Insulin was not discovered in a single eureka moment but pieced together over decades of physiological research, animal experiments, bitter personal rivalries, and at least one priority dispute that remains contested a century later. The name most associated with the breakthrough is Frederick Banting, a young Canadian surgeon who, alongside medical student Charles Best, produced a crude pancreatic extract in the summer of 1921 that lowered blood sugar in diabetic dogs. But the path from that crude extract to a treatment that could safely be injected into a dying human being required the work of biochemist James Collip and the laboratory resources provided by physiology professor J.J.R. Macleod, and the question of who truly “discovered” insulin has never had a clean answer.
What Diabetes Looked Like Before Insulin
To appreciate why the discovery mattered so much, you need to understand what a diabetes diagnosis meant in 1920. For people with what we now call type 1 diabetes, diagnosis was essentially a death sentence. In the decade before insulin became available, the most prominent treatment approach in America was severe caloric restriction. Physicians Frederick Allen and Elliott Joslin promoted extreme fasting and undernutrition as a way to prolong life, though critics called it “starvation dieting,” and some patients literally starved to death on the regimen.1PubMed Central. Why were “starvation diets” promoted for diabetes in the pre-insulin period? Children diagnosed with diabetes were kept on diets as low as a few hundred calories a day. Photographs from the era show emaciated patients who looked more like famine victims than hospital residents. The choice, bluntly, was to starve slowly or slip into a diabetic coma and die quickly. That was the backdrop against which researchers were racing to find the substance the pancreas seemed to produce.
The Pancreas Connection
The scientific trail starts well before Banting. By the late nineteenth century, researchers already suspected that the pancreas played a central role in regulating blood sugar, but the proof was indirect. The pivotal experiment came in 1889, when the German-Lithuanian physician Oskar Minkowski and his colleague Josef von Mering surgically removed the pancreas from a dog and observed that the animal rapidly developed severe diabetes. Minkowski went further, demonstrating that the disease was caused by the absence of some active substance the pancreas released into the bloodstream, not simply by a digestive problem.2PubMed Central. European research, the cradle of the discovery of the antidiabetic hormone: the pioneer roles and the relevance of Oskar Minkowski and Eugène Gley That insight reframed diabetes as a hormonal deficiency rather than a dietary ailment, and it set off a generation of attempts to isolate the missing substance.
The problem was that the pancreas produces both digestive enzymes (its exocrine function) and hormones (its endocrine function), and whenever researchers tried to grind up the whole organ and extract the hormone, the digestive enzymes chewed it up first. Trypsin, a powerful protein-digesting enzyme made by the pancreas, destroyed the very hormone scientists were trying to capture. For more than thirty years after Minkowski’s experiment, dozens of researchers across Europe and North America tried and failed to produce a stable, injectable extract. Some came tantalizingly close.
The Europeans Who Came Close
Among the most notable near-misses was the German researcher Georg Zülzer, who as early as 1906 to 1908 prepared pancreatic extracts that lowered blood sugar in diabetic dogs and even injected them into a small number of human patients. The results were promising but plagued by severe side effects from impurities, and Zülzer lacked the resources and institutional support to refine the extract further.3PubMed. 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism The disruptions of World War I then stalled European diabetes research for years.
The Romanian physiologist Nicolae Paulescu represents a more complicated case. Working in Bucharest, Paulescu developed a pancreatic extract he called “pancreine” and published results in a French-language physiology journal on August 31, 1921, demonstrating that his extract lowered blood sugar and reduced sugar in the urine of diabetic dogs.4PubMed Central. Centenary of Insulin Discovery (1921-2021): Nicolae Paulescu’s Original Contributions That date is significant: it means Paulescu’s publication appeared around the same time Banting and Best were conducting their own dog experiments in Toronto, though Paulescu never advanced to successful human trials. His supporters have argued that he deserves recognition as a co-discoverer, or even the primary discoverer, of the antidiabetic hormone.5PubMed. Nicolae Constantin Paulescu: the first explicit description of the internal secretion of the pancreas His detractors point out that pancreine was never purified enough for safe clinical use and that Paulescu did not take the final steps to turn a laboratory observation into a treatment.
Banting’s Idea and the Toronto Experiments
Frederick Banting was not a diabetes researcher. He was an orthopedic surgeon in London, Ontario, with a part-time teaching position and a struggling private practice. In October 1920, while preparing a lecture on the pancreas, he read an article describing how blocking the pancreatic duct caused the enzyme-producing tissue to wither away while leaving the islets of Langerhans, the tiny cell clusters believed to make the blood-sugar-regulating hormone, intact. A thought struck him: if you ligated the duct first and waited for the exocrine tissue to atrophy, you could then extract the hormone without trypsin destroying it.
Banting brought his idea to J.J.R. Macleod, a well-established professor of physiology at the University of Toronto who was one of the leading authorities on carbohydrate metabolism. Macleod was skeptical but gave Banting lab space, ten dogs, and the assistance of Charles Best, an undergraduate student who could perform blood-sugar measurements. In May 1921, Banting and Best began their experiments, ligating the pancreatic ducts of dogs, waiting weeks for the tissue to degenerate, then extracting what remained.6PubMed. Insulin: discovery and controversy They were inexperienced researchers and struggled with basic surgical technique and glucose measurement, losing several dogs to complications before getting usable results.7Diabetes Epidemiology and Management. The discovery of insulin
By late July 1921, they had their first clear success: a depancreatized dog given an injection of their extract showed a measurable drop in blood sugar. Over the following months, they repeated and refined the experiment, eventually discovering that they did not actually need to ligate the duct first. Fresh whole-pancreas extracts, if handled quickly enough and kept cold, also worked. Banting’s original hypothesis about duct ligation turned out to be largely unnecessary, though it had served the accidental purpose of getting him into the lab.
Collip’s Purification and the First Human Injection
The extract Banting and Best produced could lower blood sugar in dogs, but it was far too impure to inject safely into a person. It contained proteins, fats, salts, and other contaminants that would cause dangerous fevers and abscesses. This is where James Bertram Collip entered the picture. Collip was a biochemist visiting the University of Toronto on a sabbatical from the University of Alberta, and Macleod assigned him the task of purifying the extract for clinical use. Over the winter of 1921 to 1922, Collip developed a method using different concentrations of alcohol to selectively precipitate the active hormone while leaving most contaminants behind.
The first human test came on January 11, 1922, when fourteen-year-old Leonard Thompson, a boy wasting away from diabetes at Toronto General Hospital, received an injection of Banting and Best’s extract. The results were disappointing: Thompson’s blood sugar dropped only modestly and he developed a sterile abscess at the injection site, likely due to impurities. Twelve days later, on January 23, Thompson received a second injection, this time using Collip’s more refined extract. The effect was dramatic. His blood sugar fell sharply, sugar disappeared from his urine, and his clinical symptoms improved markedly.8Diabetology. Insulin Past, Present, and Future: 100 Years from Leonard Thompson Thompson lived another thirteen years, dying in 1935 of pneumonia, a lifespan that would have been unthinkable without insulin.
Over the following weeks, the Toronto team treated more patients, and the results were consistent enough that word spread rapidly through the medical community. Children who had been skeletal and near death began gaining weight and recovering energy. The transformation was so striking that physicians who witnessed it described it in almost miraculous terms.
The Nobel Prize and the Fights Behind It
The 1923 Nobel Prize in Physiology or Medicine was awarded to Frederick Banting and J.J.R. Macleod for the discovery of insulin. The decision instantly ignited a feud that had been simmering for more than a year. Banting was furious that Macleod, whom he regarded as a hands-off supervisor who had contributed little to the actual bench work, was honored instead of Best, the student who had been at his side through the summer’s experiments. Banting briefly threatened to refuse the prize entirely.6PubMed. Insulin: discovery and controversy
He relented but made a pointed public gesture: he immediately announced he was splitting his prize money with Best, making clear whom he considered his true partner. Macleod responded by splitting his share with Collip, the biochemist whose purification work had made clinical use possible.9PubMed. The history of the Nobel prize for the discovery of insulin The dueling money splits became one of the most famous episodes in Nobel history, a public display of the acrimony behind a lifesaving discovery.
Historians who have examined the lab notebooks and correspondence generally agree that the truth falls somewhere between the two camps. Banting provided the initial idea and the relentless drive to pursue it. Best performed the day-to-day experiments and glucose measurements. Macleod provided laboratory space, funding, scientific credibility, and crucial guidance on experimental design, and he directed the clinical trials. Collip solved the purification problem that turned a crude animal extract into something that could safely enter a human vein. Leaving any one of the four out of the story distorts it. The Nobel committee’s decision to name only two of them guaranteed lasting resentment.
Paulescu’s Legacy and Its Complications
The question of whether Paulescu should share credit for discovering insulin has never fully been resolved, and it is entangled with politics in a way that makes dispassionate assessment difficult. On scientific grounds, Paulescu’s publication in August 1921 described experiments that clearly demonstrated a pancreatic extract capable of lowering blood sugar. Some historians of science argue that by the standards of priority, where the first to publish an observation receives credit, Paulescu’s claim is legitimate. European researchers Zülzer and Paulescu have both been described as meeting the requirements of the priority rule for the antidiabetic hormone, with geopolitical factors including the World Wars delaying the purification process in Europe.3PubMed. 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism
However, Paulescu’s legacy is inseparable from his virulent antisemitism. He publicly promoted anti-Jewish ideology in academic and political settings and co-founded far-right antisemitic political parties in Romania in the early 1920s, playing what historians describe as a pivotal role in the spread of antisemitism in his country.3PubMed. 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism When a proposal was made in 2003 to erect a monument to Paulescu outside the International Diabetes Federation headquarters in Brussels, Jewish organizations and diabetes researchers protested, and the plan was abandoned. The episode illustrates how the question of scientific credit can become entangled with moral judgment. Paulescu’s science was real, but efforts to honor him have repeatedly foundered on the ugliness of his political life.
Early Problems with Insulin Therapy
The availability of injectable insulin after 1922 was transformative, but early insulin was far from the refined product patients use today. The first preparations were extracted from the pancreases of cattle and pigs, and they carried along proteins and peptide contaminants that the human immune system recognized as foreign. Allergic reactions were common. Local symptoms like redness, swelling, and itching at the injection site occurred in roughly one in twenty patients even decades into insulin therapy.10PubMed. Immunogenicity and allergenic potential of animal and human insulins A minority of patients developed systemic allergic reactions, and some formed high levels of antibodies against the animal insulin that made the treatment progressively less effective, a condition called immune-mediated insulin resistance.
Another visible problem was lipoatrophy, the loss of fatty tissue at injection sites, which created unsightly dents or hollows under the skin. Studies reported lipoatrophy in anywhere from about one in ten to more than half of patients receiving older, less-purified bovine and porcine insulin preparations.10PubMed. Immunogenicity and allergenic potential of animal and human insulins Research also showed that the immune system reacted more strongly to bovine insulin than to porcine insulin, since pig insulin differs from human insulin by only a single amino acid, while cow insulin differs by three. This finding gave clinicians a rationale for preferring porcine insulin in patients who developed allergies.11PubMed. Insulin allergy: differences in the binding of porcine, bovine, and human insulins with anti-insulin IgE
Supply was another chronic headache. Producing enough animal-sourced insulin to meet growing global demand required enormous quantities of pig and cattle pancreases from slaughterhouses. The supply chain was fragile and geographically uneven, and the idea that the world’s insulin-dependent diabetics were all relying on a byproduct of the meat industry made researchers anxious about long-term sustainability.
The Shift to Synthetic Human Insulin
The limitations of animal insulin drove decades of work toward producing a version identical to the human hormone. The breakthrough came in the late 1970s and early 1980s with recombinant DNA technology. Researchers figured out how to insert the gene for human insulin into bacteria, essentially turning microorganisms into tiny insulin factories. One approach involved engineering E. coli bacteria to produce the two protein chains that make up the insulin molecule separately, then combining them into the finished hormone.12PubMed. Temperature-induced production of recombinant human insulin in high-cell density cultures of recombinant Escherichia coli In 1982, recombinant human insulin became the first genetically engineered pharmaceutical product approved for sale, marking a turning point not just for diabetes care but for the entire biotechnology industry.
With human insulin widely available, the immunological problems of the animal-insulin era largely disappeared. Lipoatrophy became rare. Severe allergic reactions dropped to almost zero. Immune-mediated insulin resistance, once a real clinical threat, essentially vanished from practice. Later advances produced insulin analogs, molecules slightly modified from natural human insulin to act faster or last longer, giving patients and physicians much finer control over blood sugar throughout the day.
Why the Discoverers Gave Away the Patent
One of the most frequently cited facts about insulin’s history is that Banting, Best, and Collip sold their patent to the University of Toronto for one dollar each. The decision was deliberate and philosophical. Banting reportedly felt that profiting from a lifesaving medical discovery was ethically wrong, and the team transferred the patent to the university so that it could license manufacturers freely and ensure broad access. The university then worked with pharmaceutical companies, most prominently Eli Lilly in the United States and Connaught Laboratories in Canada, to scale up production rapidly.8Diabetology. Insulin Past, Present, and Future: 100 Years from Leonard Thompson Within a year of Thompson’s successful treatment, insulin was being manufactured on an industrial scale and shipped to hospitals across North America and Europe.
The irony of this decision has not been lost on modern observers. Insulin is now one of the most expensive recurring medication costs for patients in several countries, particularly the United States, where list prices for newer analog insulins have risen dramatically over the past two decades. The discoverers’ intention was that no one should die because they could not afford the treatment. The gap between that intention and the current reality is a source of persistent public anger and ongoing policy debate.
What the Priority Debate Tells Us About Scientific Discovery
The insulin story is often used in history-of-science courses as a case study in how discoveries really happen, which is to say, messily. The clean narrative, that Banting had a brilliant idea, tested it, and saved the world, was always a simplification promoted partly by Banting himself and partly by Canadian national pride. The more accurate version involves a flawed hypothesis (duct ligation turned out to be unnecessary), dependence on the expertise of colleagues Banting resented, and a long trail of European predecessors whose work the Toronto team built on, sometimes without adequate acknowledgment.
Macleod, for his part, spent decades after the Nobel Prize defending his contributions, which Banting’s allies systematically minimized. Collip, the quietest of the four, returned to his own biochemistry career and rarely spoke publicly about the episode. Best, who outlived the others, spent much of his later career lobbying for recognition as a co-discoverer of equal standing, and largely succeeded in the popular imagination if not in the Nobel record. The relationships among the four men never recovered. Banting and Macleod could barely be in the same room after the prize was announced.
The controversy also reveals something about how scientific credit gets assigned. Priority claims matter enormously to researchers, and the insulin case shows how factors beyond pure science, such as institutional resources, geopolitical disruption, language barriers, and personal politics, determine who gets remembered. Paulescu published in French in a Belgian journal; Banting published in English from a well-connected North American university with pharmaceutical industry ties. Zülzer worked in Germany on the eve of a world war. The science each of them did was real, but the circumstances around the science shaped whose names ended up in the textbooks.