Wartime Mass Production and the Antibiotic Era

By the summer of 1941 Howard Florey’s team at the Sir William Dunn School of Pathology in Oxford had shown that penicillin, the substance made by Alexander Fleming’s Penicillium mould, could cure infections that were otherwise fatal. They had also shown how little of it they could make. The Oxford laboratory grew the mould on the surface of broth in flasks, bedpans and ceramic vessels, and a single seriously ill patient could use up weeks of its output. Turning a laboratory success into a medicine for millions of people needed something Oxford did not have: industrial fermentation on a vast scale, in the middle of a world war.

This page follows penicillin after Oxford. It begins with the reasons British industry could not take on the work in wartime and with Florey and Norman Heatley’s journey to the United States in July 1941. It then describes the government laboratory in Peoria, Illinois, where corn steep liquor and deep-tank fermentation transformed yields, and the wartime collaborative of firms, universities and government agencies that Roswell Quinn has studied from the US government archives. It covers supply to the Allied armed forces, release to civilians in March 1945, the Nobel Prize of that year and the question of patents, Ernst Chain’s post-war work in Rome on the penicillin “nucleus” that opened the way to semisynthetic penicillins, the early appearance of resistance, and how the story of penicillin came to be told. The Oxford laboratory work itself, the lives of the two men and the science of the mould are covered on the other pages of this wing.

Table of Contents

  1. Why Britain Could Not Make Enough
  2. The Flight to America, July 1941
  3. Peoria: Corn Steep Liquor and Deep Tanks
  4. A Wartime Collaborative of Firms, Universities and Government
  5. Penicillin Reaches the Armed Forces
  6. March 1945: Penicillin for Civilians
  7. The 1945 Nobel Prize and the Question of Patents
  8. The Penicillin Nucleus and Semisynthetic Penicillins
  9. Resistance Appears Early
  10. Myth and Memory: Who Made Penicillin
  11. Key Research Papers
  12. Connections

1. Why Britain Could Not Make Enough

The Oxford results of 1940 and 1941 left no doubt that penicillin worked. The first report, “Penicillin as a chemotherapeutic agent”, appeared in the Lancet in August 1940 and described infected mice protected by the drug; the second, “Further observations on penicillin”, appeared in August 1941 and described the first human patients. The difficulty was quantity. The mould grew only where it met air, so at Oxford it was cultured as a felt floating on shallow broth, and each vessel yielded a tiny amount of a fragile substance that had to be extracted, purified and assayed by hand.

Florey hoped that British pharmaceutical manufacturers would take the process over. According to the Science History Institute’s account, only one British firm initially took up the challenge; the Australian Dictionary of Biography, in its entry on Florey, describes British industry’s response as having “proved inadequate to the task”. The reasons were those of a country at war. Factories, chemists and engineers were committed to war production, Britain was under air attack, and industrial fermentation of a delicate mould on the scale needed was untried anywhere. For a time the Dunn School went on making the penicillin for its own clinical trials in what the Australian Dictionary of Biography calls “‘Heath Robinson’ contraptions”.

The first patients made the problem plain. When the police constable Albert Alexander was treated at the Radcliffe Infirmary in February and March 1941, the team recovered penicillin from his urine to give it again, and the supply still ran out before the infection was beaten. (That episode is told in detail on the Oxford Penicillin Work page.) Florey concluded that large-scale production would have to be sought abroad.

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2. The Flight to America, July 1941

At the beginning of July 1941 Florey and Norman Heatley flew to the United States, which had not yet entered the war. Heatley was the Oxford biochemist who had designed much of the team’s extraction apparatus and its method of measuring penicillin; he knew the practical side of the process better than anyone.

In the United States they were directed to the Northern Regional Research Laboratory (NRRL) of the US Department of Agriculture at Peoria, Illinois. The laboratory’s fermentation work was aimed at finding new uses for farm products and by-products, which made it a natural home for the problem of growing a mould in quantity. Florey also had an important connection in Washington. Alfred Newton Richards, the University of Pennsylvania pharmacologist in whose laboratory Florey had worked as a young Rockefeller fellow in the 1920s, now chaired the Committee on Medical Research of the Office of Scientific Research and Development (OSRD), the federal body that organised wartime science. Richards backed the penicillin effort, and the committee became one of its main organisers.

Florey spent the summer seeking support for production and returned to Britain in mid-September 1941. Heatley stayed behind. He worked at Peoria on the first American cultures and afterwards spent time helping an American company scale up its own production. In this way the practical know-how of the Oxford team crossed the Atlantic in the person of one biochemist.

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3. Peoria: Corn Steep Liquor and Deep Tanks

The Peoria laboratory made two changes that, more than anything else, turned penicillin from a scarce substance into a mass-produced drug. Both came out of the laboratory’s background in agricultural fermentation.

Corn steep liquor

The first change was the food the mould was given. Andrew Moyer, a Peoria microbiologist, worked on improving the growth medium. A key ingredient turned out to be corn steep liquor, the concentrated liquid left over when corn kernels are soaked during the wet-milling of maize for starch. It was a cheap by-product of the Midwest’s corn industry and was available in large quantities near Peoria. Added to the broth, it raised penicillin yields enormously; Robert Gaynes, writing in Emerging Infectious Diseases in 2017, reports that Moyer suggested it when an ingredient of the Oxford medium was unavailable, and that with it the investigators produced far greater amounts of penicillin than the Oxford team had ever made. In a sense the medicine that came out of the war was the product of two natural materials working together: a common mould and the soaking water of corn.

Better moulds

The Peoria team also searched for strains of Penicillium that made more penicillin than Fleming’s. Kenneth Raper and colleagues published a study of the natural variation in penicillin production among Penicillium notatum and related species in 1944. Gaynes reports that a strain of Penicillium chrysogenum from a mouldy cantaloupe produced six times as much penicillin as Fleming’s strain. (The mould itself, and the popular story of how the cantaloupe was found, are discussed on the Penicillium Mould page.)

From surface culture to deep tanks

The second change was the way the mould was grown. At Oxford it floated on the surface of broth in thousands of separate vessels. At Peoria and in industry the work moved to submerged, or “deep-tank”, fermentation, in which the mould grows throughout a large tank of medium that is stirred and has sterile air bubbled through it. Moyer and Robert Coghill described laboratory-scale production of penicillin in submerged cultures in a 1946 paper in the Journal of Bacteriology. A single tank could replace a room full of flasks, and deep-tank fermentation became the basis of all later antibiotic manufacture. The broader history of how deep fermentation spread before and after the war has been traced by the historian Robert Bud, who notes that Chain himself was among those who carried the new fermentation methods forward after 1945.

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4. A Wartime Collaborative of Firms, Universities and Government

After the United States entered the war in December 1941, penicillin became a national priority. Quinn, in a 2013 article in the American Journal of Public Health, describes what grew up as a “penicillin collaborative”: an unusual partnership in which government agencies, universities and private firms shared information that in peacetime would have been kept as trade secrets.

Quinn gives the scale of the effort in figures:

The Science History Institute counts some 35 institutions and thousands of people who took part in the combined British and American effort. Florey summarised the state of the work for British doctors in a 1944 survey of penicillin in the British Medical Journal. Quinn presents the collaborative, with government coordinating and funding the work and firms supplying manufacturing capacity, as a historical case to set beside present-day debates over how new antibiotics are researched and developed.

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5. Penicillin Reaches the Armed Forces

The first priority for the growing supply was the armed forces. Infected wounds had killed vast numbers of soldiers in earlier wars, and the sulfonamide drugs, the first synthetic antibacterials (see the page on Gerhard Domagk and the sulfa drugs), had limits. Penicillin acted against bacteria such as Staphylococcus aureus and streptococci, the organisms behind many wound infections.

Production grew quickly once deep-tank fermentation was in place. Gaynes reports that by September 1943 penicillin supplies were sufficient to meet the demands of the Allied armed forces. Lobanovska and Pilla, in a 2017 review in the Yale Journal of Biology and Medicine, write that by the time of the D-Day landings in June 1944 supplies were sufficient for widespread military use. Popular accounts often quote a specific number of doses prepared for D-Day; that figure does not appear in the sources used for this page and is not repeated here.

Meanwhile, in Britain, Florey’s team and Mary Ethel Florey continued clinical studies of the drug in hospitals, including military hospitals, working out which infections responded and how the drug was best given. Much of this wartime clinical experience went into the two-volume book Antibiotics (1949), of which Florey was a co-author and editor.

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6. March 1945: Penicillin for Civilians

Throughout the war, civilian access to penicillin was tightly limited. Almost the whole supply went to the military, and only small amounts were released for civilian patients. The drug became famous through press reports long before ordinary doctors could obtain it.

As output rose, the controls were relaxed. Quinn records that penicillin reached the American civilian market in March 1945. Within a few years it had become an everyday medicine. For the first time doctors had a reliable treatment for many common bacterial infections, from streptococcal sore throat and pneumonia to syphilis and infected wounds; today the site’s pages on penicillin treatment of Group A strep describe one of its oldest uses that is still current.

The end of the war also opened what is often called the antibiotic era. Penicillin’s success sent researchers around the world looking for other antibacterial substances made by microbes. One of the best-known results was streptomycin, isolated from a soil bacterium in Selman Waksman’s laboratory and the first antibiotic active against tuberculosis (see the page on Selman Waksman). The search for natural antibiotics in moulds and soil organisms, made possible by the fermentation methods developed for penicillin, dominated drug discovery for the next two decades.

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7. The 1945 Nobel Prize and the Question of Patents

The Nobel Prize

The Nobel Prize in Physiology or Medicine for 1945 was awarded jointly to Alexander Fleming, Ernst Chain and Howard Florey “for the discovery of penicillin and its curative effect in various infectious diseases”. The wording recognised both stages of the story: Fleming’s 1928 observation of the mould’s antibacterial action, and the Oxford work that showed penicillin could cure infection in living animals and people. Thomas Raju’s “Nobel chronicles” column in the Lancet (1999) gives a short account of the three laureates. Florey had been knighted in 1944; Chain was knighted later, in 1969. Many of the Oxford team, among them Norman Heatley and Edward Abraham, received no share in the prize, which by its rules can go to at most three people.

To patent or not

Penicillin was not patented by its Oxford developers. The Australian Dictionary of Biography explains that in the 1940s patenting a medical discovery was widely regarded as contrary to medical ethics, and Florey held to that view. Chain, who had trained in German institutes where patenting was usual, urged that the process be patented; according to the Science History Institute, Florey refused, and the decision long troubled Chain. The disagreement between the two men is a documented part of the history and is reported here without judgement of either.

The practical result was that Florey made no fortune from penicillin; the Australian Dictionary of Biography records his estate as £29,786. Methods of manufacture developed later, including the American deep-fermentation processes, were a separate matter from the Oxford discovery. The experience left its mark: when the Dunn School later worked on the cephalosporin antibiotics in the 1950s, the Science History Institute notes that Florey this time urged that the work be patented.

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8. The Penicillin Nucleus and Semisynthetic Penicillins

Chain in Rome

In 1948 Chain moved to Rome as scientific director of the International Research Centre for Chemical Microbiology at the Istituto Superiore di Sanità, Italy’s national institute of health. There he established a new biochemistry department with a fermentation pilot plant, where new antibiotics and fermentation methods could be developed on a semi-industrial scale. Kardos and Demain, in a 2013 tribute in Applied Microbiology and Biotechnology, describe how he also helped several countries set up their own penicillin industries after the war, including the Soviet Union and China.

6-APA: the penicillin nucleus

Natural penicillin is a family of closely related molecules. Each shares a common core — the beta-lactam ring joined to a second ring — with a different chemical side chain attached. Work in which Chain collaborated with the research group of a British pharmaceutical company isolated that core on its own: 6-aminopenicillanic acid, usually shortened to 6-APA. A 1960 paper in Nature by George Rolinson and colleagues, with Chain as last author, reported that 6-APA could be formed from penicillin by enzymatic hydrolysis, using an enzyme to cut the side chain off.

The importance of 6-APA was that chemists could now attach new side chains of their own design to the natural nucleus. The resulting drugs, part made by the mould and part made in the chemistry laboratory, are called semisynthetic penicillins. Some were designed to survive stomach acid so they could be taken by mouth, some to act against a wider range of bacteria, and some to resist the bacterial enzymes that destroy penicillin; methicillin and ampicillin are early examples. Chain reviewed this whole development in a 1971 lecture published by the Royal Society, “Thirty years of penicillin therapy”.

Cephalosporins at the Dunn School

Back in Oxford, the Dunn School’s antibiotic work continued after the war. In the 1950s researchers there, among them Edward Abraham, studied a group of antibiotics from another mould, the cephalosporins, including cephalosporin C, which also contain a beta-lactam ring. Florey described this work in a 1955 lecture published in the Annals of Internal Medicine under the title “Antibiotic products of a versatile fungus”. The cephalosporins became one of the largest families of antibiotics in medical use.

Chain later returned to Britain as professor of biochemistry at Imperial College London, again with an industrial-scale fermentation pilot plant; his Nobel biography gives 1961 for the appointment, while the Science History Institute and Kardos and Demain give 1964 for his return.

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9. Resistance Appears Early

Bacterial resistance to penicillin was noticed almost as soon as the drug existed. In December 1940, before the first patient had been treated, Edward Abraham and Ernst Chain reported in Nature “an enzyme from bacteria able to destroy penicillin”, found in a strain of Escherichia coli. The enzyme, later called penicillinase, breaks open the beta-lactam ring on which penicillin’s action depends. At the time it was a laboratory observation; within a few years it became a clinical problem.

Lobanovska and Pilla report that penicillin-resistant Staphylococcus aureus had appeared in hospital patients by 1942, while penicillin was still scarce and largely reserved for the military. As the drug came into wide use after the war, resistant staphylococci spread in hospitals. Semisynthetic penicillins designed to resist penicillinase were one response; bacteria in turn found new ways around them, and strains resistant to methicillin — known as MRSA — are described on the site’s page on MRSA antibiotic resistance.

The basic mechanism is natural selection. Wherever an antibiotic is used, bacteria that happen to carry a resistance gene survive and multiply, and many bacteria can pass such genes to one another. Lobanovska and Pilla frame the history of penicillin as a source of lessons for the present problem of antibiotic resistance. The site’s animation How Bacteria Beat Antibiotics shows the process step by step.

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10. Myth and Memory: Who Made Penicillin

The “fairy tale”

The public story of penicillin took shape during the war itself, in newspapers and broadcasts, and it was a simpler story than the real one. In the popular version, a single lucky discovery by one scientist led more or less directly to a miracle drug. In a 2002 article in the Medical Journal of Australia titled “Howard Florey, Alexander Fleming and the fairy tale of penicillin”, Goldsworthy and McFarlane describe the public myth of the discovery as an archetypal “quest story”, and set against it the real story of the discovery, testing and refinement of penicillin, which they call a complex tale of accident, serendipity, oversight, conflict, the pressure of war and idiosyncratic personalities. The real sequence ran from Fleming’s observation in 1928, through a decade in which the substance was not purified or tested as a treatment, to the Oxford team’s chemistry, animal experiments and clinical trials, and the industrial effort that made the drug available.

Florey and Edward Abraham later set down their own record in “The work on penicillin at Oxford” (1951). The page on Alexander Fleming (Alexander Fleming: Penicillin, Lysozyme, and the Antibiotic Age) tells the discovery from Fleming’s side.

Norman Heatley, “the forgotten man”

Even within the Oxford story, credit was unevenly shared. Norman Heatley (1911–2004) had designed the extraction apparatus, the culture vessels and the assay method that made the Oxford work possible, and he had carried that knowledge to Peoria in 1941. He received no Nobel share and little public notice for decades. In 1991 Carol Moberg profiled him in Science under the title “Penicillin’s forgotten man”. He was appointed OBE in 1978, and in 1990 the University of Oxford gave him an honorary Doctorate of Medicine; the Oxfordshire Blue Plaques Board now commemorates him with a plaque.

Many hands

Historians now tell penicillin as the work of many hands: Fleming, who saw the effect; Florey, who organised and drove the Oxford programme; Chain and Abraham, who worked out the chemistry; Heatley, who made production and measurement possible; the Oxford clinicians and the “penicillin girls” who tended the cultures; the Peoria microbiologists who found corn steep liquor and better strains; and the engineers of the wartime collaborative who built the tanks. The story the 1945 Nobel Prize told, of three names, is accurate as far as it goes; the fuller history is the one the sources above describe.

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Key Research Papers

  1. Quinn R. Rethinking antibiotic research and development: World War II and the penicillin collaborative. Am J Public Health. 2013;103(3):426-34. PubMed PMID: 22698031
  2. Gaynes R. The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use. Emerging Infectious Diseases. 2017;23(5):849-853. DOI: 10.3201/eid2305.161556
  3. Moyer AJ, Coghill RD. Penicillin: IX. The Laboratory Scale Production of Penicillin in Submerged Cultures by Penicillium notatum Westling (NRRL 832). J Bacteriol. 1946;51(1):79-93. PubMed PMID: 16561059
  4. Raper KB, Alexander DF, Coghill RD. Penicillin: II. Natural Variation and Penicillin Production in Penicillium notatum and Allied Species. J Bacteriol. 1944;48(6):639-59. PubMed PMID: 16560880
  5. Bud R. Innovators, deep fermentation and antibiotics: promoting applied science before and after the Second World War. Dynamis. 2011;31(2):323-41. PubMed PMID: 22332462
  6. Florey HW. Penicillin: A Survey. Br Med J. 1944;2(4361):169-71. PubMed PMID: 20785574
  7. Lobanovska M, Pilla G. Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future? Yale J Biol Med. 2017;90(1):135-145. PubMed PMID: 28356901
  8. Raju TN. The Nobel chronicles. 1945: Sir Alexander Fleming (1881-1955); Sir Ernst Boris Chain (1906-79); and Baron Howard Walter Florey (1898-1968). Lancet. 1999;353(9156):936. PubMed PMID: 10094026
  9. Kardos N, Demain AL. Ernst Chain: a great man of science. Appl Microbiol Biotechnol. 2013;97(15):6613-22. PubMed PMID: 23793259
  10. Rolinson GN, Batchelor FR, Butterworth D, Cameron-Wood J, Cole M, Eustace GC, Hart MV, Richards M, Chain EB. Formation of 6-aminopenicillanic acid from penicillin by enzymatic hydrolysis. Nature. 1960;187:236-7. PubMed PMID: 14438509
  11. Chain E. Thirty years of penicillin therapy. Proc R Soc Lond B Biol Sci. 1971;179(1057):293-319. PubMed PMID: 4401412
  12. Florey HW. Antibiotic products of a versatile fungus. Ann Intern Med. 1955;43(3):480-90. PubMed PMID: 13249229
  13. Abraham EP, Chain E. An enzyme from bacteria able to destroy penicillin. Nature. 1940;146(3713):837. DOI: 10.1038/146837a0
  14. Goldsworthy PD, McFarlane AC. Howard Florey, Alexander Fleming and the fairy tale of penicillin. Med J Aust. 2002;176(4):176-8. PubMed PMID: 11913920
  15. Moberg CL. Penicillin’s forgotten man: Norman Heatley. Science. 1991;253(5021):734-5. PubMed PMID: 1876832
  16. Florey HW, Abraham EP. The work on penicillin at Oxford. J Hist Med Allied Sci. 1951;6(3):302-17. PubMed PMID: 14873930

PubMed Topic Searches

  1. PubMed: penicillin production history, World War II
  2. PubMed: deep fermentation and penicillin history
  3. PubMed: 6-aminopenicillanic acid and semisynthetic penicillins
  4. PubMed: history of penicillin resistance in Staphylococcus aureus
  5. PubMed: Chain EB, penicillin papers

Further Reading

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Connections