming worked. Beaverbrook saw the propaganda benefits to St Mary’s, as well as to the nation, and in August 1942 Fleming’s superior wrote an adulatory letter about Fleming’s achievement to The Times. This was just the beginning of a publicity campaign linking wildly optimistic prospects, the man and the drug. Florey and Chain were furious, and complained loudly to leading scientists. Who ‘really’ deserved the credit for the discovery of penicillin would be debated throughout the 20th century.

Despite the popular press, and the fears of Florey and Chain, Fleming’s name was not the only one that scientists linked with penicillin. In 1945, the three men were together awarded the Nobel Prize. At the December award ceremony in Stockholm, Chain spoke of the horrors of which human beings were capable and the scientist’s responsibility to engage with barbarism and not to retreat into their ivory towers. In 1948, he moved to Rome to head work with a new penicillin plant that came to be used as the pilot facility for scientific research, developing new technology and training a new generation of penicillin experts. Thus the Beecham company sent staff to Rome to learn about penicillin manufacture and research. On their return to Britain, they deployed their Italian research to develop their own way of making new variants. Out of respect for Chain, they included his name as an author of the scientific paper they published. One of their achievements was methicillin, with much higher resistance to most bacterial defences than its predecessors. Another was amoxicillin, still in wide use today.

Chain himself advised manufacturers around the world and greatly helped the post-war globalisation of penicillin’s production. Across Sweden, India, Germany, Italy and elsewhere, he made contributions. In 1964, he returned to London as the Professor of Biochemistry at Imperial College, where he recreated his Rome pilot plant. There, he oversaw a multitude of research projects, including work related to the fungus from which Quorn^TM is made, before retiring in 1973. Knighted in 1969, he continued vigorously publishing until his death in 1979. He would be relieved: he is remembered for his contribution to the story of penicillin.

Robert Bud is Keeper of Science and Medicine at the Science Museum.

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