Profile of David J. Mangelsdorf.

T wo decades ago, David Mangelsdorf did not expect his basic research findings to help launch an entire field of biology with farreaching implications for a raft of human diseases, including cancer, metabolic disorders, and parasitic infections. Mangelsdorf, a Howard Hughes Medical Institute investigator and a professor of pharmacology at the University of Texas Southwestern Medical Center at Dallas, began his career by cloning the cellular receptor for vitamin D, which later helped other researchers uncover the genetic basis of osteoporosis and rickets (1, 2). Insights from that initial work veered Mangelsdorf in a direction that spawned the field of orphan nuclear hormone receptors. Raised in Kingman, a sunswept town in the Mojave Desert of northwestern Arizona, Mangelsdorf says his love of nature preceded his love of science. Although much of his work has focused on molecules hidden in cells, his interest in biology began as a passion for marine life in open oceans. Impelled by the breathtaking imagery of French naval explorer Jacques Cousteau’s films of marine life, Mangelsdorf decided to become a marine biologist. “During my sophomore year in high school, I wrote to The Scripps Institution of Oceanography [in San Diego] to explore the option of marine biology as a career. I naively thought I could go there straight from high school, but Scripps did not take undergraduate students,” he says. However, Mangelsdorf learned that one of the best schools in the United States for undergraduate aquatic biology, Northern Arizona University at Flagstaff, was a mere 150 miles from his hometown. In the fall of 1977, he enrolled in the school’s aquatic biology program. While taking a beginner’s course in chemistry to fulfill the program’s requirements, Mangelsdorf met one of his early mentors, John Wettaw, a chemistry professor who introduced him to biochemistry. During the early 1980s, researchers were making strides in the march against cancer. Smitten with a 1980 Time magazine cover story on the promise of interferon treatment for cancer, Mangelsdorf soon found that his fascination with biochemistry supplanted his passion for marine biology. After graduating with a bachelor’s degree in aquatic biology in 1981, he decided to spend the next 6 years in graduate school at the University of Arizona in Tucson, studying biochemistry in the laboratory of Mark Haussler, who discovered the hormonal form of vitamin D called calcitriol. “It was Mark Haussler who really changed my mind about marine biology. I fell in love with his work,” Mangelsdorf says. WhenMangelsdorf was casting about for a doctoral project upon his arrival at Haussler’s laboratory, Haussler offered him a choice: biochemically identify the hypothetical vitamin A receptor or clone the gene for the biochemically identified vitamin D receptor. Despite the allure of the unknown in the former, Mangelsdorf picked the latter. Armed with antibodies to the vitamin D receptor, Mangelsdorf set out to clone the gene for the receptor by using a then-novel, bacteriophage-based cloning technique described in a now highly cited PNAS paper (3). A fruitful collaboration with a graduate student in the group of Baylor College of Medicine endocrinologist Bert O’Malley culminated in a 1987 paper in Science describing the drawn-out cloning of the chicken gene for the vitamin D receptor (4). Mangelsdorf’s PhD thesis won the biochemistry department’s dissertation of the year award. The award was not the only recognition that Mangelsdorf’s graduate work garnered. In 1985, NASA accepted Mangelsdorf’s proposal to conduct experiments with rodents aboard the Challenger spacecraft to study the receptor’s role in the alarming loss of bone density suffered by some astronauts returning from space. Mangelsdorf’s idea was to compare the expression of the receptor’s gene in the kidneys of rats sent into orbit with that of rats kept on Earth. “Unfortunately, it turned out that the space shuttle had to sit on the ground for almost 12 hours before we could harvest the rats’ kidneys. By that time, whatever happened in space might have been reversed by being back on Earth,” he recalls. “Nevertheless, I got to watch the space flight, send the rats up, and keep the NASA mission patch,” he chuckles. The NASA experiment may have led nowhere, but Mangelsdorf’s work bore fruit in bigger ways. Because the vitamin D receptor controls the excretion of calcium by the kidneys, Mangelsdorf’s graduate work held medical promise (5). “Until you had the sequence for the receptor’s gene, it was impossible to understand the genetic basis of diseases like vitamin Dresistant rickets, which is caused by mutations in the receptor’s ligand-binding, DNA-binding, and dimerization domains,” Mangelsdorf explains. “The cloning of the receptor was the biggest thing in the field since the discovery of the hormonal form of vitamin D,” he adds, proudly.