It is now well established that cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes.  In some cases, cancer (and other genetic diseases) can be traced back to single base changes, while in other cases, the root cause can be a large scale gain or loss in DNA sequence information.  Such large scale sequence rearrangements are an important class of mutations that not only promote cancer, but also promote aging and other genetic diseases.  A major goal of the Engelward laboratory is to help reveal genetic and environmental factors that promote large scale sequence rearrangements in mammals. By understanding the causes of sequence changes, we will become better able to mitigate disease.

There are two major classes of large scale sequence changes: those that are caused by joining of DNA ends with minimal influence from DNA sequence, and those that are caused by large scale misalignments of homologous sequences.  We are primarily interested in the latter, so called homologous recombination events, and we have applied and developed a number of approaches for detecting this class of sequence change in E. coli, yeast, mammalian cells, and in mice.  Most of the approaches developed in this laboratory depend upon a fluorescent readout, which makes it relatively fast and easy to assess the frequency of cells that harbor a particular sequence change (they fluoresce green or yellow, for example).  In this laboratory, we created the first mouse in which rare cells that have undergone a homologous recombination event at an integrated transgene can be detected via a fluorescent readout.

Using existing and novel tools developed in this laboratory, we have studied both genetic and environmental factors that modulate the frequency of homologous recombination in several species.  Some of the things that we have learned are that relatively subtle changes in the structure of DNA can induce large scale sequence changes; that either too much or too little of certain DNA repair enzymes can promote recombination events; that inflammatory chemicals are highly recombinogenic in eukaryotic cells, and that recombination events can be induced as a consequence of heritable changes in the epigenome. Ongoing studies are primarily focused primarily on the effects of radiation and inflammation on genomic stability.

In addition to studies of homologous recombination, we are also focused on technology development.  Currently, we are developing novel approaches for detecting DNA damage and for measuring DNA repair.  Using lab-on-a-chip technologies, we have created a higher throughput assay for detecting DNA damage in isolated mammalian cells, and we are optimizing methodology for applications in cancer research and environmental health.  

The Engelward Laboratory [directions]

Department of Biological Engineering

Massachusetts Institute of Technology

Office Phone for Bevin Engelward: 617-258-0260

Lab Phone: 617-253-6751

Lab Fax: 617-258-0499