Insulin Research & Innovation Legacies: Medical Research Missions

By Christopher J. Rutty, Ph.D

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

“Medical Research” was the title of Frederick Banting’s address to the Canadian Medical Association’s annual meeting in Victoria, B.C. in June, 1926. “There is no more important phase of medical science than medical research,” Banting said at the start of his speech, which was published in the CMA Journal’s August issue. At the conclusion, Banting underscored the challenges facing a Canadian physician with a pressing medical research question, or a compelling idea for how to solve it, but few, if any, practical means of carrying out the work in Canada. “When a Canadian visits the medical centres of the United States,” Banting said, “he is astounded at the money and facilities at the disposal of the workers. When we contrast the facilities offered in our own centres, we cannot blame the ambitious Canadian who sacrifices nationality for opportunity.” In October, 1920, Banting had been one of those physicians with a compelling idea, and he was also one of the lucky ones who found support from Professor J.J.R. Macleod at the University of Toronto, although that support was very modest (a small laboratory, several experimental dogs, $100 in cash, and a freshly graduated assistant).

As Banting emphasized at the end of his CMA address, the Banting Research Foundation had been established a little over a year earlier “to assist those who cannot readily obtain assistance from other sources.” Its mission, he said, was “to promote the carrying out of medical research by the men who have the ideas, by providing them with the necessary facilities.” At the time, there was no other medical research foundation in Canada, and several women would be among the recipients of research funds. The Foundation’s first fundraising campaign began in 1925, but it would take a few years of organization to build a capital fund before sufficient earnings enabled the first grants to be distributed in 1928. A portion of the Foundation’s earnings were to also support the Banting and Best Chair of Medical Research at the University of Toronto, and the research led by Banting.

Ironically, during the mid-1920s, Banting was one the best funded medical researchers in Canada thanks to insulin patent royalties, a federal annuity, an annual provincial grant to the Banting and Best Chair of Medical Research, as well as his share of the Nobel Prize and other awards. However, he was a very frustrated medical researcher. He was Canada’s first Professor of Medical Research, yet his funding was not paying off with the great insulin follow-up discovery everyone expected, including himself. He had a skilled assistant in Sadie Gairns, who had begun working with Banting in October, 1922. She had an undergraduate degree in Household Science from the University of Toronto and a Masters in Physiology completed under Macleod’s supervision. Banting would have preferred a male assistant, but when she was hired by Professor Velyien Henderson, chair of the Pharmacology Department, there were insufficient funds in the Department to pay for one. A year later, there certainly was enough money to hire a male assistant, but Banting was quite happy with Gairns, who proved invaluable for her research skills and her loyalty during a challenging period for Banting.

By the fall of 1923, Banting’s research had little to do with insulin or diabetes. Indeed, during a visit to London, Ont., on the third anniversary of his middle-of-the-night moment of inspiration, he said, “Three years ago I became engaged, two years ago last May I was wed, and today I apply for a divorce from insulin.” His last paper on the subject — “Factors Influencing the Production of Insulin” and co-authored with Gairns at Banting’s insistence — was published in January, 1924. In it, he applied what he had learned with pancreatic extracts to other glands, such as the adrenal cortex, in hopes of extracting similar substances that showed promise, such as an “universal antitoxin” that could be bigger than insulin. But he had his misgivings. In November, 1923, amidst the frenzy of the Nobel Prize news, Banting admitted, “I stand in a very precarious position, with so many people expecting something and I have nothing to offer.”

Despite a lack of success in the lab, Banting pressed on with cancer research based on preparing an extract from a human cancer tumour, but nothing much happened. Another cancer research project followed, based on a tumour that affected chickens and seemed transmissible through what would later be shown to be a virus. This suggested cancer could be created in the lab and thus an agent, Banting thought, such as a serum, antitoxin or vaccine, might be found to stop its progress. Perhaps this insight could lead to a cure for cancer. However, encouraging results would be limited and ultimately fruitless.

Apart from assistance from Gairns, Banting conducted his research alone. His personal and professional break with Macleod, who left Toronto in 1928, deprived him of potential scientific support. During the mid-1920s, Best was also unavailable as he was in England doing postgraduate work. and would not return until December 1926. Through the summer of 1925, encouraged by Dr. J.G. FitzGerald, director of Connaught Laboratories, Banting began to patch things up with Collip. There had been limited contact since Collip returned to the University of Alberta in the summer of 1922. But after the 1926 CMA meeting in Victoria, Banting arranged to meet Collip in Calgary, hoping to bury the hatchet.

In contrast to Banting, who drew the most public attention, Collip enjoyed the most success in Canadian medical research during the 1920 and 1930s. Banting’s reconnection with Collip began with a letter congratulating him on his recent research that led to the isolation of the parathyroid hormone, dubbed parathormone, which regulates the amount of calcium in the blood and its effects on bones, kidneys and the intestine. As with Banting, income from Collip’s share of insulin patent royalties soon became a significant and growing source of funding for his biochemistry research and would follow him to the University of Alberta until his move to McGill in 1928, and then to the University of Western Ontario when he moved there in 1947. In 1925, insulin royalties for Collip amounted to $8,000. In addition, Collip had brought his share of the Nobel Prize (given by Macleod) to Edmonton, which in turn attracted donations and research grants: the College of Physicians and Surgeons of Alberta donated $9,000, while the Rockefeller Foundation awarded Collip $5,000, and the Carnegie Foundation gave $10,000. With such funding, Collip was able to establish a well-equipped laboratory to match what he used in Toronto, hire research assistants, and free himself from any teaching responsibilities. Also, unlike Banting, Collip pursued further education, earning a D.Sc. in 1924 and a M.D. in 1926, both from the University of Alberta, while also engaging in his research work.

Collip’s initial focus upon his return to the University of Alberta was to manufacture insulin on a small scale for clinical use, and also to continue experiments with it. In early December 1922, Collip’s insulin was employed to revive an 8-year-old girl from a diabetic coma. The dramatic story of insulin saving her from “death’s door” drew North American press coverage. Collip’s insulin research led him to extract and test an insulin-like substance from plants, which he called “glucokinin” and initially appeared to be a promising alternative source of insulin. However, as with the initial enthusiasm surrounding Banting’s adrenal cortex extract work, Collip’s excitement about glucokinin got ahead of a clear understanding of its therapeutic value. Collip was well aware of other ongoing research elsewhere along similar lines, and he was intent on securing his claim for priority. However, it became clear that the promise of glucokinin was premature and Collip soon shifted his research focus away from plants and potential insulin sources to the special problems of animal and human physiology and health.

The discovery of insulin and its successful and very often dramatic treatment of diabetes stimulated many researchers to investigate other glands and the hormones they produced. Before insulin, extracts of adrenalin and thyroxine had been utilized to treat rare conditions. But insulin represented the first substantive hormone treatment for a disease that was neither rare nor controllable with any confidence. Collip was very much at the forefront of post-insulin glandular and hormonal research, starting with the parathyroid gland. In 1891, physiologist Eugene Gley, first showed that when the glands were surgically removed, generalized and severe muscle contractions (tetany) would occur in a patient, leading to death. It was also known that treatment with calcium salts had some effectiveness as a treatment, as were crude extracts or grafts of the gland.

Following a similar laboratory procedure as he had employed to derive insulin, Collip was able to isolate and purify the parathyroid hormone and then use it to successfully treat a child suffering from severe muscle contractions. Further building on his insulin experience, Collip sought a patent and also a partnership with Eli Lilly to develop and market the hormone treatment. However, he was soon confronted with a rival claim for similar parathyroid hormone work by a physician, Adolph M. Hanson. He was an independent physician-scientist with surgical training, based in Minnesota, who, in 1922, set up a small lab in the basement of his home to conduct experiments. In the end, Hanson won the patent fight, but Collip ultimately won the scientific credit for preparing an active extract and providing definitive proof of its biochemical activity and physiological effect. (In 1959, the University of Alberta installed a bronze tablet at the Department of Biochemistry which captured the international recognition Collip had earned for work on the parathyroid hormone.)

Collip’s multiple successes as a medical researcher in biochemistry and physiology, as well as his study of hormones, led to several invitations to move to the University of Minnesota, or to McGill University. (There had been an earlier offer from McGill, but he wanted to first establish a strong research capacity at the University of Alberta.) But in 1927, McGill asked Collip to facilitate a more robust laboratory research culture and step in as the medical school’s new chair of biochemistry. He couldn’t refuse the offer. Before accepting McGill’s invitation, Collip had held back the fact that he would be bringing his insulin royalties to Montreal, which in 1927 amounted to $13,648, or $2,500 more than the 1926 total. He did not want this asset to unduly influence the decision of McGill’s administration to proceed with his appointment. In November 1927, once Collip had agreed to the move to McGill and information about the royalties was known, he noted in a letter that if the value of the royalties kept increasing, “research should not suffer from want of money.”

Collip started at McGill on June 1, 1928. He continued with further parathyroid hormone research until early 1930 when his “luck” struck again. He extracted hormones from placenta, prompting a new phase of focused endocrinology research into sex hormones. The placental extracts caused juvenile rats and mice to mature early. Of particular significance, the extracts were active when administered orally. This work was less driven by extracting hormones to treat specific diseases or conditions, and more about developing a better understanding of the specific functions of sex hormones in human reproduction and how such functions could be regulated in response to particular problems.

Collip was able to clinically test the placental extract’s effects, for example, on patients with delayed puberty, and reported very encouraging results with treating infrequent menstruation, painful menstruation, and distressing menopausal symptoms. Collip’s placental hormone work, as well as similar work with pituitary hormones, led to the development of oestriol, Premarin, Pituitrin, and Emmenin, the latter used as an estrogen replacement. Collip’s most famous co-discovery after insulin was the isolation of the adrenocorticotrophic hormone (ACTH), which is produced by the pituitary gland and influences the action of the adrenal cortex. ACTH is often produced in response to biological stress, with its main effects being the increased production and release of cortisol by the cortex of the adrenal gland.

During the mid-to-late 1920s, Banting’s work at the University of Toronto and Collip’s at both the University of Alberta and McGill represented essentially all of the medical research being conducted in Canada. Their work was funded through insulin patent royalties and research grants and awards derived from their insulin work. Such funding had made possible the establishment or expansion of biochemical research laboratories beyond the University of Toronto, the results in the field of endocrinology being of particular significance.

Starting in 1928, the proceeds of the Banting Research Foundation began to flow and stimulate a further expansion of medical research work by grant recipients based in other Canadian universities as well as some working independently. Among the first were Dr. Bruce Chown, a pathologist at Winnipeg Children’s Hospital and physician in charge of out-patient tuberculosis and cardiac clinics; and Dr. J.L. Jackson, a lecturer in anatomy at the University of Manitoba medical school. Chown’s work was focused on pyelonephritis, a severe type of inflammation of the kidney, in children, while Jackson’s research project involved studying the histology of the thyroid gland.

At the Foundation’s Annual Meeting in November, 1930, it was reported that $30,000 had so far been disbursed, a portion for the maintenance of research work conducted in the Banting and Best Department of Medical Research. Most of the grants were designed to support the living expenses, supplies and apparatus of applicants who proposed to undertake investigations of medical problems. Between 1928 and 1931, Foundation grants were awarded to 38 applicants.

News of the Banting Research Foundation annual meetings was not just reported in the Canadian medical press, but also in elite journals like Science, Nature, and the British Medical Journal. In the February 12, 1932, edition of Science, a report on the Foundation noted that “during the past year, in spite of the exercise of great care in the selection of the problems to be supported, the trustees have expended practically the whole of their annual income.” There was, therefore, “little doubt that this foundation has contributed not a little to the development of medical research, especially in those medical schools in Canada which have the smallest incomes.”

In a February 10, 1934, report on the Foundation in Nature, it was noted that a total of 92 grants had been disbursed since 1928 among 63 individual researchers. They were based at the University of Alberta (4), the University of Saskatchewan (2), Dalhousie University (8), Queen’s University (2), the University of Western Ontario (2), the University of Manitoba (16), McGill University (26), and the University of Toronto (30). Two grantees were not affiliated with a university. There had also been at least 50 papers by grantees published in scientific journals, with a further 15 papers ready for publication. In addition, funds provided to the Banting and Best Department of Medical Research had supported research described in numerous publications on silicosis, the action of vitamins, and a variety of other topics. As was also noted in both Nature and Science in early March, 1934, the depression has increased demands for funding on the Foundation. As was reported in Science in June, 1938, after ten years since the Foundation’s first grants were made, there had been a total of 184 grants disbursed to 110 individuals in universities across the country. The list of institutions now included the University of British Columbia and Brandon College in Manitoba.

In the summary of the Foundation’s annual report for 1938-39, published in Science in April, 1940, it was noted that based on the applications recently received, “it was obvious that the modern trend of medical research is increasingly towards learning more about the formation, nature and action of substances which exert physiological effects and which, in deficiency, excess or altered forms, induce pathological states.” This trend continued, but with the onset of World War II, would soon be overshadowed by more pragmatically focused research. However, by the time Canada entered the war in September, 1939, the Banting Research Foundation was no longer the only source of medical research funding in Canada.

In February, 1938, Banting was asked to chair the newly established Associate Committee on Medical Research, which was part of the National Research Council. By then, Banting had been given the knighthood title of “Sir,” in 1934 by Prime Minister R.B. Bennett, and was serving on the National Research Council in recognition of his role as the first national spokesman for medical research in Canada. The NRC had been established in 1916 as a semi-independent, government funded body set up to coordinate and encourage all kinds of scientific research in Canada. It lacked a focus on medical research until 1935, when a new president, General A.G.L. McNaughton, pressed for the creation of a special associate committee for medical research. When Banting joined the NRC in 1937, there was still no public agency dedicated to medical research, although the NRC had been active in funding some tuberculosis, radiology and radium research.

After broad consultations, the Associate Committee on Medical Research officially launched at a special conference in Ottawa. As the Globe and Mail reported on February 19, 1938, “Banting Heads New Medical Research Body.” Initially, as Michael Bliss noted in his Banting: A Biography book, Banting had reluctantly agreed to leading the committee, apparently telling McNaughton he did not feel qualified for the job and did not really deserve his reputation. McNaughton disagreed. “You’ve got a reputation in this field and I haven’t. Whether it’s deserved or not makes no difference. You’ve got it. You can do this better [than I] and it’s your duty to do so.” Banting was not one to refuse an appeal to duty. “Yes, sir. I’ll do it.”

The committee’s first task was to survey the state of medical research in Canada to find out who was doing what research where. The fact-finding mission was a grueling trip for Banting, travelling the country and giving lots of speeches. But he was able to visit with old friends, including Collip, while visiting Montreal. The obvious challenge was that almost everyone was handicapped by having too many students, too few technicians and never enough money for research. Banting and the committee did note, however, the impressive work being done in Toronto and Montreal, and also at the University of Manitoba. During its first year, the Associate Committee received applications for $125,000 of funding, but it only had a budget of $53,000, of which only $28,000 was available for new research grants.

Canada’s entry into World War II in September, 1939, upset the Associate Committee’s plans as the scientific community and the NRC assumed a central position in all aspects of the Canadian war effort. By 1942, most of the peacetime medical research program had been suspended in favor of focused and expanding research in support of the war effort, both for the health of the military and civilian populations. As leaders of Canadian medical research, when the war began this work was directed by the three surviving members of the insulin discovery team (Macleod had died in Scotland in 1935) through the establishment of three special subcommittees.

Banting chaired the Committee on Aviation Medicine, with members of the Banting and Best Department of Medical Research heavily involved in aviation medicine studies, including developing the first anti-gravity suit to allow pilots to withstand high gravity forces without blacking out. Best chaired the Naval Medical Research Associate Committee and focused on seasickness studies. Collip, in turn, was attached to the Army Medical Research Associate Committee and he also served as vice-chair of the main medical research committee. He often took over meetings during Banting’s frequent absences, which included visits to the U.K. in December, 1939, and January, 1940, to liaison with the British Medical Research Council in its war work. Of particular interest to Banting was investigating the potential threat of bacteriological warfare through Canada’s top-secret M-1000 Committee.

On February 15, 1941, Banting received a call ordering him to take another trip to the U.K., but this time the journey would be quite different. Much had happened with the war and Banting’s work since his last overseas trip. His research, in fact, seemed under control in Canada. Banting wanted to be where the action was. But when he finally got the call, it was not clear how long he would be away. He would be flying across the North Atlantic from Gander, Nfld., as a lone passenger on a new Lockheed twin-engine Hudson bomber plane in the middle of winter. Such trans-Atlantic flights were still quite rare and had not always been successful. Several of the Hudson bombers, made in the U.S., were needed in England and were to fly over together in a ferry operation, with Banting as a passenger on one of them.

After getting the phone call with the order to depart, Banting felt worried about the flight itself, and his anxiety increased when he learned more about what would be involved and the clear risks. Sadie Gairns suggested he stay, but Banting wanted to be useful and accept his wartime duty, in spite of the risks. The excursion began on February 16th with a train trip to Montreal, where Banting met with Collip for a long talk during which they reminisced about the old insulin days twenty years earlier. In assessing who really deserved the credit for the discovery, Collip suggested it was 80% Banting, 10% Best, and 5% each to Collip and Macleod. “You know damn well we couldn’t have done a damn thing without you,” Banting replied.

The next morning, Banting boarded one of the Hudsons in St. Hubert, just outside Montreal, for the five-hour flight to Gander. But inclement weather to the east and then a local blizzard delayed his departure from Gander for several days. Banting had some time to kill and soon found himself socializing with the air crews and medical officers at the base, who were surprised to learn that their passenger was the famous doctor who discovered of insulin. What was he doing flying the Atlantic in a Lockheed Hudson in the middle of winter?

Finally, on February 20th, the crew began to pack up for the flight. Banting was alarmed to learn that three of Hudson flying team had been killed the day before, shortly after taking off from St. Hubert. Nevertheless, five of the Hudsons took off from Gander (one remained with engine trouble). Before long, radio operators on four of the bombers heard a call from Banting’s plane that they needed to instructions to turn back to Gander. Radio silence followed. They had flown 70 km over the north Atlantic when an oil cooler in one engine forced a shutdown. The plane could make it back with one engine, but then the oil cooler on the second engine also failed, leaving the plane engine-less.

The Hudsons were not well-designed for gliding. The pilot, Joseph C. Mackey, hoped to land in a flat area, but he could not avoid a crash landing. There was no fire, and both Mackey and Banting survived the crash. However, the radio operator, William Snailham, and the Flying Officer, William Bird, were both killed. Banting suffered a serious head injury and a punctured lung. As Mackey later told a Toronto Star reporter, he was able to stabilize Banting and talk to him. However, by noon the next day, February 21st, Banting had fallen into deep unconsciousness and Mackay decided to try and get help. Alone, Banting regained consciousness. He managed to get out of the plane and scrambled into a snow drift. Mackey later came back to the plane to find Banting dead. He lit some signal flares, but search planes were unable to leave Gander until 2:00 PM on the 21st.

Banting’s colleagues and the press were told the plane was missing. Search crews finally found the crash site on February 24th, just as Mackey was about to give up and trek to a railway track. A search team in a Hudson had seen the aluminum powder Mackey scattered outside, along with a message he stamped out in the snow, THREE DEAD – JOE. The official public announcement of Banting’s death was made in the House of Commons, with a private funeral held on March 3rd. Banting’s body lay in state at Convocation Hall at the University of Toronto until a state funeral service was held on March 4th. When the next meeting of the Associate Committee on Medical Research took place, the members observed a long moment of silence. Collip had been the last of Banting’s friends and colleagues to see him alive, and he was especially mournful at his death.

Collip succeeded Banting as chair of the Associate Committee on Medical Research and become the clear leader in Canadian medical research. Collip led the Associate Committee until his formal retirement in 1957, and also built a strong medical research capacity at the University of Western Ontario as its dean of medicine, starting in 1947. Meanwhile, medical research in Canada expanded and transformed during and after the war. Indeed, by the time Collip died in June, 1965, medical research had evolved far beyond what the discovery of insulin sparked in 1921 and what Banting had hoped for in his “Medical Research” speech in 1926.