Virology under the Microscope—a Call for Rational Discourse (150 virologists condemn Republican congressional oversight, dismiss the lab leak hypothesis as "unfounded", cheer gain-of-function research, and call "ill-informed" those who disagree)

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.

Just 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.

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 and – whether intentional or not – add 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.

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 have been investigated, currently the zoonosis hypothesis has the strongest supporting evidence (5–8). Zoonosis involves transmission of 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.

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-of-function 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-pandemic-pathogens-care-and-oversight (P3CO) (15) (Fig. 2), and also by the vast majority of international publishers, including the American Society of 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.

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 guided by the Biosafety in Microbiological and Biomedical Laboratories (BMBL) guidelines (16) published by the Centers for Disease Control and Prevention (CDC) and implemented by Institutional Biosafety Committees (IBCs) that manage the safety and practice of laboratory research at the local level (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 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 expertise – with appropriate oversight from Congress. 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.

The opinions expressed reflect those of the authors, and not necessarily the opinions of ASM, the authors’ institutions, or funding agencies. We acknowledge Johnny Chang for his assistance with graphics.

No funding was used to support this commentary, but we wish to disclose funding from agencies received by authors. JCA None WJA NIH DCA NIH JDB NIH BWB CIHR, NSERC LB Associazione Italiana per la Ricerca sul Cancro, ICGEB SBM NIH DB NIH, Private Foundation DBM Private Foundation DCB NIH, Private Foundation ACB NIH SB None CRB NIH, NSF, Private Foundation AJB USDA, Biotechnology and Biological Sciences Research Council (BBSRC), UK CBB NIH, DOD CEC NIH SKC NIH PC NIH AC NIH GCC NIH ARC NIH, Private Foundation JMC NIH KC NIH BD NIH MDD NIH, Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Program KD None JAD NIH, Private Foundation TSD NIH, Private Foundation, Heinz Endowments JDD Canadian Institutes of Health Research and Natural Sciences and Engineering Council of Canada DD NIH RRD NIH, USDA, Private Foundation WPD NIH, Zoetis LLC, Moderna, Coalition for Epidemics Preparedness Initiatives (CEPI) RED NIH NCE NIH, Howard Hughes Medical Institute ME NIH LWE None BAF NSF AFS NIH MLF NSF, USDA, Private Foundation LF Canadian Institutes of Health Research (CIHR) MBF NIH, Novavax, Astrazeneca, Pfizer, BARDA, Eli Lilly KF NIH, DOD, Bill and Melinda Gates Foundation MUG NIH MMG NIH, Private Foundation TG NIH DG NIH, Private Foundation AG-S NIH, DOD, Private Foundation APG NIH BAG NIH, Howard Hughes Medical Institute SPG NIH, Private Foundation FG NIH ALG None MHH NIH EH NIH NSH NIH, DOD, Private Foundation MTH NIH EEH NIH, Private Foundation BGH NIH, NSF SMH NIH ECH UK Medical Research Council, UK Medical Research Council JMH NIH MJI NIH, Via Nova Therapeutics WTJ NIH RFK NIH JPK NIH SMK NIH FK German research foundation (DFG), European research council (ERC) DMK NIH TK NIH, Moderna ML NIH LL NIH SSL NIH RAL NIH ASL NIH, Burroughs Wellcome Fund, Flu Lab, CDC BL NIH, NSF, Private Foundation DAL NIH SL NIH, Private donor's fund, Ohio State. startup fund RML NIH CBL NIH ACL NIH, Private Foundation MAL NIH JML NIH BM NIH GM NIH MTM NIH, DHS AMehle NIH, Private Foundation WAM NIH, Plant Sciences Institute, Iowa State University IM NIH CM NIH NJM NIH AMoscona NIH BCM NIH KM NIH JCM NIH EAM NIH MHN NIH JAN NIH CJN None JZN NIH CMO None AO NIH WAO NIH, Bill & Melinda Gates Foundation DAO NIH, Private Foundation JHJO NIH JSP NIH CRP NIH, Private Foundation AP NIH, Private Foundation, CDC PEP NIH JKP NIH, Private Foundation RKP NIH, DOD, Gilead Sciences, Enanta Pharmaceuticals SJP None JGP NIH DP NIH, Private Foundation MQM NIH, Private Foundation RR NIH CMR NIH, Private Foundation RJR NIH CJR NIH RS-G NIH MS NIH LMS NIH, Cornell University, Private donors, Fast Grants SS None JWS NIH SSC NIH, Private Foundation BLS NIH TS NIH, DOD GS NIH, Private Foundation VS NIH, Private Foundation GAS NIH, USDA JGS NIH KRS NIH MLS start-up funds from the University of Florida KS Australian government, NHRMC WIS NIH MSS NIH TCS NIH, USDA AWT NIH VLT NIH, Private Foundation BT NIH, DOD, Private Foundation SAT NIH SMT NIH ZT NIH KVD NIH, Private Foundation MV None NAW NIH DW NIH MPW Medical Research Council, UK (MR/W025647/1); UKRI mpox research consortium (BB/X011143/1) JBW NIH MDW NIH SKW NIH EAW NIH, Private Foundation SPJW NIH, Private Foundation, USAID, Vir Biotechnology BRGW Private Foundation CEW NIH, University of Michigan SWW NIH ADY NIH.

COVID didn’t bring the world to its knees. The governments did.

They can come up with all the different vaccines they want. I will never get a vaccine for anything from here on out.

Follow the money.

These $cient$s” fear their feeding at the public trough ending.

Lowlifes. Morons. Should all hang for crimes against humanity.

“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.”

Ok. It was a bat at a wet market.

The opinions expressed reflect those of the authors..

The 'author's' opinions are appalling and politically suspect. The actions taken by governments around the world in response
to these virologists admonitions have crippled economies, burdened social interactions, and retarded the education of countless children.

The hubris of these 'scientists' is vomit inducing.

Seems to me there is an abundance of NIH activity. It is mostly coming from that source. Maybe they should be thouroughly be investigated.

No funding was used to support this commentary, but we wish to disclose funding from agencies received by authors.

Xxxxxxxxxxxxxxxxxxxxxxxxx

How many are soroz sponsored NGO’s?

So.....Republican oversight bad, but Dem ‘oversight’ with the goal of empowering the goobermint at the people’s expense and doing an end run around the consent of the governned, just hunky dory? Yes?? Go inject yourselves, virologists!

I personally know at least one of the authors. This is just an opinion piece that speaks to the importance of funding ongoing virology research. I'm sure that many of the authors/co-signatories are concerned that all virological research will get lumped in with the type of gain of function research that was done in Wuhan. That said, I strongly disagree that the zoonoses theory of Covid-19 is the most likely. From the beginning it was always most likely a leak from the Wuhan lab where they were mutating the spike protein to target human receptors - like ACE2.

The gaslighting continues...as expected, given that a multibillion-dollar enterprise now hangs in the balance.

I’ve posted before how this ‘gain of function’ term is a red herring...to deaf ears.

But alrighty, then. /s

COVID didn’t bring the world to its knees. The governments did!

You're absolutely correct.

Virology is also pseudoscience.

I'll say again, SARS-CoV-2 supposedly virus they say that cause Covid-19 infection is nonexistent. If doesn't exist, there's no lab leak. It's all hoax and scaremongering...

All other so-called human pathogenic virus not even to cause disease.

Dr. Stefan Lanka: “All claims about viruses as pathogens are false!”

Read the link.

https://greatreject.org/dr-stefan-lanka-claims-about-viruses-are-false/

Thanks for the link. I posted an NPR article about this earlier today.

This is probably about bird flu experiments. They were manipulating bird flu virus years ago (2007 I think) And the government shut them down.

Now there is a report that minks in Spain are spreading it too each other, so they want to manipulate the virus with the excuse they need to do this to make a vaccine.

And I also posted that Ecohealth got Dept of defense money to build a biolab here in the Philippines to do research on wild animal viruses that could infect humans.

These are probably legitimate research projects, but when they continue to lie about covid, I don't trust them.

This strikes me as a very presumptuous position that these learned virologists believe they are entitled to. I guess the plebeians just don’t get a vote. Professional ethics is weak.

My opinions.

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