Banting Frederick Grant
Banting Frederick Grant
(b. Alliston, Ontario, 14 November 1891; d. near Musgrave Harbour, Newfoundland, 21 February 1941)
Youngest of the five children of William Thompson Banting and Margaret Grant, Banting grew up on a small Ontario farm and was educated in local schools. He entered the University of Toronto. to study for the ministry, but registered as a student of medicine the next year. He was attracted by the study of anatomy. When he reached the clinical years of the medical school program, he formed the resolve that his career was to be in surgery—more specifically, orthopedic surgery, an ambition inspired by C.L. Starr, surgeon-in-chief of the Hospital for Sick children. Banting became a lieutenant in the Canadian Army Medical Corps in December 1916. Arriving in England early in the new year, he was assigned to a special hospital at Ramsgate, planned as an orthopedic hospital; one of the members of the staff was W.E. Gallic, who succeeded Starr in the chair of surgery at Toronto. Banting was son sent to France; near Haynecourt, in September 1918, he suffered a shrapnel wound in the right forearm. For his conduct in action on this occasion he was awarded the Military Cross.
After the war Banting resumed his work in orthopedic surgery under Starr, but after one year he began his first and only attempt at surgical practice, at London, Ontario . His hoped-for practice was slow in growing, and since London was the seat of Western University (now the University of Western Ontario), Banting became a demonstrator at its medical school Here, for nearly a year, he taught anatomy and physiology. Under the direction of F. R . Miller, distinguished neurophysiologist, he made his first foray into medical research, carrying out with Miller experiments on the excitability of the cerebellar cortex. On 30 October 1920, Banting conceived an idea in another area of physiology . The following day he was to talk to his students on the function of the pancreas . Stopping in the medical school library, he looked at the November copy, just received, of Surgery, Gynecology and Obstetrics, in which the first article was “The Relation of the Islets of Langerhans to Diabetes, With Special Reference to Cases of Pancreatic Lithiasis,” by Moses Barron . Reviewing the literature, Barron had written, in part :
Arnozan and Vaillard ligated the pancreatic ducts in rabbits and found that within twenty-four hours the ducts became dilated, the epithelial cells were desquamated, and there were protoplasmic changes in the acinic cell… . At the fourteenth day a great deal of the parenchyma had been replaced by connective tissue . . Ssobolew ligated the ducts in rabbits, cats, and dogs He found a gradual atrophy and sclerosis of the organ with relatively intact islets and no glycosuria.
More evidence to the same effect was cited, and Barron pointed out the similarity between the degeneration that occurs in the pancreas following experimental ligation of the ducts, and the blocking of the ducts by gallstones. This meant that tying of the pancreatic ducts caused atrophy of all but a small portion of the gland, the islets of Langerhans (named by Laguesse in honor of Paul Langerhans, who first described them in a thesis presented in 1869). These islets were already thought to be the source of a hypothetical diabetes-preventing hormone, a hormone necessary for the utilization of sugar in normal metabolism. This was inferred from the absence of glycosuria after the tying off of the ducts and the atrophy of most of the gland, coupled with the important discovery by Mehring and Minkowski, in 1889, that removal of the entire pancreas from a dog was followed by all the symptoms of severe diabetes, terminating in death from inanition in the course of two or three weeks. Apparently the part of the gland that prevented the disease was the part that remained almost intact many weeks after ligation of the ducts.
Attempts to treat diabetes by oral administration of fresh pancreas or pancreatic extracts (as thyroid preparations were used when the thyroid was deficient) had all been unavailing. Neither were pancreatic extracts useful when injected subcutaneously or intravenously. Taken by mouth, such preparations might be presumed to be destroyed by digestive processes. Extracts made from the whole gland might be thought to be destroyed during extraction by the powerful ferment originating in the acinar tissue. This was Banting’s hypothesis. In the small hours of the morning he wrote in a notebook, “Tie off pancreas ducts of dogs. Wait six or eight weeks Remove and extract.”
Banting’s conception was not altogether correct, as later studies revealed. The digestive ferments of the pancreas must be activated in the bowel before they attain their destructive power; also, the islet tissue of the gland is affected, although much more slowly than the acinar tissue, by ligation of the duct. Neither was the concept altogether new. As early as 1906 Lydia de Witt, basing her experiments on the observations of Schulze, Ssobolew, and others, made extracts of the islet tissue of cat pancreas and found that they had no digestive powers but possessed distinct glycolytic properties. This work was by no means the first attempt to make use of pancreatic extracts. for Minkowski had conceived the idea and many attempts had been made to prepare such extracts. In 1908 Zuelzer, using an alcoholic extract of pancreasm, obtained favorable results in five cases of diabetes mellitus but unfortunately toxic results caused the work to be discontinued.
Meantime, Kleiner, Murlin, E. L. Scott, and Paulesco carried out physiological investigations on laboratory animals. In 1912 Scott prepared alcoholic extracts of the pancreas that were partially successful in treating experimental diabetes. He even attempted the de Witt–Banting procedure of preliminary duct–tying; probably because of excessive tightness of ligatures and consequent recanalization of ducts, complete atrophy did not take place. At this point Scott turned his energies to attempting to obtain more precise methods of estimating blood sugar. In 1913 Murlin prepared alkaline extracts of the pancreas and of the small intestine, and demonstrated that they reduce the elevated blood sugar of diabetic dogs. He found, however, that this result could be obtained by the administration of alkalies alone, and the investigation was abandoned. After the war Murlin resumed his investigations and found that the administration of perfusates of the pancreas was followed by an elevation of the respiratory quotient. Thus he could restore to the diabetic animal some of its lost power of burning carbohydrates.
F.R. Miller, deeply involved in neurophysiological research, advised Banting to put his idea before J. J. R. Macleod of the University of Toronto, a leading authority on carbohydrate metabolism. It is interesting that whereas Artur Biedl (The Internal Secretory Organs, 1913) had stated that the existence of an internal secretion of the pancreas was absolutely proved by Forschbach’s parabiotic experiments, Macleod, in the latest edition of his textbook of physiology, asserted that there was as yet no proof of the existence of a pancreatic internal secretion, nor any way as yet of disproving the theory that the islet cells were detoxification centers. Despite a great deal of activity following the work of Mehring and Minkowski more than thirty years earlier, the situation was still altogether unclear. It is easy to see why Macleod did not welcome Banting’s work as a revelation. Banting himself later remarked that if he had been thoroughly acquainted with the literature before beginning his research, he might never have begun. Macleod nevertheless agreed to give him a place to work for eight weeks, an undergraduate assistant, and an allotment of ten dogs. With tahis measure of support, Banting resigned his position at Western University and returned to Toronto.
A recent graduate, C.H. Best, who had just obtained his bachelor’s degree in physiology and chemistry, joined Banting in mid-May 1921 With another senior student, E.C. Noble, he had been engaged in experimental studies of piqûre (puncture), or Claude Bernard, diabetes. Bernard had discovered that a lesion of the floor of the fourth ventricle was followed by excessive secretion of urine that contained an abundance of sugar. In their work on this phenomenon, Best and Noble had acquired certain special knowledge of carbohydrate metabolism and a number of useful skills in the performance of the necessary tests. Best was the first to assist Banting in the new project dealing with the pancreas, and Noble subsequently joined them.
Ligation of the pancreatic ducts of a number of dogs seemed relatively simple. Next came a more difficult task—to depancreatize. They tried, but later abandoned, the Hédon procedure of removing the pancreas in two stages, and adopted a technique, which Banting developed, for complete pancreatectomy in one operation. While this was going forward, the necessary weeks elapsed for the evaluation of the dogs in which the ducts had been tied. but unhappily the pancreas had not degenerated in most of them. This, too, proved to be technical surgical problem. It was necessary to operate on all the dogs a second time, and although some were found to have fairly degenerated glands, It was decided to leave these another two weeks. Some ligatures had been too loose to black the ducts, other so tight that they caused recanalization. Therefore, in some cases Banting applied two or three ligatures at different tensions. It was 27 July before both a depancreatized dog and a duct-tied dog were ready. The signs, symptoms, and biochemistry of experimental diabetes had become familiar. Now a degenerated gland was chopped into small pieces in a chilled mortar and frozen in brine. the mass was ground up and about 100 cc. (a little more than three ounces) of saline solution were added. Of this extract 5 cc. Were administered intravenously to the depancreatized dog. Samples of blood were taken at half-hour intervals and analyzed for sugar content. The blood sugar fell from 0.200 to 0.11 percent in two hours, and at the same time the clinical condition of the dog was much improved.
Thus encouraged, the experimenters not only repeated and extended this work, gradually eliminating possible sources of error by means of control experiments, but also tried other techniques, such as that of the “exhausted gland,” for preparing the extract. Instead of the duct-tied gland they used a pancreas stimulated to the point of exhaustion t, y continued injection of secretin. A classroom experiment performed by Ranting only a few years previously was thus repeated in a modified form. This, like the first method, was clearly a very limited means of production. Believing that the fetal pancreas contains relatively more islet tissue than the adult pancreas, Banting and Best obtained fetal glands from a Toronto abattoir and extracted the active principle from them, providing it at no expense to the laboratory and in quantities that permitted repeated trials and various extractions. This was the third method of preparing what they then called “isletin.” It was based on the same fundamental idea as the others—the avoidance of trypsin—and while it made use of a more plentiful source of the new hormone that the other two methods, it, like them, did not appear capable of producing adequate amounts.
The work did not proceed in a perfectly orderly sequence, beginning with the first method and ending with the whole-gland extractions. As early as 17 August 1921, studies were made of the effect of whole, fresh gland extracts, and a page from the first notebook shows that on this date a very definite fall in blood sugar was obtained with an extract made up in Ringer’s solution and with one that had been acidified. An effective product was secured by extraction with alcohol and acid, but the result was hard to reproduce until the right PH was used in extraction. Subsequent purification also presented problems, and relative success at an early stage was the consequence of the more or less accidental precipitation that followed attempts to eliminate trypsin, which in fact was not activated. The work on the whole gland was in any cas suspended for a time, while other courses were followed. When Macleod returned from a summer in Scotland, the attempt had not only been resumed but a highly potent extract had also been prepared.
Nevertheless, much remained to be done, and Macleod enlisted the aid of the biochemist J. B. collip, who took up afresh the task of purification. Fractionation had previously been discontinued at 65 percent alcohol because at this point the trypsin, for which tests were performed, had been eliminated. Collip stepped up the percentage of alcohol and removed the greater part of it, producing a practical extract. He himself said that what he added to the team effort, beginning at this point, was “only that which any well-trained biochemist could be expected to contribute.” There is, nonetheless, a practical sense in which it is true that Collip’s work marked the first major advance beyond the stage attained by Zuelzer some fourteen years earlier. A relatively pure extract (not so good as later preparations) resulted from Collip’s fractional precipitation method, making possible the first clinical trials. Further contributions were made by Fitzgerald, Defries, E. L. Scott, Noble, Hepburn, and Latchford, as well as by Colip and by best. Much of this work was done in the Connaught Laboratories at the University of Toronto. The next phase, however, leading toward the production of insulin in commercial quantity, utilized the talents of a number of American scientists. For instance, the idea of using strong acid (Banting and Best had originally used weak acid) did not originate in Toronto. but in the United States, with Walden and Shaffer.
In January 1922 the first clinical trials of insulin (a name introduced by Macleod but suggested as early as 1910 by Sharpey-Schafer) were carried out in the Toronto General Hospital on a fourteen-year-old boy who had diabetes. From the beginning there was a marked fall in blood sugar and slightly lowered sugar excretion, but the extract then used was so unsatisfactory, by later standards, that no clinical benefit was evidenced. Daily injections soon began, resulting in immediate improvement. Much less sugar was excreted, the acetone bodies disappeared from the urine, and the boy became brighter and more active. Then, for ten days, no insulin was given. During this time sugar again appeared in the urine in large amounts, along with traces of acetone. Administration of insulin in smaller doses again resulted in lowered sugar excretion and disappearance of acetone from the urine.
The use of insulin soon became the chief resource in the treatment of diabetes, but it was early realized that diet and insulin would be complementary methods of reaching the same end. Had insulin been discovered before the great work of Frederick M. Allen was accomplished, it would not have been possible to use it so promptly and with such intelligent discretion. W.R. Campbell and A.A. Fletcher were the clinicians assigned by Duncan Graham to work out the many problems presented to their colleagues in the era of therapy that was just beginning. The earliest reports bore the names of Banting. Campbell, and Fletcher, but Banting did not participate in writing them. On one side of the street he was “no physiologist,” “no chemist”; on the other side he was “no clinician.” This situation he often found difficult.
Meantime, production and purification problems continued to demand attention, and the task of commercial production had to be solved. The Eli Lilly company was able, by November 1922, to effect a very substantial purification and concentration of the product by developing the isoelectric method of precipitation. Work carried out there and in the Cannaught Laboratories provided insulin for 250 clinicians by January 1923. J. J. Abel of Baltimore succeeded in 1926 in preparing insulin in crystalline form, and D. A. Scott of Toronto introduced the fundamental method of doing so through the employment of zinc. H. C. Hagedorn, the Danish investigator, was able to prolong the effect of insulin by adding protamine, Scott once again demonstrating that in the absence of zinc the change would not take place and there would be little or no prolongation of action.
Before the decade was out, Banting had turned to other areas of research. His almost instantaneous worldwide fame was first attested by the “Insulin rush,” the descent on Toronto of diabetic patients from many countries. Once insulin had became more generally available, this impetus waned, but the celebrity was perhaps even greater. The Nobel Prize in physiology and medicine was awarded to Banting and Macleod in 1923; Banting immediately divided his share equally with Best, and Macleod divided with collip. In the same year Banting was awarded an annuity by the Canadian parliament. He became an honorary member of most of the major scientific and medical societies of the world, and award followed each other in rapid succession. In 1930 the Banting Institute of the University of Toronto was opened, and Banting, who had been appointed professor of medical research in 1923, spent the rest of his life as director of the Banting-Best Department of Medical Research. His later research, before World War II, was devoted largely to cancer, coronary thrombosis, and silicosis.
Before, and more especially during, World War II, Banting was the leading figure in Canada’s governmental support of medical science. He was chairman of the Medical Research committee of the National research Council and chairman also of the Associate Committee on Aviation Medical Research. Much of the wartime activity of the institute was devoted to research in this sector. An important part of Banting’s own work consisted in establishing and maintaining research liaison with British colleagues through visits to England. In February 1941 he set off on such a journey and met his death in an air crash in Newfoundland.
Among Banting’s papers are “Effect on Pacreatic Extract (Insulin) on Normal Rabbits,” in American Journal of physiology, 62 (Sept. 1922), 162–176; “Internal Secretion of Pancreas,” in Journal of Laboratory and Clinical Medicine, 7 (Feb. 1922), 251–326, written with C. H. Best; “Insulin in Treatment of Diabetes Mellitus,” in Journal of Metabolic Research, 2 (Nov.-Dec. 1922), 547–604, written with W. R. Campbell and A. A. Fletcher; and “Pancreatic Extracts in Diabetes,” in Journal of the Canadian Medical Association, 12 (Mar. 1922), 141–146, written with C. H. Best, J. B. Collip, W. R. Campbell, and A. A. Fletcher. A group of important early papers by Banting, Macleod, collip, J. Hepburn, and E. C. Noble is in Transactions of the Royal society of Canada, 3rd ser., 14 , Sec. 5 (1922).
Biographies of Banting are Lloyd Stevenson. Sir Frederick Banting (Toronto, 1946; 2nd ed., rev., 1947), with a fuller bibliography in the later edition; and Seale Harris, banting’s Miracle: The Story of the Discoverer of Insulin (Philadelphia, 1946).
Lloyd G. Stevenson