Open thread: CRISPR-Cas9

2017-08-22

in Science

CRISPR-Cas9 is a powerful new gene editing technique with the promise of widespread applications in research, medicine, and industry — as well as to provoke political and moral controversy.

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. August 22, 2017 at 5:35 pm

CRISPR-Cas9 editing has been developed from a bacterial defence system that shreds the DNA of invading viruses. CRISPR stands for “clustered regularly interspaced short palindromic repeats”. These are short strings of RNA, a molecule similar to DNA, each designed to fix onto a particular segment of a virus’s DNA. Cas9 is an enzyme which, guided by CRISPRs, cuts the DNA at the specified point.

Modifying this arrangement for the purposes of genetic engineering is simple, at least in theory. Since DNA and RNA work in essentially the same ways in all living organisms, designing appropriately customised CRISPR guide molecules can induce Cas9 to cut any cell’s DNA wherever the designers choose, eliminating undesirable sequences of genetic “letters”. Since cells will then try to repair this sort of damage, genetic engineers can, by providing corrected versions of the DNA that has been deleted for use as templates which a cell can copy, encourage the repair mechanism to fix the problem in the way they had intended.

The hope was that, by being given such templates, embryos could be purged of nascent genetic disease. That hope appeared fulfilled, at least in part. By the end of the experiment, 72% of the embryos were free of mutant versions of MYBPC3, an improvement on the 50% that would have escaped HCM had no editing taken place.

In achieving this, Dr Ma and her colleagues overcame two problems often encountered by practitioners of CRISPR-Cas9 editing. One is that the guidance system may go awry, with the CRISPR molecules leading the enzyme to parts of the genome that are similar, but not quite identical, to the intended target. Happily, they found no evidence of such off-target editing.

A second problem is that, even if the edits happen in the right places, they might not reach every cell. Many previous experiments, including some on embryos, have led to mosaicism, a condition in which the result of the editing process is an individual composed of a mixture of modified and unmodified cells. If the aim of an edit is to fix a genetic disease, such mosaicism risks nullifying the effect.

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