Discoverers and developers of penicillin (act. 1928–1950)
by Robert Bud

Discoverers and developers of penicillin (act. 1928–1950) were the scientists, principally based in London and Oxford, responsible for the discovery and subsequent isolation, testing, and demonstration of the world's first widely used antibiotic, penicillin, from the late 1920s to the early 1940s. Thereafter, and as production processes were greatly enhanced, penicillin's value was proved in treating the infections of wounded soldiers during the Second World War, as well as syphilis and pneumonia. Existing anti-bacterial drugs—sulphonamides—had sufficed to treat some infections, but the range of penicillin's benefits, its speed of application, and its general lack of side-effects were taken, even by medical scholars, to justify the term ‘miracle drug’ (Thom, 1945). Penicillin's valuable wartime uses, the propaganda made of its discovery, and the numerous other antibiotics that quickly followed, have given the drug a special place in medical history. With radar and the jet engine it has been frequently cited as one of the key British inventions of the Second World War. The contested history of its discovery and early development therefore quickly acquired political and policy implications.

Discovery and development

The accidental discovery of penicillin was made in September 1928 by Alexander Fleming, a bacteriologist at the Pathological Institute, St Mary's Hospital Medical School, London, whose earlier work included a study of the anti-bacterial properties of the compound lysozyme. In 1928 Fleming noticed how a mould, observed on an unwashed Petri dish, was surrounded by a sterile ring separating it from the staphylococcus bacteria. Using techniques devised when investigating lysozyme, Fleming studied the substance's effect on different bacteria of a filtered broth of nutrient on which the mould had grown. In June 1929 he published his findings in the British Journal of Experimental Pathology. In this first period of research Fleming was assisted briefly by two research students—Stuart Craddock (1903–1972), who subsequently went into medical research, and Frederick Ridley (1903/4–1977), later an ophthalmic surgeon—who were employed to identify the chemical composition of the active agent. Both were acknowledged in Fleming's 1929 paper that identified ‘penicillin’ (the name given to the mould juice as a whole after his failure to separate the chemical agent) as a new, natural antiseptic. Fleming's work was received with some interest among London biochemists but further development was hindered by the fractured nature of the scientific community. Between 1931 and 1932 the chemist Harold Raistrick, working with Percival Clutterbuck and Reginald Lovell (1890–1971) at the London School of Hygiene and Tropical Medicine, investigated the products of the mould, successfully isolating the yellow chrysogenin dye, but not the unstable penicillin drug. Raistrick, who was also able to grow the mould reliably (and who sent a sample to the American biochemist Charles Thom, who classified it as penicillium notatum), complained that he could not interest bacteriologists in investigating the mould, while Fleming made similar comments about the chemists. Raistrick's inability to extract the active principle meant that doctors were reduced to testing the therapeutic benefit of the exudation itself. Fleming himself experimented with its therapeutic effects on animals while his former student Cecil Paine studied its use for treating eye infections at Jessop Hospital, Sheffield.

In 1938 a group of scientists at Oxford University, headed by the new professor of pathology, Howard Florey, began to take note of Fleming's results, spurred initially by a scientific rather than medical interest. Florey's research team was based at the university's Sir William Dunn School of Pathology and specialized in a multi-disciplinary approach to the connections between bacteriology, clinical pathology, and experimental pathology. Whereas earlier work had been conducted by isolated individuals or by very small groups, the Oxford team numbered at least ten scientists including and co-ordinated by Florey: Edward Penley Abraham, Ernst Chain, Charles Montague Fletcher, Florey's wife, Mary Ethel Florey (1900–1966), Arthur Duncan Gardner (1884–1977), Norman Heatley, Margaret Augusta Jennings (1904–1994), Jean Orr-Ewing (1897–1944), and A. G. Sanders. With his team of bacteriologists, biochemists, and epidemiologists, Florey ensured that the disconnections between disciplines, which had restricted progress earlier in the decade, would not be repeated. In spring 1940, using freeze-drying techniques, the Oxford group successfully separated a biologically active dry powder that, though consisting of just 1 per cent pure penicillin, proved a considerable advance. The quality of the extraction was improved by Heatley, who at the same time devised apparatus to better isolate the penicillin from the culture fluid and to increase the concentration of its final form. In March 1940 Chain, who had done most to confront the challenge of separation, tested the powder on mice and by May the team had demonstrated the drug's non-toxicity and effectiveness in preventing infection even in an impure form.

The stimulus of war made these early animal experiments hugely significant and the Oxford group's attention switched quickly to the substance's therapeutic potential. However, the relative contributions of Florey's team during this period were a matter of controversy. In particular Chain and Heatley disagreed in their accounts of the early isolation of penicillin. Relations between the two men deteriorated to the extent that Heatley refused to work for Chain and reported instead to Florey. In due course Heatley focused his attention on producing the penicillin broth while Chain and Abraham concentrated on extracting the penicillin and on its chemical composition; Sanders operated the extraction plant, Florey and Margaret Jennings (who later became Florey's second wife) undertook animal work and—with Gardner and Orr-Ewing—research on bacteriology, while Mary Florey and Fletcher carried out medical studies. In addition to Chain and Heatley these professional relationships masked complicated personal ties, notably Mary Florey's close working involvement with Margaret Jennings, whom she knew to be having an affair with her husband.

In 1939 Florey and Chain had secured funding from the Rockefeller Foundation of New York, then the richest funder of scientific research. In spring 1941 Florey was visited by the foundation's head of science, Warren Weaver (1894–1978), who was shown the Oxford group's achievements and told of their difficulty in getting British companies to develop penicillin. Weaver, convinced of penicillin's potential, secured a substantial grant and in late June 1941 Florey flew to the United States with Heatley, a choice which considerably angered Chain. There the two Britons met Charles Thom, and through his connections gained access to the newly established Northern Regional Research Laboratory in Peoria, Illinois. While Heatley worked on developing the production process at Peoria, Florey was soon travelling in America both to promote his team's work, and that now being undertaken in the USA, and to seek commercial support for future development. The success of new American extraction and manufacturing techniques meant that by D-day (June 1944) there was sufficient penicillin for the allied invasion force, and shortly afterwards also for many American civilians. In addition to the well-known work to identify, separate, and use penicillin in medical treatments, there was also a major endeavour in Britain and America to attempt to synthesize the compound. Although the synthesis itself did not prove to be commercially viable, important work was conducted in this research, such as the establishment of the compound's structure at Oxford's crystallography sub-department in 1945. This had long-term benefits for the control of fermentation processes and the development of new penicillin drugs, including methicillin, which was active against many otherwise resistant bacteria from the late 1950s.

Notwithstanding the benefits of the Oxford group's involvement with American scientific institutions and companies Florey's increasingly prominent role exacerbated tensions and rivalries among his original team. Back in Oxford, in December 1943 Florey wrote to a colleague at Yale University of ‘a frightful scramble going on amongst the chemists … I am getting very worried about getting too much credit for what is going on and if you get a chance to emphasise how much is due to Chain in particular and all the other people here’ (Bud, Penicillin, 40). The ‘other people’ to whom Florey referred now extended beyond his staff at the Dunn School of Pathology. In the neighbouring Dyson Perrins Laboratory the chemist Robert Robinson was confident of the imminence of a synthesis and recruited Wilson Baker (1900–2002) and the young chemist Trevor Williams to work with him. In the sub-department of chemical crystallography Dorothy Crowfoot [see Hodgkin, Dorothy] and her colleagues established the structure of penicillin by means of X-ray crystallography once a crystallized salt had been produced in 1943. Their findings, made in 1945 and published four years later, confirmed E. P. Abraham's correct (but previously disputed) proposal that penicillin's molecular structure—the β-lactam ring—consisted of a cyclic formation containing three carbon atoms and one nitrogen atom.

The bonds that existed between British researchers in this period owed much to Edward Mellanby, secretary of the Medical Research Council. Mellanby was anxious to distribute experience of penicillin research beyond the Oxford group. There were, for example, close links between the Oxford scientists and a group led by the chemist Ian Heilbron at Imperial College, London, and from 1942 the Ministry of Supply became responsible for the drug's production in Britain. Approximately once every six weeks, the ministry held meetings of the ‘penicillin producers' conference’, which brought together suppliers and their academic advisers, including Fleming, Raistrick, and Heilbron. Between 1943 and 1945 research findings—such as Dorothy Crowfoot's mapping of the compound's molecular structure—were kept secret, though confidential reports were published and listed in a post-war volume. Contributions from academics at the universities of Oxford, Cambridge, Manchester, and London (Imperial College), the National Institute of Medical Research, and the London Hospital were reported. Beyond the narrow circle of academic investigators were the British manufacturers who now faced the challenge of manufacturing penicillin. The citric acid manufacturer Kemball Bishop and Co. was among the first commercial producers of the liquor, which was then purified in Oxford. Advances circulated in restricted reports were provided by members of the manufacturers' conference, including teams from British Drug Houses, Boots, Glaxo, ICI, May and Baker, and the Wellcome Foundation Ltd. At ICI, for example, the biochemist William Robert Boon (1911–1994) worked on the production, purification, and crystallization of penicillin.

Recognition and depiction

The first honours awarded for the discovery and development of penicillin were carefully shared between Alexander Fleming and members of the Oxford team. In 1945 the Nobel prize in physiology applied to medicine was awarded jointly to Fleming, Florey, and Chain. Soon afterwards Britain's distinctive scientific networks became a collective ‘we’—linked through national pride, opposition to perceived American duplicity regarding the drug's development, and the emergence of a continuous narrative binding Fleming's work to the achievements made in Oxford by the early 1940s.

As early as spring 1944 the chemical giant ICI planned a documentary to celebrate penicillin's development in the United Kingdom. Part of a larger campaign to ensure the company's continued high profile after the war, this twenty-minute film was contracted to the major British production company Realist Films, and was shot by the Austrian photojournalist Wolfgang Suschitzky. The film drew on the accounts of Fleming and his Oxford counterparts, combining an account of a wounded soldier being treated with the drug with shots of Fleming making his discovery, and Florey and Chain re-enacting their laboratory work. The inclusion of the correct people was carefully managed by the film's participants and Chain specifically requested a shot of Ian Heilbron. Suschitzky was also responsible for the celebrated photograph of four members of the Oxford team (Abraham, Baker, Chain, and Robinson) taken at the university in 1944 (NPG). Through repeated telling, the story of penicillin's discovery and development became a clear narrative, with a limited number of characters, in which British research and manufacturing expertise made mass-produced penicillin a reality. A new version of the film, edited by Trevor Williams, was released in 1947.

As well as being a celebration of British expertise, the story of the discovery of penicillin served as a popular morality tale. For decades after the drug become widely known, in 1944, the subsequent American dominance of its development and production were widely depicted in Britain as a national failure to convert a brilliant discovery into a wealth-producing innovation. There was also considerable resentment at the behaviour of the Americans, who were depicted as having ‘stolen’ the discovery and who now required British companies to pay considerable sums for American manufacturing expertise, often wrongly reported in Britain as licences for American patents on a British discovery.

Despite the efforts of the Nobel Foundation and ICI to recognize the combined achievement of St Mary's, London, and Oxford, in the United States it was Alexander Fleming who received particular recognition. In May 1944 his face appeared on the cover of Time magazine, and, inside, the dour Scots bacteriologist was described as a ‘20th century seer’. The focus achieved by Fleming was a mystery to the Oxford team whose achievements had been the more recent, and, they felt, more important. Ernest Chain blamed Charles Wilson, Lord Moran, dean of the St Mary's Hospital medical school and Winston Churchill's doctor, for seeking to ensure that St Mary's was the principal beneficiary of the coverage. Fleming's biographer Gwyn Macfarlane has suggested that Lord Beaverbrook—the owner of the Daily Express and Evening Standard, a benefactor of St Mary's, and another of Moran's patients—was responsible for his newspaper group's adulation of Fleming. In his briefing to Churchill (March 1944) Moran likewise blamed Florey for giving away Britain's knowledge of penicillin to American scientists.

Accounts prioritizing the contribution of Fleming or the Oxford group competed in the post-war era. Behind the various allegiances of journalists and historians were thinly veiled political visions and models of the scientific process. For some Fleming exemplified the heroic and isolated individual achiever, tragically hindered by the short-sightedness of those around him. Thus the scientist featured as the final great figure in R. J. Unstead's hugely successful children's book People in History (1957), subtitled ‘from Caractacus to Alexander Fleming’, whose cover image—depicting Fleming alongside the explorer Sir Francis Drake—played to the popular notion of the 1950s as a new Elizabethan age of patriotic self-belief and discovery. Even today the memorial plaque at St Mary's Hospital medical school (now a part of Imperial College) acknowledges the work of Fleming alone. Others, however, highlighted the importance of later research and working practices. The author of an article in The Lancet, ‘Penicillin and modern research’ (14 January 1950), for example, argued that it was the Oxford scientists, with their emphasis on teamwork, who better exemplified the modern style of science. The memorial tablet in the commemorative rose garden—opened in June 1953 opposite Magdalen College, Oxford, where Florey had been a student—lists the ten principal members of the university team (Abraham, Chain, Fletcher, Howard and Mary Florey, Gardner, Heatley, Jennings, Orr-Ewing, and Sanders) honoured for discovering the ‘clinical importance of penicillin. For saving life, relief of suffering and inspiration of further research all mankind is in their debt’. Similarly Lorenz Ludovici's 1952 biography of Fleming (‘discoverer of penicillin’) stimulated a counterblast by the left-wing science writer Peter Ritchie Calder, who wrote an opposing account for the New Statesman based on an interview with Ernst Chain (‘The man we would not listen to’, 3 Oct 1953). With advice from Howard Florey the 1951 Festival of Britain balanced its separate coverage of Fleming with an account of the achievements of the Oxford team.

The discoverers and early developers of penicillin left a legacy that extends even beyond the world's most powerful drug. Owing largely to work undertaken in London and Oxford during the late 1920s and the 1930s, post-war expectations of medicine were transformed as the balance between prevention and cure was profoundly altered towards treatment. So too was the debate over the potential of science. In Britain penicillin would likewise conjure up an image of economic opportunities lost as well as therapy found. Yet the British pharmaceutical industry was transformed as a result of the pioneering scientific research in London and Oxford. Several of the companies that became leaders of one of the country's key manufacturing sectors, like ICI and Glaxo, could trace their pre-eminence in pharmaceuticals to their wartime experience of manufacturing penicillin.

ROBERT BUD

Sources  

R. Bud, Penicillin: triumph and tragedy (2007) · K. Brown, Penicillin man: Alexander Fleming and the antibiotic revolution (2004) · E. Lax, The mould in Dr Florey's coat (2004) · R. Bud, ‘Penicillin and the new Elizabethans’, British Journal for the History of Science, 31 (1998), 305–33 · E. Abraham, ‘Chain, Ernst Boris’, Memoirs FRS, 29 (1983), 43–91 · G. Macfarlane, Howard Florey: the making of a great scientist (1979) · R. J. Unstead, People in history: from Caractacus to Alexander Fleming (1957) · R. Calder, ‘The man we would not listen to’, New Statesman, 46 (3 Oct 1953) · L. J. Ludovici, Fleming: discoverer of penicillin (1952) · H. T. Clarke, J. R. Johnson, and R. Robinson, eds., The chemistry of penicillin (1949) · H. W. Florey and others, eds., Antibiotics, 2 vols. (1949) · C. Thom, ‘Mycology presents penicillin’, Mycologia, 37 (1945), 460–75 · ‘20th century seer’, Time (15 May 1944), 61–8


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