‘Gain-of-function’ research: What it is and who is doing it in North Carolina

·8 min read

A fiery exchange between Sen. Rand Paul and Anthony Fauci, the country’s top infection disease expert, during a congressional hearing on Tuesday is bringing attention once again to a type of research referred to as gain-of-function.

The shouting match between Fauci and Paul was about whether the National Institutes of Health had ever funded gain-of-function research at a prominent virology lab in Wuhan, China.

As the origin of the COVID-19 pandemic remains unknown, eyes have been turning toward the Wuhan lab, which is located in the city where the first cases of COVID-19 were reported.

In May, President Joe Biden called for a more thorough investigation of the origins of the pandemic, with the potential of the virus being leaked from a lab being re-examined. However, a natural origin of the virus via animal-to-human transmission is still considered most likely by scientists.

But the reconsideration of a lab leak has led to more inquiries into protocols at the Wuhan lab, including whether it was conducting gain-of-function research to make coronaviruses more transmissible.

The subset of research known as gain of function has caught the attention of many, including North Carolina Republican Rep. Madison Cawthorn, who said on Tuesday that gain-of-function research in North Carolina needed “to be stopped forthwith.”

Here are answers to some common questions about the research and its presence in North Carolina.

What is gain-of-function research?

Gain-of-function research has gone on for years and involves experiments that take viruses, or other organisms, and alters their genetic make up to gain a new ability. In viruses, this can mean making it more transmissible or perhaps more deadly.

The research is often intended to demonstrate how viruses could evolve in the near future, and give researchers something on which to test different medical treatments, like vaccines.

In theory, if you could show how one virus that isn’t dangerous to humans at the moment could evolve to attack the human immune system, you could begin preparing for a future where that virus variant exists.

Do you have questions about gain-of-function research that you would like answered? Send them to me at zeanes@newsobserver.com.

Why is gain-of-function research controversial?

This type of research has long been controversial, with many scientists saying the risks outweigh any potential insights from it.

In fact, concern over the potential danger of creating a new virus that could be highly contagious to humans led to the administration of President Barack Obama putting a moratorium on new gain-of-function research in 2014. However, this ban only applied to gain-of-function research that was being conducted on the SARS, MERS and influenza viruses.

The ban had its origins in a 2011 study involving H5N1 influenza viruses that had been modified in a lab to make airborne transmission possible between ferrets, The Lancet reported. The National Science Advisory Board for Biosecurity asked researchers not to publish their methodology for modifying the H5N1 virus over concerns that bad actors could use it to cause an outbreak in humans. (Those studies, however, were eventually released in full.)

Then in 2014, a series of security mishaps at Centers for Disease Control labs caused a re-examination of lab security across the nation, and built momentum to limiting gain-of-function research.

The ban was lifted in 2017. Now gain-of-function research is evaluated on a case-by-case basis with a review board at the U.S. Department of Health and Human Services signing off on experiments with high scientific merit.

Scientists were split on the decision, with some calling it necessary and others saying it would leave society less prepared to deal with future pandemics.

“Gain-of-function experiments allow us to understand how pandemic viruses evolve, so that we can make predictions, develop countermeasures, and do disease surveillance,” Carrie Wolinetz, head of the NIH Office of Science Policy, told The Lancet in 2018.

But Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health, told the science journal Nature that he believed most gain-of-function studies “have done almost nothing to improve our preparedness for pandemics — yet they risked creating an accidental pandemic.”

Is it being done in North Carolina?

Gain-of-function research has been done in North Carolina, most notably at the lab of UNC-Chapel Hill researcher Ralph Baric.

Baric is one of the world’s preeminent coronavirus researchers, beginning his study of the family of viruses in the 1990s before they were seen as potentially pandemic-level dangerous to humans.

Baric has used gain-of-function techniques to show how coronaviruses could evolve to infect humans and to test new vaccine methods to neutralize them.

This research, and his co-byline with a Chinese scientist on a 2015 paper, has made him the subject of many conspiracy theories over the past year over the origin of COVD-19. But the virus Baric used in the 2015 paper is a completely different strain from the one that causes COVID-19.

The 2015 paper, co-authored with more than a dozen other scientists, including one associated with the Wuhan Institute of Virology, a lab located near the epicenter of the COVID-19 outbreak, showed coronaviruses in bats were capable of directly infecting humans rather than evolving in another animal first.

Bats have been shown to be responsible for other coronaviruses in the past, like SARS and MERS, though the virus passed through a different animal host before infecting humans in those cases. To prove the theory, scientists created a a hybrid version of a bat coronavirus (the gain-of-function in this experiment) and used it to infect mice whose modified genomes mimicked human lung receptors.

This experiment was already underway when the government moratorium on gain-of-function research was imposed. But it was granted an exemption by the National Institutes of Health under a clause that allowed gain-of-function research if it was necessary to protect public health, The MIT Technology Review reported.

Baric noted in his paper the large safety precautions taken for his research, including the fact that it was done in a biosafety level 3 lab, air-locked to keep potential airborne toxins from escaping. But even at Baric’s lab, accidents have happened, including a researcher being bitten by an infected mouse.

In the paper, Baric noted that the merits of this type of research were being debated. “The potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens,” he wrote. “Scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue.”

But Baric’s work had critics. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” Richard Ebright, a molecular biologist and biodefence expert at Rutgers University, told Nature.

Gain-of-function research is not limited to viruses. A search of NIH grants to North Carolina institutions shows dozens of projects that mention the term gain-of-function, including ones at N.C. State University looking at pig models for colorectal cancer and one at Duke University that is studying how the heart repairs itself after heart attacks.

Did NIH fund Chinese gain-of-function research?

Unlike in Chapel Hill, similar research on coronaviruses at a lab in China were only done at BSL-2 safety levels, Technology Review reported.

The Wuhan lab had received funding from the National Institutes of Health, though not directly. In 2015, the NIH gave a roughly $3 million grant to the nonprofit EcoHealth Alliance to study bat-borne coronaviruses in China, NPR reported. A small part of the money — about $76,000 per year, according to NPR — went to the Wuhan lab as a subcontractor.

The NIH did not consider EcoHealth’s work with the Wuhan lab to be gain-of-function because it did not have the goal of making viruses more deadly or transmissible, Technology Review said.

“This has been evaluated multiple times by qualified people to not fall under the gain-of-function definition,” Fauci said of the funding on Tuesday.

In an interview with Technology Review last month, however, Baric expressed concern with how coronaviruses were being studied in BSL-2 labs in China, But he still believes a natural origin for the virus is more likely than it being the result of a lab leak.

Baric and 17 other scientists signed a letter earlier this year that called for a more thorough investigation of the Wuhan lab and the potential of a lab leak.

“Let’s face it: there are going to be unknown viruses in guano, or oral swabs, which are oftentimes pooled. And if you’re attempting to culture a virus, you’re going to have novel strains being dropped onto culture cells,” Baric told Technology Review. “Some will grow. You could get recombinants that are unique. And if that was being done at BSL-2, then there are questions you want to ask.”

This story was produced with financial support from a coalition of partners led by Innovate Raleigh as part of an independent journalism fellowship program. The N&O maintains full editorial control of the work. Learn more; go to bit.ly/newsinnovate.

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