Convincing Macleod

Photograph of J. J. R. Macleod, c. 1906, University of Toronto, The Discovery and Early Development of Insulin.

Dr. Frederick Banting didn’t quite know what to expect when he met Dr. John J. R Macleod (1876-1935), head of physiology at the University of Toronto, on November 7, 1920. Banting had done some research in the University of Western Ontario (UWO) medical library and found nothing that resembled his pancreatic extract idea. He had also consulted UWO professor of pharmacology J.W. Crane, who wasn’t aware of anything similar to what Banting had described. 

Before leaving for Toronto, Banting had had a long talk with a former classmate, Dr. Bill Tew, who had also started a practice in London in 1920. Tew observed that Banting’s excitement was driven, at least in part, by his frustrations in London. So Tew asked Banting whether it was worth abandoning his practice to pursue his extract scheme. Banting’s fiancé, Edith Roach, was also pressuring him to marry and settle down in London. 

Expressions of caution came from other sources as well. Banting’s mentor, Dr. Clarence L. Starr, chief surgeon at Toronto’s Hospital for Sick Children, warned him against hastily giving up on a promising practice and a teaching assignment at UWO. It was the wedding of one of Starr’s daughters on the weekend of November 5-6 that brought Banting to Toronto. But after telling some of his surgical acquaintances about his idea and of immediately giving up his London practice to pursue it, they all advised against such a radical move. However, with recommendations from Prof. Miller of UWO and Starr, Banting, a medical graduate of the University of Toronto, arranged a meeting with Macleod.

Macleod was an intimidating figure. Born in Scotland, he rose quickly in the field of physiology through his studies in Germany and England before becoming chair of physiology at Western Reserve University in Cleveland, Ohio, in 1903. While in Cleveland, Macleod focused his research on carbohydrate metabolism and diabetes. His 1913 textbook, Diabetes: Its Physiological Pathology, became a standard in the field. 

In 1916, when U of T’s chair of physiology post opened up, Sir Robert Falconer, the university’s president, courted Macleod. Macleod was interested, but unable to accept the offer at the time. However, Falconer was so impressed with Macleod’s reputation that he held the position open for a year in hopes that he could take up the post in the fall of 1918 — which is what happened. By the time he arrived in Toronto, Macleod had published six books and many articles. He also served on the editorial boards of several medical journals. What’s more, between 1918 and 1920, he was offered positions at other leading universities, but he chose to remain in Toronto. 

Photograph of J. J. R. Macleod in academic robes, c. 1923. University of Toronto, The Discovery and Early Development of Insulin.

The meeting between the illustrious American physiologist and the young London physician lasted about an hour. As Banting later recalled, it started off poorly, with Macleod initially showing little interest in his duct ligation idea. He emphasized that Banting only had superficial textbook knowledge of the work that had already been done with pancreatic extracts by many eminent and well-equipped researchers. 

Moreover, no one had yet proven that the internal pancreatic secretion even existed. The distinctive islet cells within the pancreas were clear, and it was also clear that diabetes develops in their absence. However, actually isolating the secretions the islet cells supposedly produced remained elusive. The challenge had been that, when preparing pancreatic extracts, the powerful digestive ferments of the external secretion of the pancreas effectively destroyed the internal secretion. However, as Banting argued, this was precisely the problem that the idea of ligating the pancreatic duct would solve. As the Barron article Banting had read on October 30th had shown, the effect of ligating the pancreatic duct was to destroy the cells that produced the digestive ferments even while leaving the islet cells undamaged.

Banting’s and Macleod’s subsequent summaries of the discovery of insulin, written in September 1922, do not provide full details of that initial discussion. However, Banting did note that Macleod sat back in his chair and closed his eyes while he thought for a few minutes. He then said, “This might be the means of getting rid of the external secretion.” As far as he knew, Macleod continued, this method had not been tried before. “It was worth trying…[N]egative results would be of great physiological value.” 

Banting later recalled that Macleod repeated that phrase at least three times. But the young doctor wasn’t interested in sacrificing so much of his time and energy, and giving up appointments at UWO, only to get “negative results” that would be of significant physiological importance. Emphasizing that there were no research facilities at UWO, Banting said he was willing to come to Macleod’s lab to work on the problem. “This he consented to do.” 

Macleod, in turn, recognized that Banting had considerable skills as a surgeon, as Starr could confirm. Unlike non-surgeon’s previous failed attempts to ligate pancreatic ducts, Banting stood a better chance of completing the procedure effectively. His surgical skills would also be of value if any pancreatic grafts or transplants were required.

Banting was anxious to get started and sell his house London. But Dr. Starr would not hear of it. He advised Banting to stay put until the school term was over, building up his practise and continuing to work at the UWO medical school. Starr advised Banting that he could then “try out my idea if I still desired to do it.” During that winter, Banting focused on further research into carbohydrate metabolism and diabetes. “The more I read and thought on the subject and the more subsidiary experiments which I planned, the more impatient I became.” 

Banting wrote to Macleod on March 8, 1921, suggesting that he come to Toronto from May to July, if the offer was still good. On March 11th, Macleod replied: “I will be glad to have you come here on May 15th, as you suggest, to see what you can do with the problem of Pancreatic Diabetes, which we spoke about.” 

Letter to Banting from MacLeod on March 11, 1921. The letter outlines the best time for Dr. Banting to start his research and testing, i.e. before or after Easter. University of Toronto, The Discovery and Early Development of Insulin.

In the meantime, Banting’s practise had picked up and his fiancé pressed him to stay. Banting broke off the engagement, yet he remained unsettled and indecisive. He certainly didn’t want to stay in London. Besides Macleod’s offer, he also had an opportunity to serve as a medical officer on an Arctic oil expedition. In mid-March, Banting flipped a coin to decide between the two. The Arctic expedition won, but he soon learned that the ship didn’t need a medical officer after all. Thus, apparently destined to pursue his diabetes research in Toronto, Banting closed his practice on April 26, but didn’t sell his house. He headed to Toronto to find a place to live, but he had to return to London. Finishing some work at UWO kept Banting in London before finally escaping to Toronto on May 14.

When Banting next met with Macleod, at U of T’s physiology department, the esteemed  professor still had his reservations about Banting’s knowledge and practical familiarity with what would be involved in the research — from the precise surgical procedures on dogs to careful record keeping, and a complete understanding of the course of diabetes in the dogs. While Macleod advised Banting on a research plan and surgical techniques, he knew the young surgeon would need assistance with the testing of blood sugar levels, as well as nitrogen and sugar levels in urine. Macleod invited two of his best research fellows to meet with Banting. Charles Best and Clark Noble were both fourth-year students in the Honours Physiology and Biochemistry course. They had worked for Macleod as demonstrators and research assistants. Best and Noble were good friends and needed summer work. Banting could only use, and Macleod could only afford to pay, one assistant from mid-May through the end of June. He could employ the other during July and August, if necessary. Best and Noble decided to flip a coin to decide who would work first with Banting; Best won the toss.

Portrait of J. J. R. Macleod, c. 1928. University of Toronto, The Discovery and Early Development of Insulin.

As Banting and Best were getting acquainted, Macleod was preparing a paper for the Ontario Medical Association’s annual meeting, which was to be held in Niagara Falls between May 31 and June 3. He was to be part of a symposium on diabetes; his paper, “Methods of Study of Early Diabetes,” was subsequently published in the January 1922, issue of the Canadian Medical Association Journal

The timing of his presentation to the conference and its introduction offers some insights into how Macleod viewed Banting’s research. “In the study of no other non-infectious disease has there been closer collaboration between laboratory and clinical investigators than in that of diabetes,” he said. “Indeed this was one of the first diseases in which such collaboration was attempted and it is significant that the most important steps in the advance of knowledge in this field have usually been made by men who have themselves been thoroughly familiar with the experimental investigations, often by actual participation in the work, which at the same time engaged in clinical practise.”