We shift our format this month to bring you three giants in medicine, Dr. Jesse Roth of the Feinstein Institutes for Medical Research, Dr. C. Ronald Kahn of the Joslin Diabetes Center at Harvard Medical School, and Dr. Jeffrey Flier of Harvard Medical School, as part of the JCI’s salute to the 100th anniversary of the discovery of insulin. Roth, Kahn, and Flier (Figure 1) all played instrumental roles in the discovery and description of the insulin receptor and in elucidating the critical role it plays in diabetes. See the JCI website (https://www. jci. org/videos/cgms) for the full interview with their full anecdotes and to get a glimpse of their extraordinary camaraderie. JCI: Jesse, can you set the stage for us with what the scientific world thought about metabolic signaling and membrane-bound receptors in the 60s? Roth: The story starts on July 1st, 1963, when I showed up at the NIH. I had spent the previous two years in New York with Rosalyn Yalow and Solomon Berson, working on growth hormone. I was challenged to move on to something else, so my friend Ira Pastan and I decided to develop a method to measure the first step by which hormones like insulin interact with cells to bring about their actions. In fact, in those days, most people thought that insulin immediately went into the cells, found enzymes that it could bind to, and became coenzymes. We started to label insulin with radioactive iodine, but initial efforts didn’t work well. It would bind to too many things, so we had to develop a way to make insulin that was very gently labeled so it would retain biological activity. We labeled only a small fraction of the insulin, and instead of breaking up tissues, if you worked with whole cells, that worked well. In fact, if you started out with the popular insulin-sensitive tissues, like fat or muscle or liver, it didn’t work so well. But if you went to blood cells, oh that was good. Nobody expected insulin receptors to be on the blood cells, but they were, and these were perfectly good receptors. We started to label receptors on cells from patients, and in fact, they seemed to reflect well what we thought might be the pathology of the disease. JCI: Ron, when you arrived in Jesse’s lab at the NIH, you spent about a year working on something that didn’t work so well. Kahn: My predecessor in Jesse’s lab was Bob Lefkowitz, whose name is well known as a Nobel laureate for his important work on β adrenergic receptors. Before I got to the NIH, he had been a fellow in Jesse’s lab doing pioneering work on ACTH receptors. I picked up his project, but could never quite get the experiments to work as well, since the cells had changed, and one of the critical reagents was no longer available. However, I was very fortunate that at the same time, Pierre Freychet was in Jesse’s lab working on the insulin receptor. So I jumped in and started to work with Jesse and Pierre on the insulin receptor, and unlike my work on ACTH, it was a very robust system and quite easily quantifiable. Because of that, we could really do the kinds of studies needed, not just to characterize the receptor, but to begin to investigate pathophysiologic states, looking for changes in diseases in which receptors might have reduced binding or increased binding.