Take-aways from the National Academies’ “Gain of Function” Meeting

From: CDC Public Health Image Library

From: CDC Public Health Image Library

On Monday and Tuesday I attended the National Academies’ (NAS) Potential Risks and Benefits of Gain-of-Function Research symposium held in Washington DC. The meeting was part of a US government process initiated in October that established a funding moratorium on federally funded experiments that “may be reasonably anticipated to confer attributes to influenza, MERS, or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route.”

That process also includes a review of this research by the National Science Advisory Board for Biosecurity (NSABB), and the completion of an independent Risk Assessment, supported by NIH.  (Marc Lipsitch and I published a paper in mBio this week with our views on the moratorium and the risk assessment.) The purpose of this week’s NAS meeting was to provide insights to the NIH as it considers the potential risks and benefits of this area of research.

The meeting was informative and is worth watching on the website for those with interest in these issues.  Here are 6 observations I would make coming out of the meeting:

Focus of concern - It seemed that there was a broadly held concern in the meeting regarding research that can reasonably be anticipated to create a novel respiratory virus that is both highly pathogenic as well as transmissible in a mammalian model which can predict human transmissibility. While there was no explicit voting on that issue and it was not a unanimous view, the level of shared concern was encouraging to me and suggests the potential for common ground and a path forward in the discussion. At the same time, though, some of those in the meeting who seemed to have that shared concern also seemed to continue to be supportive of the work undertaken in the last few years to engineer highly pathogenic strains of H5N1 to become transmissible in ferrets. It seems to me that these two views are inconsistent. In any event, judgments about the benefit and risks around this very circumscribed area of research are at the crux of this discussion.      

Stop using the term “GOF” - The term “Gain of Function (GOF)” is overly broad in that it includes scientific work that is valuable and does not pose serious dangers. The term GOF was first applied to this very specific research area in December 2012 in an NIH meeting on the issue. It may have been useful shorthand at the time, but it has created problems now by sweeping many types of experiments under the umbrella of the current moratorium and potential future actions in this area. “GOF” is much broader than the working definition of what I think is the area of great concern as per #1 above i.e.:  the creation of novel respiratory viruses that are both highly pathogenic as well as transmissible in mammals that are predictive of humans. For this reason, we should stop describing this work as GOF and use more precise language. Some, including Lipsitch and I, have used the term Potential Pandemic Pathogens (PPP) to describe the research area of concern. Whatever alternative language is used, it is time to change the way we discuss this.

Work that should resume - As per the comments made by prominent coronavirus scientists (Ralph Baric and Mark Denison) at the NAS meeting, no coronavirus scientists are working (or planning to propose to do work) that would create a novel coronavirus (MERS, SARS, or other) that would be both pathogenic in humans and transmissible in a mammalian model that would predict human transmissibility. Given that is the case, and given that the moratorium has led to a larger scale interruption of coronavirus research that is unrelated to PPP, it seems reasonable and prudent to end the moratorium on coronavirus related work. There is also a realm of flu vaccine development that relies on GOF techniques that do not result in the creation of PPP – that work, too, should be allowed to go forward. At the present, PPP related work would seem to be confined to highly pathogenic avian influenza research intended to confer mammalian transmissibility in ferrets (the surrogate model for human transmissibility).   

Relevance to vaccines? - Proponents of influenza PPP work described the potential benefits of the work. There is no disagreement that it can contribute to fundamental knowledge and basic science discovery. But there continued to be division in the room regarding the assertions of its other benefits, including the assertion that influenza PPP work is important in the creation of vaccines and medicines. For example, Robert Lamb said that it was time “to get rid of the mantra that GOF is necessary to make vaccines and medicines”. It was great to have Phil Dormitzer there from Novartis. But as good as he is, he was still the only one at the meeting from the vaccine industry. Given the centrality of the question of PPP relevance to vaccine and therapeutic development, more scientists from vaccine and therapeutic companies should to be part of this debate.

International implications - I thought a comment made by Barbara Johnson is worth underscoring. She said (I am paraphrasing) that other countries will follow the lead of the USG on this. If NIH funds PPP work, other countries will also pursue this work, and some of them will not be able to perform it with the same biosafety controls in place as the labs that have been funded to do this work by NIH. I think this is particularly concerning.

Accountability - We heard from Rob Weyant of CDC that if someone deliberately stole or misused one of the research pathogens at hand, they would be pursued by law enforcement consistent with the law.  But what did not get addressed in the meeting discussion is the issue of accountability should there be an accident with a PPP strain and then epidemic spread ensued. Is the scientist accountable? The institution? The local or federal government? And what would accountability mean in that case?

Finally, the panel discussion on Models of Risk Benefit Assessment was particularly useful because it helped drill into what may and may not be reasonable expectations for the risk assessment ahead. In terms of meeting participants, I was surprised by the relative paucity of leading scientists that were not directly involved in influenza and coronavirus research. Given the consequences of this debate, I would have hoped that more top scientists outside of these fields would have been invited and participated. I hope they are present in larger numbers in the debate in the time ahead. Similarly, the point was made a number of times at the meeting that there has been insufficient public input into this deliberative process. For an issue of such import, I hope that broader public engagement will occur, through inclusion at subsequent meetings and via other means of gauging public sentiment and commentary on this issue.