Jan 24, 2019

A new enzyme could make human gene editing more precise

Photo of CRISPR-Cas9 culture being done in a lab

Performing a CRISPR-Cas9 process. Photo: Gregor Fischer/picture alliance via Getty Images

Scientists were able to alter an enzyme from a thermophilic bacteria so it can be used by CRISPR to edit human genes more effectively, per a study published in Nature Communications on Tuesday.

Why it matters: CRISPR is powerful but can sometimes cause large deletions or move DNA inadvertently. To make it more precise, researchers have been testing hundreds of new enzymes. Study author Feng Zhang says Cas12b's small size and precise targeting will enable it to be used for in vivo applications in primary human cells.

Background: The Cas12b family of enzymes was first brought to attention in 2015, and led to some recent studies (here and here) better defining their uses and limitations.

  • This study's enzyme, called BhCas12b, is from a bacterium (Bacillus hisashii) that lives in hot environments like geysers and volcanoes.
  • The main problem of using Cas12b was its temperature restriction. In its natural state, it's ineffective as a gene-editing tool at the lower body temperature of humans.

What they did: Zhang, who is a core institute member of the Broad Institute of MIT and Harvard, tells Axios that the team studied its three dimensional shape and made changes they predicted would make it more active at lower temperatures.

What they found: With the modifications and its naturally small size, BhCas12b was able to cut both DNA strands without many off-targets, Zhang says, and can efficiently edit genomes in primary human T cells.

"The size of the protein matters because for many applications, it needs to be packaged into a minimal viral vector for delivery. Viruses naturally have a restricted cargo capacity, so a smaller genome editing enzyme is beneficial."
ā€” Feng Zhang

Outside perspective: Scientists not involved in this study say it shows Cas12b can be altered to become a promising CRISPR enzyme, but note that this small study should be validated with further research.

  • Ilya Finkelstein, assistant professor of molecular biology at the University of Texas-Austin, says he found it interesting they took a protein not normally functional in humans and engineered it to work. "There are hundreds of variants of these proteins. ... This suggests that the CRISPR toolkit will continue to grow."
  • Konstantin Severinov, principal investigator for Rutgers' Waksman Institute of Microbiology, says: "The study shows that Cas12b ... can be used, after some clever laboratory tweaking, for genomic editing in human cells. It may offer some advantages during editing compared to Cas9 and Cas12a."

Between the lines: Most CRISPR testing uses the first discovered enzyme, CAS9, so it's unlikely there will be a large shift to other enzymes soon, at least until they are proven to be safe and become cheaper.

  • "The one that is used by most people [Cas9] is not the best, it was simply the first to be characterised and reduced to practice. So there is clear room for improvement and many people are looking for better ones," Severinov says.
  • "[T]ime will tell whether Cas12b can take the crown from Cas9," Finkelstein adds.

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