Scientific evidence and logic behind the claim that the Wuhan coronavirus is man-made
3/15/2020
[Continues]
First important difference is what is highlighted in between two orange lines in Figure 3. Clearly, this part of the Wuhan coronavirus spike differs significantly from those of the bat virus spikes, despite the overall high identity between them. Intriguingly, this same segment of the Wuhan coronavirus resembles, on a great deal, the corresponding piece on the SARS spike protein. Indeed, this is precisely the region highlighted in Figure 2C in orange. As we have pointed out earlier, this segment contains everything needed for human ACE2 interaction. Here, it seems that this critical piece was “copied” from the SARS spike protein and then “pasted” into a bat coronavirus.
There are of course differences between these two, which may make it seem unlikely a direct “copy and paste”. However, careful examination shows that all residues essential for binding (orange sticks in Figure 2C and residues highlighted by red short lines in figure 3) are either precisely preserved or substituted with residues of similar properties. At the same time, differences lie mostly at residues non-essential for binding ACE2. Judging from this observation, one can safely envision that not only Wuhan coronavirus spike will bind ACE2 but also it will bind ACE2 exactly the same way that SARS spike does (Figure 2BC).
For the two bat coronaviruses here, given how they lack many of the key residues (what is marked by red sticks in Figure 3) for binding human ACE2, it is easy to predict that these two bat viruses would not be able to infect human.
The Wuhan coronavirus, while being almost identical to their bat relatives (ZC45 and ZXC21) everywhere else, has somehow “inherited” the critical, short piece from SARS spike to replace the incompetent piece in the bat coronavirus spike. As a result of this miraculous “replacement” in S1 — all key residues preserved and many non-essential residues changed, the Wuhan coronavirus has practically “acquired” the ability to infect humans, something its closest bat relatives do not have.
Could natural evolution achieve something this precise and, at the same time, this deceptive???
If you have not been “awed” enough, let’s move on to appreciate magic trick #2. Please look at the region marked by two green lines in Figure 3. Here only the Wuhan coronaviruses contain an additional piece, SPRRA. Importantly, this added piece allows the spike protein to be readily cleaved by a host protease enzyme – furin, a desirable property known to produce more infectious viruses in the case of influenza. Note that no beta coronaviruses in the same lineage (lineage B), except this new Wuhan coronavirus, contain such a furin-cleavage site.
Further explanation on why these changes could not have come from nature
We have briefly explained why random mutations could not result in the weird pattern of sequence identity between the Wuhan coronavirus and related bat coronaviruses, ZC45 or ZXC21. Let’s dig a little deeper here. Although the spike proteins of different coronaviruses are more likely to differ, greater discrepancy in S1 may only be expected if two viruses have been long separated during evolution and have adapted, through random mutation, to their respective hosts for a long, long time. In that scenario, the overall sequence identity would be low as well. In the present case, however, the sequence identity between either of the bat coronavirus and the Wuhan coronavirus is over 95%, suggesting these two viral lineages must have diverged from each other fairly recently. Therefore, a sequence identity of 69% for the S1 portion of spike protein is simply insane. The S1 of Wuhan coronavirus could not have originated from the S1 of a bat coronavirus, a recent common ancestor that the Wuhan virus shares with ZC45 and ZXC21, through random mutations.
Now let me explain why recombination also could not be responsible for the observed pattern.
What happens in a recombination event is that one segment of a gene can be “replaced” by a similar segment from another gene. In evolution, recombination events happen much less frequently than random mutations. When recombination happens, however, it often brings abrupt changes to certain areas of the genome.
If naturally-occurring recombination event(s) lead to the creation of the Wuhan coronavirus, how would it transpire? First, it would have to take place when an ancestor bat coronavirus, something very similar to ZC45 or ZXC21, co-existed with another coronavirus in the same cell of the same animal. Under extremely rare circumstances, recombination may occur, where a random piece in the ancestor’s genome is replaced by a similar but different piece from the other coronavirus. Importantly, to go from such ancestor to the Wuhan coronavirus, one combination event is not enough. What has to happen is that recombination has to take place twice during the evolution of the Wuhan coronavirus. In one occasion, the ancestor bat coronavirus would have to acquire, through recombination with a SARS-like coronavirus, the precise short segment of S1 that is responsible for human ACE2 interaction (region highlighted in orange in both Figure 2 and Figure 3). In another occasion, the “improved” bat coronavirus would further swap in a furin-cleavage site through recombination with yet another coronavirus that carries a furin-cleavage site between its S1 and S2 of spike.
Also, again, given the overall high sequence identity (95%) between the bat coronaviruses and the Wuhan coronavirus, it is reasonable to believe that these two diverged from each other fairly recently. Therefore, both recombination events must have taken place fairly recently as well.
Now, we know that SARS crossing over to infect human is a very rare event. To have another SARS-like sequence exist in nature so that the ancestor bat coronavirus can do recombination with is a very unlike event. Not to mention that this SARS-like virus must have a spike that binds ACE2 the same way as SARS and yet the piece of S1 that is most critical for binding ACE2 would differ with that of SARS spike only at non-essential sites. On top of that, furin-cleavge site has not been observed in any beta coronaviruses in the same lineage so far. Although similar furin-cleavage sites have been observed in other coronaviruses, none of them contains the same exact sequence. Therefore, the chance that the furin-cleavage site in the Wuhan coronavirus was obtained through recombination with another furin-cleavage-site-containing coronavirus is very low.
Now, what are chances for both of these next-to-impossible recombination events to take place? My answer is NO CHANCE. This Wuhan coronavirus cannot be coming from nature.
Why some literature has to be excluded in the analysis
Someone who has been following the recent literature on this topic would point out that the above analysis failed to take into account some crucial evidence. Such evidence, coincidentally, supports a natural origin of the Wuhan coronavirus. Then how dare I leave it out in my analysis?
The short answer: that “evidence” was very likely fabricated.
Please allow me to switch my mode now, from a scientist to a detective or a judge. If we consider this matter as a crime under investigation, then we have so far one big suspect, Dr. Zhengli Shi from the Wuhan Institute of Virology and the biosafety level 4 (P4) lab for virology research. As the top coronavirus expert in China, since the beginning of the outbreak, Zhengli Shi has been singled out as THE suspect who may have created this virus, which somehow leaked out of the P4 lab. Intriguingly, Shi published an interesting paper in Nature a couple of weeks ago (3). There she compared the freshly obtained sequence of the Wuhan coronavirus with those of other beta coronaviruses, which allowed her to delineate an evolutionary path of this new virus. All of a sudden, out of nowhere, she reported a bat coronavirus, RaTG13, which shares high sequence identity with the Wuhan coronavirus. Strikingly, between RaTG13 and the Wuhan virus, the mutational rate is low (or sequence identity is high, 98.5%) for all parts of the genome, including the spike protein. If we have questioned the origin of the Wuhan coronavirus because of the weird pattern of sequence conservation between the Wuhan coronavirus and the two bat coronaviruses, ZC45 and ZXC21, then RaTG13 does not show any concern in that regard. Here, the spike protein is just as conserved as other proteins. From the first look, it seems that RaTG13 belongs to the same small lineage as the Wuhan coronavirus and that the two must share a very recent common ancestor. Such finding strongly suggests a natural origin of the Wuhan coronavirus. This paper reporting the RaTG13 coronavirus (3) is the evidence that I “failed” to take into account in the earlier analysis.
According to credible sources, Shi has admitted to several individuals in the field that she does not have a physical copy of this RaTG13 virus. Her lab allegedly collected some bat feces about 7 years ago and analyzed these samples for possible presence of coronaviruses based on genetic evidence. To put it into plainer words, she has no physical proof for the existence of this RaTG13 virus. She only has its sequence information, which is nothing but a string of letters alternating between A, T, G, and C.[see next post]
Blog
3/15/2020
[Continues]
First important difference is what is highlighted in between two orange lines in Figure 3. Clearly, this part of the Wuhan coronavirus spike differs significantly from those of the bat virus spikes, despite the overall high identity between them. Intriguingly, this same segment of the Wuhan coronavirus resembles, on a great deal, the corresponding piece on the SARS spike protein. Indeed, this is precisely the region highlighted in Figure 2C in orange. As we have pointed out earlier, this segment contains everything needed for human ACE2 interaction. Here, it seems that this critical piece was “copied” from the SARS spike protein and then “pasted” into a bat coronavirus.
There are of course differences between these two, which may make it seem unlikely a direct “copy and paste”. However, careful examination shows that all residues essential for binding (orange sticks in Figure 2C and residues highlighted by red short lines in figure 3) are either precisely preserved or substituted with residues of similar properties. At the same time, differences lie mostly at residues non-essential for binding ACE2. Judging from this observation, one can safely envision that not only Wuhan coronavirus spike will bind ACE2 but also it will bind ACE2 exactly the same way that SARS spike does (Figure 2BC).
For the two bat coronaviruses here, given how they lack many of the key residues (what is marked by red sticks in Figure 3) for binding human ACE2, it is easy to predict that these two bat viruses would not be able to infect human.
The Wuhan coronavirus, while being almost identical to their bat relatives (ZC45 and ZXC21) everywhere else, has somehow “inherited” the critical, short piece from SARS spike to replace the incompetent piece in the bat coronavirus spike. As a result of this miraculous “replacement” in S1 — all key residues preserved and many non-essential residues changed, the Wuhan coronavirus has practically “acquired” the ability to infect humans, something its closest bat relatives do not have.
Could natural evolution achieve something this precise and, at the same time, this deceptive???
If you have not been “awed” enough, let’s move on to appreciate magic trick #2. Please look at the region marked by two green lines in Figure 3. Here only the Wuhan coronaviruses contain an additional piece, SPRRA. Importantly, this added piece allows the spike protein to be readily cleaved by a host protease enzyme – furin, a desirable property known to produce more infectious viruses in the case of influenza. Note that no beta coronaviruses in the same lineage (lineage B), except this new Wuhan coronavirus, contain such a furin-cleavage site.
Further explanation on why these changes could not have come from nature
We have briefly explained why random mutations could not result in the weird pattern of sequence identity between the Wuhan coronavirus and related bat coronaviruses, ZC45 or ZXC21. Let’s dig a little deeper here. Although the spike proteins of different coronaviruses are more likely to differ, greater discrepancy in S1 may only be expected if two viruses have been long separated during evolution and have adapted, through random mutation, to their respective hosts for a long, long time. In that scenario, the overall sequence identity would be low as well. In the present case, however, the sequence identity between either of the bat coronavirus and the Wuhan coronavirus is over 95%, suggesting these two viral lineages must have diverged from each other fairly recently. Therefore, a sequence identity of 69% for the S1 portion of spike protein is simply insane. The S1 of Wuhan coronavirus could not have originated from the S1 of a bat coronavirus, a recent common ancestor that the Wuhan virus shares with ZC45 and ZXC21, through random mutations.
Now let me explain why recombination also could not be responsible for the observed pattern.
What happens in a recombination event is that one segment of a gene can be “replaced” by a similar segment from another gene. In evolution, recombination events happen much less frequently than random mutations. When recombination happens, however, it often brings abrupt changes to certain areas of the genome.
If naturally-occurring recombination event(s) lead to the creation of the Wuhan coronavirus, how would it transpire? First, it would have to take place when an ancestor bat coronavirus, something very similar to ZC45 or ZXC21, co-existed with another coronavirus in the same cell of the same animal. Under extremely rare circumstances, recombination may occur, where a random piece in the ancestor’s genome is replaced by a similar but different piece from the other coronavirus. Importantly, to go from such ancestor to the Wuhan coronavirus, one combination event is not enough. What has to happen is that recombination has to take place twice during the evolution of the Wuhan coronavirus. In one occasion, the ancestor bat coronavirus would have to acquire, through recombination with a SARS-like coronavirus, the precise short segment of S1 that is responsible for human ACE2 interaction (region highlighted in orange in both Figure 2 and Figure 3). In another occasion, the “improved” bat coronavirus would further swap in a furin-cleavage site through recombination with yet another coronavirus that carries a furin-cleavage site between its S1 and S2 of spike.
Also, again, given the overall high sequence identity (95%) between the bat coronaviruses and the Wuhan coronavirus, it is reasonable to believe that these two diverged from each other fairly recently. Therefore, both recombination events must have taken place fairly recently as well.
Now, we know that SARS crossing over to infect human is a very rare event. To have another SARS-like sequence exist in nature so that the ancestor bat coronavirus can do recombination with is a very unlike event. Not to mention that this SARS-like virus must have a spike that binds ACE2 the same way as SARS and yet the piece of S1 that is most critical for binding ACE2 would differ with that of SARS spike only at non-essential sites. On top of that, furin-cleavge site has not been observed in any beta coronaviruses in the same lineage so far. Although similar furin-cleavage sites have been observed in other coronaviruses, none of them contains the same exact sequence. Therefore, the chance that the furin-cleavage site in the Wuhan coronavirus was obtained through recombination with another furin-cleavage-site-containing coronavirus is very low.
Now, what are chances for both of these next-to-impossible recombination events to take place? My answer is NO CHANCE. This Wuhan coronavirus cannot be coming from nature.
Why some literature has to be excluded in the analysis
Someone who has been following the recent literature on this topic would point out that the above analysis failed to take into account some crucial evidence. Such evidence, coincidentally, supports a natural origin of the Wuhan coronavirus. Then how dare I leave it out in my analysis?
The short answer: that “evidence” was very likely fabricated.
Please allow me to switch my mode now, from a scientist to a detective or a judge. If we consider this matter as a crime under investigation, then we have so far one big suspect, Dr. Zhengli Shi from the Wuhan Institute of Virology and the biosafety level 4 (P4) lab for virology research. As the top coronavirus expert in China, since the beginning of the outbreak, Zhengli Shi has been singled out as THE suspect who may have created this virus, which somehow leaked out of the P4 lab. Intriguingly, Shi published an interesting paper in Nature a couple of weeks ago (3). There she compared the freshly obtained sequence of the Wuhan coronavirus with those of other beta coronaviruses, which allowed her to delineate an evolutionary path of this new virus. All of a sudden, out of nowhere, she reported a bat coronavirus, RaTG13, which shares high sequence identity with the Wuhan coronavirus. Strikingly, between RaTG13 and the Wuhan virus, the mutational rate is low (or sequence identity is high, 98.5%) for all parts of the genome, including the spike protein. If we have questioned the origin of the Wuhan coronavirus because of the weird pattern of sequence conservation between the Wuhan coronavirus and the two bat coronaviruses, ZC45 and ZXC21, then RaTG13 does not show any concern in that regard. Here, the spike protein is just as conserved as other proteins. From the first look, it seems that RaTG13 belongs to the same small lineage as the Wuhan coronavirus and that the two must share a very recent common ancestor. Such finding strongly suggests a natural origin of the Wuhan coronavirus. This paper reporting the RaTG13 coronavirus (3) is the evidence that I “failed” to take into account in the earlier analysis.
According to credible sources, Shi has admitted to several individuals in the field that she does not have a physical copy of this RaTG13 virus. Her lab allegedly collected some bat feces about 7 years ago and analyzed these samples for possible presence of coronaviruses based on genetic evidence. To put it into plainer words, she has no physical proof for the existence of this RaTG13 virus. She only has its sequence information, which is nothing but a string of letters alternating between A, T, G, and C.[see next post]
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