A tale of two hormones

A little more than a century ago, an arc of research began that culminated in the identification of insulin by four scientists working in Toronto. With astonishing speed, this landmark discovery became a life-saving treatment for thousands of people with diabetes around the world. In time, insulin was established as the most important anabolic hormone and found its place in the pantheon of medicine’s greatest discoveries. Fifteen years ago, leptin was identified as another metabolic hormone with major catabolic effects. This story, however, is not about leptin or insulin. Rather, it is about the path to discovery for each of them and about the path to discoveries in general. It is a story of discoveries made and not made. It is about how I found my way into the world of Israel Kleiner, who, but for the mysterious winds that shape our paths, might have been the man who discovered insulin almost a century ago. I have had the privilege of listening to numerous first-hand accounts from many great scientists describing their moments of discovery. And over the course of my career, I, too, have experienced this thrill. But even before the discovery of leptin, I was fascinated by the experiences of people who have made important discoveries. My interest in great discoveries led me to The Discovery of Insulin, by Michael Bliss1. This enthralling work tells the tale of the 1922 discovery of insulin. In gripping fashion, it traces the progression of ideas that led to one of the key achievements of the twentieth century and arguably the first instance in which science provided a new lifesaving medicine for the morbidly ill. Before the discovery of insulin, a diagnosis of diabetes, particularly in children, was often equivalent to a death sentence1. The only available treatment was a starvation diet advocated by Frederick Madison Allen, a physician working at the Rockefeller Institute for Medical Research (now Rockefeller University) and a leading authority on diabetes1–5. Allen was the first to realize that diabetes was a general disorder of metabolism and that acidosis and death could be forestalled if caloric intake was restricted. When acidosis developed, calories were further reduced, and, for many, diabetes was a race between starvation and acidosis, the ultimate result of either condition often being death. The discovery of insulin by Frederick Banting, Charles Best, James Bertram Collip and John James Macleod changed the treatment of diabetes forever by providing a hormonal treatment from the pancreas that could rapidly restore bedridden, cachectic and moribund children and young adults to healthy lives. One of the many scientists who tested the ability of pancreatic extracts to treat diabetes before the discovery of insulin was Israel Kleiner (Fig. 1), a biochemist who also worked at the Rockefeller Institute between 1910 and 1919. In a study published in 1919, two years before Banting and Best published their first paper, Kleiner conclusively showed that extracts of pancreas but not other tissues could lower blood glucose in diabetic dogs6. Referring to Kleiner’s work, Bliss wrote, “of all the publications before the work at Toronto, it was the most convincing”7, and later opined that “his controls had been impressive; his follow-up discussion was a beautiful piece of scientific writing”7. Then, Kleiner’s work abruptly ceased. While history has correctly bestowed the credit for discovering insulin on the Toronto group, Bliss wrote of Kleiner, “in 1919 he was closer to success than any of them, and made no claims at all”8. Kleiner never publicly discussed why his research stopped so precipitously, other than writing four decades later “why we did not continue and isolate the antidiabetic factor is a long story and has no place in the present discussion”9. Kleiner’s story had great personal resonance for me. Here was another Jewish scientist, the grandson of immigrants, working a century earlier at the same institution as me. But on the cusp of isolating the most important hormone ever discovered, he walked away from it. How did Kleiner come to study diabetes? Why did his studies cease so abruptly? Did Kleiner and his colleagues fully understand the implications of his research? What was the personal impact of his having missed the opportunity of a lifetime? Kleiner’s work and career also raise a general question: what are the elements of a discovery? These were the questions I set out to answer.