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Genome-editing find may improve system’s precision

 CRISPR systems help bacteria defend against viral attack (shown here). These systems have been adapted for use as genome editing tools in human cells
Science Photo Library
CRISPR systems help bacteria defend against viral attack (pictured here). These systems have been adapted for use as genome editing tools in human cells

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Scientists believe they have found a better pair of molecular scissors to use with the genome-editing technique that is revolutionizing biology — an advance that could accelerate the hunt for treatments and upend a bitter patent dispute with billions of dollars at stake.

In a study published on Friday, scientists led by Feng Zhang of the Massachusetts Institute of Technology report that they discovered enzymes that cut more precisely than those now in use in CRISPR, a technique with an uncanny ability to make a beeline for a targeted stretch of DNA, snip it out, and replace it.

If the finding holds up, CRISPR — which is used in hundreds of labs around the world and even by amateurs doing “garage biology”— could become an even more powerful tool to reveal the genetic defects underlying diseases and to perhaps repair them.

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Last year Zhang and the Cambridge-based Broad Institute, where his lab is located, won the first patent on CRISPR technology, even though a similar application from scientists at the University of California, Berkeley, and other institutions predated theirs. Berkeley has asked the US patent office to reconsider the Broad’s patent, setting up what could be an expensive legal battle.

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The outcome has particular importance for companies, including some in Cambridge, that have already licensed either the Broad or the Berkeley technologies, since they might be left with rights to patents for less useful technology.

If the new enzymes turn out to be as powerful as those in today’s CRISPR systems, the patent dispute could become academic. A CRISPR system that uses a different enzyme could be the basis of new patents, said Jacob Sherkow, an expert on patent law at New York Law School.

The Broad has filed a patent application for the new CRISPR system.

Scientists contacted by Stat said more research needs to be done to show that the new enzymes are superior to the current ones.

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“The more [CRISPR] systems the better,” said biologist Kate O’Connor-Giles of the University of Wisconsin, Madison, who uses the tool to study brain development and was not involved in the new study. All sorts of tweaks could improve CRISPR, she added, but “whether or not this is true of [this discovery] remains to be seen.”

In nature, bacteria use CRISPR to attack invading viruses. In food production, this natural defense system keeps viruses from spoiling cheese and yogurt cultures.

Researchers figured out how to adapt this system to edit the genomes of many organisms, including humans, and to control where it cuts. These lab-made CRISPR systems are the cellular version of a computer’s find-and-replace function. They home to a DNA target in a cell and unleash an enzyme called Cas9 to snip the double helix. That snip eliminates a gene and, if the CRISPR system is engineered to carry a repair template, allows the cell to replace it with a new one.

Zhang’s lab, which hums with activity well into the night, is divided between scientists using CRISPR to make discoveries and those trying to improve CRISPR.

Staph and strep bacteria use Cas9 to disable viruses, but Zhang and his team suspected other bacteria might harbor better shears.

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For the new study, published in Cell, he and colleagues, including those from the National Institutes of Health and Wageningen University in the Netherlands, searched through hundreds of species of bacteria for cutting enzymes.

They discovered two promising candidates. Called Cpf1, the enzymes are found in obscure bacteria called Acidaminococcus and Lachnospiraceae. Cpf1, the team reports, successfully edited human genomes.

The new cutting enzymes have “very distinct and interesting properties” that could make them superior to the current CRISPR system, Zhang said in an interview. For one, the synthesis of CRISPR systems “will be easier and cheaper.”

Just as significant, Cpf1 cuts DNA in a different way than Cas9. The latter cuts both strands of the double helix at the same place. This is not ideal because the exposed ends of DNA can undergo mutations. It’s like what happens when fabric is snipped with a straight scissors — the edge can unravel.

Cpf1 is more like pinking shears, whose saw-toothed edges cause the cuts in a fabric to be offset. Cpf1 snips the two strands of DNA so the cut points are similarly offset. That reduces the chance of mutations and, Zhang said, should make genome editing more precise, though the new study doesn’t show whether that’s the case.

Jennifer Doudna is the Berkeley scientist who made a key CRISPR discovery in 2012 and is often portrayed as Zhang’s scientific rival; it was her patent application that lost out. She said she is “excited about the science” in Zhang’s new study, but cautioned that “it remains to be seen whether the [new] proteins will work well generally for genome editing.”

Off-target effects, in which CRISPR edits a gene other than the intended one, “may be a problem, based on the data in the paper, but it’s far too early to tell,” Doudna said. These off-target cuts also plague the standard CRISPR system.

Sharon Begley can be reached at sharon.begley@statnews.com. Follow her on Twitter @sxbegle. Follow STAT on Twitter: @statnews.