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.”
DNA- and RNA-based electronic implants may revolutionize healthcare
Implantable electronic devices can significantly improve patients’ quality of life. A pacemaker can encourage the heart to beat more regularly. A neural implant, usually placed at the back of the skull, can help brain function and encourage higher neural activity. Current research on neural implants finds them helpful to patients with Parkinson’s disease, vision loss, hearing loss, and other nerve damage problems. Several of these implants, such as Elon Musk’s Neuralink, have already been approved by the FDA for human use.
Yet, pacemakers, neural implants, and other such electronic devices are not without problems. They require constant electricity, limited through batteries that need replacements. They also cause scarring. “The problem with doing this with electronics is that scar tissue forms,” explains Kate Adamala, an assistant professor of cell biology at the University of Minnesota Twin Cities. “Anytime you have something hard interacting with something soft [like muscle, skin, or tissue], the soft thing will scar. That's why there are no long-term neural implants right now.” To overcome these challenges, scientists are turning to biocomputing processes that use organic materials like DNA and RNA. Other promised benefits include “diagnostics and possibly therapeutic action, operating as nanorobots in living organisms,” writes Evgeny Katz, a professor of bioelectronics at Clarkson University, in his book DNA- And RNA-Based Computing Systems.
While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output.
Adamala’s research focuses on developing such biocomputing systems using DNA, RNA, proteins, and lipids. Using these molecules in the biocomputing systems allows the latter to be biocompatible with the human body, resulting in a natural healing process. In a recent Nature Communications study, Adamala and her team created a new biocomputing platform called TRUMPET (Transcriptional RNA Universal Multi-Purpose GatE PlaTform) which acts like a DNA-powered computer chip. “These biological systems can heal if you design them correctly,” adds Adamala. “So you can imagine a computer that will eventually heal itself.”
The basics of biocomputing
Biocomputing and regular computing have many similarities. Like regular computing, biocomputing works by running information through a series of gates, usually logic gates. A logic gate works as a fork in the road for an electronic circuit. The input will travel one way or another, giving two different outputs. An example logic gate is the AND gate, which has two inputs (A and B) and two different results. If both A and B are 1, the AND gate output will be 1. If only A is 1 and B is 0, the output will be 0 and vice versa. If both A and B are 0, the result will be 0. While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output. In this case, the DNA enters the logic gate as a single or double strand.
If the DNA is double-stranded, the system “digests” the DNA or destroys it, which results in non-fluorescence or “0” output. Conversely, if the DNA is single-stranded, it won’t be digested and instead will be copied by several enzymes in the biocomputing system, resulting in fluorescent RNA or a “1” output. And the output for this type of binary system can be expanded beyond fluorescence or not. For example, a “1” output might be the production of the enzyme insulin, while a “0” may be that no insulin is produced. “This kind of synergy between biology and computation is the essence of biocomputing,” says Stephanie Forrest, a professor and the director of the Biodesign Center for Biocomputing, Security and Society at Arizona State University.
Biocomputing circles are made of DNA, RNA, proteins and even bacteria.
Evgeny Katz
The TRUMPET’s promise
Depending on whether the biocomputing system is placed directly inside a cell within the human body, or run in a test-tube, different environmental factors play a role. When an output is produced inside a cell, the cell's natural processes can amplify this output (for example, a specific protein or DNA strand), creating a solid signal. However, these cells can also be very leaky. “You want the cells to do the thing you ask them to do before they finish whatever their businesses, which is to grow, replicate, metabolize,” Adamala explains. “However, often the gate may be triggered without the right inputs, creating a false positive signal. So that's why natural logic gates are often leaky." While biocomputing outside a cell in a test tube can allow for tighter control over the logic gates, the outputs or signals cannot be amplified by a cell and are less potent.
TRUMPET, which is smaller than a cell, taps into both cellular and non-cellular biocomputing benefits. “At its core, it is a nonliving logic gate system,” Adamala states, “It's a DNA-based logic gate system. But because we use enzymes, and the readout is enzymatic [where an enzyme replicates the fluorescent RNA], we end up with signal amplification." This readout means that the output from the TRUMPET system, a fluorescent RNA strand, can be replicated by nearby enzymes in the platform, making the light signal stronger. "So it combines the best of both worlds,” Adamala adds.
These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body.
The TRUMPET biocomputing process is relatively straightforward. “If the DNA [input] shows up as single-stranded, it will not be digested [by the logic gate], and you get this nice fluorescent output as the RNA is made from the single-stranded DNA, and that's a 1,” Adamala explains. "And if the DNA input is double-stranded, it gets digested by the enzymes in the logic gate, and there is no RNA created from the DNA, so there is no fluorescence, and the output is 0." On the story's leading image above, if the tube is "lit" with a purple color, that is a binary 1 signal for computing. If it's "off" it is a 0.
While still in research, TRUMPET and other biocomputing systems promise significant benefits to personalized healthcare and medicine. These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body. The study’s lead author and graduate student Judee Sharon is already beginning to research TRUMPET's ability for earlier cancer diagnoses. Because the inputs for TRUMPET are single or double-stranded DNA, any mutated or cancerous DNA could theoretically be detected from the platform through the biocomputing process. Theoretically, devices like TRUMPET could be used to detect cancer and other diseases earlier.
Adamala sees TRUMPET not only as a detection system but also as a potential cancer drug delivery system. “Ideally, you would like the drug only to turn on when it senses the presence of a cancer cell. And that's how we use the logic gates, which work in response to inputs like cancerous DNA. Then the output can be the production of a small molecule or the release of a small molecule that can then go and kill what needs killing, in this case, a cancer cell. So we would like to develop applications that use this technology to control the logic gate response of a drug’s delivery to a cell.”
Although platforms like TRUMPET are making progress, a lot more work must be done before they can be used commercially. “The process of translating mechanisms and architecture from biology to computing and vice versa is still an art rather than a science,” says Forrest. “It requires deep computer science and biology knowledge,” she adds. “Some people have compared interdisciplinary science to fusion restaurants—not all combinations are successful, but when they are, the results are remarkable.”
In today’s podcast episode, Leaps.org Deputy Editor Lina Zeldovich speaks about the health and ecological benefits of farming crickets for human consumption with Bicky Nguyen, who joins Lina from Vietnam. Bicky and her business partner Nam Dang operate an insect farm named CricketOne. Motivated by the idea of sustainable and healthy protein production, they started their unconventional endeavor a few years ago, despite numerous naysayers who didn’t believe that humans would ever consider munching on bugs.
Yet, making creepy crawlers part of our diet offers many health and planetary advantages. Food production needs to match the rise in global population, estimated to reach 10 billion by 2050. One challenge is that some of our current practices are inefficient, polluting and wasteful. According to nonprofit EarthSave.org, it takes 2,500 gallons of water, 12 pounds of grain, 35 pounds of topsoil and the energy equivalent of one gallon of gasoline to produce one pound of feedlot beef, although exact statistics vary between sources.
Meanwhile, insects are easy to grow, high on protein and low on fat. When roasted with salt, they make crunchy snacks. When chopped up, they transform into delicious pâtes, says Bicky, who invents her own cricket recipes and serves them at industry and public events. Maybe that’s why some research predicts that edible insects market may grow to almost $10 billion by 2030. Tune in for a delectable chat on this alternative and sustainable protein.
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Further reading:
More info on Bicky Nguyen
https://yseali.fulbright.edu.vn/en/faculty/bicky-n...
The environmental footprint of beef production
https://www.earthsave.org/environment.htm
https://www.watercalculator.org/news/articles/beef-king-big-water-footprints/
https://www.frontiersin.org/articles/10.3389/fsufs.2019.00005/full
https://ourworldindata.org/carbon-footprint-food-methane
Insect farming as a source of sustainable protein
https://www.insectgourmet.com/insect-farming-growing-bugs-for-protein/
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/insect-farming
Cricket flour is taking the world by storm
https://www.cricketflours.com/
https://talk-commerce.com/blog/what-brands-use-cricket-flour-and-why/
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.