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Bat Virus Studies Raise Questions About Laboratory Tinkering

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In mid-2020, a team of scientists who caught bats in a cave in Laos discovered a coronavirus that was very similar to the coronavirus that began to cause havoc around the world.

Since then, some of these researchers have been studying one of these mysterious bat viruses at the High Security Institute in Paris, and how their cousin, SARS-CoV-2, is in the world. I hope to find clues as to whether it has become a threat. An estimated 15 million people have died.

Their work was scientifically fruitful. Last year, scientists discovered that the bat virus can be trapped in human cells, at least in Petri dishes.Last month, the team report More encouraging news: The virus is not particularly harmful to laboratory animals. This finding suggests that SARS-CoV-2 spread rapidly and evolved its ability to cause fatal disease only after two strains diverged on the viral evolutionary tree.

If the Lao virus jumps from bats to humans, new research suggests that it can cause mild stomach bugs rather than life-threatening pneumonia. Nonetheless, laboratory experiments like these rekindle long-standing debates among scientists about the wisdom of tinkering with viruses that are very closely associated with known pathogens.

Proponents argue that this type of data is important for understanding and preventing pandemics. For example, a new study tested whether the bat virus could evolve a “furin cleavage site.” This is a function of SARS-CoV-2 that can efficiently infect human cells.

“Our motivation was to provide insight into the origin of Covid,” said Marc Eloit, a virologist at the Pasteur Institute in Paris, who is leading the effort.

However, critics have suggested that scientists say the virus is more among people, given the small but real possibility that these modified pathogens will infect laboratory workers and escape to the outside world. He says that experiments that can spread well should not be performed.

“For me, the benefits of this study are more important than the risks,” said Dr. David Lerman, a microbiologist at Stanford University.

The bat virus at the heart of Dr. Eloit’s experiments was revealed in the summer of 2020 on an expedition to a limestone cave in northern Laos. A team of Lao and French researchers caught a bat flying from a cave and took a sample of saliva. Blood, urine, feces.

Scientists have discovered genetic material in five coronaviruses that are closely related to SARS-CoV-2. The entire virus of the strain named BANAL-236 was found in the feces of Marshall’s horseshoe-shaped bat (code indicating that the virus came from the bat’s anal swab).

Scientists returned to the lab and discovered that BANAL-236 could infect human cells by binding tightly to the same protein that SARS-CoV-2 uses for invasion. In February, researchers published these Survey results In Journal Nature.

Last month they Second wave of resultsNow being reviewed by scientific journals, where they investigated the behavior of the virus in laboratory mice and monkeys.

In one experiment, scientists injected the virus into genetically engineered mice commonly used in Covid’s research. SARS-CoV-2 replicates quickly in the lungs, just like humans, losing weight and causing death.

In contrast, BANAL-236 had difficulty colonizing the lungs of animals, producing only about 1 percent of the virus produced by SARS-CoV-2 infection.

Researchers have found that spraying the virus on the noses of two monkeys makes the virus even milder. BANAL-236 was replicated primarily in the intestine, not in the lungs.

Dr. Eloit believes BANAL-236 is milder because it lacks key features that are critical to the success of SARS-CoV-2.

After the new SARS-CoV-2 virus is created intracellularly, its peplomer transforms and has the effect of springing the crossbow. The next time the virus binds to a new cell, the primed spike protein fires a molecular bolt, which is drawn into the new host.

This shape-changing region of the spike (known as the furin cleavage site) is essential for the success of SARS-CoV-2.When scientists have Designed Viruses lacking this site have difficulty replicating and spreading to new hosts in the lungs of laboratory animals.

Acquiring a Flynn cleavage site may have been an important step in the evolution of SARS-CoV-2. To explore that possibility, Dr. Eloit and his colleagues conducted laboratory experiments, giving BANAL-236 the opportunity to evolve new traits such as furin cleavage sites.

The team is based on that research experiment Other scientists injected the bird influenza virus into chicken eggs and waited for them to replicate. Then I transferred the new virus to a new egg so that it could replicate again. Each time it was transferred, the virus had the opportunity to evolve. After 11 transfers, scientists have discovered that the influenza virus has evolved the cleavage site and is fatal to chickens.

In a similar manner, Pasteur researchers removed lung tissue from BANAL-236 infected mice and used that tissue to infect healthy animals. They then repeated this cycle to transfer the virus from mouse to mouse.

In another experiment, they infected a dish of human enterocytes with BANAL-236 and then used a new virus produced by the cells to infect the dish.

However, in both experiments, Dr. Eloit and his colleagues decided not to go up to 11 transfers, but to stop at 6 transfers.

“From a purely scientific point of view, we wanted to do more than six passages,” Dr. Eloit said. “But I didn’t want to risk adapting the bat virus to humans.”

BANAL-236 did not acquire a furin cleavage site in either experiment. The virus acquired other mutations, but was unable to ameliorate the infection of the lungs of mice.

Scientists have been conducting such evolutionary experiments, known as “continuous passages,” for over a century. actually, vaccination Many viruses, such as yellow fever, were created by growing them in the laboratory. The virus has evolved into a milder form that can be safely injected into humans in the Petri dish.

However, in 2011, there was controversy over the safety of continuous passage experiments that could generate new human pathogens. At that time, researchers were studying how the influenza virus, which causes infections in the intestines of birds, evolves into an aerial form that can infect people.

Two teams of researchers sprayed the bird flu virus on the nose of the ferret, waited for the virus to replicate, and then transferred the new virus to the new ferret. Soon the virus evolved and became better at replicating on ferrets.

Some critics said the study was so reckless that it shouldn’t be published, fearing that other researchers would copy the study and accidentally release a new pandemic strain of influenza. The US government has stopped such experiments in order to develop a new policy for determining safety.

Some studies have been started again in recent years. However, Dr. Lerman of Stanford and others complain that the current regulations are not transparent enough.

Dr. Eloit said a committee at the Pasteur Institute, which reviews potentially dangerous biological studies, has approved his team’s proposal to study new bat viruses. Scientists then experimented with the same level of security as other studies using the coronavirus known as Biosafety Level 3. BSL-3..

Dr. Tom Inglesby, director of the Johns Hopkins Health and Security Center at Bloomberg School of Public Health, said it was good for scientists to think about these potential risks. But he also said he wanted to see a clear rationale for deciding that the six passages were safe.

“It is impossible to know in advance whether these experiments will lead to more infectious or more virulent viruses,” he said. “There is no strict rule that six are safe and no more.”

But Thomas Peacock, a virologist at Imperial College London, said he thought Dr. Eloit and his colleagues were wise enough. In a previous study, he pointed out that researchers found that antibodies produced by people during Covid infection were very potent against BANAL-236. This may mean that if the virus leaks from the lab, it cannot spread that far.

“The virus will probably hit the brick walls of the general public,” Dr. Peacock said. “I have no problems with the experiment.”

Other researchers agreed with Dr. Eloit that the study could reveal when and how SARS-CoV-2 spread to people.

For Dr. Eloit, the inability of his team to generate furin cleavage sites in BANAL-236 in mouse or human enterocytes suggests that the SARS-CoV-2 strain will spill into humans after acquiring the furin site in bats. doing. He said it was not easy for the virus to acquire the Flynn site after jumping into another species of animal (sometimes called the “intermediate host”) as sold in the Chinese Wuhan market. .. “There is no strong argument in favor of intermediate hosts,” said Dr. Eloit.

But scientists who support market scenarios are looking at new results from a different perspective. They reasoned if researchers were unable to spur BANAL-236 to evolve the furin site during continuous passage experiments. leak” hypothesis I am proposing.

Edward Holmes, a virologist at the University of Sydney, said:

Dr. Peacock was reluctant to draw strong conclusions from such small experiments. “I think it’s very difficult to ask to get a flyin site after a few passes,” he said.

Dr. Eloit and his colleagues are currently investigating the possibility that the SARS-CoV-2 ancestors acquired a furin cleavage site while still in the wild bat. The virus may then have spread to intermediate hosts or directly to people exposed to bats. For example, collect bat guano, hunt and eat bats.

To test that idea, scientists are working to get more samples from bats in Laos and neighboring countries. Dr. Eloit cannot say whether their hypothesis is more likely than other hypotheses, but at least they can investigate.

“Our job as a scientist is to explore practical hypotheses that we can explore,” he said.

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