Abstract
John Baxter, circa 1995, engaged in one of his favorite pastimes somewhere north of the 45th parallel.
John grew up in Lexington, Kentucky, and was a high school letterman in both basketball and track. John was the first Kentucky high school boy to run the mile in under 4:30 and finished second in the state championships in 1958. His track prowess earned John a scholarship to the University of Kentucky, where he set school records in the 880 and mile and graduated with a B.A. in chemistry in 1962. From Kentucky, John went to medical school at Yale, where he received his M.D. in 1966. John stayed at Yale for an internship and residency in Internal Medicine, and after a research fellowship with Gordon Tomkins at the National Institutes of Health and the University of California-San Francisco (UCSF), John joined the faculty at UCSF in the Department of Medicine in 1972. He remained there for most of his career, serving as Chief of the Division of Endocrinology from 1980 to 1997, Director of the Metabolic Research Unit from 1981 to 2000, and founder of the UCSF Diabetes Center in 2001. In 2008 John left UCSF to become Chief of Endocrinology at the Methodist Hospital in Houston, Texas, and a Senior Member of The Methodist Hospital Research Institute.
John was involved in some of the very first genetic engineering efforts in the 1970s at UCSF that revolutionized the standard approach to biological research and led to the creation of the biotechnology industry. In 1977 John and colleagues reported the cloning of the gene encoding rat growth hormone—one of the first examples of cDNA cloning (1). In that same year the team also reported the partial gene sequence of human chorionic somatomammotropin (2), which led to the development of an effective hybridization probe for isolating the gene encoding human growth hormone (3). This represented the first example of a method that was subsequently developed into an industrial process for producing the quantities of human growth hormone needed for clinical use. John's image was on the cover of The New York Times Magazine in 1980 accompanied by an article describing his early contributions to genetic engineering and molecular medicine. Patents on human and bovine growth hormone by John and his co-inventors have generated royalties of more than $350 million to date for UCSF (4).
The obvious practical applications of this research led to John's involvement with the emerging biotechnology industry gathering steam in the Bay Area in the early 1980s. At that time biotechnology was an exciting new idea offering seemingly limitless possibilities and was a perfect endeavor for John with his characteristic enthusiasm and boundless energy. In 1982 John founded California Biotechnology, Inc., the developer of a brain natriuretic peptide-based product for heart failure and a fibroblast growth factor–based product for wound healing; Cal Bio was acquired by Johnson & Johnson in 1999. John also was a founder and director of SciClone Pharmaceuticals, Inc., and Calhoun Vision—SciClone developed Zadaxin, a hepatitis B and C therapeutic, and Calhoun developed an intraocular lens suitable for implantation. In 1987 John co-founded Karo Bio AB, a Swedish company focused on nuclear receptors as drug development targets. With John's help, Karo Bio brought several drug discovery projects to clinical development including one in John's favorite area: selective thyroid hormone analogs for treating metabolic disease.
John maintained an active interest in thyroid hormone action from his early days as a medical student at Yale. From a career bibliography of more than 350 published articles, John's very first publication deals with hypercalcemia in patients with thyrotoxicosis (5). John maintained his interest in thyroid hormone over the intervening years and in the late 1980s embarked on a substantial effort in collaboration with Robert Fletterick to elucidate the first three-dimensional structure of a nuclear receptor, the thyroid hormone receptor (TR) ligand binding domain (LBD). The success of this project hinged on the production of large quantities of pure TR LBD, and John's lab delivered in this regard where others had failed, with the development of a novel method of purification based on LBD conformational changes that occur with hormone binding (6). This led to the solution of the TR LBD crystal structure, which was the first of many subsequent hormone-bound nuclear receptor LBD structures. It also revealed the striking and unexpected hormone binding site encapsulated within the central core of the LBD, a feature that turned out to be a general finding for all receptors in the nuclear receptor superfamily (7).
The Baxter/Fletterick TR LBD structure is widely considered a landmark achievement that greatly aided and influenced other nuclear receptor research efforts such as understanding how co-activator proteins interact with LBDs (8), how receptor dimers form (9), and how co-repressors interact to silence receptors in the absence of hormone (10). John and his colleagues also used the TR LBD structure in extensive drug design efforts, both in academic collaborations with Tom Scanlan and via industrial collaborations with Karo Bio. John's work with Scanlan at UCSF led to the development of GC-1 (also known as sobetirome), a cardiac-sparing thyromimetic used extensively over the years as a research tool to study selective thyroid hormone action. Sobetirome is currently in clinical development (11). John's efforts with Karo Bio resulted in another selective thyromimetic, KB-2115 (also known as eprotirome), which was recently shown to be a safe and effective cholesterol-lowering agent in hypercholesterolemic patients as part of a Phase II clinical trial (12). Eprotirome is currently being studied in a Phase III trial in heterozygous familial hypercholesterolemic patients. If successful in this scenario, it will constitute the realization of John's long-held vision that the beneficial actions of excess thyroid hormone can be selectively harnessed for therapeutic benefit, particularly for the disorders that accompany metabolic disease.
By now it should be clear to the reader that John Baxter was an extraordinarily talented and driven man. His list of life accomplishments is unique and unrivaled, and the contributions he made to endocrinology will have a lasting impact on the field. Those who knew John know that he loved life and worked hard to squeeze everything he could out of every moment and opportunity that came his way. Even though he was clearly blessed with abundant skill and an exquisite mind, he was as down-to-earth as they come and offered endless encouragement and support to colleagues, collaborators, and trainees. John was generous to his colleagues and collaborators, sharing the rewards and credit that came from the success of projects in which he played a vital role. Those of us who were fortunate enough to have worked with him will not soon forget his enthusiastic nature, his unrelenting energy level, and his endearing Kentucky accent, which he must have worked hard to preserve over the decades spent in San Francisco. John was a one-of-a-kind man and he will be sorely missed.