Heads of Laboratories
Investigator, Howard Hughes Medical Institute
Senior Attending Physician
Robert and Harriet Heilbrunn Professor
Laboratory of Molecular Neuro-oncology
Robert.Darnell@rockefeller.edu
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 what allows these antitumor and autoimmune responses to 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. They also discovered that apoptotic tumor cells serve as potent instigators of this immune response in PND patients, and are developing cancer vaccines for use in small-scale clinical trials performed 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. Recent studies are following up the discovery by investigating ways in which PND tumors may try to evade immune destruction by altering the classical antiviral T cell response into an unusual and less potent response.
The lab is also interested in what the PND antigens are — what is their normal role in neurons, and why do tumors induce their expression? These questions have led Dr. Darnell’s lab to explore the function of neuron-specific RNA-binding proteins in neuronal biology and in disease, including the PND antigens Hu and Nova, and the related protein FMRP — the protein mutated in fragile X mental retardation. Recently, the lab has 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 bioinformatics, has been able to predict and validate rules governing alternative splicing and polyadenylation in vivo. The lab has extended their approach to develop functional insight into how RNA regulation, including that mediated by FMRP and microRNAs, functions in isolation and in combination within living cells. This work has been applied to the study of human disease and to physiology with a new focus emanating from a series of findings relating Nova RNA regulation to the balance of neuronal inhibition and excitation, motor neuron function in the spinal cord as well as the formation of the neuromuscular junction, the culprit behind Lou Gehrig’s disease. The work could lead to the identification of new relationships between the regulation of RNA complexity in the nucleus and the complexity of the cell itself.
CAREER
Dr. Darnell received his undergraduate degree 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, where he was chief neurology resident 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 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.
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