Some things (going by memory here) that seem to support the hypothesis:
1) Major point of differentiation for this virus is that compared to it's closest known relatives, it has acquired a furin site (eukaryotic protein cleavage site) that enhances its virulence.
2) That furin site RNA contains a non-canonical amino acid codon
3) That non-canonical codon contains a restriction site that could easily be used to track, whether, say, your added furin site is surviving multiple cell passages, by performing a restriction digest and running the fragments on a cell.
Like I said above, it's circumstantial, but this is all very normal. Both adding the furin site (how does coronavirus evolve into something more virulent?) and tracking it that way. Then all it takes is someone to get infected (EVERYONE working in biology has broken at least one lab safety rule in their life, even in BSL4) and either not be symptomatic and realize, or not say anything.
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...
See under "Addendum to Q2"
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.
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.
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:
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.
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...
>I'm not going to make new ones until you provide some actual factual responses to the ones I've already made, thanks.
Considering I started the comment chain by offering a comment about biology, that you then derailed with some link to a reddit post that I fail to see how it applied, and then insinuated I'm not "a real virologist" (by the way great job just sidestepping my rebuttall to that) I'm a bit confused at this statement. If you're interested in the scientific discussion, you're welcome to have that discussion. So far all you've done is linked to a reddit post and listed some science terms, but failed to explain how any of that refutes my initial statement.
I'm kind of an idiot. Please, explain how CRISPR/Cas9 leaving off target mutation effects rules out that CoV 2 could have been genetically altered by humans in a lab. Please explain how having a bunch of Snps compared to its closest known neighbor somehow rules out that a 4 amino acid insertion was man made. Because I'm not making those connections, but then again, I'm apparently not a virologist.
I made statements. You claim to have refuted them (although 90% of your text has been questioning the credentials of others). I fail to see how you have refuted them. Maybe it's just over my head.
Edit: To get more specific:
2.1.1) You claim the virus is mosaic. True. What is not true is the conclusion you draw from that. Being mosaic does not mean that the virus isn't altered by humans. Take for instance, the furin site, which is a multiple-amino acid insertion, with a close match to, unless I'm mixing up stories, a pangolin. That hardly seems mosaic. So here's a scenario that explains that point away:
-The virus that was altered in the lab with GoF research is not derived exactly from the published RATG-13 genome. It is from a different isolate or extraction, and therefore contains a huge amount of SNPs and other mutations, something that RNA viruses can accomplish in extremely short amount of times (which we obviously both know). This could be the difference between sampling weeks apart.
And, the mosaicity (word?) of the virus does not adequately explain the furin site insertion.
2.2.1) Again, explains the mutations, not the insertion
2.2.2) Not sure what point you're making here, or how it applies to any of mine. Obviously it looks like a bat virus, probably because it is a bat virus. Still doesn't rule out the insertion of a furin site.
2.2.3) No one is suggesting that CRISPR-Cas9 was used to make the 1200 SNPs and other mutations across the genome. Obviously those could be natural, while the furin site insertion could have been done by people. Also, there are other ways to introduce mutations and insertions into RNA and DNA. Perhaps you've heard of PCR and infectious clones?
2.3) You're making a critical assumption that what was being tested and studied was a virus intended to hurt humans. (You also hilariously admit that it is the most effective it probably could be in the earlier sentence, but I'm not sure if you realize this). My hypothesis stated in my opening comment is not suggesting that.
I'm not suggesting someone took RATG-13, made 1200 SNPs and an insertion, all using CRISPR-Cas9, to design a virus to wipe out the human race.
Let me restate my hypothesis:
Someone was working in a lab, added a furin site to an ordinary coronavirus that didn't infect some type of organism, to see if it suddenly could. And guess what, it could. And oh no, it accidentally got out.
Nothing in your post refutes that in any way whatsoever. Your post is so far off in the weeds (suggesting that someone engineered 1200 SNPs into the virus, why on earth would they do that?) or that I am suggesting it was designed to be lethal to humans (I'm not) or that it's bad at being a virus because it's not lethal (which makes it a phenomenal virus) or that it's a terrible virus to study because the spike protein is promiscuous thanks to its furin site (which makes it good at jumping species which is a great reason to study that promiscuity).
Your argument flat out does not apply to my hypothesis, which is why I assume you have wasted most of your breath attacking the credentials of the people criticizing it.
I'm only gonna address the science in your post from here on out. I want to make it clear I never insulted you or attacked your character, I only said I had no way to know you were a virologist and only could go off of your word.
I get your hypothesis now that you have fully stated it.
And here are some questions that need answers.
Where did they get the virus? It's not anything like any coronavirus we know of before SARS-CoV-2 emerged in humans, it's 1200 away from RATG-13.
What experimental question were they trying to answer? We already know that the furin cleavage site is necessary for some aspects of pathogenicity, but not the ones canonically thought important (cell entry for SARS-1 for example, since furin doesn't actually cleave SARS-1 or MERS). Why would they test a random unrelated coronavirus' site? Why not try the SARS-CoV-1 site? Or the MERS site? Why was it a furin site in the first place? And why did they do it on the weirdly promiscuous SARS-2 ACE2 and not in a virus like RATG-13?
Re: cleavage site, I go into extreme detail about how possible it is for cleavage sites to evolve in nature here and here:
-https://www.reddit.com/r/science/comments/gk6y95/covid19_did...
-https://news.ycombinator.com/item?id=26757881
It's really not that unusual for a cleavage site to evolve in nature, and especially not when we consider that furin cleavage sites are mutagenicity islands. It absolutely could have evolved from recombination with a distantly related coronavirus that has an extremely similar site.
Also, the cleavage site isn't even that long. Short stretches of nucleotides like that, upwards of 15-30 nucleotides, can absolutely evolve over the course of 50-70 years. Happens literally all the time. In influenza it happens on much shorter time scales. I provide evidence to that effect in the above posts.
Yes I actually address the idea of using recombinatorial cloning to make SARS-CoV-2 at several points in my post.
Nothing about the furin cleavage site makes it more likely to be unnatural than it is natural?
And so far, I don't see any compelling reason to believe that anyone would take a completely undiscovered and undescribed virus out of nature, not describe it or publish on it at all, and then start inserting random furin sites into it from random other coronaviruses.
Why would they be doing that? Is it technically /possible/? Yes, but I see no reason why it is more likely than a natural emergence.
Unfortunately that is impossible for two reasons:
1) Because you have inextricably tied your argument to who you are with lines like: >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.
2) Because you refused to present your argument here in a way that stands against my hypothesis, and instead relied on simply introduction of yourself and your credentials.
>Where did they get the virus? It's not anything like any coronavirus we know of before SARS-CoV-2 emerged in humans, it's 1200 away from RATG-13.
1200 mutations away from RATG-13 is how significant exactly? I will propose that it is not particularly significant. One virus I work with, I have 14 variants ranging from 300 to 500 base-pair differences. That is from passing in a laboratory only. I have one variant that has a 14000 BP deletion! (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217056/#mmi144... TABLE S2) However, it is noteworthy for that reason. That said, these are dsDNA viruses with comparatively much slower mutation rates. 1200-base differences are almost nothing.
>Why would they test a random unrelated coronavirus' site? That's a good question, and not one that I can answer suitably with this hypothesis. Perhaps because they were looking for a cleavable one?
>And why did they do it on the weirdly promiscuous SARS-2 ACE2 and not in a virus like RATG-13?
To me this is obvious. SARS-2 ACE2 is extremely promiscuous. That's a very good reason to study it - it has broad potential for cross-species jumps. If you are trying to narrow down what it is that causes the jump, you want to study on the virus that is most capable of making that jump.
>Re: cleavage site, I go into extreme detail about how possible it is for cleavage sites to evolve in nature here and here:
Again, I don't think that applies my hypothesis. Of course it had to evolve in nature. Otherwise there would be no furin site. The ability of a furin site to evolve in nature has almost no bearing on whether or not one could be inserted into coronavirus by humans, unless I'm totally misunderstanding what you're suggesting here.
>Also, the cleavage site isn't even that long. Sure, and again, this furin site likely did evolve in nature (at least in amino acid form). Whether or not it evolved in coronavirus is the topic here.
>Nothing about the furin cleavage site makes it more likely to be unnatural than it is natural? The two non-canonical arginines don't make it less likely?
>And so far, I don't see any compelling reason to believe that anyone would take a completely undiscovered and undescribed virus out of nature, not describe it or publish on it at all, and then start inserting random furin sites into it from random other coronaviruses.
I have some of viruses I work with I haven't published on yet, because I am either waiting to complete work, or they aren't significant enough compared to their peers for me to publish on them.
>Why would they be doing that? Is it technically /possible/? Yes, but I see no reason why it is more likely than a natural emergence.
OK so that's the crux of my argument. There's some interesting anomalies that point to it being a possibility. There's no way to rule it out. At the end of the day, it comes down to one opinion vs another, which is why statements like:
>The virus itself, to the eye of any virologist, is clearly not engineered.
...are so infuriating to me.
It comes down to occam's razor.
Sure, is it /possible/ that some scientist in a lab decided to use an entirely unknown and undescribed natural virus as the subject of their experiments? And use a completely out of nowhere cleavage site from a distant coronavirus that nobody talks about or really studies to do it? And then that virus escaped?
Sure.
But in order for that to be true, we need to make some new assumptions. We need to assume such a person exists, that they had that exact idea, and that it worked and they didn't tell anyone about it, or they all agreed to cover it up, and then some of them got sick (and again, covered it up) and it got out into the public, and voila, pandemic.
Or, it could have been a completely natural event that we know already happens all the time, in the contexts we know it to occur, using mechanisms that have already been described.
On a pure numbers game, on a scale of pure virus-host interactions, which do you think happens more often? People out in the provinces use bat guano as eye drops, eat bat in soups, use bat guano as fertilizer, harvest it without gloves, tour caves without any protection, etc. All of these are well-described. They are all known to occur on the scale of many thousands if not tens of thousands of events per day throughout rural China. Each one of these is a roll of the dice.
OR, how many times do we think a human contaminates themselves in a virology lab in china, working on coronaviruses? or with bats? Sure it probably happens some, but I have a hard time believing it happens more than 100 times per day in China. There just aren't that many bat colonies or virology labs.
So Occam's razor would tell us that the most likely of these two scenarios is the natural one. Is that conclusive proof? no, and I never said it was. I don't think at this point conclusive proof is possible. We're just making estimations. I've always just been making estimations.
A lab release is much less likely than a natural one, even if both are /technically/ possible.
A lot of things are /technically/ possible. On the scale of things, I think the lab leak is likely /enough/ that China should open up itself to international investigators, to show with all available evidence it probably didn't happen. But I don't think it's likely enough that we should all be condemning china, or fueling racist anti-chinese sentiment, or all the other consequences of these news stories. The consequences are right in front of you, anti-asian hate crimes are on the rise in the US, and 30+% of the US thinks the lab release is the most likely scenario.
I'm not saying we stop talking about the lab release, just that we need to put it in the proper context of probability. It is /possible/ but it really is not very /probable/.