Wylie Vale, Jr. passed away unexpectedly on January 3, 2012. He was 70 years old, still full of extraordinary vigor, much Texan humor left to share with colleagues and friends, and a host of unanswered research questions. His untimely death interrupted an ongoing and life-long quest to solve the riddles of how the brain communicates with the endocrine systems and controls a diverse array of behavioral and physiological responses. As Wylie states in a recording made during the very early phase of his career, “I work in the Neuroendocrinology Laboratory at the Salk Institute in a field that I think is opening up another new era of medicine, one in which emphasis is not on curing infections but on putting right some of the body's own mistakes. Our laboratory is working with small molecules that are made in our brains and which are used to regulate a host of activities in the body.” Wylie pursued this quest with tenacity and great success for the remainder of his career that would span nearly 50 years.
Wylie was born and raised near Houston, Texas, and always remained a true Texan in spirit. He completed his undergraduate education and received his Bachelor's degree in 1964 from Rice University in Houston. He then moved on to Baylor College of Medicine, also in Houston, where he joined the laboratory of Roger Guillemin in the Department of Physiology and Biochemistry and four years later, in 1968, obtained his Ph.D. Wylie's adventures in the Guillemin laboratory that entailed the harvesting of numerous sheep hypothalami as a source of the elusive thyrotropin releasing factor (TRF/TRH) and establishing bioassays for detecting its activity contributed to the ultimate success of the group in characterizing this small peptide in 1970. But this was only the beginning for Wylie. He remained in the Guillemin laboratory and continued his work as a postdoctoral fellow, encouraged by the success of the purification scheme used to isolate TRH and belief that a similar strategy might pay-off and reveal the nature of other hypothalamic peptides.
In 1970, Wylie, along with the Guillemin team, moved to La Jolla, California and established the Laboratories for Neuroendocrinology at the Salk Institute, lured by the beauty of the coastline and the scientific environment of the relatively young Institute. Wylie and the Guillemin team continued their efforts to characterize additional hypothalamic neuropeptides and in 1972 elucidated the amino acid sequence of gonadotropin-releasing factor/hormone (LRF/GnRH), a factor known to regulate the release of both luteinizing hormone and follicle-stimulating hormone from pituitary gonadotropes. During their search for a growth hormone (GH)-releasing factor, the team unexpectedly found an inhibitory activity that was later characterized to be a small, 14-amino acid peptide named somatostatin. Wylie made major contributions to the discoveries of these hypothalamic neuropeptides, for which Roger Guillemin received the 1977 Nobel Prize in Physiology and Medicine.
Wylie W. Vale Image courtesy of Betty Vale
The nature of yet another neuropeptide continued to intrigue Wylie and other members of the Guillemin team. In pursuit of this elusive stress peptide, Wylie, along with Jean and Catherine Rivier and Marvin Brown, established a separate laboratory at the Salk Institute in 1978 and entered a race to solve the mystery of the peptide. The laboratory was aptly named Peptide Biology Laboratory, later re-named the Clayton Foundation Laboratories for Peptide Biology but better known to those who passed through the laboratory as PBL. The temporary “shacks” that housed PBL during the first few years of its existence presented logistical challenges but also fostered cohesiveness, cooperation, youthful energy and pride. As Mark Smith, one of Wylie's first M.D., Ph.D. students and currently the Executive Medical Director of the Clinical Neuroscience Program at AstraZeneca, recalls: “My first impression of Wylie and his Peptide Biology Lab was one of youthful exuberance. Surfboards and scuba equipment occupied the makeshift labs alongside the complex sequencers and huge chromatography columns. No one was over 40, and there was great camaraderie. I knew this was going to be a fun place to be a graduate student. Thirty years later, Wylie still exuded that youthful curiosity and enthusiasm, and that is how I will always remember him.”
Wylie's group, which at that time included Joachim Spiess, ultimately succeeded and reported the isolation and characterization of the 41-amino acid corticotropin-releasing factor (CRF or as officially re-named CRH). Soon thereafter followed the characterization of the long-sought rat GH-hormone releasing factor (GRF) in 1983. The success of identifying CRF propelled Wylie and the group into the limelight and into a journey of unexpected discoveries of three more CRH-related peptides, the urocortins (Ucn 1, Ucn 2 and Ucn 3), two CRF receptor types (CRFR1 and CRFR2) and a CRF-Binding Protein. One of the early surprises in the CRF field was the discovery led by then postdoctoral/research fellow Felice Petraglia and currently a professor in the Department of Obstretics and Gynecology at the University of Siena, Italy: “Placenta was discovered to be a neuroendocrine organ: the production and secretion of CRF from trophoblast cells and its effect on ACTH release was the evidence that allowed us to elucidate a physiological implication of this neuropeptide in gestational homeostasis to stress. A possible role in the pathogenesis of preterm birth and preeclampsia was later suggested according to the evidence of hypersecretion of CRF and activin A in maternal circulation. Wylie was immediately impressed by the term ‘placenta’ and by its unique anatomy, yet able to lead and stimulate new science in this field! His intuition and creativity in research were outstanding and always ‘translational’.” Wylie and his group went on to make major contributions to understanding the signaling mechanisms and physiology of these molecules resulting in a body of work that implicates CRF and urocortins in anxiety, depression, anorexia, drug abuse and appetite control, as having broad physiological significance as local modulators of cardiac function, placenta and the gastrointestinal tract as well as in the maintenance of glucose homeostasis through actions on metabolic tissues such as skeletal muscle and the endocrine pancreas.
As Roger Guillemin fondly recalls, “Wylie was first my student from 1964 to 1968 at Baylor College of Medicine, Houston, Texas when he received his Ph.D. degree in physiology. Then, at the Salk Institute in La Jolla, California, until 1978, he was one of my collaborators in the search and isolation of LRF (GnRH), somatostatin, GRF (GHRH) and in 1981, now with his own group and one of my distinguished colleagues, he isolated CRF (CRH), which had eluded all of us since 1955. Then followed the discoveries of urocortins, several CRF receptors, their locations both in the brain and other tissues, implications in mental and behavioral events. The group around Wylie and led by him, proceeded to make modern neuroendocrinology what it is today. I have much admiration for Wylie and what he contributed without forgetting his role, now as a teacher of many students and postdocs throughout the world.” On a lighter note, Guillemin continues to reflect on the many lessons and hours that focused not only on the science but also on a passion that he and Wylie learned to share over the years, “Should I also mention that he never forgot my early teachings about Pinot Noir… … always an enjoyable getting together.”
Wylie and his collaborators also made important discoveries that benefited the TGF-β field. As far back as the 1920's, it was known that a substance contained in testicular fluids exerted feedback control on FSH secretion from pituitary gonadotropes and in the 1970's this factor was determined to be proteinaceous in nature. In 1985, Wylie and the team at PBL were one of several groups to report the isolation of inhibin, which turned out to be an unusual heterodimer of αβ subunits belonging to the large TGF-β family. A year later, the Vale group went on to co-discover activin, a ββ homodimer, which, unlike inhibin, stimulated FSH secretion. Wylie and his collaborators were quick to demonstrate the broad distribution of these subunits and appreciate the broader significance of activin and inhibin as pleiotropic agents with effects on cell secretion, proliferation, differentiation and survival. The group proposed that activin plays an autocrine/paracrine role in regulating pituitary FSH secretion and that its actions could be opposed by inhibin originating from the gonads.
Having co-discovered and characterized activin and inhibin, Wylie's team set out to isolate the receptors for these peptides and, in 1991, succeeded in characterizing the type II activin receptor (ActRII), the first member of a novel class of transmembrane serine threonine kinase receptors and the first receptor for a member of the TGF-β superfamily. This discovery led to the subsequent identification by Wylie's group and others of a dozen related serine threonine kinase receptors that are now known to be ubiquitous mediators of all signaling functions of the members of the TGF-β superfamily and to play critical roles in wide ranging aspects of cellular behavior under normal and pathological conditions. Wylie and his colleagues further identified a second type II receptor, ActRIIB, two type I receptors (ALK2 and ALK7) as well as two of several Smad signaling molecules downstream of these receptors (Xenopus Smad7 and Smad8). Recognizing the value of structural information for understanding mechanism, Wylie collaborated with Salk faculty to determine the X-ray crystal structure of the first receptor of this class, the extracellular domain of ActRII (ActRII-ECD) and later of ActRII-ECD bound to BMP7. This information allowed Wylie and colleagues to identify the determinants of activin binding to its receptors. In 2000, Wylie led yet another discovery effort and reported the identification of betaglycan (type III TGF-β receptor) as an inhibin binding protein. His group went on to elucidate the mechanism of inhibin action and proposed a model of how a high affinity inhibin:betaglycan:ActRII complex blocks activin as well as BMP signaling by sequestering ActRII away from the available pool of signaling receptors. Work led by Wylie and his collaborators also contributed to our understanding of the regulatory schemes used by activin, including the discovery of a role for Cripto as an activin and TGF-β antagonist with implications for stem cell function and tumorigenesis.
There was always an element of surprise with Wylie. He used humor to mentor and to guide. Wylie thrived on the excitement of new discoveries and simply had fun with the process. He encouraged the same in those around him. As reflected by Mary Stenzel-Poore, who received her postdoctoral training in Wylie's laboratory and currently holds a position as Professor and Chair of Molecular Microbiology & Immunology at Oregon Health & Sciences University, “Wylie was a leader in the true sense of the word. He encouraged provocative thought, gave us the license and wherewithal to pursue it and understood that risk is an essential ingredient of all great progress in science. He instilled this bold philosophy in so many that had the great joy and privilege of training with him.” He was truly a brilliant scientist yet down-to-earth and humble. Wylie's effectiveness as a mentor stemmed from his keen ability to immediately recognize the strengths in every single one of the trainees that passed through his laboratory and to tailor his dealings according to their needs. Wylie encouraged independence and creativity but also provided the necessary guidance and encouragement. Robert Sapolsky, another one of Wylie's former postdoctoral fellows, currently a Professor at Stanford School of Medicine and a world-renowned neuroscientist, recalls “Wylie, justifiably, was always proclaimed for his brilliance as a scientist, but it's not until you spent time in his lab that you could appreciate something else about him – here's a lab of 60 people, and not only did Wylie know what science everyone was doing, he somehow knew what everyone was thinking, and feeling, and feeling without them even knowing they were feeling it. He had a boggling amount of social intelligence.”
Wylie cared about the full extent of scientific work, was generous in dispensing his wisdom and provided thoughtful counsel to colleagues and trainees. Those of us fortunate enough to have worked with Wylie learned to be independent, to think “outside the box” and to take pride in our own accomplishments. In the words of Kunihiro Tsuchida, another postdoctoral trainee of Wylie's, who has since returned to Japan and is a Professor at the Institute for Comprehensive Medical Sciences at Fujita Health University, “Wylie always tried to make everyone in the lab feel happy. He also gave credit to co-workers in the lab during his talks. Wylie was a good mentor for foreign fellows as well. He had a vocabulary of many foreign languages and even knew foreign jokes. Skillful technicians in the lab helped foreign researchers to work comfortably during their stay in his lab, and many fellows felt that they would have liked to stay longer in his lab. Even after they returned to their home countries such as Japan and Italy, Wylie continued to be helpful to them and tried to give suggestions when he had a chance to meet with them. His scientific style was easygoing, but at the same time insightful and thoughtful, that is hard to imitate for other scientists. We (I) deeply miss his rare personality as an individual/mentor/scientist.”
When he passed away on January 3, 2012, Wylie Vale, Jr. was Professor and Head of the Clayton Foundation Laboratories for Peptide Biology at the Salk Institute for Biological Studies, a world-renowned leader in the field of neuroendocrinology, a recipient of many awards and honors, a devoted mentor to his current team of research scientists, postdoctoral fellows and graduate students, a co-founder of two biotech companies and, most of all, a devoted husband, father and grandfather. Wylie is survived by his wife Betty, two daughters Elizabeth and Susannah and their husbands, granddaughter Celeste, brother Shannon and his family as well as his father Wylie Walker Vale, Sr.