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Off the mark: why you should not trust theories about a man-made origin of Covid-19

The theory that the coronavirus did not get to humans in the usual way (that is, from some kind of animal), but was created in a laboratory, appeared nearly simultaneously with the initial news of an increase in the number of new cases, first in China, and then in other countries. In recent weeks, supporters of the man-made origin of SARS-CoV-2 have become active again, and the theory is being discussed not only by politicians and conspiracy theorists in foil hats, but also by some scientists. Molecular biologist and science journalist Irina Yakutenko explains why there is still no serious reason to believe that the SARS-CoV-2 virus was created artificially

The illusion of an argument

Contrary to the popular joke that the truth is born in disputes and dies in them, discussions often turn out to be useful. For example, in the scientific community, it is discussions (oftentimes conducted via scientific papers rather than face to face) that lead to the finalization, correction or rejection of a new concept. The debate about the origin of the coronavirus is deceptively similar to such a constructive exchange of evidence: both sides use many complex terms and provide mutation frequency tables and genome structure diagrams. The only problem is that this time billions of people who lack proper education and are unable to realistically evaluate the arguments of the parties, are watching.

To conduct a meaningful discussion about the possibility of a virus being created in a laboratory and the criteria that a certain virus must meet to be suspected of being man-made, the participants should at least be well versed in theory, that is, have a degree in biology. It is even better if the disputants have directly worked with the virus or any similar viruses and know which of the options available according to the theory can be practically implemented. Very often the gap between what is potentially possible and what can be realized in practice at the current stage of scientific development obviously renders many of the options untenable.

Most of those discussing the origin of SARS-CoV-2 do not possess such qualifications. In most cases, neither of the disputants has a general picture of how the processes they write about work - just like two people who last saw equations in a school textbook would discuss the workings of a supercomputer. But contrary to sophisticated technology, where most people realize their level of competence is insufficient, biology does not seem to be a tricky subject, and a huge number of people believe they can confidently judge it without having a proper education. That is why biologists are annoyed by their disputes. They know that the absolute majority of the arguments the opposite sides are fighting over have nothing to do with the crux of the matter and do not in any way prove the superiority of one version over the other - regardless of whether the disputants accept an argument as worthwhile or not. They are even more upset by the fact that in order to explain why a particular argument, in principle, does nothing to bring us closer to answering the question of how SARS-CoV-2 originated, one needs to spend a lot of time laying out the matter from the very basics to the intricacies of practical lab work. Few people are ready to spend hours doing this, skimping on their immediate responsibilities.

Are there really inconsistencies?

I will try, using a couple of popular arguments supplied by supporters of the theory of the artificial origin of the virus, to show how much effort is needed to demonstrate their inconsistency and unsuitability for a constructive discussion of the SARS-CoV-2 origins. The basic idea of ​​those who insist on its artificiality is this: some scientists, probably Chinese, created the current coronavirus in a laboratory. There are several possibilities regarding how, exactly: either through a cross-species recombination between bat and pangolin coronaviruses, or through the introduction of numerous mutations into the bat coronavirus genome, or through forcing it to mutate on its own by cultivating it on cell cultures for a long, long time (by passaging), or through all the above. Adherents of the man-made SARS-CoV-2 attempt to prove their case by pointing to some irregularities in its genome.

Similar protein regions

One of the main claims concerns the structure of the genome’s most important part, which encodes the so-called RBM region of the spike protein. The amino acids recorded in this fragment directly interact with cellular ACE2 receptors: by attaching to them, the virus penetrates under the cell membrane, infecting it. The fragment is said to be incredibly similar to the RBM region of another virus, namely the Malay pangolin coronavirus MP789. Based on that, it is concluded that SARS-CoV-2 is an artificially created hybrid between one of the bat coronaviruses (most often called the RaTG13 virus, which is the closest to the SARS-CoV-2 coronavirus known to scientists) and MP789.

Those using this argument obviously do not understand the difference between nucleotides (the basic units of DNA or RNA) and amino acids (the basic units of protein). The amino acid sequences - from which proteins are built - are encoded by the nucleotide sequences recorded in the genome. Three nucleotides correspond to one amino acid, and there can be several such triplets specifying a particular amino acid. For example, the simplest amino acid glycine can be encoded by any of the four combinations of nucleotides: CCA, CCG, CCT, or CCC. In other words, although a certain protein X, which is present in two different organisms, may have glycine in the same place, their genomes may contain different sequences. This is exactly what happens in the RBM region of the pangolin coronavirus and SARS-CoV-2: although the region is the same at the protein level, the similarity is only 86.6% at the nucleotide level - same as, for example, between RaTG13 and SARS-CoV-2. In other words, the RBM region in the SARS-CoV-2 genome and the RBM region in the MP789 genome, which was supposedly inserted into SARS-CoV-2, are two different sequences.

Cell scissors

Another common argument is the presence of so-called restriction sites near the «suspicious» genomic fragments of SARS-CoV-2 (i.e., fragments allegedly inserted by scientists), that is, sequences that are recognized by special molecular scissors, restriction enzymes. Scientists use these enzymes to cut nucleic acid sequences in different places - for example, in order to then connect them with other sequences, just as children cut and splice colored paper in different ways.

But if we analyze the genome of a living organism, we will find, depending on the size of the genome, tens, hundreds and thousands of such sites! Does this mean we were all artificially created in a giant alien laboratory? Of course not, just because there are a lot of letters in genomes, some of them may randomly form sites suitable for a particular restriction enzyme. But the genomes of humans or pangolins do not run the risk of being shredded due to the fact they have restriction sites. Restriction enzymes are bacterial enzymes microbes use to kill each other, so that the abundance of restriction sites in other creatures does not harm those creatures in any way. Moreover, since there is a huge number of bacterial restriction enzymes and restriction sites (catalogs of the most popular restriction enzymes for laboratory use include hundreds of names), one can find a sequence recognized by one or another restriction enzyme in almost any genome fragment, even a relatively short one, say, like that of a bat or a coronavirus.

Rare nucleotide combinations

A new argument the adherents of the SARS-CoV-2 artificiality theory are wont to make is the presence in the SARS-CoV-2 genome of rare codons (nucleotide triplets), atypical for that type of virus. As we have discussed, the same amino acid can be encoded by different codons, and each organism has a favorite triplet. And the furin cleavage site of the coronavirus, the favorite place of the coronavirus genome, the emergence of which is associated with the artificiality of SARS-CoV-2, two consecutive codons of the amino acid arginine, CGG, were found at once, which are usually used by mammals, not by viruses. Apparently the entire furin cleavage site was added by scientists! They turned out to be smart enough to create a new super-successful virus, but at the same time were so unskillful that they borrowed the sequence of the furin cleavage site from the genetic base of mammals, forgetting to replace the codons.

In reality, there is nothing surprising in the “wrong” codons or in the emergence of the furin cleavage site. Due to certain peculiarities of how their own genome are read, coronaviruses are prone to recombination, i.e. exchanging genome fragments with congeners. Sometimes they can capture a piece of hereditary material not from another virus, but from the host (of course, not from the genome, which is recorded on the DNA molecule in mammals, but from various RNA molecules, which are abundant in the cell) along with all its «atypical» codons. We know for certain that other RNA viruses are capable of this, such as the influenza virus and a few less well-known ones. For coronaviruses, such a recombination has not yet been shown, but there are no fundamental mechanisms that would prohibit it. The likelihood of such events is small but given that the infected cell is literally stuffed with viral RNAs, they occur on a regular basis - especially if the furin cleavage site gives the coronavirus a noticeable advantage during infection, and its carriers are fixed in the population. Finally, «non-viral» codons might have formed by chance - we see such rare triplets in many other viruses, for example, in the rabbit coronavirus HKU14, where two such codons of arginine CGG are also sequenced in a row.

Theory vs practice

In principle, we could ignore the speculation about nucleotide intricacies, because there is another reason that makes the creation of an artificial virus unlikely. It is time considerations. A layman can discuss substitutions and rare codons all he wants, but that is because he is a layman - he has never dealt with the techniques that are necessary to introduce such mutations in practice. In reality, mutations in RNA viruses can be introduced by reverse genetics, and this process often takes years, especially when we deal with large genomes, as in the case of the coronavirus. It's a very time-consuming exercise, and methods to make it less complicated and time-consuming have emerged only quite recently (just a few months ago).

Moreover, such a system must be created anew for each virus. In an interview with The Bild, Christian Drosten, head of the Berlin Institute of Virology at the Charite Clinic and one of the world's leading coronavirus specialists, compared experiments which involved targeting a real virus with new mutations to test how they affect its properties with testing a new car radio. If motorists did this using reverse genetics, then instead of buying a radio, installing it and checking the sound, they would first have to build a new car around that radio.

Another argument stemming from «realities of practical work» is that there is a limited number of cell lines that allow a virus to be passaged in cell culture for a long time, which means infecting cells, achieving the synthesis of new viral particles, and transplanting them onto new cells. They often have defects in cellular defenses - in fact, that's why viruses infect them so well. But it means that the virus does not need to acquire or save those changes that are necessary for better penetration into the cell - why carry an extra load if there are no problems with the entrance?

The most important change is the furin cleavage site: when passaged in the most frequently used Vero cells, the coronavirus loses it very quickly. Shi Zhengli's infamous laboratory at the Wuhan Institute of Virology, which is often accused of creating SARS-CoV-2, used Vero cells in its coronavirus experiments, so it would hardly have been able to preserve the furin cleavage site over years of passages. Overall, the choice of cells is critical for virological experiments: for example, there are suspicions that due to incorrectly selected cell cultures in early 2020, scientists saw encouraging results in experiments with hydroxychloroquine: in reality, when people are infected the virus enters completely different cells and uses a different entrance mechanism against which the drug is ineffective.

If we assume that Shi and her co-workers deliberately “bombarded” the virus with antibodies in cell cultures to achieve targeted selection, we would see an increased mutation rate in the spike protein (all effective antibodies target it) compared to the rest of the genome, but no such thing has been observed. The idea that instead of using specific antibodies the scientists forced the virus to change at a faster pace by using mutagenic substances boils down to cell lines again: without the need to use the furin cleavage site to enter the cell, the necessary changes in the genome would not stick, even if it took less time to acquire them. In addition, the use of such substances often leads to a certain «imbalance» in the choice of nucleotides, which is not visible in the SARS-CoV-2 genome.

It can take a long time to describe the delusions, outright nonsense and misunderstanding of the realities of scientific practice in the arguments of SARS-CoV-2 artificiality advocates, but this is exactly what I would like to avoid. It takes a lot of effort to explain, even in general terms, to a person, who is not a trained biologist, why this or that argument of the supporters of artificial origin is irrelevant. Since few of those who really understand the issue are ready to clear out all the heaps of absurdities, the same arguments keep reappearing again and again in the fierce battles waged by non-specialists. In fact, the people who have had the maximum influence on the promotion of the artificiality hypothesis are mostly layman influencers: politicians, including the US President Donald Trump, or long-time conspiracy theorists, who have nothing to do with biology. The celebrity effect works in all areas, no matter how complex the expertise needs to be - people tend to trust the judgments of celebrities in all matters, including matters lying completely outside the celebrities’ own fields of expertise.

If we briefly summarize the results of real scientific discussions about the «weirdness» of the coronavirus genome, the conclusion will be this: there are no more of them than in other viruses. SARS-CoV-2 looks quite common when compared with other coronaviruses. The pandemic it caused seems strange only because it is the first in the memory of the present generation. In 1918, people in the United States also argued that the Spanish flu was being sprayed by German submarines, although in those days artificial creation of a virus was impossible even in the minds of the most die-hard conspiracy theorists.

A crazy scenario

But suppose the theory of deliberate creation of the virus is correct. What should events look like in this case? The only scenario that consistently fits into the hypothesis is as follows: long ago some insidious (Chinese?) scientists began to breed coronaviruses of bats and/or pangolins with an incomprehensible purpose: none of the papers claimed that the viruses had been isolated (which, by the way, is extremely difficult to achieve, and Shi Zhengli's Wuhan laboratory, which succeeded in doing so, immediately published the results in Nature, one of the world's most prestigious scientific journals) or that their sequence had been determined. And this is in a highly competitive scientific environment, where every effort is made to obtain results suitable for publication. Then the scientists did something to cause the appearance of a furin cleavage site in the ancestor of SARS-CoV-2 - and again did not publish the result, although, generally speaking, it would have been a breakthrough. Instead, they apparently dumped the virus down the drain; or the modified virus escaped exactly at the time they were about to submit the paper to the journal.

Another option: scientists found and adapted for laboratory needs a new line of cells similar to the cells of our respiratory tract, in which the virus, with prolonged passage, did not lose features that allowed it to adapt to those cells, but again they kept silent about it, although such work may well have been published in the most prestigious journal (not to mention the patent money). Or scientists were creating a system of reverse genetics for the construction of coronaviruses for years, again in complete secrecy and without publishing the results, only to subsequently release the virus they spent so much effort to obtain into the wild - and not on enemy territory, but right next to their own institute. Such a development of events - many years of concealment of breakthrough efforts, and then a tragic oversight or even deliberate sabotage - resembles the script of a bad film, when the writers pile up a lot of unlikely events, and then, to explain why the hero did all those things, they declare in the finale: he was just crazy! Disappointingly uninteresting, but there is no other way to get out of such a tangle without resorting to mysticism.

A leak from the lab?

Yes, there is still a possibility of a natural virus leaking - such cases have repeatedly happened in the most secure laboratories around the world. But such a scenario can only be proved by a police investigation which apparently is not going to happen. The fact that a state can - for any reason - unilaterally deny the international community the opportunity to investigate a socially significant incident is really a serious problem. However, its discussion, of course, is not so interesting: it is clear even to people distant from politics that debates in social media and even UN declarations will not be enough to influence China. One can build the reputation of an incredibly intelligent and perspicacious analyst on endless speculation about pseudo-scientific conspiracy theories.

But in the current situation, a dialogue with the Chinese authorities is the only way to find out how everything happened. The WHO Commission, which was in quarantine for two weeks working with documents at a hotel, and then examined something in laboratories for another two weeks, requested and studied blood samples, and so on – is an attempt to create the impression that the global community has been actively resolving the issue (although it is much better than nothing, and such studies can also clarify a lot). Especially considering the fact that its leader, Peter Dasek, has a conflict of interests: the Eco Health Alliance, which he heads, has been funding the Institute of Virology in Wuhan for many years. The WHO is well aware they have no real leverage over the Chinese authorities, and Western politicians avoid asking the PRC direct questions or, even more so, demanding something, not least because they guess what the answer will be. What leader wants to present himself as a loser whose demands are defiantly ignored?

Summing up, we can state the following. The SARS-CoV-2 genome looks like a normal viral genome, and the deliberate artificial creation of a virus is so unlikely that it is hardly worth taking this hypothesis seriously in the absence of real evidence - eyewitness testimony, entries in laboratory journals, the actual samples of the virus. The version of an accidental leak of novel strains is closer to reality, but it can only be proven with the help of the police. Because the virus may as well have jumped onto a person from some kind of animal, as has happened more than once with coronaviruses: for example, the predecessor of the current SARS virus jumped onto humans at least twice, and MERS does it all the time, judging by the antibodies in camel drivers. The animal might not necessarily be a bat, SARS-CoV-2, for example, breeds well in ferrets or minks, and China is full of fur farms. The animal itself would be an ideal proof of the natural origin of the virus - and of course, scientists should take blood samples from as many animals living in China as possible. However, there is no certainty the animal will be found - nature does not always leave traces of its activities for humans, and time is working against scientists: the ancestral strain may change or disappear altogether, for example, if it had first emerged on a fur farm, where all the animals were killed after the outbreak of the epidemic.

So far, none of the arguments offered by the supporters of the artificiality of the virus have stood up to criticism: in no way do they cancel or reduce the likelihood of the null hypothesis - that the virus arose naturally, just like any other human virus. Extraordinary claims require extraordinary evidence, but there is none.

This text is also available in Russian

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