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
E-mail: darnelr@rockefeller.edu
Dr. Darnell’s laboratory focuses on understanding a group of rare brain diseases, the paraneoplastic neurologic disorders,
which 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 is interested in paraneoplastic neurologic disorders (PNDs), a group of diseases thought to arise when tumors in the body — typically breast, ovarian or lung cancers — begin to make proteins that are normally made only by the brain. Patients with PNDs carry very high amounts of antibodies specific for the neuronal proteins, a situation associated with an effective antitumor immune response but also 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 goes right and wrong in the immune system to allow these responses to develop: How are these neuronal proteins recognized as foreign by the immune system in tumor cells, and why in only some patients does this turn into an attack on nerve cells? Why do some patients react to tumors expressing these neuronal proteins, but others do not?
Dr. Darnell’s lab has shown that PND patients react to tumors with a classical anti-viral type of immune response. PND patients produce both antibodies and T cells specific to the neuronal antigens found on their tumors, suggesting that an understanding of how the immune system is activated in these patients may provide a route to a potential cancer treatment. Based on the tumor immune responses observed in PND patients, Dr. Darnell’s lab has discovered that apoptotic tumor cells can serve as potent instigators of the killer T cell immune response in PND patients. Several small-scale clinical research studies are being performed at The Rockefeller University Hospital to help scientists better understand the underlying mechanism responsible for this effective tumor immunity, and to mimic it by developing experimental cancer vaccines.
The second interest of Dr. Darnell’s lab, which grew out of his work on PND antigens, is in exploring the function of neuron-specific RNA binding proteins in neuronal biology and in disease. The functions of two proteins in particular, the PND antigen Nova and the related protein FMRP — the protein mutated in Fragile-X mental retardation — have been explored. The lab’s goal is to identify the RNAs that are regulated by these and, more generally, by a larger group of such proteins. New techniques are being developed with this goal in mind. These have been used to identify a network of more than 100 alternative exons within mRNAs made in the brain whose splicing is controlled by Nova, and are now being applied to FMRP and other RNA binding proteins that are involved in neurologic diseases. Dr. Darnell’s lab is interested in exploring the possibility that RNA binding proteins like Nova may act to change RNA metabolism in tumors.
The new techniques have provided a set of known Nova targets, and Dr. Darnell’s lab is now working to determine how that group is defined and how it functions. This research led to the discovery that the set of mRNAs regulated by Nova is involved in synaptic function, and is defining a new relationship between the regulation of RNA complexity in the nucleus and complexity in the synapse 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. from Washington University School
of Medicine in St. Louis in 1985, where he
specialized in molecular biology. Dr. Darnell
trained in internal medicine at Mount Sinai
School of Medicine and in neurology at Weill
Medical College of Cornell University, 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
appointed 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 the 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 Career
Scientist Award in 1996.
