When Xingxu Huang began thinking about correcting disease-causing mutations in the human genome, his attention turned naturally to CRISPR–Cas9. But it quickly became clear that the popular gene-editing tool wasn’t ideal for the majority of human disease mutations, which result from errors in single DNA nucleotides known as point mutations. More than 31,000 such mutations in the human genome are known to be associated with human genetic diseases. But CRISPR is not particularly efficient at correcting them.

Then Huang learnt about base editors, a new class of genome-modifying proteins that excel at single-site mutations.

Base editors chemically change one DNA base to another without completely breaking the DNA backbone. The first cytosine base editor (CBE), which chemically converts a cytosine–guanine (C–G) base pair into a thymine–adenine (T–A) base pair at a targeted genomic location, was developed in 2016 by chemical biologists David Liu and Alexis Komor at Harvard University in Cambridge, Massachusetts. Another researcher in Liu’s laboratory, Nicole Gaudelli, developed the first adenine base editor (ABE) a year later; it chemically transforms A–T to G–C base pairs.

"Base editing gives very, very good efficiency, about 40–50% efficiency for cell lines,” says Huang, a geneticist at ShanghaiTech University in China. “That’s very high efficiency compared with traditional genome editing,” which is only one-tenth as efficient, he says.

But base editors are not just more efficient than CRISPR–Cas9; they also cause fewer errors. CRISPR–Cas9 acts as molecular scissors that cut both strands of DNA. As the cell repairs the break, random bases can be inserted or deleted (indels), altering the gene sequence. Large chromosomal segments might even be deleted or rearranged. By altering just a specific nucleotide without making double-stranded breaks, base editors cause fewer unwanted mistakes.

Researchers have applied these tools across the evolutionary tree, from bacteria and yeast to rice, wheat, zebrafish, mice, rabbits and monkeys. They have used them to knock out genes, and to create and correct animal models. They have applied them in very early human embryos in the laboratory. And they might one day use base editors to treat human genetic diseases.

Please refer to Got Mutation? 'Base Editors' Fix Genomes One Nucleotide at a Time to read more. (Nature)