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Thursday, 17 November 2016 13:15

Zika Critique

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Mouse embryo brains1
Brains from 15 day old mouse embryos. Photo credit: Amy Rosenfeld.

In the last column I wrote of our first unsuccessful attempt to secure funding for our work on Zika virus. Since then we have received the reviewers' comments and now we can determine what they did not like.

Applications for research support under the NIH R21 mechanism are reviewed by a study section consisting of ~20 experts in the field. Our application, entitled 'The neurovirulence of Zika virus isolates', was reviewed by three individuals who prepared written critiques. Each reviewer scores (from 1-9 with 1 being the best) the grant application in five different areas: significance, investigator qualifications, innovation, approach, and environment. After the entire panel votes on the scores, the final impact/priority score is calculated by averaging the numbers and multiplying by 10. Currently proposals that are scored over 30 are not funded; ours received an impact score of 41.

Two of the three individuals assigned scores of between 1 and 3 for each of the five different areas; they were enthusiastic about the proposal and had few criticisms. Unfortunately the third reviewer did not like the proposal and scored it from 2-6 in the five different categories. 

The goal of our proposal was to study the neurovirulence of different Zika virus isolates in brain slice cultures from embryonic mice. We wish to understand how the virus affects brain development, and whether Zika virus isolates differ in their ability to disrupt the brain.

The main criticism from the negative reviewer was that it is not clear how results obtained in mice would apply to humans. If this criticism were valid, then no virologist would be using animal models to study viruses that cause human disease. They are called 'models' for a reason: the findings might or might not be predictive of what happens in humans. But animal models are invaluable because experimental infections of humans with viruses are not done except with a few viruses that cause little or no disease. Furthermore, experiments in animals can reveal mechanisms of pathogenesis which might be validated by observations of natural infections in humans. 

We were also dinged for providing insufficient detail on potential problems and how they would be solved. We did include some anticipated difficulties, but could not possibly include all of them due to space constraints: the R21 is limited to 6 pages. 

Apparently we did not include sufficient experimental details about the construction of infectious DNA copies of the Zika virus RNA genome, and a discussion of what we would do if we could not make this reagent. I found this criticism amusing: I was the first investigator (1981) to construct an infectious DNA copy of an animal virus genome, and I have since made many others in my laboratory. Furthermore, several laboratories have already reported the construction of infectious DNA copies of the Zika virus genome. Given the page limitations of today's NIH grant applications, it's not realistic to expect detailed descriptions of all protocols, especially not the ones for which the applicant has demonstrated expertise!

We will address all of these criticisms and resubmit the proposal with new data. I hope my description has provided some insight into the process of obtaining financial support for research here in the US. It is not the first time I have obtained negative reviews of a grant proposal, and it won't be the last time. Sometimes the critiques help you craft a better proposal, and sometimes they are unfair. For better or worse, that is nature of the system that we have, and if you want to do science research in the US, you have to deal with it.

Last modified on Thursday, 17 November 2016 15:06
Vincent Racaniello

Vincent Racaniello is a virologist at Columbia University and science communicator. He is using Zika Diaries to communicate the personal and behind the scenes experiences of his laboratory as it moves from working on poliovirus (for 35 years) to Zika virus.

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