The Discovery of Insulin

by Michael Bliss

  Kleiner had made solutions of ground fresh pancreas in slightly salted distilled water. These were slowly injected intravenously into depancreatized 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 themselves, 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 might 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 noted with emphasis).

  Kleiner began the “Discussion” section of his paper triumphantly:

  Many investigators have recognized that the best evidence for the internal secretion theory of the origin of diabetes would be an antidiabetic effect of a pancreatic preparation, administered parenterally. The experiments just described show that such a result has been obtained….

  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. These 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 do any 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 to support major animal research.39

  Another scientist whose work on pancreatic extracts had been interrupted 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 experimenting 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.

  Paulesco published his earliest findings in his 1920 treatise on physiology, written in French. These and further experiments were described in four short papers published in Comptes rendus des séances de la Société de biologie between April and June 1921. A summarizing paper was received by Archives internationales 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 diabète, de l’obésité et de l’acidose, méthode qui est issue de ces reserches expérimentales.”40

  In Germany at the same time, Georg Zuelzer was still trying to find a drug company to take up production of his extract, acomatol. 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 knowledge of diabetes is advancing rapidly enough that even the patient whose outlook seems darkest should take courage to remain alive in the hope of treatment that can be called curative.” He must have been discouraged in the next year or two as the most faithful of the cases reported in his Rockefeller study died one after another, with no cure in sight. The idea of advancing beyond diet, perhaps with a pancreatic extract, had been in the back of his mind for some time. In 1921 he began installing facilities for animal experimentation at the Physiatric Institute. He planned to try a new approach to the extract problem when they were ready.41

  One of Allen’s most faithful patients was a young girl named Elizabeth Evans Hughes. She was also his most prominent patient, for her father, Charles Evans Hughes, was one of the most visible men in the public life of the United States. Elizabeth had been born in the New York state governor’s mansion in 1907. Her father was later appointed to the Supreme Court, resigned from it to run as the Republican candidate for the presidency against Woodrow Wilson in 1916, and in 1920 became Secretary of State in the administration of Warren Harding. Later he would be reappointed to the Supreme Court and become one of its most distinguished Chief Justices.

  One of four children of Charles and Antoinette Hughes, Elizabeth grew up as a lively, intelligent little girl, never very big or strong, but otherwise normal. She had an interesting and exciting girlhood, a beneficiary of all the opportunities open to a family of American aristocrats. It was in 1918, when Elizabeth was eleven or twelve, that something started to go wrong. She would come home from birthday parties, where there had been lots of ice cream and cake, with a ravenous thirst, and would drink glass after glass of water, sometimes two quarts. She was often weak and tired in the winter of 1918–19, and showed increasing tendencies to polydipsia and polyuria. That spring she was taken to Dr. Allen. He diagnosed diabetes and prescribed an immediate fast. Whatever the fasting would do, the diagnosis was like knowing a sentence of death had been passed.

  At the onset of her diabetes Elizabeth Hughes was 4’ 11½” tall and weighed 75 pounds. After the first week’s fasting Allen put her on a very low diet, 400 to 600 calories a day for several weeks (with one day’s fasting every week), then raised it to 834 calories. He brought her weight down to 55 pounds, then allowed her to rise into the low 60’s on a diet going as high as 1,250 calories (350 on fast days). The Hughes family hired a special Joslin-trained nurse to prepare Elizabeth’s meals and help her with her tests. Every gram of food she consumed had been weighed beforehand. Sweets and bread disappeared from her diet. She lived on lean meat, eggs, lettuce, milk, a few fruits, tasteless bran rusks, and tasteless vegetables (boiled three times to make them almost totally carbo
hydrate-free). A birthday cake became a hat box covered in pink and white paper with candles on it. On picnics in the summertime she had her own little frying pan to cook her omelet in while the others had chops, fresh fish, corn on the cob, and watermelon.

  Elizabeth disliked Dr. Allen, a square-faced, jowly man who never seemed to smile, never seemed anything but strict. Charles Evans Hughes was one of the sponsors of the Physiatric Institute and had helped Allen with the legal work involved in setting it up; but Elizabeth, who spent several weeks there, found it a horrible place. She disliked her diet, and found the fast days a special nightmare – she tried to plan every minute of these days in advance so she would be distracted from the hunger. She was a vivacious, articulate adolescent, eager for all the experiences life had to offer, and apparently unaware of what was in store for her. Her nurses never told her how serious her problem was. They never told her why friends she had made at Morristown stopped writing or never appeared there again.

  She was an obedient little spartan, though, and kept her diet perfectly. She hardly ever showed sugar. Just once, at Thanksgiving, she sneaked into the kitchen and snitched a piece of turkey skin. Her nurse caught her and gave her a severe bawling out. She must never take extra food.

  Had she been untreated, Elizabeth Hughes would probably have died in the summer of 1919. With stern Dr. Allen’s stern diet, her own discipline, and her sheer strength of character, she carried on very well through the winter of 1919–20. She had a difficult time in the spring of 1920, when colds and tonsillitis threw her out of balance, and was often cut back to a diet of less than 500 calories. But she recovered that summer and fall, and at Christmas 1920 weighed in at 62¼ pounds. The winter and spring were bad again, though; by the end of March she was down to 52 pounds. Her diet in April averaged 405 calories. The doctor got her back up to 700 to 900 calories, but her weight was now at a new low plateau, between 52 and 54 pounds. At the age of thirteen, Elizabeth was a semi-invalid. There was great sorrow in the family when one of her older sisters died in 1920 of tuberculosis. While the Hughes family sweltered in Washington in the summer of 1921, Elizabeth enjoyed the fresh air and cool breezes of the Adirondacks. Her condition stayed about the same. In cheerful letters she chatted on about when she would get married and what she would do on her twenty-first birthday. Reading them must have been heart-breaking for Antoinette Hughes. The best medical talent in the world was the Hughes family’s to command. But the “curative treatment” for diabetes that Dr. Allen had written about was nowhere in sight.42

  CHAPTER TWO

  Banting’s Idea

  Frederick Grant Banting, always called Fred, was born on a farm near the small town of Alliston, Ontario, on November 14, 1891. He was of British descent, his grandfather having emigrated to Canada about forty years earlier.* His parents, Margaret Grant and William Banting, were hard-working farm people, devout Methodists, and reasonably prosperous, sober citizens. The youngest of five children, Fred enjoyed a normal farm boyhood in turn-of-the-century rural Ontario, growing up close to nature and with a deep affection for animals. He seems to have been happy at home and to have had a particularly close relationship with his mother. At local schools in Alliston he was a serious-minded but unremarkable student. “We would not have picked him for one on whom fame should settle,” his public school principal said some years later.1

  Banting went on to higher education at the University of Toronto, the province’s largest and best university. Located on the shores of Lake Ontario, about forty miles south of Alliston, Toronto was the provincial metropolis and Canada’s second-largest city, a thriving community of more than five hundred thousand. Originally uncertain of his vocation -his parents had encouraged him to think of entering the Methodist ministry – Fred dropped out of an arts course towards the end of his first year, and re-enrolled in medicine the next autumn, 1912. The university’s faculty of medicine was one of the largest, in terms of student enrolment, in North America, well-equipped, and apparently fairly well-staffed. Its teaching hospital, Toronto General, had recently been rebuilt and was one of the best anywhere. There was a growing emphasis at Toronto on research as a vital accompaniment to the teaching of a medical school.2

  Banting was an average medical student, more serious and more studious than most, shy, best at athletics. He was tallish, almost six feet, and strong, and when dressed-up could be a handsome young man, with a particularly winning broad smile and an attractive twinkle in his eye. In a less flattering light his face had “horsey” features – it was long and narrow and his mouth seemed to stretch from one side to the other – and in his manners and conversation Fred was very much the unpolished country boy. He could seem intellectually slow; his studiousness was a kind of dogged determination to get through and never won him more than average grades. In his free time he enjoyed most of the male rituals of the university, although he apparently never learned to dance, possessing, as they said, two Methodist feet. Much of his spare time was spent with his girlfriend, Edith Roach, a languages student whose father had been the Methodist minister in Alliston.

  Banting’s five-year medical course at Toronto was shortened because of the war. The class of “1T7” (Toronto, 1917) took its fifth year in the summer of 1916. “I had five pages of notes on the whole lectures of the fifth year,” Banting recalled, writing that he had “a very deficient medical training.”3 Immediately after final results were announced in December every able-bodied member of the class went off to war. Banting, who had been serving part-time in the Canadian Army Medical Corps for two years, was sent to England in 1917. He and Edith became engaged before he left.

  After a year working in hospitals in England, Captain Banting was sent to the front as a battalion medical officer. He saw a fair bit of action and received the Military Cross for his courage under fire at Cambrai, where he was wounded in the arm by shrapnel. He had a long convalescence in Britain, returned to Toronto in March of 1919, and was posted to Christie Street Military Hospital before his discharge. During his free time in the army Banting studied to take the examinations leading to the stamp of approval of various medical bodies such as the Royal College of Physicians of London and the Royal College of Surgeons. He seems to have had a deep commitment to his profession, and was gradually developing an interest in research. Before and during his military service he worked with Clarence L. Starr, the brilliant chief surgeon at the Hospital for Sick Children in Toronto, who became something of a hero and medical father-figure to him. As soon as he was free from the army, in September 1919, Banting returned to Sick Children’s as a resident in surgery, with a particular interest in orthopedics. Specialization was still fairly primitive in those years, however, and it is misleading to think of Banting as a highly trained orthopedic surgeon. Much of his surgical experience had come from treating wounded soldiers. At Sick Children’s he did general surgery.

  It is not possible to judge Banting’s ability as a surgeon. After he became world famous, and stopped doing surgery, the natural tendency of memory was to say that Fred was a highly skilled surgeon. Evidence of such skill is not contained unambiguously in his insulin notebooks. Banting was certainly experienced, for he had treated more wounds in the summer of 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 Toronto. It was my greatest ambition to obtain a place on the staff of the hospital, but this was not forthcoming.”4 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

  I

  On July 1, 1920, Banting opened an office 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 afternoon, 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 dribble 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 more than it was worth, he discovered, the kind of realization that reinforced his sense of failure. The car soon failed, too, and had to be scrapped.