Heads of Laboratories
Sean F. Brady, Ph.D.
Tri-Institutional Associate Professor
Howard Hughes Medical Institute Early Career Scientist
Laboratory of Genetically Encoded Small Molecules
Natural products — or more generally, genetically encoded small molecules — play a wide variety of roles in biology and have proved very useful in the development of small-molecule therapeutic agents. Dr. Brady’s research centers on the discovery, biosynthesis and characterization of new, genetically encoded small molecules from microbial sources, with a special focus on those produced by uncultured soil bacteria and pathogenic bacteria.
One of the key revelations from the large-scale sequencing of bacterial genomic DNA is that the approaches traditionally used for identifying new natural products only provide functional access to a small fraction of the biosynthetic gene clusters present in nature. These studies indicate that essentially all bacteria — from those with fully sequenced genomes to those not yet cultured — are rich sources of unstudied natural product biosynthetic gene clusters. Using methods from molecular biology, organic chemistry and microbiology, Dr. Brady is working to gain access to these previously inaccessible natural products and their biosynthetic gene clusters. The development of methods to functionally access the wealth of previously inaccessible natural product biosynthetic pathways known to be present in bacterial genomes should significantly increase the number and diversity of natural products available to test as probes of biological processes and therapeutic agents.
Soil microbes that have not yet been cultured outnumber their cultured counterparts by at least two to three orders of magnitude. Uncultured bacteria are one of the largest pools of genetic diversity that remain unexamined for the production of potentially useful natural products. Dr. Brady’s first research focus is the development of new strategies for studying genetically encoded small molecules produced by uncultured bacteria. Although most bacteria are not readily grown in the laboratory, making it difficult to use traditional microbiological methods to characterize the natural products they create, microbial DNA can be extracted directly from environmental samples and cloned in easily cultured bacteria. Dr. Brady has worked extensively on the development of genetic strategies to access the vast chemical and biosynthetic potential of uncultured, previously inaccessible, bacteria. This has allowed for the construction of large libraries of environmental DNA, as well as the development of methods to screen these libraries. Such culture-independent methods are leading Dr. Brady to identify new natural products, biosynthetic enzymes and bacterial signaling systems. Dr. Brady’s work has shown that large environmental DNA libraries are a promising source of both new derivatives of pharmacologically important classes of natural products as well as completely novel families of bioactive natural products. His group has begun mapping the presence of promising microbial gene clusters found in soil samples collected around the world. These maps may help guide the discovery of natural products by directing investigators to certain regions and environments.
The second focus of the Brady lab, the chemistry of human microbiome-associated and pathogenic bacteria, could one day help address the problem of drug-resistant bacteria. Pathogenic bacteria have evolved elaborate signaling systems and toxins vital to their ability to initiate and maintain infections. The annotation of completely sequenced bacterial genomes has led to the identification of natural product biosynthetic gene clusters whose predicted products do not correspond to any molecules previously characterized from these organisms. Dr. Brady uses bioinformatics to examine the genomes of sequenced bacteria, looking to identify gene clusters that could code for novel signaling molecules and toxins. By studying the complex collections of small molecules used by bacterial pathogens, he hopes to gain new insight into the molecules used during infection and, in turn, determine how to best disrupt key steps in the establishment and propagation of bacterial infections.
Dr. Brady graduated with a degree in molecular biology in 1993 from Pomona College. He received his Ph.D. in organic chemistry in 2001 from Cornell University, where he studied under Jon Clardy. In 2002 he moved to Harvard Medical School as a fellow in the Institute of Chemistry and Cell Biology. He was named an instructor in the department of biological chemistry and molecular pharmacology at Harvard Medical School in 2004 and moved to Rockefeller as assistant professor in 2006. He was promoted to associate professor in 2012.
Dr. Brady received a Howard Hughes Medical Institute Early Career Scientist Award in 2009. In 2007 he was named a Searle Scholar, an Irma T. Hirschl Scholar, an Alexandrine and Alexander L. Sinsheimer Scholar and an Arnold and Mabel Beckman Young Investigator.
Dr. Brady is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program and the Tri-Institutional Ph.D. Program in Chemical Biology.
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