William G. Kaelin, Jr., MD, and Gregg L. Semenza, MD, PhD, are the recipients of the 2012 American Society for Clinical Investigation’s Stanley J. Korsmeyer Award, in recognition of their contributions to the molecular understanding of cellular oxygen sensing and cellular adaptation to hypoxia. As a corollary, their work has defined how this sensing mechanism goes awry in broad spectrum of disorders ranging from the vascular overgrowth associated with many forms of cancer to the reduced vascular density associated with ischemic disease. The Korsmeyer Award also recognizes their successes in mentoring future physician-scientists and researchers. As recipients Drs. Kaelin and Semenza will share the $10,000 honorarium and present the Korsmeyer Lecture at the 2012 ASCI/AAP Meeting, April 27-29, in Chicago, Illinois.
Dr. Semenza, a pediatrician and geneticist, discovered and characterized HIF-1α, opening the field of oxygen biology for molecular analysis. In 1995 Dr. Semenza purified and isolated the gene encoding HIF-1α and has since discovered major roles for HIFs in organismal development and cellular homeostasis. His work showed that HIFs serve as master regulators of the cellular oxygen response by inducing the expression of the genes whose products mediate adaptive responses to changes in oxygen levels. Since then, Dr. Semenza’s laboratory has been at the forefront of translational studies of HIF gene therapy for ischemic cardiovascular diseases, wound healing, and organ transplantation; and HIF inhibitors for cancer, ocular neovascularization and pulmonary hypertension.
In highly complementary work, Dr. Kaelin as an observant medical oncologist provided a molecular explanation for the hypervascularity of the kidney and brain tumors seen in patients with germline mutations in the von Hippel Lindau (VHL) gene. He showed that VHL-deficient tumor cells produce high levels of hypoxia-inducible gene products, including VEGF, irrespective of oxygen levels. This work led to a series of key discoveries into how cells sense and respond to changes in oxygen levels. One of the most significant discoveries was that the VHL protein interacts with HIF in an oxygen-sensitive manner and suppresses tumor formation by targeting HIF for degradation. When a defective VHL-HIF interaction exists due to mutations in VHL, there are increased HIF levels that promote vascular tumor formation. Dr. Kaelin’s laboratory also discovered that oxygen-dependent proline hydroxylation of HIFs by a prolyl hydroxylase (PHD2) regulates its ubiquitination by VHL and subsequent degradation. The functional link between these components of the oxygen-sensing network is reflected by the fact that mutations in the genes encoding all three components (PHD2, VHL, or HIF) lead to hereditary polycythemia. The insights gained from defining the VHL-HIF interaction created a conceptual basis for the successful clinical testing of VEGF inhibitors for metastatic kidney cancer.
Drs. Semenza and Kaelin were elected to the ASCI in 1995 and 1997, respectively, and are the recipients of numerous honors, including membership in the National Academy of Sciences. Dr. Kaelin obtained his undergraduate (mathematics and chemistry) and M.D. degrees from Duke University. He completed training in Internal Medicine at the Johns Hopkins Hospital and was a clinical fellow in Medical Oncology at the Dana-Farber Cancer Institute. Dr. Kaelin is currently Professor in the Department of Medicine at the Dana-Farber Cancer Institute and at the Brigham and Women’s Hospital, Harvard Medical School. Dr. Semenza received his undergraduate degree (biology) from Harvard College, and M.D. and Ph.D. degrees from the University of Pennsylvania. He completed training in Pediatrics at Duke University Medical Center and postdoctoral training in Medical Genetics at The Johns Hopkins University School of Medicine, where he is currently the C. Michael Armstrong Professor of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine.
William G. Kaelin Jr. and Gregg L. Semenza receive the 2012 ASCI/Stanley J. Korsmeyer Award in the Journal of Clinical Investigation