Wylie Vale: Neuroendocrine master

To die at the height of a man's career, the highest moment of his effort here in this world, universally honored and admired, to die while great issues are still commanding the whole of his interest, to be taken from us at a moment when he could already see ultimate success in view is not the most unenviable of fates.

Winston Churchill (1940)

Wylie Vale, professor and head of the Clayton Foundation Laboratories for Peptide Biology at The Salk Institute, member of the National Academy of Sciences, and leader in the field of neuroendocrinology, passed away in his sleep on January 3, 2012 while vacationing in Hawaii. He was 70 years old and is survived by his wife Betty, his daughters Elizabeth and Susannah, his granddaughter Celeste, his brother Shannon, and his father Wylie.

Wylie Vale.

Wylie grew up near Houston; he attended St. John's School and received his Bachelor's degree at Rice University. His friends recall that young Wylie always put himself in the most rigorous and competitive environment that he could find. In football two on one drills, Wylie, at 145 lb, would get paired against Big Al (6 ft, 5 in and 235 lb) or Doc Schwartz (6 ft, 5 in and 240 lb) on the other side of the line … he loved the odds.

Wylie spent most of his career characterizing the hypothalamic hormones and other neuroendocrine peptides that regulate thyroid function, growth, reproduction, and response to stress. The presence of hypothalamic releasing factors had been speculated on beginning in the early 1950s. Roger Guillemin, then a young MD from France with a burning idea, moved to Baylor College of Medicine in Houston, where over the period of 5–10 years, he assembled a team of chemists and physiologists with the purpose of purifying and characterizing these factors. In the absence of RIAs, which were not then available, the purification of relevant factors from hypothalamic extracts relied on well-designed and specific bioassays.

Wylie joined Guillemin's laboratory as a graduate student in 1963, performing bioassays to isolate and identify thyrotropin releasing hormone (TRH). During summers, he harvested tens of thousands of sheep hypothalami from the slaughterhouses, bringing them back on dry ice for fractionation. Wylie completed his work for a PhD in Guillemin's laboratory in 1968, and he was part of the successful effort to purify TRH; guessing that a number of hypothalamic factors were still to be discovered, he continued on as a postdoctoral fellow.

Lured by the beauty of The Salk Institute (then just in its early years), the southern California coastline, and the opportunities for unrestricted research, Guillemin and his laboratory moved in 1970, where Wylie and his colleagues worked toward the purification of growth hormone releasing factor. Unexpectedly, they found that their hypothalamic fractions actually inhibited growth hormone release. Speculating that this activity represented an inhibitory factor, the scientists eventually purified and characterized a 14-aa peptide called somatostatin. The discovery of somatostatin cemented the national and international reputation of the Guillemin laboratory.

Five years after the discovery of somatostatin in 1973, Wylie established his own department along with Marvin Brown and Catherine and Jean Rivier at The Salk Institute. The separation from Guillemin was initially difficult, because it created a competitive divide between the two groups. In later years, Wylie and Guillemin would rekindle their close relationship, and Guillemin would become an ardent supporter of his scientific son and Wylie of his scientific father.

Although the move from the Guillemin laboratory was difficult logistically and psychologically, Wylie was the rock on which the group's productivity, cohesiveness, and general morale flourished. The first major aim of the laboratory was to isolate and characterize corticotropin releasing factor (CRF), which was postulated to be a substance that mediates the pituitary–adrenal response to stress. Assigned to the temporary buildings adjoining The Salk Institute's main campus, Wylie's group, which then included Joachim Spiess, succeeded in characterizing CRF in 1981. CRF has long been considered the Holy Grail in neuroendocrinology, because it was the first of the releasing factors to be sought and had frustrated the earlier efforts of Roger Guillemin and Andrew Schally, the pioneers in the field. Results from this work provided the final proof of the stress hypothesis first put forward by Hans Selye nearly 40 years earlier.

One of Wylie's great strengths was his ability to integrate new knowledge into the broadest possible context of every system that he studied. Using reagents developed from the discovery of CRF, the anatomical distribution of CRF in the brain was then studied with his Salk colleague, Paul Sawchenko. Having seen the remarkable extrahypothalamic locations where CRF is found, Wylie made the conceptual leap that CRF might be a mediator of stress-related feeling, a finding confirmed by the behavioral studies of Koob and Sutton. Based on that work, Wylie sought, with Jean Rivier (his long-time partner in peptide chemistry), to develop a CRF antagonist and use it in the clinical setting, while mobilizing a larger and more varied circle of colleagues. He also helped to found a biotechnology company (Neurocrine Biosciences) for the development of CRF-related compounds.

Although trained as a classical whole-organ physiologist, Wylie readily segued into the field of molecular neuroendocrinology. Using the structure of CRF as a starting point, his group went on to characterize a family of related hormones, the urocortins, and identify receptors for the whole CRF family of neuropeptides. In addition to their role in the stress response, Wylie and members of his laboratory showed that the urocortins also regulated cardiovascular function and glucose metabolism. Many of these discoveries have translated into new therapies, which are still in development.

In a completely separate area of investigation, Wylie, Jean Rivier, and Joachim Spiess as well as the Guillemin laboratory independently characterized activin and inhibin, reciprocally inhibitory members of the TGF-β family of growth factors that exert a wide range of effects on reproduction as well as development and cancer. Building on these discoveries, Wylie's group later identified the activin receptor, the founding member of the TGF-β receptor family, and showed that it functioned as a Ser/Thr kinase. Consistent with his collaborative approach that was very successful in his work in the CRF field, Wylie's findings with activin, inhibin, and their receptors also helped to spawn another biotechnology company (Acceleron Pharma) with potential applications for the treatment of anemia, osteoporosis, and other diseases.

Wylie's personal style was unique. He was urbane, worldly, and comfortable in any social setting. He was passionate about good music and good wine. However, Wylie also kept a collection of snakes and iguanas; you never knew which reptile would join you in the dining room. He could call up an array of Texas country witticisms that set a crowd roaring with laughter.

A few months ago, during a discussion on good parenting, Wylie pointed to a New York Times piece on seven characteristics of successful people: zest, grit, self-control, social intelligence, gratitude, optimism, and curiosity. Wylie could have been the poster child for this article. His exceptional people skills, which were an inherent quality of his nature, were instrumental in organizing his department, conducting everyday discussions with his colleagues, and setting up new biotechnology ventures. Wylie's wise counsel was sought by colleagues and friends at The Salk Institute and elsewhere. He gave unselfishly of his time and advice. His intuitive creativity and warm collegiality cannot be matched.