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Dr. Wiedenheft received his Ph.D in the joint laboratories of professors Mark Young and Trevor Douglas at the Thermal Biology Institute, where his work focused on the viruses that infect microorganisms that thrive in boiling-acid (~80C, ~pH 3) environments. After completing his Ph.D in 2007, Dr. Wiedenheft joined professor Jennifer Doudna’s lab at UC-Berkeley as a Life Sciences Fellow of the Howard Hughes Medical Institute. Dr. Wiedenheft recently joined the faculty at Montana State University, where his research team is currently focused on understanding the mechanisms of CRISPR RNA-guided adaptive immunity and how these immune systems can be leveraged for new applications in medicine and biotechnology.
Work in my lab focuses on adaptive immune systems in bacteria. Viruses that infect bacteria (i.e. bacteriophages) are the most abundant and diverse biological agents on the planet. The selective pressures imposed by these viral predators have a profound impact on the composition and the behavior of microbial communities in every ecological setting and microbial hosts have evolved various mechanisms to evade infection. Historically, our appreciation for microbial immune systems has been restricted to innate defense mechanisms (e.g. restriction modification and receptor switching), however a sophisticated nucleic acid-based adaptive immune system has recently been discovered. Bacteria and archaea acquire resistance to viral and plasmid challengers by integrating short fragments of foreign nucleic acids into the host chromosome at one end of a repetitive element known as a CRISPR (clustered regularly interspaced short palindromic repeat). The CRISPR locus is transcribed processed into a library of short CRISPR-derived RNAs (crRNAs) that each contain a unique sequence that is complementary to a previously encountered foreign nucleic acid challenger. Each crRNA is packaged into a large, multi-subunit surveillance complex that patrols the intracellular environment and ‘silences’ foreign nucleic acid targets. While the general steps required for adaptive immunity in bacteria and archaea have been identified, the mechanisms of foreign nucleic acid recognition, new sequence acquisition and RNA-guided interference are not understood. My laboratory uses molecular biology to engineer model microbes for functional and structural interrogation of the molecular machines that coordinate an effective immune response.
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