About Our Lab
Our laboratory focuses on the enzymatic generation of genomic diversity. We utilize a broad array of approaches, including biochemical characterization of enzyme mechanisms, chemical synthesis of enzyme probes, and biological assays spanning immunology and virology to study this central tactic in the constant battle between our immune system and pathogens.
From the host immune perspective, the generation of genomic diversity is used as both a defensive and an offensive weapon. On the one hand, host mutator enzymes such as Activation-Induced Deaminase (AID) seed diversity in the adaptive immune system by introducing targeted mutations into the immunoglobulin locus that result in high affinity antibodies (somatic hypermutation) or altered isotypes (class switch recombination). Related deaminases of the innate immune system can directly attack retroviral threats by garbling the pathogen genome through mutation, as accomplished by the deaminase APOBEC3G, which restricts infection with HIV. Immune mutator enzymes, however, also pose a risk to the host, as overexpression or dysregulation have been associated with oncogenesis (AID) or drug resistance (A3G).
From the pathogen perspective, alteration in key antigenic determinants at a rate that outpaces immune responses is a potent means for evasion. Further, rapid mutation may allow for the development of resistance to antimicrobials.
Our research program aims to understand mutator enzymes and pathways in the immune system and pathogens. We further aim to harness these diversity-generating systems for directed evolution of proteins. Additionally, we apply chemical biology to decipher and target these pathways, to impede the development of multidrug-resistance in pathogens or prevent the neoplastic transformations that can result from genomic mutation.
• Last updated: 11/09/2012