Robert W. Vaughan Lecture in Chemical Engineering
We are interested in building genetic systems that have extremely high mutation rates in order to speed up the evolution of target proteins and enzymes in vivo as well as to record transient information, such as lineage relationships or exposure to biological stimuli, as durable genetic information in situ. I will primarily discuss our work on building OrthoRep, a highly error-prone orthogonal DNA replication system that mutates user-selected genes at a rate of 1e-5 substitutions per base (s.p.b.) without any increase in the genomic mutation rate (1e-10 s.p.b). This ~100,000-fold mutational acceleration allows for the rapid continuous evolution of target biomolecules entirely in vivo using a simple serial passaging process amenable to extensive repetition. I will discuss the application of OrthoRep in exploring drug resistance, studying protein evolution, and evolving useful enzymes and proteins. I will also comment on the value of scalable continuous evolution in searching for and understanding old and new biomolecular function going forward.