The Synthesis of Horsepox Virus and the Failure of Dual-Use Research Oversight

On January 19, 2018, the open access scientific journal PLOS One published an article that describes the de novo synthesis of horsepox virus, the first ever synthesis of a member of the orthopoxvirus family of viruses that includes the variola virus that causes smallpox. As I have written about before, this research crosses a red line in the field of biosecurity. Given the high degree of homology between orthopoxviruses, the techniques described in this article are directly applicable to the recreation of variola virus. The synthesis of horsepox virus takes the world one step closer to the reemergence of smallpox as a threat to global health security. That threat has been held at bay for the past 40 years by the extreme difficulty of obtaining variola virus which has been eradicated from nature and is only known to exist in two WHO-designated repositories.

The reemergence of smallpox would be a global health disaster.  Prior to its eradication, smallpox killed an estimated 300 million people, more people than all the wars of the 20th century combined. Most of the world’s population is susceptible to this lethal and contagious disease since routine immunization against smallpox was discontinued after the success of the WHO’s global eradication campaign.

Per its policy on dual-use research, PLOS convened its Dual-Use Research Committee, composed of PLOS editors and outside experts, to review the manuscript. According to a statement from PLOS,

“The Committee was asked to consider the potential risks of this research, notably the risk that the study might provide new information which could be misused to construct a smallpox virus. They concluded that the study did not provide new information specifically enabling the creation of a smallpox virus, but uses known methods, reagents and knowledge that have previously been used in the synthesis of other viruses (such as influenza and polio viruses). In consideration of the benefits of publication of the research, especially the potential for improvements in vaccine development, the Committee unanimously agreed that in this instance, the benefits of publication outweigh the risks. The Committee therefore supported publication of this manuscript.”

Given the serious potential risks that this research could be used to recreate variola virus, the blanket assertion by the PLOS Dual-Use Research Committee that the benefits of this research outweighs the risks is woefully insufficient. The committee dramatically understates the risks and overestimates the benefits this research presents. The U.S. government has outlined a number of factors to consider and questions to ask about dual-use research when weighing the risks and benefits of conducting and publishing such research. Although this research did not fall under current U.S. regulations on dual-use research of concern, the authors and publisher were well aware of the risks that I and others had raised and they had an ethical responsibility to carefully consider those risks before publishing the article. Based on the statement issued by PLOS One, it does not appear that this committee tried to answer these questions in a rigorous way. If the committee has more evidence to support their risk-benefit assessment, then they should present it for public scrutiny.

The committee’s central claim, “that the study did not provide new information specifically enabling the creation of a smallpox virus, but uses known methods, reagents and knowledge that have previously been used in the synthesis of other viruses (such as influenza and polio viruses),” is misleading. In fact, the article describes how the authors overcame several obstacles and challenges to synthesizing the horsepox virus, including design of the cloned synthetic DNA fragments, modification of the DNA fragments to aid genome assembly, design of synthetic hairpin telomeres based on vaccinia DNA, and the use of a “helper virus” to reactive infectious horsepox virus. Based on these original contributions to the science of orthopoxvirus synthesis, it is difficult to understand how the committee could claim that this article does not provide new knowledge about how to successfully synthesize other orthopoxviruses such as variola.

Furthermore, it is misleading for the committee to claim that this study uses only “methods, reagents and knowledge that have previously been used in the synthesis of other viruses (such as influenza and polio viruses).” This claim is an attempt to downplay the technical feat accomplished by this paper: the largest ever viral genome to be synthesized chemically. The horsepox virus genome (212,000 base pairs) is much larger than that of either polio virus (7,500 base pairs) or influenza (13,500 base pairs) which necessitated special steps to obtain and assemble the large DNA fragments required to create the complete genome of horsepox virus. In addition, unlike polio virus, the naked DNA of horsepox virus is not infectious and requires the assistance of a “helper virus” to recover infectious virus. While this reactivation technique has been used previously with vaccinia, it has never before been used to reactivate horsepox virus or a synthetic orthopoxvirus.

Given the high degree of homology between orthopoxviruses, it is also not accurate for the committee to claim this study does not pose any risk because it “did not provide new information specifically (emphasis added) enabling the creation of a smallpox virus.” Even the authors of the paper have publicly acknowledged that these methods are directly applicable to the synthesis of variola. Professor David Evans ,who led this research at the University of Alberta, told the World Health Organization that his synthesis of horsepox virus “was a stark demonstration that that this could also be done with variola virus.” We should not be comforted by the fact that the authors didn’t actually synthesize variola–the techniques described in this article are a blueprint for doing exactly that. Given the weak and patchy safeguards on ordering synthetic DNA, this research creates a new pathway for the acquisition of variola virus and a new vulnerability for global health.

Finally, the committee does not provide any evidence supporting its claim that the study’s “potential for improvements in vaccine development” provide tangible benefits sufficient to outweigh the very real risks that this research represents. The authors of this article justify their research based on the need for a safer smallpox vaccine. This justification is disingenuous. The safety issues that the authors refer to emerged during the 2002-2003 smallpox immunization campaign in the United States when the first-generation Dryvax smallpox vaccine caused an unexpected number of myopericarditis events. The United States now stockpiles a third-generation smallpox vaccine called IMVAMUNE that does not have the cardiotoxicity side effects of earlier smallpox vaccines. IMVAMUNE is even safe enough to give to people with compromised immune systems. Furthermore, the United States is prioritizing its limited biodefense dollars on improving the existing smallpox vaccines and has no interest in developing a brand new smallpox vaccine. Indeed, last year the Department of Health and Human Services signed a contract worth up to $532 million to procure up to 132 million more doses of a freeze-dried version of IMVAMUNE. Without U.S. government funding for research and development, there is no viable business model for getting a horsepox-based smallpox vaccine through the “valley of death” in the drug development process and turning this research project into a licensed medical countermeasure.

Based on these considerations, the horsepox synthesis research is all risk and no reward. Given the known risks of this research for pioneering a technique that can be used to recreate variola virus and its questionable benefits, the publication of this article represents a failure of PLOS One to exercise its responsibility to carefully consider the biosecurity implications of the research it publishes. Other journals had rejected this article, at least in part due to concerns about the biosecurity risks it posed. At the same time, as Tom Inglesby at the Center for Health Security has pointed out, this article was also made possible by fundamental flaws in the dual-use research oversight system in the United States. Unless those flaws are fixed, the dual-use oversight system will be relegated to monitoring a shrinking slice of the life sciences research enterprise which will decrease our ability to govern emerging technologies and increase our vulnerability to the misuse of biotechnology.

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