>Why is that the case? And are there any promising theories for how we might overcome that problem? I am still quite new to CRISPR so I am unsure what people a

>Why is that the case? And are there any promising theories for how we might overcome that problem? I am still quite new to CRISPR so I am unsure what people are doing to solve this problem. As for why, I would say that the problem is that, like most proteins, Cas9 just bounces around using brownian motion and there is always just some probability of it being near the wrong piece of DNA at the right time. There's not much that can be done about that! However, we can do something about Cas9's binding affinity to sequences that are similar, but not idetnical, to the target sequence. One could imagine Cas9 binding (with lower affinity) to a sequence of 20 bases that is incorrect on a couple of bases. Indeed, much of the off-target effects come from this. So if one could modify Cas9 to only bind to the exact sequence that should reduce off-target mutations.