In the early years of his NIH career, Martin Rodbell's days were filled with Nobel Laureates whose work contributed to Rodbell's own eventual success. In 1963, Bernardo Houssay, the Argentinean physiologist and 1947 Nobel Laureate in Physiology or Medicine, came to the NIH and paid a visit to Rodbell's laboratory at the National Institute of Arthritis and Metabolic Diseases. Houssay remarked to Rodbell that the scientist who could demonstrate how hormones worked on isolated cells would make an astonishing discovery. Until this time, endocrinologists had studied hormone action on whole organs, which were conglomerations of hundreds of millions of cells. No one had been able to isolate and study the effect of hormones on individual cells
Utilizing his earlier work on cell membranes, Rodbell showed Houssay how insulin bound directly to the receptors of fat cells in order to stimulate glucose metabolism within these cells. "I was nonplussed," wrote Rodbell in 1991, "[but] Dr. Houssay was ecstatic.... Practically overnight I had become an endocrinologist."
In 1964, Rodbell published the results of these successful experiments in his groundbreaking article, "The Metabolism of Isolated Fat Cells." Rodbell's article became one of the most influential articles in endocrinology of the 1960s and 1970s. According to reports by the Institute for Scientific Information, it remains one of the most-cited scientific articles of all time. Reflecting on his famous article in 1980, Rodbell wrote, "This paper was a turning point in the direction of my research career.... From that time onward I have remained committed, for better or for worse, to investigate the molecular basis by which hormones interact with cell surface receptors and thereby alter the physiology and structure of their target cells."
In 1965, Earl W. Sutherland came to the NIH's Bethesda campus to speak on what he called the "second messenger" theory of hormone activity. Rodbell, like many young biochemists in the 1960s, was deeply influenced by the work of Sutherland, who won the 1971 Nobel Prize in Physiology or Medicine for his research on the effect of hormones, such as glucagon and epinephrine, on liver metabolism. Sutherland's research in the mid-1950s with Theodore Rall and Jacques Berthet resulted in one of the most important articles of post-World War II endocrinology, "The Relationship of Epinephrine and Glucagon to Liver Phosphorylase" (1957).
In his influential "second messenger" talk, Sutherland postulated that rather than entering a cell, a hormone--the "first messenger"--worked at the cell surface and triggered a mechanism within the cell--a "second messenger"--that executed the command initiated by the hormone. Inspired by Sutherland's "second messenger" theory, Rodbell began to collaborate with other NIH biochemists to trace the effects of different kinds of hormones on cellular receptors. By the time Rodbell began working with rat liver membrane cells in 1969, his early work on isolated fat cells had already laid the groundwork for the principles of signal transduction.