Scientists have engineered a distinctive CRISPR enzyme to selectively kill cancer cells by triggering the wholesale destruction of their DNA, offering a potential new route to treating cancers driven by mutations that have long been considered “undruggable.” The approach, detailed in a pair of studies published in the journal Nature by researchers at the Innovative Genomics Institute at UC Berkeley, the University of California, San Francisco, the Gladstone Institutes, the University of Utah, and Utah State University, centres on a CRISPR-associated enzyme called Cas12a2.
Unlike the widely known Cas9 enzyme, which acts like a pair of molecular scissors to make a single precise cut in DNA for gene-editing purposes, Cas12a2 behaves more like an indiscriminate shredder once activated. In its natural bacterial context, Cas12a2 functions as a self-destruct mechanism, a kind of cellular suicide switch that bacteria deploy to kill themselves when infected by a virus, preventing the infection from spreading further. Researchers have now repurposed that destructive mechanism as a precision therapeutic tool by programming the enzyme to activate only in the presence of a specific messenger RNA transcript, such as one produced uniquely by a cancer-causing mutation.
Once Cas12a2 detects its programmed RNA target inside a cell, it initiates what researchers describe as “chromatin shredding,” slicing apart the genetic material throughout the entire cell and triggering cell death. Because the enzyme is activated only by cells expressing the specific target RNA, healthy cells that lack the mutant transcript are left almost entirely untouched. Yang Liu, a molecular biologist at the University of Utah and an author of one of the two papers, described the system as “a molecular kill switch that recognises a particular RNA,” calling it, in effect, “programmable chemotherapy.”
A major focus of the research has been mutations in the tumour-suppressor gene TP53, which is altered in nearly half of all cancers and appears in as many as 70 to 90 percent of cases of some of the hardest-to-treat cancers, including ovarian, pancreatic, and non-small-cell lung cancer. Because TP53 mutations lack the kind of binding pockets that conventional small-molecule drugs require to latch onto a target, they have remained largely untreatable through traditional pharmacology despite their central role in tumour biology. In laboratory tests, researchers found that Cas12a2 could reliably distinguish between healthy and cancerous cell lines that differed by only a single nucleotide, destroying mutant cells while sparing their genetically near-identical healthy counterparts.
Beyond cancer, the same approach also proved effective against cells infected with human papillomavirus (HPV), a virus linked to cervical cancer and genital warts; when the enzyme was targeted to viral RNA, collaborators at Akribion Therapeutics found it reduced the growth of infected cells in laboratory dishes by more than 90 percent, again without harming healthy cells. Researchers noted that the precision on display marks a meaningful departure from conventional cancer treatments such as chemotherapy and radiotherapy, which kill all rapidly dividing cells in the body, healthy and cancerous alike, and are responsible for much of the toxicity associated with cancer treatment. The work builds on nearly a decade of basic research into Cas12a2’s underlying mechanism, led in its early stages by biochemist Ryan Jackson at Utah State University, and researchers caution that while early laboratory and mouse-model results are promising, considerable further testing lies ahead before the approach could be considered for human clinical trials.
– Ritvisha Kiran
