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.”
A new injection is helping stave off RSV this season
In November 2021, Mickayla Wininger’s then one-month-old son, Malcolm, endured a terrifying bout with RSV, the respiratory syncytial (sin-SISH-uhl) virus—a common ailment that affects all age groups. Most people recover from mild, cold-like symptoms in a week or two, but RSV can be life-threatening in others, particularly infants.
Wininger, who lives in southern Illinois, was dressing Malcolm for bed when she noticed what seemed to be a minor irregularity with this breathing. She and her fiancé, Gavin McCullough, planned to take him to the hospital the next day. The matter became urgent when, in the morning, the boy’s breathing appeared to have stopped.
After they dialed 911, Malcolm started breathing again, but he ended up being hospitalized three times for RSV and defects in his heart. Eventually, he recovered fully from RSV, but “it was our worst nightmare coming to life,” Wininger recalled.
It’s a scenario that the federal government is taking steps to prevent. In July, the Food and Drug Administration approved a single-dose, long-acting injection to protect babies and toddlers. The injection, called Beyfortus, or nirsevimab, became available this October. It reduces the incidence of RSV in pre-term babies and other infants for their first RSV season. Children at highest risk for severe RSV are those who were born prematurely and have either chronic lung disease of prematurity or congenital heart disease. In those cases, RSV can progress to lower respiratory tract diseases such as pneumonia and bronchiolitis, or swelling of the lung’s small airway passages.
Each year, RSV is responsible for 2.1 million outpatient visits among children younger than five-years-old, 58,000 to 80,000 hospitalizations in this age group, and between 100 and 300 deaths, according to the Centers for Disease Control and Prevention. Transmitted through close contact with an infected person, the virus circulates on a seasonal basis in most regions of the country, typically emerging in the fall and peaking in the winter.
In August, however, the CDC issued a health advisory on a late-summer surge in severe cases of RSV among young children in Florida and Georgia. The agency predicts "increased RSV activity spreading north and west over the following two to three months.”
Infants are generally more susceptible to RSV than older people because their airways are very small, and their mechanisms to clear these passages are underdeveloped. RSV also causes mucus production and inflammation, which is more of a problem when the airway is smaller, said Jennifer Duchon, an associate professor of newborn medicine and pediatrics in the Icahn School of Medicine at Mount Sinai in New York.
In 2021 and 2022, RSV cases spiked, sending many to emergency departments. “RSV can cause serious disease in infants and some children and results in a large number of emergency department and physician office visits each year,” John Farley, director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a news release announcing the approval of the RSV drug. The decision “addresses the great need for products to help reduce the impact of RSV disease on children, families and the health care system.”
Sean O’Leary, chair of the committee on infectious diseases for the American Academy of Pediatrics, says that “we’ve never had a product like this for routine use in children, so this is very exciting news.” It is recommended for all kids under eight months old for their first RSV season. “I would encourage nirsevimab for all eligible children when it becomes available,” O’Leary said.
For those children at elevated risk of severe RSV and between the ages of 8 and 19 months, the CDC recommends one dose in their second RSV season.
The drug will be “really helpful to keep babies healthy and out of the hospital,” said O’Leary, a professor of pediatrics at the University of Colorado Anschutz Medical Campus/Children’s Hospital Colorado in Denver.
An antiviral drug called Synagis (palivizumab) has been an option to prevent serious RSV illness in high-risk infants since it was approved by the FDA in 1998. The injection must be given monthly during RSV season. However, its use is limited to “certain children considered at high risk for complications, does not help cure or treat children already suffering from serious RSV disease, and cannot prevent RSV infection,” according to the National Foundation for Infectious Diseases.
Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants.
Both nirsevimab and palivizumab are monoclonal antibodies that act against RSV. Monoclonal antibodies are lab-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. A single intramuscular injection of nirsevimab preceding or during RSV season may provide protection.
The strategy with the new monoclonal antibody is “to extend protection to healthy infants who nonetheless are at risk because of their age, as well as infants with additional medical risk factors,” said Philippa Gordon, a pediatrician and infectious disease specialist in Brooklyn, New York, and medical adviser to Park Slope Parents, an online community support group.
No specific preventive measure is needed for older and healthier kids because they will develop active immunity, which is more durable. Meanwhile, older adults, who are also vulnerable to RSV, can receive one of two new vaccines. So can pregnant women, who pass on immunity to the fetus, Gordon said.
Until the approval this summer of the new monoclonal antibody, nirsevimab, there wasn’t a reliable method to prevent infection in most healthy infants, “nor is there any treatment other than giving oxygen or supportive care,” said Stanley Spinner, chief medical officer and vice president of Texas Children’s Pediatrics and Texas Children’s Urgent Care.
As with any virus, washing hands frequently and keeping infants and children away from sick people are the best defenses, Duchon said. This approach isn’t foolproof because viruses can run rampant in daycare centers, schools and parents’ workplaces, she added.
Mickayla Wininger, Malcolm’s mother, insists that family and friends wear masks, wash their hands and use hand sanitizer when they’re around her daughter and two sons. She doesn’t allow them to kiss or touch the children. Some people take it personally, but she would rather be safe than sorry.
Wininger recalls the severe anxiety caused by Malcolm's ordeal with RSV. After returning with her infant from his hospital stays, she was terrified to go to sleep. “My fiancé and I would trade shifts, so that someone was watching over our son 24 hours a day,” she said. “I was doing a night shift, so I would take caffeine pills to try and keep myself awake and would end up crashing early hours in the morning and wake up frantically thinking something happened to my son.”
Two years later, her anxiety has become more manageable, and Malcolm is doing well. “He is thriving now,” Wininger said. He recently had his second birthday and "is just the spunkiest boy you will ever meet. He looked death straight in the eyes and fought to be here today.”
Story by Big Think
For most of history, artificial intelligence (AI) has been relegated almost entirely to the realm of science fiction. Then, in late 2022, it burst into reality — seemingly out of nowhere — with the popular launch of ChatGPT, the generative AI chatbot that solves tricky problems, designs rockets, has deep conversations with users, and even aces the Bar exam.
But the truth is that before ChatGPT nabbed the public’s attention, AI was already here, and it was doing more important things than writing essays for lazy college students. Case in point: It was key to saving the lives of tens of millions of people.
AI-designed mRNA vaccines
As Dave Johnson, chief data and AI officer at Moderna, told MIT Technology Review‘s In Machines We Trust podcast in 2022, AI was integral to creating the company’s highly effective mRNA vaccine against COVID. Moderna and Pfizer/BioNTech’s mRNA vaccines collectively saved between 15 and 20 million lives, according to one estimate from 2022.
Johnson described how AI was hard at work at Moderna, well before COVID arose to infect billions. The pharmaceutical company focuses on finding mRNA therapies to fight off infectious disease, treat cancer, or thwart genetic illness, among other medical applications. Messenger RNA molecules are essentially molecular instructions for cells that tell them how to create specific proteins, which do everything from fighting infection, to catalyzing reactions, to relaying cellular messages.
Johnson and his team put AI and automated robots to work making lots of different mRNAs for scientists to experiment with. Moderna quickly went from making about 30 per month to more than one thousand. They then created AI algorithms to optimize mRNA to maximize protein production in the body — more bang for the biological buck.
For Johnson and his team’s next trick, they used AI to automate science, itself. Once Moderna’s scientists have an mRNA to experiment with, they do pre-clinical tests in the lab. They then pore over reams of data to see which mRNAs could progress to the next stage: animal trials. This process is long, repetitive, and soul-sucking — ill-suited to a creative scientist but great for a mindless AI algorithm. With scientists’ input, models were made to automate this tedious process.
“We don’t think about AI in the context of replacing humans,” says Dave Johnson, chief data and AI officer at Moderna. “We always think about it in terms of this human-machine collaboration, because they’re good at different things. Humans are really good at creativity and flexibility and insight, whereas machines are really good at precision and giving the exact same result every single time and doing it at scale and speed.”
All these AI systems were in put in place over the past decade. Then COVID showed up. So when the genome sequence of the coronavirus was made public in January 2020, Moderna was off to the races pumping out and testing mRNAs that would tell cells how to manufacture the coronavirus’s spike protein so that the body’s immune system would recognize and destroy it. Within 42 days, the company had an mRNA vaccine ready to be tested in humans. It eventually went into hundreds of millions of arms.
Biotech harnesses the power of AI
Moderna is now turning its attention to other ailments that could be solved with mRNA, and the company is continuing to lean on AI. Scientists are still coming to Johnson with automation requests, which he happily obliges.
“We don’t think about AI in the context of replacing humans,” he told the Me, Myself, and AI podcast. “We always think about it in terms of this human-machine collaboration, because they’re good at different things. Humans are really good at creativity and flexibility and insight, whereas machines are really good at precision and giving the exact same result every single time and doing it at scale and speed.”
Moderna, which was founded as a “digital biotech,” is undoubtedly the poster child of AI use in mRNA vaccines. Moderna recently signed a deal with IBM to use the company’s quantum computers as well as its proprietary generative AI, MoLFormer.
Moderna’s success is encouraging other companies to follow its example. In January, BioNTech, which partnered with Pfizer to make the other highly effective mRNA vaccine against COVID, acquired the company InstaDeep for $440 million to implement its machine learning AI across its mRNA medicine platform. And in May, Chinese technology giant Baidu announced an AI tool that designs super-optimized mRNA sequences in minutes. A nearly countless number of mRNA molecules can code for the same protein, but some are more stable and result in the production of more proteins. Baidu’s AI, called “LinearDesign,” finds these mRNAs. The company licensed the tool to French pharmaceutical company Sanofi.
Writing in the journal Accounts of Chemical Research in late 2021, Sebastian M. Castillo-Hair and Georg Seelig, computer engineers who focus on synthetic biology at the University of Washington, forecast that AI machine learning models will further accelerate the biotechnology research process, putting mRNA medicine into overdrive to the benefit of all.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.