The reality behind the “gain of function” legislation: Opportunities and risks

Matt McKnight & Swati Sureka

“Gain of function” (GOF) research — altering a microbe’s genetic makeup to give it additional functionality — is making headlines again. The White House is actively considering a broad set of regulatory changes, while federal and state legislators in Florida, Texas, and Wisconsin have moved to pause or ban these research activities altogether (Florida’s ban took effect in July). With the stakes continuing to rise on this topic, we thought we’d give our take on what’s going on and where we go from here.

What is GOF and why are we talking about it?

We have to start by being more precise. A wide variety of research uses “GOF techniques”, but much of it is not risky at all. This is a very broad category and we need to pinpoint where the actual risks are so we don’t artificially restrict really important research that will make us more prepared.

When people talk about concerning GOF research, what’s most often being discussed is a very small subset of GOF work on enhanced potential pandemic pathogens (ePPP). ePPP research seeks to anticipate and introduce mutations that increase transmissibility and/or virulence so that we can study host-pathogen interactions, assess transmission mechanisms and pandemic potential, and inform surveillance tools and medical countermeasures (i.e. it makes viruses more dangerous and sees how bad they could be).

Many say this is valuable to preparing for something bad to happen — though there’s substantial differences of opinion on how valuable it is. But the obvious flip side is that it’s risky. Experts estimate a substantial risk of laboratory incidents leading to accidental infections, which could increase as the number of maximum biocontainment labs grows if the right guardrails aren’t in place. Publishing the results of this research could also enhance opportunities for deliberate misuse.

Where does the policy landscape stand today?

For these reasons, the White House issued a moratorium on ePPP research in 2014, which was subsequently lifted with the establishment of the Potential Pandemic Pathogen Care and Oversight (P3CO) framework in 2017. But several gaps remain in this framework, along with the related Dual Use Research of Concern framework, and the National Science Advisory Board for Biosecurity (NSABB) published a set of recommendations for addressing them early this year.

These recommendations have stoked major debates. Many in the biosecurity community have emphasized that the U.S. policy changes, along with global alignment on them, is critical and a matter of common sense. Many in the virology community argue that they’re too vague and could hamper non-ePPP research and weaken the U.S.’s global position. Some policymakers say that they don’t go far enough, and ePPP research should be paused again or just banned.

These debates aren’t new. What has changed is that the stakes are higher now:

• The controversy over a potential laboratory leak as the origin of COVID-19 continues, at a time when the global footprint of biocontainment labs is booming and becoming more distributed;
• There are significant global concerns about lowering barriers to access for nefarious activities like bioweapons development, especially in light of next-generation AI tools;
• As geopolitical competition and conflict are accelerating, biological research capabilities are increasingly a target for foreign influence and data access, illicit activity, use of force, and disinformation.
• Pockets of immunity gaps still persist in the pandemic’s aftermath, meaning that there’s a larger-than-normal global population of vulnerable people that could be more susceptible to rapid spread of emerging pathogens — this is believed to be what’s happening in China.

These aren’t specifically GOF issues, but they’re reverberating through the GOF debate.

Where can we go from here?

As the heat rises on these policy decisions, commentators on all sides of the debate are digging their heels into the idea that scientific progress and research security are opposing forces to be balanced. And yes, policymakers do need to make tradeoffs now to strengthen oversight of risky research while minimizing barriers to other work — we should be considering additional biosafety and biosecurity measures today.

But in the longer term, binary thinking on science and security only sets us up for more cycles of blunt policy instruments and fearful resistance to safety enhancements in the future, with our best hope being to reach shaky, temporary compromises. We need to break this cycle for good, by finding a way to accelerate both science and security.

Biotechnology is critical to breaking down this binary and cultivating win-wins. To make genuine progress on the GOF issue, we need to invest in a future where we use biotechnology to reduce the need to conduct risky pathogen research without sacrificing on our level of preparedness for pandemics.

In talking to many experts about this, we see two complementary paths forward:

1. We can transition to less-risky alternative methods to study pathogens. Synthetic biology techniques make it safer, easier, and cheaper to study parts of viruses relevant to infection and immunity without having to use whole specimens that can replicate. New AI-based bioinformatic and computational tools, coupled with growing biological databases, are making strides in being able to predict how genetic mutations affect viral characteristics like transmissibility and virulence, clarify mechanisms of zoonotic spillover, and forecast what the epidemiological consequences of different biological incidents might be. We will need to pay careful attention to how we share this type of information and the models underlying it.
2. We can bolster rapid outbreak detection and response capabilities. We could also use research much more effectively, to dramatically improve our abilities to neutralize outbreaks in near-real-time. This starts with threat-agnostic early warning systems that persistently monitor for naturally-occurring and laboratory-derived or engineered threats. When threats emerge, targeted detection tools can already be developed quickly, and this is expected to get faster. Increasingly, AI-based forecasting tools can be used to select optimal response measures and inform the development of new countermeasures, like vaccines and therapeutics. Synthetic biology is accelerating the sophistication of associated platform technologies like mRNA, and in the event of an outbreak can enable high-throughput R&D by generating large libraries of viral components to screen and rapidly setting up assays to test functions like receptor binding or antibody evasion.

Safety, security, and scientific progress can and must go hand-in-hand. While we work to limit the risks of pathogen research today, we must also invest in biotechnology to pave the way to a safer future.