Reacción a "AI-designed proteins could expand the CRISPR genome-editing toolkit beyond those produced by evolution"

The Skopintsev et al. manuscript shows the potential of generative AI tools to design new-to-nature RNA-guided nucleases using TnpB scaffold (a minimal CRISPR-Cas12-like nuclease) as the proof-of-concept. The authors present a new evolution and co-evolution guided inverse folding protein design strategy, allowing to increase the divergence from the WT sequence compared to previous studies.

The study is accompanied by an extensive validation of the generated variants with gene editing assays on bacterial, plant, and human cells. Moreover, the structure of one of the most active and distinct variants was obtained using cryo-EM, revealing a novel TAM-bound conformation that was not previously described thanks to the introduced AI-designed contacts.

The main practical conclusion from the study is that it democratizes the protocol to design your own new-to-nature RNA-guided nucleases, and it shows the experimental roadmap to find the most promising ones. However, the main limitation of the design protocol is that it currently does not allow to tailor towards other specific DNA/RNA sequence motifs.