March 30 | 2023
Are the gains from gain-of-function research worth the risks?
Gail Dutton has covered the biopharmaceutical industry as a journalist for the past three decades. She focuses on the intersection of business and science, and has written extensively for GEN – Genetic Engineering & Biotechnology News, Life Science Leader, The Scientist and BioSpace. Her articles also have appeared in Popular Science, Forbes, Entrepreneur and other publications.
Gain-of-function research can make pathogens more infectious and deadly. It also enables scientists to prepare remedies in advance.
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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.”
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Gail Dutton has covered the biopharmaceutical industry as a journalist for the past three decades. She focuses on the intersection of business and science, and has written extensively for GEN – Genetic Engineering & Biotechnology News, Life Science Leader, The Scientist and BioSpace. Her articles also have appeared in Popular Science, Forbes, Entrepreneur and other publications.
December 13 | 2022
Your phone could show if a bridge is about to collapse
Researchers have tested a new smartphone app that could gather data about whether bridges are "structurally deficient" —a low-cost citizen-scientist alternative to current methods that are expensive and complex.
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In summer 2017, Thomas Matarazzo, then a postdoctoral researcher at the Massachusetts Institute of Technology, landed in San Francisco with a colleague. They rented two cars, drove up to the Golden Gate bridge, timing it to the city’s rush hour, and rode over to the other side in heavy traffic. Once they reached the other end, they turned around and did it again. And again. And again.
“I drove over that bridge 100 times over five days, back and forth,” says Matarazzo, now an associate director of High-Performance Computing in the Center for Innovation in Engineering at the United States Military Academy, West Point. “It was surprisingly stressful, I never anticipated that. I had to maintain the speed of about 30 miles an hour when the speed limit is 45. I felt bad for everybody behind me.”
Matarazzo had to drive slowly because the quality of data they were collecting depended on it. The pair was designing and testing a new smartphone app that could gather data about the bridge’s structural integrity—a low-cost citizen-scientist alternative to the current industrial methods, which aren’t always possible, partly because they’re expensive and complex. In the era of aging infrastructure, when some bridges in the United States and other countries are structurally unsound to the point of collapsing, such an app could inform authorities about the need for urgent repairs, or at least prompt closing the most dangerous structures.
There are 619,588 bridges in the U.S., and some of them are very old. For example, the Benjamin Franklin Bridge connecting Philadelphia to Camden, N.J., is 96-years-old while the Brooklyn Bridge is 153. So it’s hardly surprising that many could use some upgrades. “In the U.S., a lot of them were built in the post-World War II period to accommodate the surge of motorization,” says Carlo Ratti, architect and engineer who directs the Senseable City Lab at Massachusetts Institute of Technology. “They are beginning to reach the end of their life.”
According to the 2022 American Road & Transportation Builders Association’s report, one in three U.S. bridges needs repair or replacement. The Department of Transportation (DOT) National Bridge Inventory (NBI) database reveals concerning numbers. Thirty-six percent of U.S. bridges need repair work and over 78,000 bridges should be replaced. More than 43,500 bridges are rated in poor condition and classified as “structurally deficient” – an alarming description. Yet, people drive over them 167.5 million times a day. The Pittsburgh bridge which collapsed in January this year—only hours before President Biden arrived to discuss the new infrastructure law—was on the “poor” rating list.
Assessing the structural integrity of a bridge is not an easy endeavor. Most of the time, these are visual inspections, Matarazzo explains. Engineers check cracks, rust and other signs of wear and tear. They also check for wildlife—birds which may build nests or even small animals that make homes inside the bridge structures, which can slowly chip at the structure. However, visual inspections may not tell the whole story. A more sophisticated and significantly more expensive inspection requires placing special sensors on the bridge that essentially listen to how the bridge vibrates.
“Some bridges can afford expensive sensors to do the job, but that comes at a very high cost—hundreds of thousands of dollars per bridge per year,” Ratti says.
We may think of bridges as immovable steel and concrete monoliths, but they naturally vibrate, oscillating slightly. That movement can be influenced by the traffic that passes over them, and even by wind. Bridges of different types vibrate differently—some have longer vibrational frequencies and others shorter ones. A good way to visualize this phenomenon is to place a ruler over the edge of a desk and flick it slightly. If the ruler protrudes far off the desk, it will vibrate slowly. But if you shorten the end that hangs off, it will vibrate much faster. It works similarly with bridges, except there are more factors at play, including not only the length, but also the design and the materials used.
The long suspension bridges such as the Golden Gate or Verrazano Narrows, which hang on a series of cables, are more flexible, and their vibration amplitudes are longer. The Golden Gate Bridge can vibrate at 0.106 Hertz, where one Hertz is one oscillation per second. “Think about standing on the bridge for about 10 seconds—that's how long it takes for it to move all the way up and all the way down in one oscillation,” Matarazzo says.
On the contrary, the concrete span bridges that rest on multiple columns like Brooklyn Bridge or Manhattan Bridge, are “stiffer” and have greater vibrational frequencies. A concrete bridge can have a frequency of 10 Hertz, moving 10 times in one second—like that shorter stretch of a ruler.
The special devices that can pick up and record these vibrations over time are called accelerometers. A network of these devices for each bridge can cost $20,000 to $50,000, and more—and require trained personnel to place them. The sensors also must stay on the bridge for some time to establish what’s a healthy vibrational baseline for a given bridge. Maintaining them adds to the cost. “Some bridges can afford expensive sensors to do the job, but that comes at a very high cost—hundreds of thousands of dollars per bridge per year,” Ratti says.
Making sense of the readouts they gather is another challenge, which requires a high level of technical expertise. “You generally need somebody, some type of expert capable of doing the analysis to translate that data into information,” says Matarazzo, which ticks up the price, so doing visual inspections often proves to be a more economical choice for state-level DOTs with tight budgets. “The existing systems work well, but have downsides,” Ratti says. The team thought the old method could use some modernizing.
Smartphones, which are carried by millions of people, contain dozens of sensors, including the accelerometers capable of picking up the bridges’ vibrations. That’s why Matarazzo and his colleague drove over the bridge 100 times—they were trying to pick up enough data. Timing it to rush hour supported that goal because traffic caused more “excitation,” Matarazzo explains. “Excitation is a big word we use when we talk about what drives the vibration,” he says. “When there's a lot of traffic, there's more excitation and more vibration.” They also collaborated with Uber, whose drivers made 72 trips across the bridge to gather data in different cars.
The next step was to clean the data from “noise”—various vibrations that weren’t relevant to the bridge but came from the cars themselves. “It could be jumps in speed, it could be potholes, it could be a bunch of other things," Matarazzo says. But as the team gathered more data, it became easier to tell the bridge vibrational frequencies from all others because the noises generated by cars, traffic and other things tend to “cancel out.”
The team specifically picked the Golden Gate bridge because the civil structural engineering community had studied it extensively over the years and collected a host of vibrational data, using traditional sensors. When the researchers compared their app-collected frequencies with those gathered by 240 accelerometers formerly placed on the Golden Gate, the results were the same—the data from the phones converged with that from the bridge’s sensors. The smartphone-collected data were just as good as those from industry devices.
The study authors estimate that officials could use crowdsourced data to make key improvements that would help new bridges to last about 14 years longer.
The team also tested their method on a different type of bridge—not a suspension one like the Golden Gate, but a concrete span bridge in Ciampino, Italy. There they compared 280 car trips over the bridge to the six sensors that had been placed on the bridge for seven months. The results were slightly less matching, but a larger volume of trips would fix the divergence, the researchers wrote in their study, titled Crowdsourcing bridge dynamic monitoring with smartphone vehicle trips, published last month in Nature Communications Engineering.
Although the smartphones proved effective, the app is not quite ready to be rolled out commercially for people to start using. “It is still a pilot version,” so there’s room for improvement, says Ratti, who co-authored the study. “But on a more optimistic note, it has really low barriers to entry—all you need is smartphones on cars—so that makes the system easy to reach a global audience.” And the study authors estimate that the use of crowdsourced data would result in a new bridge lasting about 14 years longer.
Matarazzo hopes that the app could be eventually accessible for your average citizen scientist to collect the data and supply it to their local transportation authorities. “I hope that this idea can spark a different type of relationship with infrastructure where people think about the data they're collecting as some type of contribution or investment into their communities,” he says. “So that they can help their own department of transportation, their own municipality to support that bridge and keep it maintained better, longer and safer.”
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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.
December 09 | 2022
The Friday Five: Sugar could help catch cancer early
In this week's Friday Five, catching cancer early could depend on sugar, how to boost memory in a flash, a tiny sandwich cake could help the heart, and meet the top banana in the fight against Covid.
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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:
- Catching cancer early could depend on sugar
- How to boost memory in a flash
- This is your brain on books
- A tiny sandwich cake could help the heart
- Meet the top banana for fighting Covid variants
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Matt Fuchs is the host of the Making Sense of Science podcast and served previously as the editor-in-chief of Leaps.org. He writes as a contributor to the Washington Post, and his articles have also appeared in the New York Times, WIRED, Nautilus Magazine, Fortune Magazine and TIME Magazine. Follow him @fuchswriter.