CARLOS CLARIVAN/SCIENCE PHOTO LIBRARY
A storm of criticism met the claimed creation of the first genome-edited children in China last month. One reason is that the twin girls have unpredicted new mutations whose effects are unknown. But it now appears there’s a really easy way to ensure the CRISPR genome editing technique makes far more precise, predictable mutations.
The term “CRISPR genome editing” is really a bit of a misnomer. The method is most commonly used to disable genes by cutting the DNA in a specific site. When the cell repairs the cut, it typically adds or removes one or more DNA letters.
But Paola Scaffidi of the Francis Crick Institute in London suspected that these mutations might not be as random as they appear. To find out, her team induced mutations in 1500 target sites in human cells growing in a dish.
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Stunningly simple
They found a stunningly simple pattern. “We started with machine learning but we did not need it,” Scaffidi says.
It appears the sequence of the RNA that guides the CRISPR Cas9 protein to its target is crucial. If the fourth DNA letter from the end is a G, the resulting mutation is indeed relatively random. But if it’s an A, T or C the outcome is more predictable. If it’s a T, for instance, in 9 out of 10 cells a single extra T will be inserted at the target site.
If the findings are confirmed, it means the thousands of biologists around the world using CRISPR for research can make it far more precise and powerful simply by altering the guide RNAs they use. It also greatly boosts the prospects for using CRISPR to treat all kinds of disorders by correcting disease-causing mutations inside the body.
However, serious safety questions remain. Earlier this year Allan Bradley of the Wellcome Sanger Institute in the UK reported that in about 1 in 5 cells, CRISPR triggers very large deletions that have been missed by standard methods of detecting mutations. “You find what you look for,” he says.
Scaffidi’s team did not look for these large deletions, so it remains unclear whether her approach can be used to avoid inducing them.
Some groups have modified the CRISPR protein so it changes one DNA letter to another without cutting the DNA. Base editing, as this is known, might prove to be the safest approach for treating diseases, but Scaffidi’s method could still be invaluable.
Journal reference: Molecular Cell, DOI: 10.1016/j.molcel.2018.11.031
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