6 ms·

Furin cleavage sites very similar if not largely identical to this one have also been found in nature, and have been generated in nature in very short spans of

Furin cleavage sites very similar if not largely identical to this one have also been found in nature, and have been generated in nature in very short spans of time (on the order of a few decades, which is what is suspected to have happened with SARS-CoV-2). I describe the evidence in detail in this detailed longform post I wrote on reddit a few months back: Hi, I have a PhD in virology focused on emerging viruses, and a few months back I wrote a very lengthy and involved piece full of sources. And in there, I describe exactly how wrong your point 1 is. And how misguided your point 3 is. The post also won a "best of r/science 2020" award! You can find it here: https://www.reddit.com/r/science/comments/gk6y95/covid19_did_not_come_from_the_wuhan_institute_of/ https://www.reddit.com/r/science/comments/gk6y95/covid19_did... See under "Addendum to Q2"

COGlory 6y ago
I read through your post and it was incomplete and hand wavy, although that makes sense because it was written for Reddit. The bias was also obvious, and remarkably unscientific in how you approached the "problems" in a deterministic manner. You cherry picked examples (for instance, saying we can detect Cas9 mutations) that make no conclusive point (for example, there are a variety of ways to add a furin site to a genome that don't involve Cas9) but are indistinguishable as proof by the Reddit audience. The bottom line is, though, you are cherry picking arguments that lay people are more or less too unaware of their cherry picked status to argue with. As a virologist, who "engineers viruses", I also take some offense to this line: >The virus itself, to the eye of any virologist, is clearly not engineered. I also suspect that the viruses referenced in the featured article would object to that line as well.
- jeduehr 6y ago
  That's interesting, because of the scientists featured in the above article... None of them are virologists. Petrovsky, for instance, if you look at his google scholar, hasn't published a paper in a virology journal in the 10 years that I looked. He's published in some predatory journals, ones I wouldn't be caught dead publishing in. He's also gotten /close/, I guess, by publishing about tuberculosis. But it really is different and the man clearly has never done any viral biosafety work or worked or supervised work in any secure facilities working with viruses. If he did, I think he might be more cautious about being so cavalier with the probabilities here. David Relman studies the gut microbiome. I have no reason to believe you're a virologist with any training other than your word, but that isn't actually all that important to my argument. Using viruses in your research doesn't make you a virologist any more than using pens in an art school thesis makes you an expert in ballpoint pens. All of that aside, the consensus among people who actually use or study dangerous viruses in biosafety labs (both those for and against gain of function research, btw) is that the virus likely came from a wild zoonotic crossover event. Not a malicious lab leak.
  - COGlory 6y ago
    I'm going to start off by pointing out that again, almost your entire argument is an appeal to authority, which is not a scientific argument. Oh and add gatekeeping to the list as well, in support of your appeal to authority. As an aside to anyone that isn't a professional scientist reading this thread: I'd just like to issue a caution that any time some supposed "expert" is telling you that you should listen to them because of their credentials, and not the merit of their argument, you should promptly ignore them. Extra points if they tell you that the argument is too complex for you to understand. If they can't explain it to a highschooler, they don't understand it either. >I have no reason to believe you're a virologist with any training other than your word, but that isn't actually all that important to my argument. Actually, that's pretty much your entire argument. I'd rather not tie my HN identity to my real identity, as it's not unique to HN but all of my online life. All of my published work, with the exception of a single 1st author and a single 2nd author paper about CRISPR/Cas, is about viruses. Here are some micrographs of viruses I work with that I took, today: https://imgur.com/a/uDG51cN https://imgur.com/a/uDG51cN Feel free to reverse image search them or whatever. Edit: removed reference to specific lab for sake of anonymity. >All of that aside, the consensus among people who actually use or study dangerous viruses in biosafety labs (both those for and against gain of function research, btw) Ah so now the goalposts have moved from "any virologist" to "people that use or study dangerous viruses in biosafety labs". Interesting. >is that the virus likely came from a wild zoonotic crossover event. I don't, and have never disputed that. You seem to think that the 3 points I laid out were some sort of thesis about the origins of the virus. They weren't and aren't. Just some interesting data that can be used to form a coherent hypothesis about the origins of the virus. Similarly, none of the points in your "Reddit post of the year!" even remotely refute them. They cherry pick data. Present an actual argument (here) and I'll engage on it based on the merits of the argument, not either of our credentials.
    - jeduehr 6y ago
      ....I presented a lot of extremely detailed arguments backed up by references in my original post and you just dismissed them by saying they "cherry pick" data. How is that true about anything I said regarding S/NS ratios, molecular clock analysis, the mosaic nature of the virus, the presence of O-linked glycans, the promiscuity and non-species specific nature of the spike protein, etc. You conducted the mother of all handwaves and then asked me to present "actual" arguments. What? You never even approached the detail of any arguments I have made thus far. I'm not going to make new ones until you provide some actual factual responses to the ones I've already made, thanks. In case you don't want to find the link, here it is again: https://www.reddit.com/r/science/comments/gk6y95/covid19_did_not_come_from_the_wuhan_institute_of/ https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
- EMM_386 6y ago
  I agree with you that I am uncomfortable with the "hand-waviness" of the OP's response. If you are a virologist, I would really like your opinion on the science of the following document: https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.202000240 https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.2020002... Like you, I don't enjoy when facts I post are de-railed without actually addressing any of them. It happens a lot, but I try my best to not let them be the last word. There is plenty of factual information out there that makes an accidental lab-leak hypothesis strong.
  - COGlory 6y ago
    I'm unfortunately going to give an equally hand-wavy response. There's nothing in there that strikes me as factually incorrect (I could be wrong though because I am not an expert on these viruses). I did a brief genome analysis myself - only ~5% of the arginines are encoded by the CGG codon. It's also true that those two introduce the furin site, and it's hypothesized that the furin site is critical to the viruses ability to enter the human cell. It's also true that it's a large difference between the closest variant and SARS-CoV 2. There's also the fact that it's an insertion, not a mutation. i.e. the gene acquired extra amino acids, not just changing the new ones (that's one point I think is hand-waved over in the OP's comment, as he points out that there are many mutations between SARS-2 and the closest relative - which is true, but there is (to my knowledge and I'm happy to be corrected on this) only one insertion, and that is the furin site bearing two adjecent non-canonical arginine codons next to each other that also introduce a restriction site.) However, I do believe the insertion is out of frame, which is odd. If I was engineering the protein, I'd probably make the insertion in-frame to reduce variables as much as possible. So that's a point against. The paper also just glosses over that. The restriction site is interesting because to my knowledge, mammals don't produce the protein that would normally digest it (which implies that it's probably rare among infectious eukaryotic viruses), but again, I could be wrong there and am happy to be corrected. Typically, a restriction enzyme will, under the right conditions, cut the DNA (or RNA) at the restriction site. One of the interesting things here is that if I was introducing a restriction site to track GoF research, adding it directly in the thing I added greatly simplifies my life. If that restriction site goes away, I know I lost my insert. It's also nicer to use a restriction site because I can do the digest in 30 minutes on a benchtop, run an agarose gel in an hour, and know if I still have it after passaging the virus, vs say, sequencing, which is usually more expensive and takes longer. Especially if it's BSL2+ because now I need to put it over a BSL2+ sequencer. It's a hypothesis. We'll never know. There's no conclusive evidence either way, and it's absolutely something we should all be talking about, and the scientists among us should be trying to properly falsify it to the best of our ability.
- jeduehr 6y ago
  I say that we could /very likely/ detect the methods necessary to edit the virus. How do you suggest we would be able to completely engineer, from scratch, a novel virus with 1200 mutations spaced randomly throughout the genome, that would rescue properly and be capable of infecting a novel host? I know of no such modeling technology to accomplish this. All of these are phenomena that happen easily and constantly in a massive natural reservoir of any viral population. And if you think it was not strictly "engineered" but instead "evolved" selectively by hand, then how can you escape the S/NS ratio problem? How can you escape the adaptation and glycosylation problem I describe in my original post? How could you avoid the issue of adapting to the host it was evolved in, and acquiring these "lab animal" or "cell culture" specific adaptation mutants that would then need to be somehow removed. Or it likely would not infect humans with any great reproductive efficiency. And then it would have an S protein that would be a bit more adapted to humans, as it has become over the course of the last year. As it's evolving in us, it is becoming better at infecting us. If it had been evolved in humans prior to the pandemic, this would not be as necessary and it would not happen on the scale it's currently happening. And when exactly would China have started this little "experiment?" Where? With what subjects? How did they keep it secret?
EMM_386 6y ago
> Furin cleavage sites very similar if not largely identical to this one have also been found in nature I don't believe this is correct. There are no other examples of a CoV within the sub-genera Sarbecovirus of a species/strain that shows evidence of insertion of a polybasic furin cleavage site.
- jeduehr 6y ago
  Hi, never said they had to be within the sub-genera. Recombination can absolutely happen inter-genera and even inter-family. There's some evidence that Ebola got its VP40 from bats, or vice versa. Meaning that an RNA virus somehow got its nuclear regulatory factor from a bat. We have no idea in science how that happened. But we know there is homology! I can't find the link at the moment, but when I do I'll add it here. It's not actually that important to my argument. There are also examples of inter-family recombination in viruses that are much more down to earth. See here: https://www.virology.ws/2016/10/27/genome-recombination-across-viral-families/ https://www.virology.ws/2016/10/27/genome-recombination-acro... And you might be asking yourself, after reading that link "Why is it always bats?? Isn't that /suspicious/?" It's actually in keeping with everything we know about bats and their role as a viral reservoir. Lots of viruses cross paths in bats. See this other detailed post I wrote a while back: https://www.reddit.com/r/science/comments/gehvui/why_do_viruses_often_come_from_bats_a_discussion/ https://www.reddit.com/r/science/comments/gehvui/why_do_viru...
- jeduehr 6y ago
  I just wanted to add that I probably was exaggerating when I said "we have no idea how that happened." re: VP40, bats, and ebola. Best guess is: a retrovirus and an ebola-like virus infected a bat cell at the same time, the retrovirus accidentally picked up some of the bat genome, which then somehow recombined with the negative sense RNA genome of the ebola-like virus. We have no proof this happened like this, but it's the best guess. Just as an example of the crazy things that we think probably happen in the world of viruses in nature.
fighterpilot 6y ago
You seem confident that it wasn't a lab leak on the basis that Chinese scientists have no reason to lie and that the (alleged) first case wasn't a scientist. What about the CCPs long track record of cover ups and lies instills you with confidence that there isn't a top-down effort to coverup a possible lab leak? If the CCP wants a cover up, then the scientists under their employ will probably lie. Very few would be brave enough to be publicly truthful in such a situation.

COGlory 6y ago

I read through your post and it was incomplete and hand wavy, although that makes sense because it was written for Reddit. The bias was also obvious, and remarkably unscientific in how you approached the "problems" in a deterministic manner. You cherry picked examples (for instance, saying we can detect Cas9 mutations) that make no conclusive point (for example, there are a variety of ways to add a furin site to a genome that don't involve Cas9) but are indistinguishable as proof by the Reddit audience. The bottom line is, though, you are cherry picking arguments that lay people are more or less too unaware of their cherry picked status to argue with. As a virologist, who "engineers viruses", I also take some offense to this line: >The virus itself, to the eye of any virologist, is clearly not engineered. I also suspect that the viruses referenced in the featured article would object to that line as well.

jeduehr 6y ago
That's interesting, because of the scientists featured in the above article... None of them are virologists. Petrovsky, for instance, if you look at his google scholar, hasn't published a paper in a virology journal in the 10 years that I looked. He's published in some predatory journals, ones I wouldn't be caught dead publishing in. He's also gotten /close/, I guess, by publishing about tuberculosis. But it really is different and the man clearly has never done any viral biosafety work or worked or supervised work in any secure facilities working with viruses. If he did, I think he might be more cautious about being so cavalier with the probabilities here. David Relman studies the gut microbiome. I have no reason to believe you're a virologist with any training other than your word, but that isn't actually all that important to my argument. Using viruses in your research doesn't make you a virologist any more than using pens in an art school thesis makes you an expert in ballpoint pens. All of that aside, the consensus among people who actually use or study dangerous viruses in biosafety labs (both those for and against gain of function research, btw) is that the virus likely came from a wild zoonotic crossover event. Not a malicious lab leak.
- COGlory 6y ago
  I'm going to start off by pointing out that again, almost your entire argument is an appeal to authority, which is not a scientific argument. Oh and add gatekeeping to the list as well, in support of your appeal to authority. As an aside to anyone that isn't a professional scientist reading this thread: I'd just like to issue a caution that any time some supposed "expert" is telling you that you should listen to them because of their credentials, and not the merit of their argument, you should promptly ignore them. Extra points if they tell you that the argument is too complex for you to understand. If they can't explain it to a highschooler, they don't understand it either. >I have no reason to believe you're a virologist with any training other than your word, but that isn't actually all that important to my argument. Actually, that's pretty much your entire argument. I'd rather not tie my HN identity to my real identity, as it's not unique to HN but all of my online life. All of my published work, with the exception of a single 1st author and a single 2nd author paper about CRISPR/Cas, is about viruses. Here are some micrographs of viruses I work with that I took, today: https://imgur.com/a/uDG51cN https://imgur.com/a/uDG51cN Feel free to reverse image search them or whatever. Edit: removed reference to specific lab for sake of anonymity. >All of that aside, the consensus among people who actually use or study dangerous viruses in biosafety labs (both those for and against gain of function research, btw) Ah so now the goalposts have moved from "any virologist" to "people that use or study dangerous viruses in biosafety labs". Interesting. >is that the virus likely came from a wild zoonotic crossover event. I don't, and have never disputed that. You seem to think that the 3 points I laid out were some sort of thesis about the origins of the virus. They weren't and aren't. Just some interesting data that can be used to form a coherent hypothesis about the origins of the virus. Similarly, none of the points in your "Reddit post of the year!" even remotely refute them. They cherry pick data. Present an actual argument (here) and I'll engage on it based on the merits of the argument, not either of our credentials.
  - jeduehr 6y ago
    ....I presented a lot of extremely detailed arguments backed up by references in my original post and you just dismissed them by saying they "cherry pick" data. How is that true about anything I said regarding S/NS ratios, molecular clock analysis, the mosaic nature of the virus, the presence of O-linked glycans, the promiscuity and non-species specific nature of the spike protein, etc. You conducted the mother of all handwaves and then asked me to present "actual" arguments. What? You never even approached the detail of any arguments I have made thus far. I'm not going to make new ones until you provide some actual factual responses to the ones I've already made, thanks. In case you don't want to find the link, here it is again: https://www.reddit.com/r/science/comments/gk6y95/covid19_did_not_come_from_the_wuhan_institute_of/ https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
EMM_386 6y ago
I agree with you that I am uncomfortable with the "hand-waviness" of the OP's response. If you are a virologist, I would really like your opinion on the science of the following document: https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.202000240 https://onlinelibrary.wiley.com/doi/pdf/10.1002/bies.2020002... Like you, I don't enjoy when facts I post are de-railed without actually addressing any of them. It happens a lot, but I try my best to not let them be the last word. There is plenty of factual information out there that makes an accidental lab-leak hypothesis strong.
- COGlory 6y ago
  I'm unfortunately going to give an equally hand-wavy response. There's nothing in there that strikes me as factually incorrect (I could be wrong though because I am not an expert on these viruses). I did a brief genome analysis myself - only ~5% of the arginines are encoded by the CGG codon. It's also true that those two introduce the furin site, and it's hypothesized that the furin site is critical to the viruses ability to enter the human cell. It's also true that it's a large difference between the closest variant and SARS-CoV 2. There's also the fact that it's an insertion, not a mutation. i.e. the gene acquired extra amino acids, not just changing the new ones (that's one point I think is hand-waved over in the OP's comment, as he points out that there are many mutations between SARS-2 and the closest relative - which is true, but there is (to my knowledge and I'm happy to be corrected on this) only one insertion, and that is the furin site bearing two adjecent non-canonical arginine codons next to each other that also introduce a restriction site.) However, I do believe the insertion is out of frame, which is odd. If I was engineering the protein, I'd probably make the insertion in-frame to reduce variables as much as possible. So that's a point against. The paper also just glosses over that. The restriction site is interesting because to my knowledge, mammals don't produce the protein that would normally digest it (which implies that it's probably rare among infectious eukaryotic viruses), but again, I could be wrong there and am happy to be corrected. Typically, a restriction enzyme will, under the right conditions, cut the DNA (or RNA) at the restriction site. One of the interesting things here is that if I was introducing a restriction site to track GoF research, adding it directly in the thing I added greatly simplifies my life. If that restriction site goes away, I know I lost my insert. It's also nicer to use a restriction site because I can do the digest in 30 minutes on a benchtop, run an agarose gel in an hour, and know if I still have it after passaging the virus, vs say, sequencing, which is usually more expensive and takes longer. Especially if it's BSL2+ because now I need to put it over a BSL2+ sequencer. It's a hypothesis. We'll never know. There's no conclusive evidence either way, and it's absolutely something we should all be talking about, and the scientists among us should be trying to properly falsify it to the best of our ability.
jeduehr 6y ago
I say that we could /very likely/ detect the methods necessary to edit the virus. How do you suggest we would be able to completely engineer, from scratch, a novel virus with 1200 mutations spaced randomly throughout the genome, that would rescue properly and be capable of infecting a novel host? I know of no such modeling technology to accomplish this. All of these are phenomena that happen easily and constantly in a massive natural reservoir of any viral population. And if you think it was not strictly "engineered" but instead "evolved" selectively by hand, then how can you escape the S/NS ratio problem? How can you escape the adaptation and glycosylation problem I describe in my original post? How could you avoid the issue of adapting to the host it was evolved in, and acquiring these "lab animal" or "cell culture" specific adaptation mutants that would then need to be somehow removed. Or it likely would not infect humans with any great reproductive efficiency. And then it would have an S protein that would be a bit more adapted to humans, as it has become over the course of the last year. As it's evolving in us, it is becoming better at infecting us. If it had been evolved in humans prior to the pandemic, this would not be as necessary and it would not happen on the scale it's currently happening. And when exactly would China have started this little "experiment?" Where? With what subjects? How did they keep it secret?

EMM_386 6y ago

> Furin cleavage sites very similar if not largely identical to this one have also been found in nature I don't believe this is correct. There are no other examples of a CoV within the sub-genera Sarbecovirus of a species/strain that shows evidence of insertion of a polybasic furin cleavage site.

jeduehr 6y ago
Hi, never said they had to be within the sub-genera. Recombination can absolutely happen inter-genera and even inter-family. There's some evidence that Ebola got its VP40 from bats, or vice versa. Meaning that an RNA virus somehow got its nuclear regulatory factor from a bat. We have no idea in science how that happened. But we know there is homology! I can't find the link at the moment, but when I do I'll add it here. It's not actually that important to my argument. There are also examples of inter-family recombination in viruses that are much more down to earth. See here: https://www.virology.ws/2016/10/27/genome-recombination-across-viral-families/ https://www.virology.ws/2016/10/27/genome-recombination-acro... And you might be asking yourself, after reading that link "Why is it always bats?? Isn't that /suspicious/?" It's actually in keeping with everything we know about bats and their role as a viral reservoir. Lots of viruses cross paths in bats. See this other detailed post I wrote a while back: https://www.reddit.com/r/science/comments/gehvui/why_do_viruses_often_come_from_bats_a_discussion/ https://www.reddit.com/r/science/comments/gehvui/why_do_viru...
jeduehr 6y ago
I just wanted to add that I probably was exaggerating when I said "we have no idea how that happened." re: VP40, bats, and ebola. Best guess is: a retrovirus and an ebola-like virus infected a bat cell at the same time, the retrovirus accidentally picked up some of the bat genome, which then somehow recombined with the negative sense RNA genome of the ebola-like virus. We have no proof this happened like this, but it's the best guess. Just as an example of the crazy things that we think probably happen in the world of viruses in nature.

fighterpilot 6y ago

You seem confident that it wasn't a lab leak on the basis that Chinese scientists have no reason to lie and that the (alleged) first case wasn't a scientist. What about the CCPs long track record of cover ups and lies instills you with confidence that there isn't a top-down effort to coverup a possible lab leak? If the CCP wants a cover up, then the scientists under their employ will probably lie. Very few would be brave enough to be publicly truthful in such a situation.