2023 marks the 100th anniversary of the award of the Nobel Prize in medicine or physiology for the discovery of insulin, to John J. R. Macleod and Frederick Grant Banting. Here John Mellis tells the story of their achievements and fractious relationship.
Even thousands of years ago, healers were aware of a strange and rare disease causing weight loss, extreme thirst, and excessive urination. Around the 3rd century BCE, Greek physicians termed the condition ‘diabetes’ meaning ‘to go through’. Diagnosis was often done by assessing the sweetness of the urine – by tasting, or testing its attractiveness to flies or ants. The cause of the disease was a mystery, and a definitive diagnosis was likely to be a death sentence. In 1678, the Oxford physician Thomas Willis, one of the first Fellows of the Royal Society, added another term to the description – ‘mellitus’, meaning sweet or honeyed. More recently, diabetes was recognised as a fatal scourge, particularly of the young. In 1890, the reported death rate in the USA from diabetes, for children under 15 years of age, was 1.3 per 100,000, rising to 3.1 in the year 1920. A similar trend was observed in European countries. By then, several important facts had been established.
The first insight that diabetes was a complex condition was gleaned by Matthew Dobson, a physician and natural philosopher born in Yorkshire in 1732. He enrolled in the University of Glasgow when he was 18 years old, and studied under the famous chemist and doctor, William Cullen, before moving on to qualify in medicine at the Edinburgh Medical School. Dobson demonstrated conclusively that the urine of diabetic patients contained sugar, and that their blood serum was also sweet. He observed that in some patients the disease led to death within a few weeks, while others lived much longer, and suspected that there were two types of the disease. Astutely, he concluded that diabetes was some kind of imperfect digestion that affected the whole body, and not a disease of the liver or kidneys.
This prompted the Scottish military surgeon, John Rollo, to investigate dietary treatments for diabetes. In 1797, Rollo used Dobson’s test for glycosuria – sugar in the urine – to monitor the condition and prescribed a special diet consisting principally of “animal food; for breakfast, a pint and a half of milk mixed with half a pint of lime water, bread and butter; at noon, plain pudding made of blood and suet only; at dinner, game, and old meats which have been long kept, and as far as the stomach may bear, fat and rancid old meats, as pork, taking care always to eat in moderation; for supper, the same as breakfast.”
In 1889, the role of the pancreas in diabetes was clearly implicated when German physicians showed that removing the organ from dogs resulted in diabetic symptoms, and death. Twenty years before that, during his doctoral research, their compatriot Paul Langerhans had identified “islands of clear cells” scattered throughout the pancreas, which became known as the Islets of Langerhans. Their function was not known, but their role in diabetes was increasingly suspected. At the University of Aberdeen, two doctors, John Rennie and Thomas Fraser, noted that dosing diabetic patients by mouth with ‘ordinary pancreas’ had not improved the condition., and that various writers had pointed out how the Islets of Langerhans benefited from a rich blood supply and appeared to be unique. Rennie and Fraser observed that in the pancreas of most fish, the Islets were independent of the rest of the pancreatic gland. Courtesy of the Aberdeen Fish Market, they proceeded to test the effect of administering extracts of piscine Islets, in various forms, to five severely diabetic patients in the local Royal Infirmary. The effects of the treatment seemed clear in each case: a reduction in urine volume and sugar content, in one case dramatically so. Unfortunately, the dosages were small, and the patients were severely ill at the start of the treatment. Two of them died in hospital.
Growing evidence indicated that the Islets of Langerhans held some powerful secrets and secretions. In 1909, around three years after the experiments of Rennie and Fraser, the Belgian Jean de Mayer suggested that the mysterious and as yet unidentified secretion should be called insuline after the Latin for ‘island’. His suggestion went largely unnoticed until seven years later when, apparently independently, the term ‘insuline’ was used and brought into common use by the Professor of Physiology at the University of Edinburgh, Edward Albert Shäfer, one of the founders of endocrinology – the study of hormone-producing glands and their disorders. It was in 1916 within his seminal textbook, The Endocrine Organs, that he described how the Islets of Langerhans must secrete a substance which controls the level of glucose in the blood.
Many others were curious about that, too. One of them was John James Rickard Macleod. Born in Perthshire, he was educated in Aberdeen, and took his medical degree with great distinction from the city’s University. He studied biochemistry for a year in Leipzig, and then lectured in physiological chemistry at the London Hospital Medical School. He was offered the chair in physiology at the Western Reserve University in Cleveland, Ohio, at the age of just 27, and he emigrated to the USA in 1903, with his new wife, Mary McWalter, a talented artist. It was in Cleveland that Macleod developed a strong interest in diabetes and the metabolism of carbohydrates. From 1907, he published a series of papers summarised in a monograph, Diabetes: its Pathological Physiology, in which he explored the action of the nervous system, primarily on glycogen disfunctions of the liver. Initially he favoured the view that excess sugar in the blood – hyperglycaemia – was due to the over-production of sugar in the liver. However, there was mounting evidence that the real cause of diabetes mellitus might be a general inability of cells to ‘burn’ sugar.
With the outbreak of the Great War, Macleod reportedly became frustrated by the initial neutrality of the USA, and after 15 years in Ohio, he accepted the multiple roles at the University of Toronto – Professor of Physiology, Director of the Physiological Laboratory, and Associate Dean of the Medical Faculty. His career was hugely impacted at the end of 1920, when he was approached by a 29-year-old Canadian doctor, Frederick Grant Banting, with a request.
Banting, the youngest of five children of parents of Irish and Scottish descent, had served as a military doctor in France and was wounded in 1918. For his bravery in treating other wounded men, for 16 hours in the midst of battle, he was awarded the Military Cross. After the War, he returned to Canada to complete his medical training in surgery and orthopaedics. When he approached Macleod asking for help with his idea, he was in general practice in London, Ontario, having been unable to gain a hospital position. Banting’s interest in diabetes had been prompted by reading the literature on the pancreas, and in particular a paper by Moses Barron of the University of Minnesota, who realised that experiments on rabbits, cats and dogs showed that when the main pancreatic duct was closed off by ligatures, most of the pancreas dissolved away – atrophied – over a period of a few weeks. However, the Islets were left normal and intact, and the animals showed no rise is either urine- or blood-sugar levels, and in fact showed no ill effects whatsoever.
Despite his lack of expertise in either diabetes or endocrinology, Banting was enthused. Here was a method, he thought, to reduce a pancreas to its essential Islets, and possibly to isolate the hidden hormone at last. Macleod knew that this had been tried before, but he agreed to provide Banting with advice, laboratory facilities, and ten dogs, to experiment on. This was initially to transplant an atrophied, but Islet-rich pancreas into a dog which had its pancreas removed, to demonstrate the restoration of normal metabolism. Macleod also provided the help of one of his medical summer students to assist Banting in performing dog pancreatectomies, and he suggested a research plan which moved from transplants to the injection of extracts of atrophied pancreas, explaining to Banting how to prepare an extract. Two potential summer assistants, Charles Best and Clark Noble, tossed a coin to see which of them would work with Banting. The toss was won by Best, a 22-year-old student. After starting Banting and Best on the work over the first few weeks, Macleod left Toronto in the middle of June for a holiday in Scotland for the rest of the summer of 1921.
At the end of July, Banting and Best began injecting de-pancreatised dogs with saline extracts of chilled, atrophied pancreas, and observed reductions in blood sugar. When Macleod returned in September, he asked them to repeat and extend their experiments, but to abandon the surgical transplant approach. The result was a heated clash between Macleod, a methodical, careful scientist, and Banting, who was impatient, new to research, and of the opinion that he had already done enough to show the efficacy of the extract of atrophied pancreas.
By December, Banting and Best had found that they could dispense with the involved procedure of pancreas atrophication, and instead use fetal calf or cow pancreas. Banting presented the results at a New Haven meeting of the American Physiological Society showing that intravenous injections of the extract reduced blood sugar levels by around a half. However, his nervous, inexperienced presentation was not well received. The audience was highly critical – Banting was apparently unaware that others had obtained similar results years before. And just like theirs, Banting’s extract was likely to be impure, yet he had collected no data on toxic side-effects. Macleod, chairman of the session, stepped in to try to rescue him from the criticism, but Banting saw this as an attempt to steal credit, and their relationship continued to sour. Nevertheless, Macleod persuaded Professor Duncan Archibald Graham, chief physician at Toronto General Hospital, to allow the injection of a severely diabetic 14-year-old boy, Leonard Thompson, with 15ml of the beef pancreas extract. It produced only slight reductions in glycosuria and hyperglycaemia, and resulted in the formation of an abscess. The treatment was immediately stopped.
Macleod had decided to add another member to the team in the shape of James Collip, a young but knowledgeable biochemist from the University of Alberta who was on a six-month fellowship at Toronto. Collip’s addition quickly yielded improved results, though the new presence was resented by Banting, who pitted himself and Best against Collip in a race to purify the extract. Collip succeeded by using fairly standard biochemical methods to isolate and remove harmful proteins in the extract, producing pure serum for the first time. When he went to Banting’s laboratory to give him the news, he told him that he would share the purification method with Macleod alone. Reputedly it was only the intervention of Best to restrain Banting that prevented a physical attack on Collip.
At the Toronto Hospital, in January 1922, young Thompson was started on another series of injections with the purified extract. His blood sugar level dropped to normal, and his glycosuria disappeared, without harmful effects. This demonstrated for the first time the complete efficacy of the internal extract of the pancreas, a result that had been sought for more than 30 years. Glory for the team came almost immediately. Macleod presented a summary of all the research in early May to a meeting of the Association of American Physicians, and was rewarded by a standing ovation. Not for the first time, Macleod proposed that the active substance should derive its name from the Islets of Langerhans, and the term insulin became accepted.
Banting, Best and Collip filed Canadian and US patent applications on the method of extraction in early 1923. Just months later, in one of its speediest recognitions of any scientific discovery in its history, the Nobel committee awarded the Nobel Prize in physiology or medicine to Macleod and Banting, ‘for the discovery of insulin’. Since a maximum of three people can share a Nobel Prize, the glory was not equally spread, though the prize money was. Banting announced that he would give half of his to Best, and Macleod did the same for Collip. Sadly, the bitter arguments continued. Banting believed that Macleod was undeserving of a share of the Prize, and that Collip had received an undeserved share of the kudos. He insisted on an alphabetical ordering of the author names in the team’s publications (which of course, ensured that his name came first).
After the award of the Nobel Prize, Macleod resumed his other research interests. In 1928, he returned to Scotland to become the Regius Professor of Physiology at his alma mater, the University of Aberdeen, and refrained from engaging in the argument over the discovery of insulin. He later became Dean of the Medical Faculty and a member of the UK’s Medical Research Council. He died in Aberdeen in 1935, aged 59, actively researching as well as painting, motorcycling and golfing, despite suffering from chronic arthritis. He and Mary had no children.
Banting remained at the University of Toronto where he was elected to the specially-created Banting and Best Chair of Medical Research, where he focused on cancer, silicosis and the mechanisms of drowning. Further controversy ensued when he accused the Hudson’s Bay Company of exploiting and harming the indigenous population of northern Canada. In 1934, he was made a Knight Commander of the British Empire, and the following year he became a Fellow of the Royal Society. Banting was twice married, and in later life he became one of Canada’s best-known amateur painters. He died in 1941, of injuries and exposure after initially surviving the crash of the plane in which he was travelling from Newfoundland. He is memorialised in the names of many educational institutions, and by the annual Banting Lectures on diabetes.
The facilities at Macleod’s laboratory were never intended to produce large quantities of insulin, and soon after the purification process was demonstrated, a production licence was granted to the American drug company, Eli Lilly. Bovine and porcine insulin were progressively improved as a treatment for what is now known as Type I diabetes, by the addition of substances, including zinc, to prolong its effect. The amino acid structure of insulin was determined in 1951 by Frederick Sanger, resulting in another Nobel Prize. That enabled the synthesis of insulin, almost simultaneously by several researchers, in the mid-1960s, which prompted the development of fully synthetic insulin in 1975. A convenient finger-prick test to monitor blood sugar content was developed by Ian Shanks in the 1980s, resulting in a landmark patent battle with his employer, Unilever. Today, most sufferers in developed countries can control their Type I diabetes with injections or the continuous infusion of synthetic insulin by pump, and developments continue to develop an orally administered insulin.
