A young American, Israel Kleiner, became interested in pancreatic extracts and blood sugar while working with S.J. Meltzer at the Rockefeller Institute during the time 01 Allen's researches. Pioneering studies were being done there on the speed with which injections of sugar normally disappeared from circulation (that is, were assimilated by the system). By contrast, in diabetic animals much of the sugar continued to circulate. But when an emulsion of pancreas was mixed and injected along with the sugar solution, the diabetic animal handled it almost normally. Observing this, Kleiner and Meltzer began experiments to see how pancreatic extracts would affect the ability of depancreatized dogs to deal with their system's own excess sugar. They reported very promising preliminary findings in 1915, but their work was interrupted by the war. In 1919 Kleiner returned to it, running many more experiments. Late in 1919 he published his findings in the Journal of Biological Chemistry. Of all publications before the work at fishdistilled water. These were slowly injected intravenously into depancrea- tized dogs, with blood sugar readings taken before and after infusion and at later intervals. The 1919 experiments were much easier to do because the new blood testing method (Myers and Bailey's modification Of Lewis and Benedict's) required much smaller samples. In both the 1915 and 1919 series of experiments the results were the same and were important: without exception in sixteen experiments the pancreatic extract caused a decline in the blood sugar Of diabetic dogs. It was Often a very sharp decline, sometimes more than 50 per cent. Kleiner had not used any chemicals in the preparation of his extract because some of Murlin's recent work suggested that the chemicals them- selves, especially alkalis, could artificially reduce blood sugar. He ran checks on the hemoglobin content of his dogs ' blood to make sure that the effect he was getting was not just a result of the injected liquid diluting the blood, and checks on the urinary sugar to make sure some strange washing out" effect was not taking place. Emulsions made from other tissues were injected to see if the effect m ight be something any ground-up tissue could produce. They caused no significant change in the blood sugar (that they did sometimes cause a reduction in glycosuria indicated the weakness of older methods: " the mere reduction of glycosuria is no proof of a beneficial effect of any agent," Kleiner notcxl with emphasis).Many investigators have recognized that the best evidence for the in- ternal secretion theory of the origin of diabetes would be an antidia- betic effect of a pancreatic preparation, administered parenterally. The experiments just described show that such a result has been ob- tained.. His controls had been impressive, his follow-up discussion was a beautiful piece of scientific writing. There was one problem, he reported: the slight toxic symptoms, usually a mild fever, associated with the extract. "I'hese symptoms were not particularly marked, and the overall result of the work "indicates a possible therapeutic application to human beings." Before this happened, Kleiner suggested, further knowledge should be obtained. Many other tests could be run. ' 'Finally, the search for the effective agent or agents, their purification, concentration, and identification are suggested as promising fields for further work." Kleiner did not doany of that further work. In 1919 he left the Rockefeller Institute, and did not return to the problem. The only published comment Kleiner ever made on why he did not continue "and attempt to isolate the antidiabetic factor" was that it was "a long story." As far as can be determined, the university he went to in 1919 did not have the resources torupted by the war was Nicolas Paulesco, professor of physiology in the Romanian School of Medicine in Bucharest. Paulesco was already a physiologist of substantial achievement and distinction when he returned to an interest in the internal secretion of the pancreas first developed during his student years in Paris in the 1890s. In 1916 he began experi- menting with extracts. The Austrian occupation of Bucharest and then the postwar turmoil in Romania delayed his research for four years. Paulesco resumed his experiments in 1919 and published his first results in 1920 and 1921 Like Kleiner, Paulesco concentrated on measuring the impact of his extract on blood sugar. He, too, reported spectacular decreases in blood sugar after intravenous injections of a solution of pancreas and slightly salted distilled water. He also reported a decrease in urinary sugar and in the presence of ketones in blood and urine. He checked for dilution, controlled with non-pancreatic extracts, and induced fever in his dogs to show that fever itself (which his extract often caused) would not cause a reduction in the sugar content of the blood or urine. He also tried his extract on a normal dog and found that here, too, it caused a reduction in blood sugar.biologie between April and June 1921. A summarizing paper was received by Archives ;nternationales de physiologie on June 22 and published on August 31. Paulesco had done fewer experiments than Kleiner, not least because he must have been hampered by the very primitive techniques he was using for measuring blood sugars. These techniques also produced some remarkably low figures, almost certainly based on error. Unlike Kleiner, Paulesco did not set his work and its implications in the context of past and current knowledge. On the other hand his results looked very good, his experiments were more varied than anyone else's had been, and he clearly intended to persist. In his August 1921 paper he mentioned that it would be followed up by "une méthode de traitement du diabéte, de I 'obesité et de I 'acidose, méthode qui est issue de ces reserches expérimen- tales. "40 In Germany at the same time, Georg Zuelzer was still trying to find a drug company to take up production of his extract, acornatol. No one in that devastated country was very interested. VII In the conclusion to his 1919 study, even while underlining the limits of his diet treatment, Frederick Allen had tried to be optimistic. "The knowl-
1918 than some peacetime surgeons would see in a lifetime. He was also popular with the sick children at the hospital. But he was not able to win a permanent position at the Hospital for Sick Children. "Surgeons were very plentiful in *Iöronto. It was my greatest ambition to obtain a place on the staff of the hospital, but this was not forthcoming."l Instead, perhaps on the advice of C.L. Starr, and knowing that Edith would be teaching high school in a nearby town, Fred decided to set up a practice in the city of London, Ontario, about 110 miles west of Toronto. Since returning from the war he had been anxious to marry. He had come home with the veteran's usual minor vices - drinking, swearing, and heavy smoking; but he was still enough of a Victorian boy to believe, with Edith, that a wedding would not be seemly until he was earning money of his own. No self-respecting male Canadian in 1920 would live on his wife's earnings. Fred Banting was twenty-eight years old, a veteran of the world war, a well-trained doctor. It was surely time to settle down, make some money, get married, and have a family.5 1 On July l, 1920, Banting opened an office in a house he had bought on a
On July l, IYZO, Bantmg opened an otllce In a house he had bought on a corner in a residential area of London. He must have known it would take time to build up a practice in a strange city, with whose doctors he had no ties and in a profession which forbade advertising. Even so, he was not prepared for the depressing reality of his situation. Day after day in July, Doctor Banting6 kept his standard office hours, two to four in the after- noon, seven to nine in the evening, six days a week. He saw no patients at all. Not one. The first customer finally came on July 29. The patient's ' 'illness" was his friends' thirst for liquor in a province where prohibition held sway. Only doctors could dole out alcohol, and then solely for medicinal purposes. "He was an honest soldier," Banting wrote, "who had friends visiting him and he wanted to give them a drink. I gave him the prescription and considered myself rather highly trained for the barkeeping business." Dr. Banting's July income was $4.*7 Patients started to dri bble in during August, but business was miserably slow. Already in debt from his medical education, Banting had borrowed money from his father to buy the house in which he practised and lived. Every week of medical practice drove him deeper in debt. He tried to save money by cutting out motion pictures and often cooked his meals on the bunsen burner in his dispensary. To while away the time, Banting built a garage and started dabbling with oil paints. He also tinkered with the worthless old fourth- or fifth-hand car he had bought - having paid much