I've tried to pay it forward over the years with other Church lab members, friends, and really anyone who asked. As those deadlines approach this fall, I'm getting more requests for my old apps and advice. I'd thought I'd share some of that advice here more broadly in case others might find it useful, and attach a couple of my successful applications for reference (NIH New Innovator Award and Searle Scholar Award). There is a lot of survivorship bias here and everyone's situation is different, but hopefully it will help a few folks.
1. New Investigator grants are awesome. They tend to be incredibly flexible money, and that was critical in my own lab as the projects took on many forms over the years. The New Innovator Award mechanism is especially amazing, as it provides 1.5MM in direct costs that can be used pretty much however you'd like. You do not have to spend 300K/year; You can use it for lab startup early, or backload spending as your lab grows. If you purchase equipment, you can even recover some indirects depending upon your institutional rules. They take time, but are pretty fun to write as they make you figure out the arguments for why you are doing what you are doing.
2. FWIW, I think they tend to be vanity awards, and there are high enrichment of folks with glamour pubs, and come from pedigreed labs and high profile institutions. For example, I've proposed the same idea on splicing for the K99 as I did for the DP2. I got triaged on the K99, but the DP2 sailed through after unrelated but high profile publications I published. YMMV. This is not to say you shouldn't apply, but it should set your priors on how important the idea and writing will be and the chances for getting it. There will likely be folks where idea/writing matters more and others where it matters less.
3. For these types of grants, you have to think about them differently than other grants you might have written. Basically, I made arguments that we were taking new approaches to solve important problems, why I thought that approach would be successful, and why I would be uniquely qualified to take this approach. I tried to keep mine as narrative as possible. This is more akin to your faculty application than normal grants. That means selling yourself and your history a little. This feels awkward for everyone, but you kind of have to do it. Also, the grants were based mostly on preliminary experiments and future dreams rather than a long line of published research. I think they take your track record as proof you can do what you can do, rather than all the preliminary data, super detailed experimental plans and backup ideas. They are willing to give you the benefit of the doubt at this time.
4. There are many different structures and supplementary questions that go into these grants. They take some amount of time and I never included enough time trying to answer them. I included all of those odds and ends that I had to write into the pdf's below. I didn't have a ton of examples to go from, so I have no idea if they are the right way to write them. Also, things have probably have changed since 2014. For the New Innovator, I got a few examples and people approached their structures fairly differently – there is no one tried and true rule. Do your best to convey your best story, and the rest will follow.
5. If you can get some of these grants applications timed with your exciting new papers, in my opinion it can add to your perceived momentum. You won't always have control of this, because many of these awards require you to get past your institutional allotment of applications (like the Searle). There is an art to timing these in the right order; some care about what awards you already have and what you were awarded previously, some don't. If you are super competitive, you should care about this, but otherwise I just applied whenever/whatever I could in that first year without worrying about the game theory of it.
6. Most of the ones you apply for, you won't get. I think it's probably best to treat them as good opportunities to write a fun grant, and leave it at that. Write the best grant you can and move on.
7. I'm posting these grants as I submitted them. It's a little embarrassing as there are typos that I read now that are a bit mortifying. That said, it also shows you can still get these grants even if you have such typos. I'm also attaching my Summary Statement from the DP2, in case folks read it and then look at what the reviewers said.