We’ve evolved an even more powerful form of CRISPR gene editing

CRISPR gene editing

Can CRISPR be better and safer?

Ella Maru Studio / SPL

Biologists have created a highly precise tool for changing the code of DNA. It should be more powerful at fixing genes than standard CRISPR gene editing, and safer too.

Normal CRISPR gene editing can do two things: fix genes and disable them. The fixing part doesn’t work nearly so well as the disabling part.

To fix genes you have to add a bit of DNA with the correct sequence to cells, and trigger a repair process that results in it being swapped for the faulty DNA. This only works in about a tenth of cells, and hardly at all in non-dividing cells like brain cells.

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Enter David Liu of Harvard University. His team is creating tools that fix mutations by directly turning one DNA letter into another.

The challenge is that there are four DNA letters, or bases: A, T, G and C. Each can mutate into any of the other three bases, so to fix unwanted mutations, we would need to be able to edit bases in twelve different ways. Last year, Liu’s team unveiled a base editor, called BE3, that can make two changes: C to T and G to A.

Their starting point was the standard CRISPR protein. It consists of a pair of molecular scissors for cutting a DNA strand, and a guide part that binds to a specific DNA sequence. Liu’s team replaced the scissors with an enzyme that can convert Cs or Ts.

Fixing most mutations

Now Liu’s team has added a different enzyme to the modified CRISPR protein to create a base editor that changes A into G and T into C. This was far more of a challenge because no known natural enzyme does this. Instead, the team evolved one from scratch by setting up a system in which bacteria had to evolve such an enzyme in order to survive.

The new base editor, called ABE7, works extremely well. In a series of tests, it made the desired DNA letter change in over half of human cells, with hardly any unwanted mutations. “It pretty much does not generate non-desired changes,” says Liu. This makes ABE7 safer than standard CRISPR gene editing, minimising the risk of introducing mutations that could cause cancer, for instance.

Together, BE3 and ABE7 could be used to correct as many as two-thirds of the single-letter mutations that occur in people. Although they can only change 4 of the 12 possible types of single letter mutation, the ones they target are more common than others.

Journal reference: Nature, DOI: 10.1038/nature24644

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