The 2017 ICIS Honorary Lifetime Membership Award
Ganes Sen, Ph.D., The Thomas Lord Endowed Chair in Molecular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, USA
Dr. Sen receives the 2017 Honorary Lifetime Membership Award for his contributions that have advanced our understanding of the role of IFNs in antiviral responses. He has served in many capacities to the ICIS, most notably his long term involvement as editor in chief of the Journal of Interferon & Cytokine Research, and has trained many young scientists who have stayed in the field of cytokines.
Ganes C. Sen holds the Thomas Lord Chair of Molecular Biology in the Immunology Department of the Lerner Research Institute, Cleveland Clinic; he is also Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine.
Sen was born in India where he received his early education, followed by a Ph.D. in Biochemistry from McMaster University, Canada. With a fellowship from the Canadian Medical Research Council, Sen pursued post-doctoral training with Peter Lengyel at Yale University, where his long journey in interferon (IFN) research began in 1974. It was an exciting and productive time in Lengyel lab; Sen and his colleagues identified two important executers of IFN’s antiviral actions, PKR and RNase L, enzymes that were independently discovered by several laboratories around the world. In 1978, Sen joined the Faculty of the Memorial Sloan-Kettering Cancer Center and Cornell University in New York and started his own research program. There he expanded his interest in the IFN system to study not only the mechanism of action of the IFN-stimulated genes (ISG), but also the mechanism of IFN induction by viruses. These interests steered his attention to double stranded (ds) RNA, a potent viral pathogen-associated molecular pattern (PAMP), which induces IFN synthesis and mediates IFN action.
In 1988, Sen moved to the newly formed Molecular Biology department at the Cleveland Clinic, which he later chaired for a decade. At the Cleveland Clinic, Sen helped nucleate the formation of a vibrant and interactive group of cytokine researchers, which included Bryan Williams, Bob Silverman, George Stark, Tom Hamilton, Xiaoxia Li, Richard Ransohoff, Andy Larner and Ernie Borden. Here, he continued his studies on the catalytic, structural and antiviral properties of the dsRNA-activated enzymes, PKR and 2-5(A) synthetases. Sen identified several additional dsRNA-binding proteins, including PACT, the protein activator of PKR. PACT-/- mice demonstrated a role of PACT, through its interaction with PKR, in anterior pituitary development. Sen’s recent work on ISG action is focused on the Ifit family of proteins. By generating a series of Ifit -/- mouse lines, his group demonstrated that Ifit2 protects mice from viral neuropathy. Surprisingly, Ifit2 is antiviral only in neurons, not other cells, thereby demonstrating an unexpected cell type specificity of ISG action.
Sen’s early research showed that ISGs could be induced by dsRNA, without an involvement of IFN, through the activation of IRF3 by TLR3 and RIG-I signaling pathways. Recent studies by his group have shown that IRF3 is a dual action protein that mediates its antiviral action by not only inducing IFN and ISGs, but also triggering Bax-mediated apoptosis of virus infected cells. Viral and cellular RNA and DNA are recognized as PAMPs by several intracellular receptors which trigger the synthesis of IFN and other cytokines. Sen is interested in examining the role of protein tyrosine phosphorylation in mediating signaling by these receptors and has identified EGFR as a protein tyrosine kinase that is essential for signaling by the endosomal TLRs. Consequently, EGFR inhibitors prevent pathogenesis in mice caused by hyper-activation of these TLRs.
Sen’s another long-term research interest is in defining the physiological functions of angiotensin converting enzyme (ACE). Although well known for its role in blood pressure regulation, ACE is also essential for kidney and sperm functions. By designing various genetic models in mice, Sen demonstrated distinct tissue-specific and isozyme-specific physiological functions of cell-bound and soluble ACE.
Sen received the Milstein Award from the International Society for Interferon and Cytokine Research and the Boltzmann Award from the European Cytokine Society. He is a Fellow of the American Academy of Microbiology and a Fellow of the American Association for Advancement of Science. He has contributed to the scientific peer review system by serving on numerous NIH grant review panels and journal editorial boards. Since 2003, he has been the co-Editor-in-Chief of the Journal of Interferon & Cytokine Research. Sen has trained more than seventy young scientists, many of whom have excelled as independent investigators.