The Discovery of Insulin

Robert Tattersall is an internationally recognized authority on diabetes.  He received specialist training at King’s College Hospital, London and the University of Michigan in Ann Arbor.  He moved to Nottingham in 1975 where he became Professor of Clinical Diabetes.  His most recent book, Diabetes: The Biography, is part of the series Biographies of Disease which we will be looking at in the upcoming weeks.  Each volume in the series tells the story of a disease in its historical and cultural context – the varying attitudes of society to its sufferers, the growing understanding of its causes, and the changing approaches to its treatment.  In the excerpt below we learn about the discovery of insulin- a moment that changed the lives of diabetics forever.

After war service in Europe, Frederick Grant Banting (1891-1941) failed to get a surgical job at the prestigious Toronto Hospital for Sick Children and so set up as a doctor in London, Ontario. This was not a success, and to make ends meet he got a part-time job at the University of Toronto. In October 1920 he had to lecture the students on carbohydrate metabolism, about which he knew little. While preparing, he read an article about a man in whom a stone had blocked the pancreatic duct leading to atrophy of the digestive-enzyme-producing part of the gland but leaving the islets intact. This was hardly new, since it had been known for thirty years that this was what happened when the duct was tied in animals, but in his notebook Banting wrote:

Diabetus [sic]
Ligate pancreatic ducts of dog. Keeping dogs alive until ancini degenerate leaving Isletes.
Try to isolate the internal secretion of these to relieve glycosurea [sic]

Against the background of the fruitless attempts described in the previous chapter, it is not surprising that Macleod did not take Banting seriously. Macleod wrote: ‘I found that Dr Banting had only a superficial textbook knowledge of the work that had been done and no familiarity with the methods by which such a problem could be investigated in the laboratory.’ Quite apart from Banting’s ignorance, Macleod had lost interest in diabetes and was researching acid-base balance. Banting later said that during the first interview Macleod was so disinterested that he started reading letters on his desk. Nevertheless, he offered Banting a disused lab and two students, Charles Best (1899-1978) and Clark Noble (1900-78), who were to do alternate months. They tossed a coin to decide who should to the first month. Best ‘won’, but was so involved at the end of the first month that Noble agreed that he should continue.

Banting need an assistant, because he did not know how to measure blood sugar, and Macleod had wisely insisted on this as the end point of their experiments. During his research on the blood sugar of the turtle, Best had learned the new Lewis-Benedict method, which needed as little as 0.2 ml blood, whereas other methods needed 25 ml. Another stumbling block was that Banting had never done a pancreatectomy, an operation that at the time was used only in animal research. Macleod assisted at the first operation, but Banting and Best then worked alone, writing from time to time to Macleod, who replied with advice. In August 1921they depancreatized two dogs and treated one with pancreatic extract leaving the other as a control. The untreated dog died in four days which the treated one remained well. Macleod was encouraged by their results but felt that the falls in blood sugar might be due to dilution or even normal fluctuations. He suggested further experiments, to which Banting objected violently and accused Macleod of trying to steal their thunder. Nevertheless, the experiments were done. When Macleod returned in October, he had a stormy interview with Banting, who threatened to go elsewhere if better facilities were not provided. At a departmental meeting on 14 November 1921 Banting and Best gave a preliminary presentation of their work. One important suggestion at this meeting was that the best of showing that the extract worked would be if regular injections could prolong the life of diabetic dogs.

This was a logistic problem, because the duct-ligation method needed many dogs and a wait of seven weeks while the exocrine tissue degenerated. Banting’s solution was to use foetal calf pancreas, which Best got from the local abattoir. The rationale, as Sobolev had suggested twenty years before, was that it contained a high proportion of islets in relation to exocrine tissue. An important breakthrough came in December, when Banting decided to use alcohol in making extract (an idea Macleod had suggested some months before). It worked well and led them to wonder whether they could get a similar result with the more easily available adult beef pancreas. That they did must have been a surprise, because the original rationale for duct ligation was that the internal secretion would be destroyed by pancreatic enzymes. In fact, although Macleod and others believed this, it had been known since 1875 that fresh pancreas did not break down proteins. The intact gland contains an inactive precursor trypsinogen, which is converted into the protein-dissolving enzyme trypsin only by contact with duodenal juice. Around this time Banting and Best were joined by a biochemist, Bert Collip (1892-1965)-more accurately, he was foisted on them by Macleod, who regarded him as a proper scientist. Collip had come on a Rockefeller fellowship and was studying the effect of pH on blood sugar. Later he was asked to help with the purification of insulin and made rapid progress, although afterwards he downplayed his role, suggesting that any biochemist could have done the same.

Some time in December 1921 Collip began making extracts from whole pancreas and, at Macleods suggestion, tested them on rabbits. The extracts reduced the rabbit’s blood sugar, and how far it fell was a useful and cheap way of telling how potent the extract was.

The first use of insulin (an extract made by Charles Best) on a human being was on 11 January 1922. The pancreatic extracts were relatively impure, and the house physician at Toronto General Hospital described what he injected into the buttocks of 14-year-old Leonard Thompson as ’15 cc of thick brown muck’. Thompson has been on the Allen diet since 1919 and weighed only 65 lb (29.5 kg). After the injection, his blood sugar fell from 440 to 320 mg/dl (24.4 to 18.3 mmol/l), but no clinical benefit was seen. The experiment was resumed on 23 January, when he was given Collip’s extract, and now his blood sugar fell during one day from 520 mg/dl (29 mmol/l) to 120 mg/dl (6.7 mmol/l). He continued treatment for ten days with marked clinical improvement and complete elimination of glucose and ketones from his urine. Subsequently he lived a relatively normal life, although reliant on insulin injections, before dying of pneumonia in 1935.

The first clinical results were published in the March 1922 Canadian Medical Association Journal, where the authors reported that they had treated seven cases…