A Conversation with Roger Guillemin

Abstract

Introduction by Editor David Julius  In the second century ad, Galen of Pergamon was the first to describe the anatomical connection between the hypothalamus and the pituitary gland. In the 1800s, von Luska, Cajal, and others showed that this connecting structure, or stalk, contains nerve fibers as well as a plexus of capillary vessels. Such observations raised long-standing questions as to the functional nature of these connections and their relationship to neural and/or humoral communication between these two endocrine organs. Hypothalamic nerve fibers projecting to the posterior pituitary were later shown to account for the release of vasopressin and oxytocin from vesicle-rich terminals within this lobe. Up until the mid-1900s, however, it remained unclear as to how the hypothalamus controls the release of corticotropin, thyrotropin, growth hormone, and other key endocrine factors from the anterior lobe. Evidence for direct neural control was lacking, and in the 1940s the British physiologist Geoffrey Harris proposed that the hypothalamus exerts control over the anterior lobe through a humoral mechanism in which blood-borne releasing factors are delivered to the pituitary through capillaries of the interconnecting stalk (the so-called hypothalamo-hypophysial portal system), inducing cells in the anterior lobe to secrete their hormones. This model was not without controversy, and skeptics would not be satisfied until the mythical hypothalamic releasing factors had been biochemically and functionally identified. In 1977, Roger Guillemin and Andrew Schally shared the Nobel Prize in Medicine and Physiology for accomplishing this daunting and far-reaching goal. In doing so, they established the field of neuroendocrinology. In this Perspective, Dr. Guillemin, Distinguished Professor at the Salk Institute, recalls events that diverted him from a career as a country doctor in his native France to one of scientific research, first in Canada and then in the United States and France. The story of the releasing factors is legendary, not only for its scientific import, but also for the great technical challenges that beset these efforts when the advantages of protein microsequencing, molecular cloning, and other such powerful techniques were not yet available. Rather, a scale and persistence of experimentation almost unthinkable (and likely unfundable) by today's standards proved successful. Consequently, key steps in hypothalamic-pituitary signaling were elucidated, and new pharmacological strategies for treating endocrine disorders, including those affecting stature and reproduction, were realized. Following on a recent Annual Review of Physiology (ARP) advent, this Perspective takes the form of an oral history that can be read here in transcript form and viewed online. Dr. Guillemin was interviewed on August 7, 2012, at his ranch in the beautiful hills of Truchas, New Mexico (see Figure 1 ), by Dr. Greg Lemke, Françoise Gilot–Salk Chair at the Salk Institute. We are most grateful to Roger Guillemin and to his wife, Lucienne, for opening their home to ARP for this interview, as well as to Greg Lemke for guiding this lively and fascinating conversation.