Gain-of-function research is about much more than dangerous pathogens

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.

What does this look like in the modern day? For scientists, this means acting in good faith when accurately communicating not only scientific knowledge, but also gaps in their work. For the biosecurity and biosafety communities, this means building relationships and perspectives with the scientific community to ensure that innovation, safety, and security are all balanced in ways that are feasible.

And for the broader global community, including policymakers, this means engaging across the life sciences ecosystem to ask questions and seek information while also respecting that scientists are people, too. They — we! — share the same concerns that the general public does, and are doing what they can to ensure the necessary work they do is conducted safely and securely.

Concepts such as gain of function are exceptionally nuanced, complex, and have even changed over time. This creates perennial, dynamic challenges for the scientific, safety, and security communities to make substantive advances on these issues, let alone the nontechnical policymakers and public. Ultimately, these communities seek the same goal: innovative, safe, and secure life sciences research to help solve critical global issues.

Saskia Popescu is an infectious disease epidemiologist and assistant professor at George Mason University within the biodefense program, where she addresses biopreparedness and global health security. Yong-Bee Lim is a biosecurity expert who has focused on biorisk issues at the intersection of the life sciences research and emerging and converging technologies. Angela Rasmussen is a virologist specializing in emerging zoonotic pathogens at the Vaccine and Infectious Disease Organization at the University of Saskatchewan.