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Success Has Many Parents: J.B. Collip’s Role in the Discovery of Insulin

By Alison Li

Alison Li is an historian of science and medicine based in Toronto. She is the author of J. B. Collip and the Development of Medical Research in Canada (McGill-Queen’s University Press, 2003). Her current project, Wondrous Transformations: A Maverick Physician, the Science of Hormones, and the Birth of the Transgender Revolution, will be published by University of North Carolina Press.

If there is one moment when the Toronto researchers can be said to have discovered insulin, it would be late on the night of January 19, 1922, when biochemist J.B. Collip watched a relatively pure white substance precipitate out of solution. As a colleague put it years later: “Collip then actually saw insulin.”^[1]

The goal that Frederick Banting had set out to achieve when he began his research in May, 1921, was not new. In the decades before, approximately 400 researchers had attempted to extract an anti-diabetic compound from the pancreas. Several had come close. Some had succeeded in preparing a substance that lowered sugar in the blood and urine of test animals and caused the relief of the symptoms of diabetes. None, however, had been able to make an extract sufficiently pure that it could be used in humans. The few times such extracts were tried on humans, painful infections and abscesses resulted at the site of injection, making it impossible to continue with the treatment.

Through the summer and autumn of 1921, Banting and his student assistant Charles Best had not achieved any results that were not already reported in the published work of other researchers. The defining moment—when the Toronto group went beyond what had been accomplished by predecessors such as George Zuelzer, E.L. Scott, Nicolas Paulescu, John Murlin, and Israel Kleiner—came that January night, when Collip made a preparation purer than previous versions. This substance was by no means purified insulin, but it was potent and sufficiently free of contaminants that it could be safely used on a human subject. Four days later, on the morning of January 23, 1922, Dr. Walter Campbell gave the first of several doses of the extract to Leonard Thompson, a 13-year-old boy with diabetes.^[2] The results were unambiguous: the boy’s blood sugar dropped significantly, and the sugar and ketones in his urine disappeared. The absence of excess sugar in the blood, and of sugar and ketones (partially burned fats) in the urine showed that his body was now able to metabolize sugar. Thompson, who had been a listless 30 kilograms and close to death, began to feel brighter, stronger, and more active. His recovery marked the first clear evidence that this pancreatic extract could be an effective treatment for diabetes.^[3]

The insulin discovery has come to be associated with the names of Banting and Best. Indeed, Banting and J.J.R. Macleod, a University of Toronto professor of physiology, were awarded the Nobel Prize in 1923 for insulin. What might seem strange is that Banting promptly announced his intention to share his half of the award with Best, while Macleod declared he would share his portion with Collip.

Who was Collip? Why had Macleod shared his Nobel Prize with him? And what role had he played in the discovery? Indeed, we can ask why Collip’s name is not better known.

James Bertram Collip was born in Belleville, Ont., on November 20, 1892, the son of a florist, James Dennis Collip, and a teacher, Mahala Frances Vance. In his professional life, he always went by J.B. Collip rather than James, but was known to his friends and family as Bert. He attended a one-room country schoolhouse and sold cabbages from his family’s market garden. At the age of 15, he entered Trinity College at the University of Toronto, where he originally intended to study medicine. Because he was too young to enter the medical faculty, he enrolled in the honours physiology and biochemistry program instead. There, he rose to the top of his class. Collip gained a rigorous education in the biomedical sciences and a taste for original research.

After completing his Bachelor of Arts in 1912, he decided to pursue graduate work in biochemistry under the supervision of Archibald Byron Macallum, the chair of biochemistry. He earned a Master of Arts in 1913 and a PhD program in 1916, for his research on the formation of hydrochloric acid in the vertebrate stomach. Collip tried to impress Macallum by staying late in the laboratory and, in doing so, learned to love working in the quiet hours of the night.

Collip met the vibrant and fun-loving Ray Vivian Ralph, an arts student, at Trinity’s sister college, St. Hilda’s. They were married in 1915 and she became his constant companion, learning to keep a suitcase packed and ready because of his penchant for spur-of-the-moment trips. They had three children, Margaret, Barbara, and John.

In 1915, Collip joined the faculty of the University of Alberta as a lecturer in biochemistry in the department of physiology. During World War I, he taught in the department and persevered in his research, even though time and resources were scarce. In the summers, he, Ray, and their young children would go to the Pacific Biological Station in Nanaimo, where Collip studied the pigmentation of salmon and the luminescence of marine worms. He later enlisted his medical students’ help with his study of the effects of rapid breathing on the concentration of carbon dioxide in the blood.

At the end of the war, Collip was awarded a Rockefeller Travelling Fellowship. His plan was to take his family with him to spend his sabbatical of 1921-22 in Toronto, New York, and England. His leave began in April, 1921, when he travelled to the University of Toronto to work with Macleod, a respected expert in carbohydrate metabolism. One day that May, Collip sat in on a meeting between Macleod and Banting, who wanted to spend the summer attempting to prepare an extract of the pancreas to treat diabetes. Collip offered to help and gave Banting an address where he could be reached. He and his family then spent the summer visiting the marine biological stations at Woods Hole, Massachusetts and St. Andrews, New Brunswick, and returned to settle in Toronto for the autumn.

Collip was a skilled biochemist, known for his energy and flair in working up extracts. Although carrying out his own studies, Collip continued to follow the work that Banting and Best were doing under the guidance and supervision of Macleod. He offered to help and may have shared with them a new method of blood glucose analysis that he had picked up that summer at Woods Hole. Banting wanted to bring Collip in on the work, but Macleod was not yet convinced that enough progress had been made to involve others.

By December, Banting and Best had succeeded in compiling experimental evidence that extracts of animal pancreas could reduce the sugar in the blood and urine of dogs that had been artificially made diabetic. Because the work now looked more promising, Macleod agreed that Collip should be invited to participate. By December 12, 1921, Collip had begun to study the problem in earnest. In an early misstep, he asked the city abattoir for “sweetbreads” and was given thymus rather than pancreas tissue. (“Sweetbread” is a culinary term that can refer to both the thymus gland and the pancreas.) Banting liked to tell this embarrassing story at Collip’s expense. More importantly, Collip set up a series of experiments and testing methods that allowed him to quickly and systematically advance the purification problem.

First, he determined that the potency of the extract could be tested on rabbits even if they had not been made diabetic. Banting and Best had been testing the extract on a small number of dogs in which they had triggered diabetes through the surgical removal of the pancreas. That process required considerable time, effort, and expense. Using ordinary rabbits was far faster and more economical.

Second, by introducing a newly developed method of blood-glucose analysis (the Shaffer-Hartman technique), Collip gave the team a means of quickly evaluating the potency of each test batch of extract. This technique required a far smaller quantity of blood than the methods used by previous investigators. Collip could get a small sample from the ear of a rabbit and then take repeated samples without harming the animal. This approach gave him the ability to rapidly test various fractions of the extract to determine if they contained the agent that could be used to treat diabetes.

Using these methods, Collip found he was able to make swift progress. Banting and Best insisted on making the first clinical trial with an extract they had prepared. On January 11, 1922, their preparation was injected into Leonard Thompson at the Toronto General Hospital. There was no clinical benefit. While there was a small drop in Leonard’s blood sugar, other key markers of diabetes–such as the presence of ketones in his urine–were not affected by the injection. In addition, an abscess developed at the site of injection, making it clear this extract could not be used in humans.

Eight days later, Collip was working late at night in his laboratory when, using established techniques of isolating protein, he figured out a way to trap insulin by gradually increasing the alcohol concentration of the solution in which the pancreatic tissue had been dissolved.

At about 80 percent ethyl alcohol, most of the impurities came out of the solution and could be filtered off. Then, when Collip increased the alcohol level to 95 percent, a white substance precipitated out. “The problem,” he wrote, “seemed almost hopeless so you can imagine my delight when about midnight…I discovered a way to get the active principle free from all the ‘muck’ with which it appeared to be inseparably bound.”^[4] In a few short weeks, Collip had accomplished what many other researchers had failed to do.^[5]

Collip tested the purity of this substance on rabbits over the next few days. At 10 a.m. on Monday, 23 January 1922, the preparation was injected into Leonard Thompson. The strikingly good results from this second clinical test on the boy marked the first unambiguous demonstration of the use of a pancreatic extract as a therapeutic agent in human diabetes.

During this intense month of work, Collip also made several key physiological observations that were critical to the success of the Toronto team. He was the first to describe the acute hypoglycaemia which occurs when too high a dose of insulin causes the blood sugar to fall to dangerously low levels. This discovery allowed Collip to warn physicians of the danger of insulin overdose in the team’s early scientific papers. Second, he demonstrated that glucose in the blood was converted into glycogen in the liver by the action of the extract. Third, he showed that ketones in the blood and urine were eliminated when the extract was used.

These pieces of evidence were crucial. Banting and Best had succeeded only as far as showing that their extract reduced glucose in the blood and urine. But that result was not definitive and had already been established by other researchers. Collip’s experiments clearly demonstrated that the extract replaced metabolic functions missing in the diabetic patient. This compelling evidence convinced the scientific community that insulin really was a hormone in the pancreas, and the factor required by people with diabetes.

Of this incredible period of research, Collip recalled, “I have never had such an absolutely satisfactory experience before, namely going in a logical way from point to point into an unexplored field building absolutely solid structure all the way.”^[6]

In contrast, Collip’s relations with Banting were becoming more and more strained. Banting was anxious that Macleod and Collip were attempting to take credit away from him. When Collip announced to Banting and Best that he had been advised by Macleod to keep his extraction method a secret until it had been fully tested, an angry confrontation broke out.^[7] In the days that followed, the frustrations within the group mounted. What’s more, for an agonizing few months, Collip discovered he could no longer make the extract, perhaps because he lacked detailed notes, but more likely because of variations in the water pressure supplying the vacuum pumps in the laboratory. By May, these problems were solved through the concerted effort of the whole team.

In 1922, the Canadian, U.S. and British patent offices granted patents for insulin in the names of Banting, Best, and Collip; the three men immediately assigned the patents to the University of Toronto board of governors. This step was taken to ensure that no commercial entities could attempt to patent insulin for themselves. The board also oversaw the granting of licenses to manufacturers. Half the royalties went to the university for its research and the remaining half was divided among Banting, Best, and Collip for the support of their scientific work. In the years before systematic government funding of science, these royalties gave Collip access to what would be, at the time, the largest ongoing funding of medical research in Canada.

Over the years, however, Banting, Best, and their loyal supporters amplified Banting and Best’s roles in accounts of the discovery while diminishing the contributions of Macleod and Collip. At the University of Toronto, departments, chairs, and buildings were named after Banting and Best; at insulin anniversary celebrations, their names were at the forefront while those of Macleod and Collip were neglected. It was only in 1990 that the University of Toronto named the largest auditorium at the Faculty of Medicine after Macleod, one of its first two Nobel laureates.^[8]

Collip returned to the University of Alberta at the end of his sabbatical leave, assuming a new position as head of the department of biochemistry.^[9] In 1928, he took up an appointment at the department of biochemistry at McGill University, where he led a thriving research group. After insulin, he focused entirely on the problem of hormone research for the remainder of his research life. He went on to a successful career as one of the leading endocrine scientists in the 1920s and 1930s. Restless and entrepreneurial, Collip spoke, moved, and made decisions quickly. He is credited with the isolation of parathyroid hormone, the preparation of an extract of adrenocorticotropic hormone (ACTH), and identifying several anterior pituitary hormones. His collaboration with the Montreal firm Ayerst, McKenna, and Harrison on placental hormones led to the development of Premarin, used in hormone replacement therapy. By the end of the 20^th century, Premarin was one of the top-selling pharmaceutical products in the world.

In 1948, Collip became dean of medicine at the University of Western Ontario where, for fourteen years, he enjoyed the challenge of building up the medical school in a time of rapid expansion. At the national level, he was active in establishing and shaping the federal coordination and funding of medical research. By the end of his career, he had received many honours and awards and was recognized for his leading role in the development of medical research in Canada. Collip was at the forefront of a transformation of medical science from what had been the pursuit of a few select individuals in the early 20^th century to a large-scale, systematic enterprise that involved teams of professionals in dozens of university, government, and industry laboratories. He died of a stroke on June 19, 1965, at the age of 72.

Quiet and modest, Collip was uncomfortable with the bitter conflict over the insulin discovery. He and Banting became friends in later decades and Banting would say that Collip’s role had been far greater than Best’s.^[10] In February, 1941, Collip spent the evening with Banting and gave him his own sheepskin gloves just before Banting set off on a flight to Britain on a wartime mission; Banting died when the plane crashed in Newfoundland.^[11] In recent years, historians have recognized how vital Collip’s role was in the insulin discovery and now argue that he probably should have been awarded the Nobel Prize alongside Banting and Macleod.^[12] For his part, Collip usually refused to discuss those days, saying only, “I have managed pretty well through the years to avoid unpleasant arguments and discussions with former colleagues of mine…and I see no reason why I should be drawn into any such discussion now….Personally, I am quite happy to let the insulin story stand on the publications… by the group who collaborated in 1921-22.”^[13]

[1] R.F. Farquharson, Professor of Medicine, University of Toronto, was recalling a statement made by Dr. Walter Campbell. Collip Papers, Faculty of Medicine, UWO, copy of remarks made by Farquharson at N.R.C. dinner in Ottawa, November 14, 1957. Cited in Michael Bliss, The Discovery of Insulin (Toronto: McClelland and Stewart, 1982), 117 fn 54.

[2] Leonard Thompson (17 July 1908 – 20 April 1935) was 13 at the time of the injection, though he is often described as aged 14.

[3] Bliss, The Discovery of Insulin, 112-3, 117-21. Bliss’ book is the definitive account of the insulin discovery. See also Michael Bliss, “J.B. Collip: A Forgotten Member of the Insulin Team,” in Essays in the History of Canadian Medicine, ed. Wendy Mitchenson and Janice Dickin McGinnis (Toronto: McClelland and Stewart, 1988), 110–25.

[4] J.B. Collip to H.M. Tory, 25 January 1922, 68-9-144, H.M. Tory Papers, University of Alberta Archives.

[5] Joseph H. Pratt, “A Reappraisal of Researches Leading to the Discovery of Insulin,” Journal of the History of Medicine and Allied Sciences 9, no. 3 (July 1954): 281–89.

[6] J.B. Collip to H.M. Tory, 8 January 1922, 68-9-144, H.M. Tory Papers, University of Alberta Archives.

[7] Bliss, Discovery of Insulin, 118. These accounts were from versions written by Banting in 1940 and Best in 1954 which may not be entirely reliable.

[8] Michael Bliss, “The Eclipse and Rehabilitation of JJR Macleod, Scotland’s Insulin Laureate,” J R Coll Physicians Edinb 43 (2013): 366–73.

[9] At the time of Collip’s work on insulin, the department of physiology had become the department of physiology and biochemistry. In 1922, biochemistry and physiology departments were split.

[10] Bliss, “The Eclipse and Rehabilitation of JJR Macleod, Scotland’s Insulin Laureate,” 369.

[11] Michael Bliss, Banting: A Biography (Toronto: McClelland and Stewart, 1984), 300.

[12] Preface to the 25^th anniversary edition, Bliss, The Discovery of Insulin, rev. 25th anniversary ed., Chicago and Toronto, 2007. 8. For further information on Collip, see Alison Li, J.B. Collip and the Development of Medical Research in Canada (Montreal & Kingston: McGill-Queens University Press, 2003).

[13] Bliss, Discovery of Insulin, 238; J.B. Collip to John F. Fulton 4 March 1957, Collip Papers, University of Western Ontario.