Roundtable Review

Colours of Biotechnology: Mutant flu – A Potential Weapon for Bioterrorism?
Posted 20 May '14

A Black biotechnology article

The dawn of genetic engineering means scientists are able to manipulate DNA, and modify the genetic sequence of organisms for their own research ends. These technologies also have the potential to be used to create biological entities for use in bio-warfare. However, the non-systematic nature of such genetic engineering has resulted in low reproducibility as well as high costs, limiting its appeal to terrorists. This looks set to change with the increasing adoption of synthetic biology and could have an impact on the accessibility of these technologies.

In recent years, the burgeoning field of genome engineering has provided us with the means to create and edit synthetic DNA in a specific fashion. DNA assembly tools such as the Gibson assembly, circular polymerase extension cloning, sequence-ligation independent cloning and transformation-associated recombination have allowed the assembly of new DNA fragments up to sizes of 580 kb, as seen in the creation of the first synthetic genome of Mycoplasma genitalium by the J. Craig Venter Institute [1]. The building blocks of a genome can be as small as a few thousand base pairs – a size that can be commercially synthesized at a relatively low cost.

This means that we can now assemble the genomes of many known pathogenic viruses such as the 1918 Spanish flu virus [2, 3]. Tumpey et al. reconstructed the Spanish flu virus in 2005 in order to better characterise this lethal strain of flu. Their work demonstrated that it was possible to synthesize functional influenza viruses from partial virus sequence data. The group hope to gain valuable insight in to its virulence from the assembled genome, to be better prepared for potential future pandemics [4].

779px-Spanish_flu_virus_TEM_PHIL_1246_lores

Transmission electron micrograph of Spanish flu virus. Source wikimedia commons. Image in public domain.

The genomes of many viruses, including that of the Spanish flu, have been made publicly available; therefore making them accessible to potential bioterrorists. The genomes of these pathogens can also be edited and their virulence increased. Fournier et al. showed in 2012 that the currently circulating H5N1 flu virus can easily mutate to become capable of human-to-human transmission via aerosol droplets [5]. Only five gain-of-function mutations (where a mutation in a gene results in a new and important function not previously seen in the virus) were needed for successful transmission in the ferrets which were used as the model of infection.

Given the ease of genome engineering, it is possible to introduce these five mutations to other strains of influenza that are found only in water fowl. A potential killer flu could be created for which there is no available vaccination or treatment. This could be a very powerful bioweapon. Moreover, it may be possible to further engineer a modified virus for maximum morbidity and mortality by tuning the virulence genes.

The publication of the detailed methodology from Fournier et al. [5] was initially blocked by National Science Advisory Board on Biosecurity (NSABB) due to bioterrorism fears. A voluntary 60 day moratorium was also held by the top forty ‘flu scientists to allow for discussion on the hazards of this research, which could be used for good or ill. Even now, the Erasmus Medical Center is fighting in the Dutch courts to revoke the need to apply for export permits before publishing their work on the mutant flu strains [6].

Could this lead to the advent of bio-warfare? There are still lines of defence against the abuse of such dual-use research. One current measure is the enforcement of careful sequence screening by commercial companies before production – companies refuse to synthesise DNA sequences matching the genome of known pathogens [8].

Genome editing of influenza virus still remains technically challenging for a few reasons: Firstly, influenza is an RNA-based virus. Most of the genome editing techniques available now are targeted at editing DNA and require a host cell with DNA repair machinery, making the production of edited RNA more difficult. Secondly, simply stitching together different components of different viral genomes may not result in a viable progeny. Building a bio-machine is not as simple as  just piecing together different DNA fragments into one whole one – the sequence context of a gene affects its expression. Thirdly, the synthetic genome may require a host cell or existing viral machinery before it can encode a living virus, especially in the case of RNA viruses. The synthetic viral genome may therefore be inert and thus incapable of being made into a biological weapon. Lastly, if a killer virus can be easily engineered, then strains that can be used for vaccine production can also equally be engineered, giving a line of defence.

Scientists argue that this research can benefit us by increasing our knowledge of these viruses. Fournier and twenty other scientists also recently proposed further gain-of-function studies on the avian ‘flu, H7N9 [7]. They hope that this will help world governments with risk assessments in public health. They noted that controversial previous work on the mutant H5N1 has led to better understanding of influenza’s host adaptation, better vaccine development and therapeutic strategies as well as better surveillance of emerging viruses.

Dual-use research is always a double-edged sword. Institutions such as NSABB play an important role in helping decide how much of the detail of this kind of research should be released, providing an extra layer of protection [9]. Moreover, publishers can also play their part in filtering information that could potentially be abused, and encourage researchers to include discussions about biosecurity issues in their papers to raise awareness within the scientific community.

One thing that the development of nuclear power taught us is that it is not the technology that creates the weapon, but the user, and allowing continual research into such fields would help also provide defence against these potential weapons. Through these in-depth gain-of-function flu studies, we can be better prepared against flu pandemics as well as the threat of bioterrorism [3,10].

References:

  1. Gibson, D.G. et al. 2008 Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome, Science, vol. 319, no. 5867, pp. 1215-1220.
  2. Endy, D.  2008. Reconstruction of the Genomes, Science, vol. 319, no. 5867, pp. 1196-1197.
  3. Wimmer, E. et al. 2009.Synthetic viruses: a new opportunity to understand and prevent viral disease, Nat Biotech, vol. 27, no. 12, pp. 1163-1172.
  4. Tumpey, T.M. et al. 2005. Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus, Science, vol. 310, no. 5745, pp. 77-80.
  5. Herfst, S. et al. 2012. Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets, Science, vol. 336, no. 6088, pp. 1534-1541.
  6. http://blogs.nature.com/news/2013/11/mutant-flu-researchers-appeal-dutch-court-ruling-on-export-permits.html
  7. Fouchier, R.A.M. et al. Avian flu: Gain-of-function experiments on H7N9, Nature, vol. 500, no. 7461, pp. 150-151.
  8. Bugl, H. et al. 2007. DNA synthesis and biological security, Nat Biotech, vol. 25, no. 6, pp. 627-629.
  9. http://www.nature.com/news/the-risks-and-benefits-of-publishing-mutant-flu-studies-1.10138
  10. http://www.nature.com/news/us-biosecurity-board-revises-stance-on-mutant-flu-studies-1.10369
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