Heads of Laboratories
Robert B. Darnell, M.D., Ph.D.
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Robert and Harriet Heilbrunn Professor
Laboratory of Molecular Neuro-oncology
Dr. Darnell’s laboratory focuses on understanding a group of rare brain diseases, the paraneoplastic neurologic disorders, and how they arise in conjunction with immune responses to cancer. Through his work identifying the target proteins involved in the disorders, Dr. Darnell has also become interested in the role of RNA-binding proteins in the brain and in disease.
The Darnell lab studies paraneoplastic neurologic disorders (PNDs), a group of diseases thought to arise when tumors — typically breast, ovarian or lung cancers — start making proteins that are normally only made by the brain. Patients with PNDs carry antibodies that specifically target these proteins, but while this situation produces an effective antitumor immune response, it also leads to an autoimmune attack on brain tissue.
Using a combination of biochemical and genetic approaches, Dr. Darnell’s lab is asking basic questions about how these antitumor and autoimmune responses develop. The lab has shown that the immune systems of PND patients thwart tumors with what begins as a classical antiviral response: The patients’ T cells produce CD8+ killer T cells that recognize the neuronal antigens found within their tumors. In some patients there are atypical, less potent T cells present, perhaps evidence of tumor cells’ efforts to evade tumor immunity. The lab also discovered that apoptotic tumor cells serve as potent instigators of the T cell immune response in PND patients and has worked on developing cancer vaccines in small-scale clinical trials at The Rockefeller University Hospital to mimic PND tumor immunity.
This work merges with studies on what the PND antigens are: What is their normal role in neurons, and why do tumors induce their expression? These questions led Dr. Darnell’s lab to discover and explore the function of neuron-specific RNA-binding proteins in the mammalian brain. Studies have focused on proteins involved in RNA regulation in the PND antigens Hu (nElavl) and Nova, the related protein FMRP (the protein mutated in fragile X mental retardation), Argonaute (the RNA-binding protein that works together with microRNAs to regulate messenger RNA translation and stability) and others, including Ptbp2, Mbln2 and Rbfox. The function of these proteins has been studied using a general and powerful method the lab developed called high throughput sequencing–cross-linking immunoprecipitation, or HITS-CLIP, to create genome-wide maps of where RNA-binding proteins bind to RNA in living tissue. HITS-CLIP, together with analysis of knockout mice and bioinformatic approaches, led to the discovery that the position of protein binding in the messenger RNA is a prime determinant of the outcome of alternative splicing or polyadenylation, general rules applicable to many splicing factors. Recent computational improvements in analyses of HITS-CLIP maps have allowed robust genome-wide predictions of combinatorial RNA regulation and single-nucleotide resolution of protein interaction sites in the brain. The lab has also developed functional insight into RNA dysregulation in disease, including that mediated by FMRP, and revealed its mechanism of action and connection with autism spectrum disorders. Studies with Nova have led to insight into the balance of neuronal inhibition and excitation and into control of spinal motor neuron function, leading to new approaches to the study of Lou Gehrig’s disease.
These interests have begun to focus on the power of modern high throughput genomics to understand the role of RNA regulation in human disease and, in turn, led to Dr. Darnell’s involvement in the New York Genome Center.
Dr. Darnell received his undergraduate degrees in biology and chemistry from Columbia University in 1979 and earned his M.D. and Ph.D. in 1985 from Washington University School of Medicine in St. Louis, where he specialized in molecular biology. Dr. Darnell trained in internal medicine at Mount Sinai School of Medicine and in neurology at Weill Cornell Medical College with Fred Plum and Jerome Posner, where he was chief neurology resident. Dr. Darnell joined The Rockefeller University in 1992 as assistant professor and associate physician at The Rockefeller University Hospital. He was named associate professor in 1997 and professor and senior physician in 2000. In 2002 Dr. Darnell was appointed investigator at the Howard Hughes Medical Institute and named Heilbrunn Professor at Rockefeller. He is also attending neurologist at Memorial Sloan-Kettering Cancer Center, associate professor at Weill Cornell and president of the New York Genome Center.
Dr. Darnell’s awards include the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research in 2000, the Derek Denny-Brown Young Neurological Scholar Award in 1998 and the Irma T. Hirschl Trust Career Scientist Award in 1996. In 2012 he became President and Scientific Director of the New York Genome Center. He is a member of the National Academy of Sciences, the Institute of Medicine and the Association of American Physicians and is a fellow of the American Association for the Advancement of Science.
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