Abstract

Robert Darnell is a pre-eminent physician-scientist, whose translational research began with a high-risk initiative to understand the pathophysiology of the paraneoplastic neurologic disorders (PNDs). This entailed taking an out-of-the-box approach to appreciate and focus on the unique nature of these rare diseases, which offer the possibility of developing insights into tumor immunity, cancer biology, autoimmunity, and human genetics. His lab cloned the genes that underlie the disorders, which were used to discover that CD8 + killer T cells mediate naturally occurring human tumor immunity (Nature Med 1998)— providing foundational support for the field of immuno-oncology. Darnell also studied the nature of the PND antigens, discovering that many of them regulate RNA biology in unique ways. Studying the PND antigens Hu (nElavl), Nova and the related protein FMRP , his lab developed “in vivo” biochemical approaches to understand function, leading to development a breakthrough method, CLIP (Science 2003), now the gold standard for understanding RNA regulation in intact tissues. Recent discoveries have included finding that the position of protein binding in pre-mRNA determines the outcome of regulation (alternative polyadenylation (APA) and splicing (Nature 2006, 2008)), pinpointing sites of miRNA control (Nature 2009), finding that m6A RNA modification regulates APA (Ke, G&D, 2015), and that FMRP triggers ribosomal arrest to regulate translation (Cell 2011), linking FMR Ps role in intellectual disability to autism (Neuron 2012). His lab continues to generate translational discovery in Alzheimer’s disease (eLife 2016), axon guidance (eLife 2015), and viral infection (Cell 2015). Pursuing these interests in the realm of human genetics led to his role as Founding Director of the New York Genome Center (NYGC), his selection as one of an extraordinary group of HHMI Investigators (2002-present), in HHMI ’s only competition strictly for patient-oriented scientists. He was elected to the National Academy of Medicine (2010), the National Academy of Sciences (NAS; 2014), and recognized with several highly prestigious NIH awards: he is the Principle Investigator on a $40M Genome Center NIH grant, and recipient of the Directors Transformative Award by Francis Collins (2012) and the NINDS Outstanding Investigators Award (2016).