Profiles, Before and After Insulin: John James Rickard Macleod (1876-1935)

By Christopher J. Rutty, Ph.D

Lead Historian, Defining Moments Canada, “Insulin 100”.

On November 7, 1923, when Professor J.J.R. Macleod announced that he would split his half of the Nobel Prize for the discovery of insulin with J.B. Collip, he emphasized how difficult it was to divide up the insulin work and that it was very much a team effort at the University of Toronto. Eleven days earlier, Frederick Banting had announced he would share his half of the prize with Charles Best. However, as a Toronto Star reporter noted in an interview with Macleod, “You have said nothing in all this of your own share in the work, Dr. Macleod.” He replied to the reporter with a laugh, “Oh. I was only the impresario — the managing director.”

Macleod was not just expressing what might seem to be a self-deprecating characterization of his role in the discovery. He was quite accurate in describing his central and essentially managerial role in facilitating the start and progress of the discovery, and then holding it all together in the face of formidable scientific, medical, technical, ethical, economic, biological, media and personality challenges. A sense of the heavy burden, or “extraordinary pressure,” he bore from his “managing director” role is captured in a letter he wrote as Secretary of the University of Toronto Insulin Committee, to Dr. J.G. FitzGerald, director of Connaught Laboratories, on January 18, 1923. Insulin production at Connaught was limited but growing and there were pressures to distribute it more liberally, yet significant concerns about what was still to be learned about insulin’s safe use.

“We are doing our best here to keep up with the extraordinary pressure and to supply Insulin whenever possible. I am afraid that there are many who feel that we ought to go ahead more liberally, our reason for holding up a too free supply is not only the difficulty of manufacturing it but also the knowledge we have of the complications which would certainly occur if it were placed in the hands of incompetent persons. So far as we are aware there have been no deaths that are directly attributable to over-dose of Insulin and we wish very much to avoid any such occurring. The question of dosage is still very uncertain although we are working on it with all our available resources. I am torn at present between a desire to do my best for the Insulin Committee and to continue with the interesting research work, which this discovery has opened up.”

Historically, Macleod’s role in this discovery has been mostly overlooked, despite his sharing the Nobel Prize with Banting. In this iconic Canadian story, Macleod was the non-Canadian on the team, and the one who soon left Canada to escape the tensions of Toronto that had persisted, especially in his relationship, or non-relationship, with Banting. Once he returned to his native Scotland, Macleod could be easily missed. Even after historian Michael Bliss restored Macleod’s role in The Discovery of Insulin book and subsequent articles, his name still tends to fall at the end of the recitation of Banting, Best, Collip and Macleod. Indeed, as Bliss noted in a biographical lecture about Macleod, “The notion got about that Macleod had not really deserved to share in the prize awarded for the research of those men with such alliterative, assonant and Canadian names, Banting and Best.”

Macleod’s vital role in the insulin story stems from his deep conservatism as a scientist, which can be traced to his early life and education in Scotland. He was born John James Rickard Macleod on September 6, 1876, in the village of Cluny in the northeast of Scotland, the first son of a minister, Rev. Robert Macleod and Jane (McWalter) Macleod. The family moved to the city of Aberdeen when J.J.R. was young and his father was appointed to a church there. J.J.R. went to Aberdeen Grammar School and became a superior student and later entered Marischal College at the University of Aberdeen as a medical student. 

In 1898, Macleod graduated with a medical degree, his high grades earning him the Anderson Travelling Fellowship, which enabled him to spend a year in Germany at the Institute of Physiology of the University Leipzig, where he focused his interests on physiological chemistry. In 1899, Macleod left Germany for London, England, to become a Demonstrator in Physiology at the London Hospital Medical School; in 1902, he was appointed Lecturer in Biochemistry. Also in 1902, Macleod was awarded the McKinnon Research Studentship of the Royal Society while also earning a Diploma in Public Health from Cambridge University. He was quite productive during this period, publishing a series of articles on the influence of compressed air and oxygen on the gasses of the blood while also building a reputation as a lucid and concise lecturer. His reputation caught the attention of officials across the Atlantic at Case Western Reserve University in Cleveland, Ohio, and in the spring of 1903, Macleod was offered the position of Chair of its Physiology Department. In August, 1903, after marrying Mary McWalter, 27-year-old J.JR. Macleod boarded a ship for North America.

It was in Cleveland that Macleod developed his interest in researching carbohydrate metabolism, which is the body’s biochemical process for breaking down carbohydrates into energy. By 1907, his research led to an extensive series of published articles, with the main title of “Studies in Experimental Glycosuria,” in the Journal of Physiology. These formed the basis of his 1913 book, Diabetes: Its Pathological Physiology. Macleod’s understanding of diabetes at the time was focused on the role of the liver in carbohydrate metabolism and its regulation from the brain through the nervous system. His education and training in mainstream physiology in the late 1880s predated the moment when researchers, particularly Joseph von Mering and Oskar Minkowsky, discovered that the pancreas played a key role in the development of diabetes. 

Despite their findings, Macleod remained convinced the cause of diabetes was in the liver. The condition was triggered by the failure of glycogen production and storage in that organ, with the primary cause traceable to excessive nervous stimulation. As he wrote in a 1914 paper, “Diabetes is common in locomotive engineers and in the captains of ocean liners, that is to say, in men who in the performance of their daily duties are frequently put under severe nerve-strain. It is apparently increasing in men engaged in occupations that demand mental concentration and strain, such as in professional and business work.” 

This view of diabetes reflected Macleod’s limited clinical interest in, or experience with, diabetic patients, particularly those severe cases of what would be later classified as Type 1 diabetes. Despite Macleod’s own research and broad understanding of carbohydrate metabolism and experimental diabetes, he remained quite baffled by the newer ideas about hormonal action, such as with an internal secretion of the pancreas. Such ideas were increasingly inserting themselves into the otherwise familiar and comfortable models of diabetes as a nervous system and liver-focused disorder. To Macleod, the existence of such an internal secretion remained hypothetical; its mode of action in controlling carbohydrate metabolism, quite mysterious.

By 1914, Macleod’s work on experimental glycosuria had established him as one of the leading experts in the field, although this line of research seemed to have led to a dead end due to its complexity and the limitations in experimental techniques available at the time. He thus focused more generally on carbohydrate metabolism and wrote what would become his famous textbook, Physiology and Biochemistry in Modern Medicine, published in 1918. However, between 1914 and 1916, Macleod became distracted by news of World War I, and as a British citizen, increasingly unhappy about the non-participation of the United States in the war (the U.S. joined the war on April 6, 1917), and thus uncomfortable in his position at Case Western University. He was familiar with the Canadian war effort through occasional trips across the border. In 1916, Macleod spent part of the winter session in Montreal serving as Professor of Physiology at McGill University, temporarily helping after the sudden death of the former chair. At the end of that year, in fact, Macleod received an attractive offer from the University of Toronto to become the Chair of Physiology. 

In his December 16, 1916, letter to Macleod, University of Toronto president Robert Falconer wrote, “Perhaps at this time you would feel that your future usefulness might be greater within the British Empire than in the United States.” He continued: “You know something of the position of our Faculty of Medicine, also of the fine laboratory facilities that we gave to Professor Brodie, and of the life in the city of Toronto.” (Thomas Brodie was a British physiologist who became Professor of Physiology at the University of Toronto in 1908 and who, as Falconer mentioned in his letter, had recently left the university.) The current Chair of Physiology, A.B. MacCallum, would soon be leaving for an appointment as Chairman of the Dominion Commission on Scientific and Industrial Research. As Falconer further emphasized, “I only know that in Canada we are expecting that after the war we shall enter upon a new era and take a place in the outside world that we have not hitherto occupied.” Macleod was certainly tempted by this offer, but because of his commitments in Cleveland, he had to defer. However, Falconer was so impressed with Macleod’s qualifications that he was willing to hold the position open until the fall of 1918. 

By the time Macleod arrived in Toronto, he had published six books and many articles on various aspects of carbohydrate metabolism. Also of significance, he served on the editorial board of several medical journals, Physiological Abstracts, Journal of Biological Chemistry, Journal of Laboratory and Clinical Medicine, and was a member of the main professional associations focused on physiology and biochemistry. What’s more, even before he had fully settled into his position at the University of Toronto, Macleod had fielded job offers from several other leading American and British medical schools, but he was content to stay in Toronto. He focused his research on exploring centres of respiration in the body, still understanding the problem in terms of the relationship between nervous and chemical factors. But he also paid close attention to new developments in the field of carbohydrate metabolism. One was the interesting idea Dr. Frederick Banting hesitantly presented to Macleod on November 7, 1920.

As Macleod listened to Banting, he was aware that Banting’s proposed experiment — ligating the pancreatic ducts in the hope that the islet cells would remain intact so their secretions survived pancreatic degeneration — had been tried before. But as his diabetes research had been more focused on the liver, Macleod’s understanding of the exact state of research related to the atrophy of the pancreas after duct ligation may have been a little fuzzy. He did know that no one had been successful in doing what Banting proposed. From Macleod’s perspective, it made sense to give him the opportunity to try, as negative results would also be of value. At the time, the physiology laboratories in the University of Toronto Medical Building were being under-utilized and Macleod was in a position to encourage all kinds of medical research. He also recognized that Banting would need considerable direction as he was quite ignorant of the research field he was proposing to enter, inexperienced at doing research, and unsure of the methods to follow and the necessary testing procedures. 

Macleod’s expectations with Banting’s research work, in fact, were quite low, as was his perception of Banting as a scientist and as a man. He and Banting were very different on many levels and their tempestuous relationship seemed inevitable, especially once Banting’s work with Best proved successful in its initial stages and Macleod had to use his research management skills as much as his scientific skills and knowledge in order for the work to continue. Moreover, Macleod was responsible for completing the proof that the internal secretion of the pancreas had indeed been isolated, and that it be conclusively recognized as such, and that it did reliably reduce the cardinal symptoms of diabetes in experimental dogs. Other scientists had gone as far as Banting and Best, so it fell to Macleod to convince scientifically skeptical peers in the diabetes research community his young colleagues had gone even further. 

The addition of Collip to the pancreatic extract research group in December, 1921, accelerated the progress towards a more purified extract. Collip’s work also led to a better understanding of the effects of the extract on the storage of glycogen in the liver, and on clearing up ketoacidosis. Collip’s presence also added to Macleod’s research and personnel management challenges, and it ultimately was his responsibility to convince scientific peers of the veracity of the Toronto results, through correspondence, at scientific meetings, and through his connections with several medical journals. After the first tests of the extract on Leonard Thompson in January, 1922, as historian Michael Bliss succinctly put it, “Macleod was the man in charge of a situation of intense, almost unimaginable pressure, excitement, challenge and potential. The research team had found its way to a Holy Grail and now they had to present it to humanity, and to a sceptical scientific community. The packaging and presentation of the discovery would not be easy.”

Also critical was the need to learn more about the substance the Toronto team had extracted. What was its impact on the body? What was its chemical composition? What was its origin in the pancreas? Macleod personally focused on answering these key physiological questions and he also coordinated research into the extract’s clinical impact on diabetics while also organizing the Toronto group’s publications so the discovery could be presented to the world. Meanwhile, Collip and Best focused on the complex challenges of producing the extract on a larger scale at Connaught Laboratories. Macleod oversaw the larger challenges of collaboration with Eli Lilly to work out much larger scale production methods. This went on at the same time as negotiating the delicate and novel complexities of patenting insulin, as well as the licencing of its production beyond North America while ensuring the Toronto group did not sacrifice control. In the midst of all this, as Bliss emphasized, Macleod “had to hold together a team of researchers who had literally clawed at each other’s throats,” while also “protect himself from Banting’s bitter, malicious attacks on his integrity as a scientist and a man.” 

Nevertheless, according to Bliss, this was Macleod’s “finest hour.” “[H]e employed all of his experience and skills as a scientist, an administrator, and a wise human being, to keep the lid on a tremendously volatile situation, keep the work going steadily forward, organize insulin production and research, and generally carry on the elaboration of the discovery in such a way that the world of science and diabetes quickly realized that Macleod’s physiology lab at Toronto was giving it a very important, very precious gift.” In his own assessment, as he described in his “History of the Researches Leading to the Discovery of Insulin” manuscript from September, 1922, Macleod concluded, “Through concentrated effort, for the co-ordination of which I have been responsible, we have given to Science in little more than one year a practically completed piece of research work — we have proved the value of Insulin.” 

During the years immediately following the discovery of insulin and then the awarding of the Nobel Prize with Banting, Macleod returned to a subject that, for him, was the key physiological question: how did insulin function in the body to facilitate the metabolism of sugar? And for this work, the focus was on the liver, although by 1925, he realized that the principal action of insulin was in facilitating the passage of sugar into the cells. However, as he wrote in his Nobel Prize lecture, “We know nothing of the fate of the glucose which disappears [into the cell].” There was much more to learn about this mystery, but Macleod would play a diminishing personal role in trying to resolve it. He did, however, play a key role through the League of Nations to establish an international biological standard for insulin that ensured a common definition of a unit of insulin.

In 1927, Macleod was invited to return home to Scotland to become Chair of Physiology at the University of Aberdeen. For Macleod, the atmosphere at the University of Toronto had become quite difficult, especially because of his estrangement from Banting. Although they actively avoided each other, Macleod and Banting did share an interest in the arts and in painting. They were both members of the Arts and Letters Club of Toronto, although at different times. The Arts and Letters Club was where the “Group of Seven” first gathered. Macleod was a member of the Club from March, 1921, until the spring of 1923. An early patron of A.Y. Jackson, Macleod bought some of his sketches and invited him to his home for dinner. Banting would be nominated to the Arts and Letters Club in April, 1925, by Lawren Harris, another member of the Group of Seven. Banting became quite close to A.Y. Jackson, and they travelled together on painting excursions. Sometime in 1926 or 1927, Banting and Macleod each contributed paintings to a joint exhibition of doctors’ art at the University of Toronto’s Hart House. However, as Bliss noted in Banting: A Biography, it was Banting’s “virile Canadianism” that attracted more attention than Macleod’s “restrained traditionalism.”

In the summer of 1928, Macleod and his wife Mary headed back home to Scotland. As he sat in the club car on the train that was about to take him from Toronto for the last time, Macleod shuffled his feet. A friend who was with them at the train station ask Macleod why. “I’m wiping away the dirt of this city.” In the fall of 1928, Macleod assumed his new duties as Regius Chair of Physiology, although the University of Aberdeen did not have research facilities comparable to what he had become used to in Toronto. However, he was more than happy to be back home, focused on furthering medical research at the university and improving its research facilities with the help of students who had been drawn to Aberdeen by Macleod’s fame. He was one of Aberdeen’s most famous sons who was honoured by his native Scotland for his distinguished career in physiology. He also seemed to be untroubled by the unfortunate campaign against him that Banting continued into the 1930s and which occasionally, via friend’s letters, rippled from Toronto across the Atlantic.

Macleod remained an active researcher and experimenter, giving numerous lectures and publishing several papers that focused on trying to locate the area in the brain where nervous system control of carbohydrate metabolism originated. However, as Bliss concluded in a special lecture about Macleod, “The co-discoverer of insulin was never comfortable with the endocrine system.”

For Macleod, the damp North Sea climate of Aberdeen soon aggravated the onset of what would become crippling arthritis that increasingly limited his movement. Mentally, however, he remained as sharp as ever and maintained his editorial duties. Macleod’s health steadily declined during the early 1930s, with pleurisy and then pericarditis setting in, forcing him into a nursing home for two months early in 1935. Macleod was able to return home, but on March 16, 1935, he passed away at age 58. His wife, Mary, died five years later. They had no children.

Best and Collip each wrote obituaries for Macleod, with Collip’s the most perceptive. “Macleod,” he concluded, “was distinguished by cheerfulness, kindliness and patience; he was always willing to discuss the problems of his juniors sympathetically and without a trace of condescension. It was typical of him that he would not allow an enthusiastic colleague or assistant to embark on an investigation without pointing out all the technical or theoretical difficulties which would probably be encountered, and yet would supply encouragement and all the practical assistance at his disposal.” Indeed, in the insulin story and in his foreshortened career as a physiologist, J.J.R. Macleod, as he told the reporter back in November 1923, really was “the managing director,” if not “the impresario.”