A tribute: David Lorn Garbers, PhD (1944–2006)

Abstract

We are honored to present this special issue of Molecular Reproduction and Development in tribute to David Garbers on occasion of the year of what would have been his 80th birthday, a biochemist whose scientific contributions have significantly advanced the field of reproductive biology and have also led to foundational work in several other areas of medicine. Dave left us too soon and the biomedical research community lost a great scientist, mentor, friend, and family man. As scientific colleagues (HMF; GSK) and a mentee (GSK) of David, we believe that the reviews published in this special issue by our scientific colleagues reflect Dave's foundational work in the field of sperm signal transduction, metabolism, acrosomal exocytosis, chemotaxis, as well as his influence in areas of testicular function and contraception (Garbers, 1989). This breadth of contributions by Dave and his lab to the field of reproductive biology/medicine provides a suitable historical background for all young investigators in this field who had never met Dave nor were familiar with his impact on this and other scientific fields.

One anecdote encapsulates Dave's approach to science. He once spoke of the auriferous gravels of the Sierra Nevada range. There were reports that during the early days of the California gold rush one simply had to wade through streambeds in the mountains and pick up nuggets lying in plain view. The trick was that it was difficult to reach those rivers. The auriferous stream of science, he went on, was the research literature of the early years of the 20th century, replete with value but limited by the methods available at the time. Of course, the key to finding those nuggets was curiosity and scholarship. A case in point was Dave's work on sea urchin egg activation of sperm. In 1928, James Gray (1891–1975) found that eggs of the common sea urchin, Echinus esculentus, released factors into sea water that activated oxygen consumption by conspecific sperm, but the biochemical techniques of the time were not up to the task of identifying the active agents (Gray, 1928). Dave revisited this with the tools of 1960s biochemistry and the result was the characterization of the sperm-activating peptides, resact and speract. That was Dave-curious about the history of his field and adventurous enough to see the possibilities hidden therein. That approach served him well.

David grew up on the family farm in LaCrosse, Wisconsin and one cannot help to think that his love for the field of reproductive biology was influenced during his childhood while helping the family manage their farm. After receiving his bachelor's degree in animal science at the University of Wisconsin, Madison, he remained at Wisconsin and went on to obtain a masters in reproductive biology and a PhD in biochemistry under the tutelage of National Academy of Sciences members Drs. Neal First and Henry Lardy, respectively. During his postgraduate career (1967–1972) Dave studied the role of GnRH antagonists on ovarian function and was the first to establish a role for cyclic AMP in regulating sperm respiration, metabolism, and motility.

His interests in transmembrane cyclic nucleotide signal transduction and enzymology, mainly influenced by William “Mo” Cleland at the Enzyme Institute at Wisconsin, brought Dave in 1972 to the Department of Physiology at Vanderbilt University School of Medicine as a post-doctoral fellow with Nobel Laureate Dr. Earl W. Sutherland, the codiscoverer of cyclic AMP. After Sutherland left Vanderbilt for the University of Miami in 1973, Dave remained as a post-doc with Dr. Joel G. Hardman, a leading investigator in the field of cyclic GMP signal transduction (Garbers, 1990). During his post-doc years (1972–1974) Dave made significant contributions to the field of cyclic GMP signaling, mostly through his work on characterizing both the particulate and soluble forms of guanylyl cyclase. It was this work that established himself as a major scientific influence in the field of cyclic GMP signaling and cellular function and he was promoted to Assistant Professor in 1974.

Being a reproductive biologist at heart, Dave made a highly significant observation that started to explain a phenomenon that developmental biologists had made in the early twentieth century. The work of Frank Lillie, Jacques Loeb, James Gray, and Albert Tyler, among others, had established that “communication” between the eggs and sperm of a variety of invertebrate marine species occurred before fertilization and that the eggs released a factor(s) that influenced sperm function and in some cases could agglutinate sperm. This agglutination process had some of the hallmarks of an antigen-antibody complex and gave rise to what was known as the “fertilizin-antifertilizin” theory of fertilization. In this theory, a fertilizin molecule emanating from the egg would combine specifically with a fertilizin receptor on the sperm (antifertilizin), thus supporting the idea that the fertilization process involved an effector-receptor type of interaction. For example, it had been known that sea urchin sperm in the vicinity of conspecific eggs displayed changes in motility, respiration and would undergo acrosomal exocytosis. Garbers and Hardman (1975) published a landmark article demonstrating that sea urchin eggs released soluble factors that rapidly and dramatically altered intracellular sperm cyclic AMP and cyclic GMP concentrations. Subsequent work by the Garbers lab identified the component of the sea urchin egg jelly responsible for sperm acrosomal exocytosis (fucose sulfate-containing glycoprotein) that elevated cyclic AMP and peptides that modulated sperm respiration and could function as chemoattractants that elevated cyclic GMP. This work garnered interest by other investigators utilizing invertebrate and mammalian models to assess the molecular basis of communication between the egg/female reproductive tract and sperm, an area that remains of great interest today for its potential clinical, therapeutic and diagnostic applications.

Dave rose rapidly through the faculty ranks at Vanderbilt, becoming Professor of Pharmacology and Molecular Physiology and Biophysics. In recognition for his work in the field of cellular signal transduction and reproductive biology Dave was appointed to the Howard Hughes Medical Institute (HHMI) in 1976 and at the time of his death he was one of two record holders, the other being Nobel Laureate Robert Lefkowitz, for longevity as HHMI investigators.

Before moving to the University of Texas Southwestern Medical Center in 1990 as Professor of Pharmacology, the Cecil H. and Ida. M. Green Distinguished Chair in Reproductive Biology, and the Director of the Green Center for Reproductive Biology Sciences (1999), Dave's lab continued to make significant contributions to the field of reproductive biology using both invertebrate and mammalian model systems. During this time a collaboration between his and Victor Vacquier's lab provided the first evidence using sea urchin gametes that guanylyl cyclase could function both as a receptor (for egg peptides) and effector (sperm cyclic GMP generation). This observation shifted the previous thinking that nucleotidyl cylases solely functioned as effector enzymes linked to receptors. More than a decade later soluble adenylyl cyclase (ADCY10) was cloned from rat testis by Lonny Levin and Jochen Buck, and subsequently demonstrated to function as both a receptor and effector. Notably, both of these seminal discoveries were made with gametes and reproductive tissues. The Garbers lab continued to characterize the family of both plasma membrane and soluble guanylyl cyclases, demonstrating that different plasma membrane forms of guanylyl cyclase could serve as receptors for atrial natriuretic peptides, hormone/paracrine factors that regulate blood pressure and electrolyte homeostasis and for heat stable enterotoxins, small peptides produced by pathogenic bacterial that cause secretory diarrhea. These observations opened new areas of research for Dave as he and his lab pursued the roles of different guanylyl cyclase members in diverse areas such as olfaction, vision, hypertension and electrolyte imbalance. It should be noted that the evolution of Dave's research programs into these new areas of physiology all came from insights taken from the basic physiology of reproduction. Dave's collective body of work was recognized in 1992 when he was elected as a member to the American Academy of Arts and Sciences. His work on the regulation of different guanylyl cyclase members and communication between sperm and eggs was specifically cited as background supporting his membership election to the National Academy of Sciences in 1993.

As the Garbers lab continued to pursue these other areas of research outside of reproductive biology at UT Southwestern, Dave's position as the director of the Green Center came with the ability to recruit new faculty and to expand the center's mission to focus on the application of stem cells and germ cells to various aspects of biology and medicine. For example, his group identified conditions supporting the culture, transfection and differentiation of rat spermatogonial stem cells, which would permit the ability to manipulate the rat genome, an animal model that is in many ways more experimentally tractable than the mouse model. His interests also focused on the identification and function of unique germ cell molecules mediating important roles in fertilization and on the properties of embryonic, spermatogonial and neuronal stem cell maintenance and differentiation in a variety of model systems. His work on novel genes and gene products produced in the testis provided some of the earliest work related to identifying unique and innovative targets for male contraception, work which continues to this day by many other investigators. This work, and the work of others, continue to form a basis for understanding various types of infertility. Interests in the center also expanded to understanding the role of mammalian egg cytoplasmic factors in somatic cell re-programming and early embryonic totipotency.

Dave's modest and easy-going personality belied his intense scientific curiosity, imagination and broad knowledge in many different scientific areas. He was always thinking about how understanding a basic biological process in a specific discipline could be translated to other areas of biology and medicine. His highly respected research portfolio clearly demonstrated this and his laboratory was attractive for students, postdocs and visiting scientists from all over the world. His contributions continue to be honored by UT Southwestern Medical Center where an annual lectureship in his name has been established.

As editors of this special edition of Molecular Reproduction and Development, we hope you enjoy the articles in this issue and as reproductive biologists we should all be thankful that Dave was, at his core, one of us.