All research that might result in a pandemic must undergo external review

Could scientists nowadays conduct a study that risks the lives of millions, without their consent and with no external review?1 Surely, you might think, such studies could not happen anymore, not in developed countries with elaborate research ethics systems. But many such studies are legal in many countries, including the United States, to this day. Biomedical research with enhanced potential pandemic pathogens (ePPPs)—roughly, one that makes them so lethal, communicable, or resistant to existing protections that they pose a pandemic risk—“can be inherently high risk given the possibility of biosafety lapses or deliberate misuse.”2 Such research has >0 probability of accidentally releasing a pandemic-potential pathogen. More frighteningly, it has a >0 probability of being used by malevolent actors to develop the worst possible pathogens and then release them or credibly and coercively threaten to release them.3 And ePPP research is but one kind of dual-use research of concern (DURC), namely, research whose results can be benign or important (say, when successfully used for biodefense) but also destructive or catastrophic (say, when its findings are used to enhance biological weapons). Unfortunately, the probability for such catastrophic developments is not only >0 but >>0, as demonstrated by a long trail of accidental releases and by the surprising ease with which thousands of actors with biological know-how can already work to synthesize enhanced viremia.4 Many countries practicing ePPP research and other DURC lack powerful, comprehensive regulations in this area.5 One reason is that national regulatory documents on the treatment of humans in research usually concern the treatment of human participants alone. Because ePPP research, like DURC in general, rarely includes human participants, many potential regulations neglect them. Protections of lab animals apply, but they certainly do not protect the many nonparticipating humans who are put at risk. The risk to millions of nonparticipants is not only a theoretical legal possibility. A recent case of ePPP research on U.S. soil revealed at least confusion and uncertainty about where and whether institutional review over ePPP research and other DURC are needed.6 One might be tempted to dismiss risks to a study's nonparticipants as unimportant, even if there are millions of non-participants and the harm to many from, for example, human-engineered pandemics, could be fatal. Traditionally, the main focus of research ethics is the protection of the human subject. However, surely risks to nonparticipants count, and there are reasons why they must be kept especially low.7 Unlike typical human participants, the millions of potential victims of accidents or deliberate misuse of ePPP research and of DURC have never consented to take on study risks. In the United States, which funds the bulk of ePPP research and other DURC globally, the Common Rule and other human subject research regulations focus on the protection of study participants, almost to the complete exclusion of the many “bystanders” whom medical and scientific studies may put at risk.8 Some international research ethics documents consider risks to non-participating human populations,9 but they do not legally bind U.S. researchers. Existing regulations of ePPP research and other DURC cover only research funded by some U.S. federal agencies—they do not apply to research funded by other federal agencies, private funders, and foreign governments.10 That leaves unprotected the millions at risk from some studies that might spark or enable a new pandemic. In the recent case of an ePPP mentioned above, one reason cited for the lack of external review was absence of federal funding for the study itself, as opposed to basic research leading to it.11 Since February 2022, a U.S. federally appointed committee, the National Science Advisory Board for Biosecurity (NSABB), has deliberated how the United States should care for and oversee ePPP research and DURC. In December 2022, my coauthors and I sent the NSABB a public comment whose signatories included some of the world's leading bioethicists. We urged that external review for all ePPP research and DURC on U.S. soil ought to be mandated without exception and specifically, regardless of its funding source. The review and oversight of ePPP and other DURC should be independent of investigators, their institutions, and other potentially conflicted parties. In light of their special charge, the disciplinary composition of review bodies should differ from that of standard institutional review boards. The regulations and expectations from researchers should become clearer and more transparent.12 More than everything, we emphasized, ePPP research and DURC need to be reviewed externally, without exceptions. Such research sometimes has high social value, for example, by gaining a deeper understanding of the microbial genetics of pathogens with pandemic potential, which helps scientists improve vaccine response. Accordingly, a permanent moratorium on these entire categories of research would be too crude. But for much ePPP research and DURC, the expected value of the knowledge gained is questionable, and far smaller than the expected disvalue of their pandemic risks.13 Rigorous oversight would improve our ability to sift ePPP research and DURC whose social value warrants the risk from ones that are not worth it. Note what that public comment, and the current editorial, are not suggesting. They do not call for a one-size-fits-all permanent moratorium, or even low quotas, for ePPP research and other DURC, of the sort that many virologists dread.14 By contrast, unprejudiced external review for all ePPP research and other DURC, regardless of its funding source and site, remains crucial. All countries should do their part to enable it. Just as in clinical research we no longer let researchers settle whether their own study is socially valuable or ethical, external review bodies should always be the ones to make such calls when it comes to ePPP and other DURC. In January 2023, the NSABB published and approved draft recommendations on how the United States ought to regulate ePPP research and DURC. Recommendation 12 is to “promote and ensure that all research [reasonably anticipated to result in one or more of seven experimental effects thought to increase pandemic risk] conducted within the U.S. and/or supported by the U.S. government be subject to equivalent oversight regardless of funding source.”15 That would close the loopholes that we and others pointed out. But the NSABB has suggested as much in 2016.16 So far, the United States has not enacted the relevant legislation. NSABB's repeated message ought to be heard, especially now that advances in CRISPR-Cas9 and other technologies have greatly augmented the global public health risk from engineered pandemics that use the results of ePPP studies and other DURC.17 The potential externalities for our species from well-intended but potentially destructive research are not an investigator's, a single lab's, or a research institution's or funder's business alone. Nor is all this internal U.S. business. Neither pathogens nor misused information respect international borders. Private or foreign-funded ePPP research and other DURC pose grave dangers to people globally. Any weak point in the global ePPP and DURC regulation and oversight system jeopardizes us all. The United States is not the only culprit here. Currently, most countries, including some that actively pursue DURC, lack any proper DURC policy.18 Comprehensive international regulations and strong enforcement might have been the answer. But guidelines and recommendations by the World Health Organization and the Biological Weapons Convention (BWC) are not legally binding and completely lack means of enforcement.19 The BWC operates on a yearly budget smaller than that of an average McDonald's.20 In addition, these international bodies are not always attuned enough to the centrality of ePPP research and DURC's information hazards. The BWC encourages “the fullest possible exchange of information,” and WHO's new global guidance framework on these matters emphasizes especially the need for “awareness-raising activities.”21 Such well-intended truisms stand almost opposite of what is urgently needed now: a concerted effort by international organizations, bioethicists, lawyers, journal editors, and academic institutions to curb the circulation of know-how that could be used destructively by malevolent actors in ways compatible with robust scientific exchange in other areas.22 Even the NSABB recommendations are focused on curbing outbreaks or information hazards stemming directly from “research that directly involves… human, animal, or plant pathogen, toxin, or agent” only.23 That excludes information hazards that come from the development of new technologies that could serve destructive purposes, for example. Instead of just keeping our fingers crossed for no natural or human-engineered pandemic, the U.S. administration should try again to shut a major breach in global attempts to regulate ePPP research and other DURC—the one pertaining to U.S.-funded research and to research on U.S. soil. Bioethicists everywhere need to speak out for more comprehensive and rigorous U.S. and global regulations and oversight of ePPP research and of DURC in general.