3/15/2020
There has been much controversy regarding the origin of the Wuhan coronavirus. It appears that both possibilities, naturally occurring or man-made, are legitimate enough to be debated fully. However, although voices on social media are equally strong from both sides, when it comes to written pieces, there is a predominance of scientific literature and other forms of writing that were produced to disapprove the “conspiracy theory”. In contrast, not nearly as much literature or other forms of substantial writing have been put out to describe or argue for the other possibility – this virus is man-made. My goal here is to use scientific evidence and logical thinking to evaluate, and legitimate, the possibility that the Wuhan coronavirus (2019-nCoV, SARS2-CoV, etc.) is of non-natural origin.
Importantly, I will base my reasoning on solid, credible evidence; I will exclude any unqualified evidence that may have been thrown in by the Chinese Communist Party (CCP) with an intention to disturb the “investigation” and thereby cover up the truth. My role or perspective here can be considered as a combination of a scientific reviewer, a detective, and a judge on a criminal trial.
Why are people suspicious of the origin of the Wuhan coronavirus
This has a lot to do with how the sequence of this virus (in other words, its genome) compares with those of related coronaviruses.
When comparing sequences, one can compare either gene sequences or protein sequences. For viruses, however, this makes almost no difference as the whole genome of a virus is practically translated into proteins (in fact, a virus typically produces a single polyprotein by translating its entire genome and then cuts this long polyprotein at specific places to produce a set of particular proteins for specific use). Here, we will compare different viruses only on their protein sequences.
By doing such a comparison, one can see that the Wuhan coronavirus is about 86% identical to the SARS coronavirus, which caused a pandemic back in 2003. This level of sequence identity basically says that the Wuhan coronavirus could not have come from SARS, something the field agrees unanimously.
At the same time, the Wuhan coronavirus is STRANGELY similar to two bat coronaviruses, ZC45 and ZXC21. Overall, the sequence of either of the two bat coronaviruses is 95% identical to the Wuhan coronavirus. In fact, for most part of the genome, such level of identity is maintained or even surpassed. The E protein, in particular, is 100% identical. The nucleocapsid is 94% identical. The membrane protein is 98.6% identical. The S2 portion (2nd half) of the spike protein is 95% identical. However, when it comes to the S1 portion (1st half) of the spike protein, the sequence identity suddenly drops to 69%. This pattern of sequence conservation, between either of the closely related bat coronaviruses and the Wuhan coronavirus, is extremely rare and strange!
This is extremely rare because natural evolution typically takes place when changes (mutations) occur randomly across the whole genome. You would then expect the rate of mutation being more or less the same for all parts of the genome.
Could other forms of evolution lead to such a strange pattern of sequence identity? Yes, there is one evolutionary event that could lead to drastic changes in only one part of the genome. It is what is called “recombination”. We would defer to the next section to explain why recombination is also practically impossible in this case.
For now, let’s fix our eyes on the part that is seeing this sudden drop of sequence identity, the S1 portion of the spike protein.
Figure 1. Coronavirus particle with spike proteins (red) decorating its surface. Image from the CDC website (not a photo of a real virus, but a model generated based on scientific knowledge).
Spike proteins are the protrusions that you see on the outside of the virus particle (Figure 1). They are literally responsible for the name “corona” as they make the virus look like a “crown”. However, spike proteins are located here for reasons beyond decoration. They are actually the “key” that coronaviruses use to open the “lock” so that viruses can enter our (host) cells.
Figure 2 shows the structure of the spike protein of the SARS virus (such structure images are as real as photos of actual people). Given the sequence similarity/conservation here, the spike protein of the Wuhan coronavirus would look pretty much the same, which is indeed confirmed by a recent publication (1).
Figure 2. Structure of the SARS spike protein and how it binds to human ACE2 receptor. Pictures generated using the published structure (PDB ID: 6acj) (2). A) Three spike proteins, each consisting of a S1 half and a S2 half, form a trimer. B) The S2 halves (shades of blue) are responsible for trimer formation, while the S1 portion (shades of red) is important for binding human receptor ACE2 (dark gray). C) Details of the binding between S1 and human ACE2. The part of S1 that is important and sufficient for binding are colored in orange, with most crucial amino acid sidechains shown as sticks. This orange piece is presumably what’s “taken out of” SARS spike and “inserted” into a bat coronavirus spike protein, thereby creating a novel human-infecting coronavirus.
Three spike proteins have to come together to function properly as the “key”. This three-protein assembly is what they call a “trimer”. To form this trimer, you would need the blue portion of the spike protein, which is referred to as S2 of spike. This S2 part can be regarded as the part of the “key” that you hold with your fingers; it does not actually go into the lock. However, for this “key” to work, S2 has to be there and has to preserve the ability of forming trimers.
The other half of spike, the red portion or what is referred to as S1, is responsible for binding the host receptor. S1 can be considered as the portion of the “key” that literally enters the “lock”. It has to fit precisely to the delicate shape of the “lock” (host receptor) so that the “door opening” action can be accomplished. Whether or not a particular “lock” can be opened by a specific “key” is decided exclusively by this S1 part of spike. In other words, S1 of a coronavirus dictates which host(s) or cells the virus can infect.
Now you may be able to appreciate what I call extremely strange. While everything else of the Wuhan coronavirus remains almost identical to the two bat coronaviruses, the S1 portion, which dictates which host a coronavirus targets, has changed significantly from the two bat coronaviruses to the Wuhan coronavirus.
Let’s zoom in further (Figure 2C) and look at the exact part on S1 that dictates whether or not S1 binds a host receptor (in this case, the human ACE2 protein). This most critical part of S1 is a relatively small stretch of amino acids, labeled in orange in Figure 2C with important residues shown as sticks. This part includes everything needed for interacting with the human ACE2 receptor. You will see below how this segment, known to be unique to the SARS spike and sufficient for its interaction with human ACE2, is practically “copied” over by the Wuhan coronavirus.
Figure 3. Sequence alignment of the spike proteins from relevant coronaviruses, including viruses isolated from current pandemic (Wuhan-Hu-1, 2019-nCoV_USA-AZ1), closely related bat coronaviruses (Bat_CoV_ZC45, Bat_CoV_ZXC21), and SARS coronaviruses (SARS_GZ02, SARS). Region marked by orange lines is the segment important for interaction with human receptor ACE2. Crucial residues for interaction are additionally highlighted by a red stick on top. Region marked by green lines is a furin-cleavage site that exists only in the Wuhan coronaviruses but not in any other beta coronaviruses. Alignment was done using the MultAlin webserver (Multalin interface page).
Figure 3 is the sequence alignment of the spike proteins from six coronaviruses. Two are viruses isolated from current pandemic (Wuhan-Hu-1, 2019-nCoV_USA-AZ1); two are closely related bat coronaviruses (Bat_CoV_ZC45, Bat_CoV_ZXC21); two are SARS coronaviruses (SARS_GZ02, SARS). By glancing through this figure, you can easily tell that the second half of spike (690 and beyond), namely S2, look pretty much the same for all six viruses. The difference is in the front half (1-~690), or the S1 portion. Now if you look at the top four sequences — the two Wuhan coronaviruses and two bat coronaviruses, you can see that they are largely the same across the S1 half of spike. Only a couple of places are different. However, the details of these differences and the way the human and the bat viruses differ from each other here in S1, in my and many other people’s eyes, practically spell out the origin of the Wuhan coronavirus – it is created by people, not by nature.[To be continued in the next post]
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