Aug 2, 2018

One CRISPR enzyme may be better than the other, scientists say

A researcher performs a CRISPR-Cas9 process. Credit: Gregor Fischer/picture alliance via Getty Images

Researchers say they've discovered why the enzyme Cas12a may be safer and more precise than Cas9 in most cases to use with the gene editing tool, CRISPR, according to a study published today in Molecular Cell .

Why it matters: Cas9 is the first-discovered and most popular enzyme used by the CRISPR technology, but it has been known to have safety concerns. It sometimes unsafely targets the wrong gene or even deletes sections of the genome. However, Cas12a may be safer because it discriminates more strongly against mismatches than Cas9, the scientists say.

"Why don't we start with the best protein that nature has given us [Cas12a] and improve on that."
— Ilya Finkelstein, study author, assistant professor of molecular biology, University of Texas-Austin

Background: CRISPR technology can use different proteins to cut the DNA, and there is a lot of research looking into other alterations of Cas9 to improve it, as well as different proteins, like Cas12a. Both Cas9 and Cas12a rely on a 20-letter guide (or a 20-nucleotide RNA) to identify the DNA targeted for edits, but their processes are slightly different.

Some differences, per The Broad Institute:

  • Cas9 uses two small RNAs and cuts both strands of the target DNA at the same place, creating "blunt edges" that can undergo mutation when the strands repair themselves. (Although, FierceBiotech points out there are efforts to make Cas9 safer).
  • Cas12 uses a single RNA and is smaller, which can make it easier to enter cells.

What they found: Researchers from UT-Austin wanted to confirm Cas12 was more precise and to determine why. They found that Cas9 starts binding to its DNA target after reading only the 7 or 8 letters of the 20-letter code. However, Cas12a appears to read up to 18 of the letters before it binds fully, and if it finds a mismatch, it will fall off before it binds.

  • This is key, Finkelstein tells Axios, because a person can have DNA circulating around their body that have very similar letters, which may cause editing of the wrong DNA. Eventually, they hope to get Cas12a to match all 20 letters, he says.
  • However, he adds, there are also some disadvantages to using Cas12a over Cas9. For one thing, Cas12a tends to remain tightly associated with one of the two DNA molecules after the genome is cut, and they don’t know how this would impact gene editing and repair.
  • He says Cas9 acts like "superglue" while Cas12a is more similar to "velcro."

What's next: More trials are needed, and research to make it even more precise. Finkelstein says there will be "thousands" of Cas12a and Cas9 enzymes produced as scientists seek to improve the proteins, including by his laboratory, because "it's important to expand our genome editing toolkit."

"For the first time in the history of humanity, we now have access to tools that will let us control our genetic future."
— Ilya Finkelstein, University of Texas-Austin

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Data: The Center for Systems Science and Engineering at Johns Hopkins; Map: Andrew Witherspoon/Axios

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