[BITList] The first successful medical use of penicillin

[John Feltham]

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Fleming, Sir  Alexander  (1881-1955), bacteriologist and discoverer of penicillin, was born on 6 August 1881, the third of the four children of Hugh Fleming (d. 1888), farmer, of Lochfield, in the parish of Loudoun near Darvel, in Ayrshire, from his second marriage, to Grace Sterling Morton (d. 1928), the daughter of a neighbouring farmer. Hugh Fleming, whose ancestors probably came from the Low Countries, had four surviving children from his first marriage. He was sixty at the time of his second marriage, and died when Alexander (known as Alec) was seven.

Education and career

Alec Fleming's early education was in a small country school at Loudoun Moor, then at Darvel School, and finally for eighteen months at Kilmarnock Academy. At fourteen Alec and his two brothers of the second marriage went to live with a doctor stepbrother in London, where he continued his education for two years at the Polytechnic Institute in Regent Street. The next four years were spent as a clerk in a shipping office in the City, but on the advice of his stepbrother, and with the help of a small legacy, Alec Fleming became a student at St Mary's Hospital medical school, London, in 1901. He won the senior entrance scholarship in natural science, and many other class prizes and scholarships during his student career. He took the conjoint qualification in 1906, and the degrees of MB, BS of London University in 1908, with honours in five subjects and a university gold medal. A year later he became FRCS, having taken the primary examination as a student, though he never practised as a surgeon. With a very good memory, learning was seldom a burden. However, his life was never all work and no play; both as an undergraduate and as a postgraduate he was an active and proficient member of the swimming, shooting, and golf clubs, and even took some part in the drama society. Fleming had a natural combativeness and urge to win which were very apparent in the games he played. This determination to succeed was also evident in his medical and laboratory work, where he took delight in using his technical skill and inventiveness to overcome difficulties.

Immediately after qualification, like many of his St Mary's contemporaries, Fleming became an assistant bacteriologist. He joined the inoculation department and began the association with its head, Almroth Wright, which was to shape his whole career. Fleming also held for some years the post of pathologist to the London Lock Hospital. He worked with Wright in London and then in France during the First World War, and in 1920 he became lecturer in bacteriology in St Mary's medical school. Eight years later he was made professor of bacteriology in the University of London. He remained in the inoculation department, which eventually became the Wright-Fleming Institute of Microbiology, until he retired in 1948. He was made principal of the institute from 1946 to 1948, and remained an emeritus professor until 1954. Until 1942 Fleming was an accomplished metropolitan laboratory scientist whose career had been in the shadow of Wright. Then, at the age of sixty-one, he became an international celebrity because of his association with the development of penicillin. Over the next decade he was feted across the world and received 189 honours, medals, decorations, and prizes, including sharing the Nobel prize for physiology and medicine with Ernst Chain and Howard Florey in 1945. While Fleming's name became synonymous with penicillin and the antibiotic revolution of the late 1940s and early 1950s, later assessments have given more weight to the work of other scientists, most notably Chain and Florey, and to the teams in the United States that produced penicillin on an industrial scale. There is also a fascination with what Fleming himself called the Fleming myth, that is, why and how a single scientist was ever made responsible for the discovery of penicillin, and how a reserved hospital bacteriologist became an international celebrity.

Laboratory medicine at St Mary's

During his early postgraduate years at St Mary's, Fleming was research assistant to Almroth Wright, whose dominant character and fertile brain directed the general research of the inoculation department for many years. From the beginning the hallmark of Fleming's work was his technical ingenuity, especially his ability to devise apparatus of all types for tackling laboratory problems. His first published medical work, 'Acute bacterial infections', was published in St Mary's Hospital Gazette. This won him the Cheadle gold medal and led him to become an expert on skin infections, especially acne. About this time Paul Ehrlich, a leading German medical scientist, introduced chemotherapy for the treatment of syphilis. His drug was called Salvarsan and Fleming made a typical contribution by devising a simple micro-method for the serological diagnosis of this disease.

Soon after the outbreak of the First World War Wright was invited by the Medical Research Committee (later the Medical Research Council) to establish a laboratory in Boulogne to study the treatment of war wounds. Fleming, who had joined the Royal Army Medical Corps as a lieutenant (later he became a captain), was an important member of Wright's group. They worked on the bacteriology and treatment of septic wounds, showing the importance of Streptococcus pyogenes in wound infection and blood poisoning. Fleming advanced the view that the severity of wound infection was related to the presence of necrotic tissue in the wound and advocated early removal of this dead tissue. At the same time another Scot, Sir Henry Gray, had independently introduced surgical debridement to promote healing. Later, with A. B. Porteous, Fleming showed that most streptococcal infections usually occurred after the patient was admitted to the base hospital, indicating the importance of controlling hospital cross-infection. He also made a significant contribution to the knowledge of gas gangrene. Inevitably Fleming sided with Wright in the bitter public controversy over the treatment of war wounds, as their unfashionable advocacy of physiological methods (irrigating wounds with saline) went against mainstream opinion, which was in favour of antiseptic principles. On 23 December 1915 Fleming married Sarah (Sareen) Marion (1879/80-1949), daughter of a farmer, Bernard McElroy, of co. Mayo, Ireland, and herself a trained nurse. There was one son, who qualified in medicine and entered general practice.

Back at St Mary's after the war, Fleming discovered and named 'lysozyme', an anti-microbial substance produced by many tissues and secretions of the body, particularly in nasal mucus. He later suggested that lysozyme was his most important discovery, as it opened up the study of antibacterial substances that led to the discovery of the powers of penicillin and other chemotherapeutic agents. With V. D. Allison he showed its wide distribution in nature, its enzymic quality and remarkable stability, and the interesting phenomenon of the development of bacterial resistance to its action. He also developed new experimental techniques to demonstrate the diffusibility of lysozyme, which later proved useful in his studies of penicillin. Wright was encouraged by this work to propose Fleming for a fellowship of the Royal Society, though his nomination was unsuccessful. Fleming's own work on lysozyme continued for many years, but was limited by the chemical expertise available and his assumption, in line with Wright's immunological doctrines, that it was part of the body's complex immune system.

Fleming was generally acclaimed as the most skilled bench-worker among Wright's numerous colleagues and followers. He was his own technician to the end and was admired for his deft handling of glass slides and capillary pipettes. He was keenly interested in staining methods, and when Indian ink became unavailable after 1918 he introduced nigrosin in negative staining methods for demonstrating spores and capsules. He was probably the first to grow bacteria and moulds on paper or cellophane placed on top of nutrient agar, and he demonstrated the suitability of paper for bringing out the pigment of chromogenic bacteria. He left an interesting collection of 'coloured pictures', composed entirely of bacterial cultures, which he was fond of showing to royalty and other visitors to St Mary's.

Penicillin and other work

In September 1928 Fleming made the world-famous observation of a mould inhibiting the growth of bacteria, which has been seen as the beginning of the antibiotic era in the treatment of infections. Fleming was studying colony variation in the staphylococcus, the germ that causes septic infections, for a chapter he was writing for the System of Bacteriology. On his return from a holiday he noticed on a discarded plate culture that the micro-organism was absent from an area around a contaminating mould. The contaminant was Penicillium notatum, a common mould found across the world. Fleming was more interested in the phenomenon than were his colleagues, not least because of its possible similarities with the action of lysozymes. He presumed that the contamination was accidental and that the mould had entered his laboratory through an open window. He worked with the mould and its 'juice' for the next six months, in the first instance determining the number of pathogenic germs that were affected. This turned out to be quite high and he hoped that he had found a natural antiseptic that was non-toxic to humans. He set two graduates to work out the chemistry of the active substance, while he explored bacteriological and clinical problems. His hopes that he had found a clinically useful natural antiseptic were not fulfilled. One problem was that the action of the mould juice was slow-it is now known that penicillin acts by affecting the formation of cell walls in developing bacteria rather than killing adult forms. Also, in animal experiments, Fleming had difficulties in maintaining high enough concentrations around infected areas before the juice lost potency or was excreted. This work suggested that penicillin had little potential as a systemic antibacterial, but would be of limited value in the treatment of local infections. Indeed, in his first recorded clinical trial with penicillin, Fleming irrigated an infected surgical wound, using methods similar to those developed by Wright in the First World War. Fleming first spoke on this work to the Medical Research Club on 13 February 1929, and submitted his first paper to the British Journal of Experimental Pathology on 10 May. It appeared a month later. The conclusions of this paper make it clear that Fleming regarded penicillin as a new natural antiseptic, whose main properties were its effects on septic and pneumonia germs. Its great advantage was that it did not interfere with white blood cell function, which Wright and his group thought was all-important in natural immunity. Fleming also discussed the use of penicillin in bacteriological laboratories, where he used it in culture media to prevent the growth of unwanted organisms. The paper was not received as being epoch-making at the time; it was cast within the tradition of Fleming's previous work on lysozyme, Wright's notions of immunity, general scepticism towards the use of antiseptics in anything other than local infections, and innovations in bacteriological techniques.

There has been much debate on why the therapeutic potential of penicillin was not recognized in 1929. Some early biographers, perhaps influenced by the Fleming myth, claimed that Fleming immediately saw the value of his mould juice and was prevented from developing it owing to a lack of support and the antagonism of colleagues. However, it now seems that Sir Henry Dale was correct when he wrote that 'neither the time when the discovery was made nor, perhaps, the scientific atmosphere of the laboratory in which he worked, was propitious to such further enterprise as its development would have needed'  (DNB). Through the 1930s Fleming used penicillin in a small number of cases as a local antiseptic and as a laboratory reagent for selective culturing, as did a number of other clinicians. In 1931 he wrote a sceptical review on the value of intravenous germicides and, very significantly, chose not to mention penicillin in this context. However, in the late 1930s, when Chain and Florey began to test antibacterial substances, they used a culture of Fleming's mould that had been maintained at Oxford since 1929. By then, Fleming was preoccupied with other projects. One of his main tasks during the whole inter-war period was to oversee the production of therapeutic vaccines in the St Mary's laboratory, which were the source of most of its income. Its clinical and research programme was dominated by a commitment to exploiting natural immunity in the treatment of infections. Fleming continued to advocate and use vaccine therapy, which was controversial and mistrusted by many doctors. His continuing support of Wright's doctrines was typical of his constancy and loyalty to his friends and colleagues, to the inoculation department, to St Mary's, and to its staff and students.

The pivotal position of the St Mary's department in the treatment of infections in Britain was shown in 1936 when its staff, including Fleming, were pioneers in the assessment of the value of the new sulphonamide range of antibacterial chemicals. The initial expectation was that these would turn out to be another overrated product from the German chemical industry. However, Leonard Colebrook, formerly at St Mary's, had spectacular success at Queen Charlotte's Hospital with sulphonamides in the treatment of puerperal fever. The drug was also effective in pneumonia, and Fleming published on this in 1938, demonstrating his technical skill and ingenuity in devising micro-methods for measuring the concentration of these drugs in patients' blood. However, his overall assessment in 1939 was that the treatment of choice was a combination therapy of sulphonamides and vaccines.

The antibiotic revolution and the Fleming myth

In 1938 and 1939 the Oxford group working on germicides began to home in on penicillin. The first experiments with intravenous injections of penicillin on infected mice began in May 1940, with their very promising results published in August. Fleming visited Oxford to catch up with the work in September, seemingly curious about the applications being made with 'his juice'. A year later, after publication of the results of the first extremely promising clinical trials, Fleming first made public his proprietorial claims to penicillin. He crossed swords in print with the Oxford group, claiming that as well as having discovered the antibacterial properties of the substance he had recognized its potential as a systemic antibacterial drug. This contretemps in the medical press brought media attention to penicillin, which was presented initially as an accidental discovery by Fleming that had been applied by a team of researchers at Oxford. Over the next twelve months work on penicillin continued at Oxford and the government began to take an interest in developing large-scale production. Soon the United States government, as well as universities and pharmaceutical companies, became involved. While relations between Fleming and the Oxford group were not cordial, they did not prevent Fleming's obtaining enough penicillin in August 1942 to treat a case, an employee of his brother's optical firm, who subsequently recovered from severe septicaemia.

Over the summer of 1942 press reports about penicillin and its powers increased in number. The differences between Fleming, and Chain and Florey-St Mary's and Oxford-continued to simmer below the surface. However, on 31 August differences became public when a letter from Wright was published in The Times. Never one to shirk controversy or hold back in promoting his St Mary's department, Wright claimed priority for Fleming as both the discoverer of penicillin and for recognizing its value in antibacterial therapy. The following day, a letter from Sir Robert Robinson, professor of chemistry at Oxford, was published, stating that if Fleming deserved a 'laurel wreath' for penicillin, then Howard Florey should be given a 'handsome bouquet'. The press descended on both St Mary's and Oxford, but found Fleming more accommodating, and his role in the penicillin story came to dominate. The therapy attracted press attention as it promised good news at a time when the war situation was uncertain. Fleming's life, with his humble background and long road to success, made a romantic story. Moreover, the idea of the mould blowing through a window by chance and the discovery by a lone, self-effacing scientist matched contemporary notions of scientific discovery and national pride. The alternative story of a group of researchers, led by an Australian and a German Jew, working on a planned programme of state-funded work, did not strike the same chords. In the post-war years penicillin became much more than an antibacterial drug. It stood as an icon for post-war reconstruction, improving welfare, and modernization. It was often included, with nuclear power and the jet engine, as one of the science-based technologies of tomorrow's world. There was a peculiarly British slant to this picture, which was cast around the notion that the Americans who developed the drug industrially had 'stolen' a British invention.

The high profile given to penicillin changed Fleming's standing in science and medicine. On 18 March 1943 he was elected a fellow of the Royal Society, a position he had sought for some twenty years. In 1944 he was made a fellow of the Royal College of Physicians and knighted, and in October 1945 he received with Florey and Chain the Nobel prize for physiology and medicine. Publicly, Fleming and Florey shared the credit for the revolutionary antibiotic drug, even appearing on the same platform at scientific meetings. However, tensions remained and were not eased when Fleming, who was almost at retirement age, toured the world as a modern hero, while the younger Florey returned to his laboratory. On Wright's retirement in 1946, Fleming became head of the newly named Wright-Fleming Institute, but he was more often than not away receiving many and varied accolades. He travelled widely in Europe and through the Americas, north and south, as further prizes were awarded, honorary degrees by the dozen were conferred, statues were unveiled, freedom of cities granted, and streets named in his honour. Among the most notable awards were: commander of the Legion d'honneur in France, member of the Pontifical Academy of Sciences, election as rector of the University of Edinburgh (1951-4), convocation member of the senate of the University of London from 1950, member of the Medical Research Council (1945-9), and president of the Society for General Microbiology (1945-7). Besides becoming an honorary citizen of numerous cities in Europe he was a freeman of the burgh of Darvel, where he was born, and of the London boroughs of Chelsea, where he lived, and of Paddington, where his work was done. In October 1949 Fleming's wife, Sareen, died. In the succeeding years Fleming continued to travel, becoming close to Amalia Vourekas, nee Coutsouris (b. 1912/13), daughter of Harilaos Coutsouris, a physician. She was a medically qualified bacteriologist who had joined the institute in 1946. They eventually married on 9 April 1953. Fleming died suddenly from a heart attack at his home in Danvers Street, Chelsea, on 11 March 1955, in the middle of a busy schedule. He was cremated and his ashes interred in London in St Paul's Cathedral a week later.

The man and his achievements

Physically, Fleming was short and stockily built with powerful square shoulders and a deep chest, a fresh-complexioned face with a fine broad forehead, intensely light blue expressive eyes, and for many years a good crop of snowy white hair. He had great powers of physical endurance and in the days when burning the midnight oil was a regular occurrence in the inoculation department, Fleming was always the first to appear, fresh and fit, the following morning. Later he seemed to stand up astonishingly well to the heavy journeyings and junketings he had to undergo, and he kept his freshness and jaunty step to the end. He was sensitive and sympathetic, enjoyed the simple things in life, and remained humble despite all the honours which were showered upon him. He was not an easy man to know well, partly because of his natural reluctance to talk and to express his feelings. He was not a conversationalist and awkward silences were sometimes broken by awkward remarks: as one visitor put it, talking with him was like playing tennis with a man who, whenever you knocked the ball over to his side, put it in his pocket. But this was shyness, not intentional rudeness, for he liked company and had many friends in various walks of life before he became famous. He was reserved with strangers, but very sociable in familiar company. A regular at the Chelsea Arts Club for many years, Fleming was also a freemason, rising to be a grand warden.

Sir Alexander Fleming remains one of the best-known British scientists of the twentieth century. He became important for two reasons: first, his role in the development of modern antibiotics, and second, his place as an iconic British scientist. The catalogue of Fleming's published work leaves little room for doubt that he had to an unusual degree an almost intuitive faculty for original observation coupled with a high degree of technical inventiveness and skill. He made significant contributions to medical research in several fields, but until the penicillin story broke in 1942 his peers did not regard his work highly enough to seal his reputation with election to the Royal Society. At St Mary's he was a pivotal figure in Wright's department, the influence of which was felt across the hospital and in medical science and clinical practice across the country. However, there is little doubt that Florey and Chain would have developed penicillin without Fleming's work in the period 1928-32. While not well known, its antibacterial properties had been noticed by other medical scientists and used clinically. Nevertheless, Fleming's work did aid the Oxford group. It enabled them to move more quickly and encouraged them to pursue specific lines of enquiry. Thus it was entirely appropriate that Chain, Fleming, and Florey shared the Nobel prize in 1945. Those who could have felt cheated by the award were the American workers who had made many breakthroughs in scaling up production, but then the Nobel prize itself, and science more widely, have tended to value pure research more highly than applied research, and both are held in much higher esteem than experimental development. Indeed, the Fleming myth, of a lone scientist making a chance discovery that allowed infectious diseases to be conquered, was an unhelpful representation of the scientific enterprise in the post-1945 world of 'big science'. Team work, organized research programmes, private and public research and development funding, and the growing economic importance of experimental development, would all feature in an accurate account of the development of penicillin. Ironically, these were all characteristics of Fleming's main career in the inoculation department at St Mary's in the thirty-five years before penicillin entered the public domain.

Michael Worboys 

Sources  G. Macfarlane, Alexander Fleming: the man and the myth (1984) + DNB + R. Bud, 'Penicillin and the new Elizabethans', British Journal for the History of Science, 31 (1998), 305-33 + L. Colebrook, Memoirs FRS, 2 (1956), 117-27 + A. Maurois, The life of Sir Alexander Fleming (1959) + R. Hare, The birth of penicillin and the disarming of microbes (1970) + M. Weatherall, In search of a cure: a history of pharmaceutical industry (1990) + R. Hare, 'The scientific activities of Alexander Fleming, other than the discovery of penicillin', Medical History, 27 (1983), 347-72 + L. J. Ludovici, Fleming: discoverer of penicillin (1952) + R. W. Clark, The life of Ernst Chain: penicillin and beyond (1985) + G. Macfarlane, Howard Florey: the making of a great scientist (1979) + H. Swan, 'Mouldy case-notes and penicillin: a re-appraisal of Fleming's role', Proceedings of the Scottish Society of the History of Medicine (1988-90), 1-8 + J. Liebenau, 'The British success with penicillin', Social Studies of Science, 17 (1987), 69-86 + M. Wainwright, Miracle cure: the story of penicillin and the golden age of antibiotics (1990) + b. cert. + m. certs. + d. cert.
Archives BL, corresp. and papers, Add. MSS 56106-56225 + Medical Research Council, London, MSS + NRA, priv. coll. + St Mary's Hospital, London, Alexander Fleming Laboratory Museum, MSS + St Mary's Hospital, London, St Mary's Hospital Archives, MSS FILM BFINA SOUND BL NSA
Likenesses  photographs, 1940-c.1955, Hult. Arch. · W. Stoneman, photograph, 1943, NPG · H. M. Campbell, pencil drawing, 1944, NPG · J. A. Grant, lithograph, 1944, NPG · E. J. Clark, bronze bust, c.1946, St Mary's Hospital, London, Wright-Fleming Institute · E. R. Bevan, bronze head, 1948, St Mary's Hospital, London, Wright-Fleming Institute · E. R. Bevan, bronze head, 1948, Scot. NPG · T. C. Dugdale, oils, c.1949, St Mary's Hospital, London, Wright-Fleming Institute · H. Coster, photographs, 1954, NPG [see illus.] · Y. Karsh, bromide print, 1954, NPG · F. Kovacs, bronze bust, c.1955, RCP Lond. · F. Kovacs, bronze medallion, 1955, NPG · P. N. Cardew, photographs, St Mary's Hospital, London, department of audio visual communication · E. Gabain, oils, IWM · A. Zinkeisen, portrait, St Mary's Hospital, London
Wealth at death  £29,321 10s. 9d.: probate, 21 June 1955, CGPLA Eng. & Wales



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