Scientists build an “evolution engine” to rapidly reprogram proteins

Good news! Are we on the cusp of outdoing evolution? You bet!

"... The system, named T7-ORACLE ... represents a breakthrough in how researchers can engineer therapeutic proteins for cancer, neurodegeneration and essentially any other disease area.

“This is like giving evolution a fast-forward button,”  ... “You can now evolve proteins continuously and precisely inside cells without damaging the cell’s genome or requiring labor-intensive steps.” ..."

From the editor's summary and abstract:

"Editor’s summary

Continuous evolution of proteins in the lab is often slow because normal mutation rates in bacteria are very low. Diercks et al. investigated whether a highly mutagenic DNA replication system could speed up evolution in Escherichia coli without harming the host genome. They engineered an orthogonal T7 replisome that replicates only target plasmids at mutation rates 100,000 times higher than normal while leaving the rest of the genome unchanged. Using this system, the authors rapidly evolved TEM-1 β-lactamase to gain much stronger resistance to several antibiotics in under a week. This approach could greatly accelerate protein engineering and antibiotic resistance studies. ...

Abstract

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can substantially accelerate the evolution of new or enhanced protein functions.

We describe an orthogonal DNA replication system in Escherichia coli based on the controlled expression of the replisome of bacteriophage T7 (T7-ORACLE).

The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows. Engineering of T7 DNA polymerase yielded variant proteins with mutation rates of 1.7 × 10−5 substitutions per base in vivo—100,000-fold above the genomic mutation rate. We demonstrated continuous evolution using the T7 replisome by expanding the substrate scope of TEM-1 β-lactamase and increasing activity 5000-fold against clinically relevant monobactam and cephalosporin antibiotics in less than 1 week."

Scientists build an “evolution engine” to rapidly reprogram proteins | Scripps Research "A new platform developed at Scripps Research enables fast, scalable protein evolution—opening the door to new therapies and diagnostics, and to predicting resistance mutations across many disease areas."

An orthogonal T7 replisome for continuous hypermutation and accelerated evolution in E. coli (no public access)

An Orthogonal T7 Replisome for Continuous Hypermutation and Accelerated Evolution in E. coli (preprint, open access)

Fig. 1 Establishing an orthogonal replication system in E. coli based on the bacteriophage T7 replisome.