On Tuesday 29 May 2018, the Oxford Blue Plaque Society unveiled two plaques in Oxford commemorating penicillin, one on the Western wall of the South wing of Oxford’s Radcliffe Infirmary, currently occupied by the Nuffield Department of Primary Care Health Sciences, and one on the front (Southern) wall of the William Dunn School. Here Jeff Aronson notices these, two other plaques, and a memorial stone, reflects on the long history of penicillin, and includes personal memories about some of those who were involved in the Oxford work.
To the general public Alexander Fleming ranks high among famous 20th Century scientists, although public understanding of what he did is sketchy. For instance, on University Challenge, introducing a team from Imperial, Jeremy Paxman described Fleming as “the inventor of penicillin”, underlining how deep misunderstanding can go. Fleming didn’t invent penicillin; he observed the antibacterial action of a Penicillium mould. He did, however, invent the name “penicillin”, using it to describe “the filtrate of a broth culture of the particular penicillium with which we are concerned.”
Other major players in the penicillin story are publicly less well known – Howard Florey, Ernst Chain, and Norman Heatley – and others less still – Edward (EP) Abraham, AD Gardner, Charles Fletcher, Margaret Jennings, J Orr-Ewing, Alastair Robb-Smith, AG Sanders, Leslie Witts. All of them are now dead. I met four of them.
Penicillin before Fleming
Penicillin has a striking prehistory, antedating Fleming. According to Selwyn, one species of Penicillium was first isolated in 1911 from its growth on hyssop, whose therapeutic efficacy is described in the Bible (Psalm 51:7). The Aztecs have been said to have cultivated Penicillium mould on bread, extracted the active ingredient, and taken it for medicinal purposes. In his Boke of Children of 1545 Thomas Phayre recommended “the musherom that groweth upon an elder [to treat] quinsy and swellyng under the eares”. Penicillium perhaps?
In a 1949 review Florey gave several examples of the use of these types of fungi as topical applications for superficial infections. For example, he quoted Cranch, who in 1943 suggested that "The Mosse upon dead mens Sculles.., which cureth wounds", mentioned by John Parkinson in his Theatrum Botanicum of 1640, was a Penicillium. Florey also quoted information from several correspondents that folkloric use of moulds for the treatment of wounds was common in places as far apart as Brazil and the Ukraine, San Jose and Yugoslavia.
In 1883 John Burdon Sanderson, Medical Officer of Health for the London Borough of Paddington, later Waynflete Professor of Physiology and then Regius Professor of Medicine in Oxford, observed that Penicillium inhibited the growth of bacteria in a solution and prevented the overgrowth and rapid putrefaction that would otherwise have occurred in a guinea-pig’s exposed thigh muscle. A year later Joseph Lister confirmed Sanderson's findings and used Penicillium to treat a deep-seated gluteal abscess, although he never published the results of this clinical experiment. The inhibitory effect of Penicillium on bacterial growth was later confirmed by William Roberts, Professor of Medicine in Manchester, by John Tyndall, and by Thomas Henry Huxley.
The inhibitory effect of Penicillium species on bacterial growth was subsequently rediscovered on several occasions by a variety of investigators, including Gosio in Italy in 1896, Duchesne in France in 1897, and Tartakovskii in 1904, and by Lieske in Germany in 1921 and Gratia and Dath in Belgium in 1924.
However, most of these workers did not investigate the potential therapeutic value of Penicillium. Tyndall, for example, seems to have regarded the effect of the Penicillium mould as a struggle with bacteria for the fitness to survive, and he believed that the action of the Penicillium was brought about by covering bacteria completely, depriving them of oxygen, a view that Huxley disputed. Despite all this, Penicillium moulds do seem to have been used in the treatment of infections before Fleming. I have quoted the example of Lister above, and Jaumain was reported by Gratia as having treated a patient with furuncles “by a series of injections of the mycolysat” [Gratia's name for his extract of Penicillium], although this presumably meant injection directly into the furuncles rather than parenterally.
In 1929 Fleming observed that bacteria failed to grow in a culture contaminated with a Penicillium mould. He concluded that Penicillium contained a bactericidal compound. He then used a broth of Penicillium to treat a chronic infection of a colleague’s nasal antrum, without success, but in 1932 successfully treated pneumococcal conjunctivitis in a medical student at St Mary's Hospital. Meanwhile, in 1930, a Sheffield physician, Dr CG Paine, successfully used a crude filtrate from a Penicillium broth in four babies with gonococcal conjunctivitis.
Penicillin in Oxford
In 1935 Ernst Chain, one of “Hitler’s gifts” to the UK, having left Germany in 1933, arrived in Oxford to work under Howard Florey, Professor in the Sir William Dunn School of Pathology. Chain suggested trying to purify the active antibiotic principle from a species of Penicillium. Florey assigned Norman Heatley to be Chain’s technician. As Henry Harris, Florey’s successor in the same department, commented in the Florey Centenary Lecture, delivered at the Sir William Dunn School on 29 September 1998, “without Fleming, no Chain or Florey; without Florey, no Heatley; without Heatley, no penicillin.” Heatley realised that penicillin was destroyed by acid, extracted it in alkali, and successfully purified it. So, without Heatley, no Nobel prize awarded to Fleming, Florey and Chain in 1945.
Heatley was a dapper man, charming, modest, and always (when I met him) immaculately dressed. His laboratory notebooks were written in perfect copperplate. In 1990, the 50th anniversary of the first Oxford paper on penicillin, I suggested to the then Vice-Chancellor of Oxford University, Richard Southwood, that Heatley’s achievement should be celebrated by the award of an honorary degree. He agreed enthusiastically. I consulted Henry Harris. He was supportive, but “don’t let them palm him off with an MA”, the typical long-service reward for technicians (so-called academic-related staff) on retirement. I thought that it might be hard to persuade the Honorary Degrees Committee, of which I was a member, to award Heatley the higher honorary degree of DSc. I consulted Southwood again. He recalled that a few years earlier John Potter, a neurosurgeon whom I knew professionally, had persuaded the University to introduce the degree of honorary DM, which had not yet been used. I proposed the honour and the committee recommended it. Norman was delighted and received his honorary DM degree, the first to do so in modern times, in June 1990. Today the Royal Society of Chemistry has an annual Norman Heatley Award and Oxford’s Dunn School holds an annual Norman Heatley Lecture. A blue plaque commemorating Heatley was unveiled at 12 Oxford Road, Old Marston on 17 July 2010.
I met Charles Fletcher in 1991, when we invited him to Oxford to take part in the 50th anniversary celebrations of the first successful intravenous administration of penicillin. In 1941 Florey approached the Professor of Medicine in the Radcliffe Infirmary, Leslie Witts, to tell him that they had isolated an active principle from Penicillium and had tested it in animal infections. Fletcher, a junior doctor, happened to knock on Witts’s door when Florey was there, and Witts suggested that Fletcher should give some of his patients intravenous penicillin as a research project. Fletcher did so. A woman with an inoperable cancer agreed to be a preliminary test subject on 17 January; Fletcher gave her 100 mg of penicillin and an hour and a half later she developed a fever and a rigor, attributed to impurities in the preparation, although one cannot rule out an allergic reaction to the penicillin itself. The Dunn School team tried again. On 12 February Fletcher used a purer preparation, giving it to an Oxford policeman, Albert Alexander, who had multiple abscesses that had failed to respond to sulfapyridine. Fletcher reported that it was “the nearest I ever came to seeing a miracle”, but supplies ran out and the patient relapsed and died. Later patients were luckier.
The first use of penicillin in the Radcliffe Infirmary is commemorated in a plaque that hangs in the entrance hall of the main part of the Radcliffe Infirmary. The word “systematic” is not necessarily an error; the word has occasionally, albeit rarely, been used to mean systemic, the word that we would now use, and the Oxford English Dictionary lists examples from the 19th, 20th, and even the 21st centuries.
Fletcher was as gentlemanly and urbane as his persona as The Television Doctor in the 1950s had suggested, and I was keen to talk to him about his career and colleagues, some of whom I had known. His autobiography, Pioneering Physician (“as told to [the late] Max Blythe”), begun in 1991 but published only in 2016, confirms what I remember. Fletcher begins “I had fortunate origins”. He did indeed. His grandmother was a cousin of Herbert Asquith. His father was Walter Morley Fletcher, the first Secretary (we would now say CEO) of the Medical Research Council. The writer MR James was his godfather. And Fletcher received instruction from many eminent physicians: his father, of course, and Witts, but also Douglas Black, later President of the Royal College of Physicians, and Alec Cooke, who established the Oxford Medical School in the 1940s and whose memoirs were characteristically titled “My First 75 Years of Medicine”. Cooke came under my care when, in his early 90s, he was admitted to the John Radcliffe Hospital with a relatively minor illness (he lived to be 99). He was the most testing patient I ever had, bang up to date with the latest medical developments. I had to be on my toes to answer his probing questions.
I also met Edward Abraham in 1991, but spoke to him only briefly; after penicillin he went on to develop the cephalosporins. I met Alastair Robb-Smith when I was one of the physicians who looked after him in 2000 during his final illness, about which he was resigned and stoical. He was the pathologist who performed the post-mortem examinations on the patients who had received penicillin in 1941 and had succumbed to their infections when supplies of the medicine ran out or through complications of their primary illnesses.
I never met the other contributors to the 1941 Lancet paper describing the first clinical use of penicillin. In addition to Florey himself and Ernst Chain, they included AD Gardner, Director of the Medical Research Council's Standards Laboratory, which was situated in the Dunn School, and MA (Margaret) Jennings. Gardner contributed the in vitro work on the sensitivities of organisms to penicillin. Jennings was Florey's assistant, and her main contribution was to experiments on the disposition of penicillin in animals and man. Her working association with Florey lasted for the rest of his life and she became the second Lady Florey in 1967.
A stone memorial in the Rose Garden outside Oxford’s Botanic Garden, between Danby Arch and the High Street, celebrating the discovery of penicillin, was funded by New York's Albert and Mary Lasker Foundation in June 1953. The garden was designed by Dame Sylvia Crowe (1901–1997) for Magdalen College, on whose land the garden stands.
In a letter to Edward Mellanby at the Medical Research Council in 1944, Florey wrote “[No-one] should suppose that we have performed any great intellectual feats here. All we did was to do some decent experiments and have the luck to hit on a substance with astonishing properties.” In my encounters with them, Norman Heatley, Charles Fletcher, and Alistair Robb-Smith all similarly modestly downplayed their own roles in the penicillin story, but each, along with Fleming, Florey, Chain, and the others, deserves to be remembered for his contribution.
Postscript: Two more plaques
In 2014 a hexagonal Royal Society of Chemistry blue plaque commemorating Dorothy Hodgkin’s Nobel prize-winning work in crystallography was mounted on the wall of Oxford’s Inorganic Chemistry Laboratory in South Parks Road. It is in the middle of three similar plaques, the other two being devoted to discoveries related to blood glucose sensors and rechargeable lithium-ion batteries. Her work included determining the chemical structures of penicillin, insulin, and vitamin B12. There is also a conventional blue plaque on the wall of her house at 94 Woodstock Road.
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