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9th EMBL/EMBO Joint Conference 2008

Jason Chin, Medical Research Council, Laboratory of Molecular Biology, UK

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Jason Chin

Biography

Jason Chin is a Group Leader at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB), and a fellow in the Natural Sciences at Trinity College, Cambridge University, where he is director of studies in biochemistry. Jason was an undergraduate at Oxford University, obtained his PhD with Alanna Schepartz as a Fulbright grantee at Yale University, and was a Damon Ruyon Fellow at The Scripps Research Institute with Peter Schultz. Jason joined the LMB in July 2003, becoming an EMBO Young Investigator in 2005 and a tenured group leader in 2007.

His work spans chemical biology and synthetic biology. He created the first method to systematically expand the eukaryotic genetic code. He created and applied the first method to introduce photochemical probes into proteins in both prokaryotic and eukaryotic cells and map protein interactions in vivo. His work forms an intellectual basis for the biotechnology company Ambrx. The Chin laboratory has evolved and reprogrammed the ribosome, long thought un-evolvable, to enhance genetic code expansion, invented new forms of gene regulation, provided insight into ribosome function, and created new genetic codes. The laboratory continues to apply the tools they have constructed to provide insight into biological processes.

Abstract

Ribosome engineering & new genetic codes

The genetic code of living organisms allows us read the instructions embedded in our DNA genome to produce proteins that carry out the molecular functions that allow us to live. The genetic code describes the relationship by which nucleic acid codons (nucleic acid triplets) embedded in a nucleic acid tape (mRNA), are decoded for the polymerisation of amino acids into a defined protein sequence. We have demonstrated that it is possible to expand the genetic code of life by creating new versions of the key molecules that enforce the genetic code of cells. To create these new molecules for expanding the code we have experimentally extended in the laboratory some of the process that early evolution is believed to have used to arrive at the natural genetic code.

We have shown that cells and organisms with expanded genetic codes can perform new functions that cannot be performed by natural life-forms and this is allowing us to understand how natural biology works and to make new types of therapeutic molecules. At the centre of the cell's translational network is the ribosome, a highly conserved 2.5 MDa machine that syntheises polypetides using the information encoded in mRNAs. The natural ribosome is un-evolvable because mutations affect the translation of the entire proteome.

We describe the creation of parallel and independent, or orthogonal, ribosomes in cells that specifically translate an orthogonal mRNA that is not a substrate for endogenous ribosomes, and do not translate cellular mRNAs. We demonstrate the creation of translational logic functions with multiple mutually orthogonal ribosomes. Moreover we evolve orthogonal ribosome decoding and demonstrate the modular combination of orthogonal aminoacyl-tRNA synthetases that direct the incorporation of unnatural amino acids and evolved orthogonal ribosomes, highlighting how orthogonal genetic codes may be written on orthogonal mRNAs.

Finally, we highlight the evolution and application of new translational components for understanding the effect of post-translational modifications on cellular function.