REPOST: Structure Of An R01: Background and Significance

Reposted upon request of a dear friend of the blog.
In our first installment of a series on structuring an NIH R01 research grant application, we discussed in detail the first section: the Specific Aims. The Specific Aims page encapsulates the entire gist of the grant in one page, and if that is all a reviewer reads, they should feel all excited and jazzed about what you propose, or your grant is doomed.
In this post, we discuss the next section following the Specific Aims, the Background and Significance. The Background and Significance is designed to set the context for the proposed studies in terms of what is already known in the area of proposed inquiry, what key open question(s) are important, why they are important, and how the approach(es) of the proposed studies are highly suited to addressing the open question(s).

For a 25 page R01 application, a reasonable Background and Significance section will be about four or five pages, and will contain three or four figures. (Since the R01 is going to most likely become a 12 page application at some point in the not-too-distant future, just take the quantitative aspects of the advice given here and divide by 2.) This section will be divided into subsections, each of which should be headed with a substantively descriptive title.
Roughly the first page is used to lay out the most broadly conceived biological (or medical, in the case of non-basic-science proposals) context for the proposed studies, starting with the foundation of the entire field. So, if your application relates to some molecular/cellular hypothesis concerning the role of a particular signaling protein in growth-cone-mediated axonal guidance in the developing nervous system, you would start by laying out that the adult nervous system has a very complicated wiring structure, and in order to set that structure up, neurons in the developing nervous system need to send their axons to the right destinations. Then you would say that the growth cone is a specialized cellular structure that implements this navigational problem. And then you would talk about the basics of growth cone function broadly. So this subsection could be entitled “Axonal Guidance in the Developing Nervous System”.
It’s good to use schematics or model figures in the Background and Significance, as a picture is worth 1000 words. Also, you are permitted to use a smaller typeface in your figure legends than in the body text of the application! In this case, the first figure might show some axonal growth cones wending their way through the brain, or whatever.
Then over the next couple pages, you gradually become more specific about the current cellular and molecular understanding of how growth cones actually implement navigational decisions through the developing nervous system. Here you might have a schematic of the growth cone itself, showing the cellular and molecular components that make the growth cone work: cell adhesion and recognition molecules, cytoskeletal components, signal transduction components, etc. This gradual narrowing over these couple pages should end finally in a clear explicit statement of the unanswered question that arises out of the existing work in the literature. Like, “What is the role played by the cell adhesion molecule ZX-CAM in growth cone guidance?” And you also have to have made it very clear why this is an important question to address.
The headings of this section could include “Cellular and Molecular Basis of Growth Cone Navigation”, and the most specific final section could be “ZX-CAM Function in Growth Cone Navigation”
The next page to page-and-a-half should be devoted to providing methodological background, again illuminated with a schematic figure or two, and divided into titled subsections, one subsection for each technique. If you are using established techniques, explain them through reference to the literature, and explain how they are applicable to answering the important question you posed. If you are proposing the use of a novel technique–which, in general, is a good thing to be doing from a “sex-appeal” standpoint–then explain how the technique is envisioned to work (with a schematic) and would, in the ideal situation, be highly applicable to the important question you posed.
In either case, you refer forward to the Preliminary Studies, where you will be providing direct experimental evidence that the chosen approaches will be effective at answering your important question: “As will be described in detail in the Preliminary Studies section, we have validated the applicability of the blah technique for addressing the whatthefuckever question.”
Then, the most important subsection is the last paragraph of the Background and Significance, entitled “Summary of Background and Significance”. This subsection should be a completely self-contained summary of the entire argument of the Background and Significance, with each paragraph (roughly) encapsulated into a single sentence. So, you restate the general area of inquiry, why the specific important question to be addressed is important, what the chosen approaches are and why they are applicable.
This final Summary paragraph then ends with one or two special sentences, depending upon if you are proposing the use of a novel technique that you have developed for addressing your important question. If not, then you end with a sentence that explains why your proposed approach and model system is uniquely suited to addressing the important question, and why the results will be relevant in a broader context.
If you are proposing the use of a novel technique that you have developed, then you follow that sentence with a sentence explaining how your novel technique will also be applicable in a substantially broader context than just your particular important question.
And remember, every single word you write in this section (actually, the whole fucking grant) should be directed towards establishing that your question is important and your approaches are uniquely suited to answering it.