Why I Don't Believe SARS-Cov-2 Came from Nature

 The circumstantial:

• In 2015, some at the University of South Carolina corroborated with Wuhan Institute of Virology to get a wild coronavirus and make it infectious to humans (These early studies were in-vitro)
• Three pandemics in relatively rapid succession: Sars, Mers, Covid-19.
• China locked down Wuhan and did not allow intra-China travel but permitted travel to Eu and the U.S.
• China has not allowed the CDC to investigate the Wuhan Institute of Virology.
• Although Anthony Fauci said that China was being cooperative, the first CoV-2 sequences released by China were incorrect.

We've got our hands in this epidemic. Li-Meng Yan says the Chinese military released CoV-2 and there is certainly ample circumstantial evidence, it seems weird, though, that China would release it on its own people. Would they not have had the foresight to release it into one of the alleged concentration camps in China, North Korea, or elsewhere or use it to decimate unwanted groups? Coronaviruses are found in bats worldwide--they could have dropped an infected bat into one of our many caves.

Coronavirus (SARS-CoV-2, hereafter referred to as CoV-2)

"The nature of the coronavirus genome is nonsegmented, single-stranded, and positive-sense RNA. Its size ranges from 27 to 32 kb, which is significantly larger when compared with other RNA viruses. The gene encoding the large surface glycoprotein [ed., the "spike"] is up to 4.4 kb, encoding an imposing trimeric, highly glycosylated protein. This soars some 20 nm above the virion envelope" (Lai)

The spike is the virus' main tool for getting access to one of your cells. It was engineered to latch on to the Ace-2 receptor better than any other betacoronavirus. Its length may ensure better endocytosis [speculative]. Also speculative is the fact that the spikes enlarge the virus without adding appreciable mass; this means that the virus is more likely to float in air. Depending on the air's temperature and humidity, it may float above one's shoulders. In a high temperature/low density air environment, the virus will probably still float but lower to the ground. This may explain why a coronavirus was so effective in spreading to piglets with very high mortality (100%). On the other hand, the dog, with noses sniffing millimeters above the ground, would have been particularly decimated if they had had the Ace-2 receptor.***

"Compared with influenza virus HA, the six-helix bundle formed by coronavirus HR-N and HR-C is unusually long (18, 117), indicating the abundant amount of energy that can be released during the conformational transition of S2 and available for use in membrane fusion." (Li)

This represents another advantage to the S-protein's length in CoV-2--it powers the virus' membrane fusion.

"Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV [note: Cov-2 not included] were discovered in bats worldwide." (*)

The earliest coronavirus epidemic was SARS which had a greater fatality rate than the novel coronavirus but only infected about 8K. Ten years later, MERS came along with  fewer cases but with a fatality rate of about 34%. What good is a pandemic if it can easily be stopped? Eight years later, the novel coronavirus came along with lower fatality rates than the other betacoronaviruses but with far greater spread. Unfortunately, the newest virus also had considerable killing and maiming power especially in the lungs. Many other coronaviruses caused respiratory and intestinal infections in animals and humans but until SARS and MERS broke out, those were not considered highly pathogenic to humans. 

Meet the Carriers

The bat as a common carrier of coronaviruses can't be argued for three reasons, first, one out of five mammals are bats;  second, bats have few predators; and, third, they congregate and interact closely together. All the betacoronaviruses are said to originate in bats and to have made their way to the human via palm civets, camels, or pangolins. One paper did propose a pangolin -> bat -> human transmission but very few things are definitive when "contact tracing" across species. For instance SARS is said to go from bats to palm civets before going to humans but palm civets have mostly tested negative for SARS. The spread of CoV-2 to humans in China was said to be via pangolins but they weren't being sold in Wuhan at the time of the outbreak.

Everywhere you look, you find mostly far-fetched cross-species contact tracing. Except, of course, for the bat but with all those virologists testing bats for coronaviruses who knows if human to bat transmission might not be occurring instead--accidentally or otherwise. That is, if you want to prove that bats are the carriers of a particular coronavirus, all you have to do is infect one of them with the virus that you want to "prove" arose naturally. Nevertheless Dr. Li-Meng Yan points out that CoV-2 is only 96% similar to the bat coronavirus said to be the precursor and known as RaTG13** It is interesting to note that CoV-2 has even lower homology with SARS-CoV--76.47%. The implications are that identifying a direct ancestor to CoV-2 will remain elusive.

CoV-2 Evolution

There are several ways to mutate a coronavirus. I'll not attempt to prove human ingenuity vis-a-vis the genetics of the novel coronavirus because I would need to study the genetics of RNA viruses, a very arcane subject and, besides, virologists have already made the case (and the counter case) using genomic data. First, I'd like to point out a unique feature of CoV-2; namely, the genome is non-segmented. If it had been segmented, CoV-2's mutations would have had a relatively easy explanation because the big game-changer in virus genetics is the ability to mutate through recombination. The influenza genome, being segmented, readily swaps segments with its brethren (hence the H2N1, H5N3, etc. designations that pop up yearly--the H2N1 influenza virus had swapped its H segment--whatever number it was--and/or its N segment, for another virus' segment(s)). 

CoV-2 doesn't have segments but it can--seemingly haphazardly--take on genes not only from viruses that infect a host cell simultaneously but also from the host cell itself. What a sneaky way to infect. Cases have been documented wherein a virus has recombined with a host's mRNA that just happened to be in the cytoplasmic milieu. Here is probably everything we know of the mechanism: a polymerase starts to make negative copies from a positive sense RNA which had earlier been made from the virus' own negative sense RNA .

As it copies, it separates from that original strand and while still holding on to what it has already copied (the "nascent" strand), it latches onto some other +RNA and uses it to continue making the negative copy. At some point, the polymerase may end up back on the original strand where it will complete copying a genome which will be released into the environment as a mutant. Now, if I understand this process correctly, the mutant negative copy is unique--no other daughter copies are made during this cycle. This makes it hit or miss; not just in its creation but in its spread for it is only one copy and it has only one chance to infect and make progenies. To rephrase, hundreds of virions are made by a given host cell but only one is made with the right mutation. When you consider that a CoV-2 infection is dose dependent (i.e., the more virions you inhale, the better your chances of contracting the disease), you start to wonder how likely it really is that any given mutation will succeed. If, on the other hand, you've manufactured the genome in a lab, you can make billions of infectious mutant virions. Whether you can release them into a bat cave will depend on just where you made the changes--you need to ensure that you haven't changed the spike protein so that it no longer binds to any bat proteins.

The Receptor Binding Domain (RBD)

This is the area on the Spike protein that binds with the ACE-2 receptor. While the 3-D structure of the SARS-CoV and CoV-2 viruses are nearly identical there are changes in four out of five crucial amino acids on the RBD; namely 

The residues (amino acids) at positions 442, 472, 479, and 487. Why does this matter? Well, we know that recombination is the easiest way for the viruses to mutate successfully for it will have taken on RNA from another successful virus. However, no Spike protein sequence--other than that on CoV-2--is as good in binding to ACE-2. So, CoV-2, if it was naturally derived, had to replace 4 amino acids in unique and specific locations. The only mechanism that it would have for doing this is through reliance on errors made by its replicating machinery and that is too random a process to change four residues to replacements that work better at binding and which do not change the 3-D structure of the S-protein. A virology lab, to my knowledge, is not capable of engineering exacting 3-D structures but, if given a structure that already works well (SARS-CoV), it can play with protein residues and come up with SARS-CoV-2.

Am I right? I don't know, but I've never hoped so much that I would be wrong.

References

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7130985/)

  Bosch, B. J., van der Zee, R., de Haan, C. A. M., & Rottier, P. J. M. (2003). The Coronavirus Spike Protein Is a Class I Virus Fusion Protein: Structural and Functional Characterization of the Fusion Core Complex. J. Virol., 77(16), 8801–8811. doi: 10.1128/JVI.77.16.8801-8811.2003. Retrieved from https://jvi.asm.org/content/jvi/77/16/8801.full.pdf

  Lai, M. M. C., & Cavanagh, D. (1996). The Molecular Biology of Coronaviruses. Advances in Virus Research. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7130985/

  Cui, J., Li, F., & Shi, Z.-L. (2018). Origin and evolution of pathogenic coronaviruses | Nature Reviews Microbiology. Nature Reviews Microbiology. Retrieved from https://www.nature.com/articles/s41579-018-0118-9.

  scls-2020-0070_XML 1..4. (n.d.).

  Li, F. (2016). Structure, Function, and Evolution of Coronavirus Spike Proteins | Annual Review of Virology. Retrieved from https://www.annualreviews.org/doi/10.1146/annurev-virology-110615-042301

  J. Virol. 86, 3995–4008 (2012).

*From <https://revnote.io/library/sources/wAXVgci35Cht49CNy9Lkj> Clicking on this will take you to my Revnote workspace where you can see my sources and my highlighting.

**Not a misprint. This is a bat coronavirus which just happens to be called RaTG13.

***From <https://revnote.io/library/sources/wAXVXTkHLCht49CNy9Lhr> "SARS-CoV binding does not interfere with the enzymatic activity of ACE2, nor does the enzymatic activity of ACE2 play any role in SARS-CoV entry" However, just as a thought, what if we made an inhalable ACE2 inhibitor which would bind to the receptor and prevent SARS-CoV-2 from binding.