The Miracle of Isletin How a Midnight Idea Defeated a Death Sentence

1. The Era of the Death Sentence

The air in the Toronto General Hospital ward was heavy with the cloying, sickly sweet scent of acetone the smell of a body consuming itself. In early 1922, fourteen-year-old Leonard Thompson was little more than a skeletal shadow. At just 65 pounds, he was the living embodiment of the “starvation diets” of the era, where patients were restricted to a grueling 450–800 calories a day merely to delay the inevitable. Leonard was drifting in and out of consciousness, his blood sugar a staggering 520 mg/dl.

Before 1922, a diagnosis of what we now call Type 1 diabetes was a grim, inescapable verdict. For children like 14-year-old Leonard Thompson and 11-year-old Elizabeth Hughes, the future was measured in weeks or months. Leonard, once an active boy who loved football, had withered to a skeletal 65 pounds. Elizabeth, the daughter of U.S. Secretary of State Charles Evans Hughes, saw her weight plummet from 34 kilograms to a haunting 21 kilograms.

The only “remedy” available was a medical paradox: the starvation diet. Developed by doctors like Frederick Allen, this treatment required patients to consume as little as 450 to 850 calories per day.

The Cruelty of this Cure “The starvation diet” represents one of the most agonizing chapters in medical history. To prevent the rapid metabolic collapse of diabetic ketoacidosis, physicians essentially forced their patients to die of slow malnutrition instead. It was a trade-off between two different forms of death, buying the patient a few more months of a twilight existence. While these children waited in a state of suspended animation, the scientific community remained locked behind a biological barrier they could not yet breach.

2. The Invisible Barrier: Why Early Scientists Failed

The history of insulin is haunted by the “near-miss” of Eugene Gley. Between 1890 and 1901, the French physiologist conducted experiments proving that aqueous pancreatic extracts could reduce sugar in the urine of diabetic dogs. Yet, in a move that seems inexplicable today, Gley did not publish. Instead, he placed his findings in a sealed envelope and deposited it with the Société de Biologie in 1905. It remained unopened for seventeen years.

By the early 20th century, the pancreas was known to be the seat of the disease. Researchers like Georg Zülzer in Germany and Nicolae Paulescu in Romania had already produced extracts that showed promise in animal trials. However, every attempt to transition these “miracle” substances to human patients resulted in disaster fever, toxic tremors, and painful abscesses.The primary culprit was a chemical “poison” of the body’s own making: trypsin.

The pancreas is a dual-function organ. While the Islets of Langerhans produce the internal secretion (insulin), the surrounding exocrine tissue produces trypsin, a powerful digestive enzyme. When early researchers ground up the whole pancreas, the trypsin acted like a chemical acid, destroying the fragile insulin before it could be isolated. Early extracts were described as “thick brown muck.” These unrefined solutions were filled with foreign proteins that triggered violent immune responses.

This scientific wall remained standing until a young, struggling surgeon woke up in the middle of the night with a radical surgical hypothesis.

3. Banting’s “Midnight Idea” and the Toronto Team

On October 31, 1920, Frederick Banting a veteran of the Great War with a failing private practice was preparing a lecture on metabolism. After reading an article about how blocking the pancreatic duct caused the exocrine tissue to wither, he scribbled a 25-word hypothesis in his notebook. He had no research experience and famously scribbled his initial hypothesis in a notebook with the misspelled headers “Diabetus” and “glycosuria

He took this idea to John J. R. Macleod at the University of Toronto. Macleod, a world-class authority on carbohydrate metabolism, was initially unimpressed by Banting’s lack of a doctorate. He provided a small laboratory and the experimental dogs, then promptly left for a months-long trip to Europe. Notably, Banting began the work entirely without pay.

Charles Best, an undergraduate student who secured his place as Banting’s assistant by winning a coin toss against his friend, Edward Clark Noble. Though they were supposed to swap positions mid-summer, Noble eventually stepped aside because Best had become uniquely “proficient” in the surgical techniques

4.The Breakthrough Method: Duct Ligation

Banting’s “Midnight Idea” was a surgical workaround to the trypsin problem. By tying off (ligating) the pancreatic duct in a living dog, he could force the exocrine tissue the producers of the destructive digestive enzymes to degenerate and die. This left the Islets of Langerhans intact and unencumbered, allowing the researchers to extract the “internal secretion” without it being poisoned by its own organ.

“Diabetus. Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these to relieve glycosuria.”

Frederick Banting’s notebook, Oct 31, 1920

This surgical theory was sound, but the path from the notebook to the bedside would require a summer of gruelling, often bloody experimentation.

4. The Summer of Blood and Success: Dog 410 and Marjorie

The summer of 1921 was spent in a sweltering, cramped laboratory in Toronto. Banting and Best performed dozens of surgeries, inducing diabetes in test dogs and then treating them with their new extract, which they christened “Isletin.”

The first undeniable evidence of success came on July 30, 1921, with a subject known as Dog 410.

The team soon proved that this was not a temporary fluke. A dog named Marjorie (Dog 33) was kept alive for 70 days using their extract, demonstrating that long-term survival was possible through daily replacement of the missing hormone. However, the duct-ligation method was slow, surgically difficult, and yielded only tiny amounts of Isletin. To save human lives, the team needed a larger, more efficient source and a way to make the extract safe for the human bloodstream.

5. Refining the Miracle: Fetuses and Alcohol Extraction

The move from “Isletin” to the clinical-grade “Insulin” required two major technical leaps. First, Banting realized that calf fetuses from slaughterhouses provided a superior source material. Because these fetuses had not yet begun to digest food, their pancreases had not yet started producing the destructive exocrine enzymes. This provided a “naturally pure” supply of insulin that didn’t require the slow process of duct ligation.

Breakthrough Spotlight: James Collip and Alcohol Extraction. The final hurdle was the toxicity of the “brown muck.” James Collip utilized alcohol extraction to solve this. By carefully varying the concentration of alcohol, Collip discovered he could selectively precipitate the insulin while leaving the toxic proteins and impurities in the solution to be washed away. This transformed the extract from a dangerous, fever-inducing sludge into a clear, potent medicine.

The chemical refinement by Collip was the bridge that finally allowed the team to cross from the laboratory into the hospital ward for the ultimate test: Leonard Thompson’s second chance.

6. January 1922: The First Human Success

The first attempt to treat 14-year-old Leonard Thompson on January 11, 1922, was a discouraging failure. Frederick Banting, driven by ego and a desire for personal credit, insisted on using his own unrefined “Isletin” extract. The injection did little to lower Leonard’s blood sugar and caused a painful, sterile abscess at the site.

Twelve days later, on January 23, 1922, the team tried again this time using Collip’s purified insulin. The result was nothing short of a medical miracle.

Clinical Profile: Leonard Thompson
Pre-treatment Blood Sugar: 520 mg/dl
Post-treatment Blood Sugar: 120 mg/dl (within 24 hours)
Physical Outcomes: Leonard became “brighter” and more active; his medical records noted he “looked better and felt stronger.”

Leonard survived 13 more years, eventually dying at age 27 from pneumonia. At the time of his death, he suffered from severe arteriosclerosis, a complication of his long battle with the disease, but he had survived more than a decade past his original “death sentence.”This clinical triumph marked the end of the era of starvation, shifting the focus from the lab to the global distribution of a life-saving gift.

7. A Gift to the World: Patents and the Nobel Prize

The success of insulin brought immediate global fame, but also deep internal friction. Frederick Banting grew increasingly resentful of Macleod, believing the professor was attempting to claim the lion’s share of the credit for work Banting and Best had performed in the trenches.

When the 1923 Nobel Prize in Physiology or Medicine was awarded to Banting and Macleod, Banting was outraged that Charles Best had been overlooked. In a final act of scientific solidarity, Banting shared half of his prize money with Best, while Macleod shared his half with Collip.

8.The Ethics of Insulin

Despite their personal squabbles, the team shared a profound ethical conviction regarding the commercialization of their discovery. In April 1922, Banting, Best, and Collip sold the patent for insulin to the University of Toronto for just one dollar each. They believed that profiting from such a vital discovery violated the spirit of medicine.

“Insulin does not belong to me, it belongs to the world.”

Frederick Banting

In the century since Leonard Thompson’s “miracle,” insulin has evolved from slaughterhouse extracts to synthetic, lab-grown proteins. Today, however, the landscape has shifted. We have traded a “death sentence” for an “epidemic” of diabetes. While 1922 was a triumph of discovery, 2026 is a struggle of management and access. As we look toward future immunotherapies and beta-cell transplants, one must wonder: in today’s multi-billion dollar pharmaceutical landscape, could the radical altruism of a $1 patent ever happen again? Or has the “miracle” of collaboration been eclipsed by the business of the disease?

References

1. Discovery of insulin by Michel Bliss (Photo credits) A must read for all Medical History enthusiast
2. Review article The discovery of insulin P. Diem https://doi.org/10.1016/j.deman.2021.100049
3. The “miracle” discovery that reversed the diabetes death sentence. NobelPrize.org. Nobel Prize Outreach 2026. Fri. 10 Apr 2026
4. The Discovery of Insulin: An Important Milestone in the History of Medicine Ignazio Vecchio