Broad's base editing rewrites a single DNA letter — the pencil to CRISPR's scissors

CRISPR-Cas9 had been described as a molecular scalpel for editing or deleting whole genes, and it does that by breaking both strands of DNA. But a large share of human disease is written in much smaller errors: point mutations, where one chemical base among the genome's six billion letters is swapped, deleted or inserted. Such single-letter changes account for 32,000 of the 50,000 changes in the human genome known to be associated with diseases.

On October 25, 2017, two teams from the Broad Institute of MIT and Harvard published a more precise alternative called base editing. David Liu, a Harvard chemistry professor, modified CRISPR so it targeted just one base and chemically rearranged the atoms of an adenine so it read like a guanine; the cell then fixed the opposite strand to complete the change, turning an A-T pair into a G-C one. 'If CRISPR is akin to a pair of scissors, base editing is more like a pencil,' Liu said.

In cells taken from patients, Liu's team used the tool to correct the mutation behind hereditary hemochromatosis, a disorder that makes the body absorb too much iron, and to induce a mutation that suppresses sickle-cell anemia. In both studies they detected virtually no off-target effects — the unwanted insertions and deletions that worry researchers about conventional Cas9 editing. A parallel Science paper from Feng Zhang's group used a similar method to target individual letters in RNA, whose natural degradation makes the edit temporary rather than permanent.

Base editing was framed not as a replacement for CRISPR but as another option for a different job: fixing a single word instead of replacing the whole paragraph, as one Berkeley researcher put it. The A-to-G change alone could address about half of the 32,000 known disease-causing point mutations, and Liu's lab was already exploring blood disorders, neurological disorders, hereditary deafness and hereditary blindness as targets.