A New Crispr Technique Could Fix Almost All Genetic Diseases

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Crispr, for all its DNA-snipping precision, has always been best at breaking things. But if you want to replace a faulty gene with a healthy one, things get more complicated.

In addition to programming a piece of guide RNA to tell Crispr where to cut, you have to provide a copy of the new DNA and then hope the cell’s repair machinery installs it correctly. Which, spoiler alert, it often doesn’t. Anzalone wondered if instead there was a way to combine those two pieces, so that one molecule told Crispr both where to make its changes and what edits to make. Inspired, he cinched his coat tighter and hurried home to his apartment in Chelsea, sketching and Googling late into the night to see how it might be done.

{snip} The system, which [David] Liu’s lab has dubbed “prime editing,” can for the first time make virtually any alteration—additions, deletions, swapping any single letter for any other—without severing the DNA double helix. “If Crispr-Cas9 is like scissors and base editors are like pencils, then you can think of prime editors to be like word processors,” Liu told reporters in a press briefing.

{snip} Because with such fine-tuned command of the genetic code, prime editing could, according to Liu’s calculations, correct around 89 percent of the mutations that cause heritable human diseases. Working in human cell cultures, his lab has already used prime editors to fix the genetic glitches that cause sickle cell anemia, cystic fibrosis, and Tay-Sachs disease. Those are just three of more than 175 edits the group unveiled today in a scientific article published in the journal Nature.

The work “has a strong potential to change the way we edit cells and be transformative,” says Gaétan Burgio, a geneticist at the Australian National University who was not involved in the work, in an email. He was especially impressed at the range of changes prime editing makes possible, including adding up to 44 DNA letters and deleting up to 80. “Overall, the editing efficiency and the versatility shown in this paper are remarkable.”

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[Andrew] Anzalone’s prime editor is a little different. Its enzyme is actually two that have been fused together—a molecule that acts like a scalpel combined with something called a reverse transcriptase, which converts RNA into DNA. His RNA guide is a little different too: It not only finds the DNA in need of fixing, but also carries a copy of the edit to be made. When it locates its target DNA, it makes a little nick, and the reverse transcriptase starts adding the corrected sequence of DNA letter by letter, like the strikers on a typewriter. The result is two redundant flaps of DNA—the original and the edited strand. Then the cell’s DNA repair machinery swoops in to cut away the original (marked as it is with that little nick), permanently installing the desired edit.

This technique allows for far more flexibility when editing DNA. Whereas base editors could only make four types of genetic “bit” flips—changing one G-C base pair to an A-T, for example—prime editing can change any letter to any other. Prime editors also appear to make fewer mistakes. {snip}

The bigger problem, according to folks like Burgio, is that prime editors are huge, in molecular terms. {snip}.

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