BOSTON — The experiment probed a coronavirus mystery: Why is the omicron variant apparently less deadly than the original Wuhan strain?
The researchers at Boston University’s National Emerging Infectious Disease Laboratories (the NEIDL, pronounced like “the needle”) created a new version of the virus, combining the spike protein that studs the surface of omicron with the backbone of the ancestral strain.
The result: The “chimeric” virus was only a little less deadly than the Wuhan strain, killing 80 percent rather than 100 percent of laboratory mice that are particularly sensitive to the virus. But it was still much deadlier in these mice than omicron. This suggested that the spike protein wasn’t the only element of omicron making it less lethal. Another mutation had to be playing a role.
On Oct. 14, the researchers posted an early draft of their results online. Such studies usually fly under the radar. Not this one.
“Experts slam Boston lab where scientists have created a new deadly Omicron strain with an 80% kill rate in mice,” blared a headline in the Daily Mail.
Critics view pathogen research as the Wild West of science. Virologists have faced online abuse and even death threats amid fears that what they do is dangerous. Above all, conjectures that the coronavirus pandemic might have originated from secret laboratory research have cast a shadow over the field.
Independent of that rancorous debate about covid’s origin, the National Institutes of Health is preparing an overhaul of the policies on government-funded research, with draft recommendations by its biosecurity board expected to be released Friday.
The board’s recommendations, which could determine how virology experiments are conducted, will land in a politically charged environment. Republican leaders in the House of Representatives, leveraging their newly acquired subpoena power, have launched an investigation of the pandemic that will include the origin of covid and what they believe could be the involvement of American scientists and government officials.
The “lab leak theory” has revived a durable cultural meme, that of the mad scientist, of human hubris creating things that nature would not. Virologists, in turn, argue that the assault on their integrity has potentially dire consequences for public health. Covid is still sickening and killing people across the planet. The natural world teems with pathogens that could create yet another plague.
The editors of the journal of the American Society for Microbiology in December published an editorial warning that if scientists trying to protect humanity from the next pandemic continue to be viewed with suspicion, we will be “doomed to have pathogens control us, rather than vice versa.”
To probe the coronavirus’s secrets requires experiments that may involve combining two strains and seeing what happens. The creation of recombinant or chimeric viruses in the laboratory is merely mimicking what happens naturally as viruses circulate, researchers say.
“That’s what viruses do. That’s what scientists do,” said Ronald Corley, the chair of Boston University’s microbiology department and former director of NEIDL. What the scientists are definitely not trying to do, Corley quickly added, is “create scary viruses.”
Questions about the origin of the pandemic have intensified a debate that had split the mainstream scientific community long before the coronavirus overtook the world: Where should scientists and government officials draw the line between pathogen research that is beneficial and that which is too risky?
More than a decade ago, experiments in the United States and the Netherlands created versions of the H5N1 influenza virus that could be more easily transmitted among ferrets, which have lungs similar to humans and are susceptible to influenza viruses. That ignited a furor over such “gain of function” research and whether the results should be published by the leading science journals. At the time, the biggest concern was not biosafety so much as biosecurity — keeping sensitive experimental data out of the hands of terrorists and rogue scientists.
The National Science Advisory Board for Biosecurity warned of a possible “unimaginable catastrophe” and persuaded the journals to hold off on publishing. But the engineered viruses turned out to be less dangerous than originally feared. That controversy generated media attention but nowhere near the scale or ferocity of the covid origin debate.
Kristian Andersen, an infectious-disease researcher at Scripps Research, is among the scientists under attack by proponents of the lab leak theory. House Republicans have demanded that he turn over documents and communication about the origin of the coronavirus.
Andersen had initially suspected a lab leak when scrutinizing the novel coronavirus in early 2020, but upon further investigation, he and four colleagues wrote an influential article in the journal Nature Medicine concluding that SARS-CoV-2 was not engineered in a lab. He later co-authored two papers pointing to a natural viral spillover from animals sold in a Wuhan market. But he and many colleagues have been pelted with accusations that they’re part of a coverup. That speculation helped generate a backlash against pathogen research and prompted Scripps to hire security for Andersen and his lab.
“The misinformation/disinformation environment” caught the experts by surprise, Andersen said.
“Unless we fix that, it doesn’t matter what else we do. People won’t take the vaccines, they won’t take the drugs that do work, they won’t take anything,” Andersen said. “I knew the world was crazy, but I hadn’t exactly realized how crazy.”
Corley argues that it is critical for researchers to listen to public concerns and do a better job explaining what scientists are doing and why they’re doing it. These pathogens are frightening, he freely admits. His laboratory, the NEIDL, ramped up operations only after a protracted legal battle with local activists who did not want it built in a densely populated city. It is one of a handful of research laboratories in the United States with biosafety level 4 containment, reserved for the study of the deadliest pathogens, like Ebola. (SARS-C0V-2 is studied in BSL-3 labs.)
The NEIDL is basically a fortress. Hundreds of security cameras are sprinkled through the building, along with motion sensors and retina scanners. The BSL-4 chambers are their own inner building that is nested within the larger structure. Air is filtered and refiltered. Researchers in the BSL-4 labs look like astronauts getting ready for a spacewalk — fully enclosed in biosafety suits, tethered to machines that pump air into their helmets.
“I feel safer working in this building than being out on the streets walking around,” said Corley, suggesting he would be more likely to catch a bad virus outside than while working among pathogens in his laboratory.
Corley said the chimeric virus experiment received several layers of institutional review, including from the university’s biosafety committee and the Boston Public Health Commission. Despite the controversy, the researchers forged ahead, and on Jan. 11 published their peer-reviewed study in the journal Nature. The study identified a protein, nsp6, that plays a role in lessening the lethality of omicron compared with the ancestral strain.
Jesse Bloom, a computational biologist at the Fred Hutchinson Cancer Research Center who has supported investigations of a possible lab leak origin of the pandemic, said the Boston University experiment probably posed little risk of unleashing a dangerous variant into the general population. He noted that it used an early version of omicron, BA. 1, and so the recombinant virus would not have been able to compete against later, more transmissible subvariants of omicron.
Bloom said he is more concerned about experiments in laboratories across the world that involve the SARS coronavirus that began spreading in China in 2002. “If there were an accident with Sars-CoV-1, that would introduce into humans a virus that is very different from what is circulating now,” he said.
That virus spread from infected animals sold in a market, and many scientists have contended that SARS-CoV-2 most likely emerged the same way. There is no evidence that SARS-CoV-2 was in a laboratory before the outbreak. Bloom, however, asserts that the evidence for a market origin for the current coronavirus pandemic is not conclusive, and both a laboratory origin and natural spillover should be viewed as possible causes of future pandemics.
“Whatever you think about the origin of SARS-CoV-2, people need to think about both of these risks and come up with ways to neutralize them,” he said.
Concerns about pathogen research reflect a reality about science and technology: They evolve rapidly, often chaotically and without high-level oversight or regulation.
New tools and innovations in the life sciences give researchers previously unimaginable powers to manipulate living things. That’s why the global scientific community took pains in recent years to create bright lines for the acceptable use of CRISPR, the revolutionary gene-editing technology developed roughly a decade ago.
Leaders of the NIH biosecurity advisory board say their nearly year-long effort to produce recommendations for pathogen research has been challenging as they try to balance the risks and benefits.
“It’s like you’re doing a dance,” said Syra Madad, an infectious-disease epidemiologist who co-chairs one of the working groups for the biosecurity board.
The other co-chair, Gerald Parker, said “too onerous” restrictions on research could hurt American competitiveness in the life sciences. But Parker, speaking for himself and not for the biosecurity board, stressed the need to rebuild public trust in these contentious times. This is all the more important because of the global proliferation of laboratories studying dangerous pathogens, he said.
The pandemic exposed the obsolescence of current government rules on “potential pandemic pathogens,” which focus on infectious agents known to be highly lethal. But SARS-CoV-2 isn’t very deadly compared with many viruses. It’s just incredibly transmissible, and managed through its sheer contagiousness to create a global disaster. Thus the biosecurity board’s preliminary recommendations last fall said the guidelines should cover highly transmissible but not terribly lethal viruses, too.
Tom Inglesby, director of the Center for Health Security at Johns Hopkins Bloomberg School of Public Health, maintains that the federal government must make a number of serious reforms in the oversight of risky experiments. Some of those experiments probably aren’t worth the risks, he said.
“I am so pro-research. I am so pro-science. I am so for figuring things out,” Inglesby said. But, he added, “When people say, well, we have to do this work to make pathogens more transmissible, it’ll help us fight the next pandemic, what I would say is: ‘You need to tell us exactly how it’s going to help us.’”
The cruelty of pathogens before the invention of vaccines, antibiotics and other interventions is a fading memory in the developed world, even as diseases like malaria and tuberculosis continue to kill millions of people a year in impoverished societies.
Life before modern medicine was inherently vulnerable to devastating illnesses that could strike swiftly and fatally. For many people, the only weapon against disease was prayer.
In the past century, scientific discoveries and new medical technologies have prolonged lives and defanged many of the ancient pathogens. That progress continues: The coronavirus pandemic heralded the coming of effective and flexible messenger RNA vaccines that may prove invaluable in the fight against many types of viruses.
And yet, three full years into the pandemic, scientists are still trying to understand what exactly makes SARS-CoV-2 so pernicious. Scientists have published thousands of research papers about mutations in the virus, but often don’t know what those mutations do to the virus. They just know that natural selection — Darwinian evolution — is favoring the mutations for some reason.
“We know every protein, we know every [genomic] sequence, but we don’t know what makes this virus spread better than others,” said Susan Weiss, a virologist at the University of Pennsylvania who has studied coronaviruses for 42 years, having started out when coronavirus research was considered a scientific backwater.
Virologists were long focused on influenza as the likely cause of the next major pandemic. That’s where the research dollars were. Until the 2002 SARS outbreak in China, only two coronaviruses were known to circulate in humans, and they caused colds.
“The sense of urgency to understand them was fairly low. Because you got kinda sick. And then you got better,” said John Connor, a NEIDL scientist and co-author on the chimeric virus paper.
Peter Hotez, a vaccinologist at Baylor College of Medicine, notes that this century has already seen three outbreaks of disease caused by coronaviruses: SARS, then MERS (Middle East respiratory syndrome) in 2012, and covid in 2019.
Mother Nature “is not being coy with us. She’s telling us exactly what she’s going to do. She says, ‘I’m hurling another coronavirus epidemic at you every 7 to 10 years,’” Hotez said. “Mother Nature is the most advanced, sophisticated weaponeer ever invented.”
It is not researchers who are posing the threat, he argues. He points to SARS-CoV-2: It spilled into the human species in late 2019 and was already very contagious — but not perfectly so. Evolution made it better. Then better again.
Variant begat variant, and here we are today, dealing with a potentially deadly virus that has found ways to evade human immunity — and is still evolving.
Carolyn Y. Johnson contributed to this report.