Are the gains from gain-of-function research worth the risks?
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.”
Your surgery could harm yourself and the planet. Here's what some doctors are doing about it.
This is part 1 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 2 here and part 3 here.
Susanne Koch, an anesthesiologist and neurologist, reached a pivot point when she was up to her neck in water, almost literally. The basement of her house in Berlin had flooded in the summer of 2018, when Berlin was pummeled by unusually strong rains. After she drained the house, “I wanted to dig into facts, to understand how exactly these extreme weather events are related to climate change,” she says.
Studying the scientific literature, she realized how urgent the climate crisis is, but the biggest shock was to learn that her profession contributed substantially to the problem: Inhalation gases used during medical procedures are among the most damaging greenhouse gases. Some inhalation gases are 3,000 times more damaging for the climate than CO2, Koch discovered. “Spending seven hours in the surgery room is the equivalent of driving a car for four days nonstop,” she says. Her job of helping people at Europe’s largest university hospital, the Charité in Berlin, was inadvertently damaging both the people and the planet.
“Nobody had ever even mentioned a word about that during my training,” Koch says.
On the whole, the medical sector is responsible for a disproportionally large percentage of greenhouse gas emissions, with the U.S. as the biggest culprit. According to a key paper published in 2020 in Health Affairs, the health industry “is among the most carbon-intensive service sectors in the industrialized world,” accounting for between 4.4 percent and 4.6 percent of greenhouse gas emissions. “It’s not just anesthesia but health care that has a problem,” says Jodi Sherman, anesthesiology professor and Medical Director of the Program on Healthcare Environmental Sustainability at Yale University as well as co-director of the Lancet Planetary Health Commission on Sustainable Healthcare. In the U.S., health care greenhouse gas emissions make up about 8.5 percent of domestic greenhouse gas emissions. They rose 6 percent from 2010 to 2018, to nearly 1,700 kilograms per person, more than in any other nation.
Of course, patients worry primarily about safety, not sustainability. Yet, Koch emphasizes that “as doctors, we have the responsibility to do no harm, and this includes making sure that we use resources as sustainably as possible.” Studies show that 2018 greenhouse gas and toxic air pollutant emissions resulted in the loss of 388,000 disability-adjusted life years in the U.S. alone. “Disease burden from health care pollution is of the same order of magnitude as deaths from preventable medical errors, and should be taken just as seriously,” Sherman cautions.
When Koch, the anesthesiologist, started discussing sustainable options with colleagues, the topic was immediately met with plenty of interest. Her experience is consistent with the latest representative poll of the nonprofit Foundation Health in Germany. Nine out of ten doctors were interested in urgently finding sustainable solutions for medical services but lacked knowhow and resources. For teaching purposes, Sherman and her team have developed the Yale Gassing Greener app that allows anesthesiologists to compare how much pollution they can avoid through choosing different anesthesia methods. Sherman also published professional guidelines intended to help her colleagues better understand how various methods affect carbon emissions.
Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
A solution espoused by both Sherman and Koch is comparatively simple: They stopped using desflurane, which is by far the most damaging of all inhalation gases to the climate. Its greenhouse effect is 2,590 times stronger than carbon dioxide. The Yale New Haven Hospital already stopped using desflurane in 2013, becoming the first known healthcare organization to eliminate a drug based on environmental grounds. Sherman points out that this resulted in saving more than $1.2 million in costs and 1,600 tons of CO2 equivalents, about the same as the exhaust from 360 passenger vehicles per year.
At the Charité, Koch claims that switching to other anesthesiology choices, such as propofol, has eliminated 90 percent of the climate gas emissions in the anesthesiology department since 2016. Young anesthesiologists are still taught to use desflurane as the standard because desflurane is absorbed less into the patients’ bodies, and they wake up faster. However, Koch who has worked as an anesthesiologist since 2006, says that with a little bit of experience, you can learn when to stop giving the propofol so it's timed just as well with a person’s wake-up process. In addition, “patients are less likely to feel nauseous after being given propofol,” Koch says. Intravenous drugs might require more skill, she adds, "but there is nothing unique to the drug desflurane that cannot be accomplished with other medications.”
Desflurane isn’t the only gas to be concerned about. Nitrous oxide is the second most damaging because it’s extremely long-lived in the environment, and it depletes the ozone layer. Climate-conscious anesthesiologists are phasing out this gas, too, or have implemented measures to decrease leaks.
Internationally, 192 governments agreed in the Kyoto protocol of 2005 to reduce halogenated hydrocarbons – resulting from inhalation gases, including desflurane and nitrous oxide – because of their immense climate-warming potential, and in 2016, they pledged to eliminate them by 2035. However, the use of inhalation anesthetics continues to increase worldwide, not least because more people access healthcare in developing countries, and because people in industrialized countries live longer and therefore need more surgeries. Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
Certain companies are now pushing new technology to capture inhalation gases before they are released into the atmosphere, but both Sherman and Koch believe marketing claims of 99 percent efficiency amount to greenwashing. After investigating the technology first-hand and visiting the company that is producing such filters in Germany, Koch concluded that such technology only reduces emissions by 25 percent. And Sherman believes such initiatives are akin to the fallacy of recycling plastic. In addition to questioning their efficiency, Sherman fears such technology “gives the illusion there is a magical solution that means I don’t need to change my behavior, reduce my waste and choose less harmful options.”
Financial interests are at play, too. “Desflurane is the most expensive inhalation gas, and some think, the most expensive must be the best,” Koch says. Both Koch and Sherman lament that efforts to increase sustainability in the medical sector are entirely voluntary in their countries and led by a few dedicated individual professionals while industry-wide standards and transparency are needed, a notion expressed in the American Hospital Association’s Sustainability Roadmap.
Susanne Koch, an anesthesiologist in Berlin, wants her colleagues to stop using a gas called desflurane, which is by far the most damaging of all inhalation gases to the climate.
Adobe Stock
Other countries have done more. The European Union recommends reducing inhalation gases and even contemplated a ban of desflurane, except in medical emergencies. In 2008, the National Health Service (NHS) created a Sustainable Development Unit, which measures CO2 emissions in the U.K. health sector. NHS is the first national health service that pledged to reach net zero carbon by 2040. The carbon footprint of the NHS fell by 26 percent from 1990 to 2019, mostly due to reduced use of certain inhalers and the switch to renewable energy for heat and power. “The evidence that the climate emergency is a health emergency is overwhelming,” said Nick Watts, the NHS Chief Sustainability Officer, in a press release, “with health professionals already needing to manage its symptoms.”
Sherman is a leading voice in demanding action in the U.S. To her, comprehensive solutions start with the mandatory, transparent measurement of emissions in the health sector to tackle the biggest sources of pollution. While the Biden administration highlighted its efforts to reduce these kinds of emissions during the United Nations Climate Conference (COP27) in November 2022 and U.S. delegates announced that more than 100 health care organizations signed the voluntary Health Sector Climate Pledge, with the aim to reduce emissions by 50 percent in the next eight years, Sherman is convinced that voluntary pledges are not enough. “Voluntary measures are insufficient,” she testified in congress. “The vast majority of U.S. health care organizations remain uncommitted to timely action. Those that are committed lack policies and knowledge to support necessary changes; even worse, existing policies drive inappropriate consumption of resources and pollution.”
Both Sherman and Koch look at the larger picture. “Health care organizations have an obligation to their communities to protect public health,” Sherman says. “We must lead by example. That includes setting ambitious, science-based carbon reduction targets to achieve net zero emissions before 2050. We must quantify current emissions and their sources, particularly throughout the health care supply chains.”
Have You Heard of the Best Sport for Brain Health?
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:
- Reprogram cells to a younger state
- Pick up this sport for brain health
- Do all mental illnesses have the same underlying cause?
- New test could diagnose autism in newborns
- Scientists 3D print an ear and attach it to woman