Insulin in Toronto, 1921 — the discovery that started peptide pharmacology

The misspelling didn't matter. The idea did.

Diabetes mellitus had been described for centuries. Egyptian papyri mention a condition of excessive urination and wasting. The word itself is Greek for "to pass through" — a description of the relentless thirst and fluid loss that characterized the disease. By 1920, the relationship to the pancreas was known: animals whose pancreases were removed became diabetic within hours. Something in the pancreas regulated blood sugar, and without it, the body could not metabolize glucose. The "internal secretion" hypothesis — that organs might produce chemical messengers that acted at a distance — had been formally articulated since 1902, when Bayliss and Starling identified secretin. But no one had isolated whatever the pancreas was producing. The acinar cells produced powerful digestive enzymes, and every attempt to extract the islets' secretion resulted in a sample contaminated and degraded by those enzymes before it could be tested.

Banting's idea was simple and, in retrospect, obvious — which is often what correct ideas look like afterward. If he ligated the pancreatic duct, the acinar tissue would die, taking the destructive enzymes with it. The islets would remain. He could then extract whatever they were producing from a relatively clean source.

He went to Toronto to pitch the idea. John Macleod, the head of physiology at the University of Toronto, was not immediately impressed. Macleod was a serious scientist with a serious reputation, and the man in front of him was a country surgeon with no research training and an idea built on one paper read at 2 a.m. But Macleod gave him a laboratory, two dogs, and the assistance of Charles Best — a 22-year-old medical student who had just finished his undergraduate degree in biochemistry and physiology. Best was assigned partly by coin flip; his partner in the graduate program, Clark Noble, lost the toss and went on summer vacation. Macleod himself left for Scotland. The work began in May 1921.

Best knew how to measure blood glucose and urine sugar. Banting knew surgery. Together, they were not a conventional research team; they were two people working in a borrowed laboratory through a Toronto summer, operating on dogs under conditions that were crude even by 1921 standards, losing animals to infection and anesthetic errors and their own inexperience. The work was brutal and, for months, inconclusive. Dogs died. Preparations failed. Banting was spending money he didn't have on a project that wasn't working.

By late July it was working. They had a preparation — they called it "isletin" — extracted from the degenerated pancreases of ligated dogs, and when they injected it into a diabetic dog, the blood sugar dropped. The dog got up. It moved around. The effect was temporary, requiring repeated injections, but it was real. Macleod returned from Scotland and was, by this point, considerably more interested.

The problem was scale. Dog pancreases were small and required surgery to prepare. To test isletin in humans — which was, from the beginning, Banting's driving motivation — they needed a preparation pure enough to inject into a person and a supply reliable enough to treat more than one person. Macleod recruited James Collip, a biochemist from the University of Alberta who was on sabbatical at Toronto, to handle purification. Collip was the fourth figure in the story, and in some ways the one whose contribution was most immediately decisive. He spent the next weeks in a kind of biochemical frenzy, working out the precipitation conditions — the alcohol concentrations, the temperature, the pH — that could produce an extract potent and clean enough for a human trial. At one point in January 1922, he succeeded so completely that he briefly couldn't reproduce the procedure and refused to write it down, a decision that generated significant tension.

Leonard Thompson was 14 years old and weighed 65 pounds. He was dying in a bed at Toronto General Hospital, where his father had brought him as a last resort. Type 1 diabetes in 1922 meant starvation diets — the only treatment that kept diabetic patients alive was severe caloric restriction, which slowed the disease without stopping it — and Leonard had been on such a diet for two years. He was skeletal and exhausted, and without something changing, he was going to die within weeks or months. His father consented to the trial.

The first injection, on January 11, 1922, used Banting and Best's preparation, not Collip's purified version. It did not go well. Leonard's blood sugar dropped only modestly, and he developed a sterile abscess at the injection site. The trial was halted. Collip worked for twelve days to improve the purification. On January 23, Leonard received a second injection — Collip's version — and the result was, by any measure, dramatic. His blood sugar fell from 520 to 120 mg/dL. The ketonuria cleared. He felt better. He got up. He ate. Over the following days, other dying patients in the ward received injections. The same thing happened.

Word moved fast through channels that medical word moved along in 1922 — physician networks, hospital administrators, the families of diabetic patients who had been given death sentences and suddenly needed to know if this was real. It was real, but it was not yet available. Banting and Best could not produce enough extract to treat more than a handful of patients, and purification remained imprecise. Macleod negotiated a production partnership with Eli Lilly in Indianapolis, providing the industrial chemistry and scale that a university laboratory could not. By 1923, commercial insulin was available. The transformation was visible in hospitals within months: wards where young diabetics had been dying were filling with patients who were alive and, eventually, discharged.

The 1923 Nobel Prize in Physiology or Medicine was awarded to Frederick Banting and John Macleod. Banting heard the news and was furious. He had not spoken warmly about Macleod since the summer of 1921, when Macleod's absence during the critical experimental period had contributed to what Banting experienced as inadequate credit. He announced publicly that he was sharing his prize money with Best, whose exclusion from the Nobel he regarded as an injustice. Macleod, who had organized and supervised the larger research enterprise, shared his prize money with Collip. The dispute has never been entirely resolved, and the Nobel committee's reasoning has been debated by historians of science for a century. What's clear is that all four contributed something without which the outcome would have been different: Banting's idea, Best's biochemical measurement skills, Macleod's laboratory and scientific direction, and Collip's purification chemistry.

For six decades, the insulin that kept diabetic patients alive was extracted from the pancreases of slaughtered cattle and pigs. Animal insulin worked, but it differed slightly from the human molecule, and some patients developed immune reactions to it; supply was also tethered to the meatpacking industry. The next leap came in 1982, when Eli Lilly — working with the young biotechnology company Genentech, which had inserted the human insulin gene into bacteria — brought Humulin to market. It was human insulin synthesized by E. coli carrying the insulin gene, and it became the first recombinant DNA pharmaceutical approved by the FDA. Because it was structurally identical to the insulin the human body makes, it reduced the immune reactions associated with animal-derived insulin and freed supply from the constraints of animal harvesting. More than a better insulin, Humulin was a proof of principle: a complex human protein could be manufactured precisely, at scale, by programmed living cells. That demonstration seeded the entire modern biologics industry, the field that now produces everything from monoclonal antibodies to the engineered peptides studied today.

What began in that borrowed Toronto laboratory was far more than a treatment for diabetes. It was the proof that a protein produced inside the body could be administered from outside it and still work — the demonstration that the chemistry-only framework of pharmacology had been too narrow. Every peptide and biologic medicine developed in the century since, from recombinant insulin to the GLP-1 agonists, traces back to the moment a dying boy's blood sugar fell and stayed down.