Science and Engineering

Whitehead Institute for Biomedical Research

Jing-Ke Weng
Cambridge, MA
$1,000,000
June 2019

In eukaryotes, thousands of metabolic enzymes catalyze diverse chemical reactions that sustain life.  Whereas highly efficient natural enzymes evolved over millions of years, humans have made only minimal progress in designing new biocatalysts with desirable functions.  An early career researcher at the Whitehead Institute for Biomedical Research aims to develop a highly efficient and broadly applicable continuous directed evolution system for deriving any metabolic enzyme at will in eukaryotic cells.  He plans to harness the interaction between plant viruses and their host plant cells.  In this system, the progenitor enzyme-encoding gene to be selected is carried on a crippled version of the viral vector, whereas viral or plant elements necessary for proper viral particle packaging and propagation is placed in the nuclear genome of the host under a regulatable promoter.  The system is designed such that serendipitous mutations that steer the progenitor enzyme toward the desirable enzymatic function confer a selective advantage for viral vectors carrying these mutations to propagate more effectively within the host cells.  The key innovation is using ligand-regulated transcription factors to link small molecules (products of the selected enzymatic function) to the transcription of the genes that serve as the limiting factors for viral propagation in host cells.  Evolving metabolic enzymes at will has been the holy grail in humans’ attempts to design synthetic metabolic processes.  If successful, this project will have a transformative impact upon multiple fields by enabling the unprecedented capability to create new designer medicines and commodity chemicals.

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