Researchers have discovered a way to switch off the widely used CRISPR-Cas9 gene-editing system through newly identified proteins produced by bacterial viruses, an advance which could improve the safety and accuracy of its applications.
In order to discover an anti-CRISPR protein that would work against the type of CRISPR-Cas9 system most labs now use, which depends on a protein called SpyCas9 as its targeted DNA clippers, researchers from University of California, San Francisco (UCSF) in the US came up with a clever trick.
They reasoned that they should be able to identify bacteria with inactivated CRISPR systems by looking for evidence of so-called "self-targeting" - bacterial strains where some virus had successfully gotten through the Cas9 blockade and inserted its genes into the bacterial genome.
They hypothesised that these phages must encode some anti-CRISPR agent, or else Cas9 would kill the bacteria by cutting its own genome where the viral DNA had been inserted.
CRISPR-Cas9 evolved in bacteria as an immune system to protect against viral infections.
However, in the past decade it has excited both researchers and the general public as a general-use gene editing system, enabling scientists to quickly and efficiently modify genetic information and tweak gene activity in virtually any organism.
Many hope CRISPR will speed efforts to directly treat genetic disorders, among many other applications, but for the most part the technology has not yet proven quite precise enough, making occasional unintended edits along with the intended ones.
Researchers and bioethicists also worry that the technology's very power and ease of use raise the possibility that it could potentially cause harm, either intentionally or by accident.
The newly discovered anti-CRISPR proteins - which are the first to work against the type of CRISPR-Cas9 system most commonly used by laboratories and the burgeoning gene editing industry - could help resolve both problems, enabling more precise control in CRISPR applications but also providing a fail-safe to quickly block any potentially harmful uses of the technology.
To find such a switch, researchers turned to the same billion-year arms race between viruses and bacteria that produced the CRISPR system itself.
"Just as CRISPR technology was developed from the natural anti-viral defence systems in bacteria, we can also take advantage of the anti-CRISPR proteins that viruses have sculpted to get around those bacterial defences," said Benjamin Rauch from UCSF.
Using a bioinformatics approach the team examined nearly 300 strains of Listeria, a bacterial genus famous for its role in food-borne illness and found that three per cent of strains exhibited "self-targeting".
Further investigation isolated four distinct anti-CRISPR proteins that proved capable of blocking the activity of the Listeria Cas9 protein, which is very similar to SpyCas9.
The study was published in the journal Cell.
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