With an overall goal of understanding how small molecules control biological processes, the laboratory focuses on biologically active small molecules, especially those known as natural products, and their interactions with larger molecules. Projects can be divided into four groups:
A major focus of the laboratory is discovering new biologically active natural products using DNA-based approaches. Many of the most powerful drugs used today have come from microbes living in soil. Today studies on soil microbes increasingly lead to the rediscovery of known molecules. Several lines of evidence suggest that only a tiny fraction (certainly less than 1%) of the microbes that live in soil can be cultured by known techniques. Our laboratory has developed ways to capture the biologically active small molecules made by these uncultured microbes. We extract DNA directly from the environment (eDNA) and use heterologous expression in readily cultured organisms to access small molecules. This process has yielded new molecules, new biosynthetic pathways, and new microbial biology that form the basis for individual projects.
Isolation and Structure of Natural Products
The laboratory also studies biologically active small molecules in their natural, as opposed to therapeutic, context, and the small molecules that serve as biological information carriers are of special interest. One project asks how the sex pheromones of moths, apparently simple molecules, evoke biological responses with amazing potency and specificity. Other projects examine the perception of population density by fungi and C. elegans.
Protein Structure and Enzymology
Our laboratory is interested in the characterization of proteins as a means of understanding their molecular mechanisms of action, or for providing information useful in the design of therapeutically useful agents. X-ray crystallography is used as a tool for the study of macromolecular structure, while kinetic studies reveal further details about the enzymes mode of action. In particular, we are interested in projects related to human disease, such as the pyrimidine biosynthesis pathway in Plasmodium falciparum, and biosynthetic clusters of enzymes, e.g. the fee gene cluster.
Our laboratory has recently become involved in a multi-disciplinary initiative that is focused on the development of novel therapies for globally important infectious diseases, such as malaria, sleeping sickness and tuberculosis. In association with researchers at the Harvard School of Public Health, we are using high-throughput screening as a tool to discover lead compounds. The laboratory emphasizes phenotypic screens to find new targets, but there are also studies directed towards validated targets with no effective therapeutic agents. Future work would involve the synthesis of more active compounds, and identification of the molecules protein target.