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Blog / 08.27.15

Zhang lab unlocks crystal structure of new CRISPR/Cas9 genome editing tool

SaCas9
By Paul Goldsmith
In a paper published today in Cell researchers from the Broad Institute and University of Tokyo revealed the crystal structure of the Staphylococcus aureus Cas9 complex (SaCas9)—a highly efficient enzyme that overcomes one of the primary challenges to in vivo mammalian genome editing. First...

In a paper published today in Cell researchers from the Broad Institute and University of Tokyo revealed the crystal structure of the Staphylococcus aureus Cas9 complex (SaCas9)—a highly efficient enzyme that overcomes one of the primary challenges to in vivo mammalian genome editing.

First identified as a potential genome-editing tool by Broad Institute core member Feng Zhang and his colleagues (and published by Zhang lab in April 2015), SaCas9 is expected to expand scientists’ ability to edit genomes in vivo. This new structural study will help researchers refine and further engineer this promising tool to accelerate genomic research and bring the technology closer to use in the treatment of human genetic disease.

“SaCas9 is the latest addition to our Cas9 toolbox, and the crystal shows us its blueprint,” said co-senior author Feng Zhang, who in addition to his Broad role, is also an investigator at the McGovern Institute for Brain Research, and an assistant professor at MIT. “This study shows further paths forward for optimizing this technology for the benefit of global health.”

The engineered CRISPR-Cas9 system adapts a naturally-occurring system that bacteria use as a defense mechanism against viral infection. The Zhang lab first harnessed this system as an effective genome-editing tool in mammalian cells using the Cas9 enzymes from Streptococcus thermophilus (StCas9) and Streptococcus pyogenes (SpCas9). Zhang and his team continued to analyze hundreds of other Cas9s from different types of bacteria for proteins with properties that could be optimized for use in human cells, leading them to SaCas9.

Now, Zhang and colleagues have detailed the molecular structure of SaCas9, providing scientists with a high-resolution map of this enzyme. By comparing the crystal structure of SaCas9 to the crystal structure of the more commonly-used SpCas9 (published by the Zhang lab in February 2014), the team was able to focus on aspects important to Cas9 function— potentially paving the way for even smaller genome-editing tools. With the crystal structure in hand, Zhang and his team are applying this new understanding to further develop the experimental and therapeutic potential of the CRISPR-Cas9 system.

“Our ultimate goal is the application of this nuclease in gene therapy,” said Le Cong, contributing author on the study, and former member of the Zhang Lab. “Having the structure in hand enables us to create smaller, more precise, more radically-engineered Cas9s in pursuit of that goal.”

Paper cited: Nishimasu H et al. “Crystal Structure of Staphylococcus aureus Cas9.” Cell, doi:10.1016/j.cell.2015.08.007