Virology under the Microscope—a Call for Rational Discourse

ABSTRACT Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

(Continued from previous page) Emergent, Astrazeneca, Novavax, Regeneron, and the CDC, outside the submitted work. M. F. received royalties/licenses from Aikido Pharma for antiviral drug patent licensing, consulting fees from Aikido Pharma, Observatory Group, for consulting for COVID-19, and participation on Scientific Advisory Board for Aikido Pharma, outside the submitted work. K.F. has substantial financial interest in Vir Biotechnology, Inc., and is a co-founder of the company. K.F. is co-inventor of patents licensed to Vir and receives compensation for consulting for Vir. The

Commentary
ABSTRACT Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 601 years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concernsconflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, wea broad group of working virologistsseek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding muchneeded research in virology.
KEYWORDS COVID-19, Coronavirus, DURC, Gain of function, SARS-CoV-2, biosafety, influenza, pandemic, vaccines, zoonosis J ust 30,000 nucleotides of single-stranded RNA, neatly packaged as a coronavirus, brought the world to its knees socially, economically, ethically, and morally during the COVID-19 pandemic. COVID-19 has cast a harsh light on the many cracks, fissures and disparities in our public health system, and the inability to broadly come together to face a colossal crisis and focus on the needs of the most vulnerable. However, scientists worked together and responded to the threat with impressive speed, drawing on critical previous research on coronaviruses and other viral systems. Virologists, immunologists and microbiologists from around the globe collaborated together with scientists from allied disciplines, such as infectious diseases and epidemiology. They confronted the virus through research to understand its pathogenesis and transmission, through surveillance to track the emergence of variants, and through the development of rapid tests, vaccines, antivirals and monoclonal antibodies. The SARS-CoV-2 pandemic would have claimed a substantially larger number of lives and caused more economic disruption were it not for this unprecedented collaborative scientific response. Nevertheless, the SARS-CoV-2 pandemic has also brought virology under the microscope with concerns about safety of virology research and the uncertainties around the origins of SARS-CoV-2. Here we provide an evidence-based discourse to address key issues.
Virology research under scrutiny. Congress has a constitutional mandate to provide oversight to federally funded research. As a new Congress convenes in the United States, there is an opportunity for oversight hearings related to research in virology and the virology community stands ready to partner with Congress and lend our expertise. Our hope is that these hearings will highlight the enormous contributions of virology, including gain-of-function experiments, to human health (Table 1). However, we fear that some may use any such hearings to discredit virology and virologists andwhether intentional or notadd fuel to an anti-science, fear-based movement. Should such hearings lead to Congress legislating restrictions on scientific research, the outcome could impede our ability to predict, prepare, and respond to emerging viral threats. An equally devastating outcome would be to sow even more public distrust in science, which would limit our ability to confront viruses in general and increase the human burden from viral diseases.
The origin of SARS-CoV-2. A major point of contention in discussions of the COVID-19 pandemic has been the origin of SARS-CoV-2, with two major camps arguing that the virus either originated from animal-to-human transmission (zoonosis) or by a laboratory leak (1-3). Most virologists have been open-minded about the possible origins of SARS-CoV-2 and have formed opinions based on the best available evidence, as is done for all scientific questions (4). While each of these possibilities is plausible and has been investigated, currently the zoonosis hypothesis has the strongest supporting evidence (5-8). Zoonosis involves transmission of The views expressed in this article do not necessarily reflect the views of the journal or of ASM.

Commentary
Journal of Virology the virus as a consequence of close proximity between humans and wild animals, a scenario that has occurred repeatedly over time, leading to the emergence of many viruses, including Ebola virus, other coronaviruses, influenza A virus, mpox virus, and others (9-11). The lab-origin hypothesis suggests an accident at best or nefarious actors at the worst. At this time and based on the available data, there is no compelling evidence to support either of these lab-origin scenarios. It is important that scientists, the public, and public figures follow the evidence and limit speculation that can become fodder for misinformation and conspiracy theories. For example, on January 1, 2023, USA Today published an article discussing where the next pandemic could originate and disproportionately emphasized risk from manmade threats and lab accidents while minimizing the fact that most pandemics are zoonoses and never mentioning how virological research could mitigate risk (12). Unfounded accusations of a lab leak event or nefarious research in Chinese laboratories will hasten the deterioration of important partnerships between the US and China that are critical for early detection and preparedness for seasonal influenza and future pandemics. Gain-of-function research. Despite the paucity of evidence for a laboratory-origin of SARS-CoV-2, discussion of this possibility has driven a second controversy to the forefront of science policy discussion: the use of gain-of-function approaches in virology. Although the phrase 'gain-of-function' is very problematic and inexact, it is commonly used, and we will use it here cautioning all its limitations (13). The source of concern in this area is that changing a virus to add new functionality may yield a dangerous pathogen. It is important to understand, however, that gain-of-function approaches incorporate a large proportion of all research because they are a powerful genetic tool in the laboratory. These include the development of cancer therapeutics, bacterial strategies for bioremediation, and the engineering of drought-or pest-resistant crops ( Table 2). For example, some oncolytic viruses used to treat cancer mediate their effects because, using gain-offunction approaches, they have been endowed with new properties that kill tumors. At least two FDA-approved products resulted from providing viruses with new functions ( Table 2). Gain-of-function research with pathogens of pandemic potential established that avian influenza viruses have the capacity to acquire mammalian transmissibility and that bat-associated coronaviruses posed a danger to humans years before COVID-19 (Table 2). Despite these clear benefits, a narrative has developed suggesting that gain-of-function research is synonymous with high-risk or nefarious activity to engineer or enhance pandemic pathogens. In truth, gain-of-function research is a valuable experimental approach that virologists use to address essential questions. Virologists do not take their work lightly and thoughtfully propose experiments to address essential questions. Virologists do not operate in isolation to judge the risks of experiments: layers of regulation are in place such that risks are considered by individuals with diverse perspectives and expertise (Fig. 1). The vast majority of virology experiments could not enhance pandemic potential (referred to in the United States as gain-of-function research-of-concern). Those rare experiments that could are currently subject to stringent oversight through the U.S. Government under programs known as dual-use-research-of-concern (DURC) (14) and potential-pandemicpathogens-care-and-oversight (P3CO) (15) (Fig. 2), and also by the vast majority of international publishers, including the American Society for Microbiology (ASM) and the Public Library of Science (PLOS) (Fig. 3). There are clearly experiments where the risks outweigh the benefits, and it is important that mechanisms exist to prevent such experiments. However, in many cases, gain-of-function research-of-concern can very clearly advance pandemic preparedness and the development of vaccines and antivirals. These tangible benefits often far outweigh the theoretical risks posed by modified viruses. Thus, it is important that oversight mechanisms faithfully consider both risks and benefits of these types of studies. It is equally important that the mechanisms used to provide oversight of gain-of-function research-of-concern be focused on research that is indeed of concern. Identifying research of concern is complex but it is critical that safeguards be both thoughtfully designed and implemented to avoid suppressing innovation in a field essential to mitigating infectious disease threats and with the potential to transform health. Existing regulation of virology research in the United States. Without qualification, appropriate precautions should be taken to minimize laboratory accidents or the unjustified engineering of pathogens with enhanced pandemic potential. This is a shared goal for scientists and regulators. Virological research in the United States is subject to federal regulation through the Department of Health and Human Services and the U.S. Department of Agriculture for work involving human, animal, and plant pathogens. Federal policies are  (Fig. 1). The National Institutes of Health (NIH) established guidelines for the creation of IBCs in 1976 and updates these guidelines periodically. While each institution may have additional specific policies, the NIH requires that IBCs approve of research involving genetic manipulation of pathogens and that members of the local community are engaged through their inclusion on IBCs. As noted above, further oversight for A flow chart describing the steps a principal investigator must follow prior to receiving funding or initiating research considered dual-use-research-of-concern (DURC) on pathogens of pandemic potential (P3). The blue shaded box corresponds to the general practices that all investigators carry out at the institutional level described in Fig. 1. Research with the potential to enhance the properties of pathogen is referred for additional oversight. Asterisks (*) indicate an iterative process typically involving 1-3 reviews and revisions.
research involving viruses with pandemic potential exists at multiple levels, including federal funding agencies (e.g., Department of Health and Human Services, Department of Defense), institutions (e.g., colleges, universities, and research institutes), and most accredited publishers of scientific research ( Fig. 2 and 3) (17). It is important that we work to ensure appropriate and consistent implementation of these existing safeguards. We should also seek to develop international partnerships to ensure appropriate oversight is in place worldwide. While policy and infrastructure should frequently be reassessed with the goal of updating and improving biosafety and biosecurity, policy should not be changed rashly and without consideration of potential unintended consequences. Given the scientific complexities involved, such decisions should not be legislated. They should instead be made after full consideration by scientists with the relevant expertisewith appropriate oversight from Congress.

FIG 3
Publishing process for articles involving gain-of-function research-of-concern or with pathogens of pandemic potential at ASM journals. Articles in the GOF/DURC/P3 category are flagged by multiple layers at the screening stage. This process will initiate discussion among the scientific editor in chief and other subject matter experts and lead to a publication decision after careful consideration of risks and benefits.
Conclusion. As we enter the fourth year of the COVID-19 pandemic, it is clear that the scientific establishment has been the most effective shield protecting humanity from this calamity through the delivery of rapid tests, vaccines, antibody therapies, and small molecule antivirals. Millions are alive today that would otherwise be dead thanks to society's investment in creating and maintaining a vibrant scientific enterprise. In the debate on further restrictions around gain-of-function research and new regulations on virology in general, it is important to appreciate the existing framework of regulations at the federal and institutional levels. It is also critical to recognize that our ability to respond rapidly to emerging viral threats is dependent on our ability to apply the tools of modern biology to viruses. Regulations that are redundant with current practice or overly cumbersome will lead to unwarranted constraints on pandemic preparation and response and could leave humanity more vulnerable to future disease outbreaks. Gain-of-function research has been an extremely valuable tool in the development of vaccines and antivirals ( Table 2). It already has layers of regulations and checks in place to ensure that potentially unsafe research is immediately reported (Fig. 2). It is critical that policy makers, virologists, and biosafety experts work together to ensure that research is conducted safely, with the common goal of reducing the burden of disease caused by viruses.