Cas proteins like CRISPR-Cas9 have great potential for gene therapy to treat human disease and for altering crop genes, but the gene-targeting and gene-cutting Cas proteins are often large and hard to ferry into cells with viral vectors such as adenovirus. Scientists have now discovered a hypercompact Cas protein, Cas-phi, that should work better. It is half the size of Cas9 and apparently evolved inside a bacteriophage, yet efficiently snips double-stranded DNA.

The new Cas proteins were found in the largest known bacteria-infecting viruses, called bacteriophages, and are the most compact working Cas variants yet discovered — half the size of today’s workhorse, Cas9.

Smaller and more compact Cas proteins are easier to ferry into cells to do genome editing, since they can be packed into small delivery vehicles, including one of the most popular: a deactivated virus called adeno-associated virus (AAV). Hypercompact Cas proteins also leave space inside AAV for additional cargo.

As one of the smallest Cas proteins known to date, the newly discovered Cas? (Cas-phi) has advantages over current genome-editing tools when they must be delivered into cells to manipulate crop genes or cure human disease.

«Adenoviruses are the perfect Trojan horse for delivering gene editors: You can easily program the viruses to reach almost any part in the body,» said Patrick Pausch, a postdoctoral fellow at the University of California, Berkeley, and in UC Berkeley’s Innovative Genomics Institute (IGI), a joint UC Berkeley/UCSF research group devoted to discovering and studying novel tools for gene editing in agriculture and human diseases. «But you can only pack a really small Cas9 into such a virus to deliver it. If you would have other CRISPR-Cas systems that are really compact, compared to Cas9, that gives you enough space for additional elements: different proteins fused to the Cas protein, DNA repair templates or other factors that regulate the Cas protein and control the gene editing outcome.»

Apparently these «megaphages» use the Cas? protein — the Greek letter ?, or phi, is used as shorthand for bacteriophages — to trick bacteria into fighting off rival viruses, instead of itself.

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Materials provided by University of California — Berkeley. Note: Content may be edited for style and length.