Virus World

An analysis of the controversial work indicates that a one-size-fits-all regulation strategy will have consequences. As US policymakers spar over how to regulate research involving potentially harmful pathogens, a report finds that it will be difficult to do so without compromising studies that are necessary for creating vaccines and life-saving therapies. Researchers at Georgetown University’s Center for Security and Emerging Technology in Washington DC scanned the scientific literature using an artificial-intelligence tool to assess where and how often ‘gain of function’ (GOF) studies are conducted. These studies, in which scientists bestow new abilities on pathogens by, for instance, inserting a fluorescent gene or making them more transmissible, are common in microbiology research, the team found, but only a small fraction of the research involves agents dangerous enough to require the strictest biosafety precautions in laboratories. The researchers also found that about one-quarter of studies involving GOF or loss of function (LOF) — in which pathogens are weakened or lose capabilities — are related to vaccine development or testing. “I was so relieved to see a data-driven approach” to assessing GOF research, says Felicia Goodrum, a virologist at the University of Arizona in Tucson. It helps to support the argument that GOF studies are paramount in molecular virology and are necessary to study the impact of genetic mutations that pathogens acquire in nature through evolution, she says...

Full report (August 2023):

https://cset.georgetown.edu/publication/understanding-the-global-gain-of-function-research-landscape 

Research at Boston University that involved testing a lab-made hybrid version of the SARS-CoV-2 virus is garnering heated headlines alleging the scientists involved could have unleashed a new pathogen.  There is no evidence the work, performed under biosecurity level 3 precautions in BU’s National Emerging Infectious Diseases Laboratories, was conducted improperly or unsafely. In fact, it was approved by an internal biosafety review committee and Boston’s Public Health Commission, the university said Monday night. But it has become apparent that the research team did not clear the work with the National Institute of Allergy and Infectious Diseases, which was one of the funders of the project. The agency indicated it is going to be looking for some answers as to why it first learned of the work through media reports. Emily Erbelding, director of NIAID’s division of microbiology and infectious diseases, said the BU team’s original grant applications did not specify that the scientists wanted to do this precise work. Nor did the group make clear that it was doing experiments that might involve enhancing a pathogen of pandemic potential in the progress reports it provided to NIAID.  Asked if the research team should have informed NIAID of its intention to do the work, Erbelding said: “We wish that they would have, yes.”

The research has been posted online as a preprint, meaning it has not yet been peer-reviewed. The senior author is Mohsan Saeed, from BU’s National Emerging Infectious Diseases Laboratories. STAT reached out to Saeed on Monday but had not received a response by the time this article was published. In emailed comments, the university later disputed the claims made by some media outlets that the work had created a more dangerous virus. The email, from Rachel Lapal Cavallario, associate vice president for public relations and social media, said that the work was not, as claimed, gain of function research, a term that refers to manipulation of pathogens to make them more dangerous. “In fact, this research made the virus [replication] less dangerous,” the email stated, adding that other research groups have conducted similar work. In the paper Saeed and colleagues reported on research they conducted that involved creating a hybrid or chimeric virus — in which the spike protein of an Omicron version of SARS-2 was fused to a virus of the Wuhan strain, the original version that emerged from China in 2020. Omicron viruses first emerged in late 2021 and have since splintered into multiple different sub variants. The goal of the research was to determine if the mutations in the Omicron spike protein were responsible for this variant’s increased ability to evade the immunity to SARS-2 that humans have built up, and whether the changes led to Omicron’s lower rate of severity. The testing actually showed, though, that the chimeric virus was more lethal to a type of lab mice than Omicron itself, killing 80% of the mice infected. Importantly, the original Wuhan strain killed 100% of mice it was tested in.

The conclusion of the study is that mutations in the spike protein of the Omicron variant are responsible for the strain’s ability to evade immunity people have built up via vaccination, infections, or both, but they are not responsible for the apparent decrease in severity of the Omicron viruses. “Consistent with studies published by others, this work shows that it is not the spike protein that drives Omicron pathogenicity, but instead other viral proteins. Determination of those proteins will lead to better diagnostics and disease management strategies,” Saeed said in a comment circulated by the university. Research that has the potential to make pathogens more dangerous has been a hot-button issue for years. About a decade ago, a high-profile debate over whether it was safe to publish controversial studies done on a dangerous bird flu virus, H5N1, led to a re-writing of the rules around this type of work. Another review of the policy is currently underway, led by the National Science Advisory Board for Biosecurity.  The controversy around research on pathogens of pandemic potential has gained ground since the start of the Covid-19 pandemic, which some scientists and others believe may have been an accidental or deliberate result of research on bat coronaviruses at the Wuhan Institute of Virology in the Chinese city where the pandemic is believed to have begun. (There is a lot of evidence that points to the virus spreading from a wet market in the city, not the Wuhan lab. But proving something didn’t happen three years after the fact is a challenge that may be impossible to meet.)

Under NIAID’s policy, proposals to do federally funded research that could produce so-called enhanced pathogens of pandemic potential should be referred to a committee that would assess the risks and benefits of the work. The policy is known as P3CO framework. Erbelding said NIAID would probably have convened such a committee in this case, had it known that Saeed’s team planned to develop a chimeric virus. “What we would have wanted to do is to talk about exactly what they wanted to do in advance, and if it met what the P3CO framework defines as enhanced pathogen of pandemic potential, ePPP, we could have put a package forward for review by the committee that’s convened by HHS, the office of the assistant secretary for preparedness and response. That’s what the framework lays out and that’s what we would have done,” she said. Erbelding noted, however, that some of the media coverage of the study over-estimates the risk the work may have posed. “That 80% kill rate, that headline doesn’t tell the whole story,” she said. “Because Wuhan” — the original strain — “killed all the mice.” The fatality rate seen in this strain of mice when they were infected with these viruses raises questions about how good a model they are for what happens when people are infected with SARS-2. The Wuhan strain killed less than 1% of people who were infected.

Virologist Angela Rasmussen, who was not involved in the research, had some sympathy for the BU scientists, saying there is ambiguity in the rules as they are currently written. “Because so much of the definition of ePPP pertains to ‘reasonable anticipation’ of results in humans (and animal models are not always good proxies of this), it’s very difficult for researchers to say ‘Oh yes, this is ePPP,” Rasmussen wrote in response to questions from STAT. “I’d personally reach out for clarification from NIAID when in doubt, but it’s often not obvious when additional guidance is warranted. And because it’s not very transparent, it’s hard to look at other decisions NIAID has made for examples,” she said. “I’m very tired of people suggesting that virologists and NIAID are reckless or don’t care about biosafety,” said Rasmussen, a coronavirus expert at the University of Saskatchewan’s Vaccine and Infectious Disease Organization. “The problem isn’t that. The problem is that the guidelines and expectations aren’t clear for many experiments and the process isn’t transparent.”

Cited preprint in bioRxiv (Oct. 14, 2022):

https://doi.org/10.1101/2022.10.13.512134 

In the wake of the Covid-19 pandemic, we’ve heard a lot about gain-of-function research, and some of its risks, particularly regarding the possible creation of dangerous pathogens. But there’s a lot more to this field than that, including research that could potentially be quite beneficial to human society. If we focus solely on the risks, we may miss those benefits. First, we need clarity on what gain of function is. Gain-of-function is a specific type of life sciences research that confers some new or additional trait to an organism of interest. As other experts have discussed, this research covers a broad range of work for a variety of purposes. This might include directly manipulating microbes to create more salt- and drought-resistant plants to address food security in the face of a changing climate, or indirectly manipulating microbes in labs to select for positive and potentially game-changing functions, such as creating E. coli strains that can consume and degrade plastic waste. Within the context of Covid-19, one specific type of gain-of-function work has become a lightning rod in global conversations: the modification of a pathogen to increase the infectivity or severity of the disease it causes. People have understandable concerns on several fronts, including how such research is conducted, reviewed, approved, and governed, as well as how it may exacerbate biological threats from deliberate, natural, and accidental causes. However, focusing exclusively on this one type of research has created deep rifts across key communities that balance innovation with safety and security in the life sciences. These rifts have made it almost impossible to have necessary, productive conversations to address global problems while ensuring such work is done safely and securely. Narrowing the definition of gain of function to only pathogen modification that prevents or addresses pandemic-level disease outbreaks is impeding progress in this space.

Focusing predominantly on the risks can have three challenging effects. First, it may skew risk assessments to overlook the potential benefits. Critical gain-of-function work is necessary to develop animal models that reasonably mimic human infection. This step minimizes direct human experimentation and provides insights on how diseases enter and progress inside such models. This work then provides crucial insights into how scientists can develop diagnostics and medical countermeasures, including live-attenuated and other types of vaccines, to detect, diagnose, and treat individuals with such emerging diseases. Further, as we have seen with Covid-19, emerging pathogens may evolve and change over time, which means they may overcome or evade detection capabilities and therapeutic interventions: gain-of-function research plays a key role in forecasting what changes may be coming, leading to an improved understanding of these emerging and evolving pathogens for disease surveillance and medical intervention purposes. Second, an overly narrow definition ignores entire areas of research that incorporate components that involve gain-of-function work. For example, a common practice to add a “trait” to a microbe is to introduce a gene encoded on a plasmid — circular strand of DNA — into a cell, where it will express the gene of interest. As part of this process, scientists typically attach a “reporter” gene such as green fluorescent protein, which helps identify successful gene expression. Although technically the addition of green fluorescent protein is a gain of function, its use as a reporter is not a threat to human health or a significant biorisk requiring mitigation. Being cognizant of the variety of ways gain of function manifests itself across life sciences research will be critical to maximize benefits and minimize risks and confusion in this area.

Finally, policymakers must consider the impact that our current information environment has on how science is communicated and perceived by the global community. Misinformation, disinformation, and state-based propaganda are not new phenomena. However, the porous nature of information exchange in an increasingly interconnected world through the internet and social media can be a double-edged sword: While scientific information can be shared more quickly than ever, misinformation can be shared exceptionally quickly as well on scientific activities, leading to an erosion of trust in science. The eroding trust in science — encouraged by certain adversaries taking advantage of the diffuse nature of the internet — is troubling as life sciences research will be critical in the coming years to address the accelerated emergence of biological threats. Scientists predict that diseases that may cause epidemics and pandemics are likely to emerge more frequently due to factors such as climate change, large-scale migration, and destructive land-use practices that bring humans into contact with animals and insects in previously ecologically preserved locations. Given this tension between necessity and hazard, stakeholders must remain clear-eyed about what work is necessary to accomplish scientific goals while effectively mitigating major risks. Despite the challenges, there are paths to move forward to keep the life sciences innovative, address key anticipated issues in the future, and ensure that research is safe and secure. Biosecurity and biosafety are a critical part of this research, and as science evolves, so must the policies.

Addressing these challenges will require four steps.

First, we need a coordinated communication effort that addresses the current disinformation campaign realities across a vast ecosystem of science communicators and stakeholders, from official international and domestic governmental organizations such as the World Health Organization and the U.S. National Science Advisory Board for Biosecurity to local and regional efforts from academic institutions. This will involve frequent communication, coordination, and even camaraderie between key organizations and institutes that deal with life sciences safety, security, and innovation issues. Further, this effort will need to balance the difficulties of technical issues with the need to be transparent to a global audience. Second, it is important to make clear that biosecurity and biosafety efforts do not run counter to gain-of-function research, whether or not they involve potential pandemic pathogens. Biosecurity and biosafety oversight and efforts to understand potential pandemic pathogens, and such work involving gain of function, are meant to work in tandem. In the National Academy of Science’s 2004 report “Biotechnology Research in an Age of Bioterrorism,” the expert committee came to the conclusion that despite certain types of gain-of-function research that raise concerns, “policies to counter biological threats should not be so broad as to impinge upon the ability of the life sciences community to continue its role of contributing to the betterment of life and improving defenses against biological threats.” To this end, the committee identified seven categories of experiments that raise additional concerns, and offered practices and policy recommendations to mitigate the risks associated with these types of experiments. Third, there is a critical need to increase science literacy across local, regional, and global communities. Science literacy not only enables more informed individual and collective decision-making in the biorisk space, but also potentially acts as a buffer against science-related misinformation and disinformation, a prime focus for adversaries seeking to undermine local, regional, and international relationships. Finally, the global community needs to come to terms with the fact that everyone’s risk tolerance is unique, and that includes scientific research. Scientists and stakeholders in this space will likely have different risk tolerances, which creates challenges to building consensus. Therefore, it helps all stakeholders to be curious, humble, and open to communication as we continue the dialogue on the full spectrum that gain-of-function research encompasses, including the purported risks and benefits.