A mysterious something: The discovery of insulin and the 1923 Nobel Prize for Frederick G. Banting (1891–1941) and John J.R. Macleod (1876–1935)

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  • Tonse N. K. Raju

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    1. National Institute of Child Health and Human Development, National Institutes of Health. Bethesda, Maryland. USA
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T. Raju Centre for Developmental Biology and Perinatal Medicine, NICHD/NIH, 6100 Executive Blvd, Room 4B03, Bethesda, MD, 20892, USA. E-mail: rajut@mail.nih.gov

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In 1922, a 12-year-old Canadian boy, Leonard Thomson, became the first diabetic patient to be successfully treated with ‘a mysterious something’– the pancreatic extract that still awaited christening [1]. By 1923, thanks to the creative collaboration between the University of Toronto and the Eli Lilly Company, unlimited quantities of the extract became available bearing the name ‘insulin’. The same year, two of the four principal discoverers of insulin won the Nobel Prize in Physiology or Medicine, the shortest duration between a discovery and the coveted prize [2].

The term ‘diabetes’ has a Greek root meaning ‘siphon’ and a Latin root meaning ‘honey’, references to polyurea and glycosuria, two of its cardinal symptoms. In ancient India, it was called ‘madhu meha’ (sweet melody). Other names dramatizing the sad suffering of its victims were ‘pissing evil’ and ‘melting down of flesh and blood’.

Until the discovery of insulin, there had been no treatment for diabetes. Bloodletting and blistering were common. Opium was used because ‘dope dulled the despair’ and made the suffering tolerable. Some experts prescribed an abundance of sugar to compensate for its loss in the urine, while others felt that fasting followed by intense exercise helped sugar to burn. “You shall earn your bread by the sweat of your brow”, remarked a French doctor.

In 1869, Paul Langerhans, a German medical student, discovered some peculiar pancreatic cells that looked like small islands floating amid the acinar cells. These cells were later named the Islets of Langerhans. The role of these cells in diabetes however, was not known.

In 1901, Oskar Minkowski of the University of Strasbourg was testing the role of the pancreas in fat digestion. One of his depancreatized dogs, in spite of being housebroken, began to urinate constantly. Minkowski discovered that the urine was loaded with sugar, a finding similar to that seen in diabetic patients. He and others proposed that the pancreas had a set of external secretions helping digestion, and an internal secretion helping sugar control. Also in 1901, Eugene Opie of Johns Hopkins University in the United States showed that the islet cells of Langerhans were the source of the internal secretion.

These developments in the first two decades of the 20th century propelled dozens of investigators in search of the elusive pancreatic secretion that could help diabetic patients. However, such attempts began to fail miserably, in part because the process of extraction would destroy the islet cells and their chemical content. Some experts felt that the exocrine secretions of the pancreas digested the islet cell secretion. There seemed to be no way out of this mysterious impasse.

Into such a confused world of diabetes research entered Frederick Banting (1891–1941), a fledging surgeon with a part-time lecturer's position at the University of Western Ontario in London, Ontario. His knowledge about contemporary research in diabetes was superficial. On Sunday, 31 October 1920, as he was preparing for a lecture on the pancreas to medical students the next day, Banting read a paper in the November issue of Surgery, Gynecology, and Obstetrics that described an autopsy report on a patient who had pancreatic stones, completely obstructing the gland, destroying the acinar cells, but preserving the islet cells. Banting was struck by a brilliant idea: why not occlude the pancreatic ducts and allow the acinar cells to atrophy? After this, one might be able to obtain an extract from the islet cells and test it on diabetic dogs.

However, Banting neither had a laboratory of his own, nor any research experience to speak of. He took the suggestions from his friends and met Professor John J.R. Macleod (1876–1935) at the physiology department in the University of Toronto in November 1920. Macleod was an expert in glucose metabolism. He was sceptical about Banting's ideas. However, he agreed to help. He arranged for laboratory space during the following summer, since laboratories would be then less crowded. He gave some dogs for the study and helped Banting to refine key steps in the experimental design. Macleod also assigned a final year masters’ degree student, Dr. Charles Best, to provide technical assistance.

In April 1921, Banting closed his practice, sold his house, and went to Toronto to pursue research at Macleod's laboratory as planned. From May to September of that year, Banting and Best virtually lived in the laboratory, working on dogs, learning from their mistakes, and refining their experiments. There were many setbacks. Removing the pancreas was tedious. Several dogs died of infections. In some dogs, the pancreas did not atrophy, despite complete ligation of the ducts.

However, the first glimmer of hope came on 30 July 1921. When they injected the crude extract from the islet cells from another dog to their diabetic dog 401, its blood sugar concentration plummeted. Although this dog died of coma the next day, Banting and Best had shown for the first time that an extract from the islet cells reduced blood sugar [1].

Much work had to be carried out over the subsequent weeks and months. The pair confirmed their findings repeatedly, and discussed them with Macleod upon his return from a summer vacation in Scotland. Macleod began to take more interest in the studies. He recruited James Collip, an expert in biochemistry and chemical extraction, to assist in purifying the pancreatic compound. By the end of 1921, the four scientists had succeeded in extracting enough of the new compound for clinical use.

In January 1922, when his father carried Leonard Thompson into the diabetic ward at Toronto General Hospital, the boy was so emaciated and ‘reduced to skin and bone’ that a clinic secretary remarked “I’ve never seen a living creature as thin as he was”. On 23 January, Leonard received an intramuscular injection of 5 cc of the new pancreatic extract Collip had prepared, that looked like “thick brown muck” [1]. Despite a rocky course and less than expected dramatic response, Leonard miraculously recovered with subsequent doses of the pancreatic extract, becoming the world's first successfully treated diabetic patient.

Initially, Banting and Best had called the pancreatic chemical ‘iletin’, but the name ‘insulin’ eventually stuck. It was perhaps proposed by Macleod, because it had a Latin root for island and was easier to use. It did not take long for the group and others to show that insulin contained consistently predictable properties in the control of diabetic hyperglycemia. Thus it was natural that the 1923 Nobel Prize in Physiology and Medicine was bestowed upon Frederick Banting and John Macleod.

By the time the prizes were announced, the mutual relationships among the four scientists had become strained. Banting was angry that Charles Best had been left out of the Nobel Prize. He considered declining the prize altogether, but conceding to the advice of colleagues and friends, accepted the prize and proposed that he would share half of his prize money with Best. Macleod, too, followed suit by announcing to share his half of the money with James Collip. Controversies abounded about their individual roles in the discovery of insulin. Posterity has proved, however, that without the successful collaboration of all four, insulin could not have been discovered at that time [1–3].

Most of the diabetic patients treated with insulin initially were children admitted to the Hospital for Sick Children in Toronto. One, Ms. Elizabeth Evans Huges, the 17-year-old prized patient of Banting, found insulin to be “unspeakably wonderful”. She lived for 74 years [1].

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