Evaluating the Risk–Benefit Equation for Dual-Use and Gain-of-Function Research of Concern

By Michael J. Imperiale

Evaluating the Risk–Benefit Equation for Dual-Use and Gain-of-Function Research of Concern

In the twenty-first century, biology faces a problem that has previously vexed other disciplines such as physics, namely the prospect that its knowledge domain could be used to generate biological agents with altered properties that enhanced their weapon potential. Biological weapons bring the additional dimension that these could be self-replicating, easy to manufacture and synthesized with commonly available expertise. This resulted in increasing concern about the type of research done and communicated, despite the fact that such research often has direct societal benefits, bringing the dual-use dilemma to biology. The conundrum of dual use research of concern was crystallized by the so-called “gain-of-function” type of experiments in which avian influenza viruses were endowed with new properties in the laboratory such as increased virulence and the capacity for mammalian transmission. After more than a decade of intensive discussion and controversy involving biological experiments with dual-use potential, there is no consensus on the issue except for the need to carry out such experiments in the safest conditions possible. In this essay, we review the topic with the hindsight of several years and suggest that instead of prescribing prohibitions and experimental limitations the focus should be on the importance of scientific questions at hand. We posit that the importance of a scientific question for medical and scientific progress provides a benchmark to determine the acceptable level of risk in biological experimentation.

The Great Gain-of-Function (GOF) Controversy

Before considering the GOF controversy involving influenza virus, it is worthwhile reviewing what is meant by “GOF” and the limitations of the lexicon in the controversy. At the most basic level, a GOF experiment, as the name implies, is one that gives a biological entity any new property. GOF experiments can be highly beneficial and can generate pest resistant crops, microbes expressing proteins for medical therapy such as recombinant human insulin, and new cancer therapies by enhancing lymphocyte function. The controversial aspects of GOF experiments in microbiology arise when microbes are modified to have new properties that can enhance their virulence and transmissibility because such experiments raise worries about new diseases, outbreaks, pandemics, biosafety, and biosecurity.

Publication Quandaries

One of the most vexing questions of the problem of dual-use research is publication of scientific findings. In the U.S., the research community is guided by National Security Decision Directive 189, formulated in 1985, which states that all fundamental research results could be published freely. In other words, there was either open publication or classification, and nothing in between. With this binary policy, redacting papers because they might contain information useful for nefarious purposes is not an option unless export control regulations are invoked. Consequently, when faced with GOF papers containing information that could conceivably be used to enhance the pathogenicity or transmissibility of a virus, editors and journals have almost always opted for full publication, usually requiring more details from the authors about biosafety and biosecurity methods, and often publishing an accompanying editorial emphasizing the scientifically useful aspects of the research. Another major challenge to the control of DURC information is the emergence of preprint servers in biology that allow the posting of research findings before peer review and the proliferation of predatory open access journals that will publish essentially any paper for a fee. Consequently, there now exist alternative systems for publication even if standard journals decline to publish a particular article over DURC concerns. Bypassing traditional publication methods could also allow authors to avoid government scrutiny.

The Situation Today

It is not an exaggeration that the situation today regarding DURC and GOF experiments remains highly unsatisfactory. Experimental work involving GOF experiments on pathogens with pandemic potential is highly regulated with proponents of such work arguing that restrictions on experimental design are unwarranted [1] while opponents of such experiments argue that such work cannot be justified [2]. Proponents of GOF experiments have noted that data generated in such experiments is useful in epidemiological surveillance, whereas opponents have argued that such work cannot be morally justified because of its inherent risk. There is no consensus in the scientific community on whether the value of some experiments justifies the risks involved. The central problem in finding a consensus is that the value of the research cannot be measured in real time, while assessments of risk involve assumptions that can lead to widely divergent estimates. One of the most important developments in the past few decades has been a change in the zeitgeist of the field that concerns itself with DURC research and GOF experiments. In the early years of the twenty-first century, as the U.S. reeled from the 9/11 terrorist attacks, which were shortly followed by the anthrax spore attacks, the focus was primarily on biosecurity. At that time, the concern was that terrorists and state actors would use the tools of the molecular biology revolution to create new and more devastating biological weapons. However, as the years passed and no new attacks developed, combined with the attribution of the anthrax spores in mail attacks to a lone insider in a U.S. government laboratory [3], this security threat appeared to recede. At the same time, a series of unfortunate biosafety lapses in government laboratories heightened concerns about biosafety. Hence, today people (at least those outside the security community) appear to be more worried about an unintended release of a pathogen with pandemic potential than a deliberate biological attack. This change in emphasis from biosecurity to biosafety has developed slowly and could easily change if there is another deliberate biological attack or if becomes apparent that adversaries are developing biological weapons. Also contributing to an unsatisfactory situation are concerns whether such regulations as the Select Agents and Toxins list help or hinder societal security. On one hand, placing great restrictions on the accessibility to a number of agents and toxins does increase security by making them more difficult to obtain, with the caveat that these are naturally occurring agents that could be obtained from nature by a determined actor. On the other hand, there is the concern that focusing on lists and a relatively short list of agents means that the overwhelming majority of microbial threats are not on the DURC radar screen. Against this backdrop of dissatisfaction is the fact that science continues to progress very rapidly, introducing new technologies such CRISPR/Cas9, gene drives, and more efficient synthetic biology, each of which brings with it new possibilities for research that improves the human condition as well as new tools for nefarious purposes. Furthermore, as the technologies improve they are increasingly accessible to more individuals and countries for whom this type of research was previously beyond reach. Hence, the problem of DURC is likely to become significantly more urgent in the near future.

The Way Forward

In a world where new infectious agents that can rapidly spread among vulnerable populations are described on a regular basis, humanity needs a healthy research establishment focused on microbial threats. It is estimated that there are a minimum of 320,000 mammalian viruses [4]: some fraction of these are probably zoonotic events waiting to happen. As Ian Malcolm, the fictional character created by Michael Crichton in the novel Jurassic Park, stated, “Life finds a way.” Information and knowledge are the best defenses against these threats. In addition to terror from nature, a new crisis will almost certainly occur in the future arising from a deliberate attack, a new provocative paper, or another biosafety lapse. GOF experiments and DURC research are essential for preparedness and the question is not whether this research should be pursued but rather how to do it safely and mitigate risk. To date, each of the controversies has been reactive, with proponents and opponents of such experiments responding to a specific finding or study. After more than a decade of discussion on what constitutes DURC, benefits and risks of GOF experiments, regulations, pauses, and moratoriums, it is increasingly apparent that current approaches are inadequate for the challenges at hand. Given these limitations, we have proposed a new framework for DURC research that focuses on answering specific questions [5]. Hence, instead of prohibiting certain types of experimentation, we suggest that the way forward is to focus on specific scientific questions and the problems that need answers. For example, if there is a need to determine whether a particular feral virus pathogen has the capacity for mammalian infection and transmission, then GOF experiments performed in safe and controlled conditions can be justified. On the other hand, endowing HIV with new transmission properties is not a medically important GOF experiment [6]. All human activities that involve probing the unknown, ranging from space exploration to tissue culture procedures, carry some degree of risk, and it is nature of humanity to accept risk to attain progress. Opponents and proponents of this type of experimentation need to maintain open channels for continued discussion because the dialectic of ideas is likely to result in better decisions. Institutional bodies such as the NSABB need to be supported for they constitute important venues for such discussion and recommendations that mitigate risk. In fact, it is important to create similar institutions that can work at the international level since U.S.-based research is a small portion of all microbiological work done worldwide. Most importantly, we should remain optimistic that the research community can do the research necessary to obtain information critical to protect our species while minimizing the risks of such work.


[1] Fouchier, R. A., Garcia-Sastre, A., and Kawaoka, Y. (2012b). The pause on avian H5N1 influenza virus transmission research should be ended. MBio 3, e00358–12. doi:10.1128/mBio.00358-12
[2] Wain-Hobson, S. (2014a). An avian H7N1 gain-of-function experiment of great concern. MBio 5, e01882–14. doi:10.1128/mBio.01882-14
[3] Bhattacharjee, Y., and Enserink, M. (2008). Anthrax investigation. FBI discusses microbial forensics – but key questions remain unanswered. Science 321, 1026–1027. doi:10.1126/science.321.5892.1026
[4] Anthony, S. J., Epstein, J. H., Murray, K. A., Navarrete-Macias, I., Zambrana-Torrelio, C. M., Solovyov, A., et al. (2013). A strategy to estimate unknown viral diversity in mammals. MBio 4, e00598–13. doi: 10.1128/mBio.00598-13
[5] Imperiale, M. J., and Casadevall, A. (2015b). A new synthesis for dual use research of concern. PLoS Med. 12:e1001813. doi:10.1371/journal.pmed.1001813
[6] National Academies of Sciences Engineering and Medicine. (2017). Dual Use Research of Concern in the Life Sciences: Current Issues and Controversies. Washington, DC: The National Academies Press.

This is an excerpt of the journal article: A New Approach to Evaluating the Risk–Benefit Equation for Dual-Use and Gain-of-Function Research of Concern, by: Michael J. Imperiale and Arturo Casadevall. Published: 08 March 2018 in Front. Bioeng. Biotechnol.; DOI: https://doi.org/10.3389/fbioe.2018.00021 under a Creative Commons Attribution License (CC BY 4.0). 

Michael J. Imperiale
Associate Vice President

Dr. Michael J. Imperiale currently is associate vice president for research, research policy and compliance at the University of Michigan. Dr. Imperiale leads the development and review of research policy, and serves as the key point of contact for research compliance. Imperiale, Arthur F. Thurnau Professor of Microbiology and Immunology, also oversees issues surrounding responsible conduct of research and serves as the institutional Research Integrity Officer.