Smallpox, Syphilis and Salvation

by Sheryl Persson

  By the nineteenth century knowledge of digestion and metabolic processes had expanded markedly and this provided a basis for understanding diabetes. Many scientists had made their contributions and their discoveries were a series of dots, but it required someone with an incisive mind to join them up. It needed Frederick Banting to act on his ‘Eureka!’ moment.

  BANTING AND BEST, COLLIP AND MACLEOD

  The son of a farmer, Frederick Grant Banting was born in Ontario in Canada, on 14 November 1891. At school Banting was an all-rounder excelling in the classroom and on the sports field. He went on to study medicine at the University of Toronto and as part of his course worked as an intern at Toronto’s Hospital for Sick Children. When World War I broke out in August 1914, Banting immediately attempted to enlist in the Canadian army but was not accepted because of his poor eyesight; however, the following spring he enlisted in the Canadian Army Medical Service.

  Banting was quickly promoted to the rank of sergeant. So that he could complete his medical school program, the university condensed his fifth and final year, which in effect cut his training short, something he later regretted. Banting sat his final exams in October 1916 and graduated on 9 December. The following day he reported for active duty and as Lieutenant Banting sailed for Britain to his first overseas posting at the Granville Canadian Special Hospital in Ramsgate. Banting had recently become engaged to Edith Roach, a young woman from his hometown of Alliston and like many young soldiers he left his fiancée behind wondering if he would ever return.

  Banting was promoted again to the rank of captain and saw active service in France where he treated the wounded and served with distinction. Frederick Banting was awarded the Military Cross for bravery during events that took place on 28 September 1918 and in ‘recognition of gallant and meritorious’ service. According to the citation:

  ...when the medical officer of the 46th Canadian Battalion was wounded, he immediately proceeded forward through intense shell fire to reach the battalion. Several of his men were wounded and he, neglecting his own safety, stopped to attend to them. While doing this he was wounded himself [severed artery in his right arm] and was sent out notwithstanding his plea to be left at the front. His energy and pluck were of a very high order.[16]Apparently Banting had continued to tend the injuries of others for nearly seventeen hours, despite his own wound.

  After the war Banting returned to Canada but was unable to secure a staff position at Toronto’s Hospital for Sick Children where he had trained. A close friend suggested that he set up a private practice in London, a large city in Ontario that had an established medical school. A classmate of Banting’s had already started a practice there. Another compelling reason to move to London was that Edith Roach was teaching at the Ingersoll District Collegiate Institute which was nearby. Banting took the only option open to him, left Toronto and began practising medicine in London in July 1920.

  In his biography, written in 1940, Banting looked back on his experience in London as a time of misery and failure—he was unhappy, he was a newcomer, his practice was slow to develop and he was devastated when his engagement to Edith was broken off, but he also reflected that had he not gone to London he might never have started his research. It was here, he said, that, ‘I obtained the idea that was to alter every plan that I had ever made. The idea which was to change my future and possibly the future of others.’[17] The house in which Banting suffered such misery and where he read the article that would reveal the secret to saving so many lives is now called Banting House and is a national historic site.

  ***

  When Frederick Banting approached Professor John Macleod at the University of Toronto in 1921 seeking research assistance for his plan to extract insulin from a dog pancreas he knew that he did not have substantial credentials or a proven track record in research. He was grateful that Macleod, who openly expressed his misgivings, was prepared to give him the opportunity. In May 1921, Frederick Banting was ready to begin his history-making experiments and he had Charles Best to assist him. Best had only just completed his university degree and had been working in Macleod’s laboratory during the summer as a research assistant in preparation for enrolling in a Master’s program.

  Charles Best was born on 27 February 1899 in West Pembroke in the United States but he was a Canadian citizen because his father, Dr Herbert Best, was Canadian. Herbert Best had been born in 1871 in Nova Scotia and six generations of his family had lived there before him.[18]

  Charles had attended high school in West Pembroke but continued his education in Canada at the Harbord Collegiate School in Toronto and in 1916 entered the University of Toronto. But it was wartime. At the end of his first year Charles enlisted in the Canadian army and served in the artillery in Canada and England. After the war he resumed his studies and in 1921, a few weeks after receiving an Honours Baccalaureate in Physiology and Chemistry, Charles Best found himself working with Dr Frederick Banting.[19] It would prove to be a very hot and very exciting summer. The young researcher was in the right place at the right time, and in less than three months the names Banting and Best would be echoing throughout the medical world.

  Best was engaged to be married when he began his association with Frederick Banting. He met his fiancée, Margaret Mahon, in February 1919 at a dance in Rosedale and they married in 1924. During the period from 1914 to 1984 Margaret wrote and kept 80 volumes of diaries as well as keeping thousands of letters and many scrapbooks and photo albums, which are mirrors into much more than family life and her long and successful marriage.[20] Apparently in her last years Margaret threatened to destroy the love letters from her husband, but fortunately she did not. The memorabilia that she left behind are an incredible archive of historical documents providing insight into the years surrounding the discovery of insulin.

  During the summer of 1921, while Margaret was away visiting relatives, Charles Best wrote letters to his fiancée which contained candid comments about what was going on in the medical building at Toronto University as Banting and Best began their research.

  After a few setbacks, Banting and Best had developed a suitable experimental regime for the ten dogs that they had been given for their experiments. In some dogs they tied off the pancreatic ducts so the acinar cells would atrophy, but they left the islets of Langerhans in place. From other dogs they removed the pancreas entirely; these dogs developed diabetes. Some weeks later they removed the degenerated pancreases from the first group of dogs. In order to extract fluid from the islet cells in these organs, they placed the pancreases in solution, ground them up with a mortar and pestle and then filtered them through cheesecloth. The islet cell fluid was then injected into the sick dogs that had previously had their pancreases removed.[21] Within hours the blood glucose levels of these dogs improved markedly.

  In a letter to Margaret on 8 August 1921, Charles Best wrote, ‘I went back to the lab at eleven p.m. and we worked all through the night and today until two. We got fine results.’ He mentioned that he was becoming an insomniac, unable to sleep even when he had the chance.

  Charles wrote the following on 10 August:

  We have mailed our report to Dr. Macleod. He will have food for thought for a little while at least ... We are doing identical operations on the dogs. We are going to give one the extract and the other none and study the condition of each—how long each lives, etc. It will be quite a crucial test for our ‘isletin’. I am glad you asked to hear about the dogs, dear. I know you are not interested in them apart from my work.[22]While this work had been going on in Toronto, Macleod was away in Scotland on a fishing trip. When he received the report he was not convinced, but even though he raised questions about the procedures Banting and Best had used, he acquiesced to Banting’s request for a dedicated laboratory and more staff. At this point James Collip, considered to be one of the great minds of Canadian biochemistry, came on board.

  James Bertram Collip was born in Belleville in Ontario in 1892. In 1907, when he was only fifteen he e
nrolled in an honours physiology and chemistry program at Trinity College at the University of Toronto. Collip completed his doctorate in biochemistry in 1916 and accepted a position as a lecturer at the University of Alberta where he began his outstanding career in biochemical research. He worked in a somewhat primitive laboratory but within a year had produced important work in the relatively new field of internal secretions.[23] In 1921 when Collip was on a Rockefeller Travelling Fellowship he was invited by Professor Macleod to join the Banting team to assist them on the insulin project.

  When Collip arrived at the Toronto laboratory Banting and Best had already produced a crude pancreatic extract. Soon the laboratory was set up with the equipment needed for the next phase of the work. Banting did the surgical work, Best carried out the chemical assays and Collip worked on methods for the purification of the chemical extracts and in a remarkably short time had refined the technique of insulin extraction and purification (eventually the process was patented in the names of the three principal researchers, Banting, Best and Macleod, and given to the University of Toronto).[24] Professor Macleod became involved in the project on his return from his trip and from that time on directed the work.

  As the experiments continued Banting began to use cow foetuses as the source of insulin when he realised that the islets of Langerhans cells were more numerous in developing animals than in mature ones. While Collip began work in his laboratory, Banting and Best, during the week of 12–16 December, continued work on their pancreas extract. On the first day an alcoholic extraction of whole pancreas seemed to work on the laboratory dogs when administered through a stomach tube, apparently causing a blood sugar reduction from 0.42 to 0.28 in four hours.[25] They found that whole cow pancreas injected intravenously also seemed effective.

  On 14 December Banting and Best administered extracts of liver, spleen, thyroid and thymus to the dogs, all prepared the same way as the pancreatic extracts, but none of them had any effect. To make the pancreatic extract purer they then experimented with dialysis and chemicals. An injection of a piece of dried extract that had been washed twice in toluene (a colourless, liquid hydrocarbon) and redissolved in saline when administered to one of the dogs resulted in a decrease in its blood sugar from 0.37 to 0.06 over a period of four hours. Following this extraordinary moment the work became tedious and did not go well over the next week. The men varied the way they prepared batches of extract and some had no potency at all when administered to the test dog.

  According to Michael Bliss in his book The Discovery of Insulin, at this point Banting and Best decided, without revealing their plans to anyone, to try the extract that had been successful on the dog on a human diabetic. One of Banting’s classmates, Joe Gilchrist, had become diabetic in early 1917, a few months after they had graduated. In 1921 his condition was deteriorating rapidly. An index card is apparently the only record of the actual ‘first’ clinical trial and it notes that Joe Gilchrist was contacted by phone on 20 December. He obviously agreed to be a ‘guinea pig’, or ‘dog’ in this case, and was given the extract by mouth. The index card records that on 21 December there had been ‘no beneficial result’. Bliss makes the point that the extract may have worked on Gilchrist, as it had for the dog, if it had been given intravenously but the risk was too great for Banting and Best to inject something so experimental into a human. When Banting and Best reported on their findings at a meeting of the American Physiological Society on 28 December 1921 Joe Gilchrist was not mentioned.

  Frederick Banting knew that the real test of his extract would be success with a human patient. When a clinical trial was arranged at Toronto General Hospital, the university’s teaching hospital, Macleod gave James Collip the job of preparing the extract that would be used. According to Bliss, at this point Banting began urging Macleod to let him try the extract he and Best had successfully used on the test dog and unbeknown to Macleod, unsuccessfully on one human. Because Banting had no professional association with the university’s teaching hospital, and no doubt wanting to conduct the trial himself without discussing his plans, he applied to Duncan Graham, the Eaton Professor of Medicine at the Toronto Department of Medicine for a temporary appointment. Graham dismissed Banting’s request and condescendingly pointed out that he was not currently practising medicine and was not qualified to experiment on patients or to treat diabetics. Although the relationship between Banting and Macleod had never progressed beyond tense, Macleod agreed to intercede with Graham, who was a personal friend. As a result a clinical trial of the extract prepared by Banting and Best proceeded.

  The patient chosen for the trial was fourteen-year-old Leonard Thompson, a diabetic who was a public ward patient. Leonard had been admitted to the diabetic clinic at Toronto General Hospital rather than the Hospital for Sick Children so that he could receive the extract. His diabetes had been diagnosed in 1919 and Allen therapy (during which patients are required to eat a low-calorie diet) had been tried on the boy without success.[26]

  By December 1921 when Leonard was admitted to hospital he was emaciated, pale and listless, his hair was falling out, his abdomen was distended and he was too ill to get out of bed. ‘All of us knew that he was doomed,’ a senior medical student in the hospital recalled.[27] Leonard’s distressed father gave permission for Banting and Best’s new extract to be administered because he knew it was his son’s only hope.

  Best prepared the extract of whole cow pancreas using the same process that had worked on the dog early in December, and tested it again. What they delivered to the clinic was described as very thick and brown.[28] On the afternoon of 11 January, a young house physician, Ed Jeffrey, injected 15 cubic centimetres of the extract into Leonard Thompson, half the dose it was thought would be effective on a dog of the same weight. Banting and Best, who were treated like interlopers, waited in the corridor on tenterhooks hoping to get a sample of the boy’s urine to test. After being told that all samples were the property of the hospital they returned to their laboratory having been given no information at all.

  The results of the first trial were reported later in a joint publication by Banting, Best, Collip and Walter Campbell, another member of the laboratory team. Leonard Thompson’s blood sugar dropped from 0.44 to 0.32. The 24-hour excretion of glucose fell from 91.5 grams in 3625 cubic centimetres of urine to 84 grams in 4060 cubic centimetres and his ketones count continued to be strongly positive.[29] The only evident side-effect was a sterile abscess at the site of one of the injections on Leonard’s buttock. Despite the general opinion that this constituted a success the decision was made by the doctors at Toronto General not to give Leonard further injections of Banting and Best’s extract.

  Collip had continued working on the problem of purifying insulin to remove the harmful impurities and only a few days after the first trial had produced a batch of extract made from purified ox pancreas. On 23 January 1922 Collip’s extract was administered to Leonard. The almost immediate and dramatic improvement in the boy’s condition was convincing proof that the Toronto team had made a life-saving discovery. Banting and Best had made insulin, Collip had purified it and the hospital records show that Leonard Thompson received ‘Macleod’s serum’.[30] This is not untoward considering Macleod was the head of the team and of the laboratory where insulin had been produced.

  Word of the latest medical marvel spread quickly, circling the globe and giving immediate hope to thousands of diabetic people who were near death. A frenzied quest for insulin followed and appeals arrived daily in Toronto from parents desperate to save their children. As the use of insulin spread it lived up to its reputation and even patients who had lapsed into diabetic comas were making miraculous recoveries.

  ***

  Although the relationship between Banting and Macleod had always been strained, the underlying hostilities at the laboratory were becoming more obvious. The heady nature of success can sometimes do strange things to scientists. In February 1922 Macleod publicly announced the discovery, and the patent for manu
facturing the pancreatic extract was approved. All financial proceeds from the patent went to the British Medical Research Council and the discoverers were given nothing. Amidst the excitement and the tension Banting and Best published a summary of their work in April 1922. The title of their joint paper was, ‘The Effect Produced on Diabetes by Extracts of Pancreas’.[31]

  It was at this time that Banting picked up on several clues and became suspicious that Macleod wanted credit for the discovery that Banting believed was his and Best’s. As head of department, however, Macleod could expect some acknowledgment. Tension escalated when James Collip refused to reveal to Banting the method he had used to purify the insulin in the second trial. Banting was disappointed and hurt. However, rage is the emotion he is said to have exhibited when he and Macleod, not Best, were jointly named as the recipients of the 1923 Nobel Prize for Physiology or Medicine. Collip, who accepted a share of the Nobel Prize money from Professor Macleod, wrote somewhat bitterly in 1923 that the extract that Banting and Best had prepared was absolutely useless for a human subject.

  What actually happened between these four men has been debated in scientific and lay circles for decades. One of Charles Best’s two sons, Henry Best, a professional historian, threw some light on those frenetic and troubled times from his father’s perspective in a speech he delivered to the Academy of Medicine in Toronto on 24 April 1996 during the celebrations for the 75th anniversary of the discovery of insulin. Henry Best had abandoned his medical career to study history and at the time he gave the speech was in the process of writing a biography of his famous father. According to Henry, Frederick Banting and Charles Best both believed that there was a demarcation line between the discovery of insulin and its early development. They were the discoverers. John Macleod, James Collip and other members of the team made very important contributions, but at another level. Banting and Best were involved in both the discovery and the development of insulin. Banting had been motivated by Barron’s article about the islets of Langerhans, had hypothesised how insulin might be extracted, and from that moment it became Frederick Banting’s goal to convert his theory into a cure for diabetes. Banting brought his proposal to Macleod. The initial work, without which the rest would not have been possible, was carried out by Frederick Banting and Charles Best.[32] There can be no doubt about who connected all the dots.