The paper takes CRISPR/Cas9 and turns it into a targeting system for an set of enzymes that allow modification of a single DNA basepair at a specific locus in the DNA without introducing a double strand break.
The reason this is important is because a double strand break (the result of standard CRISPR) is a devastating event, introducing a risk of uncontrolled mutation. However, if you're able to modify a single basepair in the DNA in a targeted fashion, you eliminate that risk, making it much more practical to use this technology in the clinic.
There are still absolutely massive obstacles to using CRISPR in a clinical setting, but this is a very important step forward. It still remains to be seen how you get the CRISPR/CAS system into a cell (and other ancillary accessories specified in this work) reliably in a clinical context. Still early days, but a very important step.
Full disclosure: David Liu (the PI on this work) may be seen as a competitor to the lab where I did my graduate work.
So it does prevent failure in NHEJ, doesn't it? But how does it prevent offtarget effects? I mean, if the wrong guide sequence is bound, an offtarget is mutated all along, isn't it?
I think the idea is to avoid NHEJ entirely. I would guess that it's going for base-excision-repair (BER), which is why it's currently targeting either C or G bases.
If the wrong guide sequence is bound you're screwed no matter what, though I suspect they'd say that the error rate is low enough to be practically irrelevant. Not sure that's really true though, the genome is pretty big and if you screw up at even astonishingly low rates, you're still screwing up fairly frequently.
Does this answer your question, or are you asking something else?
> The problem addressed by the new technique is not the usual one discussed with CRISPR, namely, off-target effects. That refers to changing a region of the genome other than the intended one. While early genome-editing experiments had that problem, there has been “tremendous progress” in fixing it, said Dr. Keith Joung of Massachusetts General Hospital.
The reason this is important is because a double strand break (the result of standard CRISPR) is a devastating event, introducing a risk of uncontrolled mutation. However, if you're able to modify a single basepair in the DNA in a targeted fashion, you eliminate that risk, making it much more practical to use this technology in the clinic.
There are still absolutely massive obstacles to using CRISPR in a clinical setting, but this is a very important step forward. It still remains to be seen how you get the CRISPR/CAS system into a cell (and other ancillary accessories specified in this work) reliably in a clinical context. Still early days, but a very important step.
Full disclosure: David Liu (the PI on this work) may be seen as a competitor to the lab where I did my graduate work.