Leaf from the past
The discovery of insulin
Editor's Note:
This article gives a glimpse of the difficulties of medical research and how a benefit to mankind has the story of struggle, endurance and luck behind...
History of diabetes
If we consider the long and unbroken history of diabetes since its first known description in an ancient Egyptian papyrus nearly four thousand years ago, it is surprising that this disease, which had remained incurable until 1921, had not vanished by attrition in the course of the millennia.
With the gradual refinement of knowledge of the anatomy, the physiology, and even the pathology of the pancreas at the beginning of this century, many minds were occupied with the logical and scientific search for a rational therapy. It had become known theoretically that a substance such as insulin must exist, and it remained for the charmed scientist or physician to find this magic substance. As it turned out, the discovery was made by the two Canadians, Banting and Best, through a combination of circumstances that could have been neither planned nor foreseen. The situation that triggered the great discovery was Dr. Frederick G. Banting's lack of success in his private practice of surgery.
It was a fortunate situation for one doctor, as well as for mankind, when Banting's medical practice, which he had opened in Toronto in July, 1920, failed to attract a sufficient number of patients to provide a livelihood for the young orthopaedic surgeon. In fact, his practice was so bad that in the course of the first month he had seen one patient and earned only four dollars. This situation lasted from July to October. And it speaks for the enormous single-mindedness of purpose in Banting's entire personality throughout his life that he continued his daily unproductive office hours for three months without giving in to total discouragement. This absolute lack of response of the public to Banting, the surgeon, was strange considering that the young doctor was known for his distinguished military career in World War I. Overseas he had performed heroic deeds in rescuing the wounded under heavy fire, whereby he was wounded himself and for this heroism was awarded the Military Cross. His reputation of heroism, the fact that he was of local origin, and his being a graduate of the University of Toronto School of Medicine with four years of post-graduate training in orthopaedic surgery - none of these favourable elements in Banting's past induced the older and well-established Toronto physicians to make sufficient referrals to assure him of a regular income. Therefore, when the University of Toronto School of Medicine re-opened for the Autumn term of 1920, Banting applied for a university appointment which would give him access to laboratories and to the academic medical community. The appointment was granted, and he became a part-time demonstrator in the Department of Physiology and Anatomy.
The beginnings
In pursuit of his academic aspirations, Banting mapped out a course of study which he could easily follow while waiting for patients in his empty office. It was barely one month after the inception of these studies that he came upon an article which was to change the course of his life, for it laid the foundation for the subsequent discovery of insulin. This was an article by Moses Barron in the November (1920) issue of Surgery, Gynaecology and Obstetrics. This article pointed out the degenerative changes which follow the experimental ligation of the pancreatic duct, or the blocking of the duct by gall stones. Banting tells us that he was so excited by the article that he was unable to fall asleep, for he pondered upon the possibility that there was a relation between the islet cells of the pancreas and clinical diabetes. These toughts also suggested a means of extracting the islet cells by ligating the pancreatic duct. Still awake at two o'clock in the morning, he made the following notations:
Ligate pancreatic ducts of dogs. Wait six to eight weeks for degeneration. Remove the residue and
extract.(Banting's italics)
It is an experience noted by many scholars and scientists that notations resulting from such a sleepless night of nearly feverish thought often turn out to be disorganized fantasies and lack the clarity and logic they appeared to have had in the early hours of dawn. But Banting's notes and ideas were taken quite seriously by a number of professors of the University of Toronto whom he consulted concerning the use of space and facilities for experimental work. One of these men referred Banting to Professor J. J. R. Macleod, who, because of his renowned researches on carbohydrate metabolism, offered a chance of being interested in Banting's scientific project.
The results of Banting's first interview with Professor Macleod were disappointing, inasmuch as the latter remained mystified as to the purpose of Banting's researches. Macleod, who had a hard time following Banting's awkward presentation of his thoughts, reminded the young man that so far none of the mostly highly renowned physiologists had succeeded in finding proof for the existence of an internal secretion of the pancreas.
Eventually he had reached the state of such complete preparedness for his researches that he requested permission to proceed with his work earlier than had been agreed with Professor Macleod. Specifically, around the time of Easter, 1921, he asked that he should be permitted to tie the pancreatic ducts of several dogs, so that they would be ready (that is, degenerated) in May for the actual experiments. But Macleod did not grant this permission, as he felt that the dogs should be under Banting's supervision from the beginning of the work.
The experiments
The experiment began on May 17, 1921. As he had requested, Banting was to be given ten dogs and the use of a laboratory for eight weeks. For the same length of time, two graduate students in physiology, Mr. Charles Best and Mr. Nobel, were to act as assistants, each for half the time. They tossed a coin to determine who was to be the assistant for the first four weeks, and history has long recorded that it was Charles Best who won. This was extremely fortunate, as Nobel's motivation seems to have been scant - he did not return after the end of the first four-week period, and Charles Best remained Banting's collaborator. Although still a graduate student at that time, Best was well suited for this research; he was completing a course in physiology and biochemistry and conducting his own research project in the field of carbohydrate metabolism. May 17, 1921, was chosen as the starting date of the Banting-Best collaboration because it was the day after Best's final examination in the physiology course.
Apart from their scientific interest, Banting and Best were stimulated by a deep personal concern for the problem of diabetes. Best sadly recalls that, "Banting and I had watched patients with diabetes lose weight and die in diabetic coma." Best's father was a general practitioner; and about 1916 his father's sister, a trained nurse who had graduated from the Massachusetts General Hospital, came to live with the family. "She was in an advanced stage of diabetes, and died a year or two before insulin became available." Of Banting, it is said that he was a witness to quick wasting and death in coma of a young girl to whom he had a great sentimental attachment.
Besides the emotional reaction to, and scientific interest in diabetes that both young men had in common, Banting and Best were ideally matched for this research project. In the beginning Banting performed all the surgical procedures, while Best was in charge of the chemical aspects of the experiment. In the course of this initially specialized collaboration, an exchange of skills took place: Best instructed Banting in the methods of measuring blood sugar, while Banting taught Best the skill of experimental surgery. Nevertheless, Banting's initial surgical superiority so impressed Best that as late as January, 1970 - that is, nearly fifty years after that experimental period he remarked in a lecture,
"It is perhaps not generally appreciated how much we owe to the good surgical technique which Banting applied to our operations on diabetic animals. They were terribly susceptible to infection, and an incompetent surgeon might have failed to realize his objective, that was, to produce uncomplicated diabetes, either by failure to remove all the pancreas or by introducing infection which might have made the animals extremely resistant to any type of therapy."
The experiment, in short, proceeded as the excited Banting had envisaged that night after reading Moses Barron's article in S.G. and O. The two young scientists first ligated the pancreatic duct of a number of dogs. Following this, they performed pancreaectomies in normal dogs in order to become familiar with the blood and urinary finding and the general clinical conditions of the animals after pancreatectomy. On July 6, 1921, seven weeks after the ligation of the pancreatic ducts, two of the dogs were chloroformed and opened for inspection. Quite contrary to Banting's and Best's expectations, and much to their disappointment, they found that the pancreas was not degenerated and the ligature was still present in a bulbous sac in the course of the duct. Hence a second operation was indicated. Here special care was essential to avoid exaggerated tension on the ligature so as to avoid the danger of gangrene in underlying tissue. On the other hand, if the ligature was not applied tightly enough, blockage of the duct could not be achieved. To avoid either danger, the scientists arrived at a brilliant solution: instead of one crucial ligature, they applied two or more ligatures at different tensions.
On July 17 or 27 (both these dates are given by Best and Banting, respectively), the first truly depancreatized dog was available for them to begin the crucial phase of treatment. Consequently, the dog was anaesthetized, and the degenerated pancreatic residue was removed, chopped in a chilled mortar, and frozen in a salt solution. After a few further chemical processes, small portions of this extract were injected into the dog's veins. Repeated study of the depancreatized dog's blood samples indicated a rapid lowering of the blood sugar, and eventual complete disappearance of sugar from the urine; besides, the animal showed a dramatic clinical improvement.
The background
Banting's background and childhood on a farm account for his great love of, and skill with animals. He became enormously attached to the various experimental dogs and, in fact, trained them to raise their paws and hold them steady while the blood samples were taken from their veins.
Considering the age of the two youthful investigators - Banting was thirty years old, and Best, just twenty-two - the restraint of their reaction to a monumental experience is awesome. Their reaction was one of caution - no scientific publication as yet, and no press conference, not even through university channels. It was important above all to convince the sceptical Professor Macleod on his return from Scotland of the validity of their experiment, and the two young men "did not allow themselves to get too excited until they had achieved some ten definite successes." Thus they worked on and on beyond the scheduled eight weeks until Macleod's return to Toronto in the middle of September. The senior physiologist was 'not very excited' about these results and refused the two young men permission to pursue their research further, but insisted that they should repeat over and over again their basic experiments. Thus, only after they had collected data on sixty or seventy positive results, were the youthful scientists, in November of 1921, courageous enough to present their work to the Faculty of Medicine of the University of Toronto. There they met with all the enthusiasm that had been lacking in Professor Macleod's reaction.
Initially, the researchers succeeded in resisting the mounting pressure for clinical application of their discovery. This they were able to do until January 11, 1922, when the first diabetic patients were treated at the Toronto General Hospital. The very first patient, a severely diabetic boy of fourteen years, was given an injection of extract of beef pancreas which had been collected by the scientists and prepared in their laboratory. As beef pancreas was new to them and they were uncertain about its effect, they restricted themselves to using small doses so that the effect on the patient was slight rather than dramatic. Because of the difficulties in finding the proper dosage and manufacturing the extract, Banting and Best invited the bio-chemist, Dr. J.B.Collip of the University of Alberta to work on the chemical refinement of the drug. However, Dr. Collip encountered unsurmountable difficulties in this process and withdrew. Fortunately, Best was extraordinarily successful in resuming the problem of refinement and production of insulin.
The naming of insulin
A word should be said about the name insulin, which was not actually original with the discoverers of the drug. Knowing that the curative substance in the pancreatic extract was derived from the islets of Langerhans, Banting and Best used the term islet in their scientific notes of August, 1921. It was Professor Macleod, the Scot, who insisted that the internal secretion of the pancreas should be called insulin. He may have done so because a compatriot, Dr. Sharpey Schafer of Edinburgh, had suggested this name as early as 1910. According to Best, however, the word insulin was used for the first time in 1909 by a Belgian scientist, de Mayer, who was dealing with an internal secretion of the pancreas which was then still hypothetical.
Standardization of insulin
Now that the effect of insulin had become an established fact, in the autumn of 1922, Professor Macleod collected a group of workers under his direction. Their most urgent task was to establish standards for the potency of insulin. Eventually, it was established that a unit of insulin was to be the amount required to reduce the blood sugar of a normal rabbit weighing 2.5 kg to 0.045% in four hours. As it was essential to achieve a uniform strength of each unit of insulin in all countries, the Public Health Commission of the League of Nations in Geneva entered into this situation and changed the definition to the following: a unit of insulin is one-third of the amount of material required to lower the blood sugar of a 2 kilogram rabbit which has fasted for twenty-four hours, from the normal level of 0.118% to 0.045% over a period of 5 hours.
After the standardization of the unit of insulin, free clinics were established in Toronto to take care of diabetic soldiers and children. Arrangements were also made for the care of private patients. With the spread of the news of an available treatment of diabetes, clinical needs for large quantities of insulin rapidly increased; and it is largely owing to the efforts of Charles Best during the summer of 1922 that it was possible to produce sufficiently large and sufficiently purified quantities of insulin to prove the value of the drug to diabetic patients.
It was impossible, of course, to manufacture insulin speedily enough for the ever-increasing demands in the university departmental laboratories. Because of the urgency for its inexpensive manufacture, negotiations were undertaken with pharmaceutical firms. Eventually the Toronto group decided to collaborate with the Eli Lilly Company of Indianapolis in the large-scale production of insulin. According to Banting, the collaboration between the university research group and Lilly Laboratories was cordial and most successful.
Initially, large-scale production of insulin posed many problems that had not been anticipated by the discoverers. While the supply of insulin was still limited, treatment had to be restricted to severe diabetics, all of whom were required to co-operate with the investigation so as to produce information for the guidance of all physicians in the use of insulin. After much experience with the clinical use of insulin, it was found that, regardless of the severity of the disease, by carefully adjusting the diet and the dose of insulin, all patients could be maintained sugar-free. This is a highly desirable state, because Banting and Best felt certain of their evidence for the assumption that there is regeneration of the islet cells of the pancreas when they are relieved of the strain imposed upon them by a high blood sugar.
What followed
The relationship between Banting and Best remained harmonious during the year of their collaboration. They jointly published four papers on their work. In their separate publications on the insulin story, they referred to each other with mutual regard and admiration.
At the very time when the discovery of insulin had reached world-wide acclaim, Charles Best had fulfilled the requirements for a degree of Master of Arts in physiology. Thus he was probably the most distinguished recipient of the M.A. degree in the history of health sciences. Not content with this first rung on the academic ladder, he decided to complete the study of medicine and at the same time retain the position as Director of insulin production at the Connaught Laboratories of the University of Toronto. Then twenty-three years of age, Best reports having had a very busy, but a very satisfactory time, and having thoroughly enjoyed his clinical training. Instead of taking an internship, Best went to England, where he worked with Sir Henry Dale in London. There he made further studies of insulin and also began research on histamine, the subject of Sir Henry Dale's special expertise. Best concluded his academic studies in 1928 with the award of Doctor of Science degree from University College, London. On his return to the University of Toronto, he was given the chair of Applied Physiology in the new School of Hygiene, where he continued work on his early researches on carbohydrate metabolism that had originally attracted him to the insulin research project.
When Professor Macleod left the University of Toronto in 1929 to return to Scotland, he recommended that Best be made his successor. Thus Best, who had always contracted more responsibilities than is common for a young man, was appointed to the additional chair of physiology at the School of Medicine of the University of Toronto. Later he had the joy of having his name once more linked with that of his eminent collaborator in the discovery of insulin by being named to the Banting and Best Department of Medical Research. At present he still holds this position, while also being head of the Charles H. Best Institute.
Banting's life, begun on a farm in Alliston, a small rural community in Ontario, soared to unforeseen heights. Painfully shy as a person, modest and inhibited as a speaker, he was pursued with invitations to lecture and had to undergo the rewards of greatness avidly sought by others, but agony to him. For his discovery of insulin he received the Nobel prize jointly with Professor Macleod, who had made available to him the physical facilities for his research. Banting, who felt that he owed his success in large measure to Charles Best, immediately decided to share the monetary portion of the Nobel prize in equal parts with his former collaborator. Later, Banting was knighted.
Banting's professional career, after the discovery of insulin, returned for a time to the practice of medicine, which he had earlier abandoned because it had failed to provide him with a livelihood. Now that there was insulin available, he joined the clinicians in the School of Medicine and specialized in the treatment of diabetics. Under the internal pressure of keeping step with his own early meteoric success, he involved himself in further research projects on a problem which has always defied solution - Frederick Banting began the study of the aetiology of cancer. From this futile undertaking, he became involved in other research projects related to the Second World War. It was in the pursuit of a physiological project on behalf of the Air Force that he met his end, at the age of fifty, in a plane crash in 1941.
The first patient
The story of diabetes and insulin would not be complete without a last word about the first patient treated with insulin in Toronto. In January, 1922, at fourteen years of age, this patient, Leonard Thompson, was the first recipient of insulin in the form of an extract of fresh beef pancreas. Owing to the efforts of Banting and Best, he made a complete recovery which was maintained for fifteen years until, at the age of twenty-nine, he suffered a severe motorcycle accident and, during recovery from trauma, died of pneumonia.
Dr. Ilza Veith was Professor and Vice-Chairman of the Department of the History of Health Sciences, University of California Medical Centre, San Francisco.
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