What the heck is ‘gain-of-function’? Understanding the hubbub behind a scientific research method

Unless you work in a laboratory or a university, you probably don’t spend much time thinking about different scientific research approaches.

If nerdy technical phrases such as “cohort studies” and “randomized controlled trials” don’t mean much to you, odds are good you’re also unfamiliar with “gain-of-function” research.

The term broadly describes experiments that genetically alter organisms to give them new skills or enhance existing traits. It’s often used in agriculture, medicine and sustainability research.

The federal government on July 28 announced it would stop funding some of this research. So we’re here to explain what it is.

What is gain-of-function research?

Allen Segal, chief strategy officer for ASM, a professional life sciences association, likened gain-of-function research to someone trying to make their car faster by giving it different tires or altering its engine. First, you’d make the changes, then you’d test them, and along the way you might learn how each part affects how the car works.

Michael J. Imperiale, a University of Michigan professor emeritus of microbiology and immunology, said some people use “gain of function” to refer exclusively to a subset of experiments — those in which “an infectious agent such as a virus becomes more virulent.” The result, they warn, can make people sicker, spread more easily or evade a vaccine.

Why do scientists conduct gain-of-function experiments? 

It doesn’t always involve making a microbe more dangerous. The technique can make an organism easier to detect in a lab. For example, it could be used to make a microbe express a fluorescent protein so it becomes easier to see under a microscope, Segal said.

Genetically manipulating pathogens can help researchers learn how they infect, replicate and cause disease, said Felicia Goodrum, a Dartmouth College microbiology and immunology professor.

In the early 2010s, studies showed that a few mutations could make the H5N1 avian influenza virus transmissible between mammals — something previously viewed as rare or even impossible among these viruses.

That’s useful information for public health authorities, who could “look for whether such mutations are happening in birds and take action before the virus has a chance to spread in humans,” Imperiale said.

Scientists might also develop antibiotic-resistant bacteria hoping to develop drugs that work in a different manner, he said.

Gain-of-function research outcomes are seen in various ways, experts said.

Recombinant insulin used to treat diabetes was created by genetically altering the bacteria E. coli or the fungus yeast so that it produces the insulin hormone. In 2021, researchers investigating how to reduce plastic waste modified E. coli so that it converted plastic into vanilla flavoring. Some oncolytic viruses — viruses that infect and break down cancer cells — work as cancer treatments because they’ve been given new properties that kill tumors.

Does this research have risks?

It has sparked controversy more than once in the past 15 years. The H5N1 gain-of-function research prompted scrutiny and triggered the government to create guidelines and require oversight. Then, during the COVID-19 pandemic, people circulated an unproven theory that the virus, SARS-CoV-2, had leaked from the Wuhan Institute of Virology in China.

Gain-of-function’s controversy stems from fears that a manipulated pathogen could escape the confines of laboratory research, causing severe disease spread. Another concern is that bad actors could try to use the findings to deliberately cause harm.

Goodrum said stringent U.S. biosafety protocols block especially high risk gain-of-function experiments.

This research is also conducted in biosafety laboratories that are designed to prevent pathogens from accidentally escaping, Imperiale said.

“To mitigate the risk, scientists are highly trained about how to work safely with these agents, especially since they would be the first people who are exposed,” he said.

March Lipsitch, a Harvard University epidemiology professor, is among scientists who believe gain-of-function research’s benefits do not outweigh its potential risks.

Findings from gain-of-function research can’t always be applied broadly: Viral strains made in laboratory experiments aren’t guaranteed to match naturally occurring environmental viruses. Even very similar viral strains can behave differently.

“There’s a big element of randomness in evolution,” Lipsitch told the Los Angeles Times in 2024. “The fact that an experiment goes one way in the lab doesn’t mean it will go the same way somewhere else.”Goodrum sees it differently, saying a lot of gain-of-function research has vast benefit and very little risk. She said experiments are carefully reviewed by the institution planning to conduct them and the agency helping to fund them. The benefits of high-risk research should be carefully evaluated and those with little benefit should not be done — and those guardrails are in place, she said.

“Improvements are possible, but no science in the U.S. is conducted without this sort of oversight,” Goodrum said.

Has the U.S. ended funding for gain of function?

In late July, the Trump administration announced a policy that would end federal funding for what it deemed “dangerous” gain-of-function research, defined as research that “enhances a property or properties of a biological agent in ways that make it more dangerous.”

The administration listed seven criteria, any of which would mean the research would qualify as being deemed “dangerous.”

Some gain-of-function research could still receive federal funding under the policy, provided it has the potential to result in one or more of the seven outcomes that constitute dangerous gain-of-function research, but only after an independent third-party group reviews and recommends it.

During an Aug. 2 Fox News interview, Health Secretary Robert F. Kennedy Jr. accused gain-of-function research of contributing to the spread of Lyme disease, RSV and COVID-19. Research does not support that gain-of-function research created the bacteria responsible for Lyme disease or the virus behind RSV. Although the exact origins of SARS-CoV-2 remain disputed, Imperiale said there is “zero credible evidence” it was the result of a gain-of-function experiment.