Bizarre CRISPR enzyme kills cancer cells by shredding their DNA

A bacterial enzyme that indiscriminately slashes DNA (artist’s illustration) has been harnessed to kill cancer cells. Credit: KTSDesign/Science Photo Library

Scientists have exploited a peculiar CRISPR enzyme so that it fights cancer by shredding the DNA in cancer cells, causing them to self-destruct.

The enzyme can be programmed to recognize a specific messenger RNA, such as one made by a cancer cell. Once the enzyme finds its partner, it slashes the cell’s genome to pieces.

The DNA-shredding approach, reported in two papers in Nature1,2, could provide a way for researchers to kill cancer cells that express ‘undruggable’ mutant proteins that have been difficult to target using conventional medicines.

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“It’s a molecular kill switch that recognizes a particular RNA,” says Yang Liu, a molecular biologist at the University of Utah School of Medicine in Salt Lake City, and an author of one of the papers. “This is basically a programmable chemotherapy.”

A therapy that uses this approach to target head and neck cancers caused by human papillomavirus (HPV) is already in early development at Akribion Therapeutics, a biotechnology company in Zwingenberg, Germany. The goal is to produce the first clinical-trial data by 2030, says company co-founder Paul Scholz, who is head of research and development at Akribion and a co-author of one of the papers.

Bacterial defenders

CRISPR systems occur naturally in bacteria and other microorganisms, in which they act as a protective immune mechanism. Some CRISPR systems use RNAs that direct CRISPR-associated (Cas) enzymes to target stretches of DNA in viruses and other invaders. The Cas enzyme then cuts the DNA, destroying the interloper. For more than a decade, researchers have harnessed and modified such systems to edit genomes, creating their own guide RNAs to direct the Cas enzymes to a desired site for editing.

But not all Cas enzymes are equal. Nearly ten years ago, Ryan Jackson, a biochemist at Utah State University in Logan, and his colleagues set about trying to work out the mechanism of a Cas protein, called Cas12a2. Their assumption, he says, was that the enzyme would function much like other Cas proteins used for gene editing.

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