Among the most significant scientific advances in recent years are the discovery and development of new ways to genetically modify living things using a fast and affordable technology called CRISPR. Now scientists at The University of Texas at Austin say they’ve identified an easy upgrade for the technology that would lead to more accurate gene editing with increased safety.
The team of molecular biologists found conclusive evidence that Cas9, the most popular enzyme currently used in CRISPR gene editing and the first to be discovered, has less effectiveness and precision than one of the lesser-used CRISPR proteins, called Cas12a. Because Cas9 is more likely to edit the wrong part of a plant’s or animal’s genome, disrupting healthy functions, the scientists make the case that switching to Cas12a would lead to safer and more effective gene editing in their study published in the journal Molecular Cell.
The researchers found that Cas12a is choosier because it binds like Velcro to a genomic target, whereas Cas9 binds to its target more like super glue. Each enzyme carries a short string of genetic code written in RNA that matches a target string of genetic code written in the DNA of a virus. When it bumps into some DNA, the enzyme starts trying to bind to it by forming base pairs—starting at one end and working its way along, testing to see how well each letter on one side (the DNA) matches the adjacent letter on the other side (the RNA).
For Cas9, each base pair stick together tightly, like a dab of super glue. If the first few letters on each side match well, then Cas9 is already strongly bound to the DNA. In other words, Cas9 pays attention to the first seven or eight letters in the genomic target, but pays less attention as the process goes on, meaning it can easily overlook a mismatch later in the process that would lead it to edit the wrong part of the genome.
For Cas12a, it’s more like a Velcro strip. At each point along the way, the bonds are relatively weak. It takes a good match all along the strip for the two sides to hold together long enough to make an edit. That makes it much more likely that it will edit only the intended part of the genome.
The researchers said that Cas12a still isn’t perfect, but the study also suggests ways that Cas12a can be improved further, perhaps one day realizing the dream of creating a “precision scalpel,” an essentially error-proof gene-editing tool. The researchers are currently using these insights in a follow-up project designed to engineer an improved Cas12a.