|TH E N I H C A T A L Y S T||JU L Y A U G U S T 2008|
Rafael Casellas joined the NIAMS Molecular Immunology and Inflammation Branch in 2004. His laboratory focuses especially on the molecular mechanisms that maintain genomic integrity and stability in the B-cell genome as antibody genes undergo extensive mutation and recombination.
Casellas uses class-switch recombination — a mechanism that B cells use to express the various immunoglobulin classes of antibodies — as a model to study basic cellular processes. Class-switch recombination requires coordination of the transcriptional machinery, of DNA repair factors, and of chromatin-remodeling enzymes to induce a specific double-stranded break in the DNA and then to rejoin the appropriate DNA segments of the immunoglobulin region.
A "Renaissance man" in his youth, immersed largely in the humanities, Casellas turned to science when he realized that biology and genetics were also powerful at explaining the human experience-from the "taste of food to the mechanism of disease to the complexities of human behavior," he said. Genetics and molecular biology also represented the current edge to him, and Casellas has tried to maintain a position throughout his career at the forefront of that edge.
Casellas earned his doctorate at Rockefeller University in New York, working with Michel Nussenzweig on mechanisms of antibody diversification such as immunoglobulin-receptor editing and class-switch recombination. He then completed a postdoctoral stint with David Baltimore at the California Institute of Technology in Los Angeles, where he furthered his studies of B-lymphocytes.
Recent work from Casellas' laboratory has shown how repair enzymes recruited to DNA breaks inhibit RNA polymerase activity, illustrating that repair and transcription can be coordinated within the cell (Nature 447, 2007). Casellas not only demonstrated that these processes are linked, but also identified the signaling pathway, or ATM repair pathway, required to inhibit the action of the polymerase. In pursuing this research, Casellas has drawn upon the expertise of Tom Misteli and André Nussenzweig of NCI, whose labs had developed technologies that fostered his experiments.
"I really feel this is one of the best places to explore science," Casellas said, citing not only the quality of intramural collaborators but also the investigative freedom afforded by an environment not limited by the traditional grants mechanism. Casellas is now interested in mapping chromatin changes at the immunoglobulin locus during mutation and recombination, studying the mechanisms that underlie chromosomal translocations and the driving of B-cell development by small RNAs, and examining how the B-cell genome can be reprogrammed-and more. The list is long and diverse but in keeping with the kaleidoscopic inclinations of a Renaissance man.