COMMENTARY: Six policy options for conducting gain-of-function research

Dr. Lipsitch is professor of epidemiology and director of the Center for Communicable Disease Dynamics at Harvard TH Chan School of Public Health, Boston. Dr. Relman is the Thomas C. and Joan M. Merigan Professor, and co-director of the Center for International Security and Cooperation at Stanford University, Stanford, Calif. Dr. Inglesby is associate professor, University of Pittsburgh Schools of Medicine and Public Health, and director, UPMC Center for Health Security, Baltimore.


 

A meeting at the National Academy of Sciences (NAS) this week presents a tangible opportunity to spell out concrete steps for research that alters pathogens—and we mustn't let it pass by. We offer several approaches for moving forward.

Policy at a turning point

The NAS meeting marks a turning point in a year-and-a-half-long policy process to consider the risks, benefits, oversight, and regulation of experiments that are designed to create influenza and other viruses that are simultaneously highly virulent and readily transmissible by respiratory droplets between mammals.

Such viruses, which have been called potential pandemic pathogens (PPPs), raise the specter that accidental release or deliberate misuse could spark a widespread epidemic, perhaps global, transmission of a novel and highly lethal virus. Advocates counter that there are scientific and public health lessons to be learned from the results of such experiments that justify the risks involved.

Announced by the White House in the wake of a number of high-profile incidents involving dangerous pathogens in US government labs, this policy process has involved the highest levels of government and scientific organizations, including the National Science Advisory Board for Biosecurity (NSABB) and the NAS. The issue is international, and high-level discussions have occurred in Europe as well.

In the United States, attention has been focused on delineating the risks and benefits of many different kinds of "gain-of-function" (GOF) experiments involving genetic alteration of influenza and other viruses. A consensus seems to have emerged that a very small subset of these experiments—those expected to produce viruses combining high lethality and high transmissibility—pose the greatest risk and deserve special attention, with some arguing for regulation. These experiments have been termed "gain-of-function studies of concern" (GOFoc) by the NSABB. 

The NAS meeting on Mar 10 and 11 is an opportunity to move toward a resolution of the policy challenges posed by GOFoc. The meeting's agenda opens with discussions about the findings of a risk-benefit assessment (RBA) of GOF research commissioned by the NSABB and of the NSABB's response to this assessment. The RBA, prepared by a private contractor, Gryphon Scientific, was not intended to discuss policy options, and the current draft of the NSABB report makes no concrete proposals on the salient question of whether GOFoc research should be resumed and how it should be regulated.

We see that as a problem.

Several possible approaches

We urge the conveners and speakers at the NAS meeting to address this question head-on. A number of policy approaches have been put forward in various forums. Among the possible approaches are the following:

1. Lift the moratorium on GOFoc, which has covered about 11 National Institutes of Health (NIH)-funded projects, and resume US Department of Health and Human Services (HHS) departmental-level review of individual GOFoc experiments, but with concrete established criteria requiring examination of unique risks and benefits relative to safer alternatives, and with decision-making criteria and decisions public and transparent. Additionally, perhaps require that a high-level official, such as the NIH director or HHS secretary, approve all such funding requests (as is required for "Major Action" in the NIH guidelines on research involving recombinant DNA, which requires NIH director sign-off).

2. Seek international consensus with the leading national scientific funding organizations in other countries to follow a similar review process and restrictions for these experiments, as outlined in 1 (above), and possibly employing other options below.

3. Secure national and international agreement to restrict the performance of GOFoc studies to a small number of laboratories that have exceptional records of biosafety and biosecurity, experience with dangerous viruses, staff training, operation security awareness, and state-of-the-art-facilities and operate under an appropriate national policy framework that ensures the safety of the work. The World Health Organization (WHO) process for prequalifying medicines or for prequalifying quality control laboratories might be a model for this process. Alternatively, the WHO process for approving individual research activities involving the smallpox virus—permitted in only two facilities in the world—might be an appropriate model.

4. Designate a board with appropriate expertise to review individual GOFoc proposals after such proposals are flagged during the process of peer review (or through another process when the proposals are not subject to prior peer review, as in government or private laboratories). The board should be independent of the funding agency involved and of the institution proposing the work, and should have appropriate expertise in virology, biosafety, ethics, and epidemiology, among other disciplines, as well as in international security. The WHO Advisory Committee on Variola Virus Research might be a partial model. It comprises eminent international virologists and public health leaders, but a GOFoc Board would need additional biosafety and biosecurity expertise.

5. Establish clear red lines for GOFoc research that will not be supported by US government funders, similar to those defined for the use of CRISPR technology to alter the human germline. This would have to be accompanied by a process to flag and review proposals for such a restriction. Alternatively, these red lines might be codified by a modification of the Select Agent Rule to include specific GOFoc experiments with select agents as forbidden, which would broaden their applicability beyond US government–funded experiments.

6. Require the purchase by research institutions of specific liability insurance policies to cover GOFoc research. Liability insurance has the advantage of placing the estimation of risk in the hands of an impartial party (the insurer that must price the insurance policy) and internalizes the costs of accident risk so that the funded cost of such experiments adequately covers social costs.

A number of the above policies could be put into place concurrently and are not mutually exclusive.

Each of these policies has advantages and disadvantages, and we have distinct preferences for some of them over others. Our purpose here, though, is not to advocate for one over the other but to lay out concrete options for consideration and encourage a robust and specific discussion at the NAS and beyond, and a rapid move toward resolution.

Independent review essential

In such discussions, we urge a focus on means to ensure the independence of those judging GOFoc proposals from real or perceived conflicts of interest, adequate expertise among any board charged with review of GOFoc, and attention to the international dimension of the issue.

While immediate international solutions may not be at hand, the US can lead by example in taking the issue seriously and proposing a workable oversight regime. At the same time, frameworks should be designed to avoid impeding low-risk research and low-risk public health activities, which include the optimization and manufacturing of vaccines.

Given the expertise, resources, and time committed to this US deliberative process, any resulting decisions and policies will likely serve as precedents that will be emulated by much of the world.

What is essential is not to lose the momentum or focus of the scientific and policy communities on these critical questions, and not to postpone hard decisions, but rather to use this moment to develop policy solutions that will benefit public health while ensuring robust scientific progress.

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