Illustration: Sarah Grillo/Axios

Scientists announced Monday they have developed a "versatile and precise new approach" to targeting and replacing mutated genes that could eventually be used to address roughly 89% of genetic variations known to play a role in human diseases.

Why it matters: The technique, called prime editing, adds a third editing tool for mammalian cells in a manner that lessens the rate of the dangerous off-target deletions or insertions caused by the other types of tools, according to Broad Institute's David Liu, co-author of the paper published in Nature.

How it works: Liu tells a press conference that with the addition of prime editing, there are now three main ways to edit mammalian cells...

  1. The original CRISPR, which is the first and most popular gene editing tool, uses a guide RNA to locate a mutated gene plus an enzyme like Cas9 to cut the double-stranded gene helix. But, it can often cause off-target deletions and insertions.
  2. Base editors take CRISPR-Cas9 and fuse it to proteins that can make four precise DNA changes: it can change the letters C-to-T, T-to-C, A-to-G and G-to-A. But, there remain 8 other types of point mutations scientists would like to be able to target for diseases, Liu adds.
  3. Prime editing combines CRISPR-Cas9 with a reverse transcriptase. This can generate new RNA that can be directly copied into the DNA. It uses a new kind of guide RNA, called pegRNA, to make specific insertions and deletions and is able to change any of the 12 single-letter combinations in the DNA in human cells, he adds.
"If CRISPR-Cas9 and other programmable nucleases are like scissors, and if base editing is like pencils, then you can think of prime editors to be like word processors, capable of searching for target DNA sequences and precisely replacing them with edited DNA sequences.”
— David Liu, at the press conference

By the numbers: Testing on human and mouse cells in a lab, the researchers found prime editing, compared with other CRISPR techniques, showed low off-target edits at below 10%.

  • "Efficiency was high, typically 20% to 50%, depending on the kind of edit, and as high as 78%. Other CRISPR systems struggle to get into the double digits. And only 1% to 10% of prime-edited cells had unwanted insertions or deletions (“indels”) of nucleotides, compared to upwards of 90% for some older CRISPR systems," per STAT.

What they're saying: Some scientists who were not part of the study called the results "significant."

  • "If you think about CRISPR as flight — like a plane — then this new invention is kind of like a helicopter," Fyodor Urnov, a geneticist at UC Berkeley, tells NPR. "It also flies and gets you from point A to point B. But there are specific settings — like precisely landing at the top of the Salesforce tower here in San Francisco — where you could imagine that a helicopter would be better than a plane."
  • "Of course, much more work will be needed to optimise the methods and to find ways to deliver the components efficiently before they could be used clinically to treat patients, but they certainly offer promise," Robin Lovell-Badge, from the Francis Crick Institute, says to the BBC.

What's next: Liu points out that all three editing methods will be needed for specific problems and agrees that more testing is needed. He tells Axios...

"Our lab is excited by the development of prime editing, but we also recognize that it’s quite new, and additional key studies including application in animals is needed before we can fully understand its potential applications and impact. I’m optimistic that prime editing, or at least the underlying concepts developed in prime editing, will bring us closer to the 'complete toolbox.'"

Of note: The Broad Institute authors have filed patent applications on prime editing. Liu is a consultant and co-founder of Prime Medicine, Beam Therapeutics, Pairwise Plants and Editas Medicine, which are companies that use genome editing.

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Photo: Saul Loeb/AFP via Getty Images

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