CRISPR-Cas9 is a revolutionary tool in part because of its versatility: created by bacteria to chew up viruses, it works equally well in human cells to do all sorts of genetic tricks, including cutting and pasting DNA, making pinpoint mutations and activating or inactivating a gene.

Researchers have now made it even more versatile by giving it an "on" switch, allowing users to keep the Cas9 gene editor turned off in all cells except its designated target.

The redesigned Cas9 enzyme -- which the researchers refer to as ProCas9 -- is fully functional except for containing a length of protein that needs to be snipped before the enzyme can bind and cut DNA. If scientists insert a short length of protein that can be cut only by a particular enzyme, such as one used exclusively by cancer cells or an infectious virus or bacteria, that enzyme becomes a trigger to turn on Cas9.

ProCas9 essentially "senses" the type of cell it's in based on the protein-cutting enzyme -- a so-called protease -- present. "This is an extra layer of security you could put on the molecule to ensure accurate cutting," said the senior author. It also endows the Cas9 protein with programmable inputs in addition to its programmable outputs.

"There are a lot of proteases that regulate signaling pathways in cells, transform normal cells into cancer cells, and are involved in pathogen infection," said the senior author. "If we can sense these signals, we can tap into and respond accordingly to these important pathways."'

In the study published in the journal Cell, researchers demonstrated protease control of Cas9 by making it sensitive to both plant and human viruses, such as West Nile Virus. In the future, they believe this sort of technology could be used to import the CRISPR-Cas9 bacterial immune system into plants to help them fend off damaging viral pathogens.

The study shows that "we're not stuck with what nature gave us with regards to genome-editing proteins," the senior author said. "These proteins can be elaborately optimized and turned into scaffolds not found in nature but possessing the right properties for use in human cells."

https://news.berkeley.edu/2019/01/10/giving-cas9-an-on-switch-for-better-control-of-crispr-gene-editing/

https://www.cell.com/cell/fulltext/S0092-8674(18)31583-6

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcrispr-cas9-circular&filter=22