THE TRUTH BEHIND THE DISCOVERY OF INSULIN
Brandon Reines, DVM
PART 1 / PART 2
By carefully studying the pancreas, Barron discovered that the cells in the pancreas known as "acini" had degenerated because of the stone, while the Islets of Langerhans were still intact. Barron concluded that damage to the Islets of Langerhans must lead to the development of diabetes in human patients. Barron's autopsy study gave Banting the idea for removing the long- sought-after antidiabetic substance from the pancreas. He believed that if he tied off (ligated) the pancreatic duct the acini would degenerate, leaving the islet cells intact. Then, he reasoned, he could remove "insulin" from the islet cells, believing that the secretions from the acini had always rendered "insulin" inactive in all previous experiments. In his 1940 memoirs, "The Story of Insulin", Banting wrote:
It was one of those nights when I was disturbed and could not sleep. I thought about the lecture and about the article and I thought about my miseries and how I would like to get out of debt and away from worry.Realizing the critical importance of clinical investigation in the discovery of insulin, Dr. Robert A. Good, former director of Sloan-Kettering Cancer Center in New York, a world-renowned clinical immunologist, now head of the Cancer Research Program at the Oklahoma Medical Research Foundation wrote:Finally about two in the morning after the lecture and the article had been chasing each other through my mind for some time, the idea occurred to me that by experimental ligation of the duct and the subsequent degeneration of the pancreas, one might obtain the internal secretion. I got up and wrote down the idea and spent most of the night thinking about it."(9)
In a recent article in the British Medical Journal, Lord Platt maintains that clinical investigation has failed. Particularly, he indicts the heavily financed clinical investigations of America, and he states that this discipline has contributed little to the great progress in treatment and cure of disease. Instead he attributes all progress to either basic medical sciences [animal experimentation] or the pharmaceutical industry. In his audacious statement, he cites numerous examples to which he attributes no significant role to clinical investigation. Time permitted me to research only a few of his examples, and I am afraid my bias for clinical investigation insists I express a divergent view. I will cite but a single example from Platt's own material and from that argue what I believe is the ridiculousness of his position. Platt contends that insulin was discovered in a department of basic physiology and, thus, gives this discovery to the basic sciences. What was the real story? It was known from the expatiative studies of Von Mering and Minkowski that removal of the pancreas produces an increase of blood sugar. Excitement engendered by this discovery led to numerous attempts to extract an active principle to no avail. In 1920, Banting, a young physician recently returned from an army post after World War I, and apparently still having time to read, was perusing the clinical Journal Surgery, Gynecology and Obstetrics . He happened upon a paper written by Barron of Minneapolis. The focal point of Barron's paper was a single case which he as a young clinical investigator had studied at autopsy. The patient had had an apparent congenital absence of Santorini's duct and had developed a calculus in Wirsung's duct in the head of the pancreas. Behind the stone, presumably from secretory pressure, the acinar tissue had been completely destroyed, but the islets remained intact. The admonition from this experiment of Nature was clear and the "eureka experience" of Banting was so compelling that he rushed to Macleod's department of physiology in Toronto and, with great enthusiasm, presented the experimental approach to Macleod. Only then, together with the medical student Best, did he in a department of physiology proceed to execute the critical experiment. He tied off both pancreatic ducts, destroyed selectively the the acinar pancreas, leaving the islets intact, and extracted in simple aqueous solution the internal secretion of the pancreas so much sought in numerous basic science laboratories of the time. The control of pernicious anemia at about the same time was also the triumph of clinical investigation.(11)So even if one considers Banting and Best's dog experiments to have been a critical element in the discovery of insulin, it is clear that the dog experiments were inspired by clinical observations. In fact, the dog studies were not so much experiments as they were application of a new technique for removing a substance from the animal body. The dogs were being used in the same way that plants are used in medicine: as a source of potentially valuable chemicals for treatment of human disease.
Despite the rather heated controversy over the discovery of insulin that continues to this day, the events that constituted critical components of the scientific process leading to the discovery of insulin are simple and straightforward:
1) The association of diabetes mellitus with disease of the pancreas was first demonstrated by Thomas Crawley in 1788. (12) He performed an autopsy on a patient who had died from the disease and discovered multiple calculi in the organ. From Crawley's observation until the early 1900s, dozens of autopsy studies connected damage to the pancreas with diabetes mellitus. In fact, it was clearly shown that patients with extensively damaged pancreas almost always had diabetes.(13) Based upon this extensive autopsy evidence, scientists hypothesized that a substance in the pancreas controls the level of sugar in the blood. Without the substance, diabetes mellitus ensues. Thus the first critical part of the scientific process, the development of a testable hypothesis, grew out of direct observations of patients.
2) Researchers around the world attempted to extract a substance from the pancreas of various animals to attempt to isolate the mysterious substance that regulates blood sugar. It was not until the Toronto team biochemist, Dr.J.B.Collip, developed a variety of new ways of extracting insulin from ox pancreas that an effective form of insulin was finally discovered.
3) The various pancreatic extracts produced by Collip were then tested on diabetic patients until an extract was at last found that did, in fact, effectively cure certain cases of diabetes mellitus in human patients. Thus, the proof of the hypothesis that the pancreas contains insulin was achieved in the only way it could be acieved: by direct observations of diabetics. Clearly, the hypothesis and its proof - the critical component of scientific method - were based on clinical observations. Bliss himself comes close to this conclusion:
There are really only two tenable views of the 'moment' of discovery. One is that insulin had been discovered when a non-toxic preparation of it reduced the cardinal symptoms of diabetes in a human being. That happened with Collip's insulin in January 1922. And it was the distinction Toronto used in its patent hearing to ditance itself from Zuelzer and the others with their unworkable extracts. According to both insulin patents, the discoverers were Banting, Collip, and Best. To them we should probably add Macleod.From Bliss' own analysis, therefore, insulin was discovered from its effect on human patients; this is the only logical way it could have been discovered. The only animal experiments that Bliss appears to attribute any real scientific value to throughout his treatise are the dog studies of Von Mering and Minkowski in 1889. These experiments were supposedly the first "genuine proof" that a damaged pancreas leads to a drastic elevation in blood sugar, one of the cardinal symptoms of diabetes mellitus. But, as we have seen, there was already abundant autopsy evidence that pancreatic damage leads to diabetes mellitus. The only reason that Von Mering and Minkowski's experiments created such a stir was that the results were consistent with the results of the autopsy - which is really as obvious a case of putting the cart before the horse as any we have seen. The dogma of Koch's postulates was widely accepted by 1889: the postulates essentially maintain that clinical hypothesis must be "proven" by experiments on animals. Thus, according to Koch's postulates, the hypothesis that pancreatic damage leads to diabetes mellitus was not proven until Von Mering and Minkowski removed the pancreases of dogs and showed the blood sugar rise. Ironically, it was long thought that diabetes might be caused by liver damage - based on Claude Bernard's animal experiments.(15) So the animal experiments provided no clear direction and even misled the understanding for many years, though ultimately the illusion was created that animal experimentation had led to the discovery of insulin.The other view, following Darwin's maxim of credit going to the man who convinces the world, is that insulin had been discovered when convincing evidence of its existance had been presented. There is a possible argument that this criterion goes back to Minkowski and Von Mering in 1889. But the much stronger argument is that it leads to the May 3, 1922, presentation to the Associaton of American Physicians: by, at that time, the Toronto team of Banting, Best, Collip, Campbell, Macleod and E.C.Noble. On the basis of authorship of the critical paper every one of the seven was part of the discovery team.
A not uncommon layman's view of the discovery holds that without the Toronto work the world might still be without insulin. This is unlikely. The internal secretion of the pancreas ha dbeen "discovered" theoretically back in 1889; its practical isolation and therapeutic use was only a matter of time, determination, ingenuity, technical skill, and resources....(14)
COMMENTARY
I have just completed reading Michael Bliss' The Discovery of Insulin (the University of Chicago Press: 1982) which contains several revealing passages.
On page 245, Bliss states that the miracle of insulin was not "the overnight achievement of unsung genius, but ... the culmination of a world-wide, thirty-year search involving hundreds of researchers spending millions of dollars." That translates into a lot of dogs (indeed, the most encountered phrase in The Discovery of Insulin is "de-pancreatized dogs" in all its variations).
Well, after all this "research", and after 244 pages of praising dog-mutilators and calling antivivisectionists "surely some of history's most misguided idealists" (page 193), Bliss unwittingly spills the beans. On pages 245-246 he states:
"Because insulin enabled diabetics to live and propagate, and because the disease had a strong hereditary component, the effect of the discovery of insulin was to cause a steady increase in the number of diabetics. Other factors, such as rising calorie intake in the twentieth century, worked in the same direction. This increase, combined with the ongoing difficulties of insulin therapy, and with the changing mix of threats to life and the incidence of infectious disease declined, meant that diabetes posed more medical problems after the discovery of insulin than before."
John R. Abraytis, Attorney
at Law
References:
- Bliss,M. The Discovery of Insulin (Chicago: The University of Chicago Press, 1982) pp.11-12.
- Roberts,F. "Insulin". British Medical Journal, 1922, p.1193.
- Ibid.
- Ibid, p.1194.
- Macleod, J.J.R. "Insulin". Lecture to the XIth International Physiological Congress, July 24, 1923. British Medical Journal, August 4, 1923: 165-172.
- Bliss, p.205.
- Bliss, p.112.
- Bliss, p.113.
- Barron, Moses. "The Relation of the Islets of Langerhans to Diabetes with Special Reference to Cases of Pancreatic Lithiasis." Surgery, Gynecology and Obstetrics, xxxi, 5 Nov. 1920, pp.437-48.
- Banting, E. "The Story of Insulin". Unpublished manuscript, Banting Papers, University of Toronto.
- Good, R.A. "Keystones", The Journal of Clinical Investigation, 47:1466-1471, 1968.
- Opie, E. Disease of the Pancreas, Philadelphia, 1910.
- Ibid.
- Bliss, M. The Discovery of Insulin (Chicago: The University of Chicago Press, 1982), p. 209.
- Bliss, p.25.