New “evolution engine” creates super-proteins 100,000x faster

 



"This is like giving evolution a fast-forward button," says co-senior author Pete Schultz, the President and CEO of Scripps Research, where he also holds the L.S. "Sam" Skaggs Presidential Chair. "You can now evolve proteins continuously and precisely inside cells without damaging the cell's genome or requiring labor-intensive steps."

Directed evolution is a laboratory process that involves introducing mutations and selecting variants with improved function over multiple cycles. It's used to tailor proteins with desired properties, such as highly selective, high-affinity antibodies, enzymes with new specificities or catalytic properties, or to investigate the emergence of resistance mutations in drug targets. However, traditional methods often require repeated rounds of DNA manipulation and testing with each round taking a week or more. Systems for continuous evolution -- where proteins evolve inside living cells without manual intervention -- aim to streamline this process by enabling simultaneous mutation and selection with each round of cell division (roughly 20 minutes for bacteria). But existing approaches have been limited by technical complexity or modest mutation rates.

T7-ORACLE circumvents these bottlenecks by engineering E. coli bacteria -- a standard model organism in molecular biology -- to host a second, artificial DNA replication system derived from bacteriophage T7, a virus that infects bacteria and has been widely studied for its simple, efficient replication system. T7-ORACLE enables continuous hypermutation and accelerated evolution of biomacromolecules, and is designed to be broadly applicable to many protein targets and biological challenges. Conceptually, T7-ORACLE builds on and extends efforts on existing orthogonal replication systems -- meaning they operate separately from the cell's own machinery -- such as OrthoRep in Saccharomyces cerevisiae (baker's yeast) and EcORep in E. coli. In comparison to these systems, T7-ORACLE benefits from the combination of high mutagenesis, fast growth, high transformation efficiency, and the ease with which both the E. coli host and the circular replicon plasmid can be integrated into standard molecular biology workflows.

The T-7 ORACLE orthogonal system targets only plasmid DNA (small, circular pieces of genetic material), leaving the cell's host genome untouched. By engineering T7 DNA polymerase (a viral enzyme that replicates DNA) to be error-prone, the researchers introduced mutations into target genes at a rate 100,000 times higher than normal without damaging the host cells.

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