Gain-of-function research: What is it and how can the federal government better monitor it?

There have been plenty of controversies recently over something called gain-of-function research. 

Amid the highly-politicized debate over the origin of the COVID-19 virus, the term has been thrown around in the media and among lawmakers in Congress. 

More recently, Pfizer refuted accusations that it was conducting potentially dangerous gain-of-function or directed evolution research to help develop vaccines.

Now, a recent report from the Government Accountability Office (GAO), a federal watchdog agency, clarifies what exactly gain-of-function research means while also pointing out critical ways the government can improve its oversight over this type of research.

“The media isn’t always using [the term ‘gain-of-function’] properly — and it’s not just the media,” Mary Denigan-Macauley, director of public health at the GAO, said. “In Congress, they’ve been using it improperly as well.”

In short, gain-of-function is an umbrella term for a broad body of research, much of which is considered useful by scientists to better understand how viruses work and mutate, as well as how we can better detect and predict them.

In 2015, for example, researchers at the University of North Carolina in Chapel Hill manipulated a coronavirus linked to severe acute respiratory syndrome (SARS) in a lab, adding surface proteins from a separate coronavirus in bats.

The resulting virus was able to infect mice and human cells, the researchers found. They concluded that other coronaviruses could, in the future, lead to human pandemics — a portent of the COVID-19 outbreak.

At its fundamental level, gain-of-function involves mutations of viruses that lead to new functions of genes or proteins. Virologists will often conduct research that involves such mutations to better understand how viruses may become more transmissible. Usually, these mutations are conducted in relatively safe ways, such as in the lab, in animals or cell cultures, and often in pathogens not dangerous to humans.

Additionally, this type of activity can yield meaningful results. Scientists working to develop COVID-19 vaccines for AstraZeneca and Johnson & Johnson based their research on adenoviruses that were tweaked to produce the COVID-19 spike protein, according to Nature.

“Gain-of-function can have positive benefits,” Denigan-Macauley explained. “For example, we can change the function of how a pathogen works in order to boost vaccine production. Importantly, it’s just one small aspect of gain-of-function that we’re worried about.”

That small part of gain-of-function research that presents potential risks centers on “enhanced potential pandemic pathogens” — which could be harmful to humans if accidentally leaked from a lab.

Such pathogens, typically those that cause respiratory illness in humans or could spark potential pandemics, comprise “gain-of-function research of concern,” or GOFROC, a definition developed by the National Science Advisory Board for Biosecurity (NSABB).

Much of the polarized controversy around gain-of-function, especially among Republican lawmakers, refers to that subset of research. 

Sen. Rand Paul, (R-Ky.), has zeroed in on gain-of-function research in his attacks on the National Institutes of Health, claiming such research led to the COVID-19 pandemic.

Additionally, Sen. Marco Rubio, (R-Fla.), sent a letter to Pfizer CEO Albert Bourla late last month to ask if the company was manipulating the COVID-19 virus through gain-of-function research, suggesting that such activity put “profit over the concern of national and global health.”

Denigan-Macauley noted that there isn’t an official consensus on how the COVID-19 virus originated. Some researchers and organizations have concluded that the virus appeared naturally, transmitting from animals to humans.

Still, from the GAO’s standpoint, the debate is almost irrelevant to the issue of gain-of-function research. 

She said much of gain-of-function research can be valuable for public health and future pandemic preparedness. For the small part that can be dangerous, she argued that the federal government should strengthen its oversight for the future.

The GAO report honed in on the role of the Department of Health and Human Services (HHS) in particular, which oversees federally-funded potential pandemic pathogen research.

“What we found is this oversight was not always as transparent as we’d like it to be,” Denigan-Macauley said. “We also found there were gaps in [HHS’] ability to oversee the type of work that could be done specifically related to emerging pandemic pathogens. A lot of the oversight is aimed at federally-funded research, so we don’t have a good understanding of how much of this research is being conducted overall.”

The GAO listed several recommendations for HHS, such as improving transparency and clarifying the definitions of research involving potential pandemic pathogens. The agency also called on the HHS to get a clearer picture of all the gain-of-function research happening in the U.S., including in the private sector, to better monitor it.

The GAO isn’t the only one calling on the federal government to improve oversight into this research. 

An expert advisory panel at the NSABB recently released draft recommendations urging the White House to expand the definition of potential pandemic pathogens to include more pathogens. The panel also suggested limiting the amount of such research occurring by instituting additional regulations.

Those draft recommendations prompted debate among both political leaders and public health experts. Interestingly, some scientists support increased gain-of-function regulation while others express concern that such rules could hamper or overburden important research for public health.

“Gain-of-function research has been an extremely valuable tool in the development of vaccines and antivirals,” a group of virologists wrote in an article published in the Journal of Virology. “Our ability to respond rapidly to emerging viral threats is dependent on our ability to apply the tools of modern biology to viruses.”

Denigan-Macauley is the first to clarify that there certainly are public health benefits to conducting gain-of-function research but stressed the importance of increasing safety around it.

“Having awareness of the type of research that could lead to an outbreak is absolutely imperative,” Denigan-Macauley said. “We want to ensure that we’re doing any kind of related work in the most secure way we possibly can.”