Friday, 9 August 2013

The +Func H7N9 proposal...is there such a thing as Loss of Function experiments?

As I noted earlier today - VDU declares Gain of Function day (+Func), reflecting the release of an open letter declaring the intentions of leading influenza researchers to seek approvals to conduct experiments on avian influenza A(H7N9) virus. These include changes to the virus which would likely create 1 or more related, but new, and possibly much better replicating and transmitting viruses. As best we can tell, normal viral evolution has not succeeded in doing this for H7N9-and may never.

The authors note their main regions of study would be:


  • Examining whether genetic changes affect H7N9 immunogenicity 
    • Such changes could ruin future vaccine efficacy
  • Determining the ability of H7N9 to reassort into a more effective pandemic virus
  • Evaluating and identify drug-resistance mutations and evaluate therapies
    • See how long-lived drug resistance mutations are, and gauge their likelihood of affecting viral fitness
  • Performing transmission studies using "circulating strains", identifying genetic changes that exist in the better spreading strains
  • Examining reassorted viruses and viruses with altered hemagglutinin (HA) cleavage sites to see how much more pathogenic the changes make H7N9.
I don't know what to think about all this as I can see both sides of the argument. I can't venture a clear opinion because I'm not informed enough. 

As an example of that, I wonder if it would be possible to achieve some of these goals by taking what we now know to have once been a good pandemic influenza virus, and try "Loss of Function" (does such a thing exist?) studies. Essentially, work backwards from an influenza A virus with antiviral resistance, and devolve to the mutations & segments that H7N9 have now, that supposedly constrain it's pandemic potential. Return the virus to a more zoonotic state if you will. 

I know, its not the same thing. For one thing, you won't be able to track the things you don't yet know about - those mutations can probably only be found once they appear (whole-genome sequencing tech will find them), when moving forward in time. However, a "-Func" approach might tick some of the same boxes, while generating less concern for the human creation of novel viruses with pandemic potential. Like I said - I'm not informed enough.

In a sense, Fouchier, Kawaoka and colleagues have written to us and opened a door so we can peek inside and see what's coming. I think they deserve respect for that. 

Lets make use of it and join in a debate, or at least an exchange of ideas. Perhaps someone out here has experienced constructive advice to offer that could address the experimental questions the team define, but in other ways that would be less concerning?  Or have the authors already considered those approaches?

For some more eloquent thoughts and reactions to the Letter and the need for the research, try CIDRAP, Science and Nature's comments. For some background on so-called Dual Use Research of Concern (DURC), try Laurie Garrett's video.