Vagueness and Costs of the Pause on Gain-of-Function (GOF) Experiments on Pathogens with Pandemic Potential, Including Influenza Virus

Since the spring of 2012, there has been a raging controversy in scientific circles on the wisdom of carrying out so-called “gainof-function” (GOF) experiments with pathogens of pandemic potential (PPP) such as influenza virus (1). Although the phrase “gain-of-function” has been much criticized because of its inexactness, the terminology has been adopted by many, including the media, to mean experiments in which the result is a change in virulence or host tropism for a PPP. The nugget of the debate is a disagreement over the practical value of such experiments relative to the information that they produce, with opponents arguing that risk, whether from intentional release or, more likely, laboratory accidents, outweighs any knowledge gained (1). Some antiand pro-GOF experiment proponents have organized themselves into two camps, known as the Cambridge Working Group (CWG; http://www.cambridgeworkinggroup.org/) and Scientists for Science (SFS; http://www.scientistsforscience.org/), which have issued statements. However, these groups are heterogeneous, and their members have varied views on the problem. We have both signed the CWG statement, and one of us (M.J.I.) has also cosigned the SFS statement, because while we both see important benefits for GOF work involving PPP, we are nonetheless concerned about safety issues, and most importantly strongly support the common call for discussion. However, neither of us has supported the idea of a moratorium on this type of research (1, 2). In October 2014, the White House announced that the U.S. Government (USG) was implementing a “pause” of new funding for research involving GOF experiments with three respiratory viruses, influenza virus, Middle East respiratory syndrome (MERS) coronavirus, and severe acute respiratory syndrome (SARS) coronavirus, if that research could be “reasonably anticipated” to result in enhanced pathogenicity or increased transmissibility (3). They also asked that ongoing experiments which fall into this category be voluntarily stopped. During the pause, the USG has asked both the National Science Advisory Board for Biosecurity (NSABB) and the National Academies to engage in discussions aimed at determining how to assess the risks and benefits of GOF research. We ourselves have been calling for such deliberations and welcome that aspect of the White House announcement (1). The events at the Centers for Disease Control and Prevention (CDC) this summer, in which a highly pathogenic avian influenza strain was accidentally shipped to a U.S. Department of Agriculture (USDA) laboratory and in which Bacillus anthracis spores were taken out of a laboratory without proper disinfection, heightened concern both in the scientific community and in the public about whether research with dangerous pathogens is being carried out with appropriate safety measures in place. These accidents, together with a growing chorus of scientists who are worried about GOF experiments (4), seem to have precipitated the government action. Pauses and moratoriums are blunt instruments in science and carry the potential for unintended consequences. We recognize that the pause is a response from well-meaning government officials who are tasked with trying to find ways to minimize potential dangers from GOF experiments. We note, however, that depending on which interruptions of work are counted, this is at least the third pause/moratorium in this field, with the first being voluntary, the second requested by the USG (5, 6), and the third being the current pause. We have numerous concerns with this third stoppage, including the timing of the announcement relative to the ongoing debate, the vagueness in the wording of the statement, and the potential effects on the fields of influenza virus and coronavirus research. Each concern will be discussed separately. The timing of this pause is perplexing given that one might have expected this action to follow a concerted effort to explore the issues rather than to precede detailed discussions. Many have drawn the analogy between the current situation and that surrounding the advent of recombinant DNA technologies. However, there are significant differences: the discussions at Asilomar preceded a self-imposed moratorium by molecular biologists working on recombinant DNA technology (7). It seems that this should have been the case now: the NSABB could have been deliberating on this topic in the 2 years that have passed since the GOF debate began with the publication of two manuscripts describing mammalian transmission of H5N1 influenza virus (8, 9). Instead, the NSABB did not even meet, and this created a vacuum of discussion that may have contributed to the current crisis. In contrast, the government has responded to the heightened controversy by reactivating the NSABB while simultaneously calling for a pause of GOF work before a meaningful discussion. Although this course of action seems to emphasize safety and caution, it carries significant risks that we discuss below. It is also unclear to us why the pause is necessary, given that the government is already presumably providing an extra layer of review of GOF experiments that followed the prior moratoriums (http://www.phe.gov/s3/ dualuse/Documents/us-policy-durc-032812.pdf) and has asked