Four days later, on November 30, 1922, Elizabeth Hughes went home to Washington. It was Thanksgiving Day in the United States.
I have described these early cases in such detail to emphasize just how striking the effects of insulin were – much more visibly and dramatically so than insulin’s impact today, when few diabetics decline anywhere near coma before obtaining treatment. One more case study deserves to be published exactly as it was written. This is not merely a description of a splendidly successful use of insulin, but is also one of the best prose passages Fred Banting ever wrote. In later life Banting wanted, perhaps above all else, to be a writer. Here are the last few pages of the account of the discovery of insulin that Banting wrote out in longhand in 1940, and never got around to revising or polishing:
Another striking example…was the case that came to Toronto early in June 1922. I was in my office on this afternoon and a man carried his wife into the office under his arm. He was a very handsome man of 30 & he deposited in the easy chair 76 lbs of the worst looking specimen of a wife that I have ever seen. She snarled and growled and ordered him about. I felt sorry for him. I placed her in hospital more in pity for him than in regard for her.
She was one of the most uncooperative patients with which I have ever delt. It was in those early days when insulin was very scarce & precious and we endeavoured to get as much experimental knowledge as possible from each dose. She would steal candy or any kind of food she could lay hands on. She demanded that her poor husband come to the hospital early in the morning and every night he must not leave until she was asleep, yet she scolded him cursed him and treated him like nothing all day long. I could never understand why he took it all patiently, unruffled and even cheerfully. She was a terrible looking specimen of humanity with eyes almost closed with aedema, a pale and pasty skin, red hair that was so thin that it showed her scalp, and what there was was straight and straggling. Her ankles were thicker than the calves of her legs and her body had sores where the skin was stretched thin over the bones. Above all she had the foulest disposition that I have ever known. I could not understand and I marvelled at & sympathised with the poor husband.
She was in hospital some weeks and improved considerably and then he took her home. I was frankly glad to see the last of her. For his sake I had been kind. As a case to follow she seemed hopeless. I did not write to them nor did I hear from them.
A year later I was at my desk early one morning when the phone rang. A cheerful chuckling voice asked if I would be there for ten minutes. I said I would. The receiver was hung up. I went on with my correspondence.
In a few minutes I heard the outer door open and a moment later my office door was thrown wide open as in rushed one of the most beautiful women I have ever seen. She was a stranger. I had never seen her before yet she threw her arms around my neck and kissed me before I could move from where I stood. Over her beautiful head I saw the laughing face of the patient husband. I stood back. The three of us stood hand in hand. I looked at them. The husband said “Doctor I wanted you to see her now. This is the girl I married – before she had diabetes.” We laughed and talked. She was a devoted wife. He was no longer the slave but did most of the talking. I asked them many questions. As they went out he whispered “I’ll have to take some insulin myself doctor.”
Months later I received a tiny envelope with the name and a pink ribbon. A daughter. And I wondered if the little one had red hair, and I prayed she would never have diabetes.
It was difficult to find words and images to describe the transformation insulin wrought. Metaphors of salvation and resurrection were never far from writers’ and diabetics’ consciousness. Elliott Joslin, a man close to his Puritan heritage, felt the parallels between the sacred and the secular most strongly. In later life he often talked of how insulin reminded him of what he called the “Banting Chapter” of the Bible. “By Christmas of 1922 I had witnessed so many near resurrections that I realized I was seeing enacted before my very eyes Ezekiel’s vision of the valley of dry bones. Ezekiel XXXVII, 2–10:
…and behold, there were very many in the open valley; and, lo, they were very dry.
And he said unto me, Son of Man, can these bones live?
And… lo, the sinews and the flesh came upon them and the skin covered them above: but there was no breath in them.
Then said He unto me, “Prophesy unto the wind, prophesy, Son of Man, and say to the wind, Thus saith the Lord God: ‘Come from the four winds, O breath, and breathe upon these slain, that they may live.’“
So I prophesied as he commanded me, and the breath came into them, and they lived, and stood up upon their feet, an exceeding great army.25
II
Insulin was one of North America’s first great contributions to medical science and practice. Its use only gradually spread to Europe and the rest of the world. If we exclude Zuelzer and his acomatol, the first European to use insulin was Dr. R. Carrasco-Formiguera, a young Spaniard who was spending the 1921–22 year studying at Harvard. He happened to be present when Banting gave the first presentation at New Haven. In June Carrasco-Formiguera wrote Macleod asking for details so he could try insulin on a desperately ill patient in Barcelona whom he had been keeping alive in the bare hope of something like this being discovered. In September Carrasco-Formiguera and an associate, Dr. Pere González, managed to make up a brown fluid containing insulin. It was very impure. Carrasco-Formiguera had to test each batch on himself: “sometimes marked and persistent pain made me decide not to use a particular batch.” On October 3, 1922, he gave ten cc. of his extract to Francesc Pons in Barcelona. The results were promising, but the patient later died when the doctors temporarily ran out of insulin. Carrasco-Formiguera was soon treating other patients, though, and later undertook to supervise the manufacture and distribution of insulin in Spain.26 Nobody else on the continent appears to have used insulin clinically until 1923.
No one in Britain seems to have paid much attention to the reports of Banting and Best’s researches published in North America in early 1922. (The first inquiry from Britain was by a Canadian at the Royal Infirmary in Edinburgh, Jonathan Meakins, who wrote Macleod on June 17, 1922, asking for more information so he could treat a diabetic colleague. Macleod sent directions on July 8, but Meakins did not use insulin, it appears, until January 1923.)27 Word of insulin reached the highest medical circles in Great Britain virtually out of nowhere – or almost nowhere: an obscure medical school in a far-off colony – in June 1922, when Macleod wrote the secretary of the Medical Research Council conveying the University of Toronto’s desire to give the council complete British patent rights to the anti-diabetic extract. Fitzgerald of the Connaught Laboratories was in England the next month and discussed the situation with the officers of the council. It was a young organization, created by the British government just before the war as an offshoot of developments in British health insurance, and was still feeling its way. The MRC scientists were interested, but skeptical.28 Miracle cures were always being announced in medicine, even by people who should know better. Dr. Henry H. Dale, director of the biochemistry and pharmacology department of the council’s National Institute for Medical Research, suggested that he and a biochemist colleague, Harold Dudley, visit Toronto to reconnoitre the alleged discovery.29 Dale and Dudley were in Toronto in late September and early October. They also studied insulin production in Indianapolis and visited several of the American clinics. Their reaction was immediately enthusiastic. “The thing is undoubtedly a true story,” Dale wrote Walter Fletcher, the secretary of the MRC,
and the progress reflects enormous credit on all concerned with getting things to their present stage, with the very poor equipment they have had hitherto. Banting & Best are fine fellows & the whole story at this end, is perfectly straight, & there is no sign of anything but unselfish enthusiasm.30
Dale and Dudley’s report to the MRC at the end of October was a long, detailed discussion of insulin and its effects. The Englishmen were particu
larly impressed by the “striking case” of Elizabeth Hughes, whom they had seen in Toronto. They were less impressed with the situation involving the applications for patents on insulin manufacture, doubting that the patents would be sustained if challenged, worrying, as we will see, about the relationship with Lilly. They rather grudgingly admitted that patenting was probably necessary and that the MRC ought to go ahead and accept control of the British patent. At the least, Dale and Dudley wrote, holding the patent would enable the council to “exercise a moral control over the manufacturers, and would induce the latter to submit to a system of supervision, as regards this product, which the law does not enable the Council at present to enforce.” They recommended, and the council accepted, a two-streamed program under which the council would supervise experimental manufacture and clinical testing on the one hand, while working with selected manufacturers toward large-scale commercial production on the other hand.31
These arrangements were completed in mid-November. Clinical testing in Britain began in December and January, well after hundreds of lives had been saved and immense publicity generated in Canada and the United States. A leading British diabetologist, P.J. Cammidge, published a remarkably wrong-headed letter in the British Medical Journal in November, doubting that insulin would ever amount to much.32 Despite that, the news from America produced a considerable clamour for insulin in Britain, where it was estimated that at least ten diabetics died everyday.33 “I think about one hundred of my patients pray every night that you should develop diabetes mellitus,” one of the more offensive of the Harley Street practitioners wrote Fletcher in early December, implying that the MRC lacked an appropriate sense of urgency.34
In fact the council was following Dale’s advice not to get caught in Toronto’s trap of having to sacrifice crucial experimental work, which would be invaluable in manufacturing insulin, for the sake of keeping a few premature clinical users going. Its policy was designed to save the maximum number of lives in the long run, and is difficult to criticize. These were excruciatingly difficult choices.
The British parallel to the Elizabeth Hughes case was that of Paula Inge, the beautiful eleven-year old daughter of the noted theologian and dean of St. Paul’s Cathedral, W.R. Inge. Paula’s diabetes was diagnosed in November 1921. The doctor’s first estimate was that she might last only three weeks. A year later she was still alive, completely faithful to her starvation diet. In December her father began making inquiries about the possibility of insulin being available to treat Paula. When Dale informed him that it was still in the experimental stage and not available, Inge accepted the situation, writing back, “Godspeed the MRC.”35
Fewer than fifty diabetics in eight hospitals in Britain received insulin in the winter of 1922–23.36 Although Dale and Dudley made important improvements in the manufacturing process, British researchers and manufacturers experienced many of the same difficulties familiar to North Americans (as well as such extra problems as a slaughterman’s strike, combined with a Canadian embargo on the shipment of live cattle to Britain, which caused a raw material crisis).37 By the end of March, Eli Lilly and Company, which had made its production breakthrough, was offering to supply Britain with American insulin. “Plainly, the American supply cannot be kept out simply in the interests of British manufacturers while people are literally dying for want of it,” Fletcher wrote the Minister of Health, explaining why the MRC was ordering large supplies of American insulin.38 In mid-April, when the Lilly supplies arrived to supplement the small quantities produced by Burroughs Wellcome and the joint venture between Allen & Hanburys and British Drug Houses, it was possible to make insulin available to most of the seriously ill British diabetics.
Paula Inge was not among them. The story told by those who knew Dale is that she never received insulin at all. Her father’s accounts suggest that she was finally given the new treatment. But something must have been wrong with the product or the dosage, for Paula Inge fell into coma and died on Maundy Thursday in March 1923. Her parents consoled themselves with the belief that God had given them a whole year’s grace before taking their daughter. Medical science, Dean Inge thought, had done all it could for her.39
III
One of the most distinguished foreign scientists who visited North America in 1922 was Professor August Krogh of the University of Copenhagen. Krogh was the most recent winner of the Nobel Prize in physiology and medicine; for his work on capillary action during exercise he had been given the 1920 prize, one of only two awarded since 1914. Brought to the United States to lecture on his capillary work, Krogh found American medical men talking insulin everywhere he went. So he decided to come to Toronto to study insulin at first hand and consider the possibility of undertaking its manufacture in Denmark.
J.J.R. Macleod was delighted at the prospect of a visit from Krogh, hoped the Dane would be his house guest while in Toronto, and arranged special dinners and lectures. Krogh was in the city on November 23 and 24. He spent much of his time with Banting and Macleod, gave a guest lecture on the capillaries, and left for home with authorization from the University of Toronto to introduce insulin into Scandinavia.40 During the winter of 1922–23 Krogh and his associate, Dr. H.C. Hagedorn, began the organization of Danish insulin manufacture, establishing a special non-profit Nordisk Insulin Laboratory. There were vast supplies of pork pancreas available from Denmark’s bacon factories. By the end of 1923 Danish “Insulin-Leo” had joined Lilly Iletin and the British insulins in mass production.
Inquiries were coming to Toronto from as far away as Peking (where American medical missionaries hoped to make insulin) by the fall of 1922, but outside of Britain and Denmark there was no other rapid progress towards large-scale manufacture. In normal times the fiercest commercial competition might have come from Germany, with its world leadership in chemistry and pharmaceuticals. In the early 1920s, though, Germany was in chaos from the effects of the war and then its uncontrolled inflation. It would be well into 1924–25 before extensive manufacture of insulin started in Germany. In the meantime a handful of German researchers and clinicians learned about insulin, not always accurately. Carl von Noorden apparently tried insulin in late November 1922, decided it had only transitory effects, and gave up. Eighty-year-old Bernard Naunyn wrote to his former student, Minkowski, saying he did not believe the reports on insulin; they were only another case of American exaggeration.41 Minkowski, the greatest of all the pre-insulin researchers, was more careful. Having read an article by Macleod in a November 1922 issue of the British Medical Journal (his clinic apparently could no longer afford the North American journals), Minkowski wrote Toronto for off-prints and advice on where he could obtain insulin. “With the greatest impatience I am looking forward to the moment,” he wrote in January 1923, “in which the utilisation of your discovery in the interest of the patients committed to my charge shall be possible for me too.”42
A young medical student, Martin Goldner, was among those present at the moment Minkowski had anticipated. Many years later, having come to the United States and established himself as a diabetologist, Dr. Goldner wrote this description of the scene:
It was in Breslau, and I believe during the Spring Quarter of 1923, that Professor Minkowski, at his regular morning lecture, showed us students the first vial of insulin which had come to Germany. The lecture hall was crowded as always, and the entrance of the Professor was greeted with the usual tramping of feet, followed by silence. Minkowski stood in front of us, tall, quiet, his white hair and beard blending with his white coat, and he looked at us with his unforgettable eyes, understanding and kind, yet penetrating. His appearance commanded respect and admiration, as well as confidence and devotion. He had one hand in the pocket of his coat. From this he lifted the small vial.
“This,” he said, “is the first insulin to reach our country. It has been sent to me by Dr. Banting and Dr. Best, of Toronto, who have discovered it. It was once my hope that I would be the father of insulin. Now I am happy to accept the designat
ion as its grandfather, which the Toronto scientists have conferred on me so kindly.”
Loud and long tramping of the students’ feet expressed their applause. Then followed the usual case presentation. That particular morning, two patients were brought into the amphitheater, one an elderly diabetic man with an ulcer on the foot; the other, a diabetic child in keto-acidosis. The Professor discussed the conditions, and then asked to whom he should give the precious hormone, since he did not have enough for both, and could not possibly look forward to an early shipment. The students suggested the child, who appeared near death. Minkowski shook his head sadly. There was good hope, he said, that the old man’s diabetes could be improved, and his leg ulcer healed under the influence of insulin, but there was little chance of saving the child’s life, the keto-acidosis being the final stage of the disease, from which there is practically no return. Even if insulin could have had some effect, it would have been only temporary, prolonging the agony without preventing the doom; in spite of all sympathy, he said, the physician must be realistic and use cool and prudent judgment.
The students were quiet. The lecture proceeded. Many of us felt that we had witnessed a historical moment: seeing not only the old professor’s gracious acknowledgement that his life’s aim had been fulfilled by the ingenious research of younger men, but also the dawn of a new era in the treatment of diabetes – an era which would prove much more successful than the professor could have imagined.43
The Discovery of Insulin Page 23