A discussion during Global Health Week at the Medical University of South Carolina about gain-of-function research showed how difficult that research is to define. Moderator Michael Sweat, Ph.D., faculty director of MUSC's Center for Global Health, began by summarizing many people's understandings of it. His description would soon be politely challenged by a virologist.
"Basically, gain-of-function research is based on techniques in the laboratory that change microbes – viruses and bacteria – to become either more transmissible or more virulent," Sweat said.
As he prepared the audience for the debate, Sweat also noted that gain-of-function research has been part of the discussion about the possible origins of the coronavirus pandemic.
"There's been speculation, although unproven, that at the Wuhan Institute of Virology, which did a lot of coronavirus work, there potentially was gain-of-function research, and it could have led to SARS-CoV-2. So that's been a hot debate, and it's resurfaced these issues around the ethics of doing gain-of-function research."
The MUSC discussion in the Storm Eye Institute Auditorium did not focus on that controversy specifically, although both debaters said they did not believe the coronavirus pandemic was related to gain-of-function research. Instead, they looked at the pros and cons of such research more generally.
Virologist Paula Traktman, Ph.D., dean of the College of Graduate Studies and Hirschmann Endowed Professor, focused on the upsides.
Pulmonologist Patrick Flume, M.D., the Powers-Huggins Endowed Chair for Cystic Fibrosis and associate vice president of Clinical Research at MUSC, agreed to present the drawbacks.
Criticisms of gain-of-function research
Flume went first. "Yes, let's invite the cystic fibrosis doctor to debate the virologist," he joked.
He took a more serious tone as he described gain-of-function research from a critical perspective. "It's intended to focus on experiments that may increase the transmissibility and/or the virulence of pathogens," Flume said. "It's adaptation research. Scientists change things and look at the impact."
But he noted that the more he researched what gain of function really means, the blurrier things got.
Flume discussed one clear-cut case of gain-of-function research that shook up some scientists and others in 2014. Researchers studying a deadly H5N1 bird flu virus made changes that allowed it to spread more easily among ferrets, which were representative of humans in the experiment.
That raised concerns about how it might spread among people if it wound up outside of the lab. So the federal government put a moratorium on gain-of-function research. It lifted it in 2017 after the development of new processes to prevent risks to public safety.
But Flume said multiple concerns about gain-of-function research remain, in addition to the fear of a lab accident or intentional leak. For example:
- Bad actors could use published reports about gain-of-function research as blueprints for how to make pathogens more dangerous.
- Gain-of-function research could have unintended consequences for animals.
- A dangerous virus could wreak economic havoc.
- The public could lose confidence in science if a pathogen is made more transmissible and/or dangerous.
Flume also raised a financial argument. He said creating pathogens through gain-of-function research is expensive, and scientists could use the funding for better purposes.
In concluding his presentation, he said: "Gain-of-function research is only a small part of virology and microbiology research. So, we need to be careful about what we actually are discussing and deciding shouldn't happen. But I think the purported benefits of gain-of-function research are exaggerated and dependent upon subsequent downstream surveillance and therapeutics, which you're not guaranteed."
Flume stressed that when the potential outcomes of errors could be dire, even if they are rare, scientists need to be especially cautious in taking risks.
Arguments for gain-of-function research
Traktman opened her remarks by making it clear that in her view, people's assumptions about gain-of-function research aren't always on target. "I think this is a really important conversation. And the first thing I would say is that there's very little consensus on what gain-of-function research is. What you've heard about gain of function is that it's an attempt to increase virulence or increase transmissibility. And I would argue that's not the case," she said.
"What virologists have always tried to do is manipulate, provide evolutionary opportunities, mix and match to see what the relationship between genotype and phenotype is. How do viruses and bacteria change? What's responsible among their genes for how they behave?"
Traktman used the pandemic as an example of how virologists' work benefits the public. "One of the anti-COVID vaccines is based on adenovirus that has the SARS-CoV-2 spike protein inserted into it. That's gain-of-gene research. And yet, that's a licensed vaccine," she said.
"So I think gain-of-function research is much more broadly defined as understanding what things do."
Traktman said the number of experiments done to make viruses more dangerous is very small. Scientists are much more focused on using technology and other methods to examine and experiment with pathogens to understand them and find ways to help people.
"I think if you look at recent triumphs in virology – drugs against HIV, drugs against the hepatitis C virus that have changed a generation of public health – they came from day after day after day working in the lab to say, 'OK, what does this enzyme do if we swap that with another virus?' 'Does it have a bigger error rate or a lower error rate that led to drugs that are really dramatic?'"
Traktman said in her experience, people are appropriately cautious when it comes to publishing scientific journal articles about research. "When I write a publication, I have to check: 'Is this going to make the pathogen more virulent?' 'Is it going to make it more transmissible?' The article goes to an editor who has a panel of advisers on biosecurity. So in fact, there's a lot of oversight of this."
Traktman also said educational institutions such as MUSC have important roles to play. "We need students and faculty to say, 'Have you thought about this?' 'Have you thought about that?' When it comes to violations of our rules for animal studies or human studies, there's real teeth for that. So I think we need to make it clear that it's a privilege to work on infectious agents and pathogens, and you have to take that seriously."
Larger context
The MUSC Global Health Week discussion about gain-of-function research came as the U.S. National Science Advisory Board for Biosecurity considers new oversight for such research. Challenges include ensuring that restrictions don't stifle important research or make it hard for scientists to respond to a public health crisis.
The board will also consider how to regulate privately funded research, figure out what role research sites will play in deciding what's risky and consider how expensive it will be for scientists to comply with U.S. standards.
And there's the question of how to define gain of function. At the MUSC debate, Sweat, the moderator, pointed that out. "I just pick up from both of your discussions that there's a nonspecific definition of what gain of function is. I'm just wondering: 'Is there a line that we draw that we could better specify this?'"
"How long do we have?" Flume joked in response.
"It's about making sure that you have all the right things in place to be sure you've covered your bases if something could get out. But the other part of that is educating the community as to why that decision was made, why it's okay and what steps are being taken."
Traktman agreed. "I think communication is huge. I think historically, scientists haven't done a great job at that. But that's changing," she said.
"I think we also need a seat at the table. And that, I mean, that we need to be talking to community groups, the board of trustees, the hospital groups, everybody and sort of demystifying some of what the research is and explaining how it's done, what the precautions are, you know, why people do these kinds of experiments and what comes out of it."
MUSC's annual Global Health Week, open to the public, provided one such place for that.
