Heads of Laboratories
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 on one set of 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: What goes right and wrong? How does the immune system recognize these neuronal proteins as foreign in tumor cells, and why does this response turn into an attack on nerve cells in only some patients? Why do some patients react to such protein-expressing tumors while others do not?
Dr. Darnell’s 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 antibodies and 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 is developing cancer vaccines for use in small-scale clinical trials at The Rockefeller University Hospital to mimic PND tumor immunity. The scientists have also harnessed the identification of tumor-killing T cells in PND patients to transform normal T cells into ones that can recognize and kill breast and ovarian tumors.
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 explore the function of neuron-specific RNA-binding proteins in neuronal biology, in immune cells and in disease. Studies have focused on proteins involved in RNA regulation in the nucleus and cytoplasm, including the PND antigens Hu and Nova, the related protein FMRP — the protein mutated in fragile X mental retardation — and Argonaut, the RNA-binding protein that works together with microRNAs to regulate messenger RNA translation and stability. The lab developed a general technique 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 exon inclusion or skipping in alternative splicing, a general rule now found applicable to a dozen 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 in control of spinal motor neuron function, leading to new approaches to the study of Lou Gehrig’s disease.
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, and was chief neurology resident there from 1989 to 1990. In 1990 he began clinical work as a clinical assistant neurologist at Memorial Sloan-Kettering Cancer Center, where he continues to teach as an attending neurologist. He has also remained associate faculty of Weill Cornell in neurology and neuroscience. 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.
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 2010 he was elected to the Institute of Medicine of the National Academies, a member of the Association of American Physicians and a fellow of the American Association for the Advancement of Science.
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