The Discovery of Insulin was researched and written hiring a unique window of opportunity. The 1978 of Charles Best, the last surviving member of the discovery team, happened to coincide with the release of the papers of Sir Frederick Banting. Suddenly it was possible to obtain access to complete documentation of the highly controversial events at the University of Toronto in 1921-23 that led to the isolation and emergence of insulin. At the same time, many individuals who had been witnesses to or participants in the discovery, and who were approaching the end of their lives, now felt free to speak frankly for the historical record. Working on this book, I not only uncovered many new collections of documents, but also found alive two of the original patients who had been treated with insulin in Toronto in 1922. Since publication, no significant new collections of documents have surfaced, but 66 of the 68 individuals I interviewed have died. No one can talk to them individuals I interviewed have died. No one can talk to them now, except through the notes of my interviews, which themselves are now part of the archival record.
project were remarkable, exciting, and life changing. They culminated in several of the most exhausting and rewarding days of my life in Cambridge, England, with the late Sir Frank Young, a grand old man of diabetes research and British science generally, as he challenged not only my conclusions, but my spelling and commas, insisting that a book that would be read around the world and for many years be as perfectly argued and polished as possible. "Bliss," he would say, "this book will be read by Fiji Islanders and Nobel laureates. You have to get it right."
so much has happened in the world of diabetes in our time. Although I moved on to other work in the history of medicine and Canadian topics, I made a point of staying in touch with this subject, and expanded upon The Discovery of Insulin with a number of publications. The most important are Banting: A Biography (Toronto, 1984; 2nd ed., University of Toronto Press, 1992), and a scholarly article, "Rewriting Medical History: Charles Best and the Banting and Best Myth," Journal of the History of Medicine and Allied Sciences, 48 (July 1993): 253—74. Read singularly or together, these publications underline the foolishness of believing that insulin was discovered by fish
foolishness of believing that insulin was discovered by Banting and Best. As I believe I make clear in The Discovery of Insulin, it was a collaborative process, drawing on the talents of at least four people as well as the comparatively great research capacity of the University of Toronto, where for many reasons a field of medical dreams had been built. I should have been more explicit in suggesting that J.B. Collip ought to have shared the Nobel Prize for insulin with Banting and Macleod, and in criticizing the sad attempts at historical falsification engineered by Charles Best, a troubled soul. I also have published "Banting's, Best's, and Collip's Accounts of the Discovery of Insulin," Bulletin of the History of Medicine, 56 (Winter 1982-83): 554—68; and "J.J.R. Macleod and the Discovery of Insulin", Quarterly Journal of Experimental Physiology, 74 (1989): 87-96, along with several condensed
foolishness of believing that insulin was discovered by Banting and Best. As I believe I make clear in The Discovery of Insulin, it was a collaborative process, drawing on the talents of at least four people as well as the comparatively great research capacity of the University of Toronto, where for many reasons a field of medical dreams had been built. I should have been more explicit in suggesting that J.B. Collip ought to have shared the Nobel Prize for insulin with Banting and Macleod, and in criticizing the sad attempts at historical falsification engineered by Charles Best, a troubled soul. I also have published "Banting's, Best's, and Collip's Accounts of the Discovery of Insulin," Bulletin of the History of Medicine, 56 (Winter 1982-83): 554—68; and "J.J.R. Macleod and the Discovery of Insulin", Quarterly Journal of Experimental Physiology, 74 (1989): 87-96, along with several condensed
members of the insulin team:J. B. Collip and the Development of Medical Research in Canada, by Alison Li (2003); J.J.R. Macleod: The Co-discoverer of Insulin, by Michael J. Williams (Royal College of Physicians of Edinburgh, Supplement to Proceedings, 1993); Margaret and Charley: The Personal Story of Dr. Charles Best, by Henry Best (2003). E.C. Noble, who lost the famous coin toss to Charles Best, finally receives attention in M. Jurdjevic and C. Tillman, "E.C. Noble in June 1921, and his account of the discovery of insulin," Bulletin of the History of Medicine, 78, 4 (2004): 864-875. With the development of the Internet the University of Toronto has been able to make more than 7,000 pages of the original documents available on its "Discovery and Early Development of Insulin" website, http://digital.library.utoronto.ca/insulin. An Oxford-based British team has done marvelous work creating an oral
What Happened at Toronto? le discovery of insulin at the University of Toronto in 921-22 was one of the most dramatic events in the history of the treatment of disease. Insulin's impact was so sensational because of the incredible effect it had on diabetic patients. Those who watched the first starved, sometimes comatose, diabetics receive insulin and return to life saw one of the genuine miracles of modern medicine. They were present at the closest approach to the resurrection of the body that our secular society can achieve, and at the discovery of what has become the elixir of life for millions of human beings around the world. This book is an attempt to re-create the discovery of insulin as accurately and fully as can be done in a single volume. It draws on a vast body of primary source material never before available to researchers. It reflects no point of view other than a professional historian's obligation to be as objective
and fair as possible. It is written to be read by anyone from a scientist to a high school student, and especially by those in between. Many readers will begin this book believing they have a reasonably clear understanding of the discovery of insulin. It is a story told in several books, in textbook accounts, in films, tapes and television programs. In broad outline, the conventional history is something like this: By the early years of the twentieth century it was understood that the disease named diabetes mellitus involves the body's inability to metabolize or utilize its food, especially carbohydrates. It was also understood that the pancreas holds vthe key to carbohydrate metabolism. When experimental animals had their pancreases removed, they immediately lost the ability to utilize carbohydrates, the amount of sugar in their blood and urine rose sharply, and they soon died from severe diabetes. Various researchers speculated that the pancreas, which secretes digestive enzymes into the gut (its external secretion), must also produce another kind of secretion, one enabling the body to utilize its fuel. The search for the internal secretion of the pancreas had occupied a number of physiologists throughout the world, but by 1920 it had not produced any practical results. In the autumn of 1920 Frederick Banting, a young surgeon in London, Ontario, happened to be reading an article about the pancreas. Banting began thinking about the problem of the internal secretion, and late that night jotted down an idea for an experimental procedure — ligating the pancreatic ducts - that might be a way of isolating an internal secretion. He took
internal secretion, and late that night jotted down an idea for an experimental procedure — ligating the pancreatic ducts - that might be a way of isolating an internal secretion. He took his idea to his alma mater, the University of Toronto, where the Professor of Physiology, J.J.R. Macleod, was an internationally known expert in carbohydrate metabolism. Macleod was at first skeptical of Banting's suggestion, but reluctantly agreed to give him a lab and some dogs for a few weeks during the coming summer. He assigned him a young science student, Charles Best, to do the chemical tests necessary for the work, and then went off to Scotland for his summer holidays. Banting and Best experienced a number of problems with their work in that summer of 1921, the story goes, but soon found that their approach was yielding remarkable results. With the extract of pancreas they had made from duct-ligated
dogs they were able time after time to lower the blood sugar and remove other symptoms from diabetic dogs. Prof Macleod came home to a pair of excited researchers who, by the autumn of 1921, were keeping a severely diabetic dog, Marjorie, alive with their extracts. Marjorie eventually lived for seventy days before being sacrificed; until then diabetic dogs had died within a week or two of their pancreas being removed. By the winter of 1921—22 Banting and Best were giving their first papers on the internal secretion of the pancreas. They were also ready to test their extract on humans. In Toronto General Hospital a young boy, Leonard Thompson, became the first diabetic to receive insulin. His life was miraculously saved. Professor Macleod put his whole laboratory to work on insulin. An American drug firm, Eli Lilly and Company, was
Professor Macleod put his whole laboratory to work on insulin. An American drug firm, Eli Lilly and Company, was brought in to help prepare it in commercial quantities. At the same time, however, the University of Toronto patented the process in order to control the quality of insulin sold to diabetics. By 1923 insulin was being produced in virtually unlimited quantities, and was the stuff of life itself for thousands of diabetics. Late in 1923 the Nobel Prize was awarded for the discovery of insulin. It was awarded to Banting and J.J.R. Macleod. This raises what seems to be the single really controversial point about the discovery: why should Macleod have shared a Nobel Prize for work done in his lab while he was on holiday? It is fairly well known that Banting was dissatisfied with the Nobel Committee's decision. He immediately announced that he was
that he would share his half with J.B. Collip, a biochemist who had joined the team late in 1921 and worked on the development of the extract. There are several commonly held views about this problem of credit. Perhaps the Nobel Committee just made a mistake, possibly because Macleod's name was on some of the early publications. Perhaps Macleod, a German-trained professor, held Teutonic-type notions about the head of a lab meriting credit for everything done in his fiefdom. Perhaps it was a case of human weakness - perhaps Macleod deliberately tried to steal credit from the inexperienced young men who had actually made the discovery. Whatever happened, the judgment of history, at least in North America, has been to remember Banting and Best as the discoverers of insulin. And, of course, it was a magnificent discovery, a medical fairy tale come true of the lone doctor and his partner overcoming
all obstacles to realize an idea and save the lives of millions and millions of people. Surely this is truth stranger than fiction, or it is the truth that makes fiction plausible. Even at first glance, however, we are left with some curiosities. For completeness' sake, it would be interesting to know exactly why Macleod got his half of the Nobel Prize. More curious, come to think of it, who was J.B. Collip? Why did he end up with the same share of the Nobel Prize money that Banting and Best each got? More generally, why was insulin discovered by two inexperienced researchers in a city and a country which had no particular stature in the world of medical research? Was existing research so poorly developed that a total outsider could confound all the experts with a brilliant, untried suggestion? Or was there somehow a large
element of chance involved? Perhaps the Canadians were just lucky. A few readers will know that some articles have already been written on the points raised by these and similar questions. Even most experts, though, will be surprised to know how early the controversy about the discovery of insulin actually began. The first attempt at serious historical assessment of the Toronto work was made almost immediately. In December of 1922 a physiological researcher in Cambridge, England, Dr. Ffrangcon Roberts, wrote a long letter to the British Medical Journal reviewing Banting and Best's first publications. It was a scathing critique of the Toronto "The production of insulin," Roberts investigation. concluded, "originated in a wrongly conceived, wrongly conducted, and wrongly interpreted series of experiments."l Roberts was immediately rebuked for the intemperance of his
letter, indeed for writing the letter at all, by Dr. Henry H. Dale, a leading figure in British research who had recently been in Toronto studying insulin at first hand. Roberts' review, Dale wrote, was "armchair criticism," the kind of destructive comment that "seldom leads to anything but verbal controversy." Whatever might or might not finally be decided about Banting and Best's experiments, nobody could deny that a first-rate discovery had been made. "It is a poor thing," Dale scolded, "to attempt belittlement of a great achievement by scornful exposure of errors in its inception."2 Dale's view that critical discussion of Banting and Best's work amounted to belittlement of a great achievement prevailed in medical and historical circles for the next three decades. There was no point to be served, it was believed, in discussing
made in refining both Banting and Best's flawed experiments and their crude pancreatic extract. "Credit for the discovery of a preparation of insulin that could be used in treatment," Pratt wrote, "belongs to the Toronto investigators Banting, Best, Collip, and Macleod working as a team. Each of these men made an important contribution."3 Pratt's attempt to rewrite the history of the discovery of insulin prompted a sharp reply from a medical historian in Toronto, Dr. W.R. Feasby, who was also an ardent admirer of C.H. Best. The burden of Feasby's 1958 article, "The Discovery of Insulin," in the Journal of the History of Medicine, was that the conventional history of the discovery was correct in all important particulars. "The published and unpublished records of Banting and Best's work establish the fact that convincing proof of the presence of insulin was available in the summer of 1921, when they were working alone..."
Banting and Best discovered insulin, Feasby reiterated; the others helped somewhat in its development.4 Pratt had died. Feasby died before finishing the biography of Best on which he worked for several years. Frederick Banting's second wife, Henrietta, died before making any significant progress on the biography she planned to write of her husband. The Toronto doctor who took over her work, Ian Urquhart, also died. In the meantime medical historians in other countries were beginning to consider the discovery of insulin from the point of view of other people besides the Torontonians who had been working on pancreatic extracts. Before his death (the death rate among those trying to write about the discovery of insulin sometimes seems higher than it is among diabetics), a Scots medical historian, Ian Murray,
published several articles in the late 1960s and early 1970s on the search for insulin. His aim was to show how the Toronto work related to half a century of earlier investigation of the pancreas and diabetes. Insulin had not emerged out of a vacuum, but was the culmination of years of work by dozens of scientists in many countries. Murray was particularly interested in a Romanian scientist, Nicolas Paulesco, who in 1921, just as Banting and Best were starting to work, published very important papers describing successful experiments with pancreatic extracts. Unfortunately for Paulesco, the North Americans moved so quickly into the testing and production of insulin that he never got serious clinical tests of the material he called "pancréine" under way. Paulesco and his work disappeared from history. Now they were resurrected. "Banting and Best are commonly believed to have been the first to have succeeded in isolating
Now they were resurrected. "Banting and Best are commonly believed to have been the first to have succeeded in isolating insulin," Ian Murray wrote. "They have been hailed as its 'discoverers'. Their work, however, may more accurately be construed as confirmation of Paulesco's findings."5 Murray's work revived Romanian interest in a countryman who had apparently achieved so much and been so little honoured. Influenced by the impending fiftieth anniversary of the discovery, members of the Romanian School of Medicine in Bucharest launched a campaign to have Paulesco given his due. As a result of their agitation, the International Diabetes Federation decided to establish a special blue-ribbon committee to prepare a factual account of the various researches leading to the discovery of insulin. The report, published in 1971, was a careful, tightly written summary of historical knowledge about the discovery. Its conclusions,
difficult to simplify because of the subtlety of the argument, were to the effect that Paulesco might indeed have discovered insulin as a therapy for diabetes had not the North Americans been able to move so swiftly and successfully to develop the results of Banting and Best's research. Pancréine probably contained insulin — so did the pancreatic extracts prepared by several earlier researchers, especially a German named Zuelzer — but it was the Canadians who made insulin suitable for the treatment of diabetes.6 The Romanians were not satisfied. Their continued complaints about the composition and work of that committee were secondary to their deep anger at an egregious error Banting and Best had made in their first paper, published in February 1922. In their only reference to Paulesco's work, published before theirs, Banting and Best imply quite wrongly that his results were negative. It is such
complaints about the composition and work of that committee were secondary to their deep anger at an egregious error Banting and Best had made in their first paper, published in February 1922. In their only reference to Paulesco's work, published before theirs, Banting and Best imply quite wrongly that his results were negative. It is such an odd error, with apparently such devastating consequences for Paulesco's reputation. Was this why the Nobel people neglected him? the Romanians asked. The leading Romanians interested in Paulesco's rehabilitation decided that Banting and Best's misrepresentation of his work was too suspicious to explain away as a simple mistake. It was a deliberate distortion of Paulesco's work by Banting, wrote Dr. Constantin Bart in a 1976 article entitled "Paulesco Redivivus." Bart went on to deduce what he thought was the real truth behind Macleod getting half of the Nobel Prize:
Redivivus." Bart went on to deduce what he thought was the real truth behind Macleod getting half of the Nobel Prize: Macleod, well versed in the literature, must have found out about Banting's falsification and threatened him with public exposure unless Banting shared the credit and glory with him, Macleod. The history of the discovery of insulin seems to have included scientific blackmail and a vicious conspiracy to cheat Paulesco out of his rightful share of honour and prizes. Truth indeed stranger than fiction.7 Fanciful as their speculations were, the Romanians had a
Fanciful as their speculations were, the Romanians had a point in wondering why more had not been written about the events at Toronto. Their reviews of the literature on the history of the discovery alerted them to the quarrelling among the discoverers and to all the unresolved historical controversies about Banting and Best's research. With European authorities writing almost jeeringly about the "vrai panier de crabes" at Toronto in 1921—22,8 it was surely time to find out what had really happened. There was one more important publication in the late 1970s. J.J.R. Macleod had died in Scotland in 1935. Thirteen years later a copy of a document found among his papers reached North America. Dated September 1922, it was entitled "A History of the Researches Leading to the Discovery of Insulin," and was Macleod's personal account of the events at Toronto. From 1948 to 1978 the Macleod manuscript had had an underground circulation among a small circle of scholars.
Insulin," and was Macleod's personal account of the events at Toronto. From 1948 to 1978 the Macleod manuscript had had an underground circulation among a small circle of scholars. Fearful of reopening a controversy that might do no one any good, the president of the University of Toronto in the mid- 1950s had quite improperly used his influence to prevent its publication.9 Lloyd Stevenson, who had written Banting's biography many years earlier, finally published the Macleod document in the Bulletin of the History of Medicine in 1978. As the research for my book developed, Macleod's account turned out to be only one of many new documents shedding light on the discovery. It was clear from a careful reading of Macleod that Banting and Best had prepared similar accounts
at the same time in 1922. Manuscripts of these were found. In the Banting Papers was a second long account that Banting had written in 1940. So was the correspondence Banting and Best had had with Macleod in the summer of 1921. So were the original index cards on which Banting and Best had recorded the notes taken from their reading, including their note on Paulesco's prior article. Banting's original notebook, in which he recorded his first idea and the first series of experiments, was discovered. So were many other documents. Some of them were coming to light in the natural course of events, as when the University of Toronto made the Banting Papers available for scholarly research, and when the Nobel Committee of the Caroline Institute in Stockholm agreed to open its archives to qualified researchers. Others emerged because of this project. At the outset I decided to make a more determined and careful search for documents than anyone had previously undertaken, and that search was
than anyone had previously undertaken, and that search was rewarding. My aim was to carry out the historian's job of re-creating the discovery of insulin. As far as possible I wanted to work from contemporary sources. I wanted to ignore the judgments of later writers and put aside the partisan recollections of the discoverers themselves, at least until I had found out from the documents generated at the time - laboratory notebooks, correspondence, published articles, etc. - exactly what had happened. I wanted to reconstruct the insulin research dog by dog, day by day, experiment by experiment. After that it would be proper to reflect on the fallibility of the participants' memories and the validity of the scientists' claims and counter-claims.
of that drama — the tension, interludes, crises, climaxes, ironies, and occasional absurdities — exactly as it happened. In offering this history, I reject the view that the truth will lead to a belittlement of the discovery of insulin or of the discoverers. This is a book about life, disease, death, salvation, and immortality. It is a wonderful thing to be a witness to the struggles of men, weighed down with all the burdens manhood bears, to find a way of enlarging the possibilities of our human condition.
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.
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.
Another French doctor, Bouchardat, more than made up 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.4 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 Naunvn. would lock Datients in their rooms for LID to
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."5 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.6 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 often 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
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?"7 111 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
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.8 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.
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 (fles 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. OskarThe 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
\ two systems of cells. There are the
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 (fles 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
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? In an account written many years later,9 Minkowski described, 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 (iles 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? In an account written many years later,9 Minkowski described how he had kept the
how he had kept the depancreatized dog tied up in his lab while waiting for von Mering to return from a trip. Even though the animal was housebroken and regularly taken out, it kept urinating on the laboratory floor. Minkowski had been taught by his supervisor, Naunyn, to test for the presence of sugar in urine whenever he noticed polyuria. His tests revealed 12 per cent sugar in the dog's urine, the realization that it was suffering from something indistinguishable from diabetes mellitus, and the hypothesis, subsequently demonstrated in case after case, that without its pancreas a dog becomes severely diabetic. Somehow the absence of the pancreas caused diabetes. This was a great experimental breakthrough, due not just to good luck and close observation, but also to the skill of researchers who apparently were performing some of the first successful total pancreatectomies. (Much of the fair amount of skepticism
pancreatectomies. (Much of the fair amount of skepticism with which their finding was greeted related to doubts that they had actually excised the whole pancreas, for parts of it could be easily missed.)* The next problem was to discover how the pancreas regulated sugar metabolism. Was it the absence of pancreatic juice, for example, that brought on the diabetes in a depancreatized dog? Apparently not, for Minkowski confirmed the observations of other experimenters who had ligated and/or cut the ducts leading from the pancreas to the duodenum. Stopping the flow of pancreatic juice in this way caused minor digestive problems, but it did not cause diabetes. Only total pancreatectomy did. When critics pointed out that duct ligation often failed to work, for tied ducts were by-passed and new ducts often formed to replace cut ones, the French dog tied up in his lab while waiting for von Mering to return from a trip. Even though the animal was housebroken and regularly taken out, it kept urinating on the laboratory floor. Minkowski had been taught by his supervisor, Naunyn, to test for the presence of sugar in urine whenever he noticed polyuria. His tests revealed 12 per cent sugar in the dog's urine, the realization that it was suffering from something indistinguishable from diabetes mellitus, and the hypothesis, subsequently demonstrated in case after case, that without its pancreas a dog becomes severely diabetic. Somehow the absence of the pancreas caused diabetes. This was a great experimental breakthrough, due not just to good luck and close observation, but also to the skill of researchers who apparently were performing some of the first successful total
pancreatectomies. (Much of the fair amount of skepticism with which their finding was greeted related to doubts that they had actually excised the whole pancreas, for parts of it could be easily missed.) * The next problem was to discover how the pancreas regulated sugar metabolism. Was it the absence of pancreatic juice, for example, that brought on the diabetes in a depancreatized dog? Apparently not, for Minkowski confirmed the observations of other experimenters who had ligated and/or cut the ducts leading from the pancreas to the duodenum. Stopping the flow of pancreatic juice in this way caused minor digestive problems, but it did not cause diabetes. Only total pancreatectomy did. When critics pointed out that duct ligation often failed to work, for tied ducts were by-passed and new ducts often formed to replace cut ones, the French
revelation helped spread the idea that these hormones, the "vital juices" of popular lore, could be very potent. In the less exotic field of diabetes research, it certainly seemed that both theory and experimental observation pointed towards a potent hormone being produced in the pancreas to regulate metabolism.10 As soon as it was realized that the pancreas controls diabetes, attempts began to treat the disease, literally, with pancreas — just as diseases of the thyroid were being treated with thyroid. Minkowski was the first of many researchers to try to restore the pancreatic function to diabetic animals (others experimented on human diabetics) by preparing and administerin extracts of ancreas. The extracts could be
administering extracts of pancreas. The extracts could be made in a variety of ways; they could also be administered in a variety of ways, although the most obvious were orally and by injection. The important observation would be of sugar in the urine. If an extract reduced glycosuria it might be potent. It might contain the internal secretion; indeed, it might supply the proof that there actually was an internal secretion, for until its effect could be practically demonstrated, the internal secretion of the pancreas was merely a good-looking hypothesis. The results of the early experiments with pancreatic extracts were mixed, tending towards the negative. Some extracts had no effect; some had decidedly harmful effects, throwing the animals into shock or worse. Others had temporary sugar- reducing effects that were more than cancelled out by harmful side-effects — so much so that it was impossible to
tell whether it was the extract or its toxic effect on the system that was the true cause of the reduction in glycosuria. If an extract caused kidney failure, for example, it might be changing the contents and quantity of the urine without affecting the diabetic condition at all. A few researchers did report encouraging results with extracts, but others who tried to repeat their work got discouraging results. It will never be known precisely how many researchers tried giving pancreatic extracts to diabetic animals and humans. Estimates run to more than four hundred. It was an easy experiment for even a country doctor to try, but if the results were not encouraging many would decide there was no point publishing. As it was, there was no shortage of publication, on every conceivable aspect of the problem of diabetes and the pancreas, it seemed. In 1910 Opie complained that the literature on diabetes was voluminous. A few ears earlier
pancreas, it seemed. In 1910 Opie complained that the literature on diabetes was voluminous. A few years earlier Lydia Dewitt estimated that more thought and investigation was going into the islets of Langerhans than any other organ or tissue of the body.ll Despite the discouragement, the search for a workable pancreatic extract continued. Perhaps the problem with extracts was that somehow the pancreas's external secretion, or the tissues producing it, destroyed the internal secretion in the extirpated organ. Laguesse suggested using extracts made from fetal pancreases, because it seemed that the islet cells develop well before the acinar cells in gestation. If the experiment was tried, it failed. So did a number of other experiments involving fish. In certain species of fish the islet tissue had been found to be anatomically distinct from the acinar tissue, making it possible, it seemed, to get an extract
which was more purely an extract of the islets of Langerhans. Between 1902 and 1904 two Scots researchers in Aberdeen, John Rennie and Thomas Fraser, fed an extract of boiled fish islets to four diabetic patients. After inconclusive results, including a toxic reaction when they tried to inject the extract into a fifth patient, they gave up.12 The most persistent and important of the early extractors was Georg Ludwig Zuelzer, a young internist in Berlin who in the early 1900s became interested in the theory that diabetes was actually caused by adrenalin. Experimental evidence that large doses of adrenalin could produce glycosuria convinced Zuelzer that the function of the internal secretion of the pancreas was simply to neutralize adrenalin in the system. He decided to try to prove this by injecting an extract of pancreas into rabbits along with adrenalin. When no glycosuria developed, Zuelzer was encouraged to go on and
glycosuria developed, Zuelzer was encouraged to go on and see if his extract could reduce diabetic symptoms in depancreatized dogs. When it appeared to reduce the sugar excreted in the urine of two diabetic dogs, Zuelzer was encouraged to go further. Dying diabetics were hopeless cases, so it must have seemed that nothing could be lost in experimenting on them. On June 21, 1906, Zuelzer injected eight cubic centimetres of his pancreatic extract under the skin of a comatose fifty-year-old diabetic in a private clinic in Berlin. The next day he injected another ten cc. Whatever effect the extract was having on the patient's glycosuria could not be measured, for the man had lost control of his bladder and was wetting his bed. What was clear was that the patient seemed to be coming back from the edge of the grave. His overall condition improved, his
appetite returned, and his severe dizziness disappeared. But there was no more extract. The patient sank into deep coma on June 30 and died on July 2. What Zuelzer had seen was tremendously encouraging, a diabetic momentarily pulled out of coma. "Whoever has seen how a patient lying in agony soon recovers from certain death and is restored to actual health will never forget it," he wrote years later just after insulin had been discovered in Toronto. He was almost certainly referring to his first experience with his own pancreatic extract, which he named "acomatol."13 Zuelzer had immense practical difficulties carrying out his experiments. It was hard to get a supply of pancreases, for example. Workers at local slaughterhouses thought the doctor who wanted them to give him fresh sweetbreads for medical research must be a little crazy. The extract was not at all easy to make, and had a frustrating tendency to lose its
medical research must be a little crazy. The extract was not at all easy to make, and had a frustrating tendency to lose its potency (Zuelzer tested his batches on rabbits, measuring the potency by the amount of extract needed to neutralize the sugar-creating effects of a unit of adrenalin). But there were those early results, and it was obvious that a workable pancreatic extract would be a wonderful thing. When Zuelzer approached the Schering drug company with his idea they offered him financial support and technical help and applied for patents on his methods. By the summer of 1907 he was ready to try again on humans. The extract produced the amazing effect of completely suppressing for a few days glycosuria and acidosis in a twenty-seven-year-old man. Other diabetics — a six-year-old, a thirty-five-year-old, and two sixty-five-year-olds - had their symptoms dramatically relieved by acomatol. (Some others, it
appears, did not; Zuelzer reported only the most interesting cases.) On the other hand, in every case after the first two there were serious reactions to the injections: vomiting, high fevers, sometimes convulsions. Knowing that his preparation was not yet a practical therapy, Zuelzer was still confident enough to publish his results in 1908. He came to the triumphant conclusion "that it is possible through the injection of a pancreatic extract to eliminate the excretion of sugar, acetone, and acetoacetic acid by a diabetic without making any changes in the patient's diet."14 These exciting findings caught the attention of a worker in the clinic directed by Minkowski in Breslau. J. Forschbach obtained samples of Zuelzer's extract and tested it on three dogs and three humans. His verdict was negative. Yes, Zuelzer's was the first pancreatic extract to suppress glycosuria in both the short and the long run. But it did so at
glycosuria in both the short and the long run. But it did so at the cost of severe toxic side-effects, especially fever, so severe that Forschbach stopped his human experiments for fear of doing permanent damage to achieve only temporary relief. "It will be difficult to convince a patient who has been made severely ill by a single injection," he wrote, "that this result was connected to a significant beneficial effect upon his diabetes." Forschbach was fairly convinced, especially after some impotent extract caused no ill effects in one case, that the cause of the potency and the cause of the side effects were the same. So there was no future in it. Forschbach's 1909 paper on his tests of Zuelzer's extract was decidedly discouraging, and must have been more so because of Forschbach's association with the great Minkowski himself. The giants in the field had passed judgment.15
Using extracts which had gone through various stages of development through mixing the pancreas with alcohol, filtering it, treating the residue, and other chemical procedures, Scott found one formula that gave encouraging results on three of the four diabetic dogs he treated with it. Not only did their sugar excretion diminish, but "if one dared to say it," Scott wrote, the dogs "seemed even brighter for a time after the injection than before it." Like Zuelzer before him and others afterwards who observed the subjective signs of improvement in diabetic animals and patients, Scott was convinced that he had been successful. The first two conclusions of his master's degree thesis were: 1st. There is an internal secretion from the pancreas controlling the sugar metabolism. 2nd. By proper methods this secretion may be extracted and still retain its activity.
still retain its activity. Scott's thesis adviser, the noted physiologist Anton Carlson, did not share his student's confidence. Having just read of recent work by Hédon questioning the effectiveness of pancreatic extracts, Carlson worried that Scott had not sufficiently controlled his experiments. He urged that the conclusions be rewritten, probably supplying the new wording himself: It does not follow that these [good] effects are due to the internal secretion of the pancreas in the extract. The injections are usually followed by a slight temporary rise in the body temperature, and this may be a factor in the lowered sugar output. Physiologists are not agreed as to whether the internal secretion acts by diminishing or retarding the passage of sugar from the tissues into the blood, or by
increasing the oxidation of the sugar in the tissues. The pancreas extract may decrease the output of sugar from the tissues by a toxic or depressor action, rather than by a specific regulatory action of the pancreas secretion....The work is being continued in the hope of clearing up these points.17 Despite his conservatism, Carlson urged Scott to continue the research and work out his "salvation or damnation along the pancreas extract line.... There is something ahead in that line — possibly both shoals and open water. Puzzle: find the channel." Scott tried half-heartedly, attempting to buttress his urinary sugar results with studies of his extract's effect on the blood sugar of cats. He reported the "very surprising" result that it caused an increase in their blood sugar.18 Having struck a shoal, Scott veered away from pancreatic extracts to study problems relating to blood sugar. Before giving up the work, Scott chatted about it with some of
study problems relating to blood sugar. Before giving up the work, Scott chatted about it with some of the other experts in the field. One of these was a professor at Western Reserve University in Cleveland, Ohio, John James Rickard Macleod. Macleod was a Scotsman, trained in Aberdeen, Germany, and London, who had emigrated in 1903 to take his American appointment at the age of twenty-seven. He had been working for several years in the area of carbohydrate metabolism. A competent researcher and a prolific writer and synthesizer of current knowledge in physiology, Macleod was particularly knowledgeable about the literature in his field. The only knowledge we have of his discussion with Scott is that it began with a consideration of how to cure Scott's child's diarrhoea. When the talk turned to pancreatic extracts, Macleod may have discouraged the oun er man, for about this time he was workin on his own
main research contribution to the search for the internal secretion of the pancreas. Macleod was able to show that the findings of two leading Britishers, Knowlton and Starling, who thought they had a pancreatic extract which assisted the heart of a diabetic dog to utilize sugar in the blood, were not repeatable.19 Knowlton and Starling's joined Scott's and Zuelzer's in the list of apparently ineffective pancreatic extracts. Two young Americans, John R. Murlin and Benjamin Kramer, continued to fiddle with pancreatic extracts similar to Knowlton and Starling's, but their work led them off into examinations of the influence of alkaline solutions on metabolism.20 Macleod summarized the state of the search for an internal secretion in his 1913 book, Diabetes: Its Pathological Physiology. After due deliberation he concluded that there was an internal secretion of the pancreas, but suggested several
After due deliberation he concluded that there was an internal secretion of the pancreas, but suggested several reasons why it might never be captured in a pancreatic extract. The powerful pancreatic juice might destroy it; there might be no reserves of it in the pancreas to be captured by extraction; or it might exist in the pancreas only in latent form and not be activated until secreted into the blood. Macleod's own interest and his work tended to be on the behaviour of blood sugar rather than pancreatic extracts. He thought the most convincing proof of the existence of an internal secretion came in Hédon's early work (now questioned by Hédon himself) using grafts of pancreatic remnants to show that a small, isolated portion of the pancreas could stave off diabetes.21 In 1913 Dr. Frederick Allen pronounced what seemed to be the epitaph of a generation's attempts to treat diabetes with
pancreatic extracts: "All authorities are agreed upon the failure of pancreatic opotherapy in diabetes....injections of pancreatic preparations have proved both useless and harmful. The failure began with Minkowski and has continued to the present without an interruption....The negative reports have been numerous and trustworthy. "22 Frederick Madison Allen wrote with particular authority. Born in Iowa in 1876, trained in medicine in California, Allen had come east to do medical research, drifted into a poorly paying fellowship at the Harvard Medical School, and found himself working on problems of sugar consumption. The study turned into three years of intensive research concentratinon diabetes. Most research is reorted u on in
