The Discovery of Insulin by Michael Bliss
by Michael Bliss.
Copyright © 1982 by University of Chicago Press, Chicago.
Excerpted with permission of the publisher, University of Chicago Press.
This book is available at The University of Chicago Press website at www.press.uchicago.edu.
Chapter Four – A Mysterious Something
XI – While Collip was starting work in his lab, Banting and Best spent the week of December 12-16 working on their newly discovered extract of whole pancreas. That first injection of whole dog pancreas had worked on December 11. On the 12th an alcoholic extraction of whole pancreas seemed to work when administered through a stomach tube (apparently causing a blood sugar reduction from .42 to .28 in four hours). Whole cow pancreas injected intravenously also seemed potent. On December 14 and 14 Banting and Best administered extracts of liver, spleen, thyroid, and thymus, all made the same way as pancreatic extracts, to the test dog. None of them was effective. To try to make their pancreatic extract purer, they experimented with dialysis (the use of a semi-permeable membrane to filter out small molecules from colloids in a solution) and also found they could wash the residue with toluene after alcoholic evaporation to rid it of more of the fat-like lipid impurities. On the evening of December 15 they gave their second talk on pancreatic diabetes, addressing a group at Toronto General Hospital. On either that day or the next, dog 35 was given by injection a piece of dried extract the size of a match which had been washed twice in toluene and redissolved in ten cc. of saline. In four hours its blood sugar went from .37 to .06, a spectacular result.
Then things went downhill. At week's end Banting and Best made up the largest batch of extract yet, some seven hundred cc. of tissue and pancreatic juice with five hundred cc. of acid alcohol. They tested it on December 18 and found it had no potency whatsoever. They concluded that they had probably used too much acid. On the 19th and 20th another batch was made up, using just alcohol, no acid (the notebooks tend to be vague on the quantities used in these mixtures). A subcutaneous injection from this new batch had no effect. A little bit of acid was added to the final saline solution of extract and an intravenous injection was tried. The only effect was to cause the dog to vomit.
They still had some extract on hand that they knew to be potent. Perhaps in reaction to the week's disappointments, they decided, apparently without telling anyone, to try it on a human diabetic. One of Banting's classmates, Joe Gilchrist, had become diabetic in early 1917 a few months after their graduation. He took the Allen treatment and was able to carry on with gradual downhill "progress" until October 1921 when a bout of influenza shattered his carbohydrate tolerance. All the symptoms returned and he began to deteriorate rapidly.
An index card in Banting's papers is the only record of Banting and Best's first "clinical" test of their extract.
Dec. 20 Phoned Joe Gilchrist –
gave him extract that we knew to
be potent. – by mouth – empty stomach
Dec. 21 – no beneficial result.
It was not yet known that no pancreatic extracts ever work by oral administration (they are, in fact, "digested" by the proteolytic digestive enzymes). Only a few days earlier, on December 12, Banting and Best had had their apparent success giving extract via a stomach tube to one of their dogs. It might work on Gilchrist, they must have thought. But it was still too risky to inject the extract into the blood stream or under the skin of a human.
Chapter Five – Triumph
III – Fred Banting's dissatisfaction with the state of affairs in the lab had not eased. Macleod had become the quarterback of the team. Collip seemed to be doing all the running with the ball. Collip expected soon to have an extract ready to try on humans. Nothing is more evident from Banting's notes and ideas, going right back to October 31, 1920, than his belief that the real test of his work would be the one done on a human diabetic. He was determined to participate in the first clinical trial.
He might not. It was Collip, not Banting or Best, who had the job of preparing the extract which would be used in the clinic. Surely Dr. Banting would administer it, though. Not necessarily, for he had no standing at Toronto General Hospital, the university's teaching hospital, where the trial would take place. In any case, he wanted the first test to be of extract he and Best had made, not Collip, and he began urging Macleod to let him try on a human the extract he and Best were using on dog 33. To clear himself to do this, or perhaps to be in on the testing of Collip's extract, Banting apparently applied to Professor Graham at the Department of Medicine for a temporary appointment in that department to make possible his testing pancreatic extract on humans at the hospital.
Duncan Graham, an Ontario-born Scotsman, trained in Toronto, the United States, Britain, and Germany, had recently become the Eaton Professor of Medicine at Toronto, one of the first appointments made under the controversial "full-time" system. Graham was a tough cookie at all times, but particularly so when it came to protecting patients in the hospital wards under his control from premature experiments or investigations. He decided that Banting, a surgeon who was not currently in practice, has no qualifications to experiment on his patients. Banting remembered Graham saying to him, on either this or a later similar occasion, "What right have you to treat diabetics? How many of them have you ever treated? Not an easy question for Banting to answer.
Banting was nothing if not persistent, and by now must have been desperate to stop what could have only seemed more and more like some nightmarish conspiracy – Graham and Macleod were the best of friends – to push him out of the picture. We know nothing of the arguments Banting used in persuading Macleod to let him and Best try their extract on a human. Perhaps he claimed it would only be fair to give them the first chance. Perhaps he convinced the professor that the extract being used on dog 33 was not having toxic effects. Perhaps Macleod thought it wise to give Banting the reassurance he seemed to want ( Macleod did not yet know of Banting's belief that he, Macleod, was trying to push him aside, but he had noticed, after a meeting of the Journal Club at which ketonuria was discussed, that there was a "strain" between Banting and Best on the one hand and Collip on the other). Perhaps Banting just wore Macleod down. Whatever the reasons, Macleod relented and agreed to intercede with Graham to make possible a clinical trial of extract prepared by Banting and Best.
The patient chosen to receive the extract was a fourteen-year-old boy Leonard Thompson. Thompson was a public ward patient (i.e., a charity case) in the diabetic clinic Dr. Walter "Dynamite" Campbell had founded a few years earlier at Toronto General Hospital under Duncan Graham's supervision. Leonard's diabetes had been diagnosed in 1919. Allen therapy was tried. By December 1921 the boy was reduced to skin and bones. As a favor to his doctor, Campbell agreed to pull strings to have him admitted to the General Hospital rather than the Hospital for Sick Children, since the latter had not diabetic clinic. To arrange this he had Thompson's father take the boy to Duncan Graham's office. When the father walked in, carrying the boy, Graham's secretary, Stella Clutton, was horrified. "I've never seen a living creature as thin as he was," she told me sixty years later, "except pictures of victims of famine or concentration camps."
Leonard Thompson weighed 65 pounds on admission to hospital on December 2. He was pale, his hair falling out, abdomen distended, breath smelling of acetone. He was dull and listless, content to lie in his bed day after day. "All of us knew that he was doomed," a senior medical student in the hospital recalled. Campbell tried various adjustments to his hospital diet, finally settling on a regimen totaling 450 calories daily. When the boy continued to worsen, Campbell told his father that unless Banting and Best's new extract had some effect the result was inevitable. The father agreed to let them try the extract on Leonard.
Best made some extract by the process worked out in December. Whole beef pancreas was ground up in an equal volume of slightly acid alcohol. The solution was filtered, most of the alcohol was evaporated off in a vacuum still, the solution was washed twice with toluene, and the remaining watery solution was sterilized with a Berkefeld filter. Banting and Best tested the extract's potency on a dog. They may have given each other injections to make sure it was safe for humans; if so there was only a little redness in their arms. The next day they took the extracts across the street to Campbell's clinic on Ward H of Toronto General Hospital.
Campbell remembered the extract as being "a thick brown muck" in appearance. The actual injection was made by a young house physician, Ed Jeffrey. In the afternoon of January 11 he injected fifteen cc. of the (presumably diluted) extract into Leonard Thompson, seven and a half cc. into each buttock. The quantity chosen was one-half the dose it was thought would have a definite result on a dog of equal weight. The only detailed description of the scene that day is in Banting's 1940 memoir:
We went to the hospital and remained in the corridor while a houseman
injected it into the patient. We had advised Campbell concerning the time
for taking samples of blood for blood sugar estimations and also concerning
specimens of urine. We waited around for the first specimens and could
hardly contain our suppressed excitement. This was in reality the first
human diabetic to be treated. When the specimen of urine arrived we were
told that it would be tested in due course. We asked for a small sample, a
few drops, but we found that the whole sample was the property of the
hospital, that all specimens would be done together along with samples of
blood and that we would be given the results on the following day. There
was a cool atmosphere about the place but there did not seem to be
anything to do so we went back to the laboratory.
The result of the injection, as reported in a publication signed by Banting, Best, Collip, and Campbell, was as follows: Leonard Thompson's blood sugar dropped from .440 to .320. the twenty-four-hour excretion of glucose fell from 91.5 grams in 3,625 cc. of urine to 84 grams in 4,060 cc. The Rothera test for ketones continued to be strongly positive. "No clinical benefit was evidenced." A sterile abscess, caused by the impurities in the extract, developed at the site of one of the injections.
There is substantial evidence that one or two other patients also received injections of Banting and Best's extract, but there are no records or detailed references in the publications. Some of Banting's accounts in the 1920s suggest that Thompson was the one of three patients on whom the extract had some noticeable effect. Many years later Walter Campbell told Robert Noble (Clark Noble's brother) that Thompson was the only one on whom they had even bothered to do blood sugars.
Banting and Best's extract had failed. Of course a good face could be put on the results: the 25 per cent decrease in the blood sugar, the reduction of glycosuria (and Banting put a better face on the results in his Nobel Prize lecture by talking of a "marked reduction" in blood sugar and saying that the urine had been rendered sugar-free). But there was the overwhelming fact that the extract's actually very modest impact did not outweigh the reaction it caused. Even though Leonard Thompson was a very sick diabetic boy, the doctors decided not to give him further injections of Banting and Best's extract. It was "absolutely useless for continued administration to the human subject," Collip wrote in 1923, in a mood, which we will come to understand, of considerable bitterness. Banting himself accurately summed up the situation after January 11 when he wrote in his published "History of Insulin" that "These results were not as encouraging as those obtained by Zuelzer in 1908."
Banting may not have known at the time that the records of Toronto General Hospital listed Thompson as having received "Macleod's serum." When he found out about it, he did not appreciate the irony.
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