EIGHTEEN

The University of Toronto, September to December 1921

DURING THE FIRST WEEK OF SEPTEMBER 1921, BANTING DROVE TO 442 Adelaide Street North. With grim determination he set about bringing the unhappy London chapter to a swift and final conclusion. In a single day, he sold the big white house and most of his furniture. What few belongings remained he loaded into his car. He could not get away from London and all that it represented fast enough.

When he returned to Toronto, Macleod’s reply from Scotland was waiting.

Banting could remain at the university to continue his work, and Macleod assured him that he would do what he could to help him. He also agreed that Banting should use the operating room that Starr had arranged, at least until another solution could be worked out. There was a new anatomy building under construction, so there would be more operating facilities available. He advised them to be discreet in transporting dogs from one building to the other. The anti-vivisection movement had gained enough traction to make the University of Toronto administration nervous. This was yet another way that having someone like Banting on the campus was a potential liability. As far as presenting their research was concerned, his tone was generally encouraging but Macleod warned Banting that he had to ensure that there was no possibility of mistake. Macleod raised questions, no doubt intended to help Banting prepare to defend his work from the challenges that he would surely encounter in the scientific community. As was his wont, Macleod was cautious. He was known for telling his students, “One result is no result.”

Banting’s philosophy could not have been more different. To him, Macleod’s letter indicated a vote of no confidence in the work that he and Best had done and a directive to suppress his imagination. Banting began to suspect that the great professor was not taking him seriously and perhaps never had.

On September 5 Banting and Best prepared two donor dogs by duct ligation. On September 7 they depancreatized two recipient dogs; these were identified as Dog 5 and Dog 9. These would be the last experiments of the summer. Macleod was due back very soon. The pressure was on to collect as much data as possible.

While they waited for the acinar tissue to degenerate in the two duct- ligated dogs, they tried to make some isletin by the secretin-stimulation method, but the dog died two hours into the surgery. They removed its pancreas anyway. They prepared an extract according to the prescribed procedure. That night they used the last 10 cc of the old extract on Dog 9, administering it by rectum this time. It had no effect.

Intravenous doses of the new extract, on the other hand, produced a dramatic reduction in Dog 9’s blood sugar, lowering it from .30 at 6:30 p.m. to .07 by midnight. However, the injection itself appeared to cause pain to the dog. The following day’s injections were much less effective on the blood sugar, and an attempt to administer the extract rectally had no effect.

On September 12 they tried to exhaust a cat’s pancreas with secretin, but the cat died after ninety minutes of stimulation. They used its pancreas to produce an extract. They performed several experimental injections with this extract on Dog 9, including injecting the extract directly into the dog’s heart. This produced a moderate decline in blood sugar, followed by shock and death. After performing an autopsy, Banting and Best determined that Dog 9 had died from emboli, or large particles of pancreas tissue, in the extract. Apparently, in their haste they had not macerated or strained the extract thoroughly enough. The control dog, Dog 5, was euthanized. The notebook suggests that its abdomen was infected.On September 17 they again obtained extract from using the secretin- stimulation method and injected it into one last depancreatized dog. For the first time they tried the method of subcutaneous rather than intravenous injection. Best recorded the emergence of a hole the size of a quarter in the dog’s skin at the site of the injection. Also, there was considerable bleeding from a superficial vein that had been partially degraded. The dog’s blood sugar remained stable, neither rising nor falling. As these results were not definitive, they decided to suspend further experimentation until they had obtained trypsin-free extract. The summer’s work was over.

In mid-September a junior member of the faculty in the pharmacology department left and Velyien Henderson wrote to President Falconer asking permission to hire Banting as his replacement. On September 21, the same day Henderson wrote to Falconer, Macleod arrived in Toronto. In late September or early October Banting and Best met with Macleod, who strongly encouraged Banting to repeat all of his experiments in order to confirm his findings. Banting reminded Macleod of his requirements: a salary, a boy to look after the dogs, a room to work in, and repairs to the floor of the operating room. Macleod was reluctant. Why fix up the old operating room when a new one would soon be available? He also pointed out that funds were limited; by directing further funds to Banting’s project, some other researcher would suffer.

Eleven months later Banting wrote this account of the meeting:

I told him that if the University of Toronto did not think that the results obtained were of sufficient importance to warrant the provision of the aforementioned requirements I would have to go someplace where they would. His reply was, “As far as you’re concerned, I am the University of Toronto.” He told me that this research was “no more important than any other research in the department.” I told him that I had given up everything I had in the world to do the research, and that I was going to do it, and that if he did not provide what I asked I would go someplace where they would. He said that I “had better go.”

Macleod relented. Banting suggested that Macleod could take an active role in satisfying some of his doubts about the work; he could participate in the experiments. Macleod demurred. Then Banting suggested that James Bertram “Bert” Collip might play a role on the team.

Collip was a brilliant associate professor of Biochemistry at the University of Alberta in Edmonton. In the spring of 1921 he happened to be in Toronto on a prestigious one-year Rockefeller Traveling Fellowship, which was to have allowed him a year to study in Toronto, London (U.K.), and New York. He began studying the effect of pH on blood sugar under the renowned authority on carbohydrate metabolism Macleod, whom he revered and because of whom he had chosen to work in Toronto. Prior to Macleod’s departure for Scotland, he had introduced Collip to several people, including Banting.

Over the summer, Collip had expressed his interest in the isletin work. It seemed perfectly logical to Banting that Collip should join the effort, his skills being exactly those required for the next phase, but Macleod declined. It was not yet time to expand the team, he said, and he cautioned Banting to avoid thinking too far ahead. Frustrated, Banting returned to the lab to try to produce results that would convince Macleod of the validity of their work and its worthiness of additional resources.

In October, Banting appeared on the payroll as a special assistant in pharmacology, courtesy of Velyien Henderson. His pay was $250 per month. Macleod arranged for retroactive pay for the summer’s work of $170 for Best (the normal pay for a student assistant) and $150 for Banting, who had no official affiliation with the university.

In mid-November 1921 Banting contributed a new idea to the long history of attempts to isolate insulin. He remembered from his days on the farm that fetal calves received nourishment from the mother and therefore required no digestive glands until after birth. He also remembered that cows were often made pregnant before being slaughtered, because it fattened them and made them better eaters. In early December Banting and Best visited a local abbatoir where they cut out the pancreases of nine fetal calves and brought them back to the lab. From these they prepared an extract from the whole pancreatic gland of a fetal calf and injected this into a previously depancreatized (and thus diabetic) recipient dog. The result was an unmistakable decline in the blood sugar. They repeated the experiment and achieved the same result. Now they had a more reliable source of isletin. Banting reported his findings. For the first time Macleod seemed impressed.

Macleod invited Banting and Best to present a summary of their summer experiments in November at a gathering of the Journal Club of the University of Toronto Department of Physiology. Banting was not fond of public speaking, but he was fired by the desire to claim his discovery and to prove that his gamble hadn’t been a complete waste of time.

This would be the first semipublic announcement of Banting’s and Best’s work over the summer of 1921. Auspiciously, the Journal Club meeting was to take place on November 14—Banting’s thirtieth birthday. It was agreed that Banting would present the paper, Best would be responsible for showing charts and illustrations, and Macleod would introduce them. Banting asked Macleod if his name should appear on the paper. Macleod chose not to have his name included among the authors.

The day arrived at last. Macleod began his introduction, and, according to Banting, he continued past the introduction to describe the work. Essentially, Macleod presented the paper, saying all the things that Banting had intended to say. When Macleod finished and turned the meeting over to Banting, the latter was flummoxed and humiliated. (Later, Banting claimed that Macleod used the pronoun “we” throughout the introduction, although he had been in Scotland for nearly the entire duration of the experiments he was describing.) This experience cemented Banting’s resentment of Macleod. He ended the day feeling frustrated and anxious. Unable to sleep that night, he wrote in his diary, “Half my life is over.” As it turned out, he was much closer to the end of his life than that.

The paper was published in February 1922 in the Journal of Laboratory and Clinical Medicine under the title “The Internal Secretion of the Pancreas.” The authors were listed as F. G. Banting, M.B., and C. H. Best, B.A. The only mention of Macleod was in the bibliography.

Even before the paper was published, news of an important discovery in Toronto had begun to spread through the medical research community. Macleod had begun to receive letters from doctors desperate to save their doomed patients. That November, Dr. Elliott Joslin wrote:

At the meeting of the Southern Medical Association in Hot Springs, Arkansas, from which I have just returned, I heard Dr. Barker refer to experiments which you had conducted with extracts from the Islands of Langerhans. . . . Naturally if there is a grain of hopefulness in these experiments which I can give to patients or even can say to them that you are working upon the subject, it would afford much comfort, not only to them but to me as well, because I see so many pathetic cases.

Three weeks later Dr. Leonard G. Rowntree of Mayo Clinic in Rochester, Minnesota, wrote:

I have heard indirectly that you have very recently made some important discoveries in relation to the islands of Langerhans and diabetes. . . . We have a little chap four years old, who, despite everything that we have tried, is slipping awayfrom us, and if there is anything in your work which bears on the treatment of diabetes, we would greatly appreciate hearing from you.

Dr. N. B. Taylor of the University of Toronto, who attended the November meeting at which Banting spoke, suggested that Banting demonstrate the efficacy of his extract by attempting to prolong the life of a diabetic dog. Banting, Best, and Macleod agreed. Less than a week later, on December 6, 1921, a longevity experiment began involving Dog 33, later to be renamed Marjorie.

All this time the substance was known as isletin, as Banting and Best had dubbed it during their desperate summer striving. Macleod insisted that the name be changed to insulin so as not to change “terminologic horses [in the] mid-investigational stream.” He pointed out that the term insulin had been suggested by de Mayer in 1909 and was subsequently endorsed by Sir Edward Sharpey-Schafer in 1916 for the then hypothetical secretion. To Banting, Macleod’s insistence on renaming isletin was just another illustration of his own disempowerment at the hands of the great scholar.

Banting was impatient and increasingly desperate to prove himself. Even with these endless experiments confirming the active extract, were they really any closer to a clinical solution for humans? On November 23, Banting told Best that he was going to inject himself with the extract and asked Best to witness and record any results if Banting were incapacitated. Banting wrote a brief note of explanation and apology to his mother and father and pinned it to the front of his lab coat. Then he self-administered a subcutaneous injection of 1.5 cc of the extract. There was no effect. Banting recorded the fact in the laboratory notebook and left the lab utterly dejected.

When the call went out for papers to be considered for the American Physiological Society’s thirty-fourth annual meeting in New Haven, Connecticut, in December 1921, Macleod, who was then president of the prestigious organization, encouraged Banting to submit the summer’s work. Banting asked permission to add Macleod’s name to his own and Best’s as the paper’s authors in order to raise its chances of being accepted. Macleod consented. The paper was accepted.

The conference was to take place from Wednesday, December 28, to Friday, December 30, 1921. Weeks before, the rumor began to spread throughout the medical research community that something really promising had occurred in Toronto. The title of the presentation, “The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes” was listed as being authored by one member and two guests: J. J. R. Macleod, F. G. Banting (by invitation) and C. H. Best (by invitation). The poorly done experiments of the early summer were omitted from this paper.

The paper was scheduled to be delivered on Friday afternoon, the least advantageous position in the conference, when many of the attendees would be leaving to catch trains. At least three people resolved to be present to hear the paper on December 30 in New Haven, even if that session began at midnight. They were Dr. Elliott Joslin of Boston, Massachusetts; Dr. Frederick Allen of Morristown, New Jersey; and Dr. George Henry Alexander (“Alec”) Clowes, research director of Eli Lilly and Company in Indianapolis, Indiana.