Conspiracy theory and viruses
Conspiracy theory is mutating
Sergey Dobrynin, Radio Liberty
The coronavirus SARS-Cov-2, which causes the infectious disease COVID-19, is still poorly understood in many respects simply because it appeared in the human population only a few months ago. Humanity still does not know much about the peculiarities of its epidemiological "behavior" – what is the lethality of the virus, how many asymptomatic carriers it actually has, how will the change of seasons affect its spread. But this does not mean that we are completely blind: the genetic passport of the SARS-CoV-2 virus, its genome, was deciphered in the first weeks after the outbreak. Thanks to this, those who are on the scientific front of the fight against the pandemic can work: drug and vaccine developers.
The genome of the virus is also being studied by more fundamental science – bioinformatics and other scientists are literally monitoring the mutations of the new coronavirus in real time, who can tell where a new dangerous pathogen came from, and over time they will figure out where its evolution is going to lead it.
Russian Bioinformatics Mikhail Gelfand, Professor, Doctor of Biological Sciences, Vice President for biomedical Research at Skoltech and head of the Bioinformatics Center at the Institute of Information Transmission Problems of the Russian Academy of Sciences, told Radio Liberty why scientists are sure that SARS-CoV-2 was not created artificially, how often it mutates, is it worth hoping that evolution will make it less dangerous, and about how conspiracy theories are similar to viruses.
– Does humanity really know how to create artificial viruses?
– The question is what you call an artificial virus. To create a virus almost from scratch, according to a specific technical task – let's come up with a virus that will infect sparrows, but will not infect tits, and will also infect humans and South American sloths - we do not know how to do this. But, generally speaking, we are able to combine the genomes of related viruses – exactly related, and not what comes to mind. You can take proteins that perform approximately the same function in different viruses, and rearrange the genes that these proteins encode from one virus to another. This is exactly what was done in a 2015 paper published in Nature Medicine, for which conspiracy theorists clung at one time: they took a model coronavirus that infected laboratory mice, lived in the laboratory for a long time, it was easy to work with, and replaced the gene with a similar gene from the wild bat coronavirus. The experiment showed that the combined virus is able to infect laboratory mice and human cell cultures. That is, indeed, there is a real danger from bat viruses that live in wild populations. It was an important work about the danger of such a scenario, but since it was done in Wuhan (correction: in fact, the work was done at the University of North Carolina, USA, under the leadership of Ralph Barick, but with the participation of researchers from the Wuhan Institute of Virology, where the genome of the bat virus – MS was isolated), now around it a lot of conspiracy theories were born. Then people just looked carefully at the genomes of the current virus and the virus from that work and were convinced that there was little in common between them – they were nothing more than distant relatives, like all coronaviruses.
– That is, an artificial virus at the current level of biotechnology development is such a rough mosaic, here a piece from one virus, here from another, and a similar one?
– There are two main ways to work. The first way is to make a mosaic. We have viruses with known properties, and we make a virus out of them that combines these properties. It will be a puzzle, it will be immediately noticeable, it will be like Frankenstein's monster, it will be seen that he has one hand of the same color, the other hand of a different color, his eyes are multicolored. The second way is to make point changes, change one letter in the genome and see what happens, what properties the virus will have. But with point changes, the problem is as follows. When we combine genes with known properties, we roughly understand what can happen. But we do not know which point changes lead to what consequences, no one makes such experiments, because it is a very expensive and very difficult experience to change one nucleotide in a virus point–by-point. Most of these replacements will lead to absolutely nothing, to any new properties, they will simply be neutral, the consequences of the rest we cannot predict. If we want to use this method to make a virus with some specific properties, then we do not know what point replacements need to be made in order to get these properties.
When we assume that some virus is artificially created, there can be two hypotheses. Or the hypothesis of a sort of "supreme genetic engineer" who sits and cuts and glues with scissors – in our case, it does not work, because we would immediately recognize the details of this monster in the genome. The second hypothesis is the hypothesis of a genetic engineer who sits and pokes at individual letters with a screwdriver, but this hypothesis does not work because there is no such great biologist who would know where to poke.
– Would this "poking" take too much time? Too many resources?
– Rather too good an understanding, which we do not have. There are 30 thousand nucleotides in the new coronavirus, and touching each of them with a screwdriver is an unthinkable job. Not to mention the fact that in order to get new properties, you need to change not one letter at a time, but in some groups, and no one knows which ones. We don't know, but it doesn't interfere with the natural process in any way. Coronaviruses in nature often recombine if two viruses occur in the same organism. To put it lightly – a bat ate a pangolin, or a pangolin ate a bat, or they both sneezed at a hedgehog running past, in short, if two viruses ended up in the same cell, then combinations of these viruses can turn out in the offspring. When we look at the genome of such a chimeric virus, we see traces of this combination. Roughly speaking, the first half of the virus has one evolutionary history, and the other half has another, which means it is chimeric. This, in principle, is an extremely rare event even in nature, but it happens over long evolutionary periods of time and we see traces of these events. But if you are sitting in the laboratory and thoughtfully waiting for you to get such a chimera in a test tube, then it's better not to, you will die earlier, and from old age, and not from the virus.
– Is the current SARS-CoV-2 just like this, chimeric – the result of a random combination of other viruses?
– It seems that all coronaviruses are like this, everyone in history has had such a combination. This is the same process that occurs during sexual reproduction. Why are the traits of all grandmothers and all grandfathers combined in a child? Because chromosomes change their fragments. A separate question is how it happens molecular–biologically, viruses have a different process, not the one in our chromosomes, but the ideology is the same: you get offspring from two organisms that combine the traits of both. It is clear that this happens during sexual reproduction, in fact, then it is necessary, but the same thing happens in bacteria and viruses, it is the same recombination, the evolutionary basis is the same.
– Is this natural recombination different from the recombination that can be done with the help of genetic engineering, if you look at the genome? Isn't this the same Frankenstein's monster, only created by nature?
– No, it doesn't look any different. "On the edges" with artificial, genetically engineered recombination, some "scars" may still remain, but in principle, it does not differ in anything. In addition to the fact that the chimeric virus in nature continues to mutate and change all the time, and by the way its genetic sequence has managed to change, we understand that this event did not happen recently, but in the relatively distant past.
– That is, in the case of SARS-CoV-2, we see that it itself consists of pieces of other viruses, but after this combination was formed, it managed to live in it for some time and evolve in nature?
– There's an interesting story there! There is indeed a fragment of the pangolin virus in this virus, but it is not the pangolin virus that we know now, it is some older version of the pangolin virus, that is, recombination happened some time ago. Here, of course, supporters of conspiracy theories can say that somewhere in a secret basement there are pangolins who are tormented by evil Chinese scientists and isolated viruses from them ... You can come up with a wild, implausible scenario of this kind for any genetic sequence. But Occam's razor principle tells us that there is a simple natural process that leads to the same result. Why invent a crazy James Bond movie script if Grandpa Darwin has already done everything for you?
– I'm still going to ask just about such a scenario: what if some laboratory artificial combination of viruses not now, but ten years ago, flowed into the natural environment and evolved there by itself - we won't be able to distinguish it from the natural one now, will we?
– Yes, but how plausible is this story? Let's say they made a virus 10 years ago, then a young scientist had a heart attack because a professor yelled at him, the scientist fell, dropped a test tube, a bat flew by, licked what was spilled, and this virus happily jumped into the bats… Which, by the way, is already doubtful, because if this virus was created against a person, then he will live badly in a bat. But let's say he somehow survived there, hid among the bats for ten years, then flew to the market and was devoured there. As I said, this kind of wild story, absolutely incredible, can be invented for any genetic sequence. But why ? Look, the first conspiracy theories about SARS-CoV-2 were very simple: Chinese scientists concocted a virus, it leaked from the laboratory, and the 2015 article was found with a sincere confession. It was instantly checked, and it's not the same virus. There was a theory that fragments of the human immunodeficiency virus were allegedly visible in the virus and that's why it is so evil. It was an article by Indian scientists, which was published as a preprint and then was never published. I give it to my students as homework – to explain what the error is, and my students easily cope (the explanation is that the HIV sequence sites found in the SARS-Cov-2 genome are so small and non-specific that they could belong to any of a huge number of organisms. – Approx. RS).
There is more data, simple conspiracies have all been refuted, now we have to come up with an increasingly intricate conspiracy. The conspiracy theory itself mutates like a virus, and some theories are eliminated by natural selection, killed by immunity in the form of scientists, others are modified, and then the next scientists come. Wonderful Czech scientist Sonya Pekova, who in an interview again spoke about the artificiality of the virus, is such another step in the cyclical process. In two weeks, someone will come up with something else. It is very important here that the immune system – that is, science – copes with the virus of conspiracy. If it copes, the body has recovered. If science has not coped with the new conspiracy theory, it will be like in Britain, where 5G towers are being burned because they allegedly spread coronavirus. The immunity of science did not work – and here is the real harm to the body.
– Sonya Pekova says: "When I saw this sequence (in the regulatory area), it immediately seemed to me that it was not very similar to the natural one." The Czech researcher suggests that it is in this non-coding part of the SARS-CoV-2 genome that something artificial is contained, which makes it so dangerous. What do you think about it?
– The remark about the non-coding area is easily refuted. We must first explain what we are talking about. There is a virus, and there is a virus genome. Imagine a long line of 30 thousand letters. Some places in this line encode proteins, that is, this is an instruction about how to make a protein. There are proteins there that the virus needs to replicate, to copy its RNA. There are proteins that the virus needs to recognize the host cell and connect with it, this is the famous spike. There are proteins that are needed to make the host cell make new viruses. These are genes. And between them there are areas that proteins do not encode, they are needed for other purposes. For example, at the ends of the sequence there are non-coding areas that are needed for the virus to reproduce. And between the genes there are non-coding regions that tell when a gene should work, when it should not work, because some genes should work at the beginning of infection, like "polite little green men" who switch the entire system of the cell to reproduce viruses. And others should work at late stages, when the control system is completely intercepted and you just need to make new viruses by the cell's forces. The so-called non-coding regions are responsible for this entire regulation.
– And there is nothing strange in these areas?
– Yes, it is not visible, now more than three thousand variants of SARS-CoV-2 are already known, we can compare their genomes. And we see that there is no special superconservativity, nothing unique in non-coding areas compared to coding ones. There are point replacements in the same way, and this idea that the non-coding areas of this virus are special because they were taken out somewhere, or that they are special because they change less, does not work, we do not see this on real data. Where Pekova got this idea from, I do not know.
Let me also practice conspiracy theory, because if everyone can, then why can't I? Look: there is a small laboratory, two people work in it, husband and wife, do all sorts of veterinary tests, sometimes publish articles and participate in some more global projects – apparently in some technical role, because in some articles they are “average” authors, that is, not the first and not the last on the list. In biology, this traditionally means that this person is not the main one in the work, but simply helped. So it is accepted: the first author is the one who did everything, the last author is the one who came up with everything, and in the middle are the people who helped. An epidemic is beginning, and in the Czech Republic, unlike in Russia, all groups, all small laboratories were allowed to test for COVID-19. In Russia, we ruined two months because we had a monopoly of one particular group – the Novosibirsk Vector, and in other countries it is not so, in other countries they said: anyone who can participate in testing, please participate; we will check that you do not draw the results of these tests on your knee, but after that, please help us. The test is a commercial event. Private labs don't do these tests out of pure altruism. And now a small laboratory has a chance, it can declare itself with some loud statements. Like Gogol – that in the city of N there lives such a person as Pyotr Ivanovich Bobchinsky. That's cool! People will go to them, their turnover will increase, they will be quoted, everyone will know about them. This is one conspiracy theory. I can think of another one. Scientists, even good ones, sometimes say strange things when they don't really talk about their field. This may be a sincere misconception, there are plenty of such examples.
The first theory is cynical, the second is tragic in a sense, and there is a whole range of intermediate options between them.
– And yet, assumptions about the artificial origin of the new coronavirus continue to sound, including from people who at least have scientific publications. Do you think there should not be a public discussion here for the sake of establishing the truth?
– In this regard, the famous linguist, academician Andrei Zaliznyak, had a whole lecture about how in the era of the Internet the opinion of a professor becomes equivalent to the opinion of an arbitrary person. On the one hand, censorship is disgusting. On the other hand, the idea that "different opinions should sound" often stems from laziness and lack of professionalism, unwillingness to understand. When we invite various supporters of the flat earth theory to a TV show so that all opinions are presented, well, at least it's funny. Anti–fraudsters or homeopaths are worse, but since it circulates in the public space regardless of our will, we need to somehow discuss with them, there is nowhere to go. But when, in order for all points of view to be presented, a fake is pulled out, and a non-viable fake…
– Is it true that the virus "mutates very often," as Sonya Pekova claims?
– No, it doesn't mutate very often. Firstly, this part of the interview is written simply biological nonsense: it claims that this virus does not have a mechanism for checking reproduction errors. This is not true, coronaviruses have a mechanism for checking reproduction errors. It mutates with an average frequency, approximately like its relatives.
– And if you compare it with others, with the flu virus, for example?
– The flu virus mutates faster, rhinoviruses about the same. There is a fundamental difference with the flu virus. In SARS-CoV-2, the genome is one molecule, solid. And in the influenza virus, the genome is several molecules. Therefore, the process of this mixing is significantly facilitated there. Our viruses, in order to create a chimera, need to be cut and glued together, and this is a rare situation. Flu viruses, in order to create a chimera, need to get into one cell, and there these segments are randomly mixed up. Just like humans – humans have many chromosomes, and mom's and dad's chromosomes are mixed randomly. The influenza virus has a somewhat similar process, it is called "reassortment", and the main reason for the variability of influenza viruses and the fact that a new strain comes every year is not that they change point-by-point, but that a new set of segments is obtained. The coronavirus has point changes during mutation, which I follow literally every day. He will probably have about 25 substitutions per genome per year, that is, apart from non-viable variants, we observe about one replacement per two weeks in the genome. But since there are many genomes, we see many different changes.
– Is it clear which way these mutations are going?
– There are two observations. The first is that we don't see sections, at least obvious sections, where there are no substitutions at all. Such conservative islands, so that there would never be any replacements, do not seem to be visible – this is returning to the question of coding and non-coding areas. There is another thing, more interesting: it seems that there are places where substitutions occur much more often than we would expect if it were by chance. There are places in the genome where substitutions occur independently in different variants of the virus. The virus has a kind of family tree, each mutation generates a new branch, and new substitutions occur independently in the same places on different branches. This means that they are not accidental, because these replacements are found in different laboratories in different parts of the world, that is, it is not a laboratory artifact. They indicate exactly how the virus wants to change. Rather, the virus does not want anything, it is just a molecule, but from the point of view of evolution, repeated independent substitutions in the same places are a sign that these substitutions are good for the virus. This is the basic postulate of molecular evolution, the theory of evolutionary biology: if the same event occurs several times independently, this event is good for the carrier. And this is terribly interesting to deal with.
– What are these places, what do these mutations mean for the virus?
– No one knows! It's a science that happens in real time. There was one such position, now I see a second such position nearby, which means that they are connected, it is the same protein. We do not know any functional consequences of this. We just see that some part of the virus evolves not by chance.
In general, there is an interesting phenomenon here. A planetary tragedy is taking place, but paradoxically it provides a completely unique material for fundamental science. We are observing the evolution of the virus not on the scale of months and years, like the flu, but on the scale of days. In fact, it's absolutely fantastic.
– Is it true that SARS-CoV-2 has different strains, more aggressive, which was in China and from there got to Italy and other southern European countries, and less aggressive, which circulates, for example, in Germany?
– Let's first discuss what a strain is. In classical epidemiology, virology, and microbiology, a strain was something that differs in manifestations from other strains. There are strains of E. coli that are generally safe; there are strains of E. coli that cause diarrhea; there are strains of E. coli that cause acute dysentery. In classical microbiology and virology, strains were distinguished by phenotypic manifestations, and not by genetic features. This definition is a thing of the past, because now we just know specific genetic sequences. We do not need to say that this E. coli causes diarrhea, and this E. coli does not cause diarrhea, because each E. coli has a passport with a very long number, and this long number of its passport is its genome, we know it. Now we can track even point mutations, but their result no longer makes sense to call a strain.
– But in the case of influenza, we are talking about strains.
– Yes, precisely because of his multicomponent genome, which I was talking about. Because of this, the influenza virus has a discrete set of major changes when a specific variant of one segment and a specific variant of another segment are taken. Such combinations are called strains, it makes sense there, because there is this discreteness. And if we look at the coronavirus tree that is currently tormenting us, then it is very thick, there the strains differ from each other by one replacement. Most variants differ from their closest relative by one letter, while we do not yet know any differences in phenotypic manifestations. Then, of course, there will be a lot of science to look at what influenced what, but now we just don't have enough data for this. For example, I am sure that the substitutions I mentioned, which happen more often than we expect, almost certainly have some kind of functional meaning, have to do with the "behavior" of the virus, otherwise why would they occur so often? When these replacements accumulate and somehow manifest themselves functionally, then it will make sense to talk about the strain. The story that there is some more evil strain in Italy, brought directly from China, is a legend, simply because we see that in Italy there are many variants of the virus from different branches of its ancestral tree.
There is an initial virus that got to us, judging by the time projections, somewhere in the middle of November, it began to multiply and change at the same time. We see a thick, thick tree of its descendants, we can reconstruct this tree, we can trace which variant came from which, in which place the replacement took place. It turns out that the specific options that are highlighted in Italy are hanging on completely different branches of this tree. That is, there is no one strain that would be in Italy and torment the unfortunate Italians there, because Italians are tormented by many variants at once, independently imported there.
– That is, there is no branch of this ancestral tree whose representatives are more aggressive than variants of the virus from other branches?
– We don't know anything about it yet. We have all the genetic sequences, but we have no data on aggressiveness.
– But you can compare the mortality rate depending on which branch the virus was infected with.
– There are a lot of things that can be done, but now everyone is mostly busy making sure that fewer people die. Surely someone is also doing this, because it is impossible to imagine that such a data source would not be used.
As I said, there are already three thousand options, and, by the way, one of them is Russian. About 10 days ago – it was presented as a great achievement – the sequence of the Russian virus was determined, its closest ancestors were Europeans, that is, it was a European import. What's interesting about him is this: if you look at the closest relatives of the Russian virus, that is, those who have a common ancestor with him, it turns out that they are geographically very scattered. The closest ones are in Europe, but there is also Saudi Arabia, and something else. Theoretically, this is very similar to the case at the airport: imagine that a person walks around the airport who coughs at everyone, or just someone asymptomatic walks around who talks to everyone. And then those infected fly all over the world, including to Russia.
– Now Russia has its own branch, from which new mutation processes will go?
– Yes, of course. For example, there is a wonderful American branch in America, the vast majority of viruses that belong to this branch are isolated, that is, found in patients, it is in America. But representatives of this branch have also been found in Europe. And sometimes vice versa. The virus travels back and forth, mutates, and all this can be observed in real time.
– All this diversity will not prevent the creation of a vaccine?
– That's a good question. Apparently, it shouldn't, at least for short periods. And then as luck would have it. Speaking from a flashlight, the speed of replacements is still not such that the vaccine can be made meaningless very quickly.
– Within what limits? Should a good vaccine last for a year before the virus changes much?
– I do not know, I am not an immunologist, but an immunologist, in fact, will not tell you anything for sure right now, we just don't know. One can imagine a situation that there will be no protection for ten years, but there will be protection for short periods of time. People have already started making a coronavirus vaccine. There was an epidemic of SARS in 2003, they started making a vaccine, the epidemic passed, the vaccine was abandoned – why do we need to make a vaccine against a disease that no one is sick of? Then there was the Middle Eastern MERS, very evil, but, fortunately, poorly transmitted from person to person. They also started making a vaccine from him. There are some veterinary vaccines against coronaviruses. That is, in principle, the coronavirus vaccine is not prohibited by the laws of nature. The question is whether it will be possible to do it and how effective it will be. But with the resources that are being invested in it now…
– If you were betting on when an effective vaccine would appear, what time would you call it?
– From a year to two.
– So not soon?
– They definitely won't do it soon. You can't make a vaccine against a new pathogen in two months – that's the law of nature. And there seems to be no law of nature that, in principle, it is impossible to make a vaccine against coronavirus. Then there is a simple thing: if there are no fundamental problems that are not visible, then the typical deadlines for creating vaccines in an acute situation, when all resources are thrown at it, are about the same as I said. But, once again, this is just a guess.
– Even waiting for a vaccine for a year will not be very easy.
– In fact, there are two aspects with this epidemic, in one we were lucky, in the other we were unlucky. We are lucky that it is still a relatively mild virus. If it was such an evil virus as SARS-CoV-1, it would be scary, it has a catastrophic lethality, about 10 percent, MERS generally has 30. What is happening now is a fire alarm, it is not the fire itself. We were given to train humanity's readiness for a pandemic, but at the same time it is not such a pandemic that it mows down every tenth. This is an element of luck.
– Would a virus that mows down every tenth person be viable from the point of view of evolution?
– This is the second part – where we were unlucky. What is the essential difference between this virus and the others? This is two weeks of asymptomatic carrier. From an evolutionary point of view, if the virus spreads through the host for two weeks without any symptoms, then the host will die in three weeks or not, it doesn't matter. The possibilities for distribution have already been used to the fullest.
– Does this mean that mutations that are already accumulating in some places may not go in a good direction, only we don't know about it yet?
–That's right. Maybe in a good one, maybe not, here I don't want to invent. From an evolutionary point of view, in a virus with a very long incubation period, lethality is not a critical factor for natural selection. A virus that manifests immediately will inevitably evolve towards milder symptoms, otherwise it will not be able to be transmitted from one host to another. If a person gets infected and immediately dies, the virus is bad, this is an evolutionary dead end. And if a person somehow walks, sneezes sluggishly, then the virus is good, it spreads. Examples are very different. The smallpox, which humanity defeated by vaccination, lived with a person for a long time and was equally evil all the time. If I were writing another James Bond series, I would just come up with an evil scientist who combined the properties of the current coronavirus SARS-CoV-2 and the properties of SARS-CoV-1. I would make this virus an incubation period – like the current one, and lethality – like the 2003 virus. And then humanity would have sailed in full. Andamans who live on the Andaman Islands and don't let anyone in, so they would have survived. And who else... I don't even know. In this sense, we are really terribly lucky that we are only having a fire alarm rehearsal. And if we, humanity, do not get smarter from this, maybe we are on our way there.
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