The Preparation of Insulin
(Best, C. H., and Scott, D. A. (1923) J. Biol. Chem. 57, 709–723)
The story of the discovery of insulin has been well chronicled beginning with a young physician, Frederick Banting, in London, Ontario, imagining that it might be possible to isolate the internal secretions of the pancreas by ligating the pancreatic ducts to induce atrophy of the acinar cells and thereby minimize contamination of the tissue extract with digestive enzymes. Banting presented his suggestion to J. J. R. Macleod, a distinguished physiologist at the University of Toronto who provided Banting with a laboratory for the summer and some dogs for the experiments. Macleod also assigned Charles Best, a young student, to work as Banting's assistant for the summer. During the summer of 1921, Banting and Best made remarkable progress, and by fall they had isolated material from pancreas extracts that dramatically prolonged the lives of dogs made diabetic by removal of the pancreas. In the winter of 1922, Banting and Best treated their first human patient, a young boy, who's life was saved by the treatment. This was a stunning accomplishment. Consider that from the start of the research in the summer of 1921 to treating a human patient successfully in the winter of 1922, the pace, especially by current standards for clinical treatments, was remarkable.
With that achievement, Macleod, who had been initially unenthusiastic about the work, assigned his entire laboratory to the insulin project. He also enlisted the Eli Lilly Company to aid in the large scale, commercial preparation of insulin although the University of Toronto received the patent for insulin production. By 1923, insulin was available in quantities adequate for relatively widespread treatment of diabetes. Although the success of the insulin project was remarkable, the rewards for the research workers were, it seems, quite controversial. The 1923 Noble Prize in Physiology or Medicine was awarded to Banting and Macleod. Apparently, Banting was annoyed at the omission of Best and gave him half of his share of the prize. There was also, perhaps, the feeling that Macleod had done little in the initial stages of the work and was an undeserving recipient. Macleod split his share of the Prize with J. B. Collip who had made contributions to the later stages of the work on insulin purification.
After the spectacular events of 1921–1923, the University of Toronto established the Banting and Best Department of Medical Research separate from the University. Banting accomplished little during the rest of his career and died in a plane crash in 1940. Best, however, had a long successful tenure at the University of Toronto working on insulin and subsequently other important topics including the importance of dietary choline and the development of heparin as an anticoagulant.
The paper selected as this Journal of Biological Chemistry Classic is not itself “classic” in the usual sense. It reviews very well, however, a remarkable body of classic work. The information regarding various procedures that had been developed quickly and compared in attempts to improve the yield and purity of insulin also contains clues to some special properties of the protein, although so little was known at that time about the structure of insulin (or any protein) that there seemed little rationale for its purification. Insulin was crystallized in 1926 by John J. Abel (1). Virtually all of the information in this Introduction is from Ref. 2.⇓⇓
Frederick G. Banting. Photo courtesy of the National Library of Medicine.
Charles H. Best. Photo courtesy of the National Library of Medicine.
- The American Society for Biochemistry and Molecular Biology, Inc.
Abel, J. J. (1926) Crystalline insulin. Proc. Natl. Acad. Sci. U. S. A.12,132– 136
Bliss, M. (1982) The Discovery of Insulin, The University of Chicago Press, Chicago, IL
The discovery of insulin was one of the most dramatic and important milestones in medicine - a Nobel Prize-winning moment in science.
Witnesses to the first people ever to be treated with insulin saw "one of the genuine miracles of modern medicine," says the author of a book charting its discovery.1
Starved and sometimes comatose patients with diabetes would return to life after receiving insulin.
But how and when was the discovery made, and who made it?
How and when was insulin discovered?
The discovery of insulin did not come out of the blue; it was made on the back of a growing understanding of diabetes mellitus during the nineteenth century.
Experiments involving the pancreas were key to the discovery of insulin. The beta cells of the pancreas that produce insulin were discovered in 1869.
Diabetes itself had been understood by its symptoms as far back as the 1600s - when it was described as the "pissing evile" - and the urination and thirst associated with it had been recognized thousands of years before.
A feared and usually deadly disease, doctors in the nineteenth century knew that sugar worsened diabetes and that limited help could be given by dietary restriction of sugar. But if that helped, it also caused death from starvation.
Scientists observed the damaged pancreases of people who died with diabetes. In 1869, a German medical student found clusters of cells in the pancreas that would go on to be named after him.
Paul Langerhans had discovered the beta cells that produce insulin.
Other work in animals then showed that carbohydrate metabolism was impossible once the pancreas was removed - the amount of sugar in the blood and urine rose sharply, and death from diabetes soon followed.
In 1889, Oscar Minkowski and Joseph von Mering removed a dog's pancreas to study its effects on digestion. They found sugar in the dog's urine after flies were noticed feeding off it. In humans, doctors would once have diagnosed the condition by tasting the urine.
But as for the discovery of the "active ingredient" of the pancreas, numerous scientists followed the work of Minkowski and von Mering in their attempts to extract it.
Between 1914 and 1916, it was the Romanian physiologist Nicolas C. Paulescu who first extracted a pancreatic antidiabetic agent that treated dogs - but his experiments would be overlooked in favor of work by other scientists.
Banting, Best, Collip and Macleod
It was in 1921 that Canadian physician Frederick Banting and medical student Charles H. Best would be credited with discovering the hormone insulin in the pancreatic extracts of dogs.
Banting and Best injected the hormone into a dog and found that it lowered high blood glucose levels to normal. They then perfected their experiments to the point of grinding up and filtering a dog's surgically tied pancreas, isolating a substance called "isletin."
The pair then developed insulin for human treatment with the help of Canadian chemist James B. Collip and Scottish physiologist J.J.R. Macleod.
Macleod had been impressed with Banting and Best's work but wanted a retrial of the evidence. He provided pancreases from cows to make the extract which was named "insulin," and the procedures were repeated. Collip's role was to help with purifying the insulin to be used for testing on humans.
Ultimately, the first medical success was with a boy with type 1 diabetes - 14-year-old Leonard Thompson - who was successfully treated in 1922. Close to death before treatment, Leonard bounced back to life with the insulin.
The news rapidly spread beyond Canada, and in 1923 the Nobel Committee decided to award Banting and Macleod the Nobel Prize in Physiology or Medicine.