Howard Florey and Ernst Chain — Turning Penicillin into a Medicine

Table of Contents

1. Deep-Dive Articles
2. Who They Were
3. The Oxford Work on One Page
4. The Natural Source: A Mould
5. Timeline at a Glance
6. From Oxford to Mass Production
7. Later Significance
8. Key Research Papers
9. Connections
10. Featured Videos

Deep-Dive Articles

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1. Who They Were

Howard Walter Florey was born on 24 September 1898 at Malvern, Adelaide, the only son of a boot manufacturer. He qualified in medicine at the University of Adelaide in 1921 and went to Oxford that year as a Rhodes Scholar, studying physiology under Sir Charles Sherrington. After Cambridge, a Rockefeller fellowship in the United States and the chair of pathology at Sheffield (1931), he became Professor of Pathology at the Sir William Dunn School, Oxford, in 1935, a chair he held until 1962. He later served as President of the Royal Society (1960–65) and Provost of The Queen’s College, Oxford, and was made a life peer, Baron Florey of Adelaide and Marston, in 1965. He died in Oxford on 21 February 1968.

Ernst Boris Chain was born on 19 June 1906 in Berlin, the son of a chemist and industrialist. He graduated in chemistry from the Friedrich-Wilhelm University in 1930, worked on enzymes at the Charité Hospital, and for a time seriously considered becoming a concert pianist. After the Nazis came to power in 1933 he emigrated to England; the Science History Institute records that his mother and sister remained in Germany and died in the Holocaust. He worked at Cambridge under Sir Frederick Gowland Hopkins before Florey brought him to Oxford in 1935. After the war Chain directed a research centre in Rome and then became Professor of Biochemistry at Imperial College London. He died in County Mayo, Ireland, on 12 August 1979.

The two men were very different: Florey a physician-experimentalist interested in how living tissue behaves, Chain a chemist who saw problems in terms of molecules and enzymes. Historians of the work, including the Science History Institute, record that they disagreed over patenting penicillin: Chain urged it, as was usual in German institutes, and Florey declined, at a time when patenting a medicine was widely regarded in Britain as against medical ethics. The Lives and Careers article tells both stories in full.

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2. The Oxford Work on One Page

Florey had studied lysozyme, the natural antibacterial enzyme Fleming had described in the early 1920s, and recruited Chain for his biochemical skill. In 1938–39 the two began a systematic survey of antibacterial substances made by bacteria and moulds, funded by the Rockefeller Foundation, and chose Fleming’s penicillin as one of the first to study. Chain and Edward Abraham worked out how to keep the unstable substance intact by controlling acidity, keeping it cold and evaporating it under low pressure. The biochemist Norman Heatley designed the extraction apparatus, built in part from improvised vessels and tubing, and a method for measuring how strong each batch was.

On Saturday 25 May 1940 eight mice were infected with virulent streptococci and four of them were given penicillin. By the next morning the four untreated mice were dead and the treated mice were alive. The team repeated the experiment on many more mice that summer and reported the results in the Lancet on 24 August 1940 under the title “Penicillin as a chemotherapeutic agent.”

In February 1941 the first patient treated for an infection, a police constable named Albert Alexander, received penicillin at the Radcliffe Infirmary, Oxford. He improved quickly, but the supply ran out even after penicillin was recovered from his urine and re-injected, and he died on 15 March 1941. In that first series six patients were treated and four made a complete recovery; the full report, “Further observations on penicillin,” appeared in the Lancet in August 1941. The Oxford Penicillin Work article covers each step.

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3. The Natural Source: A Mould

Penicillin is a natural product. It is made by moulds of the genus Penicillium, the blue-green moulds familiar from old bread and fruit. Fleming first called his strain P. rubrum; it was later known as P. notatum and then P. chrysogenum. In 2011 a genetic study by Houbraken and colleagues re-identified Fleming’s original strain as Penicillium rubens, and a population-genetics study by Henk and colleagues found that Fleming’s preserved material belongs to the same species as the wild ancestor of today’s industrial strains.

Chemically, penicillin is a beta-lactam: its core is a small four-membered ring that blocks a bacterial enzyme, transpeptidase, which cross-links the mesh of the bacterial cell wall. Growing bacteria that cannot finish their walls burst. In December 1940 Abraham and Chain also reported an enzyme from bacteria able to destroy penicillin — penicillinase — an early sign of the resistance that would follow. During the war, the US laboratory at Peoria found that a strain from a mouldy cantaloupe made far more penicillin than Fleming’s; Gaynes puts it at six times as much. See The Penicillium Mould and the Science of Penicillin.

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4. Timeline at a Glance

• 1898 — Howard Florey born in Adelaide, South Australia (24 September).
• 1906 — Ernst Chain born in Berlin (19 June).
• 1921 — Florey graduates in medicine in Adelaide and sails to Oxford as a Rhodes Scholar.
• 1928–29 — Fleming observes and describes penicillin at St Mary’s Hospital, London.
• 1933 — Chain leaves Germany for England.
• 1935 — Florey takes the Oxford chair of pathology; Chain joins the Dunn School.
• 1938–39 — Florey and Chain begin their survey of natural antibacterial substances and choose penicillin.
• 25 May 1940 — The mouse protection experiment.
• 24 August 1940 — “Penicillin as a chemotherapeutic agent” in the Lancet.
• 12 February 1941 — Albert Alexander becomes the first patient treated for an infection.
• July 1941 — Florey and Heatley fly to the United States; the work moves to Peoria, Illinois.
• August 1941 — “Further observations on penicillin” in the Lancet.
• 1943 — By September, supplies meet the demands of the Allied armed forces.
• March 1945 — Penicillin released to US civilians.
• 1945 — Nobel Prize in Physiology or Medicine to Fleming, Chain and Florey.
• 1948 — Chain becomes scientific director of a research centre in Rome.
• 1960 — A paper co-authored by Chain reports the enzymatic route to the penicillin nucleus, 6-aminopenicillanic acid.
• 1965 — Florey made a life peer.
• 1968 — Florey dies in Oxford (21 February).
• 1979 — Chain dies in County Mayo, Ireland (12 August).

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5. From Oxford to Mass Production

Oxford could make only enough penicillin for a handful of patients, and British industry, stretched by the war, could not take on large-scale production. At the beginning of July 1941 Florey and Heatley flew to the United States. They were directed to the US Department of Agriculture’s Northern Regional Research Laboratory in Peoria, Illinois, and were backed by Alfred Newton Richards, Florey’s former mentor, who chaired the government’s Committee on Medical Research. At Peoria, Andrew Moyer improved the growth medium; adding corn steep liquor, a by-product of corn processing, raised yields enormously, and deep-tank (submerged) fermentation replaced the shallow surface cultures of Oxford.

Roswell Quinn, in a 2013 study of the US government archives, describes the wartime collaborative that followed: government agencies, universities and some twenty-one companies working under federal coordination. By January 1945 US production had reached four million sterile packages a month, and penicillin reached American civilians in March 1945. The Wartime Mass Production article follows the story.

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6. Later Significance

The Oxford work showed that a substance made by a living organism could be purified, tested on animals and given to patients as a systemic medicine against bacterial infection. It opened the search for other antibiotics from soil microbes and moulds that followed the war. Chain’s later work helped extend the penicillin family: in 1960 a paper with Chain as co-author reported that the penicillin “nucleus,” 6-aminopenicillanic acid, could be formed from penicillin by enzymatic hydrolysis, the starting point for semisynthetic penicillins. Florey’s Dunn School went on to study the cephalosporins in the 1950s.

Resistance appeared early: Lobanovska and Pilla record penicillin-resistant Staphylococcus aureus in hospital patients by 1942. Historians have also examined how the public story was told. Goldsworthy and McFarlane describe the popular account that credited Fleming alone as a “fairy tale” set against a more complex history, and Moberg wrote of Norman Heatley as “penicillin’s forgotten man.”

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Key Research Papers

1. Chain E, Florey HW, Gardner AD, Heatley NG, Jennings MA, Orr-Ewing J, Sanders AG. Penicillin as a chemotherapeutic agent. The Lancet. 1940;236(6104):226-228. DOI: 10.1016/S0140-6736(01)08728-1
2. Abraham EP, Chain E, Fletcher CM, Gardner AD, Heatley NG, Jennings MA, Florey HW. Further observations on penicillin. The Lancet. 1941;238(6155):177-189. DOI: 10.1016/S0140-6736(00)72122-2
3. Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. 1929. Bull World Health Organ. 2001;79(8):780-90. (Reprint of the 1929 paper.) PubMed PMID: 11545337
4. Florey HW, Abraham EP. The work on penicillin at Oxford. J Hist Med Allied Sci. 1951;6(3):302-17. PubMed PMID: 14873930
5. Abraham EP, Chain E. An enzyme from bacteria able to destroy penicillin. Nature. 1940;146(3713):837. DOI: 10.1038/146837a0
6. 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
7. Houbraken J, Frisvad JC, Samson RA. Fleming's penicillin producing strain is not Penicillium chrysogenum but P. rubens. IMA Fungus. 2011;2(1):87-95. PubMed PMID: 22679592
8. 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
9. 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
10. 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
11. 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
12. 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
13. Moberg CL. Penicillin's forgotten man: Norman Heatley. Science. 1991;253(5021):734-5. PubMed PMID: 1876832

PubMed Topic Searches

1. penicillin history Oxford
2. Florey HW [author]
3. Chain EB [author] penicillin
4. penicillin production history World War II

Further Reading

• Fenner F. “Florey, Howard Walter (1898–1968).” Australian Dictionary of Biography, vol. 14 (1996). adb.anu.edu.au
• Nobel Lectures, Physiology or Medicine 1942–1962: biographies of Howard Florey and Ernst B. Chain. Florey; Chain
• Science History Institute. “Howard Walter Florey and Ernst Boris Chain.” sciencehistory.org

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Connections

• Pharmacology: Notable Doctors
• Howard Florey and Ernst Chain: Lives and Careers
• The Oxford Penicillin Work, 1938–1941
• The Penicillium Mould and the Science of Penicillin
• Wartime Mass Production and the Antibiotic Era
• Alexander Fleming
• Selman Waksman
• Gerhard Domagk and the Sulfa Drugs
• Frederick Gowland Hopkins
• Mold and Mycotoxins
• Staphylococcus aureus
• How Bacteria Beat Antibiotics

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