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. '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. 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....

Scientists have harnessed artificial-intelligence models to create synthetic CRISPR proteins that edit the genome more efficiently than their naturally occurring counterparts. Such synthetic CRISPR systems could one day power discoveries in fields from medicine to agriculture. 'Much like CRISPR democratized the ability to edit DNA at will, AI-based protein design promises to allow anyone to create totally novel properties in the protein space,' says Soeren Lienkamp, a molecular biologist at the University of Zurich in Switzerland who was not involved in the research. He adds that the paper 'marries two transformative fields': AI-guided design and enzymes called RNA-guided nucleases, which can cut DNA and RNA strands. These nucleases form the backbone of the gene-editing system known as CRISPR, which uses a 'guide RNA' to direct the nuclease to a target DNA sequence. The nuclease then acts like molecular scissors and snips out the targeted material, enabling scientists to edit, delete or add genetic information. CRISPR systems are based on the machinery that bacteria use to defend themselves against viruses. The most common CRISPR nucleases, such as Cas9 and Cas12, are co-opted from bacteria....

In late 2021, Amber Salzman interviewed for a job that she had no intention of taking. A relatively new start-up company, called Epicrispr Biotechnologies, was looking for a chief executive, and it was keen on vetting Salzman ' who had decades of experience in the pharmaceutical industry ' for the role. She had said yes to the meeting only as a favour to a recruiter, who had helped her to fill a key position at another company she had worked with. Joining the start-up wasn't something she was enthusiastic about. Halfway through the meeting, she changed her mind. Salzman had watched as Stanley Qi, the founder of Epicrispr, drew diagrams on a whiteboard explaining that the company wanted to make a genetic therapy ' not by editing the code itself, but by changing the chemical markers attached to DNA, which can switch genes on or off. Then Salzman asked another team member: ''What disease are we going after'' And she said, 'FSHD'.' Salzman knew the condition all too well. FSHD, short for facioscapulohumeral muscular dystrophy, is an inherited disorder in which muscle problems first begin in the face and upper body and can spread to other parts, sometimes requiring wheelchair use. Salzman's husband of more than 35 years had several cousins and a grandmother with the disease, although he had not inherited it himself....

The research, reported on 18 March in Nature1, adds new safety features to an emerging class of cancer treatments known as chimeric antigen receptor (CAR)-T-cell therapies that are produced in the body. The development could lead to treatments that are cheaper to make and easier to administer than are those currently used against some blood cancers. At present, CAR-T therapies are made from a person's own T cells ' a type of immune cell ' which are isolated, engineered to express a synthetic protein known as a CAR and then reinjected into the body. Reprogramming T cells directly in the body would take less time, but it adds safety concerns, says Justin Eyquem, an immunologist at the University of California, San Francisco, and lead author of the study. For one thing, 'you don't want to edit other cells', he says. 'So we added multiple layers of safety.' CARs are designed to target cancer cells, allowing the engineered T cells to find and destroy tumours ' an approach that has produced dramatic remissions in some people with cancers of the blood, such as leukaemia or lymphoma....