LAUSR

On January 19, 2018, a paper describing the complete synthesis of a horsepox virus was published in PLOS ONE [1]. This is the largest virus assembled to date, and it shows that no viral pathogen is likely beyond the reach of synthetic biology. The paper and reports of its contents have attracted much comment [2–4]. As the two authors who conducted these experiments, we thank PLOS Pathogens for giving us the opportunity to address some of the issues arising from this work. At the heart of the discussion lies the fact that this is dual use research of concern (DURC) [5] because any method that can be used to assemble horsepox virus could be used to construct variola, the virus that causes smallpox. This renders our work of special relevance for the agencies tasked with ensuring that smallpox remains a disease of history. Although the world’s known variola stocks are securely stored in Russia and the United States, synthetic biology compromises this approach for securing any agent. This was shown by the reconstruction of poliovirus in 2002 [6] and has been discussed within WHO [7]. Whether secret or lost [8] stocks of variola virus still exist is unknown, but countermeasures are still stockpiled because of this recognized threat. If one looks at the opinions that have been expressed about our work, an important point concerns the possibility that it provides instructions for making variola. For good or ill, the world is full of talented scientists who do not need a blueprint to extract knowledge well described in published works [7, 9–11]. This includes papers showing how to assemble a bacmid encoding herpes simplex virus [12] and how to recover vaccinia virus (VACV) from a bacmid [13]. This does not mean this technology is still easily implemented. It is not. All modern “methods” sections omit details familiar to experts. Although variola virus DNA has been recovered from historical specimens [14, 15], it is not accessible by “mail order” [16]. The design work is tricky, 30 kbp plasmids are unstable, and the assembly reactions are inefficient. The skill set needed to do this work requires advanced scientific training, insider knowledge, and infrastructure that is not widely accessible. Our interest in testing horsepox virus as a potentially safer vaccine was prompted by phylogenetic [17–19] and historical [20–24] evidence suggesting that smallpox vaccines might have originated in horses. Considering the evidence of actual efficacy [22, 24], could a horsepox virus still serve this purpose? Gene synthesis offered a route for obtaining the virus while also providing commercial freedom to operate. But do we still need another smallpox vaccine? There is no short or simple answer to that question, although the Russian and American collaborating centers have reported to WHO that their variola stocks are still being used for ongoing vaccine research [25]. Given this lack of consensus, it seems reasonable to explore other options when considering how best to periodically replenish vaccine stockpiles.