Last week, WHO announced that a group of experts will soon be sent to China to help scientists there identify the natural source of the new coronavirus, which has claimed more than 580,000 lives worldwide. This is not done to find the culprits of the global epidemic that has broken out. The goal of the scientific expedition is much more pragmatic: The WHO, like the international community as a whole, wants to do everything in its power to prevent such extraordinary situations from happening again in the future.
In 2004, scientists were able to prevent a recurrence of the “atypical pneumonia” SARS epidemic by identifying the source of the infection and tracing its path back to the natural focus. As soon as the virus began to spread among humans again, it was quickly neutralized. Scientists are now working hard to repeat this success with the new coronavirus – but what seemed to be an identical task turned out to be a real puzzle that has already baffled researchers several times. Despite the significant similarity between the two viruses, SARS-CoV-2 has proven to be a much tougher nut to crack than its predecessor, and unraveling the mystery of its origin will not be easy. But the experience of previous epidemics gives scientists a sense of where to go with their work. In addition, the new coronavirus itself, which did not even have a name six months ago, has been studied – weakly, but still enough to have some hope of success.
To prevent a recurrence of the epidemic, scientists need to answer two questions as accurately as possible. We explain quickly, simply, and clearly what happened, why it matters, and what happens next.
The number of episodes should remain the same. The End of the Story Podcast Advertising First, where exactly – from which “natural reservoir” – did the new infection come from? In other words, what animals in the wild are carrying a virus that may pose a threat of a new global epidemic? Second, how exactly did this virus, which until recently only affected animals, “cross the species barrier” – that is, acquire the ability to spread from human to human? We need to understand what mutation caused this change and how likely it is to happen again.
Scientists at the Sabeti Lab are considered the world’s center for viral genetics. Over the past decades, experts in this lab have deciphered the genetic code and identified the origins of several dangerous pathogens, including Zika and Ebola viruses. As a result, scientists have been able to effectively control these infections: now, when a viral fever outbreak occurs, it is usually contained immediately, preventing it from becoming a full-blown epidemic.
“Every virus has its own genome – a specific DNA or RNA sequence. It is completely unique – to the extent that it can be compared to a fingerprint,” says Dr. Meta, explaining how the “virus detectives” work. “With each new infection, the genome of the virus changes slightly. Just a tiny bit, literally fractions of a percent – but this allows a connection to be made between two infected individuals,” 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 virtually identical.
The SARC-CoV-2 genome is a long sequence of RNA consisting of approximately 30,000 letters (nucleotides) arranged in a strict order. This means that during the assembly of each new copy of the virus, there are 30,000 opportunities for errors, where one letter is accidentally replaced by another. If such an error occurs, but the virus does not lose its ability to replicate, the new RNA sequence will be replicated over and over until it makes an assembly error somewhere else.
Geneticists can reconstruct the chain of infection – who infected whom and in what order. They can also understand who the very first patient was – the so-called zero patient who started the whole epidemic. Once found, it will be possible to find the animal that infected it. Chinese scientists chose this path when they noticed an outbreak of an unknown disease caused by a new virus in Wuhan. They collected samples of genetic material from all the patients available at the time, sequenced them, and began to compare them, arranging them in order of viral genome divergence. As a result, several long branching chains have formed, showing the path of infection transmission.
“This is what we call the phylogenetic tree of the virus. It shows the order in which the major mutations occurred,” explains Alina Chan, a professor at the Broad Institute, a joint genetic research center of Harvard and MIT. “On the diagram, you can see how one variation of the genome separates from another, then another branch grows out of it – and so on,” she continues. “In effect, this is a visual representation of the evolution of the virus.” Professor Chan is one of the authors of the sensational article on the origin of SARS-CoV-2, which claims that the genetically novel coronavirus is well adapted for human-to-human transmission. Therefore, the current epidemic may not be the last – if unknown close relatives of the virus emerge in the wild. In their opinion, this is not impossible.
We still do not know where the virus came from. Geneticists have not been able to trace the chains of infection in Wuhan to a single point where the spread began. There were a total of five such “starting points” that were unrelated to each other. Despite the failure to find Patient Zero, scientists are not giving up hope of eventually identifying the natural focus of the infection by other means. In early January, when Chinese scientists sequenced the RNA of the pathogen of an unknown disease (it didn’t even have a name at the time) and compared the result with the database, it became clear that it was almost 80% identical to the genome of SARS – the same virus that caused two outbreaks of “atypical pneumonia” in 2002-2004. It took epidemiologists almost half a year to find the source of the first SARS case, says Alina Chan. Similarly, by following the chain to the first infected individuals, scientists found that several of them had visited a local market where wild animals were sold, and they realized that the most likely source of infection was there. Market testing took more than a month. Geneticists had to sequentially test all the animals that might be intermediate carriers of the infection. In May 2003, their efforts paid off: an identical virus was found in the bodies of Himalayan civets.
“When the second SARS outbreak occurred in late 2003, scientists already had a rough idea of where to look for the culprits,” continued Professor Chan. “When they learned that one of the first patients was a waitress, epidemiologists immediately went to the restaurant where she worked. They found civets there, tested them for the virus, and the analysis was positive. As a result, the entire investigation was completed within a few weeks, and a large-scale epidemic was prevented. A later genetic analysis confirmed that the second outbreak was not a continuation of the first,” says Alina Chan. – In just over a year, the virus had indeed crossed the species barrier at least twice. After learning that the current Wuhan coronavirus is related to SARS, scientists realized that they would most likely have to look for its ancestor in local wildlife markets. But who to test this time – could it be civets again? The closest genetic relative of SARS-CoV-2 found in the same database turned out to be the RATG13 virus, which was discovered in bats in Yunnan province in 2013. The genomes of the two viruses were 96.2% identical.
This did not come as a surprise to scientists. A review of scientific papers published in 2007 found that there is a constant “reservoir” of SARS-related viruses in nature, often carried by bats. The authors of the article warned: “There is a high probability that the virus will pose a danger to humans, so we need to prepare for a new epidemic. This time, however, work at the Wuhan market stalled. To the geneticists’ surprise, all the samples they found in market animals turned out to be more distant relatives of the new coronavirus than the one discovered six years ago thousands of miles away. A little later, another unexpected detail emerged: of the five confirmed initial cases of infection (the “first patients”), only one could be linked to the Wuhan market. It turned out that the other four had contracted the infection elsewhere – and perhaps in different places. In any case, the main version of scientists about the origin of the virus has not been confirmed. The leading trace on the market turned out to be false.
“The problem with Covid-19 is precisely that we have not yet found a version of SARS-CoV-2 in the body of any animal that would suggest that humans were infected with this virus from animals,” Professor Chang gestures with his hands. “On the contrary, all animals found to have SARS-CoV-2 acquired it from humans. There appears to have been only one case of mass infection with the new virus in the Wuhan market. How it got there, and where and how long it had been hidden before that, remains a mystery. Scientists at University College London calculated that it would take approximately 50 years of natural evolution for the genomes of SARS-CoV-2 and its closest relative, RATG13, to diverge by 4% through a single mutation. Scientists say this is highly unlikely. It is more likely that the new coronavirus acquired this part of its genome by exchanging RNA fragments with another virus in the body of an intermediate host.
The recombination of two viruses within an organism is a relatively rare but fairly well-studied phenomenon. Thanks to this phenomenon, the first SARS appears to have crossed the species barrier by borrowing part of its genome from the Himalayan palm civet virus. The intermediate host of SARS-CoV-2 was once thought to be the pangolin – a virus similar to the “missing” fragment had previously been found in these animals. It was thought that SARS-CoV-2 got its main weapon from them – the spike protein that makes the virus contagious and allows it to enter our cells.
However, it is possible that the opposite is true – and that the spike protein was passed on to pangolins by the ancestor of today’s coronavirus. None of these versions can be completely ruled out. It is possible that scientists will come up with other theories over time. According to Alina Chan, one thing is certain about the new coronavirus: it is genetically highly adapted to be easily transmitted from person to person. “At present, however, we do not have sufficient evidence to support a specific SARS-CoV-2 adaptation scenario,” she stresses. “And it is unclear when such evidence will be found.” Samara Meta believes that sooner or later scientists will find answers to the questions posed. The main thing is not to give up the search – otherwise the epidemic will inevitably return.
Alina Chan shares this view. According to her, all conspiracy theories about the origin of the virus have long been debunked by scientists, but many continue to use them for their own purposes to score political points. “Scientists from around the world are working tirelessly to understand the biology and epidemiology of the virus, to develop treatments and vaccines, and to do everything possible to anticipate and ultimately overcome the pandemic. 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 lost sight of the real goal: to answer this question, first and foremost, to prevent new outbreaks of the coronavirus in the future,” concludes Professor Chang. Virologists at several universities in the UK believe that there is potential for a second wave. How dangerous is it?