New Endocrinology of the Brain

NEW ENDOCRINOLOGY OF THE BRAIN ROGER GUILLEMIN* In the late 1940s it became obvious, based on astute clinical observations and a series of physiological experimentation involving hypodialamic lesions as well as stimulation widi implanted electrodes, diat die fine physiological control of the secretion ofthe hormones of the anterior lobe of the pituitary somehow resided in die hypothalamus. Specialized neurons of the anterior hypodialamus were already suspected to be die anatomical center of origin of the two peptides, vasopressin and oxytocin. Striking pictures ofwhat appeared to be secretory activity of neurons of the supraventricular and paraventricular nuclei had been recognized by morphologists such as die Scharrers and Bargman . The word "neurosecretion" was coined and the concept timidly advanced diat at least these types of neurons could syndiesize some proteins with biological activity that would be carried by axoplasmic flow to the neurohypophysis from which tiiey would be released. In 1952 Du Vigneaud isolated vasopressin and oxytocin, characterized their molecular structure as diat oftwo closely related nonapeptides, and realized the total syndiesis of oxytocin—a series of remarkable achievements for which he received die Nobel Prize in chemistry in 1955. At about the same time it had also become clear that no major tract of nerve fibers was to be found between die hypodialamus and the anterior pituitary lobe. The name of Geoffrey Harris will remain associated widi die proposal diat a hypodialamic control of anterior pituitary functions could still exist if it were to utilize die peculiar network of capillary vessels that had been shown to exist between the floor of the diird ventricle and the anterior lobe of the pituitary. Such a control by the hypodialamus would thus have to be humoral in nature with some hypothetical substance being made and released by hypothalamic neurons into die portal capillaries eventually to reach the adenopituitary cells. The concept was further established in 1955 when I and Rosenberg were able to show that classical tissue cultures of pituitary cells would stop very rapidly to secrete a hormone, in this case adrenocorticotropin»Laboratories for Neuroendocrinology, The SaIk Institute, San Diego, California 92 1 12.© 1979 by The University of Chicago. 0031-5982/79/2222-0002$01.00 S74 I Roger Guillemin ¦ New Endocrinology ofthe Brain (ACTH), unless fragments ofventral hypothalamus were simultaneously cultured with the pituitary cells. Early pharmacological studies established diat the substances involved were none of the classical neurotransmitters such as acetylcholine or noradrenalin, nor could diey be vasopressin or oxytocin. Saffran and Schally in Montreal had also reached the same conclusion working independently. After a few years of pilot studies in early attempts at purification of the hypodialamic factor in which Schally and I worked together in Houston, it became obvious that the isolation and chemical characterization of these hypodialamic substances involved in controlling die functions of the pituitary gland would be a project of unsuspected and eventually gigantic dimensions. Simple assumptions and calculations showed that each hypothalamic fragment would contain only a few nanograms of die hypothalamic releasingfactors, as we began to call them. From 1960 to 1965 I eventually organized the collection ofabout 5,000,000 fragments of sheep brain containing the hypothalamus. Five tons of these hypodialamic tissues were handled in the laboratory and processed in semi-industrial scale. Eventually, in 1968, Burgus and I isolated 1 mg of a hypodialamic substance stimulating the secretion of the thyroidstimulating hormone and, the following year, established its complete molecular structure by mass spectrometry as mat of an unexpectedly simple tripeptide which was also reproduced by total syndiesis. Schally's group established a similar molecular structure for die thyrotropin releasing factor of porcine origin. A few years later Schally's group and our group isolated the gonadotropin releasing factor and it was to the credit of Schally's laboratory first to propose the correct amino-acid sequence of the luteinizing hormone releasing factor (LRF) for the material of porcine origin. A couple of months later at die SaIk Institute, Burgus and Ling showed that die amino-acid sequence of LRF ofovine origin was identical. Two years later, while searching for a growdi hormone releasing factor in collaboration with Vale, Burgus, Ling, Brazeau, and Rivier, somatostatin—an inhibitor of the secretion...