Estimates indicate that approximately 1.5 million Canadians rely on daily insulin injections to survive. Another 75, 000 may have some form of diabetes and not know it. Over 90% of diabetics have one or more modifiable risk factors -- smoking, obesity, hypertension. Diabetes is a chronic disorder in which the pancreas does not produce enough insulin to meet the body's needs or the body cannot properly use the insulin that is produced. Insulin is an important hormone for the metabolism of complex carbohydrates(sugar) in the body. When the pancreas fails to provide the body with insulin, these complex carbohydrates (sugar) build up in the blood stream. Hence, the food energy consumed each day cannot be used by the body. There are a series of symptoms associated with diabetes which include: frequent urination, unusual thirst, changes in appetite, unexplained weight loss, extreme fatigue, irritability, abdominal cramps. There are two types of diabetes: Type I & Type II. Type II represents a milder form of diabetes that often has no symptoms and is only discovered during a medical check-up. More often than not, Type II diabetes can be controlled by carefully monitoring dietary food intake. Type I diabetes requires daily injections of insulin to carefully control blood sugar levels to normal ranges. To date, there is no known cure for Type I (insulin dependent) diabetes. Insulin is not a cure for diabetes, as well, several complications due to the disease can develop. Currently in Canada, diabetes is the leading cause of death by disease. Diabetes related complications could appear as any one of the following: blindness, cardiac deficits, renal failure, non-injury related amputations and erectile dysfunction. The successful management of diabetes relies on education of the patients that requires commitment and self-responsibility, unfortunately 30 % of people with Type I diabetes and 70 % of the people with Type 2 never receive this information.
The text that follows is a short history by Dr. G. W. Manning. Manning worked for Fred Banting at the Banting Institute in Toronto. This short history was presented to the Banting Memorial High School in Alliston on December 1980. - Ed.
Banting was the born on a farm near Alliston, Ontario on November 14, 1891. He attended high school with his cousin Fred Hipwell. Their parents wanted them to study Theology. Both decided medicine was more to their interest than Theology. Hipwell eventually became a specialist in internal medicine and later did much of the clinical work on insulin. Banting, who enlisted in the Officers Training Corps when World War I was declared, graduated in Medicine in December 1916. He served with distinction during the First World War, was severely wounded and for his devotion to duty was awarded the Military Cross. Banting's chief interest following the war was Pediatric Orthopedics. He trained with the late Dr. Clarence Starr at the Hospital for Sick Children in Toronto and then moved to London in the summer of 1920 and setup practice with the late Dr. W. P. Tew. His medical practice was, indeed, very poor and Banting took on a position as demonstrator in Physiology at the University of Western Ontario. In October 1920, Banting was to give a lecture on the pancreas and from his reading and preparation for this paper came up with the idea of ligating the pancreatic duct and allowing the gland to degenerate. The idea came to him at 2:00 AM on October 31. Another researcher in 1889 (Minkowski) had suggested that if the pancreatic gland were minced up, extracted and injected into diabetic dogs it might control to disease. He, apparently, failed to recognize that acinar tissue of the pancreas destroyed at the internal secretion of the islet cells. The ligation of the pancreatic duct, allowing the pancreas some 6 weeks to degenerate, was the concept that Banting conceived and that led to the discovery of insulin. Banting was most excited and enthused over this and approached Dr. Miller, Professor of Physiology at the University of Western Ontario, who felt the facilities, space etc. were not available at Western and he advised him to approach professor J.J.R. MacLeod at the University of Toronto.
MacLeod was not impressed with Banting’s idea. He was convinced that it would not work as this had been tried many times before. He did, however, reluctantly give Banting space and facilities for an eight week summer period to carry out his proposed experiments. He also provided an undergraduate summer student Mr. Charles Best to assist Fred.
Sir Frederick Banting was a humble and a truly great man. He was a soldier, scientists, a gentleman (with a temper), and faithfully dedicated to research right up to the time of his death is death on Feb 21, 1941. Regarding his early life, of which I no little except from what I have been told by his friends and colleagues, I will not attempt to review. Sir Frederick Banting was a kind man and most helpful to all who worked with him. He preferred to be called Dr. Banting not Sir Frederick for he was not a man of pomp and splendor. He spent his life in the laboratory and with the completion of the insulin program to final clinical success, turned his interests to work on malignancy.
Banting was not a joiner, played no golf, few clubs nor was he interested in pursuing further degrees beyond the M.D. He has, of course, received numerous honorary degrees and other honors including the Nobel Prize. He, however, did have the hobby of painting, and was a great friend of A. Y. Jackson and made trips with Jackson to Northern Ontario. He completed over 240 paintings, some 38 sketches and wood carvings. These were similar to Jackson's work and the Group of Seven. Jackson has published a short book on "Banting" as a "Painter" with many black and white illustrations of Banting's work.
Banting had the initial ideas and thoughts of the possibility of insulin while working in London, Ontario. From there, as is well-known, he proceeded to Toronto where with the permission and encouragement of MacLeod and carried out the early experiments with the assistance of Charles Best, then a medical student, and later with the excellent work of Biochemist Collip, finally developed the miracle of insulin which has prolonged and saved allies of literally millions of diabetics throughout the world.
Although the insulin story is well covered by Stevenson, Bender, Feasby, Shaw and others it would seem fitting that a short review of events leading to the discovery of insulin should be included in this short history of Banting's research and his contributions in the general field of medical research. Having been provided with a small laboratory at the University of Toronto, and some eight weeks' time to carry out the experiments proposed by Banting to isolate a substance from the pancreas for the treatment of diabetes, he and Best began their first task, a study of the literature concerning the pancreas in early May of 1921. They found that diabetes was well known to even the ancient Egyptians, Hindus, Chinese and the Greeks. They also discovered that Minkowski and Von Mering in 1899 had produced diabetes in dogs by removing the pancreas. Another researcher had concluded that it was not absence of the total gland but only that portion known as the Islets of Langerhans that led to the disease. The literature, apparently, had recorded some half century of failures to find an anti-diabetic substance. Banting and Best, however, refused to be discouraged by these findings from the literature and were soon hard at work seeking to prove Banting's theory.
The lab in which they were to work was a small room on the second floor of the old medical building in Toronto which had not been in use for some time and required cleaning and refurbishing with the simple glassware and equipment available at that time. This they did themselves without assistance. The room was equipped with only the basic apparatus found in the students lab such as a centrifuge, a simple balance, bunsen burners, test tubes, syringes, some medical instruments, a sterilizer and a refrigerator. The principle that Banting had conceived in London, Ontario was to ligate the pancreatic duct, allow for some weeks for the acinar or pancreatic tissue to degenerate and then remove the gland and make an extract of the remaining islet tissue and inject this into dogs who previously had had their pancreas removed, thus producing diabetes. Soon after the literature review in May of 1921 Banting and Best commenced their work with enthusiasm to prove Banting's theory on the presence of an anti-diabetic substance within the pancreas. It was planned that Banting would perform the surgery and that Best would do the biochemical tests for sugar in the blood and urine. Of course, they would assist each other in every possible way and share the work of caring for the experimental animals. Best assisted Banting in this surgical removal of the pancreas and other surgical procedures required in the experiments. Banting operated on several dogs, tying the pancreatic ducts and from other dogs he removed the pancreas and the effects on blood and urine in addition to the welfare of the depancreatized dogs were studied. After some 6-7 weeks, two of the dogs, which had their ducts tied, were anaesthetized, and to their great disappointment it was found that the pancreas had not degenerated. Careful examination had shown that the ligature was still present in any sort of bulbous sac and that the pancreatic duct had not been sufficiently occluded and the pancreas had not degenerated. This was a great disappointment and a considerable loss of time to them. They, therefore, operated on all the duct tied dogs as second time to exert particular care has to the tensions on the ligature. For the ligature that was too tight produced gangrene and the one that was to lose failed to block the duct. This was a great disappointment for some 7 weeks of allotted time had passed. It was obvious that they could not possibly obtain a positive result in the the one more week allotted to them, but they were determined and asked for more time, which was granted. MacLeod had not yet returned from Europe. Neither Banting or Best received any salary for the summers work and Banting had been forced to sell his Ford car to pay expenses. Thus, they had to begin practically all over again and both spent practically all their time in the laboratory looking after the animals and intending to their care, feeding, etc., for they had no other assistant to help them with this work. During this period, the dogs were more than experimental animals. They became friends, the dogs seemed to understand the importance of the experiment and were certainly, according to the history, most co-operative with the experiments. At the end of July, Banting operated on one of the duct tied dogs and found that the ligature had held and that the pancreas had shrunk to about one-third of of its normal size. The gland was removed, chopped up and ground in a mortar with saline, strained and a small amount injected into a vein of a depancreatized or diabetic dog. This animal was observed very carefully and with anxiety, for there was great concern that it may have toxic effects as earlier experimenters had discovered. For a while there seemed to be no change, then later to dog showed improvement. The animal became a much more active and more important the blood sugar levels were significantly reduced demonstrating the soundness of Banting's theory.
Although they were jubilant over the result of this experiment, there was some fear that it may have been as spurious result of no real significance. Consequently they injected the substance into other diabetic dogs with the same dramatic result and now felt confident that they had isolated the anti-diabetic factor from the islets of Langerhans in the pancreas. Banting's theory had been proven, but still diabetes had not been conquered even though the groundwork had been laid and there were still problems to overcome. On Dr. MacLeod’s return from Europe he was impressed, but insisted that the whole procedure be repeated to confirm this truly admirable result. The results, of course, with further experiments were confirmed. MacLeod was convinced and the announcement of discovery was presented in papers through the Physiological Journal Club in Toronto on November 14th , and the American Physiological Society shortly before the end of year in 1921. Many publications followed.
There were, of course, many problems to be faced including purification of the extract and its use in human patients suffering from diabetes. Although Banting's theory had been proved it was obvious that experimental techniques would have to be improved to produce the anti-diabetic substance, called Isletin by Banting and Best, the name later being changed to Insulin. First of all, the period required to produce the extract, some 6-8 weeks, was too long before practical purposes and other methods were sought. First of all Banting tried to the injection of Secretin which stimulated the acinar glands of the pancreas and she felt that by doing so it might stimulate them to exhaustion leaving valid islet cells intact for extraction. This proved somewhat successful but again was not ideal. The next step, also introduced by Banting was the use of fetal calf pancreas, for remembered from his farm days that the fetus in cattle were fed by them mother and required no digestive glands until birth. Consequently, Banting and Best collected an number of fetal calf pancreases and an extract from the whole pancreatic gland from the fetal calf was prepared and when injected into diabetic dogs resulted in a dramatic fall in the blood sugar. The experiments were repeated, the same result indicated that they now had a more reliable source for the production of the active extract. At this time the substance was still known as Isletin and I believe that it was MacLeod who changed the name to Insulin. Nevertheless, even with these experiments in the method for producing the active extract they were suitable only for experimental work and possible limited clinical testing. Certainly would not provide enough insulin for general use. Furthermore, when first injected into humans, although it lowered the blood sugar, it caused an abscess to form at the site of the injection. (The first person to receive insulin was Leonard Thompson, who was nearly in a diabetic coma.) It was, therefore, apparent that the impurities causing the abscesses would have to be removed before it can be considered for clinical use.
Professor MacLeod had become completely convinced of the value of this discovery and was most enthused above further improvements and turned his attention and those of his colleagues toward the improvement of the purification and production of insulin. Somewhere about this time, December 1921, MacLeod asked J. B. Collip, biochemist, who although working with MacLeod at the time, had met Banting in the early spring of 1921 and was associated with him throughout the insulin work, was not directly concerned with the early phase of their studies until it was obvious that the extract needed further purification before it could be used in humans. Collip also was a very humble man, but they very capable and experienced biochemist and was delighted at MacLeod's invitation to be a co-worker with Banting. Dr. Collip states the part which he played and was able to contribute subsequently to the work called the team was only that which any well-trained biochemist could be expected to contribute and he stated, himself, that this was trivial by comparison to Banting's contribution. Nevertheless, we must not overlook the real contribution that Collip did make, for his work resulted in the purification of the extract such study could be injected into humans without undesirable side effects and without abscess formation, as had occurred when initially tried. Although Dr. Collip stated that any biochemist could have done what he did, this certainly is not generally accepted, for Collip was a brilliant biochemist and it is quite possible that without his contribution insulin would never have come into clinical use. After some time on this work concerned with the purification of insulin, Collip left, in 1922, for other work at the University of Alberta in Edmonton where he was appointed professor and head of the department of biochemistry, and later to McGill in Montreal in 1928 as professor biochemistry. He excelled in the field of biochemistry and the discovery of new endocrines and hormones. After at considerable time at McGill University (1928 - 1946) he came to Western and in his final years was Dean of Medicine at the University of Western Ontario from (1947 - 1961).
Although a paper on the results of the insulin research was presented at a meeting of the Toronto academy of medicine in the fall of 1921, no public announcement was made. MacLeod was not involved in the original experiments, but he did provide the opportunity for the research and later was most enthused and contributed a great deal to its final success. There is, perhaps, some misunderstanding and perhaps also confusion to the granting of the Nobel Prize to Banting and MacLeod, for in December of 1921 Banting and Best presented in the results of their work at meeting the American Physiological Society. MacLeod was President of the Association at that time and also Chairman of the meeting ,in his summary of their presentation he implied that Banting and Best were his assistants. In view of this, the reporters mistakenly assigned credit for the discovery to him. Another factor that may have had some bearing on this is that a little later MacLeod presented a paper at the meeting of the American Association of Physicians in Chicago. Neither Banting or Best belonged to the American Association of Physicians at the time and only members could present papers. Consequently, MacLeod gave the paper. This, of course, gave some further strength to MacLeod's position in the insulin story. MacLeod had no intention of taking credit for the discovery, but as has been noted he did play an extremely important role in the latter stages of the study and further development of insulin, and furthermore was an outstanding authority in the field of physiology at that time, well-known as well recognized and director of the department. I feel that this may have had some effect on Banting's later attitude towards research, for, as you know, he always gave full credit to others for their part in the insulin work and later full credit to the members of his department carrying out research studies. He emphasized that one did not work for him, but with him. The custom, however, in those early years was that the Chairman and Director of such departments as Physiology was, indeed, the leader and all who worked with him were considered as his assistants. Banting certainly changed this attitude in all of his endeavors and research were after his completion of the insulin work.
As I have stated, MacLeod was, indeed a fair man for all the early announcements and papers and finally the public announcement seemed to give him credit for the work. MacLeod, however, in September of 1922, gave a statement to a Toronto newspaper stating that published reports crediting him were false and that the idea was entirely Banting's. He went on to say in this press release that Banting's successful humble experiments had proven his theory correct. Insulin had been isolated and the physiological action of insulin was intensively studied by members of his department who worked along with Banting and Best.
In the fall of 1922 the extract was still impure and they were experiencing considerable difficulty with deterioration, sensitization, reaction, etc., although Collip had prepared an extract which could be injected into humans and was a great improvement in the purification of the product. Collip also working with rabbits discovered the dangerous effects of too much insulin producing hypoglycemia and the basis for him believe biological assay of insulin. There were still, however, problems to be overcome come the main one of which production of the product in large enough quantities to be useful clinically. Consequently, the third stage of the development of insulin was being approached and methods were found to extract insulin from the adult beef pancreas, for the supply from the tilt calves was certainly much too small and with further work, without going into details which are contained in Stevenson's book on Sir Frederick Banting, it was possible to produce insulin from the adult beef pancreas.
The final results of the whole research initiated by Banting was the production of the safe and potent extract in commercial quantity which was achieved by many individuals and groups of individuals in the year 1922. Banting has recorded that during the spring of 1922 Best had succeeded in producing fairly large quantities of insulin and sufficiently purified to prove thoroughly the value of insulin to diabetic patients Dr. Banting further reports that Dr. Clowes of the Eli Lilly Company had offered soon after the initial announcement of the discovery in December of 1922 offered the resources and assistants of the Eli Lilly Company whenever they felt that the practical application and large-scale production of the extract might be indicated. In about April of 1922, Banting and Best accepted this kind offer and collaborated with Eli Lilly in the further purification to hand production of the extract with a result that by the middle of November of 1922 The Eli Lilly Company were a first able to achieve a substantial further purification, concentration and improvement in the stability of the extract. Since the yields were small, but by January of 1923, as a result of the work carried out by Connaught Laboratories and Eli Lilly Company they were able to provide fairly considerable quantities of insulin for clinical use, and has soon as the supply became more abundant how limited supply of insulin was sent to diabetic specialists in United States and Canada Connaught Laboratories in Canada and Eli Lilly Company of United States. Insulin was first reserved for more severe diabetics, but with time and improvements it became more and more available for the treatment of diabetes in general. In the beginning patents for in some was given by Banting to the Connaught Laboratories, who had complete control of all insulin produce for a period of some 20 years or more and every batch of insulin manufactured by pharmaceutical houses had to go to the Connaught Laboratories for assessment as to potency, stability, etc.. The proceeds from this Banting decided should all go to the Connaught Laboratories for support of further research and development and he, personally, received nothing in a monetary way from the discovery and later development of insulin. Best continued for some time to work on the problem with regard to improving its potency improvements with regard to impurities, purification, etc.. However, Banting left this with Best and turned his interests to other fields of research.