Penicillin: World War II infections and Howard Florey

Howard Florey is celebrated for his major contributions to the large-scale production of the fungal product, penicillin, during World War II (WWII), leading to life-saving outcomes for many more than those with war wounds.

Howard Florey was born in South Australia in 1898. After studying medicine at the University of Adelaide he was awarded a Rhodes Scholarship to work in Oxford under Sir Charles Sherrington. After subsequently undertaking a PhD at Cambridge and a brief period as Professor of Physiology at The University of Sheffield, he was appointed to a chair in the Sir William Dunn School of Pathology at Oxford, where he remained until his retirement.

In the 1930s bacterial infections were an unimportant cause of illness and death in civilian populations were untreatable. In civilian life, diseases such as meningitis and pneumonia were frequently fatal, minor wounds could result in cellulitis or life threatening septicaemia and sexually transmitted diseases such as syphilis and gonorrhoea were serious conditions. On the battlefield it is estimated that up to one-third of lives lost were due to secondary infections.

Florey became interested in the use of natural substances to combat infections and in 1938, with biochemist Ernst Chain, began a systematic study of the antibacterial properties of substances produced by bacteria and fungi. They selected penicillin, a substance produced by the fungus Penicillium notatum, which had been described by Alexander Fleming almost a decade earlier, for further study. Chain and his colleague Norman Heatley were able to devise extraction and purification techniques which enabled them to obtain sufficient penicillin to test its efficacy in laboratory animals.

On 25 May 1940, a batch of laboratory mice were injected with a lethal dose of streptococci and half then treated with penicillin. The results were dramatic – the control mice rapidly succumbed, while all of the treated mice survived. These results attracted great interest from the scientific and military communities because, if replicated in humans, the drug had the potential to influence the outcome of WWII.

It took Florey and 16 colleagues several months to produce sufficient material to treat a handful of patients. The team worked under difficult circumstances with a lack of funding and equipment; at first penicillin was made using old dairy equipment. Hospital bedpans were later used to grow the mould and the liquid containing penicillin drained from beneath the growing mould and filtered through parachute silk.

The first patient they treated was a policeman, in whom an infected scratch had developed into a life threatening infection. He was given penicillin, and within a day began to recover. Unfortunately Florey’s team only had sufficient drug for 5 days of treatment and when their efforts to recycle penicillin from the patient’s urine failed, he relapsed and died. Because of this experience, the team then concentrated their effects on sick children, who did not require such large quantitates of the drug, demonstrating its value in a child with septicaemia and another with meningitis.

By mid-1941 the drug’s potential was widely recognised and it was clear that the team needed the help of industry to produce it at large scale. Companies in Britain were unable to help out because of the war, so later that year Florey and Heatley took a dangerous flight to the United States in a blacked-out plane. Penicillin production was declared a war project and given high priority. Florey convinced four major pharmaceutical companies (Pfizer, Abbott, Merck and Lederle) and many smaller players to become involved.

During these meetings Florey encountered a scientist from the Department of Agriculture who was searching for a new use for a thick liquid that was a by product from the milling of corn. When this liquid was used, as a substrate the yield of penicillin was increased 10-fold. A further boost was given when Mary Hunt (known as Mouldy Mary) found a species of penicillin growing on a moulding cantaloupe (P. chrysogenum) was almost 200 times as successful again in producing penicillin as P. notatum. Further modifications resulted in strains almost 1000 times as productive as Fleming’s original cultures.

By late 1943 mass production of the drug had commenced in 25,000 gallon aerated metal tanks, a process that Pfizer devised and made available to its rivals and later that year Florey was able to test the drug in soldiers in North Africa, with dramatic results especially in the treatment of gonorrhoea. Production continued to rise so that some 2 million doses were available for the D-day landings in June 1944. The results were dramatic, the survival rate for wounded soldiers rising from 4 per 100 (WWI) to around 50 per 100 and the death rate from pneumonia, falling from 18% to less than 1%. By the end of the war, many laboratories were manufacturing the drug, including Australia’s Commonwealth Serum Laboratories.

In 1943, the public health worker, Bill Keogh, convinced the war cabinet that Australia needed to be self-sufficient in penicillin and identified a young vet, Val Bazely, who was serving in an armoured regiment in New Guinea, as the man for the job. Bazely was ordered back to Melbourne and almost immediately sent to the US. He spent three months visiting major manufacturers and returned in December with a great deal of new knowledge, most of it in his head.

Bazely set himself the heroic target of producing penicillin within six weeks and worked day and night to achieve it. He produced specifications and working drawings, designed purification processes, identified suppliers and fabricators, commandeered equipment and scrounged for scarce raw material. To obtain efficient staff, he persuaded soldiers who were awaiting discharge to assist him. By February, 1944, 10 weeks after his return, a sizable quantity of material had been produced and, by April, CSL became the first company in the world able to provide penicillin to both soldiers and civilians.

Despite living in Britain for all his working life, Florey took a great interest in Australia, hosting many young post-docs in his laboratories and visiting regularly.

A paper that he wrote played a seminal role in the decision to establish the Australian National University and during 1947–1958 he was closely associated with development of the John Curtin School of Medical Research, effectively acting as its non-resident head and declining several offers of the Directorship.

Florey was an excellent experimentalist, a gifted writer and a strong and effective administrator who had the knack of getting things done. His last major role, that of President of the Royal Society was outstandingly successful, resulting in major reforms.

Florey was an excellent sportsman, who excelled at tennis. He loved to travel, was an enthusiastic photographer and found pleasure in gardening.

Once the importance of penicillin was recognised, Florey received many honours. He became a member of the Royal Society in 1941, was knighted in 1944, received the Nobel Prize in 1945, the French Legion d’honneur in 1946 and the US Medal of Merit in 1948. In 1965 he was created Baron Florey of Adelaide and later appointed to the Order of Merit.

As one of Australia’s greatest scientists, Florey has been rightly celebrated. His likeness adorns Australia’s $50 note, and his name lives on – both a suburb in Canberra and a major research institute in Melbourne are named after him.