DNA editing just got a sharp, new pencil. Researchers have built an enzyme that can perform a previously impossible DNA swap, directly changing the DNA base pair from an A●T to a G●C. The new enzyme, known as a base editor, may one day enable genome surgery that erases harmful mutations and writes in helpful ones, Howard Hughes Medical Institute (HHMI) Investigator David Liu and colleagues report October 25, 2017, in Nature.
The new system is a “really exciting addition to the genome engineering toolbox,” says Feng Zhang, an HHMI-Simons Faculty Scholar and molecular biologist at the Broad Institute of MIT and Harvard, who was not involved in the study. “It’s a great example of how we can harness natural enzymes and processes to accelerate scientific research.”
Some genome editing tools, such as the method known as CRISPR/Cas9, cut both strands of DNA and rely on the cell’s own molecular machinery to fill in the gap with the desired DNA sequence. Base editors are, in a sense, more precise tools. “CRISPR is like scissors, and base editors are like pencils,” says Liu, a chemical and molecular biologist at Harvard University and the Broad Institute.
Those pencils can rewrite the individual chemical units of DNA, known as bases. Each base on one strand of DNA joins its partner base on an opposing strand, so that the base adenine pairs with thymine (A●T), and guanine pairs with cytosine (G●C). Last year, Liu and colleagues described a base editor that could change C●G base pairs into T●A. But researchers didn’t have the ability to convert A●T to G●C, until now.
Going in, Liu and his team knew that the project was risky, because the first step involved creating an enzyme that didn’t yet exist. Postdoctoral researcher Nicole Gaudelli took on the challenge, relying in part on evolution to create an enzyme that could do the job. Gaudelli started with an enzyme called TadA that’s able to convert adenine to a molecule called inosine (which cells treat as guanine), but in transfer RNA rather than in DNA. She made larger libraries of TadA mutants into bacterial cells and required them to convert A to inosine in antibiotic resistance genes in order to survive in the presence of antibiotics. Surviving bacteria encoded TadA mutations that imparted the ability to perform the adenine-to-inosine conversion on DNA.