I strongly disagree with the implication that an adequate assessment of the risks and benefits was undertaken, and strongly disagree with the statements made by your DURC committee. This paper should not have been published.

To suggest that poxviruses are no different from influenza or polio, and therefore that the details provided here "provided no new information" [about the synthesis of smallpox], is at best misleading, and better characterized as simply wrong. I could list for you the details provided in this paper that will substantively assist those with lesser degrees of experience to synthesize smallpox. The Committee mentioned compliance with relevant regulations. Which regulations are these, and how are they relevant and specific to this work at the University of Alberta? The so-called 'forthcoming' behavior in communications consisted of a presentation to the WHO Advisory Committee of a 'fait-accompli'. To my knowledge, there was no request for guidance before the work was undertaken. And the alleged benefits from this work simply do not hold water. This work was not needed or particularly helpful towards an improved vaccine.

What I find particularly inappropriate and frankly, unethical is that this paper with its obvious risks to public health was funded by and written by a for-profit, private entity (Tonix) that stands to gain money from this work and this paper. And the authors co-founded and consult for this entity and stand to make money from it. The conflicts of interest are obvious: the public health was put at risk by a private entity and a set of author-business partners who stand to gain financially from this work. This is wrong.

This article, which reports the first ever de novo synthesis of horsepox virus, a member of the orthopoxvirus family of viruses that includes the variola virus that causes smallpox, crosses a red line in the field of biosecurity. 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 the virus which was 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.

Given the high degree of homology between orthopoxviruses, the techniques described in this article are directly applicable to the recreation of variola virus. I have previously analyzed the biosecurity risks posed by the unregulated development of capabilities to synthesize orthopoxviruses: http://online.liebertpub....
Given the serious potential risks that this research could be used to recreate variola virus, the blanket assertion of 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 US 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. 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 they have more evidence to support their risk-benefit assessment, then they should present it for public scrutiny.

The committee’s central claim is that this 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).” This is not an accurate assessment. 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 not accurate 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 kbp) is much larger than that of either polio virus (7.5 kbp) or influenza (about 13 kbp) 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 the infectious virus needs to be reactivated with the assistance of a “helper 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 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. We should not be comforted by the fact that they didn't actually synthesize variola--the techniques described in this article are a blueprint for doing exactly that.

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 vaccine called Dryvax 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 vaccine stockpile and has no interest in developing a new smallpox vaccine. 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 this journal to exercise its responsibility to carefully consider the biosecurity implications of the research it publishes.

Gregory D. Koblentz
Associate Professor
George Mason University