Of course experimental and clinical work would continue in Toronto, with the Connaught Laboratories, small and makeshift as its facility was, doing everything possible to increase insulin production for the city and for Canada. After Collip left, Best was placed in charge of Connaught’s insulin manufacture. Banting handled the clinical work through his private practice and his Christie Street patients. Macleod was to carry on experimental development. To finance the research, Macleod applied for and was awarded an $8,000 grant from the Carnegie Corporation. Part of it was to be shared with Collip, who fully intended to carry on research into insulin at the University of Alberta. Macleod himself was travelling east, to spend the summer of 1922 at the Marine Biological Station in St. Andrew’s, New Brunswick. He was intrigued by the thought that insulin ought to be easily procurable from those species of fish in which the islets of Langerhans were anatomically separate from the rest of the pancreas. Perhaps fish insulin would be easier and cheaper to produce than the dribs and drabs of semi-pure beef insulin they were struggling so hard to make in Toronto.
VIII
The University of Toronto was awakening to the importance of the discovery made in its Physiology Department and first tested at its teaching hospital. Part of the institution’s consciousness involved realizing how curious it must appear to outsiders that Banting had no university appointment (his job in the Pharmacology Department had expired) and no position at Toronto General Hospital. How strange, too, that no further clinical testing was going on at Toronto General. (According to Banting, this fact was driven home to the chairman of the hospital’s Board of Trustees, C.W. Blackwell, when on a trip visiting American hospitals he was asked everywhere about insulin and had to admit nothing was happening at his hospital and he knew nothing about insulin. Blackwell broke off his trip, came back to Toronto, and began discussing with Falconer how to get Banting at work treating diabetics at the hospital.)38
Unless something was done quickly, the university and hospital faced the prospect of losing much of the prestige attaching to what was starting to look like a very great discovery. Banting was completely outside the university. Suppose he went even further outside, and, as he had threatened at least once in the past, left Toronto entirely. He was beginning to get offers, some of them princely.*39 What an embarrassment if the principal discoverer of insulin, as most people saw him, left Canada. Even if Banting stayed in Toronto, his non-relationship with the university would be embarrassing. On the other hand, those who knew Banting’s limitations might also have realized that he was not in fact competent to direct major clinical experiments on diabetics. The clinical reports Banting was likely to produce on his own would very likely pale in comparison with those of the first-class American diabetologists. This, too, would be embarrassing. Banting may have realized it himself. As his friend Dr. D.E. Robertson put the situation to Duncan Graham, “Campbell knows all about diabetes but can not treat it and Banting knows nothing about diabetes and can treat it.” Finally, if the enterprising American clinicians got ahead of Toronto, making it possible for American diabetics to get insulin in preference to Canadians, the result might be a national outcry. Altogether it was a very delicate situation.40
Even after the insulin famine eased in May, Walter Campbell appears not to have been getting supplies of insulin for his patients. Perhaps there was too little available. Perhaps Banting, as he himself implied in 1940, was conspiring to withhold insulin from the hospital until he was given a clinical position.41 In any case, an ad hoc university committee, chaired by Falconer, met in mid-June to resolve the doctors’ conflicts. Agreement was reached on the conditions by which Banting, collaborating with Duncan Graham, Walter Campbell, and A. A. Fletcher, would have clinical facilities at Toronto General Hospital. These would also entail a university appointment for Banting. The slow grinding of the university and hospital bureaucracies, combined with Banting’s heavy schedule that summer, made it impossible, however, to get the clinic started before the latter part of August.42
IX
During July Macleod was working in New Brunswick. Best was spending a few weeks with his family in Maine. Banting was alone in Toronto. He was being deluged with requests for insulin from physicians, diabetics, diabetics’ families, people who had come to Toronto, people wondering if they should come to Toronto, people wondering if insulin could come to them. July heat in Toronto was oppressive again this year, Fred wrote Charley, “and even worse than the heat as a disturbance is that diabetics swarm around from all over and think that we can conjure the extract from the ground.” Diabetics were literally camping at the doors of the lab trying to get insulin.43
The standard reply to all inquiries was that insulin was still in the experimental stage, supplies were severely limited, and the inquirer would be informed when the situation changed. All available production was going to Jim Havens in Rochester and to Gilchrist and a handful of diabetic soldiers at Christie Street Hospital. Thinking the supply situation was improving, Banting gave in to some of the most desperate pleas; in mid-June and early July he agreed to treat a few private patients who were otherwise about to die. Four living skeletons, three children and one adult, were brought to Toronto from points in the United States and Canada.
Elizabeth Hughes was not among them. The fourteen-year-old diabetic had clung to life through the winter of 1921–22, a pathetically starved little girl, five feet tall but weighing no more than 52 to 54 pounds. In the spring of 1922 she was taken to Bermuda with her nurse to enjoy the climate. She contracted the diarrhoea epidemic on the island. Both her weight and her carbohydrate tolerance slipped further. From May 19 to June 2, 1922, Elizabeth received less than 300 calories of nourishment a day. Her weight, fully clothed, fell below 50 pounds. As indomitable a girl as ever existed, a kind of real-life duplicate of the heroines of girls’ literature, Elizabeth fought off the lassitude and despair that overtook most diabetics in the final stages of their sickness. She continued to exercise every day and made it a personal triumph to walk up the ramp to the ship that brought her home from Bermuda.
Elizabeth’s mother, Antoinette Hughes, had learned about the discovery in Toronto. Allen and other doctors told her that in this case the newspapers were right; there was something to it. On July 3 she wrote Banting to ask whether anything could be done for her “pitifully depleted and reduced” daughter. Banting’s answer on July 10 was the standard discouragement. All the Hughes family could do was try to keep Elizabeth going, hoping she would last until insulin was beyond the experimental stage. In fact it was impossible to build up her tolerance, and Elizabeth continued her drift towards death from starvation. A friend of J. J. R. Macleod’s, whose moving appeal on behalf of a poor fisherman on Prince Edward Island had met with the same response, wrote, “It is pitiful that so great a boon should be in sight, yet not in reach.”44
X
The insulin situation was a nightmare. Every attempt to increase the quantity of extract being produced in Toronto failed. When Best left on holidays, there were problems procuring pancreas. Then there was a shortage of acetone. Worse still, the quality of extract that was being produced was not good. Protein impurities caused abscesses in many of the patients; salts still in the solution made many injections excruciatingly painful.45 Strong extract seemed to have the worst side-effects, but weak extract had to be injected in painfully large doses to do any good. Banting resorted to rectal administration of extract to try to minimize the pain. There was fleeting optimism, then realization that the insulin was having no effect.46
By the end of June it seemed that the optimism after the first success with Jim Havens had also been premature. Dr. Williams was still enthusiastic about Havens’ subjective improvement and his weight gain, but wrote Banting that there was little laboratory evidence of progress. On a steady regime of eight cc. of extract a day, Havens was still excreting 200 grams of sugar and showing a blood sugar averaging .350. The boy was beginning to complain about the severe pain caused by the inject
ions, suffered from an abscess, and his morale was starting to weaken. From time to time he had to be given a day of “rest” from his suffering.
As he pondered Havens’ case, Williams became more and more interested in the possibility that a Rochester colleague, Dr. John R. Murlin, might have an alternative worth trying. Murlin was noticed in chapter one as one of the researchers who had continued work on pancreatic extracts despite the disparagement of them in the years before the war. Before being ended by the war, Murlin and Kramer’s research, which had started well, had led them into a long blind alley.47 Murlin left the pancreatic extract problem until October 1921, when Paulesco’s results encouraged him to start up again. He was making interesting progress with respiratory quotient experiments on animals when Banting came to Rochester at the end of May to give insulin to Havens. Murlin met Banting, learned more about Toronto’s methods, and, with his colleagues at the University of Rochester, launched a feverish program of extract preparation and testing. He found that extract made by Banting and Best’s methods had fatally toxic side-effects. So he worked on a wide range of alternatives, and towards the end of June told Williams he believed he had an extract that could be taken by mouth through a duodenal tube.
Williams and James Havens Sr. hesitated to have yet another experimental remedy tried on poor Jim, but the Toronto extract finally became so painful they saw little to lose in Murlin’s alternative. On July 9 and 10 Jim Havens was given massive doses of Murlin’s pancreatic potion (a hydrochloric acid perfusate). Its only effect was to make the boy violently ill. Later in the day on the 10th, Williams thought Havens was heading for coma. He quickly went back to Toronto’s less unsatisfactory extract:
I injected 8 cc. of the extract into the buttocks. He immediately complained of a sensation all over his body as though he had been poisoned, and of a profound burning in the stomach. I at once gave him by mouth a dram of soda bicarb in 12 ounces of water. This did not relieve the burning or apparently ease the symptoms, but in a few minutes he vomited more than 2 quarts of undigested food and fluid. Shortly after that intensely itching wheels [sic] broke out on his body. I thought he would die but he came out of it all right.
Havens’ father wrote to Banting that they had now backslid to just about where they had started with Jim almost two months earlier.48
Progress or not, the pressure on Banting to take more patients continued to grow. Early in July he was phoned by Dr. L.C. Palmer, a local surgeon who had been a fellow medical officer at Cambrai in 1918. Palmer had a fifty-seven-year-old, severely diabetic patient, Mrs. Charlotte Clarke, who was suffering from a gangrenous infection in her right ankle. She seemed to be under a death sentence, for only amputation could stop the spread of the infection. Severe diabetics rarely survived amputations, and in a case like this most surgeons would not even try.
Banting could not turn down a fellow soldier’s request for consultation. He decided that they should go ahead and try the amputation, using insulin. What the hell, why not? On July 10, Charlotte Clarke, who was nearly comatose, was given her first insulin. On the 11th, Palmer amputated her right leg above the knee, using a general anesthetic which he had not thought she would have been able to stand without insulin. After the operation he was still skeptical: “I did not feel that wound would heal and looked for the worst possible results,” he wrote in his summary of the case. Mrs. Clarke came out of the operation showing large quantities of acetone in her urine. Banting injected insulin to control it. “It did not seem possible that she could get better,” Palmer wrote. This was the first major operation performed on a diabetic with the help of insulin.49
It may have been responsible for precipitating yet another round in Toronto’s continuing insulin crisis. Banting wrote afterwards that he had taken five other patients off insulin to supply Mrs. Clarke. It was poor quality insulin, in any case, and there was very little of it. By mid-July, production at the Connaught Laboratories was apparently at the point of failing completely once again. Williams, who had come to Toronto in desperation to get something pure enough to use on Havens, later wrote that “Toronto insulin had become intolerable.” Banting was beside himself, Peter Moloney remembered, to get insulin to keep his patients alive.50
Could Eli Lilly and Company come to the rescue? When the firm’s work on insulin began early in June, Clowes planned to run ongoing small-scale experimental programs in tandem with a series of factory-scale attempts at mass production. A team of chemists, headed by George Walden, devoted their full time to the insulin work. The schedule called for fairly large quantities of insulin to be on hand by October.51
Lilly’s preparations, made from pork pancreas, were potent from the beginning. As always, however, it proved painfully difficult to increase the yield. The first shipment of Lilly insulin, ten five-cc. bottles labelled “Iletin,” had arrived at the physiology department in Toronto on July 3. Best, who was about to leave for holidays, immediately took four bottles of it for Banting’s clinic. George Eadie, who was doing rabbit tests on the extract in the department, reported to Macleod that he later gave Banting two more bottles because the clinic was so short of insulin.
(In New Brunswick, Macleod was distressed to learn from Eadie that R.D. Defries, acting director of the Connaught Laboratories, had written Lilly asking that future shipments be sent directly to Banting. Macleod wrote Defries to make sure the physiology department got some of the extract for testing. “Please do not misunderstand my attitude in this matter,” he told Defries, “but you must know how disagreeable and upsetting things were last winter and to avoid this I am trying in the future to have every thing work strictly according to prearranged agreements.” On his part, Banting was upset that Macleod had in the first place, “on his own initiative,” instructed Lilly to send its extract to Eadie. He also found that Macleod’s technicians had taken over the little room he and Best had used, leaving him with no lab space – or, after yet another quarrel, research money – in the medical building.)52
Clowes came to Toronto on July 16 to go over the results of Banting’s first clinical tests of “Iletin” and plan the future testing program. He was surprised to learn of Connaught’s production problems and the severe shortage in Toronto. Clowes wired Indianapolis to ship more insulin. He suggested to the Connaught chemists that they try evaporating the alcohol at still lower temperatures as well as getting a more complete separation of fats. The Lilly people had been skeptical of Toronto’s makeshift wind tunnel evaporation method from the beginning, Clowes wrote Banting after his visit. Lilly had always used vacuum distillation, and Clowes thought Toronto would be wise to scrap its system and get new vacuum equipment.53
Banting decided to go to Indianapolis to study Lilly’s method for himself. “I have a hunch that Clowes is holding out on us since he would not tell us how that [first Lilly] batch was made,” Banting wrote to Best. “And furthermore since the extract we’re making here is ‘pretty rough’, I think they might supply us with some for the patients are needing it very badly.”54 On the 23rd he went to Indianapolis with D.A. Scott, Con-naught’s latest addition to its insulin team.
Banting’s suspicions about Clowes were groundless, for the Lilly group went out of their way to help the Canadians. In fact Clowes and the Lilly family took an instant liking to Fred Banting and decided to support him every way they could. Banting and Scott were shown complete details of the production facility, and the insulin supplies Clowes had promised were waiting for Banting. J.K. Lilly described the visit in a letter to his son, Eli:
When they left Toronto, there was not a single unit left in the city. Banting…has a large number of patients, and he certainly was in trouble. We had 150 units ready for him, and when I told him he could take it back with him, he fell on my shoulder and wept, and when I told him that the next evening we would send him 150 units, he was transported into the realms of bliss. Banting is really a fine chap and we must back him to the limit.55
Probably because supplies were so limited, Charl
otte Clarke, the diabetic amputee, had been given no insulin after the seventh day of her post-operative period. Initially it seemed as though the insulin had done its job, for Palmer was able to remove the stitches from her wound and report nearly perfect healing. On July 25, however, the wound broke completely open. “The outlook was most discouraging,” Palmer wrote. “It did not seem possible to ever get the wound to heal again.” Two days later Banting was back in Toronto with his fresh supply of Lilly insulin. The wound immediately began healing again.56
XI
Banting came home convinced that Toronto had to have vacuum stills like those being used to make insulin in Indianapolis. It was expensive apparatus, costing several thousands of dollars that the Connaught Laboratories did not have. Banting decided to get the money. Most of the university’s senior administrators were out of town, so he went directly to the chairman of the Board of Governors, Sir Edmund Walker. Walker was past president of the Canadian Bank of Commerce and a commanding patron of the arts and sciences in Toronto. He agreed to see Banting in his splendid downtown office. Banting explained to Walker that $10,000 was needed immediately for better equipment in the insulin plant. Walker replied that it was quite impossible to get that amount so quickly. Such an expenditure would have to be approved by the Board of Governors. The Board would not be meeting again until the university year began in September.
Banting was furious. Several offers of financial help from wealthy Americans had been transmitted to Toronto through American doctors. One of these doctors, H. Rawle Geyelin of New York City, had particularly impressed Banting during a visit to Toronto earlier in the month. “Now Banting, I am going home to put my most severe diabetics to bed so that they will live long enough to get insulin,” Geyelin told him as they parted at the station. “Let me have some as soon as possible…and by-the-way if you need money for your research I might be able to help you.” Listening to Walker’s explanation of why the University of Toronto could not meet his request, Banting thought of Geyelin, got to his feet, and, as he remembered it in 1940, said to Walker:
The Discovery of Insulin Page 20