VI. From Embarrassment to Triumph
On December 30, 1921, Banting delivered a paper to the American Physiological Society conference at Yale University. It was entitled “The Beneficial Influence of Certain Pancreatic Extracts on Pancreatic Diabetes”, and the authors were listed as Macleod, Banting, and Best. North America’s leading diabetes researchers and clinicians were in the audience.
The session did not go particularly well. “When I was called upon to present our work I became almost paralyzed,” Banting remembered many years later. “I could not remember nor could I think. I had never spoken to an audience of this kind before — I was overawed. I did not present it well.”
The main argument that Banting and Best offered in these early presentations (as set out in their first publication, two months later, shown below) was that their pancreatic extract “has always produced a reduction of the percentage sugar of the blood and of the sugar excreted in the urine,” and therefore “we feel justified in stating that this extract contains the internal secretion of the pancreas":
The discussion at the New Haven meeting was friendly, but critical. While the audience may not have realized that Banting and Best’s notebooks (and the paper they had in press) did not in fact support the claim of always being able to reduce sugar, it was certainly prepared to ask probing questions about the extent to which the Toronto work was more promising than anyone else’s. Banting was undoubtedly asked about the toxicity of his extract, for example, with particular reference to the pattern of fever that Kleiner and Paulesco, among others, had reported. It would have been a difficult question to field, for Banting and Best had not taken temperature readings on their animals (the sole exception showed a dog running a high fever after injection).
Pointed questions may have been asked about Banting’s early surgical techniques: was he certain that his pancreatectomies, difficult to do properly under the best of conditions, had been complete? The longevity experiment begun towards the end of November was still on-going, but of course had had one dramatic failure. And many critical questions might have been asked about Banting’s original assumptions regarding the physiology of the pancreas, both before and after ligation of its ducts.
Macleod was chairing the presentation. It was evident to him, he wrote nine months later, that Banting “had not succeeded in convincing all of his audience that the results obtained proved the presence of an internal secretion of the pancreas ... any more definitely than had those of previous investigators." Macleod joined the discussion to defend work going on in his laboratory under his supervision. He too stressed the positive effects of injections, but also may have referred to Collip’s exciting findings about ketonuria and glycogen formation. The Toronto group received “little praise or congratulation, and a moderate amount of friendly but serious criticism,” Elliott Joslin wrote later about that session. They had yet to prove to the world that they had a discovery.
(The greatest enthusiast in the New Haven audience was George Clowes, the research director of Eli Lilly and Company of Indianapolis. Clowes told Macleod he thought they were on to something and offered Lilly’s services to develop the extract. Thinking the offer premature, Macleod was non-committal).
Banting felt particularly humiliated at his own inept public performance. He had been bailed out by Macleod, a man whom he had never liked, and who had also somewhat stolen his thunder at the Journal Club presentation in November. Banting was having much less to do in the lab now that no surgery on animals was required, and his and Best's disappointing results making and testing extract stood in sharp contrast to Collip’s extremely promising work.
Despite, or perhaps because of the criticism at New Haven, the Toronto group wanted to advance to trials of the extract on human diabetics. Macleod asked Collip to prepare extract for such tests. Banting, the only practicing physician in the group, may have assumed that he would now have a new role as a clinician. These hopes were immediately dashed by the Professor of Medicine, Duncan Graham, who refused to give Banting an appointment that would allow him to work with diabetics at the University’s teaching hospital, Toronto General Hospital. Banting concluded that he was deliberately being pushed out of the picture. He began muttering to people about Macleod stealing the results of his work.
Banting went to Macleod and argued that he and Best deserved the right to make the first extract that would be tested formally in the clinic (there is no evidence that Macleod ever knew about the Gilchrist trial). Although he did not yet realize how serious Banting’s accusations would become, Macleod went along with the suggestion.
On January 11, 1922, a house physician at Toronto General Hospital, Ed Jeffrey, injected fifteen cc. of extract of beef pancreas, made by Best and Banting, into the buttocks of 14-year old Leonard Thompson. Thompson was a charity case, diabetic since 1919, now reduced to less than 65 pounds on a 450 calorie diet, in severe ketoacidosis, and about to slip into a coma and die. His family consented to the trial of the extract. The extract itself was described by the chief clinician, Walter Campbell, as “a thick brown muck”. On Thompson's record it was noted that he was receiving “Macleod’s serum”.
The trial was a failure. Leonard Thompson’s blood sugar dropped from .440 to .320 percent. His 24-hour excretion of glucose fell from 91.5 grams in 3625 cc. of urine to 84 grams in 4060 cc. Tests for ketones continued strongly positive. There was no improvement in his clinical appearance, and a sterile abscess, caused by impurities in the extract, developed at the site of one of the injections. The modest effect on blood and urinary sugar was outweighed, in the clinicians’ judgment, by the reaction it caused. It was decided not to give him more extract. Injections may have been given to one or two other patients with even less impressive consequences. “These results were not as encouraging as those obtained by Zuelzer,” Banting wrote several years later.
On the night of January 19 Collip discovered a method by which he could remove many of the toxic contaminants from the extract. "I have had such a phenomenal break in my research ..." he wrote the President of the University of Alberta a few days later. "I finally unearthed a method of isolating the internal secretion of the pancreas in a fairly pure and seemingly stable form suitable for human administration ... I discovered a way to get the active principle free from all the 'muck' with which it appeared to be inseparably bound."
J.B. Collip. Letter to H.M. Tory, President, University of Alberta, Edmonton, January 25, 1922. (Reproduced from the original in the H.M. Tory Papers in the University of Albera Archives, 68-9-144). In this letter Collip describes his recent breakthrough in refining the extract and removing the toxic contaminants.
In simple terms Collip's method had involved increasing the concentration of alcohol in the mixture, which caused many contaminating proteins to be precipitated out, until he found a concentration, somewhere over 90% alcohol, at which the active principle itself was precipitated out. Other procedures removed enough of the remaining contaminants to make the resulting powder a marked improvement on any of the group's previous extracts.
On January 23rd, 1922, a Monday morning, Walter Campbell began injecting Leonard Thompson with extract made by Collip. In one day his glycosuria nearly disappeared; his ketones did disappear. His blood sugar dropped from .520 to .120 — normal. He was brighter and stronger. For the first time in recorded history, an extract of pancreas had been unambiguously successful in having a distinct antidiabetic effect on a human.
The test was the best evidence yet that the Toronto extract did contain the internal secretion of the pancreas, that the Toronto adventurers had uncovered a holy grail. While it is impossible to assign an exact date for the “discovery’' of insulin, January 23-24, 1922, were clearly the days on which the team knew they had a splendid triumph on their hands, if only (Macleod’s caution again) they could repeat it. They were able to.
After a few weeks of continuing success with Thompson and half a dozen other patients in Campbell's clinic at Toronto General Hospital, the group submitted an article to the Canadian Medical Association Journal, "Pancreatic Extracts in the Treatment of Diabetes Mellitus," by Banting, Best, Collip, Campbell, and A. A. Fletcher (by agreement the names on their publications were in alphabetical order), which announced the discovery of 'a therapeutic measure of unquestionable value". On the day the March 22 issue of the CMAJ was mailed to subscribers, the Toronto Star announced that Toronto doctors were "on Track of Diabetes Cure."
What should the substance be named? The hypothesis of its production in the pancreatic cells known as the islets of Langerhans seemed firmer than ever. Banting and Best had called their original extract “isletin” in a few notebook entries.
Macleod appears to have made the suggestion that it would be more appropriate in a multilingual world to revert to the Latin root. The word “insulin” is used for the first time by the Toronto group in a paper they prepared about their work for presentation to the Association of American Physicians in early May, 1922. It was later realized that two previous authors had suggested naming the internal secretion “insuline”.
On May 3, 1922, Macleod read the paper, “The Effect Produced on Diabetes by Extracts of Pancreas,” authored by Banting, Best, Collip, Campbell, Fletcher, himself, and E.C. Noble, to the elite of American physicians, gathered in Washington, D.C. The reaction was very different from that in New Haven four months earlier. The world’s leading diabetologist, Frederick Allen, proclaimed, “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.” “I think that this work marks the beginning of a new phase in the study and treatment of diabetes,” said the distinguished researcher Rollin T. Woodyatt. “It would be difficult to overestimate the ultimate significance of such a step.” The physicians gave the Toronto group a standing ovation.