Mouse, pangolin, laboratory: scientists cannot understand where the coronavirus came from

Last week, WHO announced that a group of experts would soon travel to China to help scientists in that country identify the natural source of the new coronavirus, which has claimed more than 580 lives worldwide. Writes about this with the BBC.

Photo: Shutterstock

This is not done in order to find those responsible for the outbreak of the global epidemic. The purpose of the scientific expedition is much more pragmatic: WHO, like the entire international community, wants to avoid the recurrence of such emergencies in the future.

In 2004, scientists already managed to prevent a repeat epidemic of SARS - precisely because, after the first outbreak, experts established the origin of the infection and tracked its path to the natural source. Therefore, as soon as the virus began to circulate among people again, it was quickly neutralized.

Now scientists are making every effort to repeat this success with the new coronavirus, although this time a seemingly identical task turned into a real puzzle in practice, which more than once led investigators to a dead end.

Despite the significant similarities between the two viruses, SARS-CoV-2 turned out to be a much tougher nut than its predecessor, and solving the riddle of its origin will not be easy.

However, the experience of past epidemics tells scientists in which direction to work. And the new coronavirus, which didn’t even have a name six months ago, has been studied - albeit poorly, but still enough to hope for success.

Go there I don’t know where

To prevent a recurrence of the epidemic, scientists need to answer two questions as accurately as possible.

Firstly, where exactly (from what “natural reservoir” did the new infection come from)? That is, which animals in the wild carry a virus that potentially threatens another global epidemic.

Secondly, how exactly this virus, which until recently only affected animals, “overcame the interspecies barrier” - that is, acquired the ability to pass from person to person. We need to understand what mutation caused this change and how likely it is that it will happen again.

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“It’s one thing when a virus is transmitted between people: we have the same immune system, the same anatomy, very similar genes,” explains Samar Mehta, one of the leading experts at the Sabeti Lab at Harvard University. “But in order to pass from an animal to humans, the virus must overcome a much higher “evolutionary barrier,” that is, change very much. That’s why this happens so rarely.”

Scientists call Sabeti Lab the world center of viral genetics. Over the past decades, experts at this laboratory have deciphered the genetic code and determined the origin of several dangerous pathogens, including the Zika and Ebola viruses. As a result, scientists were able to actually curb both of these infections: now, if an outbreak of a viral fever begins somewhere, it can usually be extinguished relatively quickly - without allowing it to develop into a full-scale epidemic.

“Each virus has its own genome - a specific DNA or RNA sequence. It is completely unique - so much so that it can be compared to a fingerprint,” Dr. Mehta explains how “viral detectives” work.

“With each new infection, the genome of the virus changes slightly. Just a little bit, literally a fraction of a percent, but this makes it possible to establish a connection between two infected people,” the expert continues. “And if my fingerprints and my brother’s fingerprints have nothing in common, then my virus and my neighbor’s virus will be almost identical.”

The SARC-CoV-2 genome is a long RNA sequence consisting of approximately 30 thousand letters (nucleotides), following each other in strict order. This means that when assembling each new copy, the virus has 30 thousand opportunities to make a mistake by accidentally replacing one letter with another.

If such an error occurred, but the virus did not lose its ability to reproduce, the new RNA sequence will be reproduced again and again until it is again mistaken when assembled in some other place.

Thanks to this, geneticists can quite accurately restore the chain through which the infection was transmitted - determine which of the patients infected whom and in what order. And therefore, to understand who was the very first patient - the so-called zero patient, who marked the beginning of the entire epidemic.

Having found him, it will be possible to find the animal from which he became infected.

Great expectations

This is the path that Chinese scientists took when they realized that an outbreak of an incomprehensible disease caused by a new virus had occurred in Wuhan.

They collected samples of genetic material from all the patients at that time, deciphered them and began to compare them with each other, placing them in the order of the divergence of the viral genome.

As a result, several long, branched chains lined up showing the route of transmission of infection.

“This is the so-called phylogenetic tree of the virus. It shows in what order the major mutations occurred,” explains Alina Chan, a professor at the Broad Institute, a joint center for genetic research at Harvard and MIT.

“The diagram shows how another genome variation splits off from one variation, then the next branch grows from it, and so on,” she continues. “In fact, this is a visual representation of the evolution of the virus.”

Professor Chan is one of the authors of a sensational article on the origins of SARS-CoV-2, which argues that the genetically new coronavirus is perfectly adapted to transmission from person to person. This means that the current epidemic may not be the last (if the virus has close relatives unknown to us in the wild).

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In her opinion, this is not at all impossible. Where the virus came from, we still don’t know. Genetics failed to reduce the chain of infections in Wuhan to one point from which the spread of infection began.

There were five such “starting points” (in no way connected with each other).

Family ties

Although it was not possible to find Patient Zero, scientists do not lose hope to establish the natural focus of the infection in another way.

Back in early January, as soon as Chinese scientists deciphered the RNA of the causative agent of an unknown disease (at that time it did not even have a name) and compared the result obtained with the database, it became clear: it is almost 80% identical to the genome of SARS - that same virus , which twice caused outbreaks of “SARS” in 2002-2004.

It took epidemiologists almost six months to find the source of the first SARS, says Alina Chan. In the same way, having reached the first infected, the scientists found out that several of them at once visited the local market where they sold wild animals, and realized that most likely the source of the infection was located there.

Testing on the market took more than one month. Geneticists had to test all animals that could potentially be intermediate carriers of the infection. In May 2003, their efforts were crowned with success: an identical virus was found in the body of Himalayan civets.

“When SARS re-emerged at the end of 2003, scientists already had a rough idea of ​​where to look for the culprits,” continues Professor Chan. — Having learned that one of the first patients worked as a waitress, epidemiologists immediately went to the restaurant where she worked. There they found civets, tested them for the virus, and the test was positive.”

In the end, the entire investigation was completed in a few weeks, and a large-scale epidemic was prevented.

“A genetic analysis later confirmed that the second outbreak was not an echo of the first,” says Alina Chan. “In just over a year, the virus actually crossed the species barrier at least twice.”

False trail

Having learned that the current Wuhan coronavirus is a close relative of SARS, scientists realized that they also need to look for its progenitor at local wild animal markets. But who to test this time - is it really the civet again?

The closest genetic relative, SARS-CoV-2, all found in the same database, turned out to be the RATG13 virus, detected in 2013 in bats in Yunnan. The genomes of the two viruses matched 96,2%.

This did not come as a surprise to scientists. Back in 2007, a review of scientific papers was published, which stated that in nature there is a constant “reservoir” of viruses related to SARS (most often they are carried by bats).

The authors of the article warned: there is a high probability that the virus will pose a danger to people. That is, we need to prepare for a new epidemic.

However, this time, work in the Wuhan market has stalled. To the surprise of geneticists, all the samples they found in market animals turned out to be more distant relatives of the new coronavirus than the one that was discovered six-odd years ago, a thousand kilometers from it.

A little later, another unexpected detail emerged: of the five confirmed first cases of infection (those “first patients”), only one could be linked to the Wuhan market. It turns out that the other four caught the infection in other, and maybe even in different places.

One way or another, the main version of scientists about the origin of the virus has not been confirmed. The market trail turned out to be false.

“The problem with COVID-19 is precisely that we still have not found a version of SARS-CoV-2 in the body of a single animal that would suggest that people became infected with this virus from animals,” the professor shrugs. Chan. “So far, on the contrary, all animals in which SARS-CoV-2 was detected received it from people.”

Amazing hybrid

Apparently, only the first case of mass infection with a new virus occurred on the Wuhan market. How he got there, as well as where and for how long he hid before this, remains a mystery.

Scientists at University College London calculated that the genomes of SARS-CoV-2 and its closest relative, RATG13, would diverge from a common ancestor by 4% that did not match by mutations alone, it would take about 50 years of natural evolution.

According to scientists, this is very unlikely. Most likely, the new coronavirus received this part of its genome by exchanging RNA fragments with another virus in the body of some intermediate host.

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Recombination of two viruses within one organism is a relatively rare phenomenon, but quite well studied. Due to this phenomenon, apparently, the first SARS overcame the interspecies barrier, borrowing part of its genome from the Himalayan civet virus.

The pangolin has long been considered the intermediate host of SARS-CoV-2; a virus partially similar to the “missing” fragment was previously discovered in these animals. It was assumed that SARS-CoV-2 received its main weapon from it - the spike protein, which makes the virus infectious, allowing it to penetrate our cells.

Although, perhaps, everything is just the opposite - and the spike protein was inherited by pangolins from the ancestor of the current coronavirus.

None of these versions can be completely ruled out. Perhaps, over time, scientists will have other theories. According to Alina Chan, only one thing can be said with confidence about the new coronavirus: genetically, it is perfectly adapted to be easily transmitted from person to person.

“However, at the moment we do not have sufficient evidence to support any specific adaptation scenario for SARS-CoV-2,” she emphasizes. “And it is unclear when such evidence will be found.”

Samar Meta is convinced that sooner or later scientists will be able to find answers to these questions. The main thing is not to quit searching, otherwise a repeat of the epidemic is inevitable.

Alina Chan thinks the same. According to her, all conspiracy theological versions of the origin of the virus have long been refuted by scientists, but many, earning political points, continue to use them for their own purposes.

“Scientists all over the world are working tirelessly. They are trying to understand the biology and epidemiology of the virus, developing treatment options and vaccines. That is, in general, they are doing everything to predict the possible development of the pandemic and ultimately cope with it. Never before has the scientific community been so united in the face of a common problem. But the question of the origin of SARS-CoV-2 has become so politicized that people have forgotten about the real purpose: the answer is needed primarily in order to prevent new outbreaks of coronavirus in the future,” Professor Chan sums up.

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