I
Elizabeth Hughes was one of several hundred North American diabetics receiving insulin that autumn. Lilly was supplying a dozen or so leading American clinicians, Sansum was still making his own insulin in California, the clinics at Toronto General and Christie Street hospitals were in full operation, and in September the university’s Insulin Committee, uneasy at the overwhelming United States presence in insulin development, decided that insulin should be made available for clinical testing in Montreal, Winnipeg, Kingston, and London, Ontario.7 Taking time from his laboratory research, Collip made the first insulin used clinically in Edmonton, Alberta. The United States list was also steadily expanded. In mid-February Clowes estimated that upwards of one thousand diabetics were receiving Iletin from more than two hundred and fifty physicians in sixty clinics in the United States and Canada.8 Clowes and the Americans were very careful to maintain Toronto’s priority in the publication of results, and generally to honour Canadian sensibilities. Nevertheless, by far the largest trials were those run by Joslin, Allen, and Woodyatt in the United States.
The early use of insulin was both a clinician’s delight and a baffling challenge. A delight because it worked so well, a challenge because so little was known about insulin and its effects, so much had to be tried. What was the proper dosage, for example? A simple question which actually begged a host of other questions. Should the dose be high enough to keep a diabetic’s urine sugar free, or should a little glycosuria be permitted? What levels of blood sugar should be aimed at? Was it necessary to worry about blood sugar at all if the urine was sugar free? How could and should the effects of insulin be spread out over twenty-four hours? Should the dosage be kept low to avoid hypoglycemic reactions? What kinds of doses were appropriate in the emergency situation of coma? And on and on and on. Relating the daily intake of insulin to that of fats, proteins, and carbohydrates posed an endless series of problems. Measuring how insulin actually worked raised yet another category of issues, some of which would be wrestled with back in the physiologists’ and biochemists’ labs. Laboratories where, it had to be admitted, the scientists still did not know exactly what insulin was. Its chemical composition was a mystery.
That mystery was solved in part in the mid-1920s, when it was realized that insulin was a protein, and later the unravelling of its exact structure in the 1950s would be a milestone in molecular biology. But in the generations since the discovery of insulin, most of the questions about its action and proper use, and others arising from them, have been and still are being investigated by thousands of researchers around the world. In the autumn of 1922 the handful of physicians who had insulin were like explorers who had found an unknown continent and were trying to map it all in a few months. Governments did not offer guidelines, help, or hindrance. To make this job just a little more challenging, the basic tool, insulin, remained in limited supply to the end of 1922, and neither the Toronto nor the Lilly product had as yet come close to being purified or standardized; the best Lilly could obtain was a potency variation from lot to lot of plus or minus 25 per cent.
In their animal research the Toronto group had discovered the potentially lethal effects of too much insulin. So the clinicians were constantly on the watch, orange juice or candy at hand, for the typical symptoms of hypoglycemia – anxiety, restlessness, sweating, trembling, sudden hunger, behaviour analogous to drunkenness – and for that reason there were perhaps fewer severe hypoglycemic reactions than there would have been otherwise. There were virtually none, for example, in Walter Campbell’s clinics at Toronto General Hospital. One night at Christie Street, however, the doctors found a hypoglycemic patient trying aimlessly to clamber up the wall. Dr. Joe Gilchrist himself had a hypoglycemic reaction on the street one day; it became more dramatic and severe every time it was described during the next thirty years. One version had Gilchrist arrested for drunkenness and his Christie Street patients trooping down to the courthouse to get their doctor out.9 Banting maintained that Gilchrist was the first human to experience the effects of an overdose of insulin,10 but Williams in Rochester may have witnessed the first truly severe hypoglycemic reaction in a human when, during the first days of treating his second patient, Lyman Bushman, about June 1922, “we threw him into profound insulin shock. He was so lifeless that the chief of our surgical staff pronounced him dead. We immediately restored him by the injection of some glucose, and it was looked upon as a miracle in the hospital.”11
Both Williams and Woodyatt had patients die from what was later diagnosed as hypoglycemic reaction.12 Allen, on the other hand, and probably many others, lost patients in coma from being too conservative, afraid to give the enormous dosages necessary in some of the most severe cases. In the period of rationing there sometimes was not enough insulin on hand to try heroic doses. And there were hard ethical dilemmas, as when Allen had to decide whether to keep giving vital supplies of insulin to a totally insane diabetic. This patient would die without insulin; rational patients badly needed it; Allen thought the large doses necessary for the patient’s survival might be contributing to his insanity. He slid around the problem by transferring the patient to a psychiatric ward at Johns Hopkins which had some insulin available.
One of the great hopes in the early days was that insulin might actually cure diabetes. Perhaps it allowed a diabetic’s pancreas to rest and the islet cells to regenerate.13 Enough of the early patients were so responsive to minute doses of insulin, or seemed able to get along with greatly reduced doses, or seemed able to do without it completely after initial recovery, that the issue was in doubt for the first year or more of experimentation. On balance, however, the clinicians were realizing that while insulin often gave their despairing patients enormous psychic regeneration, it did not seem to bring about any lasting change in a diabetic’s impaired metabolism. Banting tried a tolerance test on Elizabeth Hughes in November, for example, taking her off insulin to see how many calories she could handle without showing sugar. She reported the results to her mother:
With regard to my old tolerance test, it doesn’t seem to be panning out very well and that is why I guess we will be able to go [home] sooner than we thought. Of course nothing is the matter, only I don’t seem to be able to stand any more than my old diet of 933 calories. We have tried to raise twice both times with only two grams of fat more, but each time I either showed sugar or showed that I was very much on the edge. We are trying it out one more day, and if I show again this time I can go back on my old wonderful big diet tomorrow, thank goodness! Well this proves the marvel of insulin all right, for it shows that its that stuff alone thats carrying all of my extra calories. Isn’t it wonderful to think that just that liquid stuff does all that work for my poor old tired out pancreas? Dr. Banting thinks that on newly-developed cases their tolerance would be much more likely to be raised under this treatment, but for an old case like mine where this pancreas has had so much strain and where my tolerance has been much lowered by various setbacks he thinks the pancreas is just about done its duly, and can’t take care of even a gram more. Thank goodness for the insulin!14
As insulin was gradually purified, the incidence of pain, abscesses, and swellings caused by the injections dropped to insignificant levels. Almost all patients easily learned to give their own injections. Even so, everyone would have preferred an easier method of administration. Clinicians experimented with every other possible route – oral, rectal, vaginal, intranasal, intravenous, and by inunction (rubbing into the skin). Subcutaneous injection of insulin turned out to be the only practical method. Intravenous injection was occasionally used to get quick results in coma cases.
Quite apart from hypoglycemic problems, some diabetics sometimes barely survived taking insulin. In Woodyatt’s clinic at Presbyterian Hospital in Chicago, for example, a 78-pound boy, Randall Sprague, started receiving insulin on September 21, 1922, a day before his sixteenth birthday. For two days he received what Woodyatt referred to as “Macleod’s insulin.” It had no effect. Th
en he was started on insulin Woodyatt was making himself. It was effective, but the limited supplies of it were exhausted by October 16. So, according to Sprague,
…on October 21 I was started on the Lilly extract in a dose of 5 cc. daily. Urine sugar promptly cleared.
However, after being on Iletin for one week, I experienced a severe anaphylactic reaction with symptoms persisting for two days, including generalized skin eruption, nausea, vomiting, fall in blood pressure and profound weakness. I was very ill and thought I was going to die. To put it mildly Woodyatt was irritated by this episode and sent a telegram to Eli Lilly and Company in which I believe he advised them to discontinue distribution of the extract until its content of foreign protein was reduced. Since no other insulin was available I was off insulin for six days and urine sugar increased to as much as 30.39 grams daily and tests for acetone and diacetic acid became positive… insulin was urgently needed.
On November 4, 1922, Woodyatt insulin from a new batch was started and the dose gradually increased to 3 cc. daily. Glycosuria and ketonuria cleared.15
The next spring Sprague found he could take Lilly’s insulin without difficulty. Nearly sixty years and some 45,000 injections of Iletin later, the distinguished diabetologist and endocrinologist, Dr. Randall Sprague, wrote that account in a letter to me.
Another victim of anaphylactic reaction was Jim Havens. Poor Havens, who had so much trouble with Toronto’s early impure insulin, found out in August and September that Lilly’s preparation caused him even worse side-effects. Havens, it turned out, was one of the small group of diabetics allergic to pork insulin. Connaught’s beef insulin was still impure and painful. Havens had regressed almost back to where he had started when, in October, 1922, he started finally getting special beef insulin from Lilly.
Then there was patient No. 24 from Allen’s Rockefeller study, a fifty-three-year-old manufacturer whose life had been saved in 1914 by undernutrition. In possibly his most successful case, Allen had brought the man back from the point of death, stabilized him at 1,500 calories a day and a body weight of 97 pounds, and restored his strength so he could resume work. In December 1922 an attack of influenza shattered the man’s carbohydrate tolerance. In January 1923 he began getting insulin at the Physiatric Institute, one of only three patients in Allen’s Rockefeller Institute group who survived to receive insulin. The same discipline and courage and vitality that kept Elizabeth Hughes alive shines between the lines of Allen’s clinical reports of this case. And insulin seemed to have had the same transforming effects on patient 24 that it did on Elizabeth and so many others. In the early spring of 1923 he could walk ten miles a day.
On April 27 he suddenly developed a mysterious cough and fever. On April 28 he fell into a coma. On April 29 he died. Insulin proved useless. Allen could not explain what caused his death.16
Insulin did not free diabetics from careful dietary control and self-discipline. Some of the more reckless diabetics, or those who believed they had been cured by insulin, thought they could abandon diet, abandon insulin, or abandon both. This was a suicidal course. One of Joslin’s early patients, Thomas D., omitted insulin for five days, kept his diet, developed a mild infection, and died in coma despite the doctors’ emergency efforts with insulin. Less serious but still annoying and harmful was the disruption caused in the Toronto General Hospital clinic by a food-smuggling operation17 carried out by one of the patients who arranged for an enterprising newsboy to tie cakes and candies to the end of a string let down from a third-floor window.*
All the failures, mistakes, and problems faded into near insignificance when compared with the success the clinicians were having. It was as simple as this: insulin worked wonders, near-miracles, time after time. An eight-year-old boy was carried into Joslin’s office by his parents. He had been so hungry on his diet that he would burn his hands stealing food from a hot oven. “Dr. Joslin, do anything you want with Frederick, you can’t make him any worse”, his parents told the doctors. Two months of insulin treatment later, the mother wrote Joslin that Frederick was feeling fine and wouldn’t touch a particle of food other than his diet. He walked down town every afternoon, the neighbourhood children staring in amazement at a little boy who had not been able to go out for the past two years. “Nothing we can say based upon laboratory results can equal in importance statements of this character,” Joslin and his associates concluded in the account of this case in their first paper on insulin. They followed it with the case of Dorothy Z., a five-year-old girl who could not climb stairs when she started getting insulin, but soon could walk up and down stairs and dance with her brothers. And later in the article the case of a little Finnish child, Annie N., who came into the hospital, sank towards coma, was given insulin, and within thirty-six hours sat up in bed, played at the window, and threw a kiss to the doctor as he left her room. “It still remains a wonder,” Joslin wrote, “that this limpid liquid injected under the skin twice a day can metamorphose a frail baby, child, adult, or old man or woman to their nearly normal counterparts.”18
The most spectacular of insulin’s triumphs came when comatose diabetics were virtually resurrected by the injections. In September at the Hospital for Sick Children in Toronto, Banting and Dr. Gladys Boyd brought an eleven-year-old girl, Elsie Needham, back to life after many hours of deep unconsciousness. By January she was back at school, to all appearances a healthy, normal child, with years of life ahead of her.19 Another child restored from near coma in Toronto was Leonard Thompson, who had been readmitted to Toronto General in October “in a state of severe acidosis bordering on coma with marked dehydration.” This time the boy was put on insulin permanently.20
Allen gave insulin to the largest number of patients, 161, in the first year of clinical trials, and his 181-page report is a gold mine of clinical detail. Because of his methods he had an unusually large number of living skeletons waiting for insulin to put flesh on their bones. Also because of his methods he had a large number of former patients who had failed or refused to accept his therapy, but came back to the Physiatric Institute for insulin and found they could tolerate the reasonable diet that went with it. Frederick M. Allen was the most scientific, strictest, sternest, least emotional of the clinicians. Nevertheless, the language of transcendence crept into even his accounts.
Though the patient was an extremely poor and uneducated tenement dweller, she followed treatment with religious scrupulousness,… though she lived the life of an emaciated invalid and death from inanition seemed to be the ultimate prospect, this treatment was the only possible means whereby a patient with diabetes of this severity could have been kept alive to receive salvation through insulin….
The child has become the picture of health, and pictures of her condition before and after insulin treatment would show a miraculous contrast.21
Actually it was Dr. Rawle Geyelin who supplied the most striking of the “before and after” pictures, some of which are reprinted in this book, to accompany the classic papers in the special insulin issue of Allen’s Journal of Metabolic Research. And it was J.R. Williams who came closest to breaking the professional shell of the case-hardened clinician when he wrote of his first case, Jim Havens, “The restoration of this patient to his present state of health is an achievement difficult to record in temperate language. Certainly few recoveries from impending death more dramatic than this have ever been witnessed by a physician.”22 Rollin Woodyatt, possibly the most dedicated, certainly the most terse (his first paper on insulin was only nine pages long) of the remarkable group of diabetologists, wrote Macleod in October that “this Insulin effect is as striking and the results as brilliant as anything I have ever seen in medicine or surgery.”23
Late in November, following Clowes’ plan, the leading clinicians came to Toronto for a conference to discuss their results, co-ordinate their publications, and advise the manufacturers on dosage and standardization. The group included Allen, Joslin, Woodyatt, Geyelin, Williams, a team from Indianapolis, and Russell
Wilder of the Mayo Clinic. Between meetings, which would have included a good deal of “best case” story-telling and comparisons, Banting took several of the doctors to see his prize case, Elizabeth Hughes. She had been dreading their visit, especially having to see the humourless Dr. Allen.
Well all the doctors came at last just as we were about to sit down to lunch the way I just had a feeling they would….There were six of them and they all stood in the door and just stared at me until I got so nervous I didn’t know what to do. It seems to me that every time I looked up I met the eye of one of theirs fixed on me. It was terrible.
There were Dr. Joslin, Dr. Allen, Dr. Banting, Dr. Fletcher, Dr. Woodchat and Mr. Best. Dr. Allen acted nicer than I’ve ever seen him and Dr. Joslin was simply adorable. No wonder everybody is crazy over him. Of course these two were ushered in first and Dr. Allen said with his mouth wide open – Oh! – and thats all he did. He just kept saying over and over again that he had never seen such a great change in anyone and he actually cracked a joke as he was leaving saying he was glad to have been introduced to me or he wouldn’t have known who it was. Now I think thats very good for him. He’s grown very fat but his nose hasn’t filled out any unfortunately and its as flat as ever. Of course as he was going he gave us an invitation to come to Morristown when I came home and of course I accepted the invitation with alacrity. On the whole he conducted himself so much better than I ever thought he would that everything went off beautifully.
And Dr. Joslin is the sweetest man, all he could do was to look over at me and smile and say that he never saw anybody with Diabetes look so well. Dr. Banting…said that they had had the honor of hearing Dr. Joslin say at one of their meetings up here after he had seen me that I was the most wonderful case of Diabetes he had ever seen treated. Now think of that coming from a man like that and think of Dr. Allen probably sitting there and hearing him say it. I asked Dr. Banting if the latter had anything to say and he said no that Dr. Allen had spoken a few words during the whole time he was here. A man of few words is the word. Its a joke among the doctors though that what Dr. Allen misses in saying he always takes out in writing.24
The Discovery of Insulin Page 22
