From fortuity to human fortune by a shared focus
Robin Walsh relays how the production of penicillin and insulin demonstrates the effectiveness of good interactions.

The recent focus on physician-pharmaceutical industry relationships both on the part of the media, and healthcare professionals themselves, might give the impression that these kinds of interactions are a new thing. However, collaborations between physicians, academics and the pharmaceutial industry are not a new obsession. But historically they were approached and completed with greater success.

Academic physician Alexander Fleming's discovery of penicillin is one of the standard tales of fortuitous scientific advance - how a bacterial plate contaminated with the Penicillium notatum unexpectedly revealed the fungus' bactericidal properties. But how did we get from a messy agar plate to a mass produced drug that saved thousands of lives in the Second World War, and whose descendants are still the first line of defence in treating bacterial infections?

After his initial breakthrough in 1928, Fleming found it difficult both to cultivate the fungus, and to purify the antibiotic agent from the mould. His research was taken up in 1939 by Howard Florey and Ernst Chain at Oxford University, who perfected the isolation and purification of penicillin, and began in vivo testing in mice. They however lacked the facilities and resources to mass produce the drug for clinical trials or wider use and so sought partnerships with the pharmaceutical companies, who they hoped might have the tools they lacked to develop the drug further.

Under the shadow of the rapidly approaching Second World War, the US Office for Scientific Research and Development (OSRD) cajoled the initially wary pharma companies into focusing on the problem, and sharing their expertise with each other, and the government. At a meeting ten days after Pearl Harbour, the heads of 4 leading pharma companies agreed to start working towards mass production of the antibiotic. Florey and Chain's colleague Norman Heatley worked with Merck for several months, bringing the Oxford team's expertise in the cup-plate assay and advances in fermentation that improved productivity. His work, and the efforts of a three-way collaboration between Pfizer, Squibb and Merck, enabled Merck to produce enough of the drug to treat their first patient, Ann Miller, in March 1942, and to go on to produce thousands more doses by the end of the war.

Much like with the development of Penicillin, the clinical development and commercialisation of Insulin only reached fruition with a successful collaboration between research physicians and a pharmaceutical company. Frederick Banting was the doctor in question in this case, a former orthopaedic surgeon who began researching diabetes in 1921. His work involved isolating the islets of Langerhans from dogs by ligating their pancreatic ducts so the organ partially atrophied, and then using the extract to treat diabetes in other dogs. Banting and his colleagues Charles Best and James Collip quickly transferred their research into humans, using foetal calf pancreas extract to treat diabetic children. However, the team still had difficulty purifying the extract, and producing sufficient quantities to allow proper clinical testing or commercialisation of their new drug. The purity problem was a particular issue, with contaminants causing allergic reactions, abscesses, and pain when injected into patients.

They called on support from Eli Lilly and Company who in the spring of 1922 began work on developing the team's work further. Using pig pancreas extract, they managed to increase potency, but still had difficulties increasing the yield and achieve consistent strength of product, meaning doctors had to watch for hypoglycaemia in patients treated with the hormone. Throughout 1922, production remained erratic, and the product degenerated rapidly. Problems were compounded by the fact that the Canadian team and Lilly's team in the US used different sized rabbits in their potency tests.

Lilly's chief chemist, George Walden, then made a breakthrough; changing the pH of the pancreatic solution to the isoelectric point improved precipitation, enabling them to produce more and build up reserves of insulin for the first time. Lilly's expensive vacuum stills also helped improve production, whilst the Canadian group had to go begging for funding from benefactors to afford one. The technical and scientific expertise from each party eventually enabled them to provide a supply of insulin to thousands of diabetics across North America.

The patenting of the techniques involved in production still promised to be a thorny issue however; Lilly had trouble patenting their isoelectric precipitation method, which the Toronto group used as leverage in their negotiations. The Canadians had equal trouble obtaining a US patent for some of their innovations due to earlier patents; Lilly modified their claims to make it easier for the Toronto group to get patent office approval. There was also haggling over branding; eventually it was agreed that Lilly's trade name would be “Iletin”, modified from the Canadians' original name “Isletin” , and that the generic name of the hormone would be Insulin.

These two brief case studies illustrate that the challenges and possibilities facing contemporary healthcare collaborations are nothing new. Pharma companies can bring the resources and expertise to bear on a problem that academic institutions often lack, and their commercially oriented approach can bring results more quickly. On the other hand, physicians and academics 'blue sky' research can provide the kind of breakthroughs needed by big pharma, particularly in our era of thinning drug pipelines.

The development of penicillin shows the vital necessity of openness and team work, when the demands of the Second World War forced the government, pharma, and academics to collaborate for the greater good. The example of Insulin demonstrates how physicians can be as commercially savvy as their pharma compatriots, negotiating over patents and copyright to get the results they wanted. These stories show is that these interactions, if managed correctly, can be productive and harmonious, and most importantly, can advance medical science to improve human health.

Further reading:
Liebenau J. The British Success with Penicillin, Social Studies of Science (1987) 17:1 69-86
Rosenfeld L. Insulin: Discovery and Controversy, Clinical Chemistry (2002) 48:12 2270-2288