Nobody’s perfect. Neither CRISPR nor peer-review

nobodyPerfection is not of this world, and no technology is perfect. But tolling the bell for CRISPR because of a single preliminary study last week was premature at best. Many voices are doubting the meaning of the Nature Methods paper reporting “hundreds of unintended mutations” putatively caused by genome editing. Some researchers have already announced that critical analyses and rebuttals are forthcoming.

CRISPR is considered a simple, cheap, and very precise genetic modification technique, and this is why thousands of laboratories around the world have quickly embraced it. But very precise does not mean infallible. It is well-known that the enzyme responsible for the editing process (Cas9) may cut the DNA at points other than the intended target. Several research groups indeed have worked to develop more specific variants, such as high-fidelity Cas. The issue, therefore, is not whether CRISPR can generate unwanted mutations. The real questions are: how often do these off-target mutations occur? Do we know how to handle the inconvenience?

Experts have so far been optimistic: by adapting reagents concentration and delivery, and by using up-to-date variants, undesirable mutations become a manageable problem. A recent report produced by an expert committee for the European Commission states, for instance, that unintended effects of new biotechnologies are rare in comparison with older techniques How is it possible then that Kellie Schaefer and colleagues found over a thousand mutations generated in a single editing experiment with mice? What about investors rushing to sell their CRISPR stocks, did they get it wrong? Or is the CRISPR revolution doomed from the start?

The emerging truth is that the paper published by Nature Methods seems controversial for a number of reasons, some of which easy to understand even for laypeople. The sample, first of all, is too small to make reliable conclusions: only two edited mice and one control. “I think that this must be the first time that I have seen a publication where the number of authors (6) and affiliations (7) outnumbered the number of animals used (3)”, wrote a researcher commenting a skeptical post. If you add that the two edited mice were siblings, the suspicion arises that putative CRISPR mutations may be false positive, meaning genetic variations shared by the animals pair well before the editing process. “Bold claims need stronger data” tweeted San Sternberg, Jennifer Doudna’s former student and co-author. Further criticisms have been advanced here and here.

Eventually this paper, rather than exposing CRISPR hidden flaws, could reveal a failure in the process used by academic journals for research validation. Nobody’s perfect, as we said. Not even peer-review.

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