Are the gains from gain-of-function research worth the risks?
Gain-of-function research can make pathogens more infectious and deadly. It also enables scientists to prepare remedies in advance.
Scientists have long argued that gain-of-function research, which can make viruses and other infectious agents more contagious or more deadly, was necessary to develop therapies and vaccines to counter the pathogens in case they were used for biological warfare. As the SARS-CoV-2 origins are being investigated, one prominent theory suggests it had leaked from a biolab that conducted gain-of-function research, causing a global pandemic that claimed nearly 6.9 million lives. Now some question the wisdom of engaging in this type of research, stating that the risks may far outweigh the benefits.
“Gain-of-function research means genetically changing a genome in a way that might enhance the biological function of its genes, such as its transmissibility or the range of hosts it can infect,” says George Church, professor of genetics at Harvard Medical School. This can occur through direct genetic manipulation as well as by encouraging mutations while growing successive generations of micro-organism in culture. “Some of these changes may impact pathogenesis in a way that is hard to anticipate in advance,” Church says.
In the wake of the global pandemic, the pros and cons of gain-of-function research are being fiercely debated. Some scientists say this type of research is vital for preventing future pandemics or for preparing for bioweapon attacks. Others consider it another disaster waiting to happen. The Government Accounting Office issued a report charging that a framework developed by the U.S. Department of Health & Human Services (HHS) provided inadequate oversight of this potentially deadly research. There’s a movement to stop it altogether. In January, the Viral Gain-of-Function Research Moratorium Act (S. 81) was introduced into the Senate to cease awarding federal research funding to institutions doing gain-of-function studies.
While testifying before the House COVID Origins Select Committee on March 8th, Robert Redfield, former director of the U.S. Centers for Disease Control and Prevention, said that COVID-19 may have resulted from an accidental lab leak involving gain-of-function research. Redfield said his conclusion is based upon the “rapid and high infectivity for human-to-human transmission, which then predicts the rapid evolution of new variants.”
“It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen,” said Gerald Parker, associate dean for Global One Health at Texas A&M University.
“In my opinion,” Redfield continues, “the COVID-19 pandemic presents a case study on the potential dangers of such research. While many believe that gain-of-function research is critical to get ahead of viruses by developing vaccines, in this case, I believe that was the exact opposite.” Consequently, Redfield called for a moratorium on gain-of-function research until there is consensus about the value of such risky science.
What constitutes risky?
The Federal Select Agent Program lists 68 specific infectious agents as risky because they are either very contagious or very deadly. In order to work with these 68 agents, scientists must register with the federal government. Meanwhile, research on deadly pathogens that aren’t easily transmitted, or pathogens that are quite contagious but not deadly, can be conducted without such oversight. “If you’re not working with select agents, you’re not required to register the research with the federal government,” says Gerald Parker, associate dean for Global One Health at Texas A&M University. But the 68-item list may not have everything that could possibly become dangerous or be engineered to be dangerous, thus escaping the government’s scrutiny—an issue that new regulations aim to address.
In January 2017, the White House Office of Science and Technology Policy (OSTP) issued additional guidance. It required federal departments and agencies to follow a series of steps when reviewing proposed research that could create, transfer, or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility or virulence in humans.
In defining risky pathogens, OSTP included viruses that were likely to be highly transmissible and highly virulent, and thus very deadly. The Proposed Biosecurity Oversight Framework for the Future of Science, outlined in 2023, broadened the scope to require federal review of research “that is reasonably anticipated to enhance the transmissibility and/or virulence of any pathogen” likely to pose a threat to public health, health systems or national security. Those types of experiments also include the pathogens’ ability to evade vaccines or therapeutics, or diagnostic detection.
However, Parker says that dangers of generating a pandemic-level germ are tiny. “It is a very, very, very small subset of life science research that could potentially generate a potential pandemic pathogen.” Since gain-of-function guidelines were first issued in 2017, only three such research projects have met those requirements for HHS review. They aimed to study influenza and bird flu. Only two of those projects were funded, according to the NIH Office of Science Policy. For context, NIH funded approximately 11,000 of the 54,000 grant applications it received in 2022.
Guidelines governing gain-of-function research are being strengthened, but Church points out they aren’t ideal yet. “They need to be much clearer about penalties and avoiding positive uses before they would be enforceable.”
What do we gain from gain-of-function research?
The most commonly cited reason to conduct gain-of-function research is for biodefense—the government’s ability to deal with organisms that may pose threats to public health.
In the era of mRNA vaccines, the advance preparedness argument may be even less relevant.
“The need to work with potentially dangerous viruses is central to our preparedness,” Parker says. “It’s essential that we know and understand the basic biology, microbiology, etc. of some of these dangerous pathogens.” That includes increasing our knowledge of the molecular mechanisms by which a virus could become a sustained threat to humans. “Knowing that could help us detect [risks] earlier,” Parker says—and could make it possible to have medical countermeasures, like vaccines and therapeutics, ready.
Most vaccines, however, aren’t affected by this type of research. Essentially, scientists hope they will never need to use it. Moreover, Paul Mango, HSS former deputy chief of staff for policy, and author of the 2022 book Warp Speed, says he believes that in the era of mRNA vaccines, the advance preparedness argument may be even less relevant. “That’s because these vaccines can be developed and produced in less than 12 months, unlike traditional vaccines that require years of development,” he says.
Can better oversight guarantee safety?
Another situation, which Parker calls unnecessarily dangerous, is when regulatory bodies cannot verify that the appropriate biosafety and biosecurity controls are in place.
Gain-of-function studies, Parker points out, are conducted at the basic research level, and they’re performed in high-containment labs. “As long as all the processes, procedures and protocols are followed and there’s appropriate oversight at the institutional and scientific level, it can be conducted safely.”
Globally, there are 69 Biosafety Level 4 (BSL4) labs operating, under construction or being planned, according to recent research from King’s College London and George Mason University for Global BioLabs. Eleven of these 18 high-containment facilities that are planned or under construction are in Asia. Overall, three-quarters of the BSL4 labs are in cities, increasing public health risks if leaks occur.
Researchers say they are confident in the oversight system for BSL4 labs within the U.S. They are less confident in international labs. Global BioLabs’ report concurs. It gives the highest scores for biosafety to industrialized nations, led by France, Australia, Canada, the U.S. and Japan, and the lowest scores to Saudi Arabia, India and some developing African nations. Scores for biosecurity followed similar patterns.
“There are no harmonized international biosafety and biosecurity standards,” Parker notes. That issue has been discussed for at least a decade. Now, in the wake of SARS and the COVID-19 pandemic, scientists and regulators are likely to push for unified oversight standards. “It’s time we got serious about international harmonization of biosafety and biosecurity standards and guidelines,” Parker says. New guidelines are being worked on. The National Science Advisory Board for Biosecurity (NSABB) outlined its proposed recommendations in the document titled Proposed Biosecurity Oversight Framework for the Future of Science.
The debates about whether gain-of-function research is useful or poses unnecessary risks to humanity are likely to rage on for a while. The public too has a voice in this debate and should weigh in by communicating with their representatives in government, or by partaking in educational forums or initiatives offered by universities and other institutions. In the meantime, scientists should focus on improving the research regulations, Parker notes. “We need to continue to look for lessons learned and for gaps in our oversight system,” he says. “That’s what we need to do right now.”
The Friday Five: A new blood test to detect Alzheimer's
A new blood test has been developed to detect Alzheimer's. Other promising studies covered in this week's Friday Five include: vets with PTSD can take their psychologist anywhere with a new device, intermittent fasting could improve circadian rhythms, a new year's resolution for living longer, and a discovery in 3-D printing eye tissue.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
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Here are the promising studies covered in this week's Friday Five:
- A blood test to detect Alzheimer's
- War vets can take their psychologist wherever they go
- Does intermittent fasting affect circadian rhythms?
- A new year's resolution for living longer
- 3-D printed eyes?
Staying well in the 21st century is like playing a game of chess
The control of infectious diseases was considered to be one of the “10 Great Public Health Achievements.” What we didn’t take into account was the very concept of evolution: as we built better protections, our enemies eventually boosted their attacking prowess, so soon enough we found ourselves on the defensive once again.
This article originally appeared in One Health/One Planet, a single-issue magazine that explores how climate change and other environmental shifts are increasing vulnerabilities to infectious diseases by land and by sea. The magazine probes how scientists are making progress with leaders in other fields toward solutions that embrace diverse perspectives and the interconnectedness of all lifeforms and the planet.
On July 30, 1999, the Centers for Disease Control and Prevention published a report comparing data on the control of infectious disease from the beginning of the 20th century to the end. The data showed that deaths from infectious diseases declined markedly. In the early 1900s, pneumonia, tuberculosis and diarrheal diseases were the three leading killers, accounting for one-third of total deaths in the U.S.—with 40 percent being children under five.
Mass vaccinations, the discovery of antibiotics and overall sanitation and hygiene measures eventually eradicated smallpox, beat down polio, cured cholera, nearly rid the world of tuberculosis and extended the U.S. life expectancy by 25 years. By 1997, there was a shift in population health in the U.S. such that cancer, diabetes and heart disease were now the leading causes of death.
The control of infectious diseases is considered to be one of the “10 Great Public Health Achievements.” Yet on the brink of the 21st century, new trouble was already brewing. Hospitals were seeing periodic cases of antibiotic-resistant infections. Novel viruses, or those that previously didn’t afflict humans, began to emerge, causing outbreaks of West Nile, SARS, MERS or swine flu.In the years that followed, tuberculosis made a comeback, at least in certain parts of the world. What we didn’t take into account was the very concept of evolution: as we built better protections, our enemies eventually boosted their attacking prowess, so soon enough we found ourselves on the defensive once again.
At the same time, new, previously unknown or extremely rare disorders began to rise, such as autoimmune or genetic conditions. Two decades later, scientists began thinking about health differently—not as a static achievement guaranteed to last, but as something dynamic and constantly changing—and sometimes, for the worse.
What emerged since then is a different paradigm that makes our interactions with the microbial world more like a biological chess match, says Victoria McGovern, a biochemist and program officer for the Burroughs Wellcome Fund’s Infectious Disease and Population Sciences Program. In this chess game, humans may make a clever strategic move, which could involve creating a new vaccine or a potent antibiotic, but that advantage is fleeting. At some point, the organisms we are up against could respond with a move of their own—such as developing resistance to medication or genetic mutations that attack our bodies. Simply eradicating the “opponent,” or the pathogenic microbes, as efficiently as possible isn’t enough to keep humans healthy long-term.
Instead, scientists should focus on studying the complexity of interactions between humans and their pathogens. “We need to better understand the lifestyles of things that afflict us,” McGovern says. “The solutions are going to be in understanding various parts of their biology so we can influence how they behave around our systems.”
Genetics and cell biology, combined with imaging techniques that allow one to see tissues and individual cells in actions, will enable scientists to define and quantify what it means to be healthy at the molecular level.
What is being proposed will require a pivot to basic biology and other disciplines that have suffered from lack of research funding in recent years. Yet, according to McGovern, the research teams of funded proposals are answering bigger questions. “We look for people exploring questions about hosts and pathogens, and what happens when they touch, but we’re also looking for people with big ideas,” she says. For example, if one specific infection causes a chain of pathological events in the body, can other infections cause them too? And if we find a way to break that chain for one pathogen, can we play the same trick on another? “We really want to see people thinking of not just one experiment but about big implications of their work,” McGovern says.
Jonah Cool, a cell biologist, geneticist and science officer at the Chan Zuckerberg Initiative, says that it’s necessary to define what constitutes a healthy organism and how it overcomes infections or environmental assaults, such as pollution from forest fires or toxins from industrial smokestacks. An organism that catches a disease isn’t necessarily an unhealthy one, as long as it fights it off successfully—an ability that arises from the complex interplay of its genes, the immune system, age, stress levels and other factors. Modern science allows many of these factors to be measured, recorded and compared. “We need a data-driven, deep-phenotyping approach to defining healthy biological systems and their responses to insults—which can be infectious disease or environmental exposures—and their ability to navigate their way through that space,” Cool says.
Genetics and cell biology, combined with imaging techniques that allow one to see tissues and individual cells in actions, will enable scientists to define and quantify what it means to be healthy at the molecular level. “As a geneticist and cell biologist, I believe in all these molecular underpinnings and how they arise in phenotypic differences in cells, genes, proteins—and how their combinations form complex cellular states,” Cool says.
Julie Graves, a physician, public health consultant, former adjunct professor of management, policy and community health at the University of Texas Health Science Center in Houston, stresses the necessity of nutritious diets. According to the Rockefeller Food Initiative, “poor diet is the leading risk factor for disease, disability and premature death in the majority of countries around the world.” Adequate nutrition is critical for maintaining human health and life. Yet, Western diets are often low in essential nutrients, high in calories and heavy on processed foods. Overconsumption of these foods has contributed to high rates of obesity and chronic disease in the U.S. In fact, more than half of American adults have at least one chronic disease, and 27 percent have more than one—which increases vulnerability to COVID-19 infections, according to the 2018 National Health Interview Survey.
Further, the contamination of our food supply with various agricultural and industrial toxins—petrochemicals, pesticides, PFAS and others—has implications for morbidity, mortality, and overall quality of life. “These chemicals are insidiously in everything, including our bodies,” Graves says—and they are interfering with our normal biological functions. “We need to stop how we manufacture food,” she adds, and rid our sustenance of these contaminants.
According to the Humane Society of the United States, factory farms result in nearly 40 percent of emissions of methane. Concentrated animal feeding operations or CAFOs may serve as breeding grounds for pandemics, scientists warn, so humans should research better ways to raise and treat livestock. Diego Rose, a professor of food and nutrition policy at Tulane University School of Public Health & Tropical Medicine, and his colleagues found that “20 percent of Americans’ diets account for about 45 percent of the environmental impacts [that come from food].” A subsequent study explored the impacts of specific foods and found that substituting beef for chicken lowers an individual’s carbon footprint by nearly 50 percent, with water usage decreased by 30 percent. Notably, however, eating too much red meat has been associated with a variety of illnesses.
In some communities, the option to swap food types is limited or impossible. For example, “many populations live in relative food deserts where there’s not a local grocery store that has any fresh produce,” says Louis Muglia, the president and CEO of Burroughs Wellcome. Individuals in these communities suffer from an insufficient intake of beneficial macronutrients, and they’re “probably being exposed to phenols and other toxins that are in the packaging.” An equitable, sustainable and nutritious food supply will be vital to humanity’s wellbeing in the era of climate change, unpredictable weather and spillover events.
A recent report by See Change Institute and the Climate Mental Health Network showed that people who are experiencing socioeconomic inequalities, including many people of color, contribute the least to climate change, yet they are impacted the most. For example, people in low-income communities are disproportionately exposed to vehicle emissions, Muglia says. Through its Climate Change and Human Health Seed Grants program, Burroughs Wellcome funds research that aims to understand how various factors related to climate change and environmental chemicals contribute to premature births, associated with health vulnerabilities over the course of a person’s life—and map such hot spots.
“It’s very complex, the combinations of socio-economic environment, race, ethnicity and environmental exposure, whether that’s heat or toxic chemicals,” Muglia explains. “Disentangling those things really requires a very sophisticated, multidisciplinary team. That’s what we’ve put together to describe where these hotspots are and see how they correlate with different toxin exposure levels.”
In addition to mapping the risks, researchers are developing novel therapeutics that will be crucial to our armor arsenal, but we will have to be smarter at designing and using them. We will need more potent, better-working monoclonal antibodies. Instead of directly attacking a pathogen, we may have to learn to stimulate the immune system—training it to fight the disease-causing microbes on its own. And rather than indiscriminately killing all bacteria with broad-scope drugs, we would need more targeted medications. “Instead of wiping out the entire gut flora, we will need to come up with ways that kill harmful bacteria but not healthy ones,” Graves says. Training our immune systems to recognize and react to pathogens by way of vaccination will keep us ahead of our biological opponents, too. “Continued development of vaccines against infectious diseases is critical,” says Graves.
With all of the unpredictable events that lie ahead, it is difficult to foresee what achievements in public health will be reported at the end of the 21st century. Yet, technological advances, better modeling and pursuing bigger questions in science, along with education and working closely with communities will help overcome the challenges. The Chan Zuckerberg Initiative displays an optimistic message on its website: “Is it possible to cure, prevent, or manage all diseases by the end of this century? We think so.” Cool shares the view of his employer—and believes that science can get us there. Just give it some time and a chance. “It’s a big, bold statement,” he says, “but the end of the century is a long way away.”Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.