NO POLITICS The SARS-CoV2 Science-Based Discussion Thread

[capo]

Really interesting paper. Are you convinced by their dismissive statements about the prospects for human manipulation origin? I don't know enough to see much beyond what they are saying, but it seems their estimation is pretty leashed to the idea that the virus would be obviously Frankensteinian if it were cell or animal-passage derived. Aside from that specific implication, they also dismiss the polybasic insertion that may confer pathogenicity as evidence of monster-making, while at the same time describing how it has yet to be found in nature for this virus sub-type, and can be created in influenza by just those techniques.

I think it makes a convincing case there is no real evidence to demonstrate human manipulation while they remain open to someone providing it in the future.

I'm also about out of my depth with commenting deeper than the following, which we did touched on in another thread some time back...

Protein cleavage is a really basic and pervasive enzymatic process in all living organisms. Some of the key proteins viruses encode for are polyproteins which require multiple cleavage events just to get to a stage of useful biochemistry. Host cells are full of enzymes primed and ready to modify proteins and this is a normal phase in the life cycle of virus replication so it shouldn't be shocking that novel cleavage sites occasionally pop up and sometimes create a worthwhile gain in function, or simply an alternative route to the same destination.

I think a key thing here to remember is our ability to tinker with RNA viruses is very limited and our ability to create novel sequences installed just-so in a complex genome like coronavirus is virtually nil. What we're pretty much limited to is clumsily copy-pasting one useful segment pilfered from another singled stranded +RNA virus into another and hoping that with enough tries we could produce viable offspring with a gain in function. To my knowledge that would entail leaving some insertion fingerprints behind in the surrounding nucleotide sequences and would require having a viable inserted sequence isolated to begin with. Neither of which appear to be the case here. So we're left with good old natural selection as the primary driver, a mechanism which is both well understood and demonstrated to be readily capable of zoonosis within this viral genus.

Remember that it took years of looking just to find a natural reservoir for SARS-like viruses. In the intervening years between then and now we've now found hundreds but estimate there are probably many thousands left to discover, that's a lot of natural variation we simply don't know anything about and have no reason to assume won't pop up in the form of another SARS related novel virus.... just like this one.

There is even solid evidence that coronaviruses may exist as a quasispecies in some of their natural host species, dromedary camels being one. If that's true it is spectacularly difficult for us to catalog and anticipate the full gene pool of something like these betacoronaviruses in their natural habitat (at least with our current level of technology). You give a viral quasispecies enough access to human hosts and the likelihood of zoonosis could be far higher than previously thought possible.

https://www.ncbi.nlm.nih.gov/pubmed/24781747

[stonefly-2]

journal article on the likely origins and notable spike protein novelty in SARS-CoV2. Conclusion quoted below.

https://www.nature.com/articles/s41591-020-0820-9

Is that a long way of saying that if the virus is not lab manipulated it will be found to occur in bats in the wild?

[freespool]

Is that a long way of saying that if the virus is not lab manipulated it will be found to occur in bats in the wild?

Close relatives have been found, the closest by one way of scoring was from a cave a long way away from Wuhan. The authors speculated closer relatives might be found if more and closer caves were tested.

I think it makes a convincing case there is no real evidence to demonstrate human manipulation while they remain open to someone providing it in the future.

I'm also about out of my depth with commenting deeper than the following, which we did touched on in another thread some time back...

Protein cleavage is a really basic and pervasive enzymatic process in all living organisms. Some of the key proteins viruses encode for are polyproteins which require multiple cleavage events just to get to a stage of useful biochemistry. Host cells are full of enzymes primed and ready to modify proteins and this is a normal phase in the life cycle of virus replication so it shouldn't be shocking that novel cleavage sites occasionally pop up and sometimes create a worthwhile gain in function, or simply an alternative route to the same destination.

I think a key thing here to remember is our ability to tinker with RNA viruses is very limited and our ability to create novel sequences installed just-so in a complex genome like coronavirus is virtually nil. What we're pretty much limited to is clumsily copy-pasting one useful segment pilfered from another singled stranded +RNA virus into another and hoping that with enough tries we could produce viable offspring with a gain in function. To my knowledge that would entail leaving some insertion fingerprints behind in the surrounding nucleotide sequences and would require having a viable inserted sequence isolated to begin with. Neither of which appear to be the case here. So we're left with good old natural selection as the primary driver, a mechanism which is both well understood and demonstrated to be readily capable of zoonosis within this viral genus.

Remember that it took years of looking just to find a natural reservoir for SARS-like viruses. In the intervening years between then and now we've now found hundreds but estimate there are probably many thousands left to discover, that's a lot of natural variation we simply don't know anything about and have no reason to assume won't pop up in the form of another SARS related novel virus.... just like this one.

There is even solid evidence that coronaviruses may exist as a quasispecies in some of their natural host species, dromedary camels being one. If that's true it is spectacularly difficult for us to catalog and anticipate the full gene pool of something like these betacoronaviruses in their natural habitat (at least with our current level of technology). You give a viral quasispecies enough access to human hosts and the likelihood of zoonosis could be far higher than previously thought possible.

https://www.ncbi.nlm.nih.gov/pubmed/24781747

I think if manipulation were done by tinkering directly with gene sequences, it would leave fingerprints, at least in the context of the genes of higher organisms. Viruses aren't really homeostatic organisms, with control systems to keep them working according to design, more like just complicated chemicals, so I wonder how much easier that makes it to genetic engineer. The lengths of their genomes aren't beyond the capabilities of synthesizers to just design a sequence, then make it whole, from what I understand. Their genomes aren't part of a complicated scheme like in higher organisms. Can you just synthesize a genome that looks wild-type and have it packaged into the virus?

The stuff about homologous recombination though, I wondered if that implied they could take a strain from bats which didn't naturally infect human cells well or at all, and one from pangolins that did, and passage them together in bats or bat cells to get a natural recombinant with the pangolin affinity for human cells. I have no idea if that would be a productive way to create a bio-weapon or not, but apparently that Wuhan lab - others too? - had been working on trying to infect humans with bat coronaviruses for some time. For some reason.

I don't doubt that this could have just happened the old-fashioned way, as you describe, I think it's just an interesting question, did man intervene and how could you tell. I remember when the same question was raised about HIV.

[capo]

I think if manipulation were done by tinkering directly with gene sequences, it would leave fingerprints, at least in the context of the genes of higher organisms. Viruses aren't really homeostatic organisms, with control systems to keep them working according to design, more like just complicated chemicals, so I wonder how much easier that makes it to genetic engineer. The lengths of their genomes aren't beyond the capabilities of synthesizers to just design a sequence, then make it whole, from what I understand. Their genomes aren't part of a complicated scheme like in higher organisms. Can you just synthesize a genome that looks wild-type and have it packaged into the virus?

For one I don't agree about homeostasis, sure the virion itself has no metabolic activity but these life forms are obligate parasites. Selective pressure exists on their genome to stabilize it just as it does any other, in this case all the pressure exists to conform to the host in a delicate balance of exploitation without causing too much harm.

To the best of my knowledge we're nowhere near being able to write and assemble even just a 30kb genome, much less to be able to surgically edit an existing one in a way which targets anything with suitable precision and doesn't leave a trace. And don't forget coronaviruses are one of the very few who use error correction in their genome. This very difficult task of insertion on DNA is made virtually impossible on RNA based life forms as most of our toolkit has been built around the chemistry of DNA. Saying a laboratory could successfully write and assemble a virus like this which was stable and capable of self replication sounds to me a lot like claiming a monkey could write a Shakespearean play if you just gave it enough time on a keyboard. Right now universal heat death may happen first.

The stuff about homologous recombination though, I wondered if that implied they could take a strain from bats which didn't naturally infect human cells well or at all, and one from pangolins that did, and passage them together in bats or bat cells to get a natural recombinant with the pangolin affinity for human cells. I have no idea if that would be a productive way to create a bio-weapon or not, but apparently that Wuhan lab - others too? - had been working on trying to infect humans with bat coronaviruses for some time. For some reason.

That is absolutely something that could happen although selecting for it inside a lab host would seem impossible. In controlled conditions the resulting mutant strain wouldn't have any new cell line to exploit and there's no reason to presume it could out-compete the parent strains in an ongoing infection. That's where the natural environment comes in, a recombination event in the wild may not make the novel strain competitive in the existing host but it is now singularly able to exploit a newly encountered one.

All that is required for zoonosis is access and ability.

However I did post up a link some time prior in one of these threads in which virologists looking at this genome felt there was no evidence of recombination, rather it looked like more a stable, wild subspecies which was able to exploit a new opportunity in a single chance event.

I don't doubt that this could have just happened the old-fashioned way, as you describe, I think it's just an interesting question, did man intervene and how could you tell. I remember when the same question was raised about HIV.

It's certainly an interesting hypothesis and I don't think I've ever discounted the possibility, only that there's no evidence whatsoever to warrant the conclusion. I made the point in another thread that possible --> plausible --> probable ---> conclusion. Right now there's nothing to even get us past the first hump, when we know that this virus is capable of doing this randomly in nature it should take a lot of evidence to conclude the same thing hasn't simply happened again.

[stonefly-2]

Close relatives have been found, the closest by one way of scoring was from a cave a long way away from Wuhan. The authors speculated closer relatives might be found if more and closer caves were tested.

I think if manipulation were done by tinkering directly with gene sequences, it would leave fingerprints, at least in the context of the genes of higher organisms. Viruses aren't really homeostatic organisms, with control systems to keep them working according to design, more like just complicated chemicals, so I wonder how much easier that makes it to genetic engineer. The lengths of their genomes aren't beyond the capabilities of synthesizers to just design a sequence, then make it whole, from what I understand. Their genomes aren't part of a complicated scheme like in higher organisms. Can you just synthesize a genome that looks wild-type and have it packaged into the virus?

The stuff about homologous recombination though, I wondered if that implied they could take a strain from bats which didn't naturally infect human cells well or at all, and one from pangolins that did, and passage them together in bats or bat cells to get a natural recombinant with the pangolin affinity for human cells. I have no idea if that would be a productive way to create a bio-weapon or not, but apparently that Wuhan lab - others too? - had been working on trying to infect humans with bat coronaviruses for some time. For some reason.

I don't doubt that this could have just happened the old-fashioned way, as you describe, I think it's just an interesting question, did man intervene and how could you tell. I remember when the same question was raised about HIV.

If horseshoe bats live in caves closer than that why are they going to the far caves to get the bats for research?

[freespool]

If horseshoe bats live in caves closer than that why are they going to the far caves to get the bats for research?

They haven't looked at them all yet I guess. The researchers simply took the fact that the closest sample came from a cave 750km I think from Wuhan, and that their estimation from sequence difference to humans was that the cross-over might have occurred 40-70 years ago, to guess that a closer relative that wouldn't be so different might be found in a closer cave, explaining away both the physical and implied evolutionary time differences. It's a black art.

[freespool]

I think calling something that's an inert particle homeostatic severely stretches the concept, to the point of meaningless. However, that was a side comment.

I don't know enough genetics to critique the possibilities that homologous recombination might offer for undetectable human manipulation, I just found it an interesting phenomenon that seemed it might offer that potential- without being able to gauge the technical feasibility. What I read seemed to indicate it is a particular type of recombination that allows whole functional domains to swap between strains, increasing the likelihood that a recombination event produces a functional virus. That is, its purpose would appear to be precisely to facilitate swapping of working parts between strains. That contrasts with more typical recombination where the pieces are more likely to be random in size and insertion location and upset existing structures. How much of an evidence trail homologous recombination would leave, aside from the novelty of one domain in the context of the others I don't know. That has been one observation about the human version, that it appears related to a bat strain, but the outer spike domain contains a binding determinant region that has no bat analogs (so far found) but is similar to a strain in pangolins. So perhaps you'd only need to synthesize the RNA of the spike protein or one of its domains (or sub-domains). If it happens in nature then there is a mechanism for disrupting normal transcription integrity by jumping in a new domain's gene. Or if that couldn't be made to work, it could be a fast track to letting nature do it by directed co-infection in animals. I concede that unless you've worked in those systems trying such things, it's only speculative whether it might or might not be feasible.

[stonefly-2]

They haven't looked at them all yet I guess. The researchers simply took the fact that the closest sample came from a cave 750km I think from Wuhan, and that their estimation from sequence difference to humans was that the cross-over might have occurred 40-70 years ago, to guess that a closer relative that wouldn't be so different might be found in a closer cave, explaining away both the physical and implied evolutionary time differences. It's a black art.

My point exactly,

Bats that may or may not have a more similar virus from a cave that may or may not exist that the bats used in the studies were not collected from anyway.

[stonefly-2]

I think calling something that's an inert particle homeostatic severely stretches the concept, to the point of meaningless. However, that was a side comment.

I don't know enough genetics to critique the possibilities that homologous recombination might offer for undetectable human manipulation, I just found it an interesting phenomenon that seemed it might offer that potential- without being able to gauge the technical feasibility. What I read seemed to indicate it is a particular type of recombination that allows whole functional domains to swap between strains, increasing the likelihood that a recombination event produces a functional virus. That is, its purpose would appear to be precisely to facilitate swapping of working parts between strains. That contrasts with more typical recombination where the pieces are more likely to be random in size and insertion location and upset existing structures. How much of an evidence trail homologous recombination would leave, aside from the novelty of one domain in the context of the others I don't know. That has been one observation about the human version, that it appears related to a bat strain, but the outer spike domain contains a binding determinant region that has no bat analogs (so far found) but is similar to a strain in pangolins. So perhaps you'd only need to synthesize the RNA of the spike protein or one of its domains (or sub-domains). If it happens in nature then there is a mechanism for disrupting normal transcription integrity by jumping in a new domain's gene. Or if that couldn't be made to work, it could be a fast track to letting nature do it by directed co-infection in animals. I concede that unless you've worked in those systems trying such things, it's only speculative whether it might or might not be feasible.

So your'e saying synthetic replication, gene splicing or "cross breeding" (in a sense) could all be a means of producing a novel virus?

[freespool]

My point exactly,

Bats that may or may not have a more similar virus from a cave that may or may not exist that the bats used in the studies were not collected from anyway.

What do you read in that, I lost the train of thought? The bat viruses are so similar to the human that I don't think they think there's any doubt that's where they came from, especially since two other cross-overs from bats already happened. For that reason and because bats have killer immune systems and live in a miasma of disease, they get studied a lot. A lot of samples have been collected and sequenced, but probably there's more caves and colonies that haven't been examined yet.

So your'e saying synthetic replication, gene splicing or "cross breeding" (in a sense) could all be a means of producing a novel virus?

Guessing, not saying. I never worked in genetics and only got basic education about it. I read that starting around 5 years ago, some researchers from Wuhan started publishing and presenting at conferences about their work to get bat coronaviruses to infect people. Other scientists thought that was dicey and argued about it, but that's where it got.