Corona Mutations The Changing Virus

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Scientists are suspiciously tracking every change in SARS-CoV-2, with dangerous looking mutations regularly appearing. On the long term, though, experts hope that the pathogen could prove less aggressive.

By Philip Bethge • 15.07.2020, 11.20 Uhr

Open eyes, hollow cheeks, a face torn by dread – Edvard Munch’s painting, “The Scream,” is an icon of horror.

Some experts believe its central figure is meant to be in the grips of an illness. The first version of the painting dates back to 1893, when the Russian flu had just spread around the world. The pandemic began in Central Asia in May of 1889. It spread to China, Russia and Europe via trade routes. The epidemic reached New York in December, arrived in Montreal in January of 1890, then made its way to South America, Australia, Borneo. Its symptoms included severe fever, headache, aching limbs and fatigue. An estimated 1 million people died worldwide.

The epidemic is widely believed to have been caused by a flu virus, but researchers working with Marc Van Ranst of the University of Leuven in Belgium have a different theory. They believe the pandemic was caused by a pathogen with the abbreviated name of HCoV-OC43. HCoV-OC43 is a coronavirus.

Genetic studies suggest that the pathogen jumped from cattle to people before – much like today’s SARS-CoV-2 – setting off a health crisis. Interestingly, HCoV-OC43 is still around today, as one of seven coronaviruses that can infect humans. But the killer has been tamed: These days, the virus causes only a mild cold.

Could the same happen to SARS-CoV-2?

For half a year now, the new coronavirus has held the world hostage. Officially, more than 8 million people are or have been infected, and the virus has already claimed over 500,000 victims. Virologists, epidemiologists and hygienists are doing their best to get the situation under control. But they are also learning that SARS-CoV-2 is an unpredictable opponent.

The crisis’ outcome will depend not just on whether drugs or vaccines can be developed, but also on how SARS-CoV-2 will change biologically in the coming months and years.

Initial indications suggest that the virus could continue adapting to humans, which would be good news. Over time, viruses tend to get along better with their host, because a relatively peaceful relationship works to the pathogen’s advantage. A virus that kills fewer people has a better chance of spreading. But things can also unfold differently.

“In principle, evolution is not predictable,” says Christian Drosten, a virologist at Charité hospital in Berlin. “I am cautiously optimistic that the danger from SARS-CoV-2 will decrease, but we can’t be sure.”

It’s Here to Stay

François Balloux, a microbiologist at University College in London, is also researching the properties and genetics of the new coronavirus. “It will take a few years, at worst a decade,” he says, “then the virus will probably seem as severe to us as the seasonal flu.” He argues that all that can be said with certainty is that “the virus will be with us. We won’t get rid of SARS-CoV-2 anymore.”

The novel coronavirus has only been around for a short time, yet it is already one of the best analyzed pathogens of all time. Researchers have decoded over 50,000 genomic sequences and uploaded them to a global databank called GISAID (Global Initiative on Sharing All Influenza Data). With the help of this gene sequence, experts are investigating which points on the pathogen could be vulnerable to drugs or vaccines. They are also examining how SARS-CoV-2 is changing and how the virus spreads.

Since 2015, physicist Richard Neher from the Biozentrum at the University of Basel and U.S. biologist Trevor Bedford have been trying to better understand the course of epidemics. The experts have been tracking influenza, Zika and Ebola viruses for years with their online application called Nextstrain (Nextstrain.org). Since January 2020, the data researchers have also been looking into SARS-CoV-2.

The software on Neher’s computer turns chaotic, real-time data into a colorful pathogen family tree. The first SARS-CoV-2 genomes date back to December 2019 and to the central Chinese metropolis of Wuhan – the city where SARS-CoV-2 first appeared. From there, the family tree forks into hundreds of branches, each marking one or more mutations in the pathogen’s genome. “Most of them are insignificant, so they have no effect on the contagiousness or aggressiveness of the virus,” Neher explains. “But the mutations do give us clues about how the virus spreads.”

Thanks to their tree, Neher and his colleagues can see, for example, that SARS-CoV-2 was introduced from Asia to Europe in January and February by various paths. In Germany, the sequences of early cases in the western German state of North Rhine-Westphalia resemble samples from the Netherlands, Austria and Belgium, but differ from those in other German cases.

On average, the experts record two mutations per month on each branch of the virus family tree. Most of them are so-called silent mutations that have no effect on the properties of the virus. Some, however, stand out. And that’s where things get interesting for the researchers.

Spike Issues

Neher moves his mouse over a branch close to the root of the virus family tree. An information box appears on the screen reading “D614G,” the abbreviation for a mutation event that is currently being intensively discussed among experts.

D614G describes a change in the S-proteins, or spikes, of the virus – the club-shaped appendages that allows the SARS-CoV-2 virus to dock with human cells. A team of researchers led by Bette Korber at the Los Alamos National Laboratory say that the mutation appeared in early February and has since spread in “alarming” fashion. The scientists suspect the mutation gives the virus has an evolutionary “fitness” advantage relative to the original virus-type from Wuhan. Researchers at the Scripps Research Institute in Florida have confirmed this assessment. In viruses with the D614G mutation, the number of spikes is “four to five times greater” than in other variants – an ideal prerequisite for faster replication.

Does that mean SARS-CoV-2 will become even more infectious than it already is? There are still uncertainties. The success of certain variants of a virus doesn’t necessarily have anything to do with their genetic makeup. Other factors play a role that can be just as important – such as, in the case of SARS-CoV-2, lockdown measures, international air routes or simply chance. Researchers therefore warn against prematurely drawing a line from small genetic mutations to changes in the virus’ infectiousness or the course of the illness.

Researchers from Hangzhou in China made headlines after reporting that some variants of SARS-CoV-2 reproduced 270 times better in the laboratory than others. Drosten, however, is skeptical: “In its current condition, the study says nothing,” he says, arguing that the publication has technical defects.

Not Enough Time to Change

Much discussion has likewise focused on research into the origin of the virus by a team under the leadership of Michael Forster from the University of Kiel in Germany. The geneticist identified three different types of the SAR-CoV-2 virus. The differences between the types could be the result of a “complex founder scenario”, the researchers noted. Another explanation could be that the dominant type in Wuhan “immunologically or environmentally adapted to a large section of the East Asian population.” Other researchers have criticized the methods used in the study and, in the same journal, criticized “several serious flaws.” Forster rejects the criticism, saying that the publication is a consensus in science.

The reason for the skepticism is simple: SARS-CoV-2 hasn’t had enough time to change much. Although coronaviruses mutate constantly, they have their own repair mechanism that allows them to eradicate harmful mutations.

Only about 15 mutations separate the genome of any of the currently circulating SARS-CoV-2 viruses from the original Wuhan virus, therefore making all SARS-CoV-2 viruses largely identical. There are no different types.

And there is an additional factor holding back the virus from rapidly evolving new characteristics: So far, SARS-CoV-2 has been subject to very little selection pressure. Things are going pretty well for the virus. The pathogen can expect little resistance because very few people have developed antibodies. “With immunity within the population still low, the virus can find many easy targets,” says Michael Lässig, an evolutionary biologist from the University of Cologne.

His research group is trying to predict the evolution of viruses using mathematical models. “The mutation rate of SARS-CoV-2 is five to six times lower than that of the flu virus,” says Lässig. It is a finding that offers a glimmer of hope, because in competition with human antibodies, this level of mutability is likely not sufficient. “At some point, the majority of people will have developed immunity against the virus,” says Lässig. “If the pathogen cannot significantly develop by that point, it will disappear again or at least be severely curtailed.”

Targeting Mutations

Balloux and his team at University College London have classified the mutations that have been discovered thus far. They identified around 200 mutations in the virus’ gene pool that occurred several times independently of one another – an indication that they might offer an evolutionary advantage. They include instructions for making four important viral proteins – including one that is part of the spikes.

But Balloux says that it is still unclear how and if these mutations affect the behavior of the virus. Many of the mini imperfections, he says, are likely due to attacks from the human immune system as it tries to stop the virus from multiplying.

Using the mutation rate, the experts have at least been able to determine that the pandemic probably started between October 6 and December 11, 2019. This refutes speculation that the pandemic started last summer and was kept secret by the Chinese government.

More than anything, though, a better understanding of how the pathogen changes can be helpful in developing drugs to treat the disease it causes. “We need medications and vaccines that can’t easily be circumvented by the virus,” says Balloux. “We should therefore concentrate our efforts on the parts of the virus genome that show the least number of mutations.”

Ultimately, the only way to speculate about the future of SARS-CoV-2 at this point is to look at the behavior of other viruses. Drosten’s working group, for instance, published a paper two years ago on the first SARS virus, which claimed almost 800 victims globally between 2002 and 2003, according to the WHO.

It could potentially have been a lot worse. Researchers discovered that the first SARS coronavirus lost a small part of its genome during the epidemic, which served to weaken it. When Drosten’s team experimentally re-inserted the lost components into the genome, the virus was better able to reproduce.

“Virulence can also be lost during the process of adapting to humans,” says Drosten. What’s fascinating is that SARS-CoV-2 has also occasionally lost a piece of the same section of its genome – at least, in a subpopulation. In virus sequences isolated by researchers in Singapore, 382 genome building blocks were missing.

Is that why the COVID-19 outbreak in the country was relatively mild? It is no longer possible to answer that question with any degree of certainty. The apparently less-harmful version of SARS-CoV-2 has since disappeared again.

Der Spigel

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