jeduehr
I'm sorry, that colored a lot of my responses to you because I made unfair assumptions about what you were saying. I sent you a longer form email to your protonmail about it.
Anyway, good luck with your work.
I don't have time to address the rest of your comment I'm sorry, I have already sunk so much time into this post that I should have spent studying. This is the exam I have in 3 weeks: https://en.wikipedia.org/wiki/USMLE_Step_1 Pay particular attention to the section marked "effect on matching residency." I never should have responded or brought myself into this post in the first place.
Sorry, but I need to exit now. I hope you find the certainty you're looking for, either way. I hope you find the solace in "holding virologists to account" that you are looking for, although I'm not sure it will happen the way you are suggesting.
That's called "sealioning," a term you may have heard. https://www.merriam-webster.com/words-at-play/sealioning-int...
If you did not believe in good faith the statements you made, or have substance behind the questions you asked as though you believed them to be true (CGG for example), that is very much insincere.
I am not going to be dragged into an endless debate with someone who wants to play devil's advocate. There are people with actual misunderstandings and misconceptions about science that are out there that need our help to understand the world around them.
Why waste time like this if we agree on the basic points? This is not a socratic discussion, you are not Socrates, and I am not Plato. This is not a PhD defense. It is not an academic conference.
I'm here to talk about this with people who have legitimate concerns that they actually believe about the subject matter at hand.
And please, I'm sorry if I mischaracterized your position or your actions thus far, but that's what it looks like. If you had said at some point "just playing devil's advocate here!" or "I don't 100% believe this but what about this thing I saw?" then if I had seen that, I would have engaged in a completely different way, and likely disengaged much earlier.
Thanks for the interesting ideas, but I have to go study for exams, and procrastinate in ways that are better for both of our mental health.
Have a great day, and I hope this hasn't taken up as much of your mental energy as it has mine. Because it took up a lot of mine.
Do you think these two possibilities are equally likely?
Do you think one is more likely than the other?
Which?
You say that you find the lab possibility not very likely, so do you find the zoonotic scenario any more likely? If so, then you and I are in agreement, of a kind. You never said that above, and you definitely argued in a way that implied something else. Especially given the CGG codons.
Probabilistic thinking is the nature of the discussion in the absence of conclusive evidence. Probabilistic thinking. Heuristics. That's what I've been discussing this entire time, that's what I was talking about in my original post, and it's what your reply comments were, therefore, replying to.
I never make any claims saying either is the only possible scenario or an impossible one.
I also was not "dancing around the concrete arguments on the topic." I was directly answering arguments that had been put forth to me by random people on the internet. That's it. That's the point of the post. To answer those arguments.
I get that you've never seen it claimed that engineering made all 1200 mutations, but plenty of people claim it. You can look on my original reddit post and see people in the comments claiming it's possible because "China is so far ahead of us, they could have generated the primers 20 years ago to do something like that."
That's why it's not a strawman, I was directly answering arguments that had been made to me by people on the internet. Just because you think they are ludicrous arguments does not mean that someone has not made them. The internet is larger and more diverse in its idiocy than you have conceived of in your dreams, Horatio. etc. etc.
>2) That furin site RNA contains a non-canonical amino acid codon. To be fair, you didn't dispute this.
Hi, I have disputed the claim you've made since that the virus contains two such codons in a row. That is patently not the case in the earliest examples of the virus known. And wow, I just checked, and those three sequences from the earliest part of the pandemic I linked, they don't contain the cgg in the furin site. Literally look yourself. The earliest sequences out of China, Korea, and Iran do not have the cgg where you're talking about. It isn't there. Not that I saw, lol. Show me where it is if you find it. I just used BLOSUM similarity alignment and looked where the cleavage is supposed to be. And I don't see CGG there.
I actually address the restriction site directly in the original discussion. I don't recall you mentioning it before now. if you did, my apologies I missed it. See my comments on that copy/pasted here:
"For sticky end ligation, for example, you can examine the relative length of homologous regions around restriction enzyme cutting motifs. And sort of detect it like a photoshopped gel almost. But in sequence form. Real mutations shouldn't occur predominately around restriction enzyme motifs. But engineered mutations would. You'd have to use evolutionary comparison of similar viral species to see if there are any mutations that appear too improbable to have happened by polymerase error alone.
Is it still possible to slip one by such a method? yes, of course. Especially small insertions or deletions would be easy to hide...
[But] it literally wouldn't make sense to do it. We have established backbones that would make more sense and be easier to use. The only reason would be to "hide your work." And that's like years and years worth of genetic manipulation, several post-docs worth of work, easy. All to "hide your work." When you could just use SARS-CoV-1 and be A) more deadly, B) more "natural", and C) easier to use."
It's just really funny if we do agree about both of these being possible, but one being more likely than the other. If we both agree that the zoonotic is probably more likely, what are we arguing about? I don't disagree that it is /technically/ possible, but I also find it more likely to have occurred in nature. Restriction sites can also occur in nature, btw. This is a case of the "lottery" fallacy. There are so many goddamn restriction sites throughout any viral genome, why is this surprising?
https://pubmed.ncbi.nlm.nih.gov/11779380/
https://pubmed.ncbi.nlm.nih.gov/29270793/
https://pubmed.ncbi.nlm.nih.gov/26654122/
https://pubmed.ncbi.nlm.nih.gov/30806904/
https://pubmed.ncbi.nlm.nih.gov/16940861/ (this one says wet markets, which probably are an issue, but not as big as initially thought, and probably not the origin of CoV-2)
https://pubmed.ncbi.nlm.nih.gov/26922715/
https://pubmed.ncbi.nlm.nih.gov/27726088/
https://pubmed.ncbi.nlm.nih.gov/26689940/
https://pubmed.ncbi.nlm.nih.gov/27426214/
https://pubmed.ncbi.nlm.nih.gov/26654122/
https://pubmed.ncbi.nlm.nih.gov/30806904/
https://pubmed.ncbi.nlm.nih.gov/16940861/ (this one says wet markets, which probably are an issue, but not as big as initially thought, and probably not the origin of CoV-2)
https://pubmed.ncbi.nlm.nih.gov/27726088/
https://pubmed.ncbi.nlm.nih.gov/27426214/
People like Michael Osterholm and Peter Daszak and Vincent Muenster and Ralph Baric and Shi Zhengli have been saying this was going to happen /for years/. It was a matter of "when" not "if" to us virologists. We absolutely saw the writing on the wall and saw specifically SARS-1 and MERS and knew that meant there were likely other coronaviruses that could emerge.
But funding was always so low, because the viruses weren't currently infecting anybody! So the sampling efforts were always very minimal and underfunded!
And now, because of the lab leak theory, that has actually gotten worse, not better!
https://www.reddit.com/r/medicine/comments/gb8yye/nihs_axing...
At this point, with their market cap and increased moderation, probably less likely than the two I listed.
All new assumptions that make this theory less likely.
Sorry. :(
I don't have the time or bandwidth to re-write it at the moment. But a lot of her arguments are similar to Dr. Degerin's and also Dr. Ebright over at Rutgers. They are a small minority, like the OP says.
I tend to rely on expert consensus when it makes mechanistic sense like this one does.
Nothing, no evidence we have, makes either possibility impossible. The lab leak just requires a lot more cloak and dagger and new assumptions. Occam's razer tells me to favor the hypothesis with the least new assumptions. Hence zoonotic release is more likely in my opinion. That's truly the crux of it, the rest of it is arguing over the number of angels on the head of a pin.
Why would this support either hypothesis? The cleavage site clearly has nothing to do with RATG-13 and it is probably one of the main drivers of SARS-CoV-2 pathogenesis. See here:
-https://www.nature.com/articles/s41586-021-03237-4
-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457603/
But before you say "See! Gotcha! That means that the cleavage site is the smoking gun!"
It also looks, from a molecular perspective, like a natural recombination event. See here:
-https://www.frontiersin.org/articles/10.3389/fgene.2020.0078...
It's not super likely, because we don't have the epidemiological data (increased deaths from non-influenza pneumonia at a large scale) to support that, to my knowledge.
It's certainly possible. And it is true that our methods of detection of viruses are ill-equipped so you can assume we're almost always behind the curve a bit.
But there also isn't much more than anecdote to support this. Lots of people get influenza-based pneumonia in the winter. Could you consider the possibility that your recollection is now tainted? And that you are primed to notice those events more? It was also already a very bad flu season. See here:
-https://time.com/5758953/flu-season-2019-2020/
-https://www.medscape.com/viewarticle/924728
Another kind of issue is that early reports of "SARS-2 positive serum!" were overblown, which colored a lot of news reports on this. They basically made the tests too "promiscuous" so they also detected antibodies against common cold coronaviruses. That was a big problem. If you're curious about how tests like this work, you can check out this other post I wrote on that! Antibody tests are actually my specialty!
https://www.reddit.com/r/medicine/comments/g1ty3g/are_immuni...
Zoonosis is just a lot more likely.
All we can do is make probabilistic arguments. Inferences. Inductive reasoning.
And that sort of analysis, occam's razor based on the least new assumptions necessary to conclude the mechanism, I think the zoonotic theory is more likely.
The lab theory isn't impossible, it just requires a lot more untested and unknown assumptions.
But this event doesn't look anything like those other lab release events.
See here: https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
It's really funny you mention that because when I presented this paper in my departmental journal club, that was the #1 criticism levied. This model over-enriches for South America and under-enriches for East Asia.
Mostly it has to do with (in my opinion) their under-reliance on host-specificity and over-reliance on overall biological diversity. The Pacific Northwest is a hotbed of ecological and biological diversity in rodents among other things, but we haven't had any major outbreaks out of that area yet (knock on wood).
Papers can be wrong or whatever. Or underappreciate things. Lots of other scientists think there's a massive underappreciated reservoir of bat-related viruses in Asia. Peter Daszak is the obvious one, but also Heinz Feldmann, Christian Drosten, Peter Daniels, basically anyone who has ever studied bat viruses or influenza viruses believes there's a lot left undiscovered in Asia. That's also why several of the most recent hemorrhagic fever virus meetings from Keystone was in Hong Kong. SARS-1 is a big memory there, and not a very long ago one.
>SOMEONE in your group of international scientists should be able to confirm or deny allegations the WIV was in fact shutdown for a week in September. If no-one cannot confirm or deny this direct and very specific allegation how can anyone take seriously your claim that international civilian researchers would have any clue who was doing what kind of research in the facility or with its materials elsewhere?
My BSL3/4 was shut down all the time. For maintenance or whatever. They're facilities that go down for maintenance often because of how important it is to make them safe. Anytime an autoclave broke, or a fan broke, you had to take it down because it no longer met the biosafety standards set forth in the protocols.
I personally have no idea if it was shut down for a week in September, that's a very specific thing. Do you know exactly when a company in your line of work started doing work from home? Or when it was shut down for an internet outage? etc. etc. That's a very specific thing.
Sure I could ask around and probably figure that out. But I also don't want to, because I'm not interested in fueling your conspiracy theory when I have no idea what relevance that would have to the likelihood of a lab leak. Given how often these facilities shut down. They do it yearly as a rule, and often 4-5 times per year due to other maintenance reasons. And yes that includes brand new facilities. I cannot tell you how many times people at the BSL4 in Montana here in the US told me about facility shutdowns as reasons they couldn't conduct my experiments! It delayed my PhD a bit!
IVF is actually ALMOST the start of the process since we already had the ACE2 gene sequence. I suppose you would have to clone it and that might take a month. So altogether probably 3-4 months. Especially since it was TOP priority, like drop everything else and do this.
I'll give you an example. In my work, we had to clone Stat1 and Stat2 knockout mice, these are a model for Zika and for testing ebola vaccines and creating anti-Ebola antibodies, I published a paper all about it you can look it up in my gscholar linked elsewhere here.
Anyway, to go from idea to first generation of mouse (I didn't actually do the work, just watched someone else do it this was really early in my PhD)... it took about 6 months. And that's with a zillion other things on our plates. If it was the ONLY thing we were doing? Yeah it probably could have been done in 4 months. Probably 3 if you gave us unlimited funding and perfect facilities.
Science doesn't work the way you want it to work either, btw. It's not about wild hypotheses and conspiracies about people hiding stuff from the public. It's not about supposition and theoretical thought experiments. We rely on concrete data to make very small conclusions based on probability, and then test them.
Unfortunately, this really isn't a testable hypothesis either way. That's why the occam's razor factor matters so much here. It really is a probabilistic argument.
I never said it was impossible that this was a lab leak, only really unlikely.
And here also is an Australian strain from the beginning of the pandemic that does not have cggcgg: https://ncbi.nlm.nih.gov/nuccore/MT007544
You can't please all of the people all of the time, but you can certainly make an effort. Right now I don't really see what specific criticisms you're making other than that you don't like the way I write.
Please, let me know! Thanks
The core argument is actually one of occam's razor. Is such a recombinant /technically/ possible? Yes.
How many new assumptions does it require? A lot. Lots of people who help cover it up, lots of people who get sick and say nothing, lots of samples destroyed. And then also the epidemiological and genetic evidence doesn't support it.
How many new assumptions do you need for the zoonosis theory? Very few. It consists almost entirely of phenomena we know occur in nature, via mechanisms already described and known to occur at a frequent enough time scale to make it not just plausible, but probable.
That's the core argument.
I will say DDOS attacks on scientific databases are not that uncommon. This is the same reason that a lot of scientific publication data are now hosted by the publisher and not the scientist.
It's rarely actually a malicious "hacker," though. Usually it's some grad student somewhere pulling a really crappily made wget script out and accidentally using all the bandwidth.
Scientists aren't actually that great of programmers, yours truly included. Have I done this before with an independently hosted database? I can neither confirm not deny. Lol.
But seriously I have no idea. I get why you find this suspicious, but to me it is extremely circumstantial and I can think of a lot of mundane reasons for it.
For one, I don't know that the translation of DDOS and hacker or idiot script kiddie is nuanced enough between Mandarin and English.
This is actually extremely controversial. There's a great deal of evidence that random walks are more important than selection in fixation events. Does selection play a role? Yes! Definitely! But the evidence is mounting and almost at consensus that random chance is actually what dictates most fixation events. It just can't be /deleterious/ but it does not have to be /helpful/ to fix. The evidence shows that most mutations, on median, are neutral or slightly deleterious. But the ones that are beneficial are so beneficial that the average is neutral-to-net-positive. A lot more of it is actually stochastic than you think! A lot of the transmission between hosts, for example, is stochastic and not selective.
See these reviews/studies from Bloom, Audino, etc:
-https://elifesciences.org/articles/35962
-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173453/
-https://www.cell.com/cell-host-microbe/pdf/S1931-3128(18)301...
-https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372249/
-https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0014-3820....
-https://journals.plos.org/plospathogens/article?id=10.1371/j...
This is why it's less easy to maintain a virus at the proper S/NS ratio in the lab. It becomes too stochastic. too little selection. So your mad scientist would have to have extremely few viral genera.
You say every gene evolves more slowly than non-coding, which is true. but synonymous mutations happen at the same rate as one would expect it to occur in both.
Are you trying to say it isn't ever going to happen? From what I'm reading, there's actually no reason to believe the CGG in that site is fixed in any way. It's not always CGG. In fact, it rarely is in CoV-2 isolates. Maybe that was a fluke of the sequencer or the isolate?
Wow, now I'm starting to think Yuri just didn't do his homework.
This paper seems to suggest it uses codons extremely similarly to its neighbors, and that it doesn't use CGG often or at all. It says never: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173453/
but that's just in the isolates they're analyzing.
"All human coronaviruses analyzed in this study did not use two synonymous codons (CGC, CGG) for arginine as well as CCG for proline and UGA for stop codon at all"
The money shot is in figure B. I think Yuri in his write up is just using a random one-off sequence of SARS-2 that showed up /later/ in the pandemic. It isn't in the earliest released sequences from Korea or Wuhan or Iran (https://www.ncbi.nlm.nih.gov/nuccore/NC_045512.2) (https://www.ncbi.nlm.nih.gov/nuccore/MT126746.1) (https://www.ncbi.nlm.nih.gov/nuccore/MT121215.1). It only shows up in later sequences. It could be a result of adaptation to humans for the weird non-human cleavage site.
I couldn't find CGG in the cleavage site sequence anywhere in the early pandemic. Not in any of the earliest papers.
I could only find it in clinical sequences from later on in the pandemic, suggesting it may have been a random mutant that fixed /after/ the emergence into humans. Which pokes a big ol hole in the idea that it represents a smoking gun of genetic manipulation:
-https://www.ncbi.nlm.nih.gov/nuccore/MW269555.1 -https://www.ncbi.nlm.nih.gov/nuccore/MW672572.1
I shouldn't have taken it as a given that CGGCGG was actually there in the beginning. Looks like it wasn't It certainly isn't in the refseq.
And the thing I'm asking here is: Are you really saying you think the lab leak is /as probable/ as the zoonotic crossover? Given that the A) the CGGCGG wasn't even there when the crossover happened, B) the probabilistic arguments I've made above, and C) the fact that you can't provide any actual evidence of a mechanism? I gave you lots of mechanisms and examples of how it would happen in nature. Why is one not more likely than the other?
Hi I made this exact calculation (as have others). You can find it here: https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
Here's an excerpt of the important bit:
>>>>>>>>>>>>
SARS-CoV-2 is mutating at the rate of about 2 changes/month (68,69,70,71), out there in society, circulating in millions of humans. 2/month in the overall population of millions of tiny viruses, among 30,000 letters in each genome.
So, at the fixation rate (~2 fixed mutations/month), with all the many billions of SARS-2 viruses making copies inside all those people, how long would it take to change RaTG-13 into SARS-CoV-2?
Answer: about 50 years. 30 years before the world even knew about SARS or MERS or any other pandemic-potential coronavirus. Before we knew these viruses even existed. Before we knew they liked to live in bats (72,73,74,75). And, for the record, they didn’t even build a BSL4 (the kind of lab you really need to handle this kind of virus in animals) in Wuhan until 2016 (76).
And that estimate (50 years) is with all the many mutations that are happening in all the many infected humans during a pandemic situation.
We know that with a smaller group of lab animals (or even human subjects), the virus is much slower at “finding” mutations that “stick around” (77,78). You have to picture it kind of like a big room full of millions of slot machines. Each machine is a virus, pulling the lever each time it makes a copy of itself. And you only win a payoff when you’ve found a change in the virus that A) makes it look different, and B) doesn’t screw it up, so it can still survive and do its job (infect people). A lot of these mutations screw the virus up, so they wouldn’t be a payoff. They wouldn’t be a “fixed” mutation.
>>>>>>>>>>>>
We can't just focus on random mutation, we have to think about fixation. Because virus populations don't just evolve in one concerted direction. They evolve /outwards/ in a cloud. It's not simply A to B, it's A to B then back to A then over to C then to D, then back to B, then over to A again, then finally settled on C. A random walk.
That's why the population level data is so important.
> How many of those are in frame for an amino acid? How many of those are two in frame for arginine in a protein, next to each other?
Who said recombination events only happen in frame? Or that viruses only drift in frame?
> There are many reasons why it's unlikely. The first is pure statistics. But the statistics are almost certainly influenced by millions of years of biology.
I would respond to this if it contained any evidence other than 'statistics say it is so.'
> I don't think it's in the scientific spirit to discount other viable hypotheses.
Who said I'm discounting anything? I said it's just not very likely. Extraordinary claims require extraordinary evidence.