Policy reset and convergence on governance are needed
JASPREET PANNU, MEGAN J. PALMER, ANITA CICERO, DAVID A. RELMAN , MARC LIPSITCH, AND TOM INGLESBY Authors Info & Affiliations
SCIENCE 8 Dec 2022 Vol 378, Issue 6625 pp. 1170-1172
This transmission electron micrograph shows the H1N1 strain of swine influenza virus particles (yellow) and a host cell (brown). PHOTO: DR. KLAUS BOLLER/SCIENCE SOURCE
Life sciences research offers immense benefits and is crucial for advancements in medicine, public health, agriculture, and management of the environment. But a recent guidance framework by the World Health Organization (WHO) reminds us of the continued lack of awareness and governance structures in many countries for life sciences research that may cause harm through accident or misapplication (1). Robust risk management would enable the full realization and equitable distribution of potential benefits from the life sciences and associated technologies, and reassure the public (1). International guidelines and standards of conduct are needed (2), along with effective oversight institutions and leadership (3). The US government (USG) has played a prominent role to date and is now reviewing its biosecurity policies. We identify substantial gaps and suggest approaches to address them so as to improve US policies and usefully influence policies globally.
At the start of 2022, the National Institutes of Health (NIH) and the White House launched a review of two important US biosecurity policy frameworks, one for the oversight of “dual-use research of concern” (DURC), which outlines life sciences research that may be misapplied to pose a substantial biosecurity threat (4), and one for the oversight of work involving enhanced potential pandemic pathogens (ePPPs) (5). These policies were first established in 2012 and 2017, respectively, and were attempts to balance the benefits and risks posed by research that falls into these categories. With the passage of time, it has become clear that there are shortcomings that need to be addressed. Biotechnology has advanced with remarkable speed and impact—so have the needs and demands for benefits, along with concerns about risks.
With respect to current US policy, roles and responsibilities are inconsistent, and scope is limited. Local research institutions assess projects for the possibility of DURC, referring the work to NIH only if they view this as needed. By contrast, ePPP policy places responsibility for review with USG departments and agencies. Local institutions have no stated role, and only the Department of Health and Human Services (HHS) has enacted an ePPP policy. Both frameworks apply only to USG-funded research. This current situation probably arose from early concern by USG about overreach and the possible dampening effects on US efforts to develop defenses against naturally occurring pandemics and biological threats of deliberate origin.
It is vital to get these policies right, not only for the US, but to inspire policy development in other countries with growing life science and biotechnology sectors. Few countries have policies that fully manage these issues. Some have published guidance that addresses key elements. For example, Canada requires life science research institutions to establish dual-use policies that have been approved by the Public Health Agency of Canada. The German National Academy of Sciences (Leopoldina) has encouraged institutions to create dual-use oversight committees; many German institutions now have such committees, even though no law requires it. The WHO, too, in its recently published framework, provides valuable guidance on the kinds of interventions and policies that might diminish the risks associated with some life sciences research. Yet, many countries have not offered interventions or policies on these issues. Some have biosafety measures aimed at mitigating accidental harms but lack biosecurity oversight aimed at mitigating intentional misuse. A minority of countries have policies that articulate a clear role for their national government (6). And fewer still have policies that directly address research on PPPs.
The pandemic has dramatized the terrible impact of a highly transmissible virus. It has also dramatized the terrible inequities in the allocation and delivery of countermeasures around the world, and the disparate costs paid by different communities. If ePPP research were to cause a pandemic, it would affect everyone, not just the country that funded or approved that research. Thus, there could be a moral and ethical argument that no country should undertake research that can be reasonably anticipated to increase the risk of a pandemic, without approval by other countries, especially by those least able to prepare for and respond to pandemics. As dozens of scientists, policy researchers, and public health experts (including the authors) stated recently, “the USG [and scientific community] has an extraordinary obligation to ensure [that] USG funding or approval is not given to work that may cause an epidemic or pandemic, as well as to provide international leadership in this realm” (7).
Policy Reset
Resetting US policy on these issues is a pressing need, as is international convergence around strong, effective governance of this area of science. Among the needed revisions for US policy, several bear highlighting.
Expand the scope of pathogens to be governed
The existing ePPP framework defines a potential pandemic pathogen as one that is both highly transmissible and highly virulent, because the initial priority was to ensure that the most serious risks were addressed first. But COVID-19 has shown that with a sufficient level of transmissibility, even a pathogen with modest virulence—an infection-fatality ratio of less than 1% (as compared to Ebola Sudan, for example, which has had an average case-fatality ratio above 50%)—can cause extensive global mortality, collapse of health systems, and widespread economic shock. The ePPP framework should be modified to make explicit that work reasonably anticipated to confer efficient human transmissibility on any pathogen, including those of even modest virulence, requires careful review.
Although an experiment that selects for new routes or modes of transmission or tropism for particular cells might be reasonably expected to increase a virus’s transmissibility in humans, the degree of increase is difficult to predict with current methods. Even pathogens with transmissibility modestly above the threshold of a basic reproduction number of 1 can cause outbreaks in specific populations, resulting in substantial disruption. Indeed, the past four influenza pandemics have had estimated reproductive numbers below 2 (8). Limited predictive ability combined with the destructive potential of modestly transmissible viruses should serve as a warning about the potential impact of engineering any degree of increased transmissibility. Although the existing HHS Framework provides criteria for funding approval and other questions that government reviewers need to address in the risk–benefit assessment, there is no concomitant guidance aimed at or communicated to research institutions or investigators; updated policy should include concrete guidance for these entities and individuals.
Similarly, the DURC framework should apply to all human pathogens, not just the 15 agents that are currently stipulated. It should also include animal and plant pathogens because of possible increased risks of epizootics or epiphytotics, with attendant risks to human health owing to diminished food security. The focus on the original 15 agents presumably was intended to place greatest attention on pathogens of highest risk while limiting the burdens of oversight for research deemed less risky. The original policy called for a revisiting of the scope. Emphasis should now be placed on the anticipated results of any research on a pathogen or research that could generate a pandemic: Will the reasonably anticipated product be an agent whose transmissibility and virulence may cause it to spread unchecked by available countermeasures, leading to substantial morbidity?
Expanding the scope of these frameworks does not necessarily mean preventing this work from occurring; it means requiring research proposals to go through independent, government-led risk–benefit assessment to determine whether the work should proceed and under what conditions. To be clear, transformative advances against pathogens can be achieved without increasing the chances of the next pandemic at the same time. HHS and NIH have not yet published the current costs and numbers of personnel required for implementing the DURC and ePPP frameworks, but clearly, an expanded oversight program will require additional resources to be effective and efficient.
Examine risks and benefits in rigorous detail
Nearly all life sciences research can be performed in ways that pose minimal risk to society. However, the narrow category of work subsumed under the ePPP and DURC frameworks may pose substantial risks. Therefore, it is essential that these risks, as well as the associated benefits, be examined in detail before funding or approval decisions are made. There is no easy, algorithmic process for weighing benefits against risks, and no off-the-shelf tool that has been evaluated for this specific application. Such assessments will require careful judgments by independent experts. Under current practice, benefits are sometimes asserted without much explanation, timeframe, or supporting evidence; for example, claims are made that a project with substantial risk is important for vaccine development but without supporting evidence. The risk–benefit calculus should be more specific and standardized.
On the risk side, the USG should make clear that the ePPP and DURC review processes must evaluate the risk and potential consequences of accidents, and the potential for deliberate theft of an isolate or insider diversion, as well as the risk that information from the research could be used in ways leading to accidents or deliberate harm. Relevant information would include genome sequences of ePPPs and computational methods for designing ePPPs. For example, a growing number of practitioners can, with increasing ease, create and engineer viruses on the basis of sequence information, reflecting new scientific conditions not adequately addressed by current policy. When the results of an accident or deliberate misuse could lead to epidemic or pandemic consequences, critical questions asked in the ePPP framework should include the following: Will the benefits of this research directly result in new approaches that could diminish the potential consequences or harms of this pathogen? How critical is the information that would be gained by the proposed experiments, and are there safer ways of attaining comparable information?
Although there are costs to rigorous reviews, such reviews should be supported and structured so that they can be improved over time, and the review process itself can inspire new lines of inquiry and technical innovations for mitigating risks. Examples of experiments and approaches with acceptable risk–benefit ratios could provide useful guidance, much like case law. Dedicated research programs can provide tools and empirical data to support more effective risk–benefit analyses. Publishing the deliberations and outcome of each review would enable learning from prior assessments and provide needed implementation guidance to researchers and institutions. So far, local DURC review has been inconsistent across institutions, nonstandardized, and hindered by disincentives for investigator reporting of risks (9).
Incorporate transparency into the review process
Assessments of risks and benefits should be made available to the public. Currently, research institutions and funders are reluctant to share information even when permitted because of concerns over reputational risk; both requirements and incentives will be vital to normalize these processes, establish trust, and enable cross-organizational learning. The deliberations of the USG entity deciding on approval of any ePPP research should also be made public, especially any dissenting opinions and recusals.
Reset the review process
Many types of expertise are needed for a proper review, including experts in natural science, engineering, biosafety, biosecurity, public health, vaccine and therapeutics development, and bioethics. The USG should seek nongovernmental expertise for the review process—currently, the HHS process involves only governmental experts, and the identity of these individuals is not publicly available. Clinical and public health experts are needed, because in the event of a pandemic resulting from the work, these experts would understand what would be needed for response. Individuals whose agency might be funding or participating in the proposed work have a conflict of interest. It is important for the content and the optics of the process that they recuse themselves from decision-making. The names of the individuals involved in the review, the content of the review, and the final decisions should be made public.
Review of proposed experiments now is required only at the point when a new proposal is being considered for funding by HHS. For many good reasons, scientists change their plans after funding has been approved for their original proposal. There is a need, therefore, for a mechanism to review ePPP experiments conceived after a grant proposal is funded, but before they are performed. Others have called for the same (10).
Expand reach to all USG agencies and to any institution performing this work
Currently, the required review of ePPP work is limited to experiments funded by HHS, which includes NIH. The policy should be revised so that all agencies that fund work related to the enhancement of potential pandemic pathogens should have that work evaluated under the ePPP framework, including, as applicable, the Department of Defense, Department of Agriculture, and others. In addition, currently neither ePPP nor DURC policies apply to non–federally funded research, leaving the USG and the rest of us in the dark about such work—despite a 2016 National Science Advisory Board for Biosecurity (NSABB) recommendation that all ePPP work be subject to oversight, regardless of funding source (11). The USG should use this opportunity to develop new policies and/or legislation to close these gaps in governance. Publishers and research institutions will have a role to play in this regime, as they do for human subjects research. Similar to the policies governing human subjects research, publishers should require that reports of research involving ePPP and/or DURC have been carefully reviewed under the appropriate government oversight framework or that the work has been determined by government not to fall in these categories or require review (12). Such policies of publishers of preprints and journals would provide incentives for countries around the world to establish review systems.
Although USG, the US National Academies of Sciences, Engineering, and Medicine, and NSABB have engaged other nations in DURC, we encourage the USG, especially the Department of State, perhaps in partnership with the NSABB, to expand its efforts to promote the importance of governance frameworks for such research.
Humanity is at a critical moment in the worldwide evolution of powerful experimental capabilities in the life sciences, motivated and humbled by an ongoing pandemic, faced with the distinct possibility of both substantial harm and good from continued work on pathogens. The current policy revision process is an unusual opportunity for addressing serious gaps and challenges. If the US is successful in this policy revision effort, it could serve to create substantial momentum for important change elsewhere in the world.
Acknowledgments
D.A.R. received support from the Thomas C. and Joan M. Merigan Endowment at Stanford University. J.P., M.J.P., A.C., D.A.R., M.L., and T.I. received support from Open Philanthropy. M.L. is the director for Science at the Center for Forecasting and Outbreak Analytics, US Centers for Disease Control and Prevention, under an Intergovernmental Personnel Agreement. He is also an Honorary Faculty member at the Wellcome Sanger Institute and an External Faculty member at the Broad Institute. M.L. has received institutional funding from Pfizer, the Waking Up Foundation, and the FTX Foundation unrelated to this work. He has received honoraria from Bristol Myers Squibb and Sanofi Pasteur, and consulting fees from Merck and Janssen. The opinions expressed here are those of the authors and do not necessarily reflect those of any institution or government agency.