Scientists have exploited a peculiar CRISPR enzyme to fight cancer by shredding the DNA of cancer cells, causing them to self-destruct.

The enzyme can be programmed to recognize a specific messenger RNA, such as that produced by a cancer cell. Once the enzyme finds its partner, it chops up the cell’s genome.

The method of DNA destruction, described in two articles published in Nature^1,2could provide a way for researchers to eliminate cancer cells that express “non-drug” mutant proteins that have been difficult to target with conventional drugs.

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“It’s a molecular 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 author of one of the papers. “This is basically programmable chemotherapy.”

A therapy that uses this approach to target head and neck cancers caused by the 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, head of research and development at Akribion ​​and co-author of one of the papers.

Bacterial defenders

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

But not all Cas enzymes are the same. Nearly ten years ago, Ryan Jackson, a biochemist at Utah State University in Logan, and his colleagues set out to try to uncover the mechanism of a Cas protein, called Cas12a2. His assumption, he says, was that the enzyme would function very similarly to other Cas proteins used for gene editing.

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But test after test in the laboratory failed. “We said, ‘Well, this isn’t behaving the way we want,’” Jackson says. “I accused my students of contaminating the protein.”

Eventually, he and his colleagues, as well as another team, realized that Cas12a2 was different. After recognizing RNA sequences that matched its guide RNA, it went crazy and chewed up DNA indiscriminately, causing the infected cell to stop growing.^3,4. In the wild, this could limit the spread of an infection through the population.

“How the hell does nature come up with a trick like that?” says Rene Bernards, a cancer geneticist at the Dutch Cancer Institute in Amsterdam. “But whatever. We can make good use of it.”

targeted killer

Now, two teams of researchers have done just that. Both focused their attention on cancer, and specifically tumors caused by mutant proteins that scientists have struggled to address using conventional means. One group targeted their Cas12a2 toward RNA produced by cells, including those with a mutation in the TP53 gene, which is altered in up to half of all cancers. The other group focused on RNA made from a mutated version of the KRAS gene. Mutant KRAS proteins can cause cells to grow out of control and are responsible for some of the deadliest cancers.