avances en Diabetología Av Diabetol. 2010;26:373-82

Historical perspective From pancreatic extracts to artificial pancreas: history, science and controversies about the discovery of the pancreatic antidiabetic hormone V: The controversy. Who discovered insulin? A. de Leiva-Pérez1, E. Brugués-Brugués1,2, A. de Leiva-Hidalgo1,2,3,4 1Fundación DIABEM. 2Servicio de Endocrinología y Nutrición e Instituto de Investigación. Hospital de la Santa Creu i Sant Pau. Barcelona. 3Centro de Historia de la Ciencia. Universitat Autònoma de Barcelona. 4CIBER-BBN-ISCIII

The Nobel Prize controversy were provided by two members of the objection was to making an award on “he- The 1923 Nobel Award Nobel Committee: John Sjöqvist, Profes- resy evidence” from unknown persons or of Physiology or Medicine sor of Chemistry and Pharmacy, and Hans on statements in the two appraisals, like In April 1923, a total of 57 nominations Christian Jacobaeus, Professor of Internal “it is beyond doubt”, or comments as with merits were reviewed by the Nobel Medicine. Sjökvist arrived to the same ”things that are thought as very possible”; Committee. The examiners concluded conclusion as A. Krogh: the prize should the Assembly should take only verifi able that the discovery of insulin was of funda- be divided between Banting and Macleod. facts. The Committee reconsidered and mental importance. The archives of the Professor Göran Liljstrand was the Secre- reconfirmed its previous recommenda- Karolinska Institute depict that Macleod tary of the Nobel Committee from 1918 to tion. August Krogh was identifi ed as the and Banting were nominated for the fi rst 1960. He was a great friend of August source of the “heresy evidence”; he time in 1923: Banting by G.W. Crile (Cle- Krogh. The archives of the Royal Swedish emphasized that he made the joint recom- veland) and August Krogh and Macleod Academy of Sciences keep an interesting mendation based on his visit to Toronto. by G.N. Stuart (Cleveland) and August correspondence between Krogh and Lil- On October 25, 1923, the nineteen Krogh. There was also a joint nomination jestrand. The Committee concluded that Professors of the Caroline Institute, vo- of Banting and Macleod from August although the discovery was initially ted by secret ballot. The Nobel Award of Krogh. Written evaluations of Banting Banting’s idea alone, Macleod’s guiding Physiology and Medicine was jointly and Macleod’s scientific contributions hand helped Banting’s idea to reach such granted to Frederick Grant Banting and a happy culmination. John James Richard Macleod, “for the Date received: 15th July 2010 The Faculty members of the Karolinska discovery of insulin”, one year before. th Date accepted: 7 September 2010 Institute (Royal Caroline Institute), the Banting decided to share his monetary Correspondence: Nobel Assembly, as its October 11 mee- fraction of the prize with Charles H. Prof. Alberto de Leiva-Hidalgo. Fundació DIABEM. ting, decided to send back the proposal to Best; Macleod did the same with James Cartagena, 245, 1-5. 08025 Barcelona. E-mail: [email protected] the Committee for reconsideration. The B. Collip (fi gure 1).

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Figure 1. Nobel Prize Diploma to Banting and Macleod

The protests In December 1922, Dr. F. Roberts, phy- Figure 2. A) Letter from Paulescu to Banting (February 5, 1923), who did not reply. B) Letter from siologist from Cambridge, had already re- Paulescu to the Nobel Commission (November 6, 1923) (Courtesy of Dan Angelescu). Available on: http://www.library.utoronto.ca ported in a letter to the British Medical Journal a serious criticism to Banting and Best’s work in their fi rst two publications Banting did not reply. On November 6, Archives Internationales de Physiologie, in the Journal of Laboratory and Clinical 1923, Paulescu claimed to the President Paulescu described the various attempts to Medicine.1 Roberts claimed that the pto- of the Nobel Commission (fi gure 2) that treat one male patient with “thin diabe- teolytic enzyme (trypsinogen) existing in his work had been stolen by the Canadian tes”, and a woman with “obese diabetes”. the pancreatic gland needs to be activated research group, and he asked for justice. In both cases the intravenous administra- by enterokinase secreted by the small in- Paulescu enclosed a copy of his article tion of pancréine induced favorable testine; therefore, there were no physiolo- “Recherche sur le rôle du pancréas dans outcomes regarding the symptoms, blood gical basis for the duct-ligation experi- l’assimilation nutritive” published in Ar- glucose levels and glycosuria. Neverthe- ment. chives Internationales de Physiologie de less, the development of a toxic syndrome Shortly after the announcement of the Liège on the 31st August 1921 (accepted with high fever obliged to the interruption Nobel Committee’s decision, various re- on the 22 June). Paulescu’s article had of clinical experiments afterwards. searchers claimed against such a provision. been published six months prior to Ban- On April 1922, the University of Toron- Georg Ludwig Zuelzer sent furious letters ting and Best’s article “The Internal Se- to submitted a formal application for an of protest from Berlin, pleading for some cretion of the Pancreas” (Journal of Labo- USA patent granted to Charles Best and recognition of his priority. Ernest Lyman ratory and Clinical Medicine, issue of James Bertrand Collip. The USA govern- Scott called the attention to his experi- February 5, 1922). ment rejected the application, in order to ments in the fi eld. In his opinion, the prio- protect the rights of the ACOMATOL pa- rity of isolation and in the development of “Je vous demande la permission de protester tent already granted to George L. Suelzer fundamental principles involved in extrac- contre le fait que cette distinction [Nobel] a été on May 28, 1912. The process fi nally en- tion clearly belonged to the work reported accordée à des personnes qui ne la méritaient ded with the provision of a patent registry from the laboratory of Chicago.2 The me- point. En effet, la découverte de ces effets in November 1922, shared by the Univer- thod of fi nal purifi cation was not necessary physiologiques et thérapeutiques m’appartient sity of Toronto (INSULIN) and Eli Lilly for obtaining the active principle. John Ra- toute entière (…). Dans ces articles, ils n’ont (ILETIN) (fi gure 3). ymond Murlin argued that he had perfor- fait que répéter ce que j’avais dit bien avant Accordingly to the Bylaws of the Nobel eux sur la diminution de l’hyperglycémie et de med, at earlier times than the researchers la glycosurie, de l’urée sanguine et urinaire, de Foundation: “To be considered eligible from Toronto, both experimental and clini- l’acétonémie et de l’acétonurie, sous for an award, it is necessary to be nomi- cal studies with the pancreatic extracts. Is- l’influence des injections intra-veineuses de nated in writing by a person competent to rael S. Kleiner made no claims. l’extrait pancréatique, chez un animale diabé- make such a nomination. A personal On February 5, 1923, Nicolae C. Pau- tique (…).” (N.C. Paulescu. November, 1923) application for an award shall not be con- lescu had written Banting, asking for mu- sidered. Each year the prize adjudication tual correspondence regarding their re- On April 10, 1922, the license application shall embrace such nominations as have search activities (fi gure 2); Paulescu sent 6254, PANCRÉINE, was registered. In been submitted during the preceding twel- to Toronto his main publications of 1921. the issue of March 5, 1923, of the journal ve months up to February 1”. 3

374 Historical perspective V: The controversy. Who discovered insulin? A. de Leiva-Pérez, et al.

complete, and inadequately documented. He ended: “it seems to me that I have the PANCREINE (N.C. Paulescu) right and even the duty, to re-establish the License application # 6254, truth and to protest against a process ne- issued by the Romanian Ministry of Industry. April 1922 ver permitted in science, in re-establis- hing the facts with total accuracy”.4 In 1923, Paulescu had already published the results of attempts at purifi cation of pan- créine, in an effort to make it suitable for use in humans.5 He studied the effects of acidic and basic solutions, heat and alcohol, on the USA Patent. impurities in his extract, and found them all November, 1922 ISLETIN / INSULIN inadequate. In his textbook of medicine pu- blished in 1930,6 Paulescu showed his em- bitterment and disappointment: “Formerly, I used to believed taught that a scientist F.G. Banting C.H. Best J.B. Collip J.J.R. Macleod may work in safety, because I was convin- ced that the date of his publications shelte- Figure 3. red him from any iniquity. Unfortunately, today, I am forced to acknowledge that I was completely wrong”. August Krogh and Hans C. Hagedorn A decisive person in the concession of the Nobel Award to Banting and Macleod, as it was mentioned before, was August Krogh, a renowned Danish scientist, who had obtained in 1920 the Nobel Prize in Physiology and Medicine for his disco- very of the mechanism of regulation of capillary fl ow in the skeletal muscle. In 1922, August Krogh traveled to the USA with his wife Marie (also a scientist). Ma- rie Krogh had been found a year before to have maturity onset diabetes. The renow- ned American diabetologist Elliot P. Jos- August and Marie Krogh Hans Christian Hagedorn lin informed August and Marie Krogh that insulin had just been discovered and puri- Figure 4. August Krogh, the Nobel Prize of 1923, Hans C. Hagedorn, and his wife Mary fi ed in Toronto. They decided to extend their trip and spent some days in Toronto Paulescu was never nominated. Only Nobel Committee in regards to Paulescu’s (November 23-25, 1922) as Macleod’s Banting and Macleod were nominated in protest could have been different. Instead, guests. Krogh met also Banting (during 1923, Collip and Best were only nomina- they remained silent, probably to avoid da- those days, the other members of the To- ted years later, in 1928 and 1950, respecti- maging the reputation of the Nobel Prize ronto team were out of town). vely. Therefore, Paulescu could have never and the Karolinska Institute. During his stay in Toronto, August received the prize. Furthermore, the In 1924, Paulescu submitted a docu- Krogh obtained a license to manufacture Bylaws of the Foundation also point out ment to the Romanian Society of Biology, insulin in Denmark. He started to produce that once a prize has been awarded, it can- in which he reviewed the chronology of the anti-diabetic hormone immediately af- not be withdrawn, and no further Nobel his own experiments, their results, and the ter he returned to Copenhagen (in fact, the Prizes can be given for the same discovery. publications in which they appeared. He fi rst Danish diabetic patient to receive in- Von Mering was nominated in 1902 and discussed the isolation of pancréine, and sulin was treated on March 1923). Marie’s 1906. Minkowski was nominated in 1902, how he established a unit of measurement diabetes was successfully treated with in- 1906, 1912, 1914, 1924, and 1925, but ne- for it. Paulescu reviewed the work of Ban- sulin (she died of breast cancer in 1943). ver awarded. However, the attitude of the ting and Best which he felt ineffi cient, in- Hans Christian Hagedorn was the perso-

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Figure 5. Letter of Best to Pavel and Blue index note card. Author: C.H. Best. Toronto, Ca. Fall 1921. Notes have been made on both sides in Best’s hand. The first side is initialed C.H.B. in the bottom corner. Although Paulescu’s article indicated that he was obtaining positive results using pancreatic extract, the notecard indicates that the significance of Paulescu’s work was not appreciated due to a misquotation, substituting the phrase ‘non bon’ for Paulescu’s original ‘non plus’. Source: Online Library of the University of Toronto. Banting Collection. Available on: http://link.library.utoronto.ca/insulin/ index.html

nal physician of Marie. Together with Ha- the credit for the idea behind the work or misinterpreted them because of their gedorn (figure 4), Krogh founded the which led to the discovery, undoubtedly poor French, nobody knows well enough. Nordisk Insulin Laboratorium in 1923, goes to Banting, who is a young and Professor Ion Pavel, from Bucharest, the starting point of a successful Danish apparently very talented man. However, wrote to Charles Best complaining about pharmaceutical company, today known as he would defi nitely not have been able to the wrong paragraph included in the fi rst Novo Nordisk. carry out the investigations, which from article published by Banting and Best, re- In 1918, Hagedorn, in joint forces with the start and during all stages, have been garding the work of Paulescu. Years later, the pharmacist Bierger Norman Jensen, supervised by Professor Macleod.” Best apologized for the crucial misinter- published a micromethod for the determi- In a letter dated February 4, 1924, to pretation (letter to Ion Pavel dated Octo- nation of blood glucose that has been the Göran Liljestrand (also referred by Linds- ber 15, 1969; fi gure 5). method of choice for more than 40 years.7 ten), August Krogh wrote: “I understand Hagedorn invented protamine insulin in that the prize to Banting and Macleod ig- “I regret very much that there was an error in collaboration with Norman Jensen and In- noring other coworkers has not been met our translation of Professor Paulescu’s article. ger Wostrup, patented in 1936.8 Hagedorn with absolute consent on the other side of I cannot recollect, after this length of time, founded the Steno Diabetes Center in Co- the Atlantic Ocean and that especially exactly what happened (…). I do not remem- penhagen, and was its Chief-Physician for Banting is offended by the fact that Best ber whether we relied on our own poor French or whether we had a translation made. In any 26 years. He developed diabetes, gangrene was not included. However, I am convin- case I would like to state how sorry I am for and major amputation, and suffered of ced that the correct choice was made.” this unfortunate error and I trust that your Parkinson’s disease for many years. From As Lindsten concluded in the mentioned efforts to honour Professor Paulescu will be 1966 became a permanent patient at the article, “it seems reasonable to assume rewarded with great success.” Steno. He died of coronary thrombosis in that Krogh’s nomination had some impact 1971. on the awarding of the prize to Banting Upon his return to Europe, Krogh pro- and Macleod. After all he was a Nobel Beyond Toronto. posed Banting and Macleod for the Nobel Laureate and had, in addition, personal Glory to the Canadian research team Prize. As cited by Jan Lindsten (member knowledge of the situation in Toronto”.9 Macleod decided to cooperate with Eli Li- of the board of the Nobel Foundation bet- lly after the successful outcome of the ween 1979 and 1990, and member of the The crucial misinterpretation early clinical trials. The agreement was Swedish Royal Academy of Sciences, Banting and Best’s paper, published in reached in May 1922. The rabbit convul- among other distinctions), August Krogh February 1922, mentioned Paulescu’s ear- sive test devised by Collip was used for summarized in the following way his rea- lier research, but reported incorrectly that standardization; within 6 months, more sons for proposing Banting and Macleod: the injections of pancreatic extract made than 100,000 rabbits were utilized. “With the information which I personally by Paulescu into dogs had produced no Shortly after the purifi cation of insulin have obtained in Toronto, and which also, effects. That was in fact the opposite of (Collip), the pharmaceutical company Eli although less clearly so, emerges from the what Paulescu had stated. Whether they Lilly started large-scale production of the published works, one may conclude that intentionally distorted Paulescu’s words, pancreatic extract. The Lilly’s chemist

376 Historical perspective V: The controversy. Who discovered insulin? A. de Leiva-Pérez, et al.

Walden evolved a method of purifi cation by isoelectric fractionation which signifi - cantly improved both yield and potency and made large-scale production possible. Early in 1923, the supply of insulin was adequate to meet the requirements of va- rious institutions selected to study its cli- nical use, and to supply with insulin the entire North American continent. In Great Figure 7. Britain the patent rights were assigned to Ion Pavel the Medical Research Council.10 (1897-1991) The Toronto team was praised with ho- nours, and received also major press cove- at similar conclusions: “(...) there can rage and publicity (figure 6). Banting be little doubt of the existence of a pan- achieved a sudden and outstanding fame. creatic secretion, that via the blood All kind of newspapers trumpeted his suc- stream (...) fi nally alleviates some of the cess. He was made honorary member of symptoms of diabetes...”. many medical societies. In May 1923, the • In 1923, J. Murlin wrote: “(...) mention Ontario Government provided him with should be made (...) of the favorable re- the Banting and Best Chair of Medical sults reported by Paulescu (1921) (...). Research. It included a non-teaching pro- He found that the intravenous injection fessorship for Banting, an annual grant of of a sterile extract into depancreatized $10,000 to pay Banting’s salary, and an dogs brought about a diminution or even additional amount of $10,000 for reim- a temporary suspension of the hypergly- bursement of the discovery period; Ban- cemia (...) and the excessive production ting gave $2,500 to Best. The Canadian (...) of urea and ketone bodies”.12 (12) House of Commons offered Banting a li- • In 1924, C. Funk declared in Paris: “In Figure 6. An excerpt from a newspaper. Toronto fetime annuity of $7,500. star weekly [Mar 26, 1922]. Source: Online 1920 and 1921, Dr. Paulesco of Roma- In conclusion, the Toronto’s team’s in- Library of the University of Toronto. Banting nia, and Drs. Banting and Best of the creasingly important reputation, not only Collection. Available on: http://link.library.utoronto. University of Toronto, proved in a deci- in scientifi c and academic circles, but also ca/insulin/highlights.cfm sive manner that the pancreas contains among the general public, made it diffi - an antidiabetic substance that has been cult to raise the question about the priority With the snap of the Second World War, given the name of insulin”.13 in the discovery of insulin, and the role of the political problems that arouse in Ro- • In 1926, A. Sordelli and J.T. Lewis, Paulescu in it. mania and the ascension to power of the from Buenos Aires, wrote: “In 1921 Communist party in 1947, Paulescu’s fi - (...) Paulescu communicated his com- Paulescu forgotten gure submerged in the oblivion. The com- pleted experiments with an extract pre- Shortly before dying, Paulescu declared munists, who considered Paulescu an ene- pared by aqueous maceration of the (1931): my of the Party, for his religious and pancreas. The results are identical to political ideas, erased his fi ngerprints of those obtained by Banting in discove- 14 “Formerly I believed and maintained that a the history of the Romanian science. ring insulin”. scientist can work in perfect safety, convinced • P. Trendelenburg, in Berlin, wrote in as I was that the date of his publications pro- The reappraisal of Paulescu 1934: “Shortly before the description of tected him against any injustice. Unfortunately, There have been numerous attempts by the discovery of insulin (1921) Paules- I am obliged to admit now that I was utterly scientists and historians to make public the co achieved full success with extracts mistaken in this regard. I am not dominated by scientifi c prestige of Paulescu and his merits. which lowered the blood sugar of pan- pride and I struggle against this odious vice. createctomized dogs within one hour of Indeed, on publishing my discovery I never for Early Statements parenteral administration”.15 one moment thought of publicity, which could • Paulescu received a letter from E.L. have affected my modesty that I consider one of the first qualities of a scientist. But I cer- Scott, dated 5 November, 1921, decla- Ion Pavel tainly cannot accept another, more odious de- ring that the results of his own work wi- Ion Pavel (fi gure 7), a Romanian physio- fect, that of the theft of someone else’s th pancreatic extracts at Columbia Uni- logist, dedicated fi fteen years of his life to scientific property.”11 versity in 1921, and the experiments investigate about the history of the disco- published by Paulescu in 1921, arrived very of insulin. He published a series of

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the discovery of insulin, and particularly the contribution of Paulescu, I wish to say the following. I have throughly studied the documents you have sent me and I have also discus- sed the case with colleagues, especially with professor Ulf von Euler, president of the Nobel Foundation and, as you know, himself a physiologist and endocrinolo- gist of the highest reputation. We agree that no doubt your viewpoints in connection with the planned celebra- tion of the 50 years anniversary of the dis- covery of insulin to a certain extent are justifi ed. As you know well the Nobel Prize to Banting and Collip [here, a mistake; Collip instead of Macleod] has been criticized by many, especially the fact that Best was not included. In my opi- nion, Paulescu was equally worth the award. As far as I know, Paulescu was Figure 8. Letter of Pavel and Mincu on behalf of the Romanian Academy to the President of the Nobel not formally proposed, but naturally the Institute (October 1969) Nobel Committee could have waited another year. articles and books where he stressed the Romanian Academy) wrote a letter to The attitude of the Nobel Committee in merits of Paulescu in this field, and Prof. Arne Tiselius, Director of the Nobel the exceptionally diffi cult and controver- addressed several protests to the Nobel Institute, claiming for Paulescu’s priority sial case of the prize for the discovery is Committee and to the International Dia- in the discovery of insulin (fi gure 8). expressed by professor Göran Liljes- betes Federation (IDF). (For further rea- Tiselius’ answer was the following: trand (formely secretary of the Commit- ding, see references 16-20.) tee) in the book ‘Nobel, the Man and his In October of 1969, Prof. Pavel and “Returning to the question raised in your Prizes’ (edited by the Nobel Foundation, Prof. S.M. Milcu (Vicepresident of the letter of Oct.30 1969 about the priority of Elsevier Publishing Co., Amsterdam, 1964). Unfortunately there is no mechanism by which the Nobel Committee would do an- ything now in this or similar cases. Perso- nally, I can only express the hope that in an eventual celebration of the 50th anni- versary of the discovery of insulin due re- gard is payed to the pioneer work of Pau- lescu. With my kindest regards, Sincerely yours, Arne Tiselius” Ian Murray Prof. Ian Murray (fi gure 10), Professor of Physiology at the Anderson College of Medicine in Glasgow, Scotland, Vice-pre- sident of the British Association of Diabe- tes, and founding member of the Interna- tional Diabetic Federation, claimed that Figure 9. Arne Tiselius (1902-1971) and his answer Paulescu was the true discoverer of insulin.

378 Historical perspective V: The controversy. Who discovered insulin? A. de Leiva-Pérez, et al.

Nobel Prize cannot cover a ‘forgetting’ whether it is inadvertent or erroneous. An international tribunal is able to correct history without reducing the honor of its perpetrators. This means therefore that if it is not possible to condemn the Nobel Prize jury for ignoring a pioneer, it will be the same for those who, 50 years later, Figure 10. Murray I. Paulescu and would pass by the works of the true disco- the isolation of insulin. (Ref. 21: verer. We must understand that this is not Journal of the History of Medicine and Allied Sciences. 1971;26: a question of pushing aside those that ha- 150-7) ve been rewarded with the Nobel Prize – Paulescu himself would not have sought In an article for a 1971 issue of the Jo- explanation on their error, however, that– but only of placing he who showed urnal of the History of Medicine and seems to me somewhat naïve”. the way beside them, if not before them”.10 Allied Sciences, “Paulescu and the Isola- • Murray to Pavel (February 29, 1972): In the end, though, no Romanian was tion of Insulin”,21 Murray wrote: “My suggestion is that IDF should ins- included in the Committee, which was titute a Paulesco Memorial Lectures- formed by: F.G. Young (UK), President of hip. The lecture at each triennial mee- the Committee, elected also as President “The fascinating story of the discovery of insulin still provokes controversy (...). Insufficient re- ting would be given by someone of of the IDF at the end of the Buenos Aires cognition has been given to Paulescu, the dis- merit”. Congress, and Best’s personal friend tinguished Romanian scientist, who at the time (Best was still alive and had a great in- when the Toronto team were commencing their Eric Martin fluence in scientific circles). The other research had already succeeded in extracting For Eric Martin, Professor of Medicine, members of the Committee were: R. Haist the antidiabetic hormone of the pancreas and University of Geneve, “it is beyond denial (Canada), who worked with Best, and proving its efficacy in reducing the hyperglycae- that Paulesco was the fi rst to provide an successor to the Chair of Physiology in mia in diabetic dogs (...). His results, published exemplary demonstration of the antidia- the Toronto University; W.J.H. Butterfi eld in August 1921, proved convincingly that he betogenic and antiketogenic effect of a (UK); Rolf Luft (Sweden), and P. Ram- had succeeded in isolating the antidiabetic hormone of the pancreas and demonstrating its pancreatic extract (...). We should stress bert (France). action in lowering the blood sugar in both dia- the cardinal importance of the discovery Frank George Young (1908-1988)’s betic and normal dogs (...). Banting and Best of Paulesco, a discovery known to the Ca- work about diabetes began under J.J.R. are commonly believed to have been the first to nadian physicians but poorly interpreted Macleod at Aberdeen, and then C.H. Best have succeeded in isolating insulin. They have by them, with the result that determinative at the University of Toronto. In 1935 he re- been hailed as its ‘discoverers’. Their work, studies of the Romanian physiologist have turned to University College, London. however, may more accurately be construed as been left in the shade”.22 Then he was appointed to the Scientifi c confirmations of Paulescu’s findings (...). There Staff of the Medical Research Council’s can be no doubt that pancréine and isletin were IDF Report of the Special Committee National Institute for Medical Research, identical. Unfortunately both these extracts caused such local irritation when injected sub- set up to present to written summary under the Directorship of Sir Henry Dale, cutaneously that administration by this route of work leading up to the discovery of mentor and friend of Charles H. Best (as a was impossible.” insulin, 1971 matter of fact, Dale had proposed Best for In the VII Congress of the International Dia- the Nobel Award, in 1950). Young was a betes Federation celebrated in Buenos Aires Vice-president of the British Diabetic As- During years, Murray maintained written (August 1970), a Special Committee was sociation from 1948, President of the Euro- correspondence with Pavel (letters inclu- created to devise a summary on the research pean Association for the Study of Diabetes ded in Pavel’s book “Correspondence developments related to the discovery of in- (1965-1968), and President of the Interna- Lending Support to the Priority of N.C. sulin. Initially, Dr. Witte (Secretary of the tional Diabetes Federation (1970-1973). Paulescu in the Discovery of Insulin”). IDF), had invited Romania to send a delega- The report was published in 1971 (fi fty Some lines from this correspondence ex- te to the meeting, and Rachmiel Levine, years after the discovery of insulin) with the plicit the thoughts of Murray about the President of IDF from 1967 to 1970, had su- title “Report of the Special Committee set Paulescu affair. ggested the name of Prof. Pavel. up to present to written summary of work • Murray to Pavel (November 11, 1969): In a letter to Murray, Pavel wrote: “I leading up to the discovery of insulin”. It “It is satisfactory to have his (Best’s) will raise the problem at Buenos Aires. I started with a foreword from Young, and an admission that they were so wrong in intend to fi nd some scientists ready to su- introduction that established that: “There their reference to Paulesco’s work. The pport our point of view which is: the was no intention to detract in any way from

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the contributions of Banting, Best and Ma- For further reading about the 1970 Re- cleod in Toronto in 1921-1922 but rather to port of the IDF, consult the works of Pav- pay tribute to others whose published obser- el,19 Ionescu-Tirgoviste and Dwor- vations formed part of the background in schak.23-27 Pavel maintained a long time which the investigations of the group in To- and intensive correspondence with both ronto began fi fty years ago”.11 Murray and Young in defence of the prior- The report stressed above all the impor- ity of Paulescu’s achievements.17 In one of tance of the clinical application of insulin these letters, Young openly showed to carried out by the Toronto team, without Pavel his personal relationship with the Figure 11. paying too much attention to the impor- researchers from Toronto, as well as his Michael Bliss tance of the physiological step. Therefore, attempts to be as objective as possible in the work of Paulescu and the other pio- the contents of the IDF offi cial report. sense a reparation for the dead, or a neers was diminished, and the report ig- discharge of the liability of the living nored the chronology of events. The fo- Young to Pavel (June 23rd, 1971): “It was my (...). His research (...) was the culmina- llowing extracts of such a report are loss that I could not have known personally Prof. tion of years of experimental work of 12 reproduced in the following paragraphs: N.C. Paulesco. As a young research student I precursors, colleagues and himself. spent a period in Abardeen with the late Prof. This great advance, perhaps equivalent J.J.R. Macleod, and in Toronto with Prof. C.H. EXTRACTS: in some respect to the discovery of the Best. In Toronto I also came to know Prof. J.B. If the isolation of a substance involves the pre- therapeutic virtue of penicillin, remains Collip and Dr. F.G. Banting. I knew Dr. C.-H. Best 30 paration of it in pure form, as indeed the word unacknowledged”. most intimately and am a great admirer of him isolation does imply, Banting and Best did not • John Waller declared: “(...) It became personally and of his research activities (...). In isolate insulin. What they did was to produce for clear that Paulesco had performed es- my capacity of Chairman of the International the first time pancreatic extracts containing that Committee which has now submitted its report, sentially the same experiments as Ban- substance which were suitable for subcuta- I attempted to be as objective as possible and ting and Best. The only difference was neous injection into animals and man, such to ignore all but evidence published in medical that he started earlier and, by working treatment being highly effective in controlling and scientific journals at the time of the disco- with much more care, achieved greater the symptoms of diabetes mellitus in diabetic very of insulin, or shortly afterwards”. success. It was also undeniable that the dogs and human patients… Romanian had published his data There can be little doubt that Paulesco, as well months before the Toronto team had as Banting and Best, obtained a pancreatic ex- 31 tract which contained insulin, and that the Recent statements even written their fi rst paper”. pancréine and the insulin present in the crude • Prof. R. Luft, when participating in an extracts in which the hormone was first obtai- anniversary symposium on insulin, in Among others, important attemps to resu- ned, are the same substance. 1972, described Macleod as a manager rrect Paulescu’s work have been under- Undoubtedly, Professor N.C. Paulesco should be and promoter who “put Collip and Lilly taken by Prof. Nicolae Hâncu (Cluj-Na- given special credit for the successes with which Company into business”.28 A former poca University in Romania), Prof. his experimental observations were crowned. But Chairman of the Nobel selection Com- Constantin Ionescu-Tirgoviste (University more than experimental physiology was needed mittee told the NIH that in his view, the of Medicine and Pharmacy Carol Davila if insulin was to become available in the form, 1923 award to Banting and Macleod was in Bucharest, Director of the Institute N. and on the scale, in which it was quickly needed the worst error of the Commission.29 Paulescu of Diabetes, Nutrition and Meta- for the therapeutic use. The resources required involved not only the large-scale production of • James Theodore Nicolas emphasized bolic Disease, and member of the Roma- material of a refinement that ensured no irritant the misquoting in the English transla- nian Academy), and Francisc I. Dwors- reaction on subcutaneous injection into a human tion by Banting and Best of the Paules- chak, that have devoted several books to being, but also the biological standardization of cu’s statement which appeared in his the subject. Other scientists and physi- the hormone and the extensive clinical testing of major French publication, to provide a cians that have stressed the merits of Pau- the standardized product. directly contrary meaning. In relation lescu in the discovery of insulin are E. The Nobel Prize that was given to Banting and with this incident, he remembered the Sharpey-Schafer, Jean Pirart, Dorothy Macleod was awarded for work which the thought of Wilfred Totter, expressed as Hodgkin, and in Spain, L.F. Pallardo and Professorial Staff of the Caroline Institute consi- his Hunterian Oration in 1932 (one year J.L. Rodríguez Miñón. dered to be of great importance, theoretically after Paulescu’s death): “With the pro- and practically. The practical importance of the investigations initiated by Banting and Best is cess of time it will become increasingly Michael Bliss witnessed by the fact that since 1922 countless diffi cult to separate the commemoration Michael Bliss (fi gure 11), Professor of numbers of diabetic people have been able to of the dead from the responsibility for History of Medicine at the University of live normal lives. their treatment during life, or to believe Toronto, published in 1982 “The Disco- that posthumous honour is in any real very of Insulin”, where he describes in de-

380 Historical perspective V: The controversy. Who discovered insulin? A. de Leiva-Pérez, et al. tail the experiments carried out by the Ca- friends were deeply upset at the way in nadians, highlighting above all Macleod which Best was able to continue his cam- and Collip’s contribution.32 paign of self-aggrandizement. Eleven years after the publication of (…) From time to time in the 1960s “The Discovery of Insulin”, Bliss publis- Charles Best would received letters from hed an article in the Journal of the History Romania, inquiring into Banting and of Medicine and Allied Sciences.33 We co- Best’s research and its relationship to that py here some revealing fragments. of a distinguished Romanian physiologist, “This essay traces the continuation N.C. Paulesco, who had published his re- and elaboration of the Banting and Best sults just before Banting and Best began myth after Banting’s 1941 death. Best their work. Best politely replied to the then became the chief spokesman for the queries but by now was unable or unwi- view that the two young researchers had lling to enter into renewed controversy. discovered insulin on their own in 1921, Perhaps it was just as well, for Paulesco’s and had been deprived of their full share chief admirer, I. Pavel, had substantial Figure 12. Paulescu’s statue near the Faculty of Medicine, University of Bucharest of the consequent glory because of the evidence to show that rigorous applica- machinations of Macleod, Collip and tion of the standards of evidence being their friends. During the next thirty years used by Best to justify the claim that he Toronto, as the result of a collaboration Best and his friends championed a Ban- and Banting had discovered insulin in the building on the original work of Banting ting-and-Best version of the discovery of summer of 1921, would very likely lead to and Best. Throughout his later life Char- insulin which featured a substantial en- the realization that priority in the disco- les Best worked very hard and with consi- largement of Best’s part in the story. very of insulin belonged to Paulesco. derable temporary success, to convince Their version of historical correctness Through the 1970s, the argument for everyone of his and Banting’s claims to be became increasingly convoluted and Paulesco’s priority gained strength and the sole discoverers of insulin. In the long diffi cult to maintain as the years went by, recognition, until by the early 1980s it run he failed. however, because of outsiders’ interest was on its way to becoming a new or- (…) At time Best’s distortions of the and the obstinate refusal of the fourth thodoxy in medical history and endocri- historical record seem to amount to a de- party in the research, J.B. Collip, to play nological circles. The Paulesco case was liberate, unethical exercise in falsifi cation ball. Charles Best himself seems to have based on the realization that, in fact, Ban- which verges on scientifi c fraud. In the la- had a deep psychological hunger for re- ting and Best had not produced results ter years of his life Charles Best appears cognition as a discoverer of insulin. Iro- more impressive than Paulesco’s. Indeed, to have had a profound psychological nically, by the end of his life, the view of as Banting had had the honesty to write of hunger for recognition, a serious ego-pro- Banting and Best as insulin’s discoverers the fi rst clinical test of their extract, the blem, many thought, which overwhelmed was beginning to backfi re, because it had results had not been as impressive as tho- his good sense.” established the pre-conditions for other se produced by another predecessor, Zue- historians to deny any Toronto resear- lzer, in 1908. The fi nal irony of the Ban- Glory to Paulescu, 2001 chers a signifi cant role in insulin’s disco- ting and Best myth was that it could not Paulescu was elected posthumously mem- very. meet its own incomplete criteria; ber of the Romanian Academy in 2001. A (…) By 1956 Best was involved in seve- Banting’s and Best’s research was so ba- bronze statue in honor of the Romanian ral projects design to secure his role in dly done that, without the help of Macleod scientist was inaugurated in Bucharest (fi - the insulin adventure. On one occasion he and Collip, and a much more subtle view gure 12), on the occasion of the 80th anni- literally asked the director of the Conn- of the constituents of the discovery of in- versary of the publication of Paulescu’s aught Laboratories to rewrite the history sulin, the two young Canadians would be paper on his discovery of pancréine. To of the discovery of insulin published in fated to disappear form medical history. the ceremony came, among others, Ion one of its handbooks. Asked about the Paulesco affair in Iliescu, President of Romania at that mo- (…) J.B. Collip died in 1965. Through- 1971, Best dismissed all of his and ment, and Sir George Alberti, President of out all of these controversies Collip had Banting’s predecessors with the comment the IDF. After the ceremony, Alberti pu- refused repeteadly to be drawn in or offer that ‘none of them convinced the world of blished an article in Diabetes Voice in written comment. He had always main- what they had. This is the most important which he declared: “I recently had the tained that the truth about the discovery thing in any discovery. You’ve got to con- enormous honour to unveil a large bronze of insulin was to be found in the scientifi c vince the scientifi c world. And we did.’ statue of Nicolae Paulescu in Bucharest publications of those years and that per- The decision of the Nobel Committee in together with the President of Romania. haps someone would be able to piece it 1923 showed that the world was convin- The occasion was the 80th anniversary of together after they had all died. Collip’s ced that insulin had been discovered in the publication of Paulescu’s seminal pa-

381 Av Diabetol. 2010;26:373-82

per on his discovery of insulin (…). My 4. Paulescu NC. Traitment du diabéte. (Documents 18. Pavel I. Le cinquantenaire de la découverte de own view is that Paulescu’s observations établissant la priorité.) C.R: Soc. Roum. Biol. l’insuline. La priorité de cette découverte. Le 1924;49:714-6. Diabète. 1970;18:172. were fundamental to our understanding of 5. Paulescu NC. Quelques reactions chimiques et 19. Pavel I. Comments on the Report of the Special insulin, but the Canadians were the fi rst physiques appliquées à l’extrait aqueux du pancréas Commission of Buenos Aires (IDF) on Summary to treat patients successfully. Suffi cient pour le debarrasser des substances proteiques en Work Leading Up to the Discovery of Insulin. News excés. Arch Int Physiol. 1923;21:71-4. Bulletin of the IDF. 1971;17:74. credit was not given to the oustanding 6. Lancereaux F, Paulescu NC. Traité de médecine. 20. Pavel I, Sdrobici D. The Role of Paulescu in the 34 work of Paulescu”. Vol. IV. Sibiu : Imprimerie de L’Ecole Militaire, Discovery of Insulin. Isr J Med Sci. 1971;8:488. 1930;63-4. 21. Murray I. Paulesco and the Isolation of Insulin. J Conclusion 7. Hagedorn HC, Norman Jensen B. Hist Med Allied Sci. 1971;26:150-7. Blodsukkerbestemmelse. Ugeskr f Ireger. 1918;80: 22. Martin E. Problems with priority in the discovery of We conclude that the bestowal of the 1217-20. insulin. Schweiz Med Wochenschr. Nobel Prize to Banting and Macleod was 8. Hagedorn HC, Norman Jensen B, Krarup NB. 1971;101:164-7. done with very great haste and without Protamine insulin. JAMA. 1936;106:177-80. 23. Ionescu-Tirgoviste C, Iocara S. Documents due deliberation and that Paulescu’s me- 9. Lindsten J. August Krogh and the Nobel Prize to regarding the discovery of insulin and its clinical Banting and Macleod. Nobel Archives. Available on: utilisation. Bucarest: Romanian Academy Publishing rits were forgotten and diminished for a http://nobelprize.org/nobel_prizes/medicine/ House, Ilex Publishing Home, 2005;256. long time. Banting and Best’s article from articles/lindsten/index.html 24. Ionescu-Tirgoviste, Idem., p.270. February 1922 was just a confi rmation of 10. Murray I. The search for insulin. Scot Med J. 25. International Diabetes Federation (1971): Report of 1969;14:286-93. the Special Committee set up to present a written Paulescu’s results. If just only some 11. Paulescu cited in: Pavel I. The Priority of N.C. summary of work leading up to the discovery of people should receive the credit for the Paulescu in the Discovery of Insulin. [Weber M. insulin. News Bulletin of the IDF. 1971;16:29-40. discovery of insulin ought to be Paulescu, Book Reviews]. JHR. 1984;5:101-5. 26. Ionescu-Tirgoviste C. The Re-discovery of Insulin. for his defi nition of the physiological pro- 12. Murlin J. Progress in the preparation of pancreatic Bucarest: Geneze, 1996. extracts for the treatment of diabetes. 27. Dworschak FI, Ionescu-Tirgoviste C. Paulescu and perties of the pancreatic extract and his Endocrinology. 1923;6:519-35. Collip: Insulin’s Unsung Heroes. Bucarest: Editura experimental research on animals, and 13. Funk C. Histoire et consequences practiques de la Ilex, 2008. Collip, who purifi ed the extract and made découverie dés vitamins. Paris: Vigot Frères Edit., 28. Goldner MG. Insulin, in retrospect [Discussion]. Isr J 1924;73. Med Sci. 1972;8:492-3. possible the clinical utilisation in man. ■ 14. Sordelli A, Lewis JT. Insuline. Buenos Aires: Los 29. Wade N. Nobel follies. Science. 1981;211:1404. Institutos Bacteriológicos del D.N. de H. y de 30. James TN. Paulesco. S Afr Med J. 1992;82:123-5. References Histológica de la F.C.M., 1926;7. 31. Waller J. Fabulous Science. Oxford: Oxford 1. Roberts F. Insulin [Letter]. BMJ. 1922;1193-4. 15. Trendelenburg P. Die Hormona, ihre Physiologie University Press, 2002;240-1. 2. Scott EL. Priority in the discovery of a substance und Pharmakologie. Berlin: Julius Springer Verlag, 32. Bliss M. The Discovery of Insulin. Chicago: derived from the pancreas, active in carbohydrate 1934;293. University of Chicago Press, 1982, 2007. metabolism. JAMA. 1923;81:1303-4. 16. Pavel I. The Priority of N.C. Paulescu in the Discovery 33. Bliss M. Rewriting Medical History: Charles Best 3. Nobel Statutes. Retrieved from the Nobel of Insulin. Bucarest: Editura Academiei, 1976. and the Banting and Best Myth. J Hist Med Allied Foundation website. Available on: http:// 17. Pavel I. Correspondence Lending Support to the Sci. 1993;48:253-74. nobelprize.org/nobel_organizations/ Priority of N.C. Paulescu in the Discovery of Insulin. 34. Alberti G. Lessons from the history of insulin. nobelfoundation/statutes.html Bucarest: Editura Academiei, 1986. Diabetes Voice. 2001;46:33-4.

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