For all its supposed genetic editing finesse, CRISPR’s a brute. The Swiss Army knife of gene editing tools chops up DNA strands to insert genetic changes. What’s called “editing” is actually genetic vandalism—pick a malfunctioning gene, chop it up, and wait for the cell to patch and repair the rest.

It’s a hasty, clunky process, prone to errors and other unintended and unpredictable effects. Back in 2019, researchers led by Dr. David Liu at Harvard decided to rework CRISPR from a butcher to a surgeon, one that lives up to its search-and-replace potential. The result is prime editing, an alternative version of CRISPR with the ability to “make virtually any targeted change in the genome of any living cell or organism.” It’s the nip-tuck of DNA editing: with just a small snip on one DNA chain, we have a whole menu of potential genetic changes at our fingertips.

Prime editing was hailed as a fantastic “yay, science!” moment that could conceivably repair nearly 90 percent of over 75,000 diseases caused by genetic mutations. But even at its birth, Liu warned that CRISPR prime was only taking its first toddler steps into the big, wild world of changing a life form’s base code. “This first study is just the beginning—rather than the end—of a long-standing aspiration in the life sciences to be able to make any DNA change at any position in an organism,” he told Nature at the time.

Flash forward two years. Liu’s gene editing ingénue took some stumbles. Despite its precise and effective nature, prime editing could only edit genes in certain types of cells, while being less effective and introducing errors in others. It also failed when trying to make large genetic edits, particularly those that require hundreds of DNA letters to be replaced to fix a disease-causing genetic mistake.

But the good news? Toddlers grow up. This week, three separate studies advanced prime editing, helping the CRISPR tool grow into a more sophisticated DNA-editing genius.

Two teams, based at the University of Massachusetts Medical School and the University of Washington, reworked the tool’s molecular makeup to precisely cut out up to 10,000 DNA letters in one go—a challenge for prime editing 1.0. A third study from the tool’s original inventor probed its inner molecular workings, identifying protein friends and foes inside the cell that control the tool’s genetic editing abilities. By promoting friendly interactions, the team increased prime editing’s efficiency in seven different cell types nearly eight-fold. Even better, the “foes” that block prime’s editing potential were identified using CRISPR—in other words, we’re witnessing a full circle of innovation whereby gene editing tools help build better gene editing tools.

A Primer for CRISPR Prime

Prime editing burst onto the gene editing scene for its dexterity and precision. If the original CRISPR-Cas9 is a dancer with two left feet, prime editing is a highly-trained ballerina.

The two processes start similarly. Both rely on a molecular “zip code” to target the tool to a specific gene. In CRISPR, it’s called a guide RNA. For prime editing, it’s a slightly modified version dubbed pegRNA.

Once the guides tether their respective dance partners to the gene, their routines differ. For CRISPR, the second component, Cas9, acts as a pair of scissors to snip both DNA strands. From here, cells can either throw out parts of a gene, or—when given a template—insert a healthy version of a gene to replace the original one. The cost is molecular surgery. Just as an incision might not fully heal, a double-stranded break to the DNA can introduce errors into the genetic code, leading to unexpected effects that vary between cells.

Prime editing was the sophisticated upgrade set to fix that. Rather than cutting both DNA strands, it lightly nips one chain. From there, it can delete or insert genetic code based on a template without relying on the cell’s DNA repair mechanism. In other words, prime editing opened a new universe o...