The Discovery of Insulin

by Michael Bliss

  Prodded by Banting, Starr talked with Macleod in December, telling him of Banting’s situation in London, and asking him whether there was enough likelihood of “anything real” coming out of the idea to warrant Banting giving up his position in London and coming to Toronto for several months. Macleod probably reminded Starr of the long history of failure in the search for the internal secretion and of Banting’s comparatively unimpressive qualifications. Starr apparently told Macleod that Banting was a well-trained surgeon.28 “He thinks it is very problematical,” Starr wrote Banting, “and while he is very much interested in your presentation of the case to him, yet he feels as I do, that probably it would be unwise for you, at this time to give up your work there, and come here to undertake this work. He suggested also that you might possibly come in in the summer and put in a month or two then.”29

  Starr advised Banting to stay in London. He probably believed that Banting was using the research idea as an excuse to get out of his discouraging situation. Surely the thing for Banting to do was to settle down and work hard at building up his practice. As well, Banting already had a useful and promising connection with a medical school. Starr urged him to “stick to your post… I feel you have a great future there if you stick right with it.”

  Banting took Starr’s advice, and settled down to spend the winter in London. He later claimed that he had returned to London from Toronto “more determined than ever to try the experiments. I read widely on the subject of carbohydrate metabolism and even read a little about diabetes. The more I read and thought on the subject and the more subsidiary experiments which I planned, the more impatient I became.”30

  Whatever reading he did, Banting made no entries about carbohydrate metabolism in the little notebook he used to record ideas and research proposals. When Macleod saw him later he was no more impressed with Banting’s knowledge than at the first meeting. And in fact Macleod did not hear from Banting again for almost four months. It was not until March 8, 1921, that Banting wrote Macleod saying he would like to spend the second half of May, plus June and July, in Macleod’s lab, “if your offer for facilities to do the research still holds good.”31

  Banting was actually considering a number of different things to do with the rest of his life. His practice was picking up, and his income rising, well beyond the break-even point by February. Edith, by all accounts, was encouraging him to settle down with his practice. His work as a demonstrator at Western and assisting Professor Miller had apparently gone well.32 That, plus his interest in research, may have encouraged him to consider the possibility of full-time university work. He may have gone so far as discussing the possibility with the dean of medicine at Western either before or after his conversations with the people at Toronto; if so, the dean held out no hope of Banting getting the salary he wanted to support himself in a research job.33 In March Banting was working on several experiments in Miller’s lab, none of them relating to carbohydrate metabolism. On the same day that he wrote Macleod about summer plans, he also wrote to C.S. Sherrington, the distinguished professor of physiology at Oxford, asking his advice on an idea he had to study reflex action in the hind-limbs of kittens and dogs.34

  In his letter to Macleod, Banting suggested that he might start a bit early, coming to Toronto during the Easter holidays “to do” half a dozen dogs so they would be ready for investigation in May. Macleod replied promptly that he would “be glad to have you come up here on May 15, as you suggest, to see what you can do with the problem of Pancreatic Diabetes,” but explained that it would not be advisable to do operations over the Easter holidays. Between the end of holidays and mid-May everyone was so busy with exams and winding up the term that no one at the lab would have free time to supervise the animals, “and this supervision, as you know, is of extreme importance in all researches of this character.”35

  Even then, however, Banting had apparently not made up his mind whether he wanted to work in Macleod’s or any other lab. His moods undoubtedly varied with the state of his practice and, above all, his romance. Some time during the winter or spring Edith apparently broke off the engagement, returning the ring.36 At a time like that, Banting wanted nothing more than to get a long way away from his problems. He and Bill Tew talked that winter about joining the medical service of the Indian army and even wrote for details. A bit closer to home, Banting heard of an expedition going to the Mackenzie River valley in Canada’s Northwest Territories to drill for oil. They were apparently considering taking a medical officer with them. The head of the expedition lived in St. Thomas, just a few miles from London. About the middle of March, Banting recalled (which would be after he had written Macleod proposing to come to Toronto for the summer), he decided to stake his future on the toss of a coin. “Heads I was to do the research, tails I was to go to the Arctic to search for oil.” Three out of five tosses came up tails. The Arctic won.

  So Banting took the next train to St. Thomas to see the oil man. “He explained that he was not sure of taking a medical officer, but that if they took one, I could have the job.” During March and April, 1921, when Banting is popularly thought to have been waiting with “gnawing impatience and mounting eagerness” to start searching for the internal secretion of the pancreas in Toronto,37 he was actually waiting for a letter offering him a job as doctor to an oil expedition. A letter finally came saying the group had decided not to take a doctor.38

  V

  “Since nothing presented itself,” Banting wrote of his schemes for escaping from London, “I turned the key in my office on the morning of April 26, 1921, parked my suitcase at the station on the way to my last class at the medical college and took the noon train for Toronto.”39 He was committed to the work now, even though Dr. Starr was still advising against it.40 With no idea how the research would turn out, Banting paid enough attention to Starr that he did not, as some have thought, immediately close out his affairs in London. He kept his house and could have gone back again if the experiments failed.

  Banting met again with Macleod to plan the work. Macleod was no more impressed now than earlier with Banting’s knowledge of previous research on the problem or of the techniques he might use in the lab. But the work was to go forward. Again, there is no authoritative record of what was said at the meeting, or meetings. “I worked out with Dr. Banting a plan of investigation,” Macleod wrote sixteen months later, “the first step of which was to render one or two dogs diabetic by extirpation of the pancreas so that he might make himself familiar with the cause of this condition in animals….At the same time I advised him to tie the ducts in several other animals so that the gland might be suitably degenerated….” Macleod also advised Banting to use Hédon’s method of pancreatectomy and gave him references to Hédon’s work in the literature.41

  At one of their meetings, apparently the one in which Macleod gave Banting complete directions for the work, Banting met J.B. Collip, a professor at the University of Alberta who had an interest and some expertise in the study of glandular secretions and the making of tissue extracts. Collip, who had a Ph.D. in biochemistry from Toronto, was passing through on his way for a summer’s study in Massachusetts, and was consulting with Macleod about coming to work at Toronto for part of his sabbatical the following year. He planned to work on a very different problem from the one Banting and Macleod were discussing, but would have found the talk interesting. Several years earlier he had published a good summary article on internal secretions and he had recently been giving animals injections of different kinds of tissue extracts, measuring their impact, along with adrenalin, on blood pressure.42

  Whatever experimental techniques Banting and Macleod planned to use, the results would be measured by tests on urine and blood. Banting had no practical knowledge of how to do this kind of chemical testing – in fact, as his original October 31 note seems to indicate, he may not have been aware of the sophisticated methods of blood testing available to researchers – and would obviously need help. Banting later remembered that he
had asked Macleod for an assistant from the beginning, but although one would expect to find it, there is no reference to an assistant in any of the letters they exchanged about the work.43 Perhaps the matter did not come up until May. Or it might have come up earlier and Macleod, knowing he had student fellows on hand, had assured Banting it would not be a problem.

  One day in May, Macleod introduced Banting to the two student assistants he had employed through that winter, Charles Best and Clark Noble. They were fourth-year students in the Honour Physiology and Biochemistry course, picking up extra money as demonstrators and research assistants for Macleod. Both were planning to do a Master of Arts degree with him the next year. Macleod had mentioned Banting in his lectures that winter, Best remembered, saying that he might be coming to Toronto to work on the pancreas. Now Banting explained his hypothesis to Best and Noble.44 They were going to assist him. It was probably on that same day that Macleod also showed Banting the little room in the physiology department once used for surgical research. Nobody had operated in it for more than a decade, though. As Banting remembered it, the room “contained the truck and dirt of the years.”45

  Macleod held out no false hopes when he talked to Noble and Best about assisting Banting. This kind of research, going after the internal secretion, had been tried many times before and had always failed. “There is always a chance,” Noble remembered him adding. Banting later heard, apparently from Best, that Macleod told the two students that the project would probably go up in smoke, but they would at least learn something about surgery from the work; also, as good scientists, “we must leave no sod unturned.” Macleod apparently left it to Best and Noble to decide how they would divide the time to be spent with Banting.46

  The practical problem of arranging the assistance was that in its normal rhythm the University of Toronto went on holidays in July and August. Term appointments and salaries, such as Best and Noble enjoyed, ended on June 30. But Banting intended to work in July, and presumably would need help then. So one of the two students would have to split his summer holidays, taking some time off in May or June and then working in July while the other was on holidays. The contemporary evidence suggests that Best and Noble flipped a coin to see who would go first, and therefore not have to work in July. There is no evidence for the legend in Toronto that the prospect of working with Banting on his wild idea was so unattractive that Best went first because he lost the toss. Actually it was the prospect of having a broken summer holiday that was unattractive. Research with a surgeon like Banting would be interesting no matter what the results. So the winner of the toss would work first with Banting. Best won.47

  VI

  Banting was in London for most of the first half of May. On the morning of Saturday, May 14, he presided at an exam for Western’s fourth-year medical students. After the exam they gave their demonstrator a box of cigars. Banting “escaped” from London on the next train.48 Best wrote his last exam on Monday, May 16. Either that day or early the next,49 Banting and Best cleaned up the physiology department’s filthy operating room. They washed the walls and the ceiling. Just as they were about to mop the floor, someone from the floor below complained that water was leaking through. So they cleaned the wood floor of the little room on their hands and knees.

  Banting had brought his instruments with him. Towels for the operation had to be borrowed. When everything was ready, on Tuesday May 17, Macleod joined them to begin the first experiment.50

  CHAPTER THREE

  The Summer of 1921

  The plan of attack was to start with pancreatectomies on several dogs. Banting could get used to doing the operation, Best could practise his blood and urine tests, and both of them could become familiar with the diabetic condition as it develops after pancreatectomy. These first dogs would soon die from their diabetes. In the meantime, following Banting’s idea, the pancreatic ducts would be ligated in several other dogs. They would recover and live more or less normally, but over a period of several weeks their pancreases, unable to secrete juice into the duodenum, would gradually atrophy or degenerate. Then, in the crucial experiment, Banting would re-operate on these dogs, remove the atrophied pancreas, and see if he could somehow use that material, which he believed would contain the internal but not the external secretion, to improve the condition of still more dogs made diabetic from pancreatectomy. Using Banting and Best’s original notebooks, it is possible to describe these experiments almost day by day and dog by dog. Most readers should not find it necessary, though, to keep careful track of these dogs or their numbers. Banting and Best sometimes lost track themselves.1

  I

  Banting had probably never done a pancreatectomy, an operation used almost solely in animal research, so Macleod was present to assist and instruct on the first dog. A brown Spaniel female, number 385 in the university’s records of dogs used in its labs, was fully anesthetized, strapped to the operating table, and its belly opened by an incision down the middle of the abdomen. Clamps held the abdomen open while the surgeons worked on the pancreas. Removing the pancreas mainly involved cutting it away from the mesentery tissue to which it was attached, while taking care to ligate the many blood vessels which supply the pancreas before cutting through them. Otherwise the bleeding could be uncontrollable. It was important, as well, not to damage nearby blood vessels supplying other organs, or those organs themselves.*

  Macleod had decided that Hédon’s two-step method of pancreatectomy should be used. The whole pancreas would not at first be removed. Instead, after most of the pancreas had been dissected, a remnant (which Banting called a pedicle), with its blood supply intact, was pulled up through the abdominal wall and sutured or grafted just under the dog’s skin. The pedicle gave the animal continued pancreatic function so it would not immediately become diabetic. Instead, the dog could recover from the trauma of the surgery and the incision would heal. About a week later, when the dog’s systems had recovered, the researchers could briefly anesthetize the animal, do the second stage by snipping away the pedicle, and then make their observations as the now totally depancreatized, but otherwise healthy animal developed diabetes.2

  It was not very complicated in theory, and was the kind of operation that could become routine as a careful researcher or surgeon developed experience. The first steps on dog 385 seemed to go well. After the pedicle had been sewn under the skin, the abdomen was closed up, the urethra was enlarged for catheterizing later on, and the dog was allowed to recover. The first operation on May 17 took about eighty minutes.

  The next day, Wednesday, Banting and Best began work on their own. The pair had a lot to learn. The first dog they tried to work on died from an overdose of the anesthetic. Another dog survived the anesthetic, but it was a very small animal, and Banting had great difficulty getting at and ligating the blood vessels supplying the lower end of the pancreas. He found himself working in a pool of blood. The dog died after the operation.

  They tried again on Thursday, using a larger dog and a longer incision. There was much less bleeding and the dog, number 386, survived. The first dog, 385, was not healing properly, however. It died on Friday. Banting did an autopsy, concluding that he had to be more careful not to interfere with the major blood vessels; he also decided not to sew the pedicle under the skin, but rather to surround it with a “rubber cigarette” so it could be drained from time to time. He cut through the skin of dog 386, which was in bad shape, to allow its graft to drain. No luck. Dog 386 died the next day, Saturday the 21st.

  They had worked on four dogs that week. All were dead. There was nothing to do but start a fifth, dog 387, which was operated on that Saturday. Learning from his mistakes, Banting seems to have operated more carefully. He brought the pedicle out to the surface of the skin, placed the finger from a rubber glove around it, and sutured it directly to the surface for easy access and drainage. There was not much bleeding. “Operative prognosis good,” Banting noted for the first time. He came in to the lab the next day, Sunday, and must have
been pleased to find the dog in fair condition.

  With dog 387 apparently healing from the first stage of its pancreatectomy, Banting and Best were ready to start work on the dogs whose ducts were to be ligated. Again they found the going difficult. The first dog they ligated – it was the same kind of major surgery as pancreatectomy except that Banting went into the abdomen to tie the ducts rather than take out the pancreas – died three days later from infection. The second dog recovered and healed, but Banting noted that he was not sure he had actually found and ligated the ducts. They are small and difficult to find; Banting realized he might have just ligated a piece of pancreatic tissue. The third ligated dog survived two days before dying of general infection. There is only a summary note about it: did Banting tear out the missing page in his notebook from sheer frustration? By week’s end seven of the ten dogs they had experimented on in the first two weeks of the research were dead.

  Banting must have worried about the rate at which he was going through the University of Toronto’s dogs. Early the next week a dog appears in his notebooks with the same number as the one that had just died. The double-numbering is occasionally repeated later in the summer. He and Banting did not steal dogs, Best remembered, but bought them on the streets of Toronto for one to three dollars each. He remembered Banting leading one back to the lab by his tie.3 They would not bother asking how their suppliers procured dogs. If any dog-napping was done to supply the university’s animal labs, as Torontonians occasionally feared, and the anti-vivisectionists in the city, whose activities greatly worried medical researchers, regularly charged, at least technically it was not by Banting and Best.