@Yggdrasil I think you're wrong there. There are various methods developed in very recent times which have been shown to increase the fidelity of cleavage.
a Cas9-FokI nuclease combination was shown to reduce off-target effects by requiring dimerization and two gRNA sequences to achieve a DSB. My understanding was that the gRNA still served as the means of targeting the DNA, and the attached FokI domains were used as a nuclease, to replace the nuclease function of dCas9 (de-activated Cas9). FokI simply requires dimerization to act as a nuclease (see "Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing" http://www.nature.com/nbt/journal/v32/n6/full/nbt.2908.html). Within that paper it's referred to as wild-type FokI nuclease that was attached to dCas9, used on multiple sites.
My understanding is that the Zinc-finger part of the ZFN is the DNA-binding domain, FokI is simply a nuclease attached to the Zinc-finger protein (https://en.wikipedia.org/wiki/Zinc_finger_nuclease), same with TALENs, TALE is the DNA-binding domain and FokI is simply an attached nuclease. The main problem I thought was the efficacy of cutting and maybe that's where protein engineering might be needed.
Given the availability of the ZF nickase technique (where a pare of FokI dimers is converted to a nickase rather than a nuclease), if you can find further efficiency gains (as I recall efficacy is quite poor even in a Zinc finger-nickase), you could use with Cas9 to the point it would require dimerization to make a single nick - thus 4 gRNA sequences would be required to make a single DSB. You've also got the achievement of enhanced specificities through use of tru-gRNA (truncated gRNAs - reduces undesired mutagenesis some 5,000 fold http://www.nature.com/nbt/journal/v32/n3/full/nbt.2808.html), so my conclusion is that if you get these two working in concert with improvements in predictive software, you're gonna end up with Cas9 of quite a high targeting specificity.
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