5 ms·

Sorry but what molecular evidence suggests it evolved in the wild, exactly? We haven’t identified a single predecessor mutation between the original bat Coronav

by rzz3 5y ago

Sorry but what molecular evidence suggests it evolved in the wild, exactly? We haven’t identified a single predecessor mutation between the original bat Coronavirus and SARS-CoV-2, nor have we identified infections from the time period that are geographically between the habitat of the carrier bats and Wuhan. No one is disputing that it’s based on a bat coronavirus, but the thesis is that the bay coronavirus was modified in the lab and then leaked.

mikeyouse 5y ago
Nah, lab modifications have very obvious fingerprints - not of which exist in any of the samples. Separately from that, we've found nearly every mutation that was given as evidence of manipulation arising naturally in other populations. [Polypasic FCS: https://twitter.com/MichaelWorobey/status/1471546513281019905 https://twitter.com/MichaelWorobey/status/147154651328101990..., ACE2 Receptor Binding is ancestral and evolvable trait: https://mobile.twitter.com/tylernstarr/status/1489257185825591303 https://mobile.twitter.com/tylernstarr/status/14892571858255..., Natural insertions at s1/s2 cleavage: https://www.sciencedirect.com/science/article/pii/S096098222030662X https://www.sciencedirect.com/science/article/pii/S096098222... site, etc. etc.] Who's actually claiming lab manipulation any more?
- rzz3 5y ago
  Isn’t some of the so-called gain of function research (and I do mean in the broadest sense) effectively controlled evolution over many cycles such that it evolves the correct mutations? And though I know the paper was retracted, what about those HIV-1 inserts? 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.
  - mikeyouse 5y ago
    > Isn’t some of the so-called gain of function research (and I do mean in the broadest sense) effectively controlled evolution over many cycles such that it evolves the correct mutations? 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-SARS-CoV-2-spike-deletions-mostly-suppressed-within-infected-airway-epithelium-says-study.aspx 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/ 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.
    - nradov 5y ago
      Thanks for the explanation. 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?
      - mikeyouse 5y ago
        I wasn't familiar with that theory, so leaning on others here (I'm taking out the cites since it really muddles the readability but they're in the source file). This all makes sense to me; > 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. [https://www.cell.com/cell/pdf/S0092-8674(21)00991-0.pdf https://www.cell.com/cell/pdf/S0092-8674(21)00991-0.pdf]
- tripletao 5y ago
  There's little question that most of SARS-CoV-2's genome evolved naturally in bats, especially the spike given its close identity to BANAL-52. I believe that SARS-CoV-2 is very unlikely to have been derived in a laboratory from any known virus, including RaTG13. I'm not sure how you'd distinguish between a novel naturally-evolved virus and a laboratory chimera of two such viruses, though. 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-grant-darpa/ 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.
  - mikeyouse 5y ago
    I mean, sure anything's possible -- but WIV had the biggest program to sample coronaviruses because there are so many coronaviruses in China and they've had epidemics caused by zoonotic spillover in the past. The reason there were funding proposals of all sorts to study bat coronaviruses is because literally everyone in virology was terrified of a bat coronavirus like covid19. I don't think "the west" fully appreciates how much SARS changed research in China. > 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=ShowCleanInputPage&decorator=reo 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.
- hlbjhblbljib 5y ago
  and labs are incapable of combining naturally sourced mutations.

by rzz3 5y ago

mikeyouse 5y ago

Nah, lab modifications have very obvious fingerprints - not of which exist in any of the samples. Separately from that, we've found nearly every mutation that was given as evidence of manipulation arising naturally in other populations. [Polypasic FCS: https://twitter.com/MichaelWorobey/status/1471546513281019905 https://twitter.com/MichaelWorobey/status/147154651328101990..., ACE2 Receptor Binding is ancestral and evolvable trait: https://mobile.twitter.com/tylernstarr/status/1489257185825591303 https://mobile.twitter.com/tylernstarr/status/14892571858255..., Natural insertions at s1/s2 cleavage: https://www.sciencedirect.com/science/article/pii/S096098222030662X https://www.sciencedirect.com/science/article/pii/S096098222... site, etc. etc.] Who's actually claiming lab manipulation any more?

rzz3 5y ago
Isn’t some of the so-called gain of function research (and I do mean in the broadest sense) effectively controlled evolution over many cycles such that it evolves the correct mutations? And though I know the paper was retracted, what about those HIV-1 inserts? 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.
- mikeyouse 5y ago
  > Isn’t some of the so-called gain of function research (and I do mean in the broadest sense) effectively controlled evolution over many cycles such that it evolves the correct mutations? 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-SARS-CoV-2-spike-deletions-mostly-suppressed-within-infected-airway-epithelium-says-study.aspx 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/ 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.
  - nradov 5y ago
    Thanks for the explanation. 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?
    - mikeyouse 5y ago
      I wasn't familiar with that theory, so leaning on others here (I'm taking out the cites since it really muddles the readability but they're in the source file). This all makes sense to me; > 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. [https://www.cell.com/cell/pdf/S0092-8674(21)00991-0.pdf https://www.cell.com/cell/pdf/S0092-8674(21)00991-0.pdf]
tripletao 5y ago
There's little question that most of SARS-CoV-2's genome evolved naturally in bats, especially the spike given its close identity to BANAL-52. I believe that SARS-CoV-2 is very unlikely to have been derived in a laboratory from any known virus, including RaTG13. I'm not sure how you'd distinguish between a novel naturally-evolved virus and a laboratory chimera of two such viruses, though. 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-grant-darpa/ 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.
- mikeyouse 5y ago
  I mean, sure anything's possible -- but WIV had the biggest program to sample coronaviruses because there are so many coronaviruses in China and they've had epidemics caused by zoonotic spillover in the past. The reason there were funding proposals of all sorts to study bat coronaviruses is because literally everyone in virology was terrified of a bat coronavirus like covid19. I don't think "the west" fully appreciates how much SARS changed research in China. > 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=ShowCleanInputPage&decorator=reo 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.
hlbjhblbljib 5y ago
and labs are incapable of combining naturally sourced mutations.