Banting2 - TEXTS AN D DOC UMEN TS BANTING’S, BEST’S,...

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Unformatted text preview: TEXTS AN D DOC UMEN TS BANTING’S, BEST’S, and COLLIP’S ACCOUNTS OF THE DISCOVERY OF INSULIN With an Introduction by Michael Bliss In the Fall 1978 issue of the Bulletin (52: 29S~515‘), Lloyd Stevenson " 'ntroduced i]. R. Macleod’s “History of the Researches Leading to the Discovery of Insulin.” This document, which had been written in Septem— ber 1922 at the request of Colonel Albert Gooderham and never previously published, was obviously of great historical interest, being a contemporary account of the discovery of insulin by one of the members of the discovery team. The following documents are the contemporary accounts of the dis— covery written by the other three members of the team. Like Macleod's, these accounts have not been previously published. They are preceded by the letter Gooderham wrote to Macleod, Banting, and Best on 16 September 1922, which resulted in the preparation of three of the four manuscripts. manuscripts. Albert Gooderham wrote his letter in his capacity as Chairman of the Insulin Committee which had been established by the Board of Governors of the University of Toronto to handle all matters relating to the patenting and other use of insulin. In his introduction to the Macleod document, Stevenson commented on the impossibility, past and possibly present, of locating a copy of the Macleod manuscript in “the gothic vaults of the University of Toronto." Instead he used a copy which had been kept by Macleod and was found among his personal papers long after his death. While the University of Toronto no longer stores its documents in anything resembling “gothic vaults,” and while the voluminous records of the Insulin Committee have recently been recovered for the University, it is still impos— sible to locate the copies of Macleod’s, Banting’s, or Best's accounts that were given to Gooderham. They seem to have disappeared, perhaps in the dis- posal of his personal papers by his family or in one of the periodic house- cleanings of University records over the years. The copy of Banting’s account published here is from a typescript contained in his papers at the Thomas Fisher Rare Book Library of the University. Identical copies of C. H. Best’s account are in his papers, recently donated to the Fisher Library; on deposit in the library of the Wellcome Institute in London, England; and in the papers of his would-be biographer, the late W. R. Feasby, at the Canadian Diabetes Association in Toronto. 'wfivnv\vr‘ “J w/ “A rrK sin 1 l ll'irj iiist‘t’n'r'r} oi insulin “7*? By the time of (Z‘rooderham's lfilt‘l‘d. B. Collip had left the University oi Toronto, where he had worked during his 1921 22 sabbatical year, to reSume his duties at the University of Alberta in Edmonton. (io<’>derhani chose not to write Collip, but instead asked each of the others to outline (lollip’s contribution to the discovery When Macleod wrote Collip about this procedure, Collip drew tip an itemized list of his contributions to the insulin research 'I'wn drafts of it exist in fragments oi t rillip's correstmnrlenre the version printed here is the text ol an undated, signed statement by Collip. prepared from the earlier dratts. which is preserved in his papers in the library ofthe Faculty of Medicine ofthe University of Western Ontario While very different from the other documents, it deserves publication along with them, particularly because so much of the controversy at the time (and later) swirled around the work done by Collip after he joined the team in December 1921. Stevenson’s introduction to the Macleod document raises the question of why these histories were treated so gingerly by the University of Toronto for so many years. At one time, Stevenson writes, a president of the Univer— sity, Sydney Smith, threatened him with legal action if he persisted with his interest in quoting from Macleod’s account. Of course Smith’s action, taken in the mid—19505, was improper. It was also a blufi, for the University in no way controlled the copyright to i]. R. Macleod’s work. Presidential corre spondence in the University Archives and in the C. H. Best papers indicates that Smith’s interest in the matter was caused by the knowledge that publica tion of Macleod’s account would cause Best, one of the most distinguished members of the University’s faculty, to insist that his own and Banting’s accounts also be published. Collip, at that time Dean of Medicine at Western, would inevitably have become embroiled in the controversy because of the extremely serious (and only partly justified) charges levelled at him in Banting‘s account. Banting, of course, had died in 1941. Taking counsel with Western’s president, G. E. Hall, and worrying that a full-scale rehashing of the insulin controversy would not be good for Best’s uncertain health, Smith decided to use his influence to keep the lid on all of these documents. As Collip had predicted and believed proper, the “hid— den” history of the discovery of insulin would not emerge until all of the principals were dead. Best was the last to die, in 1978. When I decided in 1979 to attempt to write a history of the discovery of insulin I knew nothing of these matters; no one did at the University of Toronto, which has a minimal institutional memory. The only document still being deliberately “suppressed” was Banting’s account, kept in a section of his papers restricted at the discretion of the head of the Fisher Library, who was respecting a decision taken years earlier by a (now—defunct) university committee on the Banting Collection. When I explained my interest in Banting it was immediately decided to make the account available to me and 2.: \III ii, t“ 1H: “llité‘gl Vii. to any other qualified researcher interested in the discovery of insulin Publication, it was agreed, would follow as soon as enough research was availal‘ile to make possible an appreciation otthe strengths and weaknessci oi Banting s viewpoint in the contevt oi the events of 19A) 22 at loronto in the winter of l939~~40, a year before his death, Banting drafted a much longer account which he provisionally entitled "The Story of Insulin. .~\pproxiinately one hundred pages in typescript, never revised from Bani ing's first draft, the document is an invaluable source for tlte historian or biographer, but does not easily lend itself to publication. it is rambling. often poorly-written, unreliable, and difficult to excerpt. Access to it has been on the same principles as to Banting’s 1922 account. I am currently attempting to arrange single-volume publication of all of the basic documents relating to the discovery of insulin; this would include “The Story of insulin” as well as Banting and Best’s notebooks, also available at the Fisher library Albert Gooderham wrote to Banting, Best, and Macleod in the hope that the differences in their versions of events could be reconciled and one authoritative history ofthe discovery agreed upon. C. H. Riches, the Universi ty’s patent attorney, was pressing him for such a unified account, and imporv tant discussions were about to take place with G. H. A. Clowes, research director of Eli Lilly and Company (which was by then collaborating with the University in the development of insulin) and two representatives of the Medical Research Council of Great Britain, H. H. Dale and Harold Dudley. Anyone who reads the following documents, combined with the Macleod account, will realize how great and bitter the differences were that had to be reconciled. Between Banting and Macleod, in particular, there had been a complete clash of temperaments and breakdown in personal relations. Bant- ing had also quarrelled bitterly with Collip, so much so that the January 1922 confrontation between them over methods of preparing insulin, was in facr violent. Banting’s extreme dislike of both Macleod and Collip in 1922, as well as his oppressive fear of losing credit for the discovery he felt followed from his great idea, makes his account of events the most passionate and least reliable of these documents. I had originally hoped to present these accounts with detailed editorial annotation to correct errors, highlight points of disagreement, etcetemi It was soon realized that such footnoting would take up more space than the documents themselves, and would lead to a complete re—telling of the his tory of the discovery. Therefore I have followed Stevenson’s practice with Macleod’s account and present the documents exactly as they were written. For a reconciliation of their authors’ differences, biases, distortions, errors, and other unclear points, a task which Colonel Gooderham abandoned in 1922, readers should consult my book, The Discovery of Insulin, published in Canada by McClelland 8: Stewart and in the United States by the University of Chicago Press. l . i.,.,.i-,. x, iildkull: ALBERI MUDDERHAMS lFl l‘lilt 'I‘oronto, (.rinatla it» Sept l‘L’Z My dear Dr. Banting: lMat‘leod, Bestj In view of the articles which have appearcd in the press regarding tht discovery of “insulin and or the t.insatistactor'v relationships which seem tc exist between l’rof tVlaclcod. Di Banting and Mr Best. regarding the contri bution which each has made towards this discover}, 1 ant rnr‘ist atixtous tr, restore the harmony of our Committee, that we may all work together in the future unitedly. in order to bring this about, it would be desirable to give, me a typewrit ten statement of your understanding of the discovery of “Insulin” right from the very start and its production to date. I am asking the others to do the same. In the absence of Prof. Collip I would appreciate if you would incor— porate in your statement an outline of his contribution to this work. I would then compare these statements and see wherein they differ, and ask you three gentlemen to meet at any early date with a view to harmonizing these statements with me. I feel that we should have as a result a connected account of the work from the very start, which would be available to anyone desiring information and which would be agreed upon by each member. This would, in my opinion, clear up all our misunderstandings and we would adjust this matter between ourselves before Dr. Clowes, and the gentlemen from England arrive. This understanding is urgent, as Mr. Riches requires me to give him such a statement in order that the question of the patents and of amended patents which are now necessary, may be proceeded with at once, Please be good enough to think this over carefully as I feel that this is the only way in which a satisfactory settlement of our difficulties can be made. I will be at your service almost anytime to do what I can to get everything working in harmony. Yours sincerely, ALBERT GOODERHAM F. G. BANTING [THE DISCOVERY OF INSULIN] Early in November 1920 while reading an article by Moses Barron in Surgery, Gynaecology and Obstetrics, on the Islets of Langerhans in relation to diabetes, the idea presented itself to me that since the ascinous but nor the insular tissue degenerates after the pancreatic ducts are tied, by this means ggfi .‘tlltllAlzl. 35H??? an extract of the islet tissue might be obtained, without the destroying influence of the pancreatic juice T he idea above mentioned occurred to me about 2 am. The next morning I went to see Dr. Miller. Professor of Physioli ogy, Western University, Iondon, with whom I was then working. He said that the idea had not been worked out so far as he knew. Dr. Crane, Profes sor of Pharmacology, did not know of any work on the subiect I next looked up every available reference in the library of the medical school, but found no work pertaining to the subject. I went to 'loronto and talked the matter over with Dr Starr, then with Professor Macleod. on November 6th My interview with Professor Macleod lasted about an hour. I told llllll carefully what I had planned, and to my disappointment he did not seem at all interested, and put me off by saying that many men had worked for years in well—equipped laboratories and had not proved that there was even an internal secretion of the pancreas. I then repeated my ideas to him, and he sat back in his chair with closed eyes for some time. Then he began to talk. He thought that “this might be the means of getting rid of the external secretion.” As far as he knew this had never been tried before “It was worth trying" and “negative results would be of great physiological value.” This latter phrase he repeated at least three times. This was not very encouraging, for I was not inclined to give up ap— pointments in Surgery and Physiology in London to get “negative results of great Physiological importance.“ I told him that there were no facilities in London, and that I would come to his laboratory to work if he would allow it. This he consented to do. I wanted to sell out in London, but Dr. Starr would not hear of it. He said that he would talk with Prof. Macleod and let me know. I do not know the trend of the conversation, but Dr, Starr strongly advised me to keep to surgery till the school term was over, and then to try out my idea if I still desired to doit. I left London on conclusion of the term, May 14th. When I arrived at the Physiological Department the work was discussed. Mr. C. H. Best was to assist me for three weeks, and Mr. Noble for three weeks, thus giving me six weeks. Professor Macleod apologized to Best and Noble, telling them that “it would likely all go up in smoke but would be a good operative training, and we must leave no sod unturned.” He instructed me how to do the first operation (the Hedon method of Pancreatectomy); the only time I have ever seen him in the operating room. Best was to be my assistant for the first three weeks, having tossed with Noble for who would be firsr. We arranged to do blood sugar, total sugar excreted, total nitrogen, and record the diets, etcetera. Early in june the professor sailed for Scotland. During June and July Best and myself (for Noble had decided that he would let Best do his share of the work) tied the pancreatic ducts on about six dogs, and had run a number of controls on the Hedon operation. Finally on July 3lst, 1921, we had both a diabetic dog and a dog on which the ducts The lustmerx mt Insulin get; had been tied for seven weeks. The duo. tied dog was killed with an over dose of chloroform and the pancreas removed, and mascerated in ice cold Ringersol. The blood sugar dropped after the injection, and our positive results Were commenced. Various things Were tried with the extract, as shown in the articles on the work at this time (In this history I do not wish to give a detail of the findings so much as 1 do as to how the findings came about). All went merrily till the latter part ol September. when the prolessoi returned. We had been waiting all Summer to tell him of our results, and to get things that we needed for the laboratory. The place where we were operating was not fit to be called an operating room. Aseptic work had not been done in it for some years. The floor could not be scrubbed properly, or the water would go through on the laboratories below. The walls could not be washed for they were papered and then yellow washed. There were dirty windows above the unsterilizable wooden operating table. The operat ing linen consisted of towels with holes 'in them. It was made more difficult to get things because I had been given six weeks to get results, and overtime was not in any person‘s line, and, worst of all, no one took me seriously, since the professor had said that “it would likely go up in smoke,” We had a number of dogs die of infection despite our utmost care, and finally we were compelled to operate in the research operating room of the Pathology Building. Shortly after Professor Macleod’s return (the last week in September) I asked him for four things: 1. A salary, because I was already deeply in debt and could not borrow more money; 2. A room to work in, for we had been working in a room which was not private; 5. A boy to look after the dogs, for we frequently had to clean the cages and operating room ourselves; 4. The floor of the operating room repaired. Professor Macleod was not inclined to give us these demands and said that if he gave us these things some other research would suffer. I told him that if the University of Toronto did not think that the results obtained were of sufficient importance to warrant the provision of the aforementioned requirements I would have to go some place where they would. His reply was “As far as you are concerned, I am the University of Toronto." He told me that this research was “no more important than any other research in the department.” I told him that I had given up everything I had in the World to do the research, and that I was going to do it, and that if he did not provide what I asked I would go some place where they would. He said that I “had better go." I rose to go, but the professor softened a little and finally decided that he could get a boy and a room and that the operating room might be made waterproof by tarring the floor. €60 ,XlltiiALl ESE l‘.~'~ I would have left the University of lUl’Lnlit) at this time had not Professor Henderson secured for me an appointment in Pharmacology, and had l not promised Professor Fitzgerald that I would HO! leave Toronto without con- sulting him. (I told the results of experiments trout time to tune during the “summer to i—‘rotessors Henderson and Fitzgerald) it might be pointed out here that l have never at any time held an llppi?ll7.f111t,‘l'tl in the l‘trépartment oi Physiology of the l‘i’llVBI'Sll} of loronto. During the Summer the work, for the most part. was done in the De partment of Physiology, but total nitrogen estimations were done in the Department of Biochemistry. Some operations were done in the surgical research operating room, Histological sections were made for us in the Department of Pathology. and the Connaught Laboratory gave us the facilities of the operating room at the farm, and three calves for exhausted gland experiments. At the Physiological Journal Club Meeting of November 14th, it was arranged that Best show the charts and that 1 give a resume of the work of other investigators, and the development of our research. Professor Macleod in his remarks gave everything that I was going to say and used the pro» noun “we” throughout The following day students were talking about the remarkable work of Professor Macleod. Very little progress was made between October lst and the middle of November. At this time a new era was introduced by the discovery that the pancreas removed from foetal calves contained the antiidiabetic principal, and that the subStance could be extracted with saline. The idea came to me in the following manner: Laguesse found that the Islets were more plentiful in foetus and newborn, hence there should be more internal secretion in the newborn. I thought first of using pancreas of newborn, then I thought of producing abortion in dogs and u'sing the pancreases thus obtained. Then it occurred to me that there might be a time in development when the internal but not the external secretion would be present. This idea finally presented itself about 2 am. November 16, 1921. The next day Best and I went to the Davies Abbattoir and secured a number of pancreases of foetal calves, made an extract, injected it into a diabetic dog, and the blood sugar fell. 1 later found that Ibraham had shown that the foetal pancreas of under four months development did not contain proteolytic enzymes. On December 6, 1921, some mascerated foetal pancreases were placed in alcohol and allowed to stand. The alcohol was filtered till clear and then evaporated to dryness in a warm air current. The residue was dissolved in saline and injected into a diabetic dog, #23. The blood sugar fell from .26 to .11 in five hours. This was the first positive result of extract made by al- coholic extraction. On December 8th I placed the pancreas removed from dog #55 in alcohol. On December 8th it was mascerated, filtered to dryness, redissolved in saline, and injected into dog #35. Blood sugar fell from .46 to .18 in four hours. This was the first alcoholic extract made from whole pancreatic gland. t -“Ww. \ .N_.m an»... the thLtt‘tl‘» m itisutu: at» On December 11th the whole pancreas of a UNV was t hopped lit hydrochloric acid in 95% alcohol) masrerated, filtered evaporated. t‘ililil sifted in saline. and given intravenously to dog #35. Blood sugar fell mini .28 to ll in {out hours This um the firs/ tit/vole glam? extract (3] beer 1 Wm ‘I‘e'as Dr. colhp had from time, to time asked nic- ii there was anything ht (‘Hlllt‘l do i was very anxious that the work advance more rapidly. i asked Professor Macleod three or tour times if Dr (Zollip could do portions «it work, but he advised against it l was \ery anxious to find out if glycogen could be stored in the liver of a depancreatized dog if extract were adminis tered. l formulated an experiment and Best and 1 depancreatized two dogs in the surgical research, gave them extract and glucose, and Dr, (Zollip did glycogen estimates. He told Professor Macleod the results. This occurred about one week before Christmas holidays. Collip began working on the biochemistry of the extract about this time. Before be commenced Best and 1 were using alcohol extracts of the whole beef pancreas. [Ed note: The following clause, typed on the same machine, is pinned to the surviving typescript of this document] and had found that the active principal was insoluble in 95% alcohol, but that it was soluble in 80% alcohol, and that on the addition of 95% alcohol to an 80% alcoholic solution of the active princi pal the solution became opalescent. At the sixth Annual Meeting of the American Association of Biological Sciences held at New Haven December 1921 Professor Macleod had his name first on the paper on the program, and although 1 gave the paper he discussed it using the term “we” throughout the discussion. 1 was the only one who gave a paper to the Physiological Section who was not asked to respond to his paper. Professor Macleod was chairman at this meeting. It must be remembered that at this time Professor Macleod had not done one single experiment, nor had he contributed one idea of value except estima» tion of haemoglobin before and after extract. After the work had been reported at New Haven it was evident that interest was stimulated in other centers. I was anxious that Toronto Univer sity should take up the problem and should lead in its development. I had at various times asked Professor Macleod for more workers. He refused me. I discussed the matter with Professor Henderson, and he said that he would ask Professor Macleod. Professor Henderson discussed the matter with Pro- fessor Macleod, and told me later that Professor Macleod had said words to the effect that the scientific world would think he was silly if he gave up his work on Anexemia for the investigation of this extract, since its success had not yet been proved. On December 24, 1921, alcoholic extract was administered to Dr. Jos, Gilchrist by mouth and the daily output of sugar in the urine recorded, the diet being kept constant. There was no reduction in the daily amount of sugar excreted, On January 10, 1922, Birkfeldted sterile extract made by Mr. Best and I‘M H 3.9-! til l“ myself was given to [its (‘ampbell and Fletcher of the Department «)l t\iedicine, to be tested on a boy in the Toronto General Hospital. I had applied for a temporary appointment in the Department of Medicine under the direction ofa senior physician for the purpose of testing pancreatic extracts on the human. This application was not granted. I was not allowed to even so much as examine the urine or blood obtained from the above case At this time no agreement was madt- concerning reporting results of the clinical tests. A 33% fall in blood sugar followed the administra tion of the first dose of the extract to a human l‘ieing. Unfortunately, this extract contained too high a percentage of protein and other solids, and an aseptic abscess followed its administration. Shortly before january 25, 1922, Dr. Collip, who had been working in the laboratory of Dr. Harding, in the Pathological Building, announced that he had developed a process by which he could obtain an extract which contained no protein and no lipase. On being asked his methods of prepara- tion he refused to tell them. This was a breach of a gentlemen's agreement amongst Dr. Collip, Mr. Best, and myself, as we had agreed amongst our- selves to tell all results to each other. Dr. Collip discussed this new prepara- tion with Professor Macleod and secured the consent of Professor Macleod to keep the process a secret. I believe that Dr. Collip at this time endeavoured to patent this process, and was only prevented from doing so by Professors Macleod, Hunter, and Henderson. Dr. Collip refined extract which was made by Mr. Best, sending the refined extract to the wards for clinical tests. About this time the Connaught Laboratories took up the problem of small scale production for further clinical investigation. With Dr. Collip in charge of production they secured a room in the basement of the south wing of the medical building and installed what we thought then to be advisable equipment. They supplied us with materials for the extraction. The physiological investigation was taken up by Professor Macleod and problems allotted to various pairs of workers. From the 1st. of February to date Professor Macleod has been in charge of the physiological investigation of Insulin. He has carried out this investiga‘ tion in a most admirable manner. I cannot conceive of more work being accomplished in a shorter length of time than was accomplished in the Department of Physiology between February lst. andjuly lst. and this is the result of teamwork under the direction of Professor 1}. R. Macleod. All results of the investigation carried on during this time are published in “The Transactions of the Canadian Royal Society” under the names of those en— gaged in the research in alphabetical order. Dr. Collip, although placed in charge of the production of Insulin in the Connaught Laboratory, did not work in the Connaught Laboratory but dab‘ bled in physiological properties of the extract. He reported results to Profes— sor Macleod as his own which were not his own. v «*w-awmmfi i lltt. Dtsctncry Ul insulin “mi. lt] writing the joint paper that appeared in the March number of tin: (fianadian Medical AssociationJournal Dr Collip claimed that he was the first to make extracts front the whole gland by the use of .tlmhoi lie :tlst‘ claimed to have made the first extract that was administered to a human diabetic Professor Fitzgerald pointed out that these statements were um correct. and forced Dr (‘ollip to correct them. Clinical liGCSllgilllt)Il was carried on by Hrs (.rtntpbell and l‘lett'ltt-t public ward patients of thc 'l'oronto (.ieneral Hospital 011 February 19th Dr. (Lollip found that he was unable to refine extratt by his method, and was unable to keep up his supply to the wards. During the following six weeks, or longer, no extract was available for clinical tests. i believe the reason for this to be that Collip, wishing to keep his process a secret, had not kept careful records. The whole investigation was thus held up and after securing the consent of Professor Macleod, Mr. Best and myself commenced where we had left off in January to work on the refining of the extract. During the next two months most valuable work was done by Mr. Best. He worked intensively and about the middle of May he succeeded in again obtaining an extract sufficiently refined for administration to the human. Shortly after this at a meeting of the Connaught Laboratory it was decided that Collip be no longer in charge of production, and that this position should be filled by Mr. Best. The Soldiers’ Civil Re-establishment gave me an appointment at Christie Street Hospital in charge of the diabetic clinic, and from May 16th, 1922 until September let the clinical investigation was carried on in Christie Street Hospital, for the most part. In writing the first two papers no allowance for credit was given to the Department of Pharmacology. I think that this is unfair to Professor Hender— son, because in the first place, I would not have stayed in Toronto had it not been for Professor Henderson; and in the second place, Professor Hender— son made more personal sacrifice in order that this work might be done in Toronto than did Professor Macleod. Professor Henderson did not ask that I correct prescriptions or mark laboratory records of the students. He did this work himself in order that my time might be free for the carrying on of this research. Professor Henderson did this purely unselfishly, and has never asked for credit for doing this. Furthermore, my appointment was in Pharmacology. Professor Macleod carried on research on Anexemia until about the lst of February, 1922. At this time he moved out all the apparatus and began work on carbohydrate metabolism. Until about August 1922 the idea was prevalent throughout the United States and England that Professor Macleod was the originator of this re— search. I base this statement upon the following evidence: 1. On May 3rd Professor Macleod reported the work before the Associa— tion of American Physicians. Here again Professor Macleod’s name preceded } xiii lislii iii is all others on the program it has been reported to me that Professor Macleod gave a fair account of the work. It would appear, however, from Dr. Joslinis letter of May 4th to the Boston Medical and Surgicaljournal, copy of which is attached, that the consensus or opinion tn the United states: was to the effet‘t that this work originated it ith Professor Macleod. As far as i know Professm Macleod has not publicly corrected this impression in the Boston Medical and Surgical Journal. 2. On September 6th an article was published “I the Star copied from the London Times, in which Professor Bayliss, of the University of London England, states that Professor Macleod is the originator, and that to him all the credit should be given, This statement was presented to Professor Mac leod by Mr. Best on the following morning. Professor Macleod refused to refute it on the grounds that he did not wish to enter into newspaper controversy. Mr. Best asked Professor Macleod if he thought it was unfair to Dr. Banting. Professor Macleod’s reply was "Banting will have to get used to it.“ Subsequently, Professor Macleod was interviewed by Mr. Greenaway of the Star, and he again refused to refute the statement of Professor Bayliss. I asked Mr, Greenaway to leave the room and explained to Professor Macleod that if he did not refute it himself there were several who, knowing it to be false, would correct it. Professor Macleod then wrote a statement for the Star refuting the statement of Professor Bayliss. 3. Letters from patients to Professor Macleod, and patients sent by vari- ous physicians, namely, Dr. Geyelin, of New York City; Dr. Howland, of Baltimore; and Dr, Woodyatt, of Chicago These patients were sent by these doctors to Professor Macleod as the originator, in order that he might treat them. Copies of letters are attached. 4. An article in the British Association Journal, September 9th, 1922, copy of which is self—explanatory. , APPENDIX There are various other incidences which indicate a lack of trust and co—operation on the part of Professor Macleod; for example: 1. A few days before leaving for his summer holidays he appointed Dr. Eadie as official tester of the extract, and instructed on his own initiative, the Eli Lilly Company to send all extract to Dr. Eadie. 2. Previous to Professor Macleod’s leaving for his summer vacation I asked him for the privilege of working in the laboratory during the summer; he was agreeable to this. After his departure I went to the laboratory and found that Mr. Page was using the metabolism cages and the room that was previously occupied by Best and myself, and that it would be six weeks or longer before facilities would be available. 3. In the June number of the Canadian Medical Association Journal Professor Macleod wrote an editorial in which the work done during 1921 ,. _... “my”... ....... She: Hmvrtt‘ry "! irznttir: mi, was summarized into one paragraph Ht: also stated that the large scale preparation of extract was being done in the Department of Physiology by the aid of funds granted by the (Tonnaught laboratory of the Uniyersity oi furotito. this was not the case as the preparation of extract was done in thr tionnaught laboratory 4. Professor Macleod gave sufficient information in .tdtrtnce to in V’t'oodyatt of chicago and Dr. :uansun oi banta Barbara to enable them it, prepare extract and test cases 5. 'l'hat Professor Macleod has depictiatcd my efforts to my Work l> evidenced by the fact that he led Dr. Arnold of Ottawa to believe that l was “lucky enough to have the idea“ but that it was really he himself who had been the means of bringing the investigation to a successful issue. 6. Before Professor Macleod left for his summer vacation he refused to give me $3,000. which was promised to me for clinical investigation. I have learned that Professor Collip has been sent a cheque for $500. which was half of his share. On September 5th I again asked Professor Macleod for $3,000. and he informed me that it would be necessary to make requisition for the apparatus required and bring it to him for his signature before payment. This seems to me to indicate Professor Macleod’s lack of trust in me. All these points of difference might have been reasonably and easily explained to me had Professor Macleod wished to do so. C. H. BEST A REPORT OF THE DISCOVERY AND THE DEVELOPMENT OF THE KNOWLEDGE OF THE PROPERTIES OF INSULIN During a course of lectures on carbohydrate metabolism by Dr. Mac- Leod [sic], mention was made of Dr. Banting coming to Toronto to put to ex- perimental test an idea develOped by Dr. Banting which it was thought might lead to the discovery of an efficient pancreatic extract. Dr. MacLeod stated that previous attempts in this field had been unsuccessful. I met Banting early in May 1921, and learned from him the details of his hypothe— sis. Dr. MacLeod asked me to assist Banting in this work for a period of four weeks. Mr. E. C. Noble was to have worked for two weeks but did not see fit to leave his other work for so short a period. My work was to obtain records on dogs depancreatized by two stage operation of the blood and urinary sugars, and urinary nitrogen. Dr. MacLeod advised us not to give extract until a certain G2N ratio had been established. He advised making extract of degenerated gland with alcohol. I assisted Banting during the months of May andjune in the legitation of the pancreas ducts of a number of dogs. Assisted Banting in the performance of partial pancreatectomy. Banting assisted me in chemical studies. We were not able to obtain GzN ratio which Dr. Mac— m“, «in HAN Hitw Lend thought indicative to complete diabetes tint experiments were in this stage when Dr. MacLeod left for Europe. We continued to be unsuccessful during the month ofluly. (ilonditions in the operating room made it impos \lltle for its to keep wounds stet ile lnfet lion tontimtetl to boilth its in spite of our own efforts to keep things clean. Early in August we decided to [relmot'e the degenerated gland and make an extiatt of it with tliilletl anifitial blood tliingers solution; ihtr procedure we described in our first paper We injected this extract in an .tnimal which did not have the correct ratio. The result was encouraging but not conclusive as the animal died the. following day Because of the trouble lin l)l.\ii)\’t‘l\ nut |ll§qféuv m, - in my opinion the principal work which Dr (’iollip pertOrmed was to determine the highest concentration of alcohol [in] which the active princi ple was soluble. In regard to the use of normal rabbits as test objects. there is consider able doubt as to whom belongs the credit of the idea. Dr. Collip was first to put the idea into effect. He also did the first glycogen estimation on animals which l tlepancreatized. Dr. Banting and i talked this idea over previonsi» but did not have the opportunity to put it to experimental test. Dr. Collip did the first quantitative estimation of acetone bodies before and after administration of the extract. The work on respiratory quotients l l l was performed by Dr. Hepburn and myself. i had been desirous of perform- ing this experiment at an earlier date, but had been unable to obtain the apparatus. The work on the experimental hyperglycaemia, as indeed all the work in the Physiological Laboratory after Christmas, 1921, was carried out under Dr. MacLeod’s directions. In the winter of 1922, I was supposed to work in the Department of Physiology, but in reality spent most of my time in superintending the collection and initial concentration of material which was then handed over to Dr. Collip for completion. For a long period Dr. Collip was unable to obtain any active material. At that time I began to devote my entire time to the preparation of the extract. Having tried out many points which I thought I might prove to be at fault, I at length obtained results, which showed that our trouble was probably due to the vicissitudes of water pressure, and the effect of this upon the tempera- ture of the material which we were distilling. Time and distillation was also greatly effected by the water pressure. Dr. MacLeod suggested that in order to avoid the use of vacuum water pumps we return to the use of air evapora- tion, which Banting and I had used in our early experiments. To this end a tunnel was devised, which after some experimental work was adapted to rapid evaporation. The tunnel procedure supplied extract for the Physiology Department, and for several cases under Banting's supervision for several months. The Eli Lilly Company then demonstrated that Electric vacuum pumps were efficient, and the tunnel has been abandoned. My report of the development of this work is given in less detail than I had previously intended doing, caused through conversation with Dr. Bants ing and Dr. MacLeod. I am sure there will be very few controversial points. from infection which developed in the interval required for a dog depart- creatized in two stages becoming diabetic, I suggested at this time that we should perform the complete pancreatectomy at the initial operation. We obtained much better results with the latter method, and have used it entirely since that time. We posted the results of our first two experiments to Prof. MacLeod. In that letter we outlined our probable procedure for the next two months. We received an answer from Dr. MacLeod in about a month after our letter was posted. In this month we performed many of the experiments recorded in our first paper. Practically the only new experiment reported in the first paper and performed subsequently to the opening of school year 1921 was the work on hemoglobin estimates before and after injecting the extract. This experiment was suggested by Dr. Macieod and proved that the reduc- tion of blood sugar after administration of extract was not a dilution phenomenon. The work during the fall months reported in our two papers was per- formed entirely by Banting and myself. We had the benefit of Dr. MacLeod‘s advice, but as he states, we were given the opportunity to conclusively prove the efficiency of our extract upon diabetic animals, and as will be stated subsequently diabetic patients, before the other members of the Physiologii cal Staff participated in this work. As stated in our second paper we were able to prepare extract from the pancreas of foetal calves. This originated from an idea of Banting’s, and resulted in a much greater supply of extract. Preparation of the extract of the whole gland was performed by Banting and myself jointly. The idea of using alcohol in extracting was fairly obvious as far as I can ascertain. It occurred to Dr. MacLeod, Banting and myself independently. By using extract made from the whole gland a completely depancreatized animal was kept alive for seventy days. In addition to the results published in our first two papers, we also prepared an extract which was administered to two patients. We obtained 25% lower in the blood sugar, but the material produced severe local reac— tions. We found that the active anti—diabetic principle was soluble in alcohol up to 50%, but was insoluble in 95%. We found also that fat solvents did not dissolve or damage the active principle. J. B. COLLIP THE CONTRIBUTION MADE BY J. B. COLLIP TO THE DEVELOPMENT OF INSULIN WHILE HE WAS IN TORONTO 1921~22 (1) The production of a state of hypoglycaemia in normal rabbits fol- lowing the administration of a potent pancreatic extract. First experi- ments—December 12, 1921. any, \ili ll'\l’i fill-3» (‘3) The preparation of crude but potent extracts ol pancreas as follows: Fresh pancreas was ground and mixed with an equal volume ml 95% alcohol. The mixture after thorough agitation was strained through cheesecloth and then filtered. The filtrate was Concentrated in a vacuum still to US its volume either with or without the addition of 1 drop ol glacial acetic acid per 100 c c of filtrate before the concentratit‘m pix; cess was started. (j) The observation (December 1921) that little or no effect was pro duced in anaesthetized dogs by the administration of pancreatic extracts. Those observations suggested the liver as a seat of action of the potent principle. (4) The storage of glycogen in the liver of a depancreated dog following the administration of potent pancreatic extract. (The demonstration of this phenomenon was first made in December 22, 1921). The experiment was planned and carried out by Banting, Best and Collip. (5) The observation that ketosis is abolished in depancreatized animals by the use of potent pancreatic extracts. (6) The discovery of a method of preparing insulin in semi-pure form suitable for human administration. (7) The use of normal rabbits as a means of assay of the insulin used in treating the first clinical cases. (8) The observation that insulinated rabbits develop characteristic symptoms when the blood sugar has fallen to a low level. (9) The observation that these symptoms can be antidoted to a degree by adrenalin and can be controlled by glucose. (10) The observation that marked hypoglycaemia was manifested in an etherized dog following the administration of highly potent insulin. (11) The producrion of a large part of the insulin preparation used by various members of the enlarged collaborating group during the early months of 1922. MEDICO-HISTORICAL NEWS AND ACTIVITIES CORRESPONDENCE AND REPORTS l‘WEN’l'Y-FIVE YEARS AGO; HENRY E. SIGERIST ( 1891 w l957) Twenty—five years ago, in 1957, Henry E. Sigerist died, having spent his last decade in Pura, Switzerland, far from the madding crowd's ignoble strife, And a madding crowd of a special sort there was in the 19505 in the United States: among all the good will and good humor there was much backbiting and rancor, for this was the lamentable era of Joe McCarthy, Russophobe junior senator from Wisconsin and red~baiter extraordinary, whose “um-American” antics disgraced Congress and in the end dis~ gusted it, along with President Eisenhower and the nation, Sigerist had published, in 1957, an enthusiastic book about Russian medicine: he would inevitably have been a target for outrageous barbs and arrows. His views about the distribution of health care, seen in the context of Medicare and of a somewhat chastened profession, might Dtnvc'r‘nu (\n 'rwvn VIH‘TAn‘r AY' inl‘v‘vr‘vivrs t. u —/ u -/,t -hs ...
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