Frederick Ausubel Laboratory

http://ccib.mgh.harvard.edu/ausubellab.htm

Simches Research Center
185 Cambridge Street
Boston, MA 02114
phone: 617-726-5969
fax: 617-726-5949

Frederick M. Ausubel is Professor of Genetics at Harvard Medical School and the Ernst Winnacker Distinguished Investigator in the Department of Molecular Biology at Massachusetts General Hospital. Dr. Ausubel received his B.S. in Chemistry from the University of Illinois in 1966 and his Ph.D. in Biology from the Massachusetts Institute of Technology in 1972. Formerly, he was Assistant and Associate Professor in the Department of Cellular and Developmental Biology at Harvard University.

Dr. Ausubel’s scientific work concerns host-microbe interactions. In the 1970s and 1980s, his laboratory worked on the molecular basis of symbiotic nitrogen fixation, the process by which legumes, in concert with a bacterial symbiont, convert atmospheric nitrogen into ammonia. Currently, the laboratory is investigating microbial pathogenesis and host defense in the plant Arabidopsis thaliana and the nematode Caenorhabditis elegans. The laboratory has also adopted a genomics approach to study virulence in the opportunistic bacterial pathogen Pseudomonas aeruginosa strain PA14, which remarkably is a “multi-host” pathogen of both plants and animals. The laboratory is particularly interested in those aspects of pathogenesis and the host innate immune response that have been conserved in evolution.

Dr. Ausubel was elected to the National Academy of Sciences in 1994, the American Academy of Microbiology in 2002, and the American Academy of Arts and Sciences in 2003. In addition to serving on a variety of editorial boards, Dr. Ausubel is founding editor of the widely-read Current Protocols in Molecular Biology.

Research

Our interest in chemical biology stems from the development of a model pathogenesis system that involves the infection of the nematode Caenornabditis elegans with a variety of human bacterial and fungal pathogens. Because C. elegans is small enough to fit into a well in a 384-well microtiter plate and because various pathogens cause persistent lethal infections in the C. elegans intestine, we have been able to develop screens for compounds that “cure” C. elegans of either a bacterial or a fungal infection (Moy et al., 2006; Breger et al., 2007). 

In published work carried out in collaboration with Eleftherios Mylonakis’ lab at MGH and Kim Lewis’ lab at Northeastern University, we have performed pilot screens of a limited number of defined small molecule compounds or natural product extracts and identified substances that promoted the survival of worms infected with the bacterium Enterococcus faecalis or the yeast Candida albicans. Interestingly, a subset of the identified compounds appear to act differently than traditional antibiotics or antifungals in that they improve worm survival at concentrations that do not inhibit the growth of the free living pathogen.  Thus, this screening methodology allows the identification of new classes of anti-infective compounds that either act in the worm by stimulating innate immunity or that act in the pathogen by inhibiting virulence mechanisms. 

Currently, in collaboration with the Chemical Biology and Imaging groups at the Broad Institute, we are developing fully automated high-throughput C. elegans screens that utilize a COPAS Biosort robot to dispense worms into 384-well plates, an automated screening microscope to image each well, and the program CellProfiler to process the images to quantify worm survival.

References:

Moy, T.I., A.R. Ball, Z. Anklesaria, G. Casadei, K. Lewis and F.M. Ausubel (2006).  Identification of novel antimicrobials using a live-animal infection model. Proc. Natl. Acad. Sci. USA 103:10414-10419.