Researchers at Rice University used an AI-assisted protein-evolution platform called Sequence Display to create new variants of a compact CRISPR enzyme — SlugCas9 — able to edit DNA stretches that were previously hard to reach. The work was published in Nature Communications and reported on 4 November 2026.
The obstacle was PAMs, short DNA sequences that act as docking sites for the Cas9 enzyme. Without recognising a suitable PAM, the enzyme cannot precisely edit the neighbouring stretch. SlugCas9, a popular compact Cas9, recognised four PAMs of interest only weakly: it would slip off or fail to bind them.
With Sequence Display, the team generated large sequence-activity datasets, which AI used to identify the most promising protein sequences for each function. According to the researchers, promising candidates were found within a week — a pace contrasting with earlier attempts, which had little success evolving other Cas9 variants for those same PAMs.
In the proof of concept, the evolved variants edited, in cultured cells, sites in the APOC3 and PCSK9 genes, associated with coronary heart disease risk. The edits introduced potentially protective genetic changes linked to lower risk — but the limit matters: the result was shown in cultured cells, not in people, and it is not an available treatment.
The broader value, according to corresponding author Han Xiao, is the method: rapidly evolving Cas9 enzymes (and other proteins) tailored to complex technical requirements, rather than relying on a single generic enzyme. The study addresses difficult NNAN-family PAMs and underlines that compact enzymes are easier to deliver but recognise few targets — exactly the bottleneck the new work tries to loosen.
Image credit: illustrative Cas9 structure image, via Wikimedia Commons.
Sources: MedicalXpress / Rice University (4 November 2026); Nature Communications, Cheng et al. (published 30 October 2026).
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