Currently, my laboratory focuses on the CRISPR-Cas system, a RNA-based adaptive immune system found in bacteria that protects against invasion by viruses and plasmids. Mechanistic studies of the CRISPR-Cas system is contributing to ongoing efforts aimed at exploiting this system to both protect domesticated bacteria (such as those used in food and pharmaceutical production) and combat human pathogens and the spread of antibiotic resistance. Moreover, RNA-guided nucleases from the CRISPR-Cas system are currently being adapted for genome editing and regulation strategies in a wide variety of organisms, including humans. Indeed, the potential of the CRISPR-Cas toolkit is just being realized and studies centered on understanding how the CRISPR-Cas systems function represents an important need. To this end, my laboratory has provided structural and mechanistic insight into how CRISPR-Cas systems identify and destroy their DNA targets.
We seek to understand the molecular mechanisms of macromolecular assemblies that organize, express, and preserve the cell’s genetic information. We are particularly interested in developing kinetically accurate, atomic-resolution depictions of the dynamic assemblies that control DNA replication, gene regulation, and chromosome superstructure, and in exploiting this knowledge for chemotherapeutic development.
My laboratory aims to understand the molecular mechanisms regulating eukaryotic signaling of pathways. This knowledge provides the framework needed to interpret how alterations to a pathway, such as additional proteins, mutations to pathway components, or small molecules, modulate activity and could help guide targeted therapies. To achieve this, my lab employs a multi-prong approach that combines cell-based assays, biochemistry, enzymology, biophysics, and structural biology.
Malaria, a disease caused by protozoan parasites, is one of the most dangerous infectious diseases, claiming millions of lives and infecting hundreds of millions of people annually. Malaria parasites contain an essential organelle called the apicoplast that is thought to have arisen through endosymbiosis of an algal cell which had previously incorporated a cyanobacterium. Due to its prokaryotic origin, the apicoplast contains a range of metabolic pathways that differ significantly from those of the human host. We are investigating biochemical pathways found in the apicoplast, particularly those required for the biosynthesis and modification of fatty acids. This metabolism should require several enzyme cofactors such as pantothenate, lipoic acid, biotin and iron-sulfur clusters. We are interested in these cofactors, how they are acquired, how they are used, and whether they are essential for the growth of blood stage or liver stage malaria parasites. We approach these questions with a combination of cell biology, genetic, biophysical and biochemical techniques.