A molecular scalpel for unwanted cells: new research co-authored by BIIE's Chase Beisel turns a CRISPR enzyme into a programmable cell killer
A study just published in Nature and co-authored by BIIE faculty member Chase Beisel demonstrates that the CRISPR nuclease Cas12a2 can selectively eliminate eukaryotic cells based on a chosen RNA signature - opening a versatile route to remove virus-infected cells, enrich gene-edited cells, and target cancer cells carrying specific mutations.
A cell's identity is shaped in part by which of its genes are active at any given moment. That activity pattern can, in principle, be used to distinguish a diseased cell from a healthy one, or a successfully edited cell from one that escaped editing. Translating that principle into a reliable way to selectively eliminate unwanted cells, without harming their neighbours, has long been a sought-after capability across medicine, biotechnology, and agriculture.
CRISPR systems already provide such capabilities in bacteria, but the same nucleases have proven much harder to repurpose for cell elimination in eukaryotes. The Cas9 and Cas12a enzymes typically used for gene editing introduce DNA cuts that eukaryotic cells repair efficiently without driving cell death. Cas13 nucleases, which target RNA, tend to silence individual transcripts rather than reliably eliminate the cell.
Cas12a2 behaves differently. Once triggered by a complementary RNA target, it indiscriminately shreds any DNA it encounters. Earlier work, also co-authored by Beisel, established this property in bacteria. The new study shows what happens when Cas12a2 is unleashed inside a eukaryotic cell.
Working in yeast and several human cell lines, the team - led by Paul Scholz (Akribion Therapeutics), Ryan Jackson (Utah State University), Chase Beisel, and Yang Liu (University of Utah) - found that Cas12a2 generates extensive double-stranded DNA breaks specifically in cells expressing the target RNA, driving cell-cycle arrest and apoptosis. Cells lacking the target sequence proliferated normally, even when grown alongside targeted cells. The activity was sensitive to single-nucleotide mismatches. Critically, across the conditions tested, no unintended activation was detected.
The authors illustrated the approach across three scenarios. They selectively eliminated human papillomavirus–positive cervical cancer cells, both in culture and in a patient-derived xenograft mouse model of head and neck cancer. They enriched populations of gene-edited cells by killing those that had not undergone the intended edit, working with both indel-based and prime editing. And they selectively eliminated lung cancer cells carrying the KRAS G12C oncogenic mutation while sparing cells with the wild-type sequence, including cells that had become resistant to Sotorasib, an FDA-approved drug targeting the same mutation.
By making cell elimination programmable via a guide RNA, Cas12a2 opens a route to act on cells that are otherwise difficult to drug, including those defined by mutations in non-coding regions, viral integrations, or single-base substitutions. Translating the approach into clinical applications will require continued work on guide design, delivery, and specificity, which the research team is actively pursuing.
The study, RNA-triggered cell killing with CRISPR-Cas12a2, can be accessed directly in Nature.
Disclaimer: The research described in this article was carried out at the Helmholtz Institute for RNA-based Infection Research (HIRI) and partner institutions. No part of this work was conducted at BIIE.
Supported by the European Research Council, the R. Gaurth Hansen Family, and the US National Institutes of Health.