Big 5 questions anticipating Mitalipov human embryo CRISPR paper

The human embryo CRISPR paper with Shoukhrat Mitalipov as senior author is coming soon.

It will reportedly be focused on the use of CRISPR to genetically modify viable human embryos for reversal of a disease-associated mutation. While strangely press already broke early on this paper last week, as much as a week before the paper comes out, and that press suggests very positive data, how clear will that be from the paper itself?

Here are some ideas on the big 5 questions (some include nested questions) likely to come up from this now eagerly-anticipated paper:

• 1. How much residual off-target activity was there and if it was very low, how was that achieved? How low does it have to be where someday this hypothetically could be used for actual reproduction with a strong expectation of safety and efficacy? Was WGS done on many embryos to look comprehensively for unpredicted off-target activity?
• 2. At the target site, were indels ever created instead of the desired precise edits?
• 3. Is the goal of Mitalipov and the larger team on this paper to actually use this approach in the germline for heritable human gene editing within say 5 years? If so, how will it be limited to just that and not other applications such as infertility or trait modification? What kind of ethics review went into this paper and how does it compare to the NAS report on human gene editing?
• 4. Will others use this paper as a foundation to argue for a more permissive policy on human germline edits?
• 5. And/or conversely will there be a political reaction here in the US (and maybe elsewhere) leading to restrictions on human CRISPR research or other areas of innovative research in the US?