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Thursday, 08 December 2016 19:41

Responding to Zika Critique

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The apparent disarray of a Zika virus laboratory is belied by an underlying order. The apparent disarray of a Zika virus laboratory is belied by an underlying order.

In the last installment of Zika Diaries, I wrote about our disappointment on not receiving a good score on our NIH grant application. We are planning on resubmitting the proposal, and to do that we must address the criticisms of the reviewers. I have gone through this process many times, and it is important to remain level-headed and not insult the reviewers. Here are some examples of what I am thinking in response to the reviews, and the words I will actually send to NIH.

When resubmitting a grant proposal for reconsideration, the first page consists of how the applicant addresses the comments of the reviewers. I have reviewed many revised grant applications over the years, and I have written many myself. Most of them begin in this way:

"We thank the reviewers for their insightful comments, which have helped us to prepare a stronger and more focussed application."

What we really mean is the following:

"Most of the reviewers points are either misinformed or irrelevant to the proposal, and demonstrate a lack of familiarity with the field and a failure to carefully read what we have written. We thank the reviewers for delaying funding of our work."

Let's move on to our application to study Zika virus neurovirulence. One set of proposed experiments involves an isolate that does not replicate in the mouse brain. We had proposed to study the mutations in this viral genome that cause a loss of neurovirulence. One reviewer did not like these experiments and wrote that this isolate has been passaged extensively in mice and its loss of neurovirulence might reflect its passage history and not its authentic neurovirulence.

Here is the response I'd like to write:

"Apparently the reviewer has either not read the extensive literature on viral neurovirulence, of if he/she has read it, does not understand its implications. If he/she had been familiar with this literature, he/she would not have made such an obviously uninformed statement."
Here is what we will actually write:

"A common approach to studying viral determinants of neurovirulence is to passage viruses in different hosts until this property is reduced or lost. The mutations that accompany such attenuation can be identified, providing insight into the mechanisms of neurovirulence. An excellent example is the attenuated Sabin strains of poliovirus vaccines, which were produced by passage in animals. The study of these viruses in our laboratory and others has lead to great insight, over the past 30 years, on the basis of poliovirus neurovirulence."

Another criticism of our application was our proposal to develop infectious DNA clones of Zika virus isolates. The reviewer wrote that we did not provide sufficient experimental details, including the possibility that infectious clones cannot be obtained.

Here is the response I’d like to write:

"Are you serious? One of the principal investigators of this proposal, Vincent Racaniello, developed the first infectious DNA clone of an animal virus in 1981, and has since published many others. You think he doesn't know how to do this? Plus, four different labs have published on infectious DNA clones of Zika virus in the past year—so obviously it can be done!!"

Here is what we will actually write:

"We appreciate the reviewer's concern about our ability to produce infectious clones of Zika virus isolates. We do not believe that this goal will be a problem, as the co-principal investigator, Vincent Racaniello, has extensive experience in producing such reagents, and four laboratories have reported the development of infectious DNAs of Zika virus in the past year."

The last criticism is the most galling: the reviewer wants to know how to extrapolate our studies in mouse brain cultures to human infections.

Here is the response I'd like to write:

"Since when are results obtained in animals assumed to extrapolate to what is found in humans? Have you never heard the saying, 'mice lie, monkeys exaggerate?' They are called animal 'models' for a reason: they model aspects of a viral disease. Without animal models, our understanding of the basics of how viruses cause disease would be very limited."

Here is what we will actually write:

"Results obtained in animal models cannot be extrapolated to humans. However, our findings will provide information on how Zika virus damages the brain, and the results can be used to interpret observations of damage in human Zika virus infections."
Those of us working in scientific research often receive critiques of our grant applications or papers that we submitted for publication. In most cases it's necessary to respond to these critiques to obtain funding or to publish a paper. I'm sure that the responses that many of us provide are quite different from what we are thinking.

Last modified on Friday, 09 December 2016 13:00
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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