The Discovery of Insulin

by Michael Bliss

  Chart 5: The effect of extract on the sugar in Leonard Thompson’s urine. Taken from the 1922 published report.

  The creature who had received more pancreatic extract than Leonard Thompson or any other animal was Banting and Best’s dog Marjorie, depancreatized on November 18 and still receiving her daily extract late in January. There are hardly any published or unpublished records of Marjorie’s condition. From January 21 to 23 Banting and Best discontinued their extract, and reported that the dog became so weak she could hardly stand. There was “decided improvement” when extract was given again on January 24 and 25.63

  Marjorie had now lived for seventy days after her pancreatectomy, far, far longer than untreated dogs normally survived. On January 27 she was chloroformed. Perhaps it was a logical time to end the experiment, but Banting also remembered that the dog had abscesses from its injections and that the scarce supplies of extract were needed for “more acute experiments.”64 The confrontations and quarrels over credit may also have brought on the decision to kill the dog. As the dispute raged over who had been able to produce how effective an extract, Marjorie’s longevity became increasingly important to Banting and Best as clinching proof that they could make potent, non-toxic extracts. It was, and is, unfortunate that they had such poor records of Marjorie, a state of affairs which may have contributed to Macleod’s doubting whether the dog’s pancreas had been completely removed.65 It was apparently to resolve such doubts that a careful autopsy was done on Marjorie by an “independent and impartial” (Banting’s words) pathologist at Toronto General Hospital. Dr. W.L. Robinson found that Marjorie still had a small nodule of pancreatic tissue, about three millimetres in diameter, in the submucosa of her duodenum. He could not find any islet cells in it. “It does not seem likely that so small a piece of pancreas could be responsible for the maintenance of the life of the animal, but, of course, the experiment is not finally conclusive,” Banting and Best wrote in their account.66

  In most early published references to Marjorie this qualification was included.67 Whether or not the nodule of pancreas that Banting missed had made a significant difference in Marjorie’s condition can never be known. In point of fact, the autopsy finding, combined with Banting and Best’s very sketchy reports, greatly reduced the value of their longevity experiment. The realization of this, despite the fact that he and Best were personally entirely certain of their results with Marjorie, must have increased Banting’s insecurity. The ambiguity surrounding Marjorie was another in the series of deeply depressing experiences Banting had endured since mid-December.

  VIII

  By February 1922, testing of the extract was going ahead in several directions. Six more patients in Campbell’s and A. A. Fletcher’s clinic at Toronto General Hospital were treated, all with favourable results. The respiratory quotient experiments were begun on dogs in January. A promising result on a diabetic dog led to a test on Banting’s classmate, Joe Gilchrist, in mid-February.68 Gilchrist came into the lab and breathed into the elaborate apparatus while the researchers measured his normal respiratory quotient, his respiratory quotient after an injection of sugar, and then his respiratory quotient after an injection of sugar plus extract. It shot up, from an initial 0.74 to 0.90, clear evidence to them that Gilchrist’s system was burning carbohydrates. That one injection also cleared the sugar from his urine and helped him shake off his mental and physical lethargy.69 Further respiratory quotient tests on two of Campbell and Fletcher’s patients were also successful, as were ongoing studies of the extract’s effect on ketonuria and glycogen formation in dogs. To help standardize the injections a rough test of potency was worked out in which one “rabbit dose” was defined as the amount of extract necessary to lower the blood sugar of a normal rabbit by 50 per cent (to the point where it became convulsive) in one to three hours.70

  Banting and Best spent some time in February writing a paper on their animal experiments since mid-November. They gave a paper entitled “The Internal Secretion of the Pancreas” to local doctors at Toronto’s Academy of Medicine on February 7; it was later published in the Academy’s bulletin. It should not be confused with the first major paper, under the same title, which was published that month in the Journal of Laboratory and Clinical Medicine. In the same month a three-paragraph summary or abstract of the New Haven presentation appeared in the Proceedings of the American Physiological Society, published in the American Journal of Physiology. It had been written by Macleod and was also headed “The internal secretion of the pancreas” (by F.G. Banting, C.H. Best, and J.J.R. Macleod). Banting and Best’s second major paper, entitled “Pancreatic Extracts,” appeared in the Journal of Laboratory and Clinical Medicine in May. Like the first paper, it is a straightforward description of the experiments on depancreatized dogs. The paper contains no surprises, except when it is compared with the original notebooks and the surprising number of factual errors – eighteen – are noticed. In this final research report of their work together, Banting and Best conclude that they had made “highly potent extracts” which were “however somewhat toxic, and they are apt to cause local abscesses at the point of injection.”71

  Other people were ready to write about the work, too, notably Roy Greenaway of the Toronto Star. “The newspapers got wind of what we are doing and through some agents of their own had enough information of a haphazard type from which they could at any time piece together a garbled account of the work,” Macleod wrote to a friend. “They kept constantly prodding us for more information until at last we were compelled to publish….”72 By the end of the third week in February there was enough clinical and experimental evidence to support a preliminary publication. The paper was entitled “Pancreatic Extracts in the Treatment of Diabetes Mellitus.” Its authors were listed as Banting, Best, Collip, Campbell, and Fletcher.

  After background material and a description of Banting and Best’s experiments leading to the obtaining of active whole beef extract, the paper dealt with the grey area between Collip and the rest as follows:

  As the results obtained by Banting and Best led us to expect that potent extracts, suitable for administration to the human diabetic subject, could be prepared, one of us (J.B.C.) took up the problem of the isolation of the active principle of the gland. As a result of this latter investigation, an extract has been prepared from the whole gland, which is sterile and highly potent, and which can be administered subcutaneously to the human subject. The preparation of such an extract made possible at once the study of its effects upon the human diabetic, the preliminary results of which study are herein reported.

  The results of the clinical tests were described, with special emphasis on “L.T.” (Leonard Thompson). The conclusions were carefully qualified, but the paper’s key sentence was clear enough: “These results taken together have been such as to leave no doubt that in these extracts we have a therapeutic measure of unquestionable value in the treatment of certain phases of the disease in man.”73 The paper was sent to the Canadian Medical Association Journal so that it would receive quick publication.

  IX

  Fred Banting had little to do with the writing of this paper or the clinical work it reported.74 He was doing very little work of any kind in the lab, and seemed to have no role in the ongoing research, either the experimental or the clinical. It had all passed into the hands of the experts – Macleod, Collip, Duncan Graham, and Campbell. “Best and I became technicians under Macleod like the others,” Banting wrote bitterly in 1940. “We were asked for the extract as it was required for their experiments. We were asked to provide depancreatized dogs and other surgical work. Neither plans for experiments nor results were discussed with us.”75 He began to think about moving on, perhaps to other kinds of research. On February 4 he made a note to himself about the cure for cancer lying in the discovery of some solution, “chemical or internal secretion,” that would stop the multiplication of cells. Through February and into March he read and jotted down notes about cancer research.76

 
; Banting had been living and working under intense emotional pressure for the past several months – in fact, all things considered, for the past year and a half of uncertainty about his work and his future. In a sense, despite the triumph of the research, his future was just as uncertain as ever. Would he get credit for his work? What would become of him? What about his personal life? This last question seems to have been constantly on his mind, and his 1922 desk calendar indicates that in addition to all of his professional worries there were more crises in the ongoing relationship with Edith Roach:

  March 11: Edith came

  March 12: Edith went

  March 14: Edith phoned

  …

  March 17: The most human letter E ever wrote

  Letter of farewell

  …

  March 19: Phoned Edith.*77

  Banting’s attendance at the lab fell off more. The only way he could overcome his black despair at night was to drink himself to sleep. When he could not get alcohol any other way he stole the 95 per cent pure alcohol being used in the production of pancreatic extracts at the lab. “I do not think there was one night during the month of March, 1922, when I went to bed sober.”78

  Banting’s friends knew of the situation, particularly his sense of having started the work, against all odds, and then seen it taken over by others just when the good results came in. One of these friends, Dr. G.W. “Billy” Ross, a former teacher of Banting’s, had probably alerted the Star reporter, Greenaway, who was one of his patients, to the work on the pancreatic extract. Through Ross, Greenaway met Banting and Best. He prepared a long article for the Star to coincide with the publication of the March issue of the C. M. A. Journal. “Toronto Doctors on Track of Diabetes Cure” was the Star’s headline on March 22, the day the C. M. A. Journal, containing the scholarly article, was mailed to its subscribers.

  Greenaway quoted extensively from the journal article, had interviewed Macleod, and his story contained pictures of the four men – Banting, Best, Collip, and Macleod (“Have They Robbed Diabetes of its Terror?”). But Greenaway had also interviewed Banting at length, and presented the story as very much the work of Banting and Best. The article, especially one of its sub-headlines, “Banting stakes his all on the results,” was the first to tell the story of the discovery from Banting’s point of view.

  While it created a minor flurry of interest in the Toronto press, and a short Canadian Press wire story was printed in many cities, the March announcement and publication did not capture much public attention outside Toronto. The press was always announcing miracle cures that never amounted to much; in the professional world of medicine the Canadian Medical Association Journal was an obscure publication with little circulation outside Canada. A much more important presentation of the results of the Toronto work was scheduled to take place seven weeks later at the conference of the Association of American Physicians in Washington, D.C.

  X

  In Bucharest, Romania, a few weeks after the Toronto group’s first successful clinical tests, N.C. Paulesco decided he was ready to try his pancreatic extracts on humans. As yet, Paulesco knew nothing about the work in Toronto. He, too, was using extracts of whole beef pancreas procured from a local abattoir, but he was still using saline (slightly acidified and then neutralized) as his extractive. His first clinical test was on a forty-three-year-old teacher, Frère M.H., given extract on February 25 and several times afterwards. On March 3 a fifty-two-year-old woman, Madame S.G., became Paulesco’s second test case.

  Paulesco still prepared his extract by the methods reported in his 1921 papers. Because this aqueous extract had caused toxic side-effects in his dogs when injected intravenously (effects, he wrote, “qui la rendent inapplicable dans la pratique médicale”), Paulesco decided to administer it to humans by the safer method of rectal insertion. His patients took their extract, in quantities ranging from 125 to 1,000 cc, forced in through a 90-centimetre-long red rubber tube. Paulesco measured their urinary sugar and took occasional blood sugar readings.

  The extract had no immediate effect on the patients that could not be duplicated by doses of saline alone. Paulesco thought that after several days’ treatment there was a slight diminution of glycosuria and some clinical improvement. He found this somewhat encouraging. Working with depancreatized dogs, he continued through 1922 to experiment with ways of making and administering his extract. His most remarkable result came on March 24 when, according to his publication a year later, an intravenous injection of extract reduced a diabetic’s blood sugar from .260 on injection to .040 eighty minutes later, and in another hour to .000! Paulesco’s articles, which continue into 1924, make no mention at all of hypoglycemic symptoms, or any symptoms at all produced by this condition of “véritable AGLYCÉMIE.”79

  In April 1922 Paulesco applied for a Romanian patent on pancréine and his method of making it. He received his patent, but during the next year, in which he was apparently handicapped by lack of money, made no further progress with his work.80 There is no evidence that pancréine was ever used successfully to treat humans.

  XI

  Sometime in April the Toronto group prepared a paper summarizing all the work so far: Banting’s idea, Banting and Best’s early experiments, Collip’s purification, the clinical results, the hypoglycemic effects, the respiratory quotient, liver/glycogen, and ketonuria findings. For the first time a name was given to “this extract which we propose to call insulin.” There are no records of the discussion leading to the use of this name. It was apparently suggested by Macleod that a term based on the Latin root for “island” would be more useful internationally than Bantingand Best’s “Isletin.” It is not clear whether the naming provoked more controversy. If “insulin” replaced “Isletin” partly because the purified extract of whole pancreas was very different from Banting and Best’s crude extract of degenerated pancreas, Banting and Best did not record their objections or make an issue of the naming. No one made an issue of whether or not Toronto could prove that insulin came from the islets of Langerhans. Nor did anyone realize at the time of naming that in a neat piece of scientific one-upsmanship, the word “insuline” had been proposed to describe the hypothetical internal secretion of the pancreas by E.A. Schafer in 1916. Schafer, at that time, did not know that J. de Meyer had made the same suggestion in 1909.81

  The paper was another cautious presentation – (“While these observations demonstrate conclusively that the pancreatic extracts, which we employed, contain some substances of great potency in controlling carbohydrate and fat metabolism in normal and diabetic animals as well as in patients suffering from diabetes mellitus, we cannot as yet state their exact value in clinical practice”) – and it ended with an ominous reference to “serious difficulties” encountered in attempting to prepare the extract on a large scale. The paper was entitled “The Effect Produced on Diabetes by Extracts of Pancreas,” and its authors were Banting, Best, Collip, Campbell, Fletcher, Macleod, and E.C. Noble.

  All of the authors had agreed that Macleod would present the paper at the meeting of the Association of American Physicians.82 He gave it during the noon-hour session on May 3, 1922. A transcript of the ensuing discussion was published. Dr. S. Solis-Cohen briefly described a pancreatic extract that was being used, with mixed results, on patients at the Jewish Hospital in Philadelphia. Allen mentioned that his animal experiments with a pancreaticoduodenal serum were producing reductions in glycosuria and hyperglycemia. But neither wanted to detract from the Toronto presentation. “This study so careful and comprehensive, this work so thorough in its execution and so clear in its presentation, may justly be called epoch-making,” Solis-Cohen said. “I am glad that I have been privileged to hear the paper.” Allen, the world’s leading diabetologist, said, “If, as seems to be the case, the Toronto workers have the internal secretion of the pancreas fairly free from the toxic material, they hold unquestionable priority for one of the greatest achievements of modern medicine, and no one has a right to divide the
credit with them.”

  Rollin T. Woodyatt, who had talked to Macleod before the meeting, announced that he was convinced that Macleod “and his associates” had actually been able to extract the internal secretion of the pancreas. “I think that this work marks the beginning of a new phase in the study and treatment of diabetes. It would be difficult to overestimate the ultimate significance of such a step.” Woodyatt moved that the association tender a standing vote of appreciation to Macleod and his associates. Joslin, who was also there, could not remember such an action in the twenty years he had been involved in the Society.83

  It is probably impossible to specify one time in all the events described in the last three chapters when it could be said that insulin had been discovered. Nor was there a single definite first announcement of the results of the Toronto work begun by Banting and Best on May 17, 1921. This meeting, fifty weeks later, came close. On May 3, 1922, the Toronto group, speaking through Macleod, announced to the medical world that they had discovered insulin. They presented a complete summary of their work. Their presentation convinced their listeners that Toronto had made an epoch-making medical discovery. It was a great triumph.

  They knew it. “We had it made,” Walter Campbell remembered fifty years later.84 He had been there to glory in the moment. Fred Banting and Charley Best were not in Washington for the triumph. They had decided not to go, excusing themselves by saying the trip was too expensive.85