The Discovery of Insulin

• Introduction
• Chapter 1 The Ancient Scourge: Diabetes Before 1921
• Chapter 2 Starvation and Despair: The Allen Treatment Era
• Chapter 3 A Late-Night Inspiration: Frederick Banting’s Notebook
• Chapter 4 Seeking an Audience: The Meeting with J.J.R. Macleod
• Chapter 5 The Toronto Laboratory: Summer of 1921
• Chapter 6 An Unlikely Partnership: Charles Best Joins the Lab
• Chapter 7 Early Trials: Pancreatic Ducts and Depancreatized Dogs
• Chapter 8 Dog 92:

In the autumn of 1920, a diagnosis of juvenile diabetes was not a medical challenge; it was a swift and agonizing death sentence. Children stricken with the disease withered away before their parents’ eyes, their bodies unable to process the energy from the food they ate. Medical science was powerless to stop the devastating wasting process. The only known treatment was a brutal, near-total starvation diet that prolonged life by a few miserable months or, at best, a couple of agonizing years. Wards in the world’s prestigious hospitals were filled with skeletal, semi-comatose children waiting for the inevitable. Yet, in the span of just a few months during the hot Toronto summer of 1921, a desperate, brilliant, and deeply volatile team of researchers unlocked a secret of human biology that would empty those wards and rewrite the history of medicine forever.

This book is the narrative history of the discovery of insulin, an extraordinary medical breakthrough that transformed diabetes from a fatal affliction into a manageable chronic condition virtually overnight. Set against the backdrop of the University of Toronto’s modest laboratories, this is not a sterile story of smooth scientific progress, but a deeply human drama. It is a chronicle of a lonely, struggling surgeon who had a late-night flash of inspiration; an eager young graduate student who risked his future on an unproven theory; a skeptical, world-renowned physiologist who provided the platform; and a brilliant biochemist who purified the muddy extract into a lifesaving miracle. Together, these four men—Frederick Banting, Charles Best, J.J.R. Macleod, and James Collip—achieved what the greatest minds in European science had failed to do for decades.

Beyond the undeniable clinical triumph, this narrative explores the intense, often bitter human rivalries that simmered beneath the surface of the breakthrough. Scientific discovery is rarely a solitary, harmonious endeavor, and the race to isolate insulin was no exception. As the potency of their extract became clear and the prospect of global fame loomed, professional jealousy, clashing egos, and disputes over intellectual ownership threatened to tear the Toronto team apart. This internal friction culminated in one of the most controversial Nobel Prize decisions in history, leaving a legacy of resentment that lasted for decades. By examining the personal letters, laboratory notebooks, and historical records of the participants, this book reconstructs the feverish atmosphere of the laboratory and the high-stakes boardroom battles that shaped the public narrative of the discovery.

Moreover, the story of insulin is the crucible in which modern endocrinology and medical research ethics were forged. The Toronto breakthrough forced the medical community to grapple with unprecedented questions about the commercialization of life-saving discoveries. The decision to patent insulin, the partnerships forged with pharmaceutical giants like Eli Lilly, and the challenges of mass production under immense public pressure established the templates for how university research is translated into global clinical therapy today. Readers will gain a profound understanding of how this singular event bridged the gap between nineteenth-century experimental physiology and the multi-billion-dollar biotechnology industry of the modern era.

For the reader, this book offers more than a historical timeline; it is an immersive journey into a pivotal moment of scientific triumph and human endurance. You will walk through the smelling, chaotic laboratories of 1921, witness the heartbreak and hope of the earliest clinical trials on dying children, and navigate the complex ethical dilemmas that still resonate in medicine today. Ultimately, The Discovery of Insulin is a testament to the power of scientific curiosity, the messy reality of collaboration, and the enduring hope that even the most ancient and devastating scourges of humanity can be conquered.

To understand the desperation that filled the wards of the Toronto General Hospital in the early 1920s, one must first travel backward through millennia of medical helplessness. For almost the entirety of recorded human history, to be diagnosed with diabetes mellitus was to receive a death sentence that was as agonizing as it was absolute. The disease did not kill swiftly like a cholera outbreak or a bullet on a battlefield; instead, it dismantled the human body piece by piece, dissolving its muscles and tissues into fluid, and leaving its victims to perish of extreme exhaustion and starvation.

The earliest known record of this devastating condition dates back to 1552 BCE, preserved on a roll of papyrus discovered in the ruins of Thebes by the German Egyptologist Georg Ebers. The Ebers Papyrus, a compilation of Egyptian medical lore, describes a mysterious disease characterized by "the melting of the flesh" and an "accumulation of urine." Even then, the chief symptom was unmistakable: an insatiable thirst coupled with a relentless, voluminous passing of water. The ancient Egyptian physicians, powerless to halt this rapid wasting, prescribed remedies consisting of sweet beer, elderberries, milk, and flower fibers. Needless to say, these early concoctions did nothing to slow the progression of the disease.

As the centuries passed, the clinical description of the ailment grew more precise, even as the understanding of its underlying cause remained stubbornly out of reach. By the first century CE, the Greek physician Aretaeus of Cappadocia provided a vivid, haunting portrait of the condition. It was Aretaeus who gave the disease its enduring name, deriving "diabetes" from the Greek word meaning "to pass through" or "siphon." He observed that the disease was a moist coldness, where the kidneys and bladder did not cease emitting urine.

Aretaeus wrote that life with diabetes was short, disgusting, and painful. He described how the patient’s fluid intake was immediately followed by corresponding output, as if the body were a mere pipe through which water flowed. The flesh, he noted, melted down into urine, and the sufferers were plagued by an unquenchable thirst, dry mouths, and parched skin. If they abstained from drinking for even a brief moment, their mouths became dry and their bodies burned. The end was always the same: a state of profound drowsiness, rapid breathing, and death.

For generations of physicians who followed Aretaeus, the most baffling aspect of the disease was its bizarre chemistry. Patients literally starved to death while consuming vast quantities of food. No matter how much bread, meat, or fat a diabetic ingested, their limbs grew thinner, their cheeks more hollow, and their physical strength vanished. They were hungry all the time, yet they withered away. It was as if some internal fire was consuming the very substance of their beings, leaving only a skeletal frame and a sweet-smelling, sticky urine.

The sweet nature of this urine became the definitive diagnostic tool for the disease. In ancient India, Ayurvedic physicians noticed that certain patients produced urine that attracted swarms of ants. They called the condition madhumeha, meaning "honey urine," and noted that it tended to affect wealthy individuals who consumed excessive amounts of rice, flour, and sugar. Across the globe, early healers diagnosed the condition by tasting the patient's urine themselves.

This crude diagnostic method was codified in Western medicine during the seventeenth century by Thomas Willis, an eminent English physician and co-founder of the Royal Society. In 1674, Willis published a treatise in which he described the urine of diabetic patients as being "wonderfully sweet, as if it were imbued with honey or sugar." He appended the Latin word mellitus, meaning "honey-sweet," to the existing term diabetes, thereby distinguishing it from diabetes insipidus, a different water-balance disorder where the urine is tasteless.

While Willis succeeded in naming the monster, neither he nor his contemporaries had any inkling of what caused the body to lose its ability to process sugars. Medical theories of the eighteenth century blamed the kidneys, the stomach, the nervous system, or even the blood vessels. Treatments reflected this profound confusion. Patients were subjected to bloodletting, blistering, and forced purging. They were fed diets consisting almost entirely of rancid meat, or conversely, forced to consume massive quantities of sugar to replace what was lost in their urine. Others were dosed with heavy metals, ammonia, and opium to quiet their nervous systems. All of these interventions failed, often accelerating the patient's demise.

The first true glimmer of scientific light emerged in the late eighteenth century through the work of Matthew Dobson, an English physician practicing in Liverpool. In 1776, Dobson conducted a series of elegant experiments on the urine of diabetic patients. By boiling the urine, he managed to isolate a white, cake-like residue that tasted precisely like common sugar. Crucially, Dobson also analyzed the blood serum of his patients and discovered that it, too, possessed a sweet taste.

Dobson’s findings shifted the medical consensus. Diabetes was not merely a disease of the kidneys, as had been believed for two thousand years. The kidneys were not manufacturing the sugar; they were simply filtering an excess of sugar that was already circulating in the bloodstream. The problem lay deeper within the body’s metabolic machinery, in its inability to assimilate the nutrients derived from food.

Despite this breakthrough, the clinical reality for patients remained grim. As the nineteenth century progressed, the industrialization of Europe and North America brought about a rise in sedentary lifestyles and diets rich in refined carbohydrates, leading to an apparent increase in the prevalence of diabetes. While the milder, adult-onset form of the disease (what we now know as Type 2 diabetes) could sometimes be managed for years through careful moderate eating, the juvenile-onset variety (Type 1) was swift and merciless.

For a child diagnosed with juvenile diabetes in the nineteenth century, the prognosis was a matter of months. Parents watched in horror as their vibrant children suddenly became constantly thirsty, bed-wetting, and lethargic. Within weeks, the children lost twenty, thirty, or forty percent of their body weight. Their breath began to smell of overripe apples or nail polish remover—a sign of ketoacidosis, though no one yet understood the chemical term. Finally, the child would slip into a deep, unarousable coma, breathing heavily in a desperate attempt to expel the acid buildup in their blood, until their heart simply stopped.

The frustration of the medical establishment was palpable. Prominent physicians wrote of the sense of defeat they felt when a diabetic child entered their clinic. They could diagnose the condition with absolute certainty, but they could offer nothing to save them. The hospital wards dedicated to diabetes were places of quiet, agonizing tragedy, where the only real medical duty was to comfort the grieving parents and ease the child’s final hours with small doses of morphine.

The turning point in the search for the biological cause of diabetes came from the laboratories of nineteenth-century Europe, where the young discipline of experimental physiology was beginning to challenge ancient medical dogmas. Foremost among these pioneers was the French physiologist Claude Bernard. In the 1840s and 1850s, Bernard conducted groundbreaking research into the role of the liver in carbohydrate metabolism. He discovered that the liver stores glycogen, a starch-like substance, and converts it into glucose, which is then released into the blood to fuel the body’s tissues.

Bernard’s work demonstrated that the body did not rely solely on dietary sugar; it actively produced and regulated sugar internally. He hypothesized that diabetes was caused by an overproduction of glucose by the liver, driven by an imbalance in the nervous system. While his neurological theory ultimately proved incorrect, Bernard had established a vital principle: glucose regulation was a complex, internal chemical balancing act managed by specific organs.

The next major piece of the puzzle fell into place quite by accident in the German university town of Strasbourg in 1889. Oskar Minkowski, a brilliant young physician, and Joseph von Mering, a prominent pharmacologist, were engaged in a heated debate regarding the digestion of fats. Von Mering believed that the pancreas, a pale, carrot-shaped gland nestled behind the stomach, was essential for breaking down dietary fats in the intestine. Minkowski disagreed, arguing that digestion could proceed without it.

To settle the dispute, Minkowski performed a delicate surgical operation on a healthy laboratory dog, completely removing its pancreas. The dog survived the surgery and awoke from the anesthesia. A few hours later, an alert laboratory assistant noticed something unusual: the dog, which had previously been house-trained, was urinating constantly and copiously on the laboratory floor.

Minkowski, intrigued by this sudden change in behavior, collected a sample of the dog’s urine. He tested it for sugar using a standard chemical reagent. The result was unmistakable. The urine was loaded with glucose. In removing the pancreas to study fat digestion, Minkowski and von Mering had inadvertently produced a perfect experimental model of diabetes.

This accidental discovery electrified the scientific world. For the first time, researchers had a clear, localized target. The pancreas was somehow responsible for preventing diabetes. If the organ was removed, the body lost its ability to regulate blood sugar, resulting in the rapid onset of the disease.

However, the exact mechanism of this pancreatic control remained deeply mysterious. The pancreas was well known to be an exocrine gland, producing digestive juices that traveled through a small duct into the small intestine to help digest food. But Minkowski soon demonstrated that if he tied off this pancreatic duct, preventing the digestive juices from reaching the intestine, the dog suffered from digestive difficulties but did not develop diabetes. It was only when the pancreatic tissue itself was entirely removed that the disease occurred.

This meant the pancreas had a dual function. It produced digestive enzymes for external secretion into the gut, but it also produced some internal substance, secreted directly into the bloodstream, that governed sugar metabolism.

To prove this "internal secretion" hypothesis, researchers turned their attention to the microscopic anatomy of the pancreas. Decades earlier, in 1869, a young German medical student named Paul Langerhans had noticed small, distinct clusters of cells scattered throughout the main tissue of the pancreas like tiny islands in a vast sea. Langerhans did not know what these cells did, and he simply described them in his doctoral thesis before moving on to other research.

In 1893, the French histologist Édouard Laguesse suggested that these microscopic clusters, which he named the "islets of Langerhans" in honor of their discoverer, might be the source of the internal secretion that regulated blood sugar. While the surrounding acinar cells produced the digestive enzymes, Laguesse proposed that the islet cells produced a hormone that prevented diabetes.

By the turn of the twentieth century, this theoretical hormone had even been given a name, long before anyone had actually seen or isolated it. In 1909, the Belgian physician Jean de Meyer proposed calling this hypothetical active principle "insulin," derived from the Latin word insula, meaning island.

The scientific challenge was now clear, yet devilishly difficult: find a way to extract this elusive hormone from the islets of Langerhans. If a researcher could isolate this internal secretion and inject it into a diabetic patient, they could theoretically replace the missing hormone and cure, or at least control, the disease.

The race was on, and during the first two decades of the twentieth century, several brilliant researchers came tantalizingly close to success. In Germany, Georg Ludwig Zuelzer prepared a series of pancreatic extracts that he tested on diabetic dogs and even on a few human patients. In 1908, Zuelzer managed to reduce the sugar in a comatose diabetic patient's urine and temporarily bring him out of his coma. However, his extracts were crude, contaminated with foreign proteins from the pancreatic tissue, and caused severe side effects, including high fevers and violent convulsions. Out of funds and facing opposition from conservative medical authorities, Zuelzer was forced to abandon his research.

Similar near-misses occurred in the United States and Europe. In Chicago, E.L. Scott, a young researcher working under challenging conditions, developed an extract that successfully lowered blood sugar in dogs, but his work was dismissed by his superiors who believed his results were merely the result of a generalized chemical reaction. In Romania, Nicolas Paulesco, a distinguished professor of physiology, developed a highly potent pancreatic extract that he called "pancreine." By 1920, Paulesco had demonstrated that his extract could dramatically lower blood sugar and ketones in diabetic dogs. However, his work was interrupted by the chaos of the First World War and went largely unnoticed by the international scientific community, which was dominated by English- and German-language journals.

The fundamental obstacle that stymied all of these early researchers was a cruel biological irony. The pancreas is a self-destructing organ. The moment the pancreas is removed from an animal and minced to create an extract, its powerful exocrine digestive enzymes—such as trypsin—are released. These enzymes immediately begin to digest and destroy the delicate protein hormone produced by the islets of Langerhans.

Every investigator who tried to grind up a pancreas to extract the active ingredient was unwittingly destroying the very thing they were trying to find. The digestive juices were eating the insulin before it could be isolated.

As the year 1920 drew to a close, the search for the internal secretion of the pancreas had reached a frustrating impasse. The theoretical framework was solid: the islets of Langerhans produced a hormone that controlled sugar metabolism, and the absence of this hormone caused diabetes. Yet, the practical hurdle of isolating this hormone from the destructive digestive enzymes of the pancreas seemed insurmountable.

To the medical establishment, the prospect of finding a cure seemed as remote as ever. The scientific papers on pancreatic extracts were buried in academic libraries, regarded by most practicing physicians as interesting but impractical laboratory curiosities. In the clinics and family homes of the era, the daily reality of diabetes remained a grim struggle against time, marked by hunger, wasting, and the inevitable descent into coma. The world was waiting for someone who could break through the biological barrier of the pancreas, but few suspected that this breakthrough would come not from the celebrated research institutes of Europe, but from a modest, struggling medical practice in a small town in Ontario, Canada.