Field of Science

Are we innovative yet?

NIH wants its applicants to use somewhere between half a page and a full page of the 12-page proposal to explain how their proposals are innovative. Here's NIH's instructions:
  • Explain how the application challenges and seeks to shift current research or clinical practice paradigms.
  • Describe any novel theoretical concepts, approaches, methodologies, instrumentation, or intervention(s) to be developed or used and any advantage gained.
  • Explain any refinements, improvements, or new applications.
Other advice, from Jeffrey Benovic and Bruce Freeman):
  • Significance is why the work is important to do.
  • Innovation is why the work is different from (better than) what has been done before.
  • Definition of innovation: a new device or process resulting from study & experimentation; the act of introducing something new.
  • How will research in your field change as a result of your work?
  • Demonstrate the potential gains are not merely incremental.
  • Explain why concepts & methods are novel to one field or novel in a broad sense (or both).
  • Summarize (sans detailed data) novel findings to be presented as preliminary results in Approach
  • Focus on innovation in study design & outcomes
Morgan Giddings also emphasized describing specific ways the field will be different if our work is funded and successful.

The field is recombination (in its broad sense, everything from the molecular mechanisms to the evolutionary consequences), and we're going to fully characterize recombination between related strains. That is, we're going to find out (i) the properties of the recombination tracts and (ii) the probabilities of recombination for ~all differences between the strains. This will be done using deep sequencing of single and pooled recombinant genmes, and will give an extremely comprehensive picture of recombination across the ~40,000 snps and 300 indels and rearrangements that distinguish these two strains. Then we're going to use recombination to map genes responsible for the very low transformation frequency of one of the strains.

I've been making lists of things that are innovative about what we propose, but what's lacking is a coherent narrative that ties them together. So I'm going to just start listing them here and see if a narrative comes together...
  • This will be the first time that all of the recombination of a single recombinant genome (from a single transformation event) has been identified for any organism. And we're going to do it many times (50? 100?). Maybe include actual numbers - how many recombination tracts do we expect to characterize? how many breakpoints? Relate to how many actual recombination tracts have already been characterized (I'd have to dig into the literature...)?
  • By using deep sequencing to measure the frequency of recombination at tens of thousands of SNPs and indels we will characterize the full spectrum of sequence factors affecting recombination. The scale will be unprecedented. How many SNP-conversion events do we expect to detect? How many indel-conversion events?
  • We are breaking down the previously necessary tradeoff between high resolution and broad scope. Deep sequencing of tine genomes lets us have it all!
  • We will develop new analytical tools, to analyze recombinant genomes.
Paragraph about Aim III:
  • Nobody else is focusing on the causes of the poor transformability of many strains of 'transformable' species.
  • Will use genome sequencing of recombinants with altered transformability to identify recombination tracts carrying the responsible alleles. This may seem wasteful but is very efficient; one lane of sequencing (even without multiplexing) is likely to define a stretch of no more than 1 kb. (If the difference is a snp and not an indel - we should have done the phenotyping! This is a pitfall we need to write about.)
  • This will (we think) be the first time that the QTL mapping methods used for eukaryote genomes are applied to bacteria. (Is this right? We need to clarify the relationship between QTL mapping and sequencing. Is anyone sequencing recombinant genomes of yeast?) They were developed out of necessity for the very large eukaryote genomes, but, now that sequencing bacterial genomes is so cheap, are very efficient when applied to bacteria that lack the sophisticated genetic tools available for E. coli and B. subtilis. We're one of the first to start using deep sequencing to replace conventional molecular biology analysis (well, 'one of' is a cop-out as I don't really know...).
Maybe the narrative could reflect/reinforce the narrative of the Specific Aims and Significance sections: "Haemophilus is bad, recombination is devaluing our only weapons (vaccines and antibiotics), but finding out the ground truth about between-strain recombination can let us better predict and prevent it." Or at least emphasize that we're applying this innovation to a pathogen

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