I don’t want to ask you to speculate out of the blue, but if you feel qualified: do you think it’s possible that COVID originated outside of a lab but that China has lied about the timeline to avoid embarrassment? That’s always struck me as a plausible scenario, one that seems to fall by the wayside in these conversations.
Either way the molecular evidence doesn’t incriminate them. So it is frustrating how people buy into the political arguments not realising just how good molecular arguments are.
Who's actually claiming lab manipulation any more?
Either way, empirically we have no conclusive evidence of natural origin (of the stages between the original bat coronavirus and the original Wuhan variant) nor of a lab leak. One also does not preclude the other; a virus of natural origin could still leak from a lab that studies such viruses.
Yeah, this is called passaging but it's very unlikely (nearly impossible) that it was used here -- you'd have to start with a very close predecessor, much closer than Ratg13, and the work in cell cultures usually ends up deleting the FCS since it's not a very stable mutation unless being actively selected for. So to perform the subculturing necessary to gain all of the various mutations that set sars cov2 apart would surely destroy it's ability to infect humans. (https://www.news-medical.net/news/20210208/Furin-cleavage-SA...)
> And though I know the paper was retracted, what about those HIV-1 inserts?
That the paper was retracted should tell you enough, but what was missed at the time is that ratg13, which was unambiguously of natural origin also has the same alleged HIV-1 inserts (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033698/). So it's pretty clear that the 'HIV-1 inserts' are just a common feature of ratg13-like coronaviruses.
> Either way, empirically we have no conclusive evidence of natural origin (of the stages between the original bat coronavirus and the original Wuhan variant) nor of a lab leak.
Right, but this is actually strongly suggestive of natural origin. We know what lab manipulation looks like and sars cov2 has none of these signs - in this case the absence of evidence actually is instructive.
There is a hypothesis that the virus was modified in a lab by passaging it through transgenic animals that had more human-like respiratory systems. So that could account for its ability to infect humans. I don't necessarily believe that really happened (seems far fetched), but it's there any way to completely disprove that hypothesis?
> A specific laboratory escape scenario involves accidental infection in the course of serial passage of a SARSr-CoV in common laboratory animals such as mice. However, early SARSCoV-2 isolates were unable to infect wild-type mice. Although murine models are useful for studying infection in vivo and testing vaccines, they often result in mild or atypical disease in hACE2 transgenic mice. These findings are inconsistent with a virus selected for increased pathogenicity and transmissibility through serial passage through susceptible rodents. Although SARS-CoV-2 has since been engineered and mouse-adapted by serial passage, specific mutations in the spike protein, including N501Y, are necessary for such adaptation in mice. Notably, N501Y has arisen convergently in multiple SARS-CoV-2 variants of concern in the human population, presumably being selected to increase ACE2 binding affinity.
> If SARS-CoV-2 resulted from attempts to adapt a SARSr-CoV for study in animal models, it would likely have acquired mutations like N501Y for efficient replication in that model, yet there is no evidence to suggest such mutations existed early in the pandemic. Both the low pathogenicity in commonly used laboratory animals and the absence of genomic markers associated with rodent adaptation indicate that SARS-CoV-2 is highly unlikely to have been acquired by laboratory workers in the course of viral pathogenesis or gain-of function experiments.
Basically if you wanted to study sars cov2 in transgenic mice with adapted hACE2 receptors, there are obvious mutations that you would engineer into the virus to make it more stable and pathogenic. None of these mutations existed in the first samples. But importantly, when covid was spreading in humans, these same mutations naturally appeared through convergent evolution in several variants. Contrary to many claims, the virus wasn't close to being optimized for pathogenicity which would've been the ostensible purpose of GoF research. It really "acts" like it was recently passed to an intermediate host, then fairly quickly began to infect humans.
The mere fact that we can make genetic modifications that are well hidden doesn't add any information to the story since there's no evidence at all of anyone in the lab using those techniques and the resulting virus has a bunch of strange mutations that both made it more pathogenic in some respects and much less in others -- but the hard to predict ones made it more pathogenic and the easily missed ones made it less pathogenic.
It's not solely the presence/absence of restriction sites that would indicate a lab-engineered virus. All scientists are basically using the same set of tools in terms of computation models and molecular techniques -- so when you see a spike protein that is "optimized for ACE2 binding" as many breathless people claimed -- you can tell that it actually isn't all that well optimized, and the genetics / stats package that would have been used to design the variant actually indicate several better options if you were trying to achieve high-efficiency ACE2 binding [see the discussion paragraph here: https://journals.asm.org/doi/10.1128/JVI.00127-20]
There are other indicators as well -- the additional proline in the FCS makes no sense from an engineering standpoint since it could very easily corrupt nearby helices, block the protease activity, or mess up binding through misfolding. Any competent engineer would have used a different amino acid there if they were trying to find a spacer -- or would have added another arginine to the beginning of the sequence to roughly double the odds of cleavage.
So you have to simultaneously believe they're very competent at the molecular engineering needed to silently design viruses, but incompetent enough to use inefficient inserts and miss obvious, readily predictable areas to make it more pathogenic. Until we find a precursor virus or a whistleblower, we're down to weighing probabilities and I'd put "engineering using seamless recombination" very, very low on the list.. like below 0.01%.
I disagree. Your assumption that an engineer eill always go for the "most optimum" solution every time is flawed. If I have a more pessimum way to get 90% of the way there in hand, and need to wait two weeks for the most optimum component, I'll go with what gets me a result to get an interim datapoint to see if I'm even barking up the right tree.
>The mere fact that we can make genetic modifications that are well hidden doesn't add any information to the story since there's no evidence at all of anyone in the lab using those techniques and the resulting virus has a bunch of strange mutations that both made it more pathogenic in some respects and much less in others -- but the hard to predict ones made it more pathogenic and the easily missed ones made it less pathogenic.
Zhengli had extensive experience with those methods, picked up from years working with Ralph Baric and as someone who trains others, I assure you, you teach what you know works, and a student will generally build off of what their teacher knows for a fact works. You use the tools you have around you, and I'll wager they had a bunch more inventory from that work than otherwise. Do you happen to have copies of records of digestion kit purchases from around the time in question, and the ability to cross-check with WIV inventory records? If your answer is no, you have no business trying to rule it out as a possibility.
>It's not solely the presence/absence of restriction sites that would indicate a lab-engineered virus. All scientists are basically using the same set of tools in terms of computation models and molecular techniques -- so when you see a spike protein that is "optimized for ACE2 binding" as many breathless people claimed -- you can tell that it actually isn't all that well optimized, and the genetics / stats package that would have been used to design the variant actually indicate several better options if you were trying to achieve high-efficiency ACE2 binding [see the discussion paragraph here: https://journals.asm.org/doi/10.1128/JVI.00127-20]
Explain to me why the FCS codes for the motif most common in human beings if it's evolutionary route was through intermediate hosts, and not predicated on the fact that most laboratory tools are going to have a human centric bias to them (humanized mice, digestions being made for tge human genome benefitting from increased acailibility based off of economies of scale, thereby satisfying all prerequisite assumptions of how they got there by "bored stocker of lab does what they always do)? Also explain to me why the intermediate virus was not only not sampled earlier, but even now still comes to light out of concerns of cross-contamination? Given, if you went ahead and lined up some samples on a machine with a known tendency misalign, I can't account for not putting buffer space between samples, but in a way this just solidifies the lab origin even more. People make mistakes handling highly pathogenic material. Hence the absurd level of risk with GoF, and the warranted not putting the case down til an exhaustive accounting of what went on is arrived at with adverse inference being warranted at continued attempts to mislead or further muddy the waters.
>So you have to simultaneously believe they're very competent at the molecular engineering needed to silently design viruses, but incompetent enough to use inefficient inserts and miss obvious, readily predictable areas to make it more pathogenic. Until we find a precursor virus or a whistleblower, we're down to weighing probabilities and I'd put "engineering using seamless recombination" very, very low on the list.. like below 0.01%.
You're acting like people are thinking this was a specifically engineered bioweapon. I ain't one of em. Research is more organic. It's called "The Art" for a reason. I'm 100% comfortable this is an outcome of someone with the best intentions doing and experiment, getting more of a hot tamale than they bargained for, not paying enough attention during handling or disposal, and then having a bad time. This is the case no virologist period wants to be considered. That they are human, prone to mistakes that can cause lethal outbreaks, and that the rest of society should just let the entire thing rest because it was just nature, (with or without a guiding hand).
I'm sorry, I don't buy it. Find me an intermediate host that doesn't have "lab animal" or "GoF" subject written all over it, and we can talk.
Yuri Deigin did a write up: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744920/
Ptoject E.V.I.D.E.N.C.E is still a mountain of circumstantial evidence that are in favor of availability of motive, means, and opportunity. Ralph Baric and Shi Zhengli, and their research students would have had more than enough reasons to actually do digestions that don't leave restriction sites. When you're out to create a virus to base a vaccine off of, or to quantify a risk factor relating to making a zoonotic jump you don't want your tools of the trade leaving kerf lines that'll interfere with immunological response formation.
There's a couple other articles that have been written up by prominent bioethicists, and there's evidence of malfeasance in terms of funding GoF research indirectly.
The case stands. Preponderance of evidence warrants further investigation. Not the opposite. If it were truly so unlikely, why was the last decade filled with such interest in being able to do seamless inserts and viral reconstruction?
No, no, no. I'm sorry. Just. Not. Buying. It.
The WIV had the biggest program in the world to sample novel coronaviruses from nature. In DEFUSE, they sought DARPA funding to make chimeras of such viruses, with novel FCSs. That proposal was rejected for safety concerns, but we don't know what work continued with other funders.
https://theintercept.com/2021/09/23/coronavirus-research-gra...
Your links above support the possibility that SARS-CoV-2 is natural. They don't exclude that it's unnatural, though.
> I'm not sure how you'd distinguish between a novel naturally-evolved virus and a laboratory chimera of two such viruses, though.
BLAST sequencing against known viruses would do the trick. (https://www.viprbrc.org/brc/blast.spg?method=ShowCleanInputP...)
You could come up with a conspiracy theory to say they were hiding their most dangerous pathogens as part of a defense program so we wouldn't have access to the sequences of the progenitor viruses -- but the fact that we had staff helping in WIV and literally no intelligence has come out to that effect blunts the theory in my view.
I'm 99%:1% confident it was natural spillover and probably 75%:25% that no lab had ever seen the virus before the first people got sick.
Sars cov2 was a bat virus -- so it needed an intermediate mammal host with human-like ace2 receptors to spread to humans. So WIV would have had to have developed this unnaturally, which we would be able to "see" in the DNA or it happened naturally. Those two things don't seem remotely 50:50 likely to me.
And interesting odds. In your p = 24% case where it's natural spillover but a lab had seen the virus before people got sick, are you assuming that a researcher got infected with a naturally-evolved virus, whether directly from an animal on a sampling trip or from a culture in the lab? It's hard to see why they'd be concealing their prior knowledge of the virus otherwise.
I'd personally bet maybe 20% lab-manipulated (by a DEFUSE-like path), 50% naturally-evolved but accidentally released by researchers, 30% true natural. I'm less sure that SARS-CoV-2 needed a non-bat animal host given BANAL-52's spike, though that leaves the question of how BANAL-52 got so closely-adapted to human ACE2 rather mysterious. (I wonder if SARS-CoV-2 but with the BANAL-52 spike would infect humanized mice? I guess that's exactly the kind of curiosity that might have started this pandemic...)
As to the abundance of coronaviruses, I assume you're aware that the closest bat viruses have been collected far from Wuhan, and Dr. Shi herself didn't expect spillover in Wuhan:
> We have done bat virus surveillance in Hubei Province for many years, but have not found that bats in Wuhan or even the wider Hubei Province carry any coronaviruses that are closely related to SARS-CoV-2. I don't think the spillover from bats to humans occurred in Wuhan or in Hubei Province.
https://web.archive.org/web/20201206204844/https://www.scien...
SARS-1 emerged far from the bat caves too, but wildlife trafficking there was quickly identified as the likely conduit. I understand there's some debate as to whether civet cats (and not some other animal) were actually the proximal host for SARS-1, but that's still much stronger evidence of zoonosis than we have for SARS-CoV-2.
My understanding is that bats like the chinese horseshoe have perfectly suitable ACE2 receptors for getting infected by sars-cov-2 as-is, and that the main reason for wanting an intermediate host is to explain how the virus got in contact with humans because humans don't really interface physically with bats, but I'm totally out of my depths here. The article linked below makes it sound like the virus can infect a wide variety of mammals, including bats and humans, with or without the now famous furin cleavage site, so it doesn't seem like the smoking gun lab-leak proponents like to brandish it as.
https://www.news-medical.net/news/20200420/ACE2-receptor-exp...
https://medium.com/advances-in-biological-science/explained-...
It's extremely unlikely that the jump was from bats -> humans just based on how 'optimized' the ACE2 binding and furin cleavage sites are. It's theoretically possible that it happened at some time in the past, and then serial passage in humans led to the more 'optimized' virus but that seems pretty unlikely too.
https://twitter.com/jbloom_lab/status/1440309655087902720?la...
I've seen no explanation for why the spike of a bat virus would be so well-adapted to human ACE2, but apparently that one is. That's an argument against the need for an intermediate host, whether that host is natural (e.g. a non-bat wild animal) or not (e.g. hACE2 mice in the lab).
But if it turns out that, say, there was an isolated outbreak in some rural area a few months earlier known to the authorities who covered up because they thought they had it under control (whilst also knowing it was new and SARS-like and worthy of study at their coronavirus lab) that would be hugely damaging for the Chinese government even if it spread naturally
But again, it’s speculation on my part.