CALIFORNIA: A powerful form of DNA-editing machinery discovered in bacteria might enable us to make much bigger changes to genomes than is currently possible with CRISPR-based techniques. However, it is uncertain whether it will work in human cells. Patrick Hsu at the Arc Institute in California has dubbed this new genome editor the “bridge editing” system because it physically links, or bridges 2 pieces of DNA.
This system can alter large sections of a genome. Hsu’s team discovered how sequences of “parasitic” DNA in bacteria naturally use this system to replicate and how it might be adapted for genome editing.
“We are excited about the potential to make much broader genomic changes beyond what we can currently do with CRISPR,” Hsu says. “We think this is an important step towards the broader vision of genome design.”
Since its debut in 2012, CRISPR gene editing has revolutionized biology, being used for various purposes, with the first CRISPR-based treatments approved last year. However, the basic form of CRISPR, using the Cas9 protein, is more of a gene destroyer than a gene editor. The standard CRISPR Cas9 protein has two parts: one that pairs with a guide RNA molecule to find specific DNA sections, and another that cuts the DNA at the target site. The cell repairs the damage, and Cas9 cuts it again, causing mutations during the repair process.
Biologists prefer making more precise changes, so they have modified CRISPR proteins to edit DNA directly instead of relying on cell repair mechanisms. Base editors can change a single DNA letter without cutting the DNA, and prime editors can turn an extra section of guide RNA into DNA and add it to the target site. These advanced forms of CRISPR could treat many conditions, with several human trials underway, but some diseases require more sophisticated genome alterations.
Numerous teams are exploring new methods, including using the mechanism of genetic parasites called IS110 elements, which cut and paste themselves within a genome. Hsu’s team is the first to fully understand how this works. The bridge-editing system includes a recombinase protein that pairs with a guide RNA, specifying two DNA sequences to target. One sequence specifies the site to be altered, while the other specifies the DNA to be altered. This system can add, delete, or reverse DNA sequences of virtually any length without leaving extra DNA fragments, or scars.
“The discoveries reported are indeed exciting, and the underlying biology is truly remarkable,” states Stephen Tang at Columbia University in New York. However, bridge editing has only been demonstrated in bacterial cells or test tubes. Whether and how well it will work in complex cells like those of humans is still unknown. But even if initial tests in human cells fail, the system could likely be modified to work eventually.
