and hypoglycemia, 109
Reed, Walter, 189
Rennie, John, 29, 170
Respiratory quotient, 101, 108, 122, 198, 227
Riches, C.H., 174–76, 180
Ringer’s solution, 68, 72
Roach, Edith, 46–48, 55–56, 74, 124, 235–36
Roberts, Ffrangcon: criticisms of Banting and Best, 13–15, 203–8
Robertson, D.E., 143, 152
Robinson, W.L., 122
Rochester, N.Y., See Havens, Murlin
Rockefeller Foundation, 98
Rockefeller Institute, 34–38, 40–41, 82, 160
Romania. See Paulesco
Root, Howard, 150
Ross, George W. “Billy,” 125, 216, 220–23
Royal Infirmary, Edinburgh, 165
Royal Society of Canada, 140
Royal Society of London, 196, 224
Royalties, 139, 142, 240
Rubber gloves, 60n
Russell, Thomas A., 221
Ryder, Ted, 244–45
Salvarsan, 245
Sansum, W.D., 140–41, 149, 156, 190
Schafer, A. E., 127
Schering company, 30
Scott, D.A., 147, 183–86, 240
Scott, A.H. (Mrs. E.L.), 238
Scott, Ernest Lyman, 54, 87, 97, 104–6, 176
research of, 31–33, 40
relation to Toronto work, 206–11, 238
Secretin, 27
stimulation experiment, 77–78, 80, 204, 210
Shaffer, Phillip, 180–81
Shaffer-Hartmann blood test, 93, 100
Sharpey-Schafer. See Schafer
Sherrington, C.S., 55
Shouldice, E.E., 98
Sick Children’s Hospital. See Hospital for Sick Children
Simcoe County, 213
Sjöquist, John, 226–29
Smith, W., 183–85
Société de Biologie, Paris, 170
Society for Experimental Biology and Medicine, 183
Soldiers Civil Re-Establishment, Department of, 135
Solis-Cohen, S., 127
Somogyi, Michael, 180
Southern Medical Association, 95
Sprague, Randall, 159
Squibb, E.R. & Son, 239
Stacey, Charles P., 232
Star, Toronto, 114–15, 123, 125, 191, 194–95, 231–32
Starling, E.H., 27, 33, 210
Starr, Clarence L., 46–47, 51, 54–56, 73, 89, 115
“Starvation” therapy. See Diabetes
Stearns company, 181
Stengel, Alfred, 190
Stevenson, Lloyd, 14, 17
Stewart, G.N., 225
Strasbourg, 25
Stuart, C.A., 222
Surgery, Gynecology and Obstetrics, 49
Sweetbreads, 25, 29, 99
Taylor, N.B., 91
Tew, William, 48, 51
Thompson, Leonard, 12
tests on, 112–13, 117, 120–21, 124, 130, 161, 210, 246
death, 212–43
Thyroxin, 130, 132
Toronto General Hospital, 12, 45, 48, 101, 111–15, 122, 130, 134–35, 189, 242–43
diabetic clinic, 141–43, 153, 157–60, 200, 242
Toronto, University of, 17, 45–46, 58, 82–84, 148–49, 189
Surgical Research Committee, 89
and insulin patents, 133, 137–38, 177–78, 240
collaboration with Lilly, 138–40, 174–80
Insulin Committee, 18, 140, 156, 171, 173–80, 190, 240
policy re Banting, 111–43
Macleod defends, 198
resources of, 189, 211
not honouring discovery, 215
honours discovery’, 220, 233, 241
post-insulin research at, 242
Tory, H.M., 110
Toxicity of extracts, 28–32, 41, 88, 113, 116–17, 123, 126, 177, 207
Tricresol, 93, 172
Trypsin, 76–77, 80–81, 203–5
United Kingdom: insulin rights for, 139
introduction of insulin to, 165–67, 173–74, 187
United States: first use of insulin in, 136
rights to insulin manufacture, 139
insulin commercially available, 188
University Hospital, Edmonton, 182
University of Toronto. See Toronto, University
University of Western Ontario, 14, 48, 51, 54–55, 58, 239, 241
Urquhart, Ian, 5
Vanderlip, Frank A., 191
Varsity, 232
Vivisection. See Anti-vivisectionism
Voronoff, Serge, 213
Walden, George, 146, 172, 180
Walker, Sir Edmund, 148, 220
Warner, W.P., 182
Washington University, St. Louis, 180
Western Reserve University, 32, 51, 225
Western University. See University of Western Ontario
Wilder, Russell, 162, 220
William Davies Company, 92
Williams, John R., 135–36, 145–46, 150, 157–62, 176–77, 220
Wilson Laboratories, 176
Winter, L.B., 183–85
Woodyatt, Rollin T., 39, 127, 137, 140, 149, 177, 220
tests insulin, 156–62, 183
Yale University, 104
Yeast extract, 182–85
Zuelzer, Georg Ludwig, 16, 32–33, 87, 165
experiments of, 29–31, 42, 97
recognition by FGB, 113, 207
patent, 176–77
relation to Toronto work, 207–11
and Nobel Prize, 227, 233
afterwards, 238
* Sometimes, if you were a careless male, the doctor could make a Holmesian diagnosis the moment you walked into his office. The dry white sugar spots on your shoes or pants gave it away.
* The more common story of this discovery is that Minkowski’s attention was directed to the dog’s urine because a lot of flies were being attracted to it because of the sugar. Minkowski explicitly denied this version.
* I return to Zuelzer’s methods and his problems on p. 177 below.
* A distant relation, a London cabinet-maker named Banting, caused such a stir in 1864 with his method of reducing corpulence by avoiding fat, starch, and sugar, that the verb “to bant,” with such derivatives as “banting,” “bantingize,” “bantingism,” entered the language to refer to weight reduction through dieting.
* Banting sometimes told his friends that the patient’s problem was syphilis. The two explanations are not mutually exclusive, but do clash with the notation in his account book that his $2 fee was for “baby-feeding.”
* It is not clear whether rubber gloves were worn during these pancreatectomies. Physiologists doing experimental work on animals, especially animals like dogs which had fairly tough constitutions, were still rough-and-ready in their methods. Later in the twenties and thirties at Toronto researchers commonly did pancreatectomies without gloves, using their finger-nails to scrape the pancreas away from the splenic artery. Those who remember Banting’s own operating techniques from the 1930s contradict each other: some say he followed standard bare hands practice; others say that as a surgeon, who had first worked on humans, he was a stickler for sterilization. Of course the bare hands and finger-nails would have been well scrubbed.
* Was it really the first dog to receive Banting and Best’s extract? In his 1940 “Story of Insulin,” Banting described an earlier experiment, never previously mentioned:
During Best’s absence [late in June] I had tested the effect of the extract of degenerated dog pancreas on a depancreatized dog whose blood sugar was 460 mg percent. Following the injection the percentage fell to almost normal and the condition of the dog improved in an astounding manner. I did not write down the results of this experiment in our notebook. I was so fearful in the first place that this result would not be obtained and when I did get the result I did not think anyone would believe it. This, the first extract tested, was given in the evening and I worked alone all night and finished the r
eadings on the blood sugars in the morning light of the early hours after dawn. No one knew but myself (Banting 1940, p. 28).
The trouble with Banting’s description of this incident is that it is impossible to correlate with the known facts about the experimental dogs in June. None of the diabetic dogs during Best’s absence had a blood sugar near .46, for example. More important, all of the duct-ligated dogs can be accounted for in the whole series of experiments from May through August. Banting could not have obtained degenerated dog pancreas in June. The only way to make his story fit with known facts about the life and death of his dogs is to suppose that he actually used the fresh pancreas from dog 399, which he took out on June 23. If that happened and gave the result Banting indicates, it underlines the egregiousness of the error mentioned on p. 76 below. More likely, Banting misplaced the whole incident in time and memory. If it took place at all, it was probably early in August, when a supply of extract of degenerated pancreas was available. I suspect that Banting is wrong in saying Best was not present and that the incident was not recorded in the notebooks. My guess is that the incident is the administration of extract to dog 406, their second dog, with briefly sensational results. The germ of truth in Banting’s account may be that this experiment was never described in any of the published papers. Another possibility is that he is describing an unnoted administration of extract to dog 409, a control dog which was dying during the night of August 14–15. Banting may have been alone in the lab that night; the dog’s last noted blood sugar was .46, and Banting, with extract on hand, might well have been tempted to try once again on this new dog.
* It is very difficult to know what effects most of Banting and Best’s injections of pancreatic extract actually had, as opposed to the apparent effects recorded in the notebooks. The impact of intravenous injections of active extract would have been very quick, perhaps only a matter of a few minutes. Many of Banting and Best’s blood sugar readings, taken at one, two, or, in this case with dog 92, four-hour intervals, might have missed the period of maximum effect. In some cases, in fact, apparently unfavourable results might have been due to a “rebound” effect of higher blood sugar after the true impact of intravenous injections. A further difficulty in knowing what was actually happening to the dogs’ metabolic condition stems from our complete ignorance of the strength of the early extracts. For other problems with Banting and Best’s results, see the discussion on pp. 106–8 and 203–11.
* As Banting and Best may have realized later when they chose not to mention their in vitro experiments in their publications, the recorded results were inaccurate. The extract could not have had any effect on sugar in a test tube. The temporary thought that it did, of course, would have further convinced Banting and Best that they were on the right track.
* The two cats, perhaps accompanied by rabbits, whose ducts were ligated on August 11, were never referred to again.
* “Paulesco has recently demonstrated the reducing effect of whole gland extract upon the amounts of sugar, urea and acetone bodies in the blood and urine of diabetic animals. He states that injections into peripheral veins produce no effect and his experiments show that second injections do not produce such marked effect as the first.”
† This judgment of mine does not go unchallenged. One of the distinguished physiologists who read this passage in manuscript commented, “That’s completely pie in the sky. I don’t think anyone could have presented such a plan at the time. They were all fumbling in the dark.”
* Was the death perhaps caused by an as yet unrecognized hypoglycemic reaction? Banting and Best thought it was shock, for a double dose of the same extract produced no reaction when injected into a normal dog. Later, however, they thought it might have been hypoglycemia. It does not seem possible, on the basis of the evidence extant, to know what had happened to the dog. No autopsy was done, apparently because Banting and Best just wrote it off as a failed longevity experiment. Banting 1923, A, B.
* This was probably taken for granted, as it would be by any scientists in a similar situation. But Banting in his 1922 account suggests that he, Best and Collip had explicitly agreed to tell their results to each other. In his 1940 account he elaborates as follows:
Collip, Best and I stayed together [at New Haven] in the same hotel and were together a good deal. Naturally we talked incessantly about the work. There were so many problems that were opened up and demanded immediate investigation that it was agreed that Best and I take Collip into partnership – and that we should pool all results and share alike in all publications; that all results should be confided to each and all of us. It was a gentleman’s agreement and we shook hands on it. I had no suspicion at that time but I believe Best had. Collip was to work on refining the extract – Best and I were to test the extracts and continue the physiological investigations.”
* Macleod and Collip may have been deeply disturbed for a further reason if my ordering of events is incorrect in placing the discovery of the hypoglycemic reaction before January 11. If Collip only discovered it after January 11, as is possible, then he and Macleod would have been appalled at the thought of a clinical test having been held before animal tests revealed the hormone’s potentially fatal side-effect. Collip’s accounts, 1923 K.L, go out of their way to stress how thoroughly the working of the extract had been investigated before it was used successfully on humans.
* There is no certain knowledge, but the memory of those who were on the spot is that Edith was insisting that Banting give up the work, resume practice, and settle down.
* Small bribes appear to have been necessary to forestall customs’ inquiries about the strange substances.26
* Some of the concrete offers are cited in the endnote, but one bizarre encounter, described by Banting in his 1940 account, deserves special mention:
I was sitting in my room one evening. It was raining hard. I was called to the phone and a man asked if he could see me. He said he would come up immediately. Λ few minutes later he arrived. He was a big man and there seemed hardly room for him. He looked about and his first words were, “Well for God’s sake”.
I sat at my desk and he sat on the only other chair, which was of the hard stiff back kitchen variety. “So this is where you live.” “Well you are a damned fool.” “Now listen to me” and he proceeded to tell me how the wife of a friend of his had been under the care of the best Doctors in New York and despite the diet treatment she got worse and worse. She had been given insulin and she felt entirely different. He knew the woman. She had tried everything and “knew them all”, you could not fool her. She was all for insulin. That was good enough for him. All I had to do was to hand over the patents to a group on Wall Street and he would guarantee me $1,000,000 cash. Insulin would be patented in every country in the world. Ten percent royalty would be collected. The company would keep five & I would be given 5% royalty in addition to the $1,000,000 cash. A chain of clinics would be established across the United States and Canada one or two in every large City. I would be Medical Director and would have all the clinical cases for study and could have all the laboratories I desired. I would thus be relieved of financial responsibilities, being independently wealthy, and could devote myself to scientific research. I need not even see patients if I did not wish – “except a few very wealthy ones by appointment”. My time would for the most part be my own. They would look after the whole organization.
To me as I sat in my little room filled with smoke, it was not even a temptation. It meant that the suffering diabetic would be exploited.
When he had finished I only asked him one question. “What would you do for the poor diabetic who could not pay?” He replied, “that can be easily worked out, they can be treated in an out patient clinic”. “Not good enough”, I replied. “I am afraid you do not understand the situation. The indigent diabetic is our greatest problem. Every effort must be made to reduce the cost of insulin and remove the necessity of expensive diets so that they can look after themselves.”
He said that there was one more thing that he would like to point out. “If such a scheme as I have outlined is not followed, then you will have every doctor in the USA making money out of the diabetics, and they will form clinics and make the money out of diabetes that you should be making.”
“I am afraid this scheme is not very attractive to me.” He then gave me proof of his financial backing. He gave me his card and asked me to think it over and get in touch with him. He phoned long distance from New York a couple of nights later. He could not understand why I still declined.
This incident took place in the summer of 1922, probably late in August. It is impossible to know how accurately Banting remembered the encounter and whether the American visitor was a reputable businessman or a fly-by-night promoter. I suspect the latter. Nonetheless, the incident was important in reinforcing Banting’s belief that he had turned down incredible fortunes to keep insulin in Canada.
* Banting also collected fees from his private patients, but these appear to have been very modest, much less than fashionable physicians traditionally charged those who could afford to pay.
* It was his unwillingness to control his own and his patients’ diet properly that caused the infamous Canadian quack, Egerton Y. Davis, to disbelieve in insulin until the effects of rationing were observed during the Second World War. See Harvey Cushing’s biography of Sir William Osier.
* The great Lilly rabbit hunt, undertaken at a time before the animal supply industry had developed, was one of the firm’s more herculean efforts. So was the job of getting the rabbits bark in captivity when they managed to break free, creating a hopping pandemonium in the hallways of the Lilly Science building.
* Zuelzer’s patent specified several methods for making extract. Most of these started with allowing fresh pancreas to “self-digest,” i.e., letting the activated digestive enzymes destroy the protein matter in the glands. Zuelzer did not believe the internal secretion was a protein. It is. Self-digestion was a very likely way of destroying it, thus producing inactive extracts.
But Zuelzer did not always wait for self-digestion, and sometimes proceeded quickly, apparently using first saline and then alcohol as extractives. In neither his patent application nor his publications did Zuelzer specify his methods clearly. In 1926, at a time when there was some worry that Murlin might be organizing a challenge to Toronto’s patent situation, the Insulin Committee tested all of Zuelzer’s methods. In twenty-two experiments, Toronto’s chemists twice were able to produce an extract that lowered blood sugar. But it was very impure, causing severe shock. They could not purify it by any of Zuelzer’s methods, nor could they produce the “fine, grey, feebly smelling powder” Zuelzer claimed to have obtained. They left open the possibility of his having achieved his results by some other method (IC, Zuelzer file, report enclosed in Hutchison to Riches, Oct. 17, 1926). Zuelzer’s biographer, Mellinghoff, also complains about his vagueness regarding his methods. A view, expressed later by Macleod, that Zuelzer’s human patients may have been suffering from hypoglycemic reactions, does not seem consistent with either their symptoms or the likely potency of the extract. It may be that some of Zuelzer’s post-1911 animal tests, using extraction methods he never published, did produce hypoglycemic convulsions.
The Discovery of Insulin Page 45
