There's a promising new way to fix genetic tweaks that cause disease

Alissa Ambrose/STAT

For all the hoopla about CRISPR, the revolutionary genome-editing technology has a dirty little secret: it’s a very messy business.

Scientists basically whack the famed double helix with a molecular machete, often triggering the cell’s DNA repair machinery to make all sorts of unwanted changes to the genome beyond what they intended.

On Wednesday, researcher unveiled in Nature a significant improvement — a new CRISPR system that can switch single letters of the genome cleanly and efficiently, in a way that they say could reliably repair many disease-causing mutations.

Because of “the cell’s desperate attempts” to mend its genome, said Harvard University biologist George Church, “what often passes as ‘genome editing’ would more appropriately be called ‘genome vandalism,’” as the cell inserts and deletes random bits of DNA where CRISPR cuts it.

Because the new version of CRISPR avoids that mess, it “offers a huge step forward,” said Church, who was not involved in the discovery, and whose 2013 paper helped launch the CRISPR frenzy. “It is arguably the most clever CRISPR gadget to date.”

If the CRISPR invention lives up to its promise — the experiments were done in cells in lab dishes, not whole animals or people — it could fix misspellings in DNA that cause Tay-Sachs, neurofibromatosis, sickle cell, cystic fibrosis, and other devastating inherited diseases, as well as mutations that raise the risk of diseases as common as cancer and Alzheimer’s.

Alissa Ambrose/STAT

Harvard University biochemist David Liu and post-doctoral fellow Alexis Komor, who led the work, have filed a provisional patent application on their invention, which changes one-letter misspellings in DNA called point mutations. Liu is a consultant to and cofounder of Editas Medicine, a genome-editing company in Cambridge, Mass., that went public in February. Church is also a cofounder of Editas.

“Most known human genetic variations associated with disease are point mutations,” said Liu. “Current gene-editing methods aren’t particularly good at correcting those.”

The problem addressed by the new technique is not the usual one discussed with CRISPR, namely, off-target effects. That refers to changing a region of the genome other than the intended one. While early genome-editing experiments had that problem, there has been “tremendous progress” in fixing it, said Dr. Keith Joung of Massachusetts General Hospital.

But another problem remains.

The workhorse of the CRISPR system is an enzyme that cuts DNA. In some cases, simply cutting out a disease-causing gene might be enough to achieve a cure, as with cancer-causing genes. If deleting a gene isn’t sufficient, and a replacement gene is also required to treat a particular disease, CRISPR can carry substitute DNA, such as a healthy cystic fibrosis gene.

But genomes don’t take kindly to being cut. When the CRISPR enzyme whacks the double helix, the cell tries to “get the broken ends back together,” Liu said. Molecules in the cell grab the four basic components of DNA — represented by the letters A, T, C, and G — from the cellular soup and cram them into the cleaved DNA like someone pushing spackle into the crack of a Ming vase; other molecules cut out segments of DNA.

“Having these random insertions or deletions is unhelpful,” Liu said.

For nearly two years he, Komor, and their colleagues tried to improve that aspect of CRISPR. They replaced its usual cutting enzyme with a dud called “dead Cas9.” Like blunt scissors biting down on fabric, dead Cas9 can latch on to DNA but not cut it. Then they attached two other proteins that change one DNA letter to another and lock it in place. So far, of the 12 possible changes (A to T, C to G, G to C …), the new system can make two: C to T and G to A.

But at least 3,000 inherited diseases are the result of a C that should be a T or a G that should be an A, including Franconi anemia and some cancers. “And we’re in the middle of an all-out effort to do the other 10,” Liu said.

NOW WATCH: Watch science writer Carl Zimmer explain CRISPR in 90 seconds