In recent weeks, scientists have sounded the alarm about new variants of the coronavirus that contain a handful of small mutations, some of which make the vaccine less effective.
But it is not just these small genetic changes that are of concern. The new coronavirus tends to mix large parts of its genome when making copies of itself. Unlike small mutations, which are like typos in the sequence, a phenomenon called recombination looks like a big copy-and-paste error in which the second half of a sentence is completely overwritten with a slightly different version.
A tidal wave of new studies suggests that recombination could potentially alter the virus in dangerous ways. But in the long run, this biological machinery could provide a silver lining, helping researchers find drugs to stop the virus in its tracks.
“There is no doubt that recombination is taking place,” said Nels Elde, an evolutionary geneticist at the University of Utah. “And it’s probably a little undervalued and may even come under the new variant of concern.”
The coronavirus mutations that most people have heard of, such as those in the B.1.351 variant that were first detected in South Africa, are changes in a single ‘letter’ of the long genetic sequence of the virus, i.e. RNA. Because the virus has a robust system for proofreading its RNA code, these small mutations are relatively rare.
Recombination, on the other hand, is abundant in coronaviruses.
Researchers at Vanderbilt University Medical Center led by virologist Mark Denison recently studied how things go wrong during replication in three coronaviruses, including SARS-CoV-2, which causes Covid. The team found that all three viruses ‘extended’ recombination shown when repeated separately in the laboratory.
Scientists are concerned that recombination could add different variants of the coronavirus to more dangerous versions in someone’s body. The B.1.1.7 variant first detected in Britain, for example, had more than a dozen mutations that suddenly appeared.
Dr. Elde said that recombination mutations of different variants that arose together over time within the same person, or that were co-infected at the same time, could come together. For now, he said, the idea is speculative: “It’s really hard to see these invisible scars from a recombination event.” And while it is possible to become infected with two variants simultaneously, it is rare.
Katrina Lythgoe, an evolutionary epidemiologist at the Oxford Big Data Institute in Britain, is skeptical that co-infection occurs frequently. “But the new variant of concern has taught us that rare events can still have a big impact,” she added.
Recombination may also allow two different coronaviruses of the same taxonomic group to exchange their genes. To investigate the risk more closely, Dr. Elde and his colleagues compared the genetic sequences of many different coronaviruses, including SARS-CoV-2 and some of the relatives in the distance who are known to infect pigs and cattle.
Using specially developed software, the scientists highlighted the places where the viruses’ sequences were aligned and matched – and where not. The software has suggested that many of the recombination events during the past few centuries have involved the evolution of the virus segments that made the protein of the peak, helping the virus enter human cells. This is worrying, the scientists said, because it could be a route by which one virus essentially equips the other to infect humans.
“Through this recombination, a virus that can not infect humans can recombine with a virus like SARS-CoV-2 and take the sequence, and it can infect humans,” said Stephen Goldstein, an evolutionary virologist who worked on the study.
The findings, which were published online Thursday but have not yet been published in a scientific journal, provide new evidence that related coronaviruses are quite promiscuous in terms of recombination with each other. There were also many rows that appeared in the coronaviruses that apparently came out of nowhere.
“In some cases, it almost seems like seconds are falling from outer space, from coronaviruses that we don’t even know about yet,” said Dr. Elde said. The recombination of coronaviruses in different groups has not been thoroughly studied, in part because such experiments may need to be reviewed in the United States due to security risks.
Feng Gao, a virologist at Jinan University in Guangzhou, China, said that although the new software from the researchers in Utah found unusual sequences in coronaviruses, it did not provide evidence for recombination. It may be simple that they have developed this way on their own.
“Variety, no matter how much, does not mean recombination,” said Dr. Gao said. “It could very well be caused by great diversification during viral evolution.”
Scientists have limited knowledge about whether recombination can cause new pandemic coronaviruses, said Vincent Munster, a viral ecologist at the National Institute of Allergy and Infectious Diseases, who has studied coronaviruses for years.
This evidence is still increasing. In a study released in July and formally published today, dr. Munster and his associates suggested that recombination is likely how both SARS-CoV-2 and the virus behind the original SARS outbreak in 2003 both ended with a version of the ear protein that allows them to deftly enter human cells. That vein protein binds to a specific access point in human cells called ACE2. The article calls for greater surveillance of coronaviruses to see if there are others who use ACE2 and therefore may pose similar threats to humans.
Some scientists study recombination machinery not only to ward off the next pandemic, but also to fight the one.
In his recent study on the recombination of three coronaviruses, dr. Denison of Vanderbilt, for example, found that blocking an enzyme known as nsp14-ExoN in a mouse coronavirus causes recombination events to decrease. This suggests that the enzyme is essential for the ability of coronaviruses to mix and match their RNA as it repeats.
Now Dr. Denison and Sandra Weller, a virologist at the University of Connecticut School of Medicine, are investigating whether this insight can treat people with Covid.
Certain antiviral drugs such as remdesivir fight infections by acting as RNA attractants that promote the virus replication process. But this medicine does not work as well as some had hoped on coronaviruses. One theory is that the nsp14-ExoN enzyme eliminates the errors caused by this medicine and thus saves the virus.
Dr. Denison and Dr. Weller, among others, is looking for drugs that can block the activity of nsp14-ExoN, which can make inhibitory and other antiviral drugs work more effectively. Dr. Weller compares this approach to the cocktail therapies for HIV, which combine molecules that act on different aspects of the virus’ replication. “We need combination therapy for coronaviruses,” she said.
Dr. Weller notes that nsp14-ExoN is shared in coronaviruses, so a drug that successfully suppresses it can act against more than just SARS-CoV-2. She and Dr. Denison are still in the early stages of drug discovery and testing different molecules in cells.
Other scientists see the potential in this approach not only to make drugs like remdesivir work better, but also to prevent the virus from correcting any replication errors.
“I think it’s a good idea,” said Dr. Goldstein said, “because you would be pushing the virus into the so-called ‘bug disaster’ – basically that it would mutate so much that it would be deadly to the virus.”