The Discovery of Insulin

by Michael Bliss

  Collip thought he had won the race, or at least the experimental scientists’ heat. On March 21, 1923, he announced to a New York City meeting of the Society for Experimental Biology and Medicine that he had discovered a new hormone, present in yeast, onions, barley roots, sprouted grains, green wheat leaves, bean tops, lettuce, “and probably universally present in plant tissue,” a hormone which appeared to be “just as essential to the metabolism of sugar in the plant as a similar hormone, produced in the higher animal by the islets of Langerhans, is to the metabolism of sugar in the animal.” Collip suggested that the new hormone, the plant equivalent of insulin, be named glucokinin. He concluded his communication with a confident prediction:

  That this hormone will be useful in the treatment of diabetes mellitus in the human subject there can be little doubt. Judging by the results obtained on diabetic animals it will in some ways be much superior to “Insulin.” Its effect develops slowly and is long maintained.93

  Collip was determined not to be done out of credit for this discovery. Learning of Winter and Smith’s work on yeast, he fired off a telegram to the British journal Nature, claiming coincident priority with them for the yeast work and drawing attention to his glucokinin announcement.94 In the spring of 1923, he rushed long, detailed descriptions of his experiments into print. Admissions that the work was still incomplete were counterbalanced by claims that his discovery opened up “a new field of investigation of great scope in plant physiology.” In April Collip reported that he was ready to start testing glucokinin on a human diabetic. If it proved clinically serviceable, he noted, it might be better than insulin because its effect developed more slowly and lasted longer. As well, it would be readily available everywhere.95

  The press learned of Collip’s research. “Green Onion Tops to Cure Diabetes” was the heading most newspapers put on a Canadian Press dispatch late in April describing the discovery of glucokinin. The reporter predicted that in the near future it would supplant insulin, giving final victory over diabetes.96 Collip wrote Macleod saying how annoyed he was at the “most undesirable publicity” (his students, it seemed, had talked to reporters), but was still convinced that he was on the right track. “The other day I got the first lawn grass of the season,” he added in the same letter, “and from 200 g. of green grass I obtained an extract which caused convulsions in a 13 oz rabbit the day following the administration.”97

  The depancreatized dog lived for sixty-six days on just three injections, its urine being sugar-free most of the time. In his next papers Collip revealed that glucokinin had another remarkable characteristic: the blood of a rabbit made hypoglycemic by glucokinin could be used to make another rabbit hypoglycemic, and so on through several more rabbits. With such powerful animal passage of the active principle, he predicted in June, “the production of this potent serum in quantity can be very readily carried out.”98

  Back in Toronto, Best and Scott continued their vegetable research, rushing their findings into print, drawing attention to the fact that Collip’s work and theirs was conducted over the same period of time. By using Connaught’s new methods of insulin preparation, they reported, they had made extracts of potatoes and beets that rapidly produced convulsions in normal rabbits, just as insulin did. These convulsions could be relieved by dextrose, just as the insulin convulsions could.99

  This was work done at the Connaught Laboratories. In the Department of Physiology, Macleod was much more skeptical about the search for the “pseudo-insulins.” One of his assistants re-did Winter and Smith’s experiments on yeast, and disagreed with their interpretation of their results. “My impression is that they have shot off half-cock,” Macleod wrote. “There is certainly something wrong with this work….It looks to me as if these boys had been carried away by their enthusiasm and have published unwisely.” Macleod was puzzled by Collip’s work on glucokinin, finding it difficult to know what to make of such strange findings by a colleague whose ability he respected so highly, but was nonetheless able to suggest various problems with Collip’s findings: many substances produced hypoglycemia, some of them through damaging the liver; glucokinin might simply be stimulating insulin production from the pancreas of the rabbits; blood pressure was a complicating factor; and so on. Macleod did not respect Collip’s rush to claim priority, mentioning to Dale how annoyed he was at the “foolishness” Collip’s cable to Nature reflected. “It is incredible that he should have done such a silly thing although there may have been extenuating circumstances which I do not know of.” And then he added one of his rare bitter remarks: “If every discovery entails as much squabbling over priority etc. as this one has it will put the job of trying to make them out of fashion.”100

  VII

  Collip spent the summer of 1923 trying to make glucokinin work. The more he published, the more qualifications and doubts crept into his work. Had his dogs really been totally depancreatized, no matter what the gross autopsies found? Were the rabbit tests truly reliable? Any rabbit starved long enough was bound to become hypoglycemic, whether injected with extracts or not. In any case, was the very slow hypoglycemic effect, produced by large doses of these vegetable extracts, really comparable to the powerful action of insulin? Did Collip actually know enough about glucokinin to test it on a human? Nothing more was said of the impending clinical test. Indeed, Collip had nothing at all more to say about glucokinin after a paper written in June. He published very little in the rest of 1923 and in 1924. He is said to have passed his own epitaph on these experiments a year or two later when he told a colleague, “You’re right; I don’t think there’s any insulin in potato peels.”101

  Winter and Smith’s clinical tests of their yeast extract did no special harm, but led nowhere.102 Best and Scott carried on work on a purified beetroot extract into 1924, but became more interested in a series of experiments that seemed to show the presence of substantial quantities of insulin everywhere in the mammalian body.103 Like Collip’s glucokinin work, and as the chemists working on standardizing insulin were also realizing, all of these results showed a great deal about the unreliability of blood sugar testing on rabbits.

  People continued literally to fish for insulin. During the winter of 1922–23, Macleod’s fish insulin had been clinically tested by Walter Campbell. It worked just as well on humans as pork or beef insulin, and for many species of fish was easier and cheaper to extract from the pancreatic tissue, gram for gram, than was the insulin coming out of slaughterhouses. The only obstacle to commercial production of insulin from the sea was the cost of collecting the raw material. It was an easy matter for meat-packers to cut out pancreases at an early stage in their animal dis-assembly lines. How could a similar procedure work in the fishing industry?

  Macleod sent two of his students, Clark Noble and N.A. McCormick, to spend the summer of 1923 in Atlantic Canada working on the raw material problem. “It will be a great achievement if you can cheapen the production of insulin,” Macleod wrote Noble. And went on, revealingly, “I will await your further reports with great expectations. If we could produce with our comparatively simple equipment in the laboratory as much insulin as the extravagantly furnished insulin factory, and at a much lower cost-it would of course be a great thing and might cause certain highly distended bubbles to burst.”104

  It turned out that the sculpin and and monk-fish and skate Macleod had worked with were not practical sources of supply, largely because the fishermen did not normally take them. The students discovered, however, that cod and pollock islet tissue could be easily snipped out and was just as loaded with insulin. They ran elaborate experiments measuring the cost of having small boys cut out islet tissue and store it in alcohol during the dressing of cod onshore. Then, to see if a year-round supply could be obtained, they spent a week on an Atlantic trawler as guests of the very interested National Fish Company. The students learned that it was impossible to gather islets of Langerhans as fast as the fishermen gutted one catch of cod and washed the mess overboard to be ready for the
next. The summer’s results were inconclusive, not living up to Macleod’s great expectations.105

  There were other strategies and other experiments. American Bureau of Fisheries experts were calculating the cost of collecting shark pancreas in Florida waters (“Sharks Join War on Diabetes”), and at least one shipment came to Lilly for testing. Krogh in Denmark and the MRC people in Britain ran experiments on a wide variety of fish. Henry Dale wished he were young enough to go to sea himself in search of insulin. Just as well he did not, for the zoologist who was sent out in mid-winter got caught in one of the worst gales in years and was lucky to survive.106

  VIII

  In the meantime the final arrangements were worked out in North America for the sale of insulin through normal channels. A several months’ delay was caused when disparities in unit strength between Connaught’s and Lilly’s product led to another change in the basic unit. Toronto had determined to “discipline” the Americans for having adjusted their rabbit unit almost at will.107 The change took the British completely by surprise. Having based their unit originally on the Lilly unit, they would have to make an expensive, unforeseen change. While Lilly took the matter more or less philosophically, using it to generate more appeals for Toronto to go slow on licensing competitors, Dale was outraged by this latest “arbitrary and inconsiderate” dictation from “those blundering Toronto amateurs.”108 He soon realized, however, that the inconvenience was much less than they had first thought: the British stock of experimental rabbits had gradually developed a tolerance for insulin, causing the British unit to increase in strength, unknown to the manufacturers, by just about exactly the amount Toronto was dictating. There was, as it were, hardly a hare’s breadth of difference in the units.* So no change was necessary to make the adjustment.109

  The British were also finding that they could do without imported American insulin. The MRC had decided to protect British diabetics from becoming dependent on foreign supplies. Ignoring all the Lilly arguments that the lowest possible prices were in diabetics’ best interests, the MRC stopped importing the foreign product in the summer of 1923. Domestic production seemed adequate to meet the demand. Actually it was not, and with Britain facing an insulin famine in September, the MRC once again had to order emergency supplies of Lilly insulin. These were duly shipped, without a word of complaint about the restrictive British policy. Dale, who had so distrusted Lilly a year before, commented on “the willingness of the Lilly firm to be used by us, even to assist the development of British manufacture.”110

  For the time being, Lilly’s attention was focused on their giant American market. Even under the restrictions in force since January, distribution had expanded to the point where twenty to twenty-five thousand American diabetics were receiving insulin from about seven thousand physicians in mid-September 1923.

  By mid-October, dozens of clinical and popular articles had been published to educate the doctors and public about insulin, the unit had been adjusted to conform to Toronto’s standards, new labels had been prepared, the price had been reduced to half of January’s level, and “Iletin (Insulin, Lilly)” was ready to go on the market. For months the company had been patiently explaining to its salesmen why the product everyone was clamouring for could not be made freely available. “Now Gentlemen,” the salesmen’s newsletter said at last, “we place in your hands for development,

  The Greatest Advance in Medicine for Fifty Years.”

  CHAPTER EIGHT

  Who Discovered Insulin?

  Insulin may not have been the greatest, but it was certainly one of the most important medical discoveries of the modern age. To be sure, it had not come out of a vacuum. Most people were not aware of the specialized background from which insulin came: the years of work by hundreds of researchers on the pancreas and diabetes, the evolution of endocrinology as an important field of research, the improvements in chemistry leading to quick, accurate blood sugar tests, and other developments. The man on the street did know, however, that he lived in an age when many great things were being achieved in medicine. The microbe-hunters, such as Pasteur and Koch, had found the causes of dreaded infectious diseases, surgeons like Lister had made operations a way of saving rather than taking lives, and humanitarians ranging from Florence Nightingale to Walter Reed and William Osier had shown that medicine was a healing, helping profession. By the twentieth century in North America, foundations were beginning to pour millions of dollars into medical research, the modern hospital had taken shape, and the public had begun to expect that doctors would cure sickness.

  In a sense, insulin emerged as a result of some of the institutional effects of the good image modern medicine already enjoyed in the early twentieth century. Fifteen years or so before Fred Banting went to see J.J.R. Macleod to talk about the article he had been reading, the people of Ontario had decided, through their government and public-spirited private citizens, to modernize the University of Toronto. They were particularly interested in creating a first-rate faculty of medicine in which advanced research as well as teaching would be carried out in conjunction with a great hospital. They completely rebuilt and reorganized Toronto General Hospital to be the great hospital.1 The belief that medical research would produce great benefits for humanity had been in the air, inspiring these developments in Toronto. Few could have imagined how spectacular the reward would be.

  Spectacular is the right word. Insulin did have spectacular effects, and was almost immediately hailed as a miracle “cure”. Its discoverers, as we have seen, were themselves aware that medical history was being made. The collections of press clippings kept by Banting’s friends, the other researchers, and Toronto’s own Insulin Committee, save an immense amount of digging as we consider how insulin and the men who found it were received.

  I

  Most medical people despised the press, holding attitudes not totally unfamiliar today. Reporters tended to be suckers for every quack, half-quack, over-eager scientist, or naive country doctor who thought he had a serum to cure tuberculosis, a herbal remedy for cancer, or a new surgical procedure to rejuvenate the aged. When the newspapers were not wasting space on undeserving medical stories, they were over-playing legitimate news, getting their facts wrong, and generally making a nuisance of themselves interfering in the lives and practices of busy professionals. Doctors’ deep suspicion of what they read in the newspapers and even in the less-carefully edited of the medical journals, helps to explain some of the early skepticism about insulin in countries like Britain: Oh, the Americans are always curing everything; this week it’s diabetes. Even in Canada and the United States it was some months before there was enough confirmation of the unlikely news from Toronto to convince wire services and the more skeptical doctors and editors that insulin was, indeed, the real thing.

  The confirmation came in a typically confused way, as newspapers learned about clinical trials in their own cities and wrote them up as though a cure for diabetes had been discovered by local doctors. One of the first widespread American reports about insulin, for example, highlighted Sansum’s work in California, implying that the experts at the Potter Clinic had turned Toronto’s theoretical work into a practical reality.2 A few days later, a report in the Philadelphia Ledger, entitled “Find Diabetes Cure Dr. Stengel Says,” was reprinted across the United States. Its effect in Toronto was to produce a wave of letters addressed to Dr. A. Stengel, the University of Toronto, asking for information about the diabetes cure he had discovered. In Philadelphia the result was an angry letter of denial to the Ledger from Dr. Alfred Stengel of the University of Pennsylvania.3

  The question of whether or not insulin was a “cure” for diabetes gave the newspapers all sorts of trouble. Surely if the stuff caused sick people to become totally normal again it was a cure. Even fairly knowledgeable medical people themselves had trouble with the concept, especially if they knew of the early hope that insulin really did cure diabetes. On the other hand, it was vitally important not to lead diabetics to believe t
hat a cure was at hand, for fear of their celebrating by abandoning diet. Newspapers tended not to catch qualifications. All the Toronto newspapers published a comment made by Dr. Lewellys Barker at one of the celebrations for insulin: “Today the diabetic may if he choose, eat, drink and be merry, and tomorrow he will not die.” Only one of the papers added Barker’s immediate qualification, that they still had to follow dietetic rules.4 And yet medical people themselves talked and wrote about “Victory over Diabetes”, and how “No one need die today who is suffering from diabetes.”5 It wasn’t a cure, but it was a conquest. Perhaps the press’s trouble with doctors wasn’t all the journalists’ fault.

  The best advertisements for insulin were the diabetics whose lives had been saved by it. The most prominent of these was Elizabeth Hughes, whose progress was chronicled across North America. She, too, disliked the reporters, whose stories brought not very welcome letters and visits from other diabetics. Writing her mother about her latest weight gain, Elizabeth added, “…please don’t let on to a newspaper reporter! Haven’t they been horrible though. I hate to be written up like that all over the country and I think its cheapening to the discovery. Poor Dr. Bantings even gotten to the place where doctors are beginning to kid him about advertising his discovery through me.”6

  Other patients and their relatives were delighted to talk about insulin. The Corbett family of New York City told the world of how they had bought the cemetery plot in which to bury Joe, a young school teacher, and how they would now laugh and cry when they drove by it. Frank A. Vanderlip, former president of the National City Bank, was back at his desk after insulin treatment, telling reporters that he had an appetite like a hired man and could eat even the dishes that a diabetic “dare not look in the eye.” Mrs. Thomas Dixon, wife of the author of The Clansman (from which “Birth of a Nation” had been made), was another of the prominent Americans treated in Toronto. The Star reporter noted how her eyes shone as she talked of Dr. Banting and his work.7