maddeningly imprecise because of the The History of Insulin difficulty of measuring the physiological effect of various interventions. The secret MICHAEL BUSS, PHD of the pancreas could not be uncovered without better tools. The development of methods that permitted rapid serial readings of THE PREHISTORY OF INSULIN — many or D.A. Scott in the U.S., were, in blood glucose levels was a precondition Insulin received its name before it was fact, administering active insulin. But it for the eventual breakthrough. By 1919, discovered. In 1889 in Germany, Oskar was impossible to present clear evidence an advanced researcher, Israel Kleiner, Minkowski and Joseph von Mering ob- of benign hormonal action because of so working at the Rockefeller Institute, was served that total pancreatectomy in ex- many toxic contaminants in their prepa- able to show that intravenous injections perimental animals leads to the develop- rations. Beginning in 1906, for example, of aqueous solutions of ground fresh ment of severe diabetes mellitus, and Zuelzer occasionally was able to reduce pancreas had a regular hypoglycemic ef- began the speculation that a mysterious glycosuria and acidosis in human dia- fect. Only a pattern of slight toxic effects substance produced by the pancreas is betic individuals; but the results were of his extracts prevented him from at- responsible for metabolic control (1,2). accompanied by such severe, life-threat- tempting the administration to human Supporting evidence for the hypothesis ening reactions that workers in diabetic individuals, which, if successful, gradually mounted: It included observa- Minkowski's laboratory dismissed his would be judged real proof of discovery. tions of the relationship between diabe- work as inconclusive and dangerous (4). Unfortunately for Kleiner, he left the tes and damage to the pancreatic cellular Even so, there was so much im- Rockefeller Institute that year for a uni- system known as the islets of Langer- pressionistic evidence supporting the ex- versity that did not have the resources to hans, as well as the discovery and eluci- istence of a pancreatic internal secretion, support major animal research and he dation of the physiology of internal or emanating from the islet cells, that, in abandoned the work. Other investiga- endocrine secretions. By the first decade 1909, a Belgian investigator, J. de Meyer, tors, such as Paulesco in Romania, were of the 20th century it was widely hypoth- proposed it be named "insuline" (5). In making very slow progress because of esized that an "internal secretion" of the 1916, E.A. Schafer in Britain indepen- inadequate funding and hopelessly prim- pancreas controls carbohydrate metabo- dently suggested the same name (6). itive experimental techniques (7,3). lism (3). Much truth is in the notion, again clari- But no one could demonstrate fied by hindsight, that insulin was sitting that the internal secretion actually ex- there waiting to be isolated or "discov- BANTING'S RESEARCH— In 1920, isted. Minkowski himself was the first of ered." It almost certainly would have Frederick Grant Banting was a 22-yr-old innumerable researchers and physicians been found during the second decade of physician and surgeon attempting to who administered pancreas solutions, the twentieth century, but the work of launch a general practice in the small orally and by injection, to diabetic ani- Central European researchers, such as Canadian city of London, Ontario. With mal and human subjects in the hope of Zuelzer and the Romanian physiologist, time on his hands, he accepted a dem- replacing the missing substance. Results N.C. Paulesco, was utterly disrupted by onstratorship in surgery and anatomy at were decidedly mixed and inconclusive. World War I. London's Western University. On Mon- Experiments in which extracts of the On the other hand, careful stu- day, 31 October, he had to talk to phys- pancreas appeared to reduce glycosuria dents of carbohydrate metabolism knew iology students about carbohydrate me- often were unrepeatable or marred by that there might be other explanations tabolism, a subject with which he was strange patterns of fever and other reac- (relating to the nervous system or other not particularly familiar. Late Sunday tions. With the wisdom of hindsight, we pancreatic mechanisms) for the relation- night, as part of his preparation, he read now know that many of these experi- ship between pancreatic failure and dia- the leading article in the November issue menters, such as Georg Zuelzer in Ger- betes. And experimentation had been of Surgery, Gynecology and Obstetrics, a discussion of "The Relation of the Islets of Langerhans to Diabetes with Special Reference to Cases of Pancreatic Lithia- From the Department of History, University of Toronto, Toronto, Canada. sis," by Moses Barron (8). Barron's unre- Address correspondence and reprint requests to Michael Bliss, PhD, Department of History, markable report stimulated a train of University of Toronto, Canada, M5S 1A1. thought in Banting's mind that caused him, sometime after midnight, to jot DIABETES CARE, VOLUME 16, SUPPLEMENT 3, DECEMBER 1993 Bliss down this idea: "Diabetus Ligate pancre- glycemic effects. When Macleod returned reductions of glycemia and glycosuria, had atic ducts of dog. Keep dogs alive till in September, he urged Banting and Best no effect on ketoacidosis or the patient's acini degenerate leaving islets. Try to iso- to repeat and amplify their experiments. subjective presentation, and resulted in the late the internal secretion of these to re- He discouraged Banting from venturing formation of a sterile abscess. "These re- lieve glycosurea" (9). down the grafting road and, after some sults were not as encouraging as those ob- Banting enjoyed dabbling in re- friction with the young doctor, supplied tained by Zuelzer in 1908," Banting later search and was unhappy in his fledgling more space and dogs. wrote. Treatment was immediately discon- practice. He returned to his alma mater, By December, Banting and Best tinued (11). the University of Toronto, and ap- had accumulated further evidence that On January 23, a new series of proached J.J.R. Macleod, professor of their extract often reduced the blood glu- injections began. Thompson responded physiology, with a proposal to engage in cose of diabetic dogs. After experiments immediately. His glycosuria almost dis- summer research to test his "Diabetus" with fetal calf pancreas and then with appeared, his ketonuria did disappear. idea. Macleod, a noted expert in carbo- fresh beef pancreas, Banting found he His blood glucose dropped to normal. hydrate metabolism, doubted that a nov- could dispense with the cumbersome He was brighter and stronger. For the ice could succeed where masters had duct-ligation/atrophication procedures first time in history there was clear, un- failed. However, he may have seen some (though he never quite realized that in ambiguous evidence that scientists were value in Banting's hypothesis that the doing so he had disproven his original able to replace the function impaired in internal secretion was somehow being hypothesis of an antagonism between the diabetes. This was the demonstration of nullified in pancreatic extracts by the ac- pancreatic secretions). Because of Best's the isolation of the internal secretion of tion of the externally secreted digestive inexperience, Macleod and Banting de- the pancreas that the world had awaited ferments. By ligating the pancreatic cided to addJ.B. Collip to the research for 30 years. ducts, Banting hoped to induce atrophi- team. Collip, a biochemist from the Uni- It wasJ.B. Collip, the biochemist, cation of the acinar cells and eliminate versity of Alberta, was visiting Toronto to who had produced the successful ex- the external secretion, thus liberating the work with Macleod and had expressed tract. He had developed a method of internal secretion. Banting's training as a an interest in the pancreas work. extraction that involved changing the surgeon would serve him well in such The first presentation of the To- concentrations of slightly acidic alcohol research; it also predisposed him to an ronto research, read at the New Haven solutions of chilled beef pancreas (it is interest in grafting experiments as the meeting of the American Physiological not clear which members of the research second stage in his work. In an age be- Association on 30 December 1921, was team first suggested using acid alcohol) fore the rejection phenomenon was un- not well received. In their inexperience until he was able to precipitate out the derstood, several experts had suggested and haste, Banting and Best had been active principle relatively free from toxic pancreatic grafts or transplants as a sloppy and muddled. Their lack of data contaminants. It was a major improve- promising direction in the search for the on the side-effects of their extracts, for ment on Banting and Best's methods, the elusive secretion. With surplus facilities example (which were almost certainly single most important step forward in at hand in his very well-equipped labo- pyrogenic, as others had been), meant the discovery process (12,13). ratory, Macleod agreed to give Banting that it was difficult to convince anyone Unfortunately, the triumph was space, dogs, and a student assistant for a that their findings were better than those marred by bitter personal rivalries; summer "fling" at the problem. One of of Kleiner and others. The team's most Banting and Best believed that Collip and Macleod's summer students, Charles recent experiments, notably evidence Macleod were conspiring to take over Best, won a coin toss to see who would compiled by Collip on the extract's ap- control of the work and credit for its start work with Banting (3). parent restoration of glycogen mobiliza- success. Physical and verbal confronta- Banting began his research, as- tion in the liver and its ability to clear tions often disrupted the research.