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In a brilliant, definitive history of one of the most significant and controversial medical events of modern times, award-winning historian Michael Bliss brings to light a bizarre clash of scientific personalities. When F. G. Banting and J. J. R. Macleod won the 1923 Nobel Prize for discovering and isolating insulin, Banting immediately announced that he was dividing his share of the prize with his young associate, C. H. Best. Macleod divided his share with a fourth member of the team, J. B. Collip. For the next sixty years medical opinion was intensely divided over the allotment of credit for the discovery of insulin. In resolving this controversy, Bliss also offers a wealth of new detail on such subjects as the treatment of diabetes before insulin and the life-and-death struggle to manufacture insulin.
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About the Author
Michael Bliss is University Professor Emeritus at the University of Toronto, a recipient of the Order of Canada, and an honorary Fellow of the Royal College of Physicians and Surgeons of Canada. He is the award-winning author of many books, including William Osler: A Life in Medicine and Harvey Cushing: A Life in Surgery.
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THE DISCOVERY OF INSULIN
By Michael Bliss
The University of Chicago Press Copyright © 2007 Michael Bliss
All right reserved.
Chapter One A Long Prelude
A person becomes diabetic when the body starts losing the ability to utilize its fuel. The food taken in is no longer fully transformed, or metabolized, into energy. Instead, nutrients begin passing through the system; hence the origin of "diabetes," from the Greek word meaning siphon or pipe-like.
A seventeenth-century English surgeon called diabetes "the pissing evile." The frequent and voluminous urination by severe diabetics (as much as ten to fifteen quarts a day), accompanied by their unquenchable thirst, had caused the disease to be recognized thousands of years before by the Egyptians and Greeks. In the first century A.D., Arataeus described the disease as "a melting down of the flesh and limbs into urine." When early physicians found that the urine of diabetics was sweet to the taste, they realized it was heavy with sugar. Gradually the Latin word for honey/ sweet, "mellitus," was added to distinguish the disease from diabetes insipidus, a pituitary disorder in which a large volume of sugar-free urine is passed (containing no sugar, the urine is insipid to the taste). Diabetes mellitus was also called the sugar disease or the sugar sickness. That was a fair description, for the most obvious problem in diabetes mellitus is the body's failure to be able to burn much of the simple glucose made from its food, especially from carbohydrates. Instead of being absorbed into the cells, the glucose remains in the bloodstream. The kidneys normally remove sugar from the body's waste water, but in a diabetic's system the sugar overload is too great. Glucose spills into the urine; the quantities of urine greatly increase; and as the body loses liquids a terrible thirst develops as the system craves renewal. Its craving for sugar leads to a terrible hunger, especially for carbohydrates.
Frequent urination (polyuria), constant thirst (polydipsia), and excessive hunger (polyphagia) are the classic symptoms of diabetes. They are often accompanied by fatigue or weakness, and then rapid weight loss as the body begins to fail from lack of nourishment.
Diabetes seems to be brought on by a variety of factors. It is most commonly found in people over forty whose metabolic system has had to work hard during their lives to cope with over-nourishment leading to obesity. That kind of "maturity-onset" (or type 2) diabetes often develops gradually over many years, and the early symptoms are hardly noticeable. In younger people, however, the system's failure is more commonly sudden and serious. "Juvenile-onset" (type 1) diabetes may in some instances have a viral cause. In both types, however, there is often an hereditary predisposition to diabetes, an inherited genetic or systemic weakness that worsens, either gradually or suddenly, under the influence of other factors.
Tasting the urine was doctors' original test for diabetes. Early in the nineteenth century chemical tests were developed to indicate and measure the presence of sugar in the urine, that is, the condition of glycosuria. A patient showing glycosuria was generally deemed to be diabetic (other disorders that could cause sugar in the urine were far less common than diabetes and were usually ignored), so diabetes was sometimes defined as a condition in which glycosuria exists.
Perhaps the continual thirst and the constant pissing would develop gradually, as it often did in adults. Perhaps a ten-year-old boy would suddenly want quarts and quarts of milk or water, or be eating to extremes ridiculous even in a ten-year-old. A severe illness might set off the symptoms, which could also include a constant itching in the genital areas, erratic skin sensations, sometimes blurred vision. The symptoms would mount until you visited your doctor. He tested the urine, found sugar, and pronounced you diabetic. By the early twentieth century, urine tests were often being made routinely on hospital patients and as part of life insurance examinations; these disclosed a substantial number of fairly mild diabetics.
But there was no agreement on the exact definition of diabetes. Diagnostic methods were uncertain and changing. So were statistical methods. This all meant that it was impossible to know how many diabetics there were in any given country in, say, the year 1920. There tended to be more diabetics among peoples who were prosperous and well-nourished rather than among the poor and lean. In the early twentieth century the disease was particularly noticed among wealthy Jewish people, and seems to have been most visible in the richest countries, notably the United States and Germany. As nations became richer and peoples became better nourished, and as vaccines, anti-toxins, and sanitary measures began to reduce the death rate from infectious diseases, the prevalence of diabetes was increasing. By 1920 between 0.5 and 2.0 per cent of the population of industrialized countries had diabetes.
It was easier to diagnose diabetes than it was to treat the disease. Without treatment the "progress" of diabetes was downwards. The effects of the disease were far more wide-ranging than weight loss and a general weakening of the system. The blood vessels of the eyes and lower extremities of an untreated diabetic are particularly liable to be damaged. Longstanding diabetics often suffered from cataracts, blindness, and severe foot and leg infections which were often accompanied by gangrene. They had lowered resistance to disease of all kinds, and were as likely to be destroyed by tuberculosis or pneumonia as by the deterioration caused by diabetes itself. Boils and carbuncles plagued diabetics, often fatally. Doctors often let gangrene and other operable conditions take their course because few diabetics survived the complications and trauma arising from surgery. All wounds healed badly. Severely diabetic people were often impotent or sterile; those women who could conceive were seldom able to carry the foetus to full term.
The infections and the other complications were often the cause of death in older diabetics whose condition developed slowly. In the young, and in the severely diabetic older patients, the diabetes itself destroyed the body, often very quickly. The life expectancy of juvenile diabetics was less than a year from diagnosis. The wasting away of the flesh from lack of nourishment could be dreadful in itself: "When he came to the hospital he was emaciated, weak and dejected; his thirst was unquenchable; and his skin dry, hard and harsh to the touch, like rough parchment." But the breakdown was more general, for the body was unable to metabolize its fats and proteins properly either. As it struggled to assimilate fats in place of carbohydrates, the system became clogged with partially burned fatty acids, known as ketone bodies. When the doctors found an abundance of ketones in the urine (ketonuria), they knew the diabetes was entering its final stages. They could smell it, too, for some ketone bodies were also volatile and were breathed out. It was a sickish-sweet smell, like rotten apples, that sometimes pervaded whole rooms or hospital wards.
The diabetic suffering from acid-intoxication or acidosis (often used synonymously with ketosis) was losing the battle. Food and drink no longer mattered, often could not be taken. A restless drowsiness shaded into semi-consciousness. As the lungs heaved desperately to expel carbonic acid (as carbon dioxide), the dying diabetic took huge gasps of air to try to increase his capacity. "Air-hunger" the doctors called it, and the whole process was sometimes described as "internal suffocation." The gasping and sighing and sweet smell lingered on as the unconsciousness became a deep diabetic coma. At that point the family could make its arrangements with the undertaker, for within a few hours death would end the suffering.
Turn-of-the-century doctors tried to neutralize the fatty acids by giving comatose diabetics alkali solutions, most commonly sodium bicarbonate. The procedure was seldom effective in the early stages of diabetic coma, never effective in deep coma. If diabetes was to be treated at all, it had to be in the early stages. Perhaps something could be done about the sugar problem.
Like almost all other patients, diabetics before the mid-1800s were done more harm than good by doctors' bleeding and blistering and doping. The last vestige of these futile practices was the use of opium to treat diabetes; it was still being mentioned by William Osler in 1915, and in 1919 the leading American diabetologist, Frederick Allen, complained that the opium habit in diabetic treatment "is very difficult to break even at the present time." Opium dulled the despair.
Another treatment lasting into the twentieth century was based on the notion that a diabetic needed extra nourishment to compensate for the nutritive material flowing out in his urine. Therefore the patient should eat as much as possible. A French doctor in the late 1850s, Piorry, refined the idea and advised diabetics to eat extra large quantities of sugar. A physiologist who became an advocate of his views had the misfortune to become diabetic himself, practised what he preached, and died very quickly. In the early 1900s there were still ignorant diabetics and ignorant doctors for whom diabetes therapy involved increasing the sugar consumption. Even sophisticated doctors were constantly tempted to try to help diabetics gain weight. Allen believed it was still vital to combat "the modern fallacy of replacing through the diet the calories lost in the urine."
The first important advance came when doctors gradually came to espouse the reverse of the extra-feeding idea. If the system could not handle all its food, perhaps it should not be given so much food to try to handle. Perhaps the extra food diabetics took in because of the body's lust for nourishment actually increased the strain on the system, making things worse. Carbohydrates seemed particularly villainous. If the diabetic's body could not metabolize them, perhaps he should be given a diet low in carbohydrates.
Another French doctor, Bouchardat, more than made tip for Piorry's disaster by beginning to work out individual diets for his diabetic patients. Already experimenting with the use of periodic fast days, on which no food would be taken, Bouchardat observed the actual disappearance of glycosuria in some of his patients during the rationing while Paris was besieged by the Germans in 1870. He also noticed that exercise seemed to increase a diabetic's tolerance for carbohydrates. "You shall earn your bread by the sweat of your brow," Bouchardat remarked to a patient pleading for more of what was then everyone's staple.
The unwillingness of diabetics to follow diets was and still is the single most difficult problem physicians had to face as they tried to treat the disease. The important late nineteenth century Italian specialist, Cantoni, isolated his patients under lock and key. A disciple of his system, the German physician Bernard Naunyn, would lock patients in their rooms for up to five months when necessary to obtain "sugar-freedom." Because diabetes was then thought to involve only a failure of carbohydrate metabolism, the diets contained a minimum of carbohydrates and a very high proportion of fat, sometimes extremely high if a doctor believed he should replace lost calories and build up a diabetic's weight and strength.
Any low carbohydrate diet, even if fats more than compensated for the calories lost, was unappetizing over a long period of time. So it seemed a great breakthrough in 1902 when the German, von Noorden, announced his "oat-cure" for diabetes. Suddenly a diabetic could increase his carbohydrate rations so long as they were in the form of foods made from oatmeal. An enormous research effort was begun by nutritionists to find out what it was that made oatmeal more assimilable than other carbohydrates (bananas, the von Noordenites found, seemed to be the next best). Actually, the oat-cure was only the most popular of a long line of carbohydrate "cures" offered from time to time - the milk diet, the rice cure, potato therapy, and others. There may be a direct link between these early fads in diet therapy for diabetes and popular fad diets of the late twentieth century.
Low-carbohydrate diets did often reduce or eliminate glycosuria (leading almost as of ten to the conclusion that the diabetes was cured, followed by a resumption of normal diet, followed by more glycosuria). Milder diabetics, usually older ones, who kept to a diet reasonably well were sometimes able to live with their disease for years without too much discomfort. Severe diabetics, especially children, seemed seldom helped by high-calorie, low-carbohydrate diets. They deteriorated almost as quickly as before, and in fact it was later argued that the high fat content of the diets speeded the development of acidosis leading to coma. Like cancer, diabetes was not a satisfying disease to treat. (It could be financially rewarding to treat, of course, particularly if a doctor specialized in mild cases and thereby claimed a high success rate as measured by the long lives of his patients; it also helped if all patient deaths from infections, tuberculosis, or other complications were not counted as deaths from diabetes.) A British doctor made a famous flippant remark about a French diabetologist: "What sin has Pavy committed, or his fathers before him, that he should be condemned to spend his life seeking for the cure of an incurable disease?"
The quip was actually a tribute to the dedication of medical scientists. Their basic strategy in the search for a cure for diabetes involved first finding the cause of the disease. The common-sense assumption that the problem was in the stomach gradually faded as physiologists came to understand the role of other organs in metabolism. Claude Bernard, for example, showed that it is the liver, transforming material assimilated in digestion, that dumps sugar into the bloodstream. So perhaps diabetes was a liver disease. Except that from the middle of the nineteenth century there was a gradually accumulating body of evidence from autopsies on diabetics that the disease was sometimes accompanied by damage to a patient's pancreas - and, more important, that patients with extensively damaged pancreases almost always had diabetes.
The pancreas is a jelly-like gland, attached to the back of the abdomen behind and below the stomach. It is long and narrow and thin, irregular in size, but in humans usually measuring about 20 x 6 x 1 centimetres and weighing about 95 grams. To the layman the pancreas appears to be a not very interesting cluster of blobs of fleshy material. Animal pancreases, along with thymus glands and sometimes testes, have long been considered delicacies; their gourmet name, sweetbreads, appears to have nothing directly to do with sugar or diabetes.
The main function of the pancreas appeared to be to produce digestive enzymes. These are secreted through the pancreatic ducts into the duodenum (or small intestine), where they become the important constituents of the juices working to break down foodstuffs passing down the alimentary canal. Surely a straightforward enough job for an organ.
Close studies of the pancreas under the microscope revealed a situation not quite so straightforward. In 1869 a German medical student, Paul Langerhans, announced in his dissertation that the pancreas contains not one, but two systems of cells. There are the acini, or clusters of cells, which secrete the normal pancreatic juice. But scattered through the organ and penetrating the acini in such a way that they often seem to be floating in a sea of acinar cells, Langerhans found other cells, apparently unconnected to the acini. He declared himself completely ignorant of their function. Several years later the French expert, Laguesse, named these mysterious cells the islands or islets of Langerhans (î les de Langerhans). He suggested that if the pancreas has some other function in the system besides secreting digestive juice, the islet cells are probably involved.
Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in the medical clinic of the University of Strasbourg. Oskar Minkowski and Joseph von Mering had disagreed on whether or not the pancreatic enzymes were vital to the digestion of fat in the gut. To settle the issue they decided to try the very difficult experiment of removing the pancreas from a dog, and then observing the result. What would happen to digestion without pancreatic juice?
Excerpted from THE DISCOVERY OF INSULIN by Michael Bliss Copyright © 2007 by Michael Bliss. Excerpted by permission.
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Table of ContentsPreface
Introduction: What Happened at Toronto?
1. A Long Parade
2. Banting's Idea
3. The Summer of 1921
4. "A Mysterious Something"
6. "Unspeakably Wonderful"
8. Who Discovered Insulin?
9. Honouring the Prophets
10. A Continuing Epilogue