key: cord-296028-hqrd1e8p authors: Rozell, Daniel J. title: Assessing and Managing the Risks of Potential Pandemic Pathogen Research date: 2015-07-21 journal: mBio DOI: 10.1128/mbio.01075-15 sha: doc_id: 296028 cord_uid: hqrd1e8p nan H5N1 virus experiments occur in special facilities (BSL-3ϩ) and, using the Erasmus MC facility as an example, he estimated that the risks are much lower due to extra physical barrier biosafety measures, lab personnel vaccinations, and available antiviral therapeutics. Thus, he estimated the risk of a laboratory-acquired infection (LAI) to be less than 1 ϫ 10 Ϫ7 per person-year. Taking into account that any infected lab worker would have already been vaccinated against a homologous H5N1 virus, would be taking antiviral medication, and would be quarantined, Fouchier estimated that a lab-induced pandemic would occur every 33 billion years-more than twice the known age of the universe. He concluded with the observation that there have been no confirmed influenza virus LAIs or releases in decades, which suggests current measures are sufficient. A reply by Lipsitch and Inglesby (12) questioned Fouchier's claim that virology labs are safer than other BSL-3 labs. They also noted that Fouchier's calculations incorrectly accounted for the uncertainty associated with 0 observed events (13) . Furthermore, the assumption of 0 events was claimed to be unreasonable, because viral LAIs have occurred in non-U.S. facilities (14) . In separate comments, Klotz (15) argued that Fouchier's calculations were based on the wrong method of calculating the elapsed time of escape for an LAI and that the estimate for an LAI was too low. A reply by Fouchier (16) argued that Klotz did not provide "scientific justification" for higher estimates. Within this debate among competing risk estimates, there appears to be disagreement as to not only what constitutes the appropriate methodology, but also what constitutes evidence. For example, Fouchier (16) does not believe that recent laboratory errors (most notably at the CDC) constitute relevant data, because either the errors did not result in LAIs, the pathogen was not an engineered avian influenza virus, or the work was not conducted specifically in a BSL-3ϩ laboratory. However, critics contend that these errors demonstrate the general failure of laboratory safety procedures upon which Fouchier's calculations depend. Adding to this concern is a study (17) that estimated a 5% to 15% probability that a laboratory escape event would go undetected. Likewise, investigative reporting on U.S. labs (18) suggested that laboratory accident records are poorly tracked, generally underreported, and difficult for the public to access. A review of these various assessments suggests that the most useful contribution of a single independent quantitative risk as-sessment may be to standardize the language of the debate. It is difficult enough to assess the quality of the data and validity of assumptions of each risk assessment. Further comparisons are made nearly impossible because of use of inconsistent units (e.g., escape probability, risk per lab-year, and risk per worker-year) and different treatments of uncertainty (e.g., point estimates versus 95% confidence intervals). By using a single RBA as a starting point, hopefully the various stakeholders will at least be able to argue using the same mathematical framework. Despite the NIH request for a comprehensive quantitative riskbenefit analysis, there is acknowledgment that this may not be possible. During the NRC symposium (10), both Baruch Fischhoff and Ronald Atlas discussed the difficulty of estimating benefits from the GOF research or, more generally, any basic research, due to its unpredictable and serendipitous nature. Likewise, the public health benefits of GOF research are difficult to estimate because they are conditioned on factors outside the laboratory (19) . That is, while the risk of accidental release is largely controlled by laboratory conditions, the beneficial use of any discovered knowledge depends on the existing public health system, which varies widely among communities, regions, and nations. For example, 1 year into the 2009 influenza pandemic, there was still only enough vaccine for one-quarter of the world's population (20) . Further complicating a benefits analysis are the multiple ways in which evidence can be interpreted. For example, during the NRC symposium, it was widely acknowledged that genetic analysis of PPPs currently could not predict the resulting phenotype (21) . Critics of GOF research argued that this lack of predictive ability severely limits the benefits of this line of research for any practical therapeutic purposes (e.g., vaccine design). However, proponents argued that this lack of knowledge was the very reason that GOF research should continue. Thus, an argument against the current practical value of the research is being interpreted by others as a supportive argument from the perspective of basic science. In this case, interpretation of a benefit is a subjective value judgment. The GOF controversy includes many other value-laden debates regarding risks, benefits, and assessment methodologies. For example, proponents argue that GOF research has a unique scientific value (22) , while critics argue that the scientific value may be no greater than that of safer alternatives, which should be considered an opportunity cost in an RBA (23) . The debate also extends to disagreements regarding: the practical value of GOF experiments to policy makers (23, 24) , how we should count and compare the various ways of valuing research (e.g., intrinsic value versus instrumental value) (25, 26) , and how publication criteria should compare public health risk(s) to scientific merit (27, 28) . Considerable disagreement even exists regarding ancillary effects, such as the impact of the various moratoria and regulations on the decisions of young scientists to work in virology (29) (30) (31) . The GOF controversy even includes debates over definitions. As discussed at the NRC symposium (10), GOF research is already widely used for multiple beneficial and largely benign purposes, including increasing vaccine yields (32) , expanding genomic sequence surveillance databases (33) , and creating animal models of human viral infections to aid further research. Furthermore, naturally arising GOF mutations are common in research labs that work with RNA viruses. Because the current state of science is unable to predict what genomic changes will increase danger, we cannot be sure what experiments will result in new undesirable traits. Proponents of the 2014 moratorium argue that the wording was specific enough that only 18 federally funded projects were affected and that public health surveillance and vaccine development activities were exempt (5) . Rather, proponents accuse critics of the moratorium of attempting to widen the definition of what might be banned in hopes of weakening support for any restrictions. This is not the only debate over terminology. It has been argued that the use of the term "pandemic" itself is an "apocalyptic rhetorical device" (24, 34) that preempts any reasonable discussion of risks and benefits by appealing to our innate fear of rare but catastrophic events. However, this assumes that the risk of a pandemic is actually rare, despite considerable disagreement among informed scientists regarding the likelihood of such an event. Ironically, labeling the use of "pandemic" as rhetorical sophistry may itself be a rhetorical trick if it is used to dismiss a category of serious claims without due consideration of merit. Ultimately, the purpose of summarizing and critiquing some of the arguments within the GOF/PPP debate is to emphasize the many epistemic and ethical value judgments inherent to RBA and to provide evidence for prior claims that a consensus-building quantitative assessment is unlikely (1). This naturally leads us to wonder if there is a better alternative. Fischhoff suggests that, rather than use RBA to only inform the eventual policy decision, it should instead be used to improve research design (10). Lipsitch and Galvani (35) made the same argument for improving GOF/PPP research design, but in the context of responsible research principles. They argued that most GOF/PPP experiments are not ethically justifiable because they do not meet the criterion of yielding humanitarian benefits not attainable by safer alternatives. One approach to improving research design is to use the design principle of inherent safety (36) (37) (38) , which focuses on attempting to eliminate material hazards in research and manufacturing. In contrast, conventional risk management generally focuses on reducing the likelihood of an accident through safety procedures and equipment. The formal inherent safety concept is frequently used in the chemical and nuclear engineering communities but it has not been widely adopted by scientists and engineers in other fields (39) . While this idea seems to be common sense, it is a departure from most previous work on biosafety and biosecurity (14, 40) , which was focused on improving risk management through formalized processes and training. The continued emphasis on these methods is unfortunate, given the generally poor record of implementation (41, 42) . An additional benefit of the inherent safety concept is its ability to address security concerns (43) . For example, a traditional safety measure, such as removing all ignition sources near an explosive material, is of little security value; malevolent actors will bring their own ignition source. Likewise, terrorists are attracted to hazards that already instill public dread. Inherently safe design makes terrorism more difficult by removing the exploitable hazard. Because safety has traditionally been the concern of engineers at the production level, the R&D community often fails to consider these principles in the early stages of research when the most impact can be made (44) . However, inherent safety in research is sometimes recognized in hindsight. A CDC report (45) that summarized an internal review of the June 2014 exposure of laboratory workers to potentially viable Bacillus anthracis at a CDC bio-Letter to the Editor terrorism response lab noted that an avirulent strain could have been used as a substitute in the experiment. It is also interesting that in its list of responses, the report focused primarily on revised biosafety protocols and procedures. A reference to reducing the hazard (i.e., inherent safety) was made only within the fifth of eight recommendations. The calls for inherently safe design appear to have yielded some consensus from the opposing camps in the GOF/PPP controversy. One sign during the NRC symposium was provided by Yoshihiro Kawaoka, a principal investigator of one of the two original studies that started the debate (46) , who endorsed the idea that some research could be conducted with alternative techniques, such as loss-of-function studies, use of less-pathogenic viruses, and phenotypic analyses (10) . Proponents of inherently safe PPP research have also been buoyed by recent successes. For example, Langlois et al. (47) showed that species-specific microRNA targeting can be used to conduct relevant animal model PPP research that still poses low risks to humans. As Michael Imperiale stated, "You can develop safer approaches to do these types of experiments; it just needs a little bit of imagination on the part of researchers" (10) . As summarized here, many of the disagreements within the GOF/PPP debate involve epistemic and ethical value judgments that suggest that definitive quantitative risk-benefit analysis is not possible. This does not devalue RBA; it is still useful as a tool for engaging experts and the public in a conversation about riskbenefit tradeoffs. However, if calls for RBA become knee-jerk responses to what are essentially quantitatively intractable technological risk problems, everyone will be disappointed. RBA works best when expectations are realistic. When data are plentiful and there are no moral or cultural differences among the stakeholders, RBA can generate "answers" for policy formulation. However, for emerging technologies and controversial research where data are sparse and uncertainty is high, putting a number on a subjective quantity only engenders suspicion. The question of whether the benefits of GOF/PPP outweigh the risks is unlikely to be resolved by an independent formal RBA. However, this question may become less relevant if safer approaches can achieve the same goals. That is, inherently safe design may be the best compromise solution for the GOF/PPP controversy. Because the inherent safety principle will not be invoked unless a risk is perceived, the appropriate next step is to regard the eventual results of the RBA as a tool for risk exploration, which then inspires more inherently safe research. Over the long term, changing the biosafety/biosecurity culture in the life sciences to emphasize inherent safety principles will help avoid similar heated controversies in the future. Risks and benefits of gain-of-function experiments with pathogens of pandemic potential, such as influenza virus: a call for a science-based discussion mBio addresses the pause in gain-offunction (GOF) experiments involving pathogens with pandemic potential (PPP) The H5N1 moratorium controversy and debate Conducting risk and benefit analysis on gain-of-function research involving pathogens with pandemic potential Moratorium on research intended to create novel potential pandemic pathogens The unacceptable risks of a man-made pandemic The consequences of a lab escape of a potential pandemic pathogen. Front Public Health 2:116 Monitoring select agent theft, loss and release reports in the United States-2004 -2010 Airborne transmission of influenza A/H5N1 virus between ferrets Potential risks and benefits of gain-of-function research: summary of a workshop Studies on influenza virus transmission between ferrets: the public health risks revisited Studies on influenza virus transmission between ferrets: the public health risks revisited Probability of adverse events that have not yet occurred: a statistical reminder Strengthening risk governance in bioscience laboratories Comments on Fouchier's calculation of risk and elapsed time for escape of a laboratory-acquired infection from his laboratory Comments on Fouchier's calculation of risk and elapsed time for escape of a laboratory-acquired infection from his laboratory Containing the accidental laboratory escape of potential pandemic influenza viruses Inside America's secretive biolabs Great expectations-ethics, avian flu and the value of progress Perspective: ill prepared for a pandemic Improving pandemic influenza risk assessment An epistemological perspective on the value of gain-of-function experiments involving pathogens with pandemic potential Can limited scientific value of potential pandemic pathogen experiments justify the risks? mBio Reply to "Can limited scientific value of potential pandemic pathogen experiments justify the risks Valuing knowledge: a reply to the epistemological perspective on the value of gain-of-function experiments Valuing knowledge: a reply to the epistemological perspective on the value of gainof-function experiments An avian H7N1 gain-of-function experiment of great concern The decision to publish an avian H7N1 influenza virus gain-offunction experiment Vagueness and costs of the pause on gain-of-function (GOF) experiments on pathogens with pandemic potential, including influenza virus A brain drain due to increased regulation of influenza virus research is highly speculative Reply to "A brain drain due to increased regulation of influenza virus research is highly speculative Influenza gain-of-function experiments: their role in vaccine virus recommendation and pandemic preparedness Use of highly pathogenic avian influenza A (H5N1) gain-of-function studies for molecularbased surveillance and pandemic preparedness The apocalypse as a rhetorical device in the influenza virus gain-of-function debate Ethical alternatives to experiments with novel potential pandemic pathogens What you don't have, can't leak Inherently safer plants How to make inherent safety practice a reality Developments in inherent safety: a review of the progress during 2001-2011 and opportunities ahead Biosafety risk assessment methodology Biosafety controls come under fire Can biosecurity be embedded into the culture of the life sciences Promoting inherent safety Are we too risk-averse for inherent safety? Report on the potential exposure to anthrax Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies