As the H5N1 avian influenza virus races across the globe, killing wildlife, livestock and even some people, scientists and health officials say we are on the brink of a new global pandemic. I am concerned that they are being forced to stand up.
However, it is difficult to predict when, where, and how this will happen. Some researchers blame this, in part, on the guardrails the federal government has put in place around gain-of-function research.
The term refers to experiments that seek to understand the virus’s potential to adapt to new hosts, spread more easily, survive longer in the environment, and worsen symptoms in infected people. Although many scientists see this approach as an important tool for conducting biological research, other experts have long complained that it is unacceptably dangerous – the new coronavirus At a laboratory in Wuhan, China, whose reputation has been further tarnished by persistent speculation that the virus that causes the pandemic was created in a gain-of-function experiment.
As a result, many virologists have turned away from this research to avoid the stigma and regulatory red tape. Some people on the ground say this has deprived officials of valuable information that could help them predict and prepare for H5N1’s next move.
“If that research were more widely accepted, do you think we would have a better understanding of this virus and what it does next? Or how quickly it could change? ? Or what does that require?” asked Richard Webby, director of the World Health Organization’s Collaborating Center for Research on the Ecology of Influenza in Animals and Birds. “yes.”
Felicia Goodrum, a molecular virologist at the University of Arizona, said gain-of-function studies could help health officials recognize worrisome H5N1 mutations and identify targets for antiviral drugs and vaccines.
“Without that, we’re just flying in the dark,” she said.
Critics of research in this area don’t think so. They argue that the work is too dangerous and could allow pathogens to multiply and escape into environments where people have no natural immunity. Worse, they claim, it could fall into the hands of violent criminals and be used as a biological weapon.
Mark Lipsitch, a professor of epidemiology at Harvard’s T.H. Chan School of Public Health, said those risks outweigh the promise of research that may not be as helpful as proponents suggest.
Lipsitch said that to contain an outbreak, scientists and health officials need to know which animals are infected, which people are infected, and how many of them have contracted the virus. They argue that it is a matter of what symptoms they experienced as a result.
“These are basic epidemiological and veterinary questions,” Lipsitch said. “I can’t think of any route through which gain-of-function research could inform, much less answer, these questions.”
An animal handler collects a blood sample from a dairy cow vaccinated against avian influenza in July in Ames, Iowa.
(USDA Agricultural Research Service, via Associated Press)
The controversy dates back to 2011, when two independent research groups conducted gain-of-function experiments that showed that influenza can be transmitted through the air among ferrets used to model the behavior of influenza in humans. It was announced that the H5N1 strain had been generated.
H5N1 was first identified in geese in China in 1996 and quickly spread to bird species in Asia, jumping onto people hundreds of times along the way. More than half of known infections were fatal.
Given the high mortality rate and the geographic spread of the virus, then-President George W. Bush prompted the creation of a $7.1 billion program to prepare for the virus’s inevitable arrival in the United States. He spearheaded the creation of a national network as well as a global surveillance and preparedness network through the WHO. He also committed federal funds to stockpiles of vaccines and antiviral drugs, as well as millions of dollars in laboratory research.
Amid this outpouring of support, Professor Yoshihiro Kawaoka’s team at the University of Wisconsin in Madison and Professor Ron Fouchier’s team at Erasmus University in the Netherlands simultaneously began experiments with H5N1, introducing genetic mutations into RNA and determining how We investigated whether these changes occur from the virus that has passed through the virus. You will be able to pass easily between birds and you will be able to pass between humans efficiently.
Kawaoka and his colleagues combined the H5 hemagglutinin gene from the avian influenza virus with the gene from the 2009 H1N1 swine influenza virus. They then induced the hybrid to evolve so that it could combine with mammalian cells rather than bird cells. They found that four mutations in the H5 gene were sufficient to create a virus that could be transmitted between ferrets in adjacent cages.
Meanwhile, researchers in Fouchier’s lab only tinkered with H5N1. They added a handful of mutations that fueled previous influenza pandemics and infected ferrets. The virus didn’t spread naturally at first, so scientists helped spread the virus by transferring it from an infected animal’s nose to a healthy ferret. After 10 such passages, the virus had evolved to the point where it could spread naturally from one ferret to another.
Dr. Arturo Casadeval, an immunologist and infectious disease physician at Johns Hopkins University, said the study provided valuable confirmation that avian influenza viruses can cause human pandemics.
“Until these experiments were conducted, we did not know whether H5N1 had the biological ability to transmit to mammals,” he said.
But they also highlighted the risk that scientists could accelerate the threat. “This was a prime example of true capability acquisition,” Casadevall said.
Due to concerns that information from their research could be misused, Kawaoka and Fouchier voluntarily suspended their research in 2012, and their paper underwent thorough security review by the U.S. National Scientific Advisory Committee on Biosecurity. It was first published after passing the gender test. Gain-of-function research resumed the following year.
Fears were reignited in 2014 when federal labs mishandled smallpox, anthrax and H5N1 samples. No one became ill, but the move led to a three-year freeze on federal funding for gain-of-function experiments involving particularly dangerous pathogens, until stricter oversight rules are put in place.
Plans for such experiments currently go through multiple layers of review at the prospective researchers’ institutions. If the study received funding from the National Institutes of Health, additional reviews will follow.
“There are many regulatory hurdles to ensure adequate risk mitigation,” said Seema Lakdawala, a virologist who studies influenza viruses at Emory University. “We’re all being extra careful because no one wants to be accused of doing something dangerous.”
A biohazard suit hangs in a biosafety level 4 laboratory at the U.S. Army Medical Research Institute of Infectious Diseases at Fort Martin. Detrick, Maryland
(Patrick Semanski/Associated Press)
Even if a research project is approved, these obstacles can delay it by several months or more, she said. Uncertainty acts as a deterrent, especially for scientists early in their careers.
“Doing gain-of-function research is certainly uncomfortable,” Goodrum says. “We are discouraging people from entering the scene.”
For some, the timing couldn’t be worse.
At least 65 people have been infected with the H5N1 virus in the United States since it arrived in North America in 2021, according to the Centers for Disease Control and Prevention. Most of the cases involve workers at dairy farms and poultry farms, where symptoms include conjunctivitis and conjunctivitis. Upper respiratory tract irritation – tends to be mild. But in two cases, including a patient in Louisiana and a teenager in Canada, people became seriously ill.
The CDC said there is no evidence that the virus is directly transmitted from person to person. Scientists expect the situation to change sooner or later. With the influenza pandemic in full swing, the risks are increasing.
“What I fear most today is the recombination phenomenon between substances circulating in cows and seasonal influenza,” Casadevall said. If both viruses infected the same mammal at the same time, their components could mix and create a “strain of the virus that can very easily infect humans, but to which humans have no immunity.”
“This is a gain-of-function experiment happening in nature,” he added.
This is a point Webby also suggested, saying that gain-of-function experiments are much safer in a sealed biosafety level 3 laboratory with special ventilation systems and other precautions “than on a farm.” he pointed out.
However, Lipsitch and colleagues say the fact that viruses are constantly mutating and changing calls into question the validity of gain-of-function studies. Viral strains concocted in the laboratory do not necessarily match those that appear in the environment.
“Evolution has a large element of randomness,” Lipsitch said. “The fact that an experiment goes in one direction in the lab does not mean it will go in the same direction elsewhere.”
Three rod-shaped H5N1 influenza virus particles are seen in a pair of color transmission electron micrographs.
(CDC and NIAID)
Even if it’s a close match, Lipsitch said, “There is compelling evidence that what we learn in one strain can be reversed in very closely related strains.” . Therefore, generalizability is very low. ”
He cited a paper in which Kawaoka and Fouchier experimented with a “more mammalian-friendly” mutation of H5N1 and applied it to a slightly different version of the virus. In this case, the researchers found a “completely different effect.”
These shortcomings make it difficult to justify the research risks, said Nicholas Evans, a bioethicist at the University of Massachusetts Lowell.
“I think what remains unanswered in the gain-of-function debate is, ‘What is the social value of these studies?'” he says.
For Evans, there appears to be little, especially given the lack of urgency in the government’s response.
“This particular piece of very niche biological research on H5N1 would have resulted in a significant change in an epidemic that has been largely characterized by a lack of interest from federal agricultural and public health regulators. That’s kind of nonsense for me to say,” he said.
Kawoaka declined to discuss his research, and Fouchier could not be reached.
Michael Imperiale, a virologist at the University of Michigan in Ann Arbor, said Kawaoka and Fouchier’s experiments are extremely useful as a blueprint for what to watch out for as the virus spreads around the world. Ta. And he was surprised to see more people not talking about their worth.
“No one seems to have pointed out the fact that these gain-of-function experiments have given us important information that the virus can jump,” Imperiale said.
Other gain-of-function experiments conducted on H5N1 several years ago showed that the real-world virus spreads more easily through the air, becomes more infectious to cells in the respiratory tract of mammals, and develops resistance to antiviral drugs. informed scientists about potential mutations that could be obtained. medicine.
“The experiment 10 years ago was very useful,” Lakdawala said. “It helped me prepare better.”
But Goodrum said that won’t be the case in the future unless the scientific community defends the research and challenges its negative image. “It is very likely that we will be less prepared for the next pandemic than we were for the last one.”
