Preparing for the pandemic

Cross-posted from Nature Student Voices.

Is some research too dangerous to be published? Lab-made strains of bird flu have raised questions about state involvement in mitigating the threat from “dual use” research. Henry Stanley explains

In November 2011, a Dutch group succeeded in making a highly pathogenic variant of avian flu (H5N1) which, if released, could cause a global pandemic. Ever since, a storm has raged as scientists and governments worldwide attempt to deal with the findings and how they should be safely disseminated—if at all.

H5N1, the avian flu strain which caused so much concern in the past decade, is poorly transmitted between birds and humans, and its spread has been limited mostly to those who worked with infected poultry. While only a few hundred cases were confirmed, the WHO estimates that sixty per cent of those infected died from the disease. By comparison, the seasonal H1N1 virus is easily spread but rarely fatal, killing only the very young, the elderly and the infirm. This difference in transmissibility is crucial and sets the two strains of the virus apart.

Dr Ron Fouchier’s team, based at the Erasmus Medical Center in Rotterdam, have found that five mutations in two genes in H5N1 marry bird flu’s lethality with seasonal flu’s airborne transmissibility between mammals, creating a strain which its creator describes as “probably one of the most dangerous … you can make”1. The 1918 flu pandemic that killed between 50 and 100 million had a comparatively low mortality rate2, with no more than one in five infected dying3. That the new superstrain is only five point mutations away from wild H5N1 shows that the virus could easily acquire genetic changes which would make it a highly contagious killer. More concerning still, the mutations observed are all present in nature, but have so far only occurred separately in various wild strains of the virus. Genetic recombination—as occurs when an individual is infected with multiple strains of the virus—could randomly produce the ultra-lethal variant.

Another researcher, Yoshihiro Kawaoka, made a somewhat different discovery. He combined the H5 gene—a variant of hemagglutinin, the protein which allows flu virus to recognize and fuse with vertebrate cells4—with the rest of the genome from a seasonal H1N1 virus from 2009, and found that, while the new virus spread rapidly between ferrets (the model organism of choice for studying flu), it was no more lethal than seasonal flu. Importantly, current antivirals and flu vaccines were effective against it5. Before publication, Science sent Kawaoka’s draft manuscript to the US National Science Advisory Board for Biosecurity (NSABB) for counsel, as is standard practice when carrying out “dual use” research, or work which has the potential to threaten public health. The NSABB, an organization known to generally exercise a light touch when it comes to such research3, advised that the paper be altered, with experimental and genetic details redacted and released to scientists on a ‘need to know’ basis6.

The team’s work has sparked fears that the virus could be weaponized by being reassembled from the published data, amidst other concerns. The facility in which work on the virus was done is at biosafety level 3+ (BSL-3+). Critics argue this doesn’t reflect the true threat accidental release poses, arguing that maximum-security BSL-4, which demands all lab workers wear positive pressure suits and be subjected to multiple decontamination steps, be the required standard for working with such a dangerous pathogen.

Fouchier is unimpressed with the furore. He doesn’t think that an as-yet theoretical bioterrorist attack merits censorship of vital science. “Bioterrorists can’t make this virus; it’s too complex, you need a lot of expertise.” Besides which, the NSABB doesn’t properly weight the public health benefits gained from a better understanding of potential future flu strains, he says. He draws comparisons with the 1975 Asilomar Conference, in which scientists agreed to a voluntary code of conduct regarding then-emerging recombinant DNA research, except that those restrictions were agreed by the scientific community as a whole, whereas the moratorium on publishing work on mutant H5N1 is a top-down imposition7. He hopes that by developing and studying these very virulent strains we can better understand how the flu virus develops the ability to spread as an aerosol, and insists that no half-measures will do8. Moreover, the NSABB’s recommendations expose the vagaries of censoring science: who exactly ‘needs to know’? Other, less-secure labs working on H5N1 may unwittingly produce an ultra-virulent strain; these labs presumably ought to have access to Fouchier and Kawaoka’s sequence data6.

Nonetheless, Fouchier, Kawaoka and thirty-seven coauthors signed an open letter declaring a sixty-day hiatus in research on highly pathogenic H5N1 strains to provide time for the debate on the appropriateness of their work to be carried out9. Fouchier insists the moratorium is a response to the threat of the NSABB taking matters into its own hands to regulate biological research directly, and only a temporary measure as he waits for the US government to decide how best to proceed. “My preference,” he states in a recent radio interview8, “is to publish in full.” Kawaoka agrees, claiming that enough information already exists publicly to allow the production of an H5-bearing pandemic virus, and that any attempts to redact papers would be unwieldy and unworkable5.

While the number of fatalities may be small, John Oxford, Professor of Virology at Queen Mary University of London, points out that the equivalent of two million life-years were lost in the recent bird flu outbreak, mostly from young people. That more people were not killed, he says, was a direct result of the measures taken to stop the spread of the virus and of research into its mechanism8. This view, that it would be short-sighted to censor research on H5N1, is shared by many in the scientific community. Others are more guarded: Kwok-Yung Yuen, Chair of Infectious Disease at the University of Hong Kong, is well aware of the insights the work provides and the potential benefit to public health. But at the same time he believes that partly-censoring the research would at least buy time to develop and stockpile vaccines against H5N1 to pre-empt an epidemic (be it natural or man-made)10.

The January 19 issue of Nature gave a cross-section of views from biosecurity, infectious disease and global health experts. Their opinions were divided, with some calling for part-redaction, some expressing concern at lab infections and others at the threat of accidental release of virus from a secure facility10. The WHO is convening a meeting in Geneva in mid-February to which flu experts—and an NSABB representative—will be invited11. In the meantime, it is hoped a consensus will emerge in the two months before the hiatus ends.

  1. Enserink, M. Scientists Brace for Media Storm Around Controversial Flu Studies. ScienceInsider, November 2011 

  2. Taubenberger J. and Morens, D. 1918 Influenza: the Mother of All Pandemics. Emerging Infectious Diseases, January 2006; doi:10.3201/eid1201.050979 

  3. A deadly balance. The Economist, December 2011  2

  4. Goodsell, D. Hemagglutinin. PDB-101, April 2006; doi:10.2210/rcsb_pdb/mom_2006_4 

  5. Kawaoka, Y. H5N1: Flu transmission work is urgent [online]. Nature, January 2012; doi:10.1038/nature10884  2

  6. Fouchier R., Herfst S., Osterhaus A. Restricted Data on Influenza H5N1 Virus Transmission [online]. Sciencexpress, January 2012; doi:10.1126/science.1218376  2

  7. Enserink, M. Ron Fouchier: In the Eye of the Storm. Science 335 (6067): 388-389, January 2012; doi:10.1126/science.335.6067.388 

  8. Redfern, M. Material World [radio]. BBC Radio 4, January 2012  2 3

  9. Fouchier R., García-Sastre A., Kawaoka Y. & 36 co-authors. Pause on avian flu transmission studies. Nature 481, 443 (January 2012); doi:10.1038/481443a 

  10. Fouchier R. et al. Preventing pandemics: The fight over flu. Nature 481, 257–259, January 2012; doi:10.1038/481257a  2

  11. Branswell, H. Researcher at heart of bird flu studies controversy reveals details of his findings. Winnipeg Free Press, January 2012