A Tale of Two Hormones

LASKER BASIC MEDICA L COMMENTARY RESEARCH AWARD A tale of two hormones Jeffrey M Friedman “Der Mensch denkt, Gott lenkt.” (“Man equivalent to a death sentence1. The only avail- Kleiner’s story had great personal resonance proposes, God disposes.”) able treatment was a starvation diet advocated for me. Here was another Jewish scientist, the —German proverb by Frederick Madison Allen, a physician work- grandson of immigrants, working a century ing at the Rockefeller Institute for Medical earlier at the same institution as me. But on A little more than a century ago, an arc of Research (now Rockefeller University) and the cusp of isolating the most important hor- research began that culminated in the identi- a leading authority on diabetes1–5. Allen was mone ever discovered, he walked away from it. fication of insulin by four scientists working the first to realize that diabetes was a general How did Kleiner come to study diabetes? Why in Toronto. With astonishing speed, this land- disorder of metabolism and that acidosis and did his studies cease so abruptly? Did Kleiner mark discovery became a life-saving treatment death could be forestalled if caloric intake was and his colleagues fully understand the impli- for thousands of people with diabetes around restricted. When acidosis developed, calories cations of his research? What was the personal the world. In time, insulin was established as were further reduced, and, for many, diabetes impact of his having missed the opportunity of the most important anabolic hormone and was a race between starvation and acidosis, the a lifetime? Kleiner’s work and career also raise found its place in the pantheon of medicine’s ultimate result of either condition often being a general question: what are the elements of a greatest discoveries. death. The discovery of insulin by Frederick discovery? These were the questions I set out Fifteen years ago, leptin was identified as Banting, Charles Best, James Bertram Collip to answer. another metabolic hormone with major cata- and John James Macleod changed the treatment bolic effects. This story, however, is not about of diabetes forever by providing a hormonal Israel Kleiner’s magnificent paper leptin or insulin. Rather, it is about the path treatment from the pancreas that could rapidly In 1889, Josef von Mering and Oskar to discovery for each of them and about the restore bedridden, cachectic and moribund Minkowski observed that removing a dog’s path to discoveries in general. It is a story of children and young adults to healthy lives. pancreas resulted in polyuria, polydipsia and discoveries made and not made. It is about how One of the many scientists who tested the diabetes10. After Eugene Opie noted that the I found my way into the world of Israel Kleiner, ability of pancreatic extracts to treat diabe- islets of Langerhans in the pancreas were often who, but for the mysterious winds that shape tes before the discovery of insulin was Israel destroyed in humans with diabetes, the crucial our paths, might have been the man who dis- Kleiner (Fig. 1), a biochemist who also question became how this structure controlled covered insulin almost a century ago. worked at the Rockefeller Institute between sugar metabolism11. One possibility was that I have had the privilege of listening to numer- 1910 and 1919. In a study published in 1919, the islets of Langerhans produced a hormone, ous first-hand accounts from many great sci- two years before Banting and Best published referred to then as an ‘internal secretion’, entists describing their moments of discovery. their first paper, Kleiner conclusively showed that regulated glucose concentrations in the And over the course of my career, I, too, have that extracts of pancreas but not other tissues blood. Beginning with Georg Ludwig Zuelzer experienced this thrill. But even before the dis- could lower blood glucose in diabetic dogs6. in the early 1900s12, a number of scientists covery of leptin, I was fascinated by the expe- Referring to Kleiner’s work, Bliss wrote, “of all began to test the possibility that the pancreas riences of people who have made important the publications before the work at Toronto, it might make a hormone that controls blood discoveries. My interest in great discoveries was the most convincing”7, and later opined sugar levels, although definitive evidence of led me to The Discovery of Insulin, by Michael that “his controls had been impressive; his this was lacking. Thus, although Joseph Pratt Bliss1. This enthralling work tells the tale of the follow-up discussion was a beautiful piece of and Macleod had concluded that individuals 1922 discovery of insulin. In gripping fashion, scientific writing”7. with diabetes were missing an internal secre- it traces the progression of ideas that led to one Then, Kleiner’s work abruptly ceased. While tion from the pancreas and that a pancreatic of the key achievements of the twentieth cen- history has correctly bestowed the credit for extract could be used to treat diabetes13,14, this tury and arguably the first instance in which discovering insulin on the Toronto group, Bliss view was not universal. In 1913, Allen wrote, science provided a new lifesaving medicine for wrote of Kleiner, “in 1919 he was closer to suc- “though pancreas feeding may have at a least a the morbidly ill. cess than any of them, and made no claims at digestive value in some cases of diabetes, injec- Before the discovery of insulin, a diagnosis all”8. Kleiner never publicly discussed why his tions of pancreatic preparations have proved of diabetes, particularly in children, was often research stopped so precipitously, other than both useless and harmful. The failure began writing four decades later “why we did not with Minkowski and continued to the pres- Jeffrey M. Friedman is at The Rockefeller continue and isolate the antidiabetic factor is ent without an exception”15. Forty-two years University, New York, New York, USA. a long story and has no place in the present later, in a letter to Kleiner, Allen acknowledged e-mail: [email protected] discussion”9. that it was Kleiner’s pioneering discovery that xii VOLUME 16 | NUMBER 10 | OCTOBER 2010 natURE MEDICINE commentary entered the graduate school at Yale, then ence of the pancreas the circulation rids itself called the Sheffield Scientific School, and easily of the intravenously introduced dextrose; did research in the laboratory of Lafayette but that it is unable to do it satisfactorily in the Mendel18. Mendel was one of the intellectual absence of the pancreas”26. This distinction is giants at the school and is now considered to important because, starting with the brilliant be the father of nutrition research in the US. work of Claude Bernard showing that the liver Mendel and his colleagues had developed an can synthesize glucose27,28, the prevailing view apparatus that allowed them to selectively was that diabetes primarily results from glu- deprive an animal of specific nutrients and cose overproduction. We now know that both used it to show that animals require essen- overproduction and decreased consumption tial amino acids that cannot be synthesized contribute to the disease, and Kleiner and endogenously19. Among many other contri- Meltzer’s results were the first to show that butions, he also reported the consequences of insulin regulates glucose use. vitamin A deficiency19. Although the complete data set was not Kleiner’s thesis was entitled Studies in published until 1919, Kleiner’s and Meltzer’s Intermediary Metabolism, and his research preliminary report was the first to show a ben- focused on pyrimidines, with the ultimate eficial effect of a pancreatic extract on blood goal of understanding more about the func- glucose levels in diabetic dogs6. The only prior tion of nucleic acids18. After teaching at report measuring blood glucose after injection Tulane University in New Orleans for a of pancreatic extracts showed an increase rather year, he applied to the laboratory of Samuel than a decrease in blood glucose levels29. The Meltzer at the Rockefeller Institute, express- implications of Kleiner’s and Meltzer’s findings, Figure 1 Photograph of Israel Kleiner as he ing an interest in returning to research20. By published seven years before Banting’s and neared retirement as a professor of biochemistry 1910, the Rockefeller Institute had already Best’s first paper, were reported in a prominent at the New York Medical College. established a reputation as one of the leading article in the New York Times on August 19, non-university research institutes in the world 1915 under the headline “Find Diabetes Cause, pancreatic extracts lowered blood glucose that and one of the few places in the US that pro- Now Seek a Remedy: Rockefeller Institute had helped to change his opinion, as he wrote, vided funding for research21. Simon Flexner, Doctors Say Disease is Due to a Failure of the “I can corroborate Joseph H. Pratt’s statement the director, had assembled a group of highly Pancreas”26,30. that you announced a pancreatic extract with distinguished international scientists whose However, efforts to seek a remedy were sugar-reducing properties something like eight mission was to address problems of human soon interrupted. The world was at war. The years before the announcement by Banting and health. In 1904, Samuel Meltzer was the first research enterprise at Rockefeller was dis- Best”16. physiologist appointed at the Institute22. rupted and, regarding to this period, Kleiner The controversy about whether diabetes Meltzer was a highly distinguished member later wrote, “in the meantime, the first World results from a deficiency of a hormone made of the National Academy of Sciences, and his War had come about and interfered with much by the pancreas existed largely because the most notable achievement is the development of this work”9.

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