The Discovery of Insulin
Page 35
There were also stunning, distressing ironies. Because insulin enabled diabetics to live and propagate, and because the disease has a strong hereditary component, the effect of the discovery of insulin was to cause a steady increase in the number of type 1 diabetics.17 Far more seriously, a rising calorie intake in the twentieth century, generating in some countries what was characterized as an epidemic of obesity, along with increased longevity almost everywhere, began to create in practically every country in the world massive numbers of new late-onset or type 2 diabetics. At the beginning of the twenty-first century diabetes, in its several manifestations, was more prevalent, posing more medical problems, than it had been before the discovery of insulin, and all the projections were that the situation would get much, much worse.
The clichés are worth repeating. The discovery of insulin was only the beginning. Or it was the end of the beginning. Diabetes is a far more complicated disease than anyone realized in the early 1920s. The appearance of insulin raised as many questions as it answered. Every part of every answer raised more questions.
The high incidence of complications, even among insulin-users, was substantially responsible for the founding of support organizations, such as the American Diabetes Association, the British Diabetic Association and the Canadian Diabetes Association in the 1940s, and the gradual resurgence of research. In the 1960s, impatient American parents of diabetic children organized the Juvenile Diabetes Foundation with an evangelical determination to replace insulin therapy with a cure for diabetes.
In some ways progress seemed inevitable. The structure of the insulin molecule came to be understood, generating pioneering knowledge and several Nobel Prizes. Whereas the Toronto researchers had worked in almost total ignorance of how insulin makes possible the body’s combustion of nutrients, discovery of the cellular mechanisms of insulin and glucose transmission made it possible to differentiate forms of diabetes. The discovery of other metabolic hormones, ranging from glucagon through leptin, began to fill in the picture of hunger and the responses it triggers. On a practical level, by the 1970s vast improvements in glucose monitoring made possible much more precise insulin dosage and diabetic control – and in the 1990s the Diabetes Complications and Control Trial firmly established the value of tight control for insulin-users. The rise of diabetes education from the 1960s through the 1990s, a key way of empowering insulin-users and attempting to minimize the impact of type 2 diabetes, was vitally important in reducing the ravages of diabetes. Therapeutic breakthroughs such as laser surgery for eye problems, kidney dialysis, and the assault on heart disease provided vital treatment for complications.
From time to time there were fears that supplies of animal pancreas would not be adequate to meet growing demand for insulin. While the Japanese did briefly make insulin from whales during World War II, there were never serious shortages of beef or pork pancreas. All concern about the insulin supply faded in the 1980s when first Eli Lilly, then Novo-Nordisk, began selling genetically-engineered human insulin, the first and still one of the greatest triumphs of recombinant DNA technology. Soon it was possible to create “designer” insulins and insulin analogues, and other substances to facilitate insulin’s action, the aim being to make the achievement of diabetes control easier.
The need to inject insulin was a problem that could also be tackled by designing better injection systems, ranging from painless insulin “pens” to high-tech insulin pumps or “artificial pancreases.” Eighty-five years after diabetic patients began calling for an alternative to injection as an insulin-delivery system, pulmonary delivery of inhaled insulin finally became technically safe and feasible. In the meantime surgically centred teams of researchers (led by a group based at the University of Alberta) had finally been able to achieve Banting’s dream of transplanting islet cells into the bodies of human diabetics, enabling some of them to go without insulin for significant periods.
The search for something better than insulin had started with Collip’s glucokinin and Allen’s myrtillin in the 1920s, and it continued through the development of several generations of oral hypoglycemics. While most new drugs proved more effective than the ones they replaced -some were even thought to stimulate partial regeneration of beta cells in the pancreas – none was able to replace the need for insulin injections in type 1 diabetes. For millions of type 1 diabetics around the world, and increasing millions of type 2 diabetics, injections of the hormone are just as vital today as they were for Leonard Thompson, Jim Havens, Elizabeth Hughes, Elsie Needham, Ted Ryder, and their fellow sufferers so many years ago.
Health care workers hope some day to turn insulin therapy and some forms of diabetes into matters of only historical interest. Can a vaccine be developed to protect against the viral triggers of type 1 diabetes? Can determined public health campaigns – a new war against obesity, paralleling the twentieth century’s assault on tobacco use – induce in populations the good dietary habits that will reduce the incidence and increase the control of type 2 diabetes? Can human weakness, human hungers, be overcome?
Thousands of researchers, spending billions of dollars every year, are attacking all of the questions relating to diabetes and insulin, while many more thousands of clinicians and educators serve in the trenches of diabetes care. The difference between the world-wide effort of the twenty-first century and the events in Toronto in 1921–23 is like that between the exploration of space and the flight at Kitty Hawk in 1903. Nameless astronauts now fly space shuttles; the Wright brothers won the immortality. The immortality of the discoverers of insulin was particularly deserved, in the sense that for diabetics it was much more than a matter of just getting a new hormone off the ground. All the later questions, even the current ones, are secondary to the one answered in 1921–22 in Toronto. With insulin, the stone was rolled away, and diabetes became a matter of the quality of life, not the speed of death.
Fred Banting, J.J.R. Macleod, Bert Collip, and Charley Best knew they were making medical history. Their struggle for credit was fired by each man’s desire to have his place in history, to have the only kind of immortality open to us. This is surely not an ignoble aspiration. But perhaps the group in Toronto misjudged both their situation and posterity’s viewpoint. They did not realize that those who understood history would eventually come to honour all of them. Above all, we would honour their achievement.
Notes
Complete citations for the manuscript collections and publications referred to in these notes are provided in the list of sources. Some of the citations in these notes to cases, files, etc. in manuscript collections may be no longer accurate if, as has been the case with the Insulin Committee records, they have been moved or reorganized. The following abbreviations are used in these notes:
BP: Banting Papers
CP: Collip Papers
FP: Feasby Papers
IC: Insulin Committee records
MP: Macleod Papers
MRC: Medical Research Council records
UWO: University of Western Ontario
Introduction: What Happened At Toronto?
1 Roberts 1922.
2 Dale 1922.
3 Pratt 1954; Pratt manuscript.
4 Feasby 1958.
5 Murray 1971; also Murray 1969.
6 International Diabetes Federation 1971.
7 Bart 1976; also Pavel 1976.
8 Décourt 1976.
9 Correspondence regarding the document accompanies the Pratt manuscript at the University of Toronto, and is also contained in the CP, UWO and in the Feasby papers.
Chapter One: A Long Prelude
1 Quoted in Wrenshall, et al.1962, p. 36.
2 Osier 1915, p. 438; Allen 1919, p. 9.
3 Allen 1919, pp. 10, 27.
4 Ibid., pp. 24–25.
5 Ibid., pp. 31, 37.
6 Ibid., pp. 42–45.
7 Quoted in Allen 1919, p. 29; the speaker was Sir William Gull.
8 Opie 1910, p. 317.
9 Houssay 1952.
11 J.J.R. Macleod estimated 400 in an interview, BP, 47, p. 89. For summaries of the use of extracts, see Allen 1913, p. 813f; Macleod 1926, pp. 55–56; Kleiner 1959; Cheymol 1972; Opie 1910, p. 102; Dewitt 1906, p. 193.
12 Cheymol 1972 states that the foetal extract was tried. But see Allen 1913, p. 815: “Apparently no one has ever tried the interesting possibility of feeding the glands of new-born or foetal animals, in which the islets have a relatively high development and little external secretion is present.” Rennie and Fraser 1907.
13 Zuelzer 1923. For the experiments, see Zuelzer 1907, 1908; Zuelzer, Dohrn, Marxer, 1908. On Zuelzer generally, see the useful short study by Mellinghoff 1971.
14 Zuelzer 1908, p. 316 (translation).
15 Forschbach 1909 (translations).
16 Mellinghoff.
17 E.L. Scott Papers, case 2, Carlson to Scott, Oct. 7, 17, 1911; A.H. Scott, 1972; Scott 1912; Magner 1977. The view advanced by Scott’s widow, that Carlson tampered improperly with Scott’s conclusions, is not warranted. The extreme claims in her book (A.H. Scott 1972) are undercut by the published papers and by the unpublished letters in the E.L. Scott papers.
18 Scott 1913; Scott papers, Carlson to Scott Oct. 17, 1911.
19 Macleod 1926, p. 59.
20 Murlin and Kramer 1913, 1916, 1956.
21 Macleod 1913, pp. 90–92.
22 Allen 1913, pp. 813, 815, 816.
23 Ibid., p. vi.
24 Allen and Sherrill 1922A, pp. 394, 115, 110.
25 Allen 1919, pp. 410–11.
26 Ibid., pp. 184–85, 376, 248.
27 Ibid., p. 202.
28 Allen and Sherrill 1922A, p. 419.
29 Allen 1919, p. 411.
30 Ibid., p. 579.
31 The only published account of Allen’s career is Henderson 1970. Henderson is also the custodian of Allen’s papers, which include a revealing manuscript autobiography. The Physiatric: Institute is also described in the Toronto Star, July 20, 1923.
32 Woodyatt 1921; Allen 1923.
33 Joslin 1917, p. 471; also Joslin 1919, p. 18.
34 See the very misleading chart on the first page of the early editions of Joslin’s diabetic manual.
35 Kicnast 1938.
36 Joslin 1946; Wilder 1946, Campbell 1946.
37 Allen 1913, p. 813.
38 Myers and Bailey 1916.
39 The paper is Kleiner 1919; the quote is from Kleiner 1959; see also Kleiner and Meltzer 1915. Attention is drawn to Kleiner’s work in Goldner 1972A, B, C. The problem of animal facilities is Dr. Goldner’s conclusion, letter to the author.
40 Paulesco 1921B. Most of the relevant Paulesco material is reprinted in Pavel 1976, the best introduction to the controversy.
41 Allen 1919, p. 595; MP, Allen to Macleod, Feb. 8, 1922.
42 BP, Elizabeth Hughes file, Elizabeth Hughes letters to her mother.
Chapter Two: Banting’s Idea
1 Toronto Telegram, Jan. 18, 1923.
2 Flexner 1910; for the background of reform in Toronto, see Bliss 1978.
3 Banting 1940, p. 9.
4 Ibid., p. 12.
5 Very little was ever written down about Banting’s romance with Edith. Except for a brief account in Hipwell 1970, stories of their tangled affair have been passed on orally. The tip of the iceberg may surface in the very unreliable biography by Harris, 1946. My judgments are based partly on these sources, partly on interviews, particularly with Edith’s cousin, Spencer Clark. For Starr advising Banting to go to London, see Stevenson 1946.
6 He was actually a Bachelor of Medicine (M.B.); Toronto did not award an M.D. as a first degree in medicine until a few years later. Banting received his M.D. in 1922.
7 Banting 1940, p. 13; BP, 26, Account book.
8 Banting 1940, p. 14; see also note 5 above.
9 Banting 1940, p. 21; Barr 1977.
10 BP, 5, Lecture notes, therapeutics; Banting 1940, p. 7.
11 Banting 1940, p. 16. Banting apparently subscribed to the journal. Both Stevenson and Harris write that Banting had borrowed the copy of the journal from Western’s library. They were misled by the fact that years later, during a visit to London, Banting autographed and underlined the library’s copy of that issue, to show the article’s importance. Canadian Diabetic Association, Scrapbooks, undated clipping from the London Free Press, mentioning the visit and the underlining.
12 Banting 1940, p. 17.
13 There is a bare possibility that Banting’s whole account of the inspiration by the Barron article is a confused reordering of events. In a letter to Banting of Dec. 14, 1920 (BP, 1), C.L. Starr suggests that if Banting had not seen “an article in the November issue of Surgery, Gynecology and Obstetrics on this subject,” he might look it up. By the date of that letter Banting had spoken to and written Starr about his idea. Starr had also spoken to Macleod after Macleod had talked to Banting. Is it not odd that Starr would not have known how important the Barron article was in inspiring Banting’s proposal?
A second odd piece of evidence is Macleod’s statement in his 1922 account, describing their first meeting, that Banting “formed this idea while reading in a textbook of surgery.” The reliability of Macleod’s statement is considerably reduced, however, by his having prefaced it with the clause, “as stated in the first paper published on the work.” In fact, in the first published paper Banting and Best cite the Barron article as the source of Banting’s inspiration. Nevertheless, Macleod might have been buttressing an accurate memory of what Banting said to him with an inaccurate memory of the citation in the first paper.
It would be unlikely but not totally surprising if new evidence came to light showing that Banting did not read the Barron article until after he had become interested, as a result of his lecture preparations or other reading, in searching for the internal secretion.
14 Banting 1929. In his 1940 memoir, using quotation marks, Banting wrote that he wrote: “Ligate pancreatic ducts of dog – wait eight to ten weeks for degeneration. Remove remnant and extract.” Stevenson 1946 changes the wording slightly: “Tie off pancreas ducts of dogs. Wait six or eight weeks. Remove and extract” (p. 67). Stevenson gives no source. Stevenson and Banting 1929 are the two wordings given in Colombo’s Canadian Quotations, where Stevenson’s version is given first and tailed by Colombo “the fourteen most important words in medical research in Canada” (p. 33).
15 Academy of Medicine Notebook.
16 This account of the next day is based on Banting 1922 and 1910. It follows Banting’s version of when he spoke with Tew, rather than Tew’s memory (that Banting talked to him on the evening of Oct. 30), which is relied upon in Stevenson and Harris.
17 Banting 1940, p. 23. Banting said he spoke to Starr, W.E. Gallic, D.K. Robertson, and L.B. Robertson. It may be that he spoke to some of these after he had seen Macleod.
18 Macleod 1922/78. Comments on the validity of this hypothesis are reserved until pp. 203–8.
19 Banting 1940, p. 23 (in the 1922 version: “To my disappointment he did not seem at all interested”); Macleod 1922/78.
20 Macleod 1922/78. In 1940, p. 24, Banting added, “He told me that he had worked for fourteen years on carbohydrate metabolism and had given it up and was commencing on anoxemia.” This is plausible, but lacks supporting evidence.
21 For the later statements, see Banting 1929, 1940.
22 Academy Notebook, June 9, 14, 1921.
23 Allen 1913, pp. 834–36.
24 Banting 1922. In 1940, p. 23, Banting described his repeating his ideas this way: “A hot iron gives off steam when cold water is thrown upon it. It was the first time I had ever seen the famous professor and I was not overpowered with either the man or his knowledge of research. I told him that I did not care who had worked nor how long and that I wanted only ten dogs and an assistant for two
months.”
25 Macleod 1922/78: “I would place every facility at his disposal and show him how the investigation should be planned and conducted.” Banting 1922: “He consented.”
26 Banting 1922.
27 Macleod 1922/78, appendix, Banting to Macleod, Nov. 21, 1920.
28 Banting 1940, p. 25. Starr had trained Banting. Is it noteworthy that he apparently did not call Banting an excellent or skilful surgeon?
29 BP, 1, Starr to Banting, Dec. 14, 1920. Compare Macleod 1922/78: “I told Dr. Starr that although it was taking considerable chances I thought the research was well worth proceeding with.”
30 Banting 1940, p. 24. Also Banting 1929: “The next four months were spent in reviewing the available literature.” In his 1922 rough draft he wrote, “The idea grew and as time went on I devised more experiments. These were always written in my black book which I kept for writing down ideas and the place of reference.” This passage was not in the 1922 final draft, which does not mention any reading or experiments that winter.
31 Macleod 1922/78, appendix, Banting to Macleod, March 8, 1921.
32 BP, 1, Starr to Banting, May 2, 1921.
33 Stevenson 1946, p. 71. Stevenson cites no source and dates this conversation before November 7. A consideration of all the circumstances suggests the conversation might have been plausible and held later; no other evidence exists, however.
34 Academy Notebook, Banting to C.S. Sherrington, March 8, 1921:
My plan is to cut the spinal cord in the lower thoracic or lumbar region in new-born kittens and dogs. Following this I wish to make a study of the reflexes of the hind-limb at various periods of growth of the animal. I am anxious to see how these reflexes may compare with those of the normal animal.
It appears to me that such observations would indicate whether such a movement as walking was developed as a reflex or as a “voluntary” (cortical) action.
Miller had advised Banting to write. Banting kept Sherrington’s March 21 reply that the question had “some promise” and offering advice about technique.