The Discovery of Insulin

by Michael Bliss

  46 IC, Committee on Clinicians file, Macleod to Williams, June 30, 1922; BP, Whitehall file.

  47 Murlin’s block came when he and Kramer found that the anti-glycosuric results obtained from administering an alkaline extract of pancreas could be achieved by administering a simple alkaline solution alone. That finding led Murlin to distrust his much more important results showing an increase in the respiratory quotient of some of his dogs that received extract. See Murlin and Kramer 1916, 1956.

  48 BP, Havens file, J.S. Havens to Banting, July 14, 1922; Williams to Banting, July 11. Williams did not tell the Toronto people he was trying Murlin’s extract, but mentioned it in a Feb. 25, 1939, letter to Best (historical files, Best Papers, BI). The most detailed story of Murlin’s work with extracts is in Murlin, Clough, Gibbs, and Stokes 1923. See also the various articles by Murlin and his associates in the Proceedings of the Society for Experimental Biology and Medicine, XX, 1922–23.

  49 BP, Clarke file, notation by Palmer; Banting 1940, p. 76e.

  50 Lilly archives, XRDc, Williams to Clowes, Jan. 27, 1958; interview with Moloney.

  51 IC, Clowes to Macleod, March 14, 1923.

  52 IC, University of Toronto Miscellaneous file, Eadie to Macleod, July 7, 1922; MP, Macleod to Defries, July 14, 1922; Banting 1922.

  53 BP, 1, Clowes to Banting, July 18, 1922.

  54 Best family papers, M.M. Best scrapbook, Banting to Best, July 21, 1922.

  55 Lilly archives, J.K. Lilly to Eli Lilly, July 26, 1922.

  56 BP, Clarke file.

  57 Banting 1940, p. 72e; also BP, 1, Banting to Falconer, Aug. 5, 1922; Falconer Papers, box 76.

  58 BP, 1, Clowes to Banting, Aug. 8, 11, 1922.

  59 Lilly archives, XBLk, J.K. Lilly to Clowes, Aug. 4, 8, 1922.

  60 Ibid., Aug. 8.

  61 Ibid., Aug. 8, 11.

  62 Ibid., Aug. 4, though this may be an error by J.K. Lilly; the historical memory at Lilly is that testing was delayed in Indianapolis until Joslin gave his first injections.

  63 Lilly archives, Joslin address at the dedication of the Lilly Research Laboratories, Indianapolis, October 1934.

  64 Joslin, Gray, and Root 1922; FP, 1924 file, Feasby transcript of dictation by Joslin, Nov. 22, 1957.

  65 Kienast, 1938. In her recollection the author dated this event in March 1922, a very unlikely time. I believe she was wrong, and that these days in August are the most likely dates of the scenes she remembered so vividly. Possibly they took place in May when Allen went to the A.P.A. meeting.

  66 BP, 1, Allen to Banting Aug. 16, 1922; Elizabeth Hughes file.

  67 BP, Elizabeth Hughes file; EH to her mother, Aug. 22, 1922.

  68 BP, Elizabeth Hughes file.

  69 EH to her mother, Aug. 22, Oct. 1, 1922.

  70 Banting 1940, p. 65a; with telling, Banting’s one suit became shabbier and shabbier, covered with dog hairs and dung.

  71 Ibid., p. 59.

  72 EH to her mother, Aug. 22, 1922.

  73 Ibid., Oct. 6.

  Chapter Seven: Resurrection

  1 Banting 1940, pp. 77–8.

  2 EH to her mother, Sept. 24, 1922.

  3 Ibid., Sept. 29, Oct. 1.

  4 Ibid., Oct. 17.

  5 Ibid., Oct. 25.

  6 Ibid, Oct. 14.

  7 IC, Minutes, Sept. 1,22, 1922; MP, folder 342, Duncan Graham to Macleod, Aug. (misdated July) 14, 1922.

  8 MRC 1092/19, Clowes to H.H. Dale, Feb. 12, 1923; Lilly archives, XRDe, General Letter to Salesmen, #13, Feb. 20, 1923.

  9 Stevenson 1946, p. 140; Gilchrist, Best, and Banting 1923.

  10 Banting 1924.

  11 Best Papers, BI, historical file, Williams to Best, March 13, 1939.

  12 This and all other material on the clinical testing is drawn from the papers published in the November 1922 issue of the Journal of Metabolic-Research, which was not actually published, however, until May 1923.

  13 See the clinical papers and MP, Macleod to E.H. Starling, Nov. 7, 1922.

  14 EH to her mother, Nov. 19, 1922.

  15 Dr. Randall Sprague to author, Oct. 27, 1980.

  16 Allen and Sherrill 1922B, pp. 811–16.

  17 BP, 48, p. 118, undated newspaper clipping.

  18 Joslin, Gray, and Root 1922.

  19 Hospital for Sick Children, Annual Report 1923, p. 21. Testing was slow to get under way at the Hospital for Sick Children, where Banting had been a resident, apparently because Dr. Allan Brown, the hospital’s head of medicine, did not like Banting. They were finally reconciled by Dr. D.E. Robertson. See Banting 1940, p. 60.

  20 Macleod and Campbell 1925, p. 77.

  21 Allen and Sherrill 1922B, pp. 811, 831.

  22 Williams 1922, p. 734.

  23 IC, Woodyatt file, Woodyatt to Macleod, Oct. 4, 1922.

  24 EH to her mother, Nov. 26, 1922.

  25 Lilly archives, Joslin address at the opening of the Lilly Research Laboratories, 1934.

  26 MP, R. Carrasro-Formigucra to Macleod, May 19, 1922; IC, Spain file, Carrasco-Formiguera to Macleod, Oct. 5, 1922; Carrasco-Formiguera 1922, 1972. In his 1972 article he misdates the injection as October 4.

  27 IC, Great Britain (General) file; MRC, 1092/5, Meakins to Fletcher, Jan. 30, 1922.

  28 Interview with Sir Harold Himsworth, Sept. 30, 1980.

  29 MRC 1092–23, Fletcher memorandum, July 7, 1922.

  30 Ibid., Dale to Fletcher, Sept. 26, 1932.

  31 Ibid., H.H. Dale and H.W. Dudley, “Report to the Medical Research Council of Our Visit to Canada and the United States… “, Oct. 30, 1922; W. Fletcher memorandum for members of the MRC, “Insulin Treatment of Diabetes”, Nov. 8, 1922.

  32 Cammidge 1922A. He compounded his misjudgement five months later by declaring that the insulin treatment, for the average patient, was “a will-o’-the-wisp, reliance upon which usually ends in disappointment.” Cammidge 1922B.

  33 MRC 1092/17, Fletcher to the Minister of Health, April 7, 1923.

  34 MRC 1092/1 A, O. Leyton to Fletcher, Dec. 5, 1922. A question was asked in the House of Commons as to why the council was “throwing obstacles in the way” of insulin production: House of Commons, Debates, Dec. 13, 1922.

  35 For Paula’s illness see Inge, Diary, pp. 72, 85, and Personal Religion, pp. 87f. There is no written record of the Dale-Inge exchange, but it was told to me by half a dozen people, including Dale’s daughter. The one reference to Inge’s inquiries in the MRC records is 1092/1 A, G. Adami to Fletcher, Dec. 8, 1922.

  36 MRC 1923. In addition to the supply problem, a deliberate decision had been made to concentrate on a few very severe cases rather than spread insulin thinly among many patients.

  37 See MRC 1092/10, Fletcher to Sydney Holland (Viscount Knutsford), Jan. 8, March 2, 1923.

  38 MRC 1092/17, Fletcher to Newman, March 28, 1923.

  39 See note 35 above.

  40 For Krogh’s visit see IC, unsorted, Krogh to Macleod, Oct. 23, Dec. 16, 1923; Best family papers, Macleod to Krogh, Oct. 27, Nov. 7; BP, 7, handwritten note by FGB, Nov. 24, 1922, in Notes on Diabetes file; also Paulson 1975.

  41 Nelken 1972; Lusk 1928, p. 650.

  42 IC, unsorted, Minkowski to Macleod, Jan. 12, 1923.

  43 Best Papers, BI, historical file, sent to Best by Dr. Goldner.

  44 BP, 9, Best to Clowes, Aug. 28, 1923; see also IC, France file, and IC, Lorne Hutchison report to the Insulin Committee, Jan. 14, 1925.

  45 Gley 1922.

  46 BP, 1, Paulesco to Banting, 5 fév. 1923.

  47 Macleod 1922A; Cammidge 1922A. It was another two decades, however, before it could be shown conclusively that insulin was produced in the beta-cells of the islets of Langerhans.

  48 IC, Woodyatt file, Macleod to Woodyatt, Sept. 7, 1922.

  49 Macleod 1922A; Dale 1959 for the estimate of Connaught’s yield.

  50 Connaught Laboratories Archives, HI, Best to J.C. Fitzgerald, Nov. 11, 1922; IC, Macleod to E.H. Mason, Macleod to Charles Hunter, Sept. 23, 1922; BP, 47, clipping May 17, 1923.

/>   51 Connaught archives, Best to Fitzgerald, Nov. 11, 1922.

  52 Dale 1959, p. 6: “Dudley, by systematic trial, soon found that the real key to success was to conduct all filtrations at reactions sufficiently far, in either direction, from the isoelectric point, to prevent the loss of insulin by absorption, especially on clogged filters.”

  53 IC, unsorted, Clowes to R.D. Defries, March 13, 1923.

  54 Walden’s description of his process is enclosed in MRC 1092/23, Clowes to Dale, Jan. 17, 1923. See also IC, unsorted, Clowes to Defries, March 13, 1922; Lilly archives, K.W. Wantland, “Notes on Insulin Extraction 1922”, Sept. 2, 1966.

  G.H.A. Clowes’ research report for 1921 (Lilly archives, XRDe) mentions that Walden had been working that year on the isoelectric points of materials suspended in various preparations marketed by Lilly. Techniques involving adjustments of H-ion concentration had only recently been introduced in the early 1920s and were not yet applied routinely, which may explain why, even if he knew the method, Walden took several months to make it work with insulin. Collip’s accounts indicate that he, too, had earlier fiddled with adjustments of the isoelectric point, but to no avail.

  55 MRC 1092/23, Clowes to Dale, March 16, 1923; also IC, unsorted, Clowes to Macleod, March 14, 1923.

  56 The cost for those who had to pay was even higher during the experimental period. Connaught charged Banting $1.00 per cc. (old unit) for his insulin; most patients used two to five cc. daily. At the Potter Clinic in Santa Barbara the cost of insulin was $10.00 per patient-day in August, reduced to $3.00 by February (IC, Sansum to Macleod, Feb. 16, 1923).

  57 IC Minutes, Feb. 14, March 5, 1923. IC, Clowes to Macleod, March 7, summarizes the group’s understanding of what it wanted to do with the public statements:

  Physicians are to be informed in the statement that on account of the risks associated with the use of Insulin, everything possible should be done to safeguard the patient and consequently those desiring to use it should read literature referred to, and should visit one of the group of clinics now using Insulin in different parts of the United States in order to familiarize themselves with the best means of adjusting the dosage, thus safeguarding their patients against risk of overdose and also learning how to treat acidosis and coma. The statement in question to be so worded that the whole responsibility for the use of Insulin will be put on the shoulders of the doctor, it to be made clear that only those having a knowledge of metabolism and possessed of adequate clinical and laboratory facilities could hope to handle Insulin successfully. The statement to be so worded as to frighten off utter incompetents and yet not to positively restrict the use of Insulin to those who were prepared to visit one of the clinics. This course, as Sir Robert Faulkner [sic] pointed out, would put the responsibility entirely up to the individual doctor and could never be construed as reflecting on the status of any member of the medical profession.

  58 MRC 1092/17, Insulin Committee (Great Britain), Minutes, May 16, 1923.

  59 MRC 1092/25, Dale to Dr. R. Obrian, Jan. 31, 1924; 1092/17, Fletcher to Sir George Newman, Jan. 23, 1924; 1092/17, I.C. (U.K.) Minutes, Jan. 29, 1924. Fletcher wrote (1092/2 to Elliott, Jan. 30) that the Insulin Committee had decided that “They cannot force practitioners to educate themselves, and they cannot dictate, even to panel practitioners, about their methods of work. You will realise that we are very far yet from a State Medical Service! Waste and disaster attending Insulin use are probably no greater than those attending the use of other means in other directions, e.g., the use of pituitrin at child-birth. The view taken is that the only cure for the present evil is the spread of knowledge by the papers or text-books which the experts are writing or may write, and of course more generally by improvements in medical education.”

  60 MRC 1092/10A, Clowes to Riches, July 20, 1923.

  61 IC, Clowes to Macleod, April 14, March 14, 1923.

  62 BP, 1, Banting to F.M. Allen, Aug. 31, 1922. “Adrenaline” was actually the original scientific term; when Parke Davis managed to trade-mark “Adrenalin” for the United States, American scientists had to fall back on the Greek-derived “epinephrine”.

  63 IC, Clowes to Macleod, Sept. 5, 1922; Clowes to Best, Sept. 12; Minutes, Sept. 22.

  64 MRC 1092/23, Dale to Fletcher, Sept. 26, 1922; also 1092/23, Dale and Dudley’s report to the MRC, Oct. 30, 1922.

  65 IC, Digestive Ferments file; see also Armour, Harrower, and Hoaxes files.

  66 See Mackenzie Wallis 1922, Crofton 1922.

  67 MP, Murlin to Macleod, Sept. 25, 1922; E.L. Scott to Murlin, Sept. 8, Murlin to E.L. Scott, Sept. 25, in A.H. Scott 1972, pp. 143–4; Scott Papers, case 3, Murlin to Scott, Sept. 5, Oct. 10, 1922; IC, Minutes, Sept. 28, 30, 1922; IC, “W” file, Murlin to C.H. Riches, Oct. 7, 1922; Sutter and Murlin 1922; Murlin 1922; Clough, Stokes, Gibbs, Stone, and Murlin 1923.

  68 IC, Patents United States file, Collip and Best application; Banting, Campbell, and Fletcher 1923.

  69 The patent applications, amendments, etc., and most of the relevant correspondence is in the IC, Patents United States file. It includes C.E. Hughes to Hon. Thomas E. Robertson, Nov. 24, 1922. Also BP, 1, Banting to Hughes, Nov. 21, 1922, reply Nov. 25; IC, “W” file, Macleod to Woodyatt, Nov. 29, 1922.

  For Williams’ “espionage” see IC, Committee of Clinicians file, Williams to Macleod, Nov. 27, 1922; Lilly archives, XRD2f, Williams to Clowes, Nov. 15, 1922. James Havens Sr. was also in Washington at the time of the hearing and might have been involved.

  70 Collip and Best’s first application on May 22, 1922, had been for a patent on the process only. On advice from the Lilly people, Toronto decided to file a separate application in Best’s name, dated June 19 (Collip was in Alberta at the time), on the anti-diabetic pancreatic product. In December the Collip-Best application was amended to include the product as well as the process. IC, Patents United States file.

  71 IC, Minutes, Dec. 11, 1922; BP, 1, Banting to Falconer, Jan. 27, 1923; also BP, patent files, esp. George Schley to Eli Lilly & Co., Aug. 22, 1922.

  72 IC, Minutes, Sept. 30, 1922.

  73 IC, Minutes, Dec. 30, 1922; Macleod to Clowes, Jan. 2, 1923.

  74 IC, Clowes to Macleod, Jan. 8, April 14, March 14, 1923. There is no doubt that the Lillys laid down the law on Iletin. Clowes tried to argue to Toronto that they had misinterpreted his personal views for a company commitment.

  75 IC, unsorted, J.K. Lilly to Clowes, Jan. 3, 1923.

  76 IC, unsorted, Clowes to Defries, March 13, 1923; also Clowes to Macleod, March 14.

  77 IC, March 16, 1923; also Minutes, March 16.

  78 IC, unsorted, Riches to Macleod, April 3, 1923.

  79 IC, Minutes, April 2, 1923; IC, unsorted, Macleod to Dr. John Howland, April 2, 1923.

  80 Earlier, it seems, Shaffer had consented to Lilly patenting the method. See MRC 1092/23, Macleod to Dale, Jan. 17, 1923. Shaffer was a purist who wanted to have nothing to do with commercialism or patenting. Defries’ reminiscences of that visit, related to me by Dr. Neil MacKinnon, were that Shaffer had at first flatly refused to have anything to do with Toronto’s and Lilly’s fights. The Torontonians might as well go home, but of course he would show them around St. Louis first and they would dine together. At the end of that meal Shaffer said to Defries: “Get rid of the lawyer.” When they were alone, Shaffer said that the day together had convinced him that Toronto wasn’t in it for the money, but really was interested in the good of humanity. “How can I help you?” he said. The work in Shaffer’s lab is described in Somogyi 1951.

  81 IC, Clowes to Macleod, April 8, 1923. While Lilly always believed that Walden’s method had priority over Shaffer’s, this would have been impossible to prove. The discoveries actually were independent and simultaneous, and Shaffer might have had a claim to priority by virtue of a public announcement of his discovery in December 1922. See Doisy, Somogyi, and Shaffer 1923.

  82 IC, Minutes, April 15, 1923; also correspondence in the AMA file, especially Macleod to W.A. Puckner, April 20,
in which he writes that the Iletin matter is “a concession to Eli Lilly & Company in consideration of their having agreed to turn over to the University of Toronto all patents applied for by them covering improvements in their original method of manufacture.”

  83 MP, P.A. Shaffer to Macleod, Oct. 10, 1923. IC, Lilly, Clowes to Macleod, Nov. 2, 1936, in which he suggests that the Lilly concession had saved Toronto from losing credit.

  84 Collip 1923G.

  85 Best and Scott 1923A. Macleod and Noble had also tried adding insulin to yeast and sugar, with no result: Macleod 1926, p. 139.

  86 Collip 1923B; MP, Collip to Macleod, July 18, 1922.

  87 IC, Collip file, Collip to Macleod, Jan. 22, 1923; Collip to Defries, Jan. 4; MP, folder 342, Collip telegram to Macleod, Feb. 9, 1923: “So much of my time is going into insulin production that urgent research problems are being sacrificed. A sufficient supply of insulin to care for our few cases here must now be available from Lilly. You are supplying Vancouver and others, why not Edmonton, and thus give me a fair chance at the research side?”

  88 Collip 1923D, p. 520. Collip was influenced by findings of Winter and Smith in Britain to the effect that insulin’s function was to create gamma-glucose, which they thought might be the essential form of sugar in all animals and plants.

  89 The correspondence about yeast is in MRC 1092/13, especially two letters of Hopkins to Fletcher on Feb. 20, 1923. See also Winter and Smith, 1923C, D.

  90 Best and Scott 1923A.

  91 MRC 1092/19, Clowes to Dale, April 3, 1923. Lilly’s thoroughness also included an experiment on a human pancreas, recovered about four hours after death. It contained no active insulin. Lilly archives, XRDqb, Laboratory notes, vol. 1, p. 57.

  92 IC, clippings file, Minneapolis Forum, Feb. 9, 1923. The Fleischmann yeast company observed the race with interest and enthusiasm, supplying Toronto with free yeast for its experiments.