How much expertise is it realistic to expect grant reviewers to have?

In @brembs's response to reviewer 1's feedback he's clearly frustrated that the reviewer did not have the proper expertise to review his proposal.

And I would definitely agree that in an ideal world, reviewers would only make comments in areas where they have expertise. But here's my question: in today's world, as a practical, strategic matter, how much expertise is it realistic to expect grant reviewers to have?

The same question occurred to me as I was reviewing @alexanderpico's Pathways4Life proposal. The proposal went into quite a bit of detail about gamification strategies and software implementation. And these were things I definitely appreciated — but was it wise to assume that the real reviewers at the NIH would have expertise in those areas? I'm asking the question because I don't know the answer.

And a final note: Thinklab aims to move us towards a world where grant writers can always expect experts in the field reviewing their proposals! We want experts involved because they can help grant writers actually improve the science! But given the world we live, I think there's another valuable service Thinklab can provide. We can help grant writers make their proposals more appealing to a broader audience — appealing to people with a level of expertise that we would expect the real reviewers to have.

Maybe it's a common problem that grant writers assume too much expertise from reviewers? What does everyone think?

Those are good and relevant questions that all of us have to consider when writing an application. In the end, it is hard to know who will receive the proposal, but this kind of proposal usually has a track record of being reviewed by experts in the field.

In Reviewer #1's comments were two main themes which I would expect anybody with at least postdoctoral experience in the broad field of neurogenetics to have heard about:
1) The issue of mRNA degradation vs. sequestration in the RNAi process is so basic and well-known that it is even covered in Wikipedia (besides our paper and my blog post). So it would have been both very easy and very quick to look it up in case it wasn't clear (it should have been clear!).
2) The distinction between polyclonal and monoclonal antibodies is not only basic undergraduate biology, their use in biomedical science generally is also currently hotly debated in very broad and prominent forums. You'd have to have slept through undergraduate classes and spent the last year or two in a cave, not to be aware of the differences and why monoclonal ABs are superior to polyclonal ABs.

Finally, the last major issue of Reviewer #1 was a suggestion that we had already covered in the grant, even with a figure and using different (more recent and refined) references than the one they cited. Reviewer #1 probably doesn't necessarily have to be aware of these two latest techniques we propose - that's why we mention them in the proposal and illustrate them with a figure.