One hundred years of insulin

An alternative history

Features

Professor Angus Brown, University of Nottingham, UK

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https://doi.org/10.36866/122.14

We are approaching the centenary of the discovery of insulin, the greatest medical breakthrough of its time. It elevated Sir Frederick Banting to the status of national hero, honoured with countless awards including a knighthood and a Nobel Prize. To this day Banting remains the youngest Nobel Laureate in Physiology or Medicine, receiving the Prize in 1923 at 32 years of age.

Prior to the discovery of insulin, a diagnosis of type 1 diabetes was a death sentence. Patients were typically pre-pubescent children presenting with weight loss, excessive thirst, hunger and glucosurea. The only effective treatment was a calorie-restricted diet that starved the body of carbohydrates that fuelled the hyperglycaemia and coma that inevitably preceded death. Intensive research in the three decades preceding Banting’s work identified the islets of Langerhans in the pancreas as the source of the internal secretion believed to regulate blood glucose. Several research groups had demonstrated the ability of crude extracts of pancreas to reduce glucosurea in diabetic dogs, but the side effects resulting from impurities in the extract precluded progression to clinical trials.

Insulin was discovered at the University of Toronto, Canada, by a group of four researchers: Frederick Banting (1891 – 1941), John Macleod (1876 – 1935), Professor Charles Best (1899 – 1978) and Professor James Collip (1892 – 1965) (see Figure 1). Banting, although trained as a surgeon, was intrigued by the role of the internal secretion of the pancreas in the development of diabetes mellitus. He proposed to Macleod, Professor of Physiology at the University of Toronto, the idea of ligating the pancreatic ducts in dogs in an attempt to destroy the acinar cells that produce the digestive enzymes (the external secretion), suspected of destroying the internal secretion. The atrophied pancreas, which should be devoid of external secretion while retaining the internal secretion, would be grafted into another dog rendered diabetic by total pancreatectomy and the urine glucose measured to test the effectiveness of the graft.

Macleod, an expert on carbohydrate metabolism, was attracted to Banting’s skills as a surgeon, clearly a considerable asset when applied to grafting. Macleod supplied Banting with a laboratory, dogs, and an assistant, undergraduate student Charles Best. The promising results of the early experiments encouraged Macleod to extend funding, and to recruit biochemist James Collip to oversee the successful purification of the internal secretion, which MacLeod named insulin from the Latin, insula, meaning island, referring to the pancreatic islets.

But it could all have been so different (Table 1).

Discovery vs. invention

A discovery is a lesser achievement than an invention, the former requiring a “find” of an existing entity, whereas the latter requires creation. Inventions are considered the pinnacle of scientific achievement, since they originate in the imagination of an individual(s), without whose insight they would not exist, such as Einstein’s theory of relativity or Darwin’s theory of evolution by natural selection. The discoveries of insulin and the structure of DNA were areas of intensive research, and had Banting et al, and Professor James Watson and Professor Francis Crick failed in their endeavours, others would rapidly have succeeded, in the case of insulin within a few years and with DNA likely within a year.

Among the relatively recent medical discoveries including the smallpox vaccine, antibiotics, anaesthesia, oral contraceptives and chemotherapy, the discovery of insulin was the most accessible of the low-hanging fruit. It was based on a straightforward premise understandable by any competent researcher: the islets of Langerhans in the pancreas produce the internal secretion (insulin), which controls blood glucose levels. Given that hyperglycaemia resulting from insufficient pancreatic insulin production is the cardinal feature of diabetes mellitus, judicious preparation of pancreatic extracts would isolate insulin, which could be used to treat diabetic patients. The relative simplicity of the idea and the urgent need to develop effective therapies to treat diabetes attracted up to 400 research groups by 1920, who attempted isolation of insulin. They all failed. A confounding factor, accepted by many contemporary researchers, was that the external secretion degraded the insulin, accounting for its unpredictable potency, thus a means of isolating the insulin from the external secretion was required before the purification process could be applied to homogenised pancreas. This concept was wrong, as the external secretion was stored in the pancreas in an inactive form, but it led to delays in progress as researchers tried in vain to develop methods for removing the external extract.

Banting and Best’s initial experiments showed promising results, but toward the end of 1921 they were unable to produce sufficient extract using the ligature procedure. More out of desperation than insight, they prepared extract from whole dog pancreas, then cow pancreas, both of which were successful in reducing blood glucose levels. Given the momentum of the research, Banting and Best never stopped to consider the profound implications of their results: the external secretion does not degrade the internal secretion, and Banting’s idea to ligate the pancreatic ducts was wrong and could not lead to success. At the suggestion of Macleod they used alcohol as a solvent, and were soon joined by Collip who successfully isolated an extract of sufficient purity to test on diabetic patients. The treatment of diabetic patients with subcutaneous injection of insulin was not only a major advance in treatment of diabetes, but established an important clinical principle. Many other diseases also result from a deficiency in a naturally produced compound e.g. Parkinson’s disease and Addison’s disease result from deficiencies in production of dopamine and cortisol, respectively. As with diabetes, they can be treated by exogenous introduction of the deficient compound.

A bitter victory

This brief account glosses over the incompetence, failure, ignorance, conflict, misunderstanding, suspicion, fear and finally triumph that defined the project. The core conflict lay in Banting’s belief that Macleod was taking undue credit and stealing his data. While it was true that Macleod did not carry out any of the experiments, he did fund, support and advise on the project and was justified in referring to “our” experiments when presenting the data at conferences.

This transformed Banting’s already heightened feelings of simmering resentment into hatred and relations within the group were irrevocably damaged. The final insult to Banting’s already fragile ego was Collip’s rapid success in purifying the extract where he and Best had failed. Controversy relating to Nobel Prize awards is common, but it is unusual that a nominee threatens to refuse the prize in protest to sharing the award with a colleague. Banting would rather sacrifice the most prestigious award in science than share it with the charlatan Macleod. Wiser counsels soon prevailed and for the sake of the reputation of the University of Toronto he accepted the award, sharing half of his prize with Best.

Many of Banting’s colleagues in Toronto considered him a mediocre scientist; whatever his own research talents they were overshadowed by those of his two colleagues, Macleod and Collip. However, it is vital to realise, as Banting himself never could, that the success of the discovery of insulin lay in the collaborative effort of four individuals, a Scot, an American and two Canadians, each of whom contributed complementary skills to tackle the problem. Banting displayed astute judgement in approaching Macleod, the most suitably qualified researcher in Canada, with his proposal. Macleod recruited Best, whose personality meshed with Banting and they formed a supportive and effective partnership. The introduction of Collip to the group was an inspired idea, his expertise in biochemical techniques far superior to those of Banting and Best. Banting’s claims for credit always reverted to his idea. That the idea was not original (at the start of the experiments Banting was unaware of the majority of the diabetes literature), or even correct, escaped Banting. What he did not appreciate was that his idea was the catalyst that allowed him access to a functional, well- funded laboratory, and most importantly the privilege of working with three equivalently passionate and committed researchers who laboured together towards a common goal.

A war hero’s legacy

What is Banting’s legacy? He is often described as a country boy who had difficulty adapting to cosmopolitan city life. He was also a decorated war hero who selflessly dedicated himself to helping his fellow soldier. Although naïve as a researcher he struck gold with his idea about diabetes, which precipitated the discovery of insulin. However, he was unable to rejoice in his discovery and the countless lives it saved, and later became frustrated with his inability to reproduce his success in the field of cancer research. He died in a plane crash on a secret military mission to England in 1941 as part of a study on aviation medicine.

I think of Frederick Banting in the following context. Images of diabetic patients in Toronto prior to the introduction of insulin still have the power to shock, as current patients receive treatment before they reach such a wretched and emaciated state. The resurrection of Teddy Ryder and Elizabeth Hughes, among the first diabetic patients successfully treated with insulin, is a testament to its life-saving effects. No patient in 1922, their families, or the embattled doctors treating them would argue that insulin therapy was anything other than a miracle.

Read more about the history of insulin in this article by the author.

References

Bliss M (1983). The Discovery of Insulin. McClelland and Stewart Limited. Toronto.

Bliss M (1992). Banting: A Biography. University of Toronto Press Inc. Toronto.

Bliss M, Gzowski P (1984). The biography of Frederick Banting, discoverer of insulin. [Online] CBC

Digital Archives. Available at: https://www.cbc.ca/archives/entry/insulin-the-biography-of-frederick-banting/ [Accessed 27 May 2021]