Precise gene-editing technique offers hope for inherited diseases
A modification to a gene-editing technique that enables scientists to more precisely recode genetic material could offer hope for currently untreatable inherited diseases. The CRISPR-Cas9 technique, created by the Broad Institute of MIT and Harvard, uses “base editing” to change DNA and RNA molecules. The technique could be used to alter genetic mutations responsible for many diseases. The tool “rewrites” genetic code, rather than deleting and replacing whole strands of DNA. A team of Chinese researchers reported a world-first demonstration of the technique on a human embryo is September.
The human genome contains six billion DNA letters, or chemical bases known as A, C, G and T. These letters pair off—A with T and C with G—to form DNA’s double helix. Base editing, which uses a modified version of CRISPR, is able to change a single one of these letters at a time without making breaks to DNA’s structure.

That’s useful because sometimes just one base pair in a long strand of DNA gets swapped, deleted, or inserted—a phenomenon called a point mutation. Point mutations make up 32,000 of the 50,000 changes in the human genome known to be associated with diseases.

In the Nature study, researchers led by David Liu, a Harvard chemistry professor and member of the Broad Institute, were able to change an A into a G. Such a change would address about half the 32,000 known point mutations that cause disease.

To do it, they modified CRISPR so that it would target just a single base. The editing tool was able to rearrange the atoms in an A so that it instead resembled a G, tricking cells into fixing the other DNA strand to complete the switch. As a result, an A-T base pair became a G-C one. The technique essentially rewrites errors in the genetic code instead of cutting and replacing whole chunks of DNA.

“Standard genome-editing methods, including the use of CRISPR-Cas9, make double-stranded breaks in DNA, which is especially useful when the goal is to insert or delete DNA bases,” Liu said on a conference call with journalists on Tuesday. “But when the goal is to simply fix a point mutation, base editing offers a more efficient and cleaner solution.”

Liu said base editing isn’t meant to be a replacement to traditional gene editing with CRISPR, but rather another option for altering the genome in an attempt to correct disease. If CRISPR is akin to a pair of scissors, base editing is more like a pencil, he said.

Previously, researchers had created base editors capable of making the opposite kind of swap—changing a G into an A. Substitutions of a G for an A in certain parts of the DNA represent about 15 percent of disease-associated point mutations. In September, Chinese researchers reported that they used one of these editing tools in an embryo to remove the genetic mutation that causes anemia.

Working in cells taken from patients, Liu and his colleagues used their base-editing tool to correct a point mutation that causes hereditary hemochromatosis, a disorder that causes the body to absorb too much iron from food. This excess iron can build up over time and cause liver cancer and other liver diseases, diabetes, heart disease, or joint disease.