TimeCapsule Insulin’s centenary: the birth of an idea Robert A Hegele, Grant M Maltman At 2:00 h on Oct 31, 1920, Frederick G Banting, a surgeon practising in London, ON, Canada, conceived an idea to Lancet Diabetes Endocrinol 2020 isolate the internal secretion of the pancreas. The following week, he met with noted scientist John J R Macleod in Published Online Toronto, ON, Canada, and they developed a research plan. By August, 1921, Banting and his student assistant October 29, 2020 Charles H Best had prepared an effective extract from a canine pancreas. In January, 1922, biochemist James B Collip https://doi.org/10.1016/ S2213-8587(20)30337-5 isolated insulin that was sufficiently pure for human use. On Oct 25, 1923, Banting and Macleod received the Nobel Department of Medicine, Prize in Physiology or Medicine for the discovery of insulin. Here, we recount the most relevant events before and Department of Biochemistry, after the fateful early morning of Oct 31, 1920, which culminated in the discovery and clinical use of insulin. and Robarts Research Institute, Schulich School of Medicine Introduction Captain and posted near the front line in France. At the and Dentistry, Western University, London, ON, The discovery of insulin in Canada ranks among the Battle of Cambrai in September, 1918, he suffered a Canada (R A Hegele MD); and leading triumphs of medical research; but is there an shrapnel wound to his dominant right arm, which Banting House National appropriate date to observe the centenary of this became infected and healed slowly. Although he received Historic Site of Canada, landmark achievement? There are several candidate the Military Cross for valour, he most likely endured Diabetes Canada, London, ON, Canada (G M Maltman BA) milestones in the timeline that culminated in the post-traumatic stress disorder.10 Correspondence to: isolation of insulin suitable for human use (figure 1). For After recovering and returning to Canada in early 1919, Prof Robert A Hegele, Robarts instance, on May 17, 1921, Frederick G Banting and Banting worked at the Toronto Military Orthopaedic Research Institute, Western Charles H Best (under the supervision of Hospital, Toronto, ON, Canada. That summer he entered University, London, ON N6A 5B7, John J R Macleod) commenced preclinical studies at the a year-long surgical internship at the Hospital for Sick Canada [email protected] University of Toronto, Toronto, ON, Canada. On Children, Toronto, ON, Canada, under the departmental Aug 3, 1921, Banting and Best’s crude extracts from the chief, Clarence L Starr. In 1920, Banting next ventured pancreas of a dog first showed activity in reducing 200 km west of Toronto, ON, to London, ON, Canada, hyperglycaemia in a pancreatectomised dog. Activity was intending to establish a private medical and surgical first shown in humans on Jan 23, 1922, when practice in the midsized community. With his father’s Leonard Thompson, a 14-year-old patient with type 1 assistance, he bought a house at 442 Adelaide Street on diabetes at Toronto General Hospital, Toronto, ON, the city’s east side, now a national historic site and Canada, responded spectacularly to injections of a museum (figure 2; video). The ground floor of the yellow- See Online for video purified insulin extract that was prepared by brick home housed Banting’s practice, whereas his living James B Collip. Any of these dates would merit quarters were on the second floor (figure 2B). Business consideration to commemorate insulin’s centenary. was slow from the outset: he cared for an average of However, we propose that the foundational event two patients per month. By the autumn, concerns about occurred months earlier in London, ON, Canada. The cash flow forced him to work a second job as an instructor events that followed are well documented in numerous in the Departments of Surgery and Physiology at the sources, including the definitive classic book, Western University medical school, London, ON, The Discovery of Insulin, written by the late historian Canada. He kept ahead of the undergraduate medical Michael Bliss in 1982,1 along with Bliss’s biography of students and received favourable teaching assessments. Banting2 and others.3–14 Here, we recount the events He also volunteered as a research assistant to before and after the morning of Oct 31, 1920, which Frederick R Miller, Western University’s Professor of transformed the field of endocrinology. Physiology, who studied cerebellar function in a feline model system.16 Banting and London, ON, Canada Sir Frederick Grant Banting was born on Nov 14, 1891, in The birth of an idea Alliston, ON, Canada, a village 70 km north of Toronto, On Saturday, Oct 30, 1920, Banting dropped by the ON, Canada.2 He was an average student, whose work medical school library to review journals in preparation ethic gained him entry into the University of Toronto, for his lecture on the pancreas, which was scheduled for initially for theological studies. In 1912, he transferred to the Monday. He noted an article of interest in his copy of the Faculty of Medicine and chose surgery as his specialty. the November issue of Surgery, Gynecology and Obstetrics.8 His classmate was Norman Bethune, who later served in That evening, having completed his lecture notes, he Mao Zedong’s army and helped to reform medical care turned to the article by Moses Barron of the University of in China.15 Having already enlisted for service in Minnesota, Minneapolis and Saint Paul, MN, USA.17 World War 1, Banting completed his accelerated medical Barron had published four case reports; in patient 4, a degree in December, 1916, and reported for duty as stone blocked the pancreatic duct, leading to atrophy of medical officer in the Canadian Army Medical Corps. the exocrine pancreas, but preserving the islets of Arriving in England in spring 1917, he was promoted to Langerhans.17 The patient did not develop diabetes. www.thelancet.com/diabetes-endocrinology Published online October 29, 2020 https://doi.org/10.1016/S2213-8587(20)30337-5 1 TimeCapsule Nov 23–24, 1922 August Krogh visits Toronto, ON, Canada Aug 19, 1922 Nov 8, 1920 Eli Lilly ships insulin to Toronto, ON, Canada Banting meets Macleod June 3, 1922 Patent application by Collip and Best Oct 31, 1920 Banting’s idea March 22, 1922 Publication of results Sept 6, 1876 Dec 9, 1916 July 1, 1920 Jan 23, 1922 John J R Macleod born Banting Banting opens medical practice in Activity of purified extract in a human receives MD London, ON, Canada with diabetes 1880 1890 1900 1910 1920 1921 1922 1923 Nov 14, 1891 1917–18 May 17, 1921 Aug 27, 1923 Frederick G Banting born Banting in Europe for Banting and Best Banting appears on World War 1 begin experiments cover of Time magazine Aug 3, 1921 Oct 25, 1923 Activity of crude extracts in a Nobel Prize awarded to pancreatectomised dog Banting and Macleod Figure 1: Timeline related to the discovery of insulin Barron associated this observation with animal Macleod experiments in which the pancreatic duct had been John James Rickard Macleod was born on Sept 6, 1876, ligated, but in which no diabetes (ie, no glycosuria) near Dunkeld, UK. An outstanding student at Aberdeen developed unless there was observable injury to the University, Aberdeen, UK, he received his Bachelor of islets. Barron deduced that the islets secreted a hormone Medicine and Bachelor of Surgery in 1898. In 1899, he into the bloodstream that controlled glucose metabolism. studied physiological chemistry in Leipzig, Germany, on After reading this article,17 Banting seemingly had a a scholarship. In 1900, he worked as a demonstrator of so-called eureka moment. He envisioned a potential physiology at the London Hospital Medical School, approach to isolating a pancreatic extract related to London, UK, and in 1902, he earned a Diploma of Public diabetes. He was so enthused by his idea that he Health from Cambridge University, Cambridge, UK. telephoned his neighbour and former classmate, Remarkably, in 1903, he was offered the Chair of William Tew, and engaged him in a long discussion.18 Physiology at Western Reserve University in Cleveland, Banting later wrote “It was one of those nights when I OH, USA, where he initiated his lifelong interest in was disturbed and could not sleep. I thought about the carbohydrate metabolism. He was a disciplined lecture and about the article...Finally about two in the aggregator and synthesiser of knowledge. In 1913, he morning after the lecture and article had been chasing published a 1000-page textbook entitled Physiology and each other through my mind for some time, the idea Biochemistry in Modern Medicine, of which he personally occurred to me. I got up and wrote down the idea and wrote more than 90%. spent most of the night thinking about it.”8 Figure 3 Macleod served on the editorial board of the Journal of shows the page from his loose-leaf notebook where he Biological Chemistry and other journals, and procured scrawled “31” over the original entry of “Oct 30/20”: leadership roles in professional organisations, rising, “Diabetus. Ligate pancreatic duct of dog. Keep dogs alive in 1922, to the presidency of the American Physiological till acini degenerate leaving Islets. Try to isolate internal Society. His publication record established him as a secretion of these to relieve glycosurea.” The spelling global authority on carbohydrate metabolism. In 1918 errors are ironic but are characteristic of Banting’s (more than a year after Banting had graduated) the personal writings. This note time stamps the initiating University of Toronto used its growing endowment to event for the discovery of insulin and all that followed.