Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2?
biorxiv.org
biorxiv.org
It's important to know whether or not the authors picked BsaI & BmBI blind, before looking at the genome. If they picked BsaI & BmBI with knowledge of the SARS-CoV-2 genome, that doesn't dodge the multiple comparisons problem and the p-values aren't reliable. I guess it depends on how many other commonly used type IIS endonucleases there are. The authors use 214 to generate their null hypothesis distribution for the CoV restriction maps but say only 6 are specifically amenable to BAC cloning.
The "wild type distribution" null distribution for fragment length (Figure 3C) being a simulation (permutation of known CoV genomes, split at randomly selected restriction sites) bothers me. On the first read I thought it was a distribution of fragment lengths in real viruses. Does synthesizing virtual genomes by permutation produce a realistic distribution of fragment lengths?
You could never convince me that these restriction enzymes were picked blindly, no bioinformatician I have ever met does science this way. There is a preliminary period of exploratory data analysis which is done before any hypothesis is put forward, and data dredging and leakage are rampant in the literature.
That's not to say that the spacing of BsaI/BsmBI restriction sites isn't noteworthy, just something to keep in mind.
To your point however, could someone comment on the suitability of BsaI/BsmBI for the in vitro assembly of synthetic coronaviruses? Is it all just about finding sites in the genome at the right locations which can be turned into restriction sites without disrupting any existing functional genetic elements? or is there more to it than that. If a research team were to come along and decide they wanted to engineer their own coronavirus, how likely would it be that they would choose these restriction enzymes?
These are very commmon enzymes. Perhaps the most common today.
The GP comment is sort of misleading...you wouldn't just pick enzymes at random to do this analysis. You'd pick the enzymes in common use. These count.
> Is it all just about finding sites in the genome at the right locations which can be turned into restriction sites without disrupting any existing functional genetic elements? or is there more to it than that.
You can add or remove sites using different techniques, such as PCR mutagenesis.
> If a research team were to come along and decide they wanted to engineer their own coronavirus, how likely would it be that they would choose these restriction enzymes?
Highly likely.
I said pick blind, not at random. I recommend reading https://info.umkc.edu/drbanderson/p-hacking-and-the-problem-...
To fairly make a critique like that, you need to have at least some evidence that a selection bias was applied for no other reason than to affect the p-value. Otherwise, literally every study can be accused of "p-hacking". Here, there's a very good, obvious explanation for the choice that they made, and therefore all you can really say is that the results might be different if you looked at a different set of enzymes.
BsaI has been used in high throughput assembly techniques such as Golden Gate assembly and Golden Braid assembly.
Golden Gate assembly is an extremely robust method for building modular genetic components. For example, one can create plasmids (circular pieces of DNA) with billions of variants of the spike proteins, each carrying a different combination of mutations. Then, those plasmids are transfected into corona viruses and incubated in a tissue culture. Now, one usually let natural selection do its thing and the most infective variants replicate in the tissue much faster and take over the population.
Having said all that, type 2s restriction sites usually are cut out during assembly so I'm not sure how having those is a good evidence for engineering. Actually, the opposite is true. Having none at all is one evidence which is very much suspicious
First and foremost the central claim is that 5 potential restriction binding sites versus 2 means that SARS-CoV2 is non natural. That does not necessarily follow. Just as SARS-CoV2 is unusually infectious and damaging to humans it could just happen to have an additional 3 restriction binding sites. So there is nothing inconsistent with natural selection of viral characteristics, only a comparison between wild and lab viruses.
Second, the evidence for the wet market origin is trivialized. That argument points out that genetic drift is well characterized and the presence of two closely related SARS-CoV2 variants cultured from the wet market is extremely strong evidence that is where the virus initially appeared. Both arguments make use of detailed genetic evidence, but the wet market argument based on genetic drift is quite robust while this alternative theory merely presents similarities while not ruling out natural selection.
Thirdly, this paper emphasizes the strong impact of the COVID pandemic and asserts that understanding the origins of the virus would necessarily aid in preventing future pandemics. This does not clearly follow. Especially if the virus had natural selection origins there is no clear and obvious way of systematically reducing risk. Simply living or traveling where host populations like bats live could be enough to generate exposures and it is not simple to clear people off of rural habitations.
These second and third criticisms are not direct against the evidence and logic presented, but show a dangerous level of sloppiness in the research that makes this paper appear more like slanted analysis from someone with an agenda than a critical thinking scientist genuinely interested in the truth and therefore needing to consider alternatives and potential falsification of the hypothesis.
OP _literally_ said that.
Just because "show a dangerous level of sloppiness in the research" was used in both sentences does not mean they are saying the same thing at all.
The OP's second and third criticisms were:
"the evidence for the wet market origin is trivialized."
and
"Thirdly, this paper emphasizes the strong impact of the COVID pandemic and asserts that understanding the origins of the virus would necessarily aid in preventing future pandemics. This does not clearly follow."
While "saying that the pandemic was a bad thing and that there is value in understanding its origin" might approach a summary of the third criticism it doesn't address the second - more serious - criticism at all.
"Additionally, because the final product does not have a Type IIS restriction enzyme recognition site, the correctly-ligated product cannot be cut again by the restriction enzyme, meaning the reaction is essentially irreversible"
https://en.wikipedia.org/wiki/Golden_Gate_Cloning ----
The choice of focusing on a particular RE pair also smells of p-hacking. Their claim that BsaI/BsmBI makes for easy mixing/matching genomes doesn't make sense in this day and age, when you can use other techniques to make hybrids more effectively (eg, you are not restricted to the natural location of those restriction enzyme sites)
https://twitter.com/jbkinney/status/1583267221047869441
https://twitter.com/jbkinney/status/1583248052969562112
https://journals.plos.org/plospathogens/article?id=10.1371/j...
EDIT: Kinney also asserts here that they left the sites in a final assembled genome (i.e., the genome of a replication-competent virus). I'm still trying to figure out if that's true, though.
I assume you're referring to Pekar et al. here? The two lineages are literally just two SNPs apart, so it's near-impossible to distinguish whether they arose from two separate introductions, or just from two super-spreading events after cryptic evolution in humans from a single earlier introduction. Pekar builds an epidemiological model that purports to find that evolution in humans is p ~ 0.5% unlikely; but that result is highly sensitive to the assumptions in that model, most notably their choice of a scale-free infection network (and thus power-law distribution of number of other people each patient infects). Robustness to that infection network isn't studied.
The author of this endonuclease fingerprint preprint also has a preprint on Pekar's model,
https://www.biorxiv.org/content/10.1101/2022.10.10.511625v1
Note that I'm criticizing Pekar here, not endorsing the endonuclease preprint. I don't have a great sense of the correct Bonferroni correction (to borrow Prof. Balloux's framing) to apply to the latter's probabilities.
I strongly disagree. If of natural origin, there are a plethora of simple controls that could be implemented. Control doesn't necessarily need to be perfect. Some simple controls could be restrictions or bans on Commercial trade or transport of high-risk animals. If not of natural origin, it obviously indicates that BSL4 controls are inadequate or inconsistently applied. A simple but perhaps costly solution might be to not certify bsl4 Laboratories in dense Urban settings.
> A: The coronavirus research in our laboratory is conducted in BSL-2 or BSL-3 laboratories. [...]
https://web.archive.org/web/20210727042832/https://www.scien...
Typically you're more concerned about what's getting into your BSL-2 hood than out.
That claim is not in the paper at all. The argument is based on the length of longest fragment and could apply to any number of restriction binding sites.
"the evidence for the wet market origin is trivialized."
It's a statistical analysis of viral genomes. The wet market evidence is unrelated.
Your third point is arguing in favor of ignorance and defeatism. "there is no clear and obvious way of systematically reducing risk" because we do not understand the origin. If we did, there may very well be; e.g. restrict trade in civet cats. Simple actions like this have controlled pandemics in the past.
https://www.sciencedirect.com/science/article/pii/S009286742...
>Failure to comprehensively investigate the zoonotic origin through collaborative and carefully coordinated studies would leave the world vulnerable to future pandemics arising from the same human activities that have repeatedly put us on a collision course with novel viruses.
https://www.nature.com/articles/s41591-020-0820-9
> Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events.
No, you've completely misunderstood the analysis. The number of restriction sites is not what is important. It's the location of the sites, and the spacing between them. This is suspicious, and has a high degree of variability, as is shown in Figure 3c. They also generated 100,000 random mutations to RaTG13 and BANAL52, and found that only ~1.2% and 0.1% of these, respectively, had restriction maps as deviant as the one found in SARS CoV2 (Figure 4).
The spacing here alone is suspicious, but couple with the number of synonymous (silent) mutations, and you're looking at an outcome extremely unlikely to be found in nature.
https://www.biorxiv.org/content/10.1101/2022.10.18.512756v1....
Extremely unlikely events happen when an extreme amount of attempts are made, and natural selection amplifies them if they increase fitness
From the layperson article:
> In wild viruses, these cutting/pasting sites are randomly distributed because there's no evolutionary pressure for the virus to be thusly cut and pasted in nature. In infectious clones, however, the humans behind the screen tend to modify restriction sites in a regular way. For any given restriction enzyme or set of enzymes, the set of all cutting sites is called the “restriction map”, and looking at these restriction maps helps us see the fingerprint of infectious clones.
> It turns out, the sticky ends produced by BsaI/BsmBI digestion of SARS-CoV-2 are all unique, non-palindromic, and all contain at least one A or T - all criteria either required or recommended for in vitro genome assembly.
One of these premises is that their work properly models reality, there seems to be a lot of well informed doubt by subject-matter experts.
Another is that an event with a probability of 0.1-1% is exceptionally rare, its occurrence thus being most likely artificial, and with that I disagree, by looking at endless counter-examples nature provides.
Is the fact that humans found some optimization a proof that any occurrence of it is man-made? I believe most people would say it isn't.
The model is fine. There's no more "well informed doubt" than for any other paper. You can certainly debate the details of what they did, but none of this debate is substantial enough to invalidate the work.
What you're seeing is a group of people who have largely pre-judged the outcome, inventing reasons to reject an experiment that disagrees with their prior conclusions. This always happens, in any scientific domain. Nonetheless, there are also a large number of well-informed people who see this as an interesting result. If you don't listen to both groups, you will be misled.
This could also be selection pressure - right? Ie imagine 99,000 yield viruses that are non viable… you’d see the same behavior of rare traits being common.
But regarding your broader question: there's no reason to believe that thesse viruses experience any selective pressure for the number or location of cutting sites of the particular enzymes being investigated here. They're bacterial enzymes, entirely unrelated to coronaviruses.
> Recap: BsaI/BsmBI are particularly useful restriction enzymes to use if you wanted to study a bunch of chimeric coronaviruses like the close relatives of SARS-CoV-2. The SARS-CoV-2 BsaI/BsmBI cutting sites look regularly-spaced (ish). The maximum fragment length is in the bottom percentile of all CoVs digestions in the idealized fragment-number range, the bottom 0.07% for all type IIS digestions within the idealized range, and the number of fragments is also in the idealized range. The SARS-CoV-2 BsaI/BsmBI restriction map looks a lot more like known pre-COVID infectious clones than a wild coronaviruses. All sticky ends are unique & meet other nice criteria for good assembly. All mutations separating these sites from close relatives are silent, and there’s a significantly higher rate per nucleotide of silent mutations within BsaI/BsmBI recognition sites than the rest of the viral genome.
> The odds of meeting any one of these criteria vary, from 1%-0.07% of having such a small maximum fragment length to 1/250 to 1/100 million odds of having such high concentration of silent mutations within BsaI/BsmBI recognition sites. The odds of meeting every single one of these criteria are even smaller. Much smaller.
https://alexwasburne.substack.com/p/a-synthetic-origin-of-sa...
So it's not just "5 vs 2" sites, it's the spacing of the sites, the fact that the site mutations are silent, and the fact that the "sticky ends" are unique.
This paper should move your needle toward "synthetic origin". Similar to how some other papers published in the last few months (the wet market paper among them) should have moved your needle toward "natural origin".
Exterminating all the bats is an option. It would be our first purposeful extinction and would no doubt cause many problems. We need to at least weigh up the possibility. Then we can run the risk benefit analysis.
Smallpox? And extinction of Guinea worm is in process.
Is that true? I mean I understand why people would be curious, but does it really matter, in terms of what we need to do? We know that viruses _can_ spillover from animals to people, and we know that viruses in a laboratory setting _could_ plausibly get released in an accident. In terms of what we need to do to prevent (as far as possible) it happening in the future, I don't know that I believe that the answer to which one happened in the case of covid-19, is all that important.
Again, I see why people would care. But as long as we know that both are realistic possibilities (and we do), it doesn't matter moving forward.
I saw Marc Lipsitch give a talk with a back-of-napkin "Expected mortality from gain of function research" estimate in...I want to say 2013.
We know there's zoonotic spillover events of a number of scary pathogens, including the last two epidemic coronaviruses.
In a global sense of preventing future pandemics, an either/or framing is immensely flawed.
Not to mention if your goal is just to point out the ethical lapses of the Chinese government, you don't really need any extra ammunition.
You can't have go unpunished specialists conspiring (or at best, just unconsciously covering their ass) when they're the ones that are supposed to be on the front lines preventing and fighting epidemics !
P.S.: Wow, I just remembered... this lampooning hits quite differently now !
Evidence of lab negligence should not become a reason to neglect or defund research and prevention about animal spillover risks. Unfortunately, the two problem classes are synergic rather than mutually exclusive.
If we knew that this pandemic came from a lab, that would have massive implications for how tightly we control this type of lab research - both in terms of whether we do the gof research, and also in how we run and regulate the labs. Surely you can imagine the reaction if, hypothetically, the world knew that this coronavirus was made in a lab and then escaped?
I'm amazed that you think otherwise - it's one of the nice things about hn that I occasionally encounter views that are so different from my own.
It is when literally this week a version with an 80% kill rate but with the spread of the most transmissible was made in a lab for no good reason.
How many would die if that leaked out and the only reason it’s been made is just so some academic can get their name in a paper and earn some grant presumably.
The idea of we just have to trust that these labs are secure and competent enough when the fact they’re even making something so deadly raises questions about their competence. We need to start judging the people making these things with the potential to kill millions the same as we would anyone else building something that had the potential to kill millions.
I don’t see why playing with Weapons of Mass Destruction in a random lab is just considered fine when the weapon is invisible and can live inside your body or a mouse. At least Fat Man and Little Body couldn’t be carried off base by a single person.
Experts on the matter (I read a book recounting smallpox research, not a domain expert myself [0]) were concerned more about the publishing of that research than about the research being done, since proliferation is deemed very easy in the field. You don't need resources as with nuclear weapons to reproduce research like that.
(Edit: typo)
[0] The Demon in the Freezer by Richard Preston
It will not be 100% efficient, but reduction can be achieved.
An 80% kill rate of mice that are genetically engineered to express human ACE genes. For comparison, the original SARS-CoV-2 strain killed 100% of those humanised mice. Those rates aren't the same among human populations.
It was a modified version bringing the kill rate down from 100% to 80% in lab mice specifically bread to be weak to this virus.
Obviously if it is possible that COVID came from a lab then we should act as though it did - the best case is these labs are catastrophes still waiting to happen. And I suspect so is the web of international travel we've built up over the last few decades.
But at a population level, the human race can't process the implications of that. People are profoundly evidence based - we won't see action until there is evidence that a risk is manifesting. Which is possibly why people care about whether COVID originated in a lab or outside one.
> "The evidence we find is independent of other genomic evidence suggestive of a lab origin of SARS-CoV-2, such as the furin cleavage site (FCS) found in SARS-CoV-2 yet missing from all other known sarbecoviruses. However, the BsaI sites in SARS-COV-2 flank the S1 gene and S1/S2 junction, and a similar design has been used before for substitutions in this region. The restriction map alone also does not indicate the lab of origin."
> 100,000 random in silico mutants were generated for both RaTG13 and BANAl-20-52...Only 1.2% of RaTG13 mutants resulted in a BsaI/BsmBI restriction map with a larger z-score than SARS-CoV-2. BANAL52 is the closer relative to SARS-CoV-2 by over 200 nucleotides, yet only 0.1% of mutants yielded z-scores as great or greater than SARS-CoV-2
1.2% of 100,000 is a weird way to express an occurrence rate. Because 1.2% is a little over 1 in 100. Which means from random perturbation they generated almost 1,200 candidates which would also match their conclusions. The 0.1% mutant number would still be about 100, by sheer random chance.
They also don't support this argument with any reference to the observed mutation rates of any of their candidates in the environment. How often, in nature, do we expect a new mutation to arise? They claim to use data for nucleotide substitution frequencies, so they're addressing the fact that mutation is a process with a temporal component, but not what the time span is.
If 1 in 100 commercial jetliners crashed every year, we'd regard that as so common as to make commercial aviation unsafe.
They then conclude:
> It’s unlikely such an idealized reverse genetic system would evolve by chance from the close relatives of SARS-CoV-2
From 1 in 100 occurrence rates? Of a virus?
Now we do in fact have data on how frequently viral mutation happens. During cell cultures it appears to be about at a rate of 9e-7 substitutions per nucleotide per replication cycle of 12 hours for RaTG13 (reproduced from culture in animal tissue too[2]). With a ~29,800 BP genome, that means 0.02 nucleotide substitutions on average per replication cycle. So about 25 days for a single virus strain, serially replicating, to substitute 1 base pair.
Of course, this is all ignoring the fact that viral mutation is highly parallel - which they also do not mention in reference to this conclusion. How many mutations are necessary to generate a z-score match which would fool their detection method? 1, 2, 10? How many potential restriction enzyme cleavage sites exist which would become cleavage sites by a single base-pair flip? What's the dynamic addition/removal rate of restriction enzyme sites expected to be? We have per nucleotide estimates for this for RaTG13, so it's also not an independent variable: to achieve the distribution of cleavage sites they propose, what is the mean-number of mutations for it to happen in the 1 in 100 candidates which achieved it? A virus doesn't explore it's mutation space serially, it explores it in a massively parallel way every single replication cycle.
This paper leads with some very specific claims, is based purely on simulation, and fails to ask obvious control questions based on it's own methods.
[1] https://doi.org/10.1371/journal.ppat.1000896 [2] https://doi.org/10.1371/journal.ppat.0030005
The real question is how probable it is if such a naturally mutated virus actually develops into a pandemic. First it has to spawn from nature and then it also has to be lucky enough to cause a pandemic.
You have to multiply those two probabilities as well. And only then you have a model that can be compared to what happened with the SARS-CoV-2, is it still that likely to be a natural spill over?
Is this going to be yet one more of those “will be withdrawn after peer scrutiny but by then it is too late because the false meme has been injected into the public consciousness” things?
"Scientists publish papers not because the paper is the end of science, but because it is a unit of research that is valuable to share with others so that others can use this brick of knowledge and either build with it… or find its weakness and break it down...We wrote our entire analysis in R and shared our code with the world. I tried SO hard to check every single line of code and make our pipeline clear & easy to reproduce. However, despite nearly giving myself stomach ulcers checking every line and stressing about these findings, it’s possible someone finds a mistake in our work. We don’t share this work happily - this is the saddest paper I’ve ever written. We’ve shared our code precisely for that reason: we want you to see exactly what we’ve done, and if we’ve done something wrong we are open to hearing it."
As to your original concern, it is a valid one. I wrote this is response to pre-prints popularized via the press earlier this year:
-> Make bold, unjustifiable claims in the preprint; -> Ensure widespread coverage in the science press; -> Walk back those claims during peer-review; -> Get published; and then -> Watch blue checks tout original claims as "Fact!"
https://mobile.twitter.com/BallouxFrancois/status/1583165259...
https://twitter.com/matias_kaplan/status/1583235087067336704
https://twitter.com/jbkinney/status/1583267221047869441
I'd worry about their false discovery rate, for the same reason I worry about the large number of parameters in Pekar's epi model. It's still an interesting result, though.
Where did you read that? Kinney explicitly asserts the opposite, but I can't figure out what he's referring to. Someone else linked to Figure S9 from their 2017 PLOS Pathogens paper, which indeed seems not to contain the site in the final assembly. I've edited my other comment here to reflect that.
https://twitter.com/acritschristoph/status/15834864034169692...
This is the real kicker to me:
> What about missing sites? The authors propose that someone made a bizarre combination of additions and deletions of cut sites. RecCA matches SARS-CoV-2 at all missing sites because other viruses do. E.g. this one: similar to RpYN06 not just at the mutation, but the entire region.
Clear evidence of recombination across the whole region and not just mutations to manipulate the cut site.
And Francois Balloux seems to have deleted his twitter account this morning.
Jesse Bloom said he'd try reproducing with a wider range of natural viruses and potential synthetic assembly strategies. Unless and until that still gets an interesting p value, I'd agree this is oversold.
Nobody gains anything in silence however.
They only get withdrawn if they go against the narrative. Any kind of paper that says masks work, lockdowns work, or any paper suggesting Covid is worse than any virus ever… it’s totally cool to share publicly. Doesn’t even matter if it is poorly constructed or turns out to be false.
Sort of like if you shaved the fur on a hyena and discovered a "THIS END UP" tattoo on its skin.
An ironically fitting end for them would be that it is true, they get all similar research banned, and then the next virus is zoonotic and nobody is prepared for it due to not doing any research.
edit: added "ironically"
A nicer thing to wish for is that it leads to better safety an accountability protocols.
1) It makes the pandemic deterministic (bad lab security means an outbreak) instead of stochastic (wildlife spillover). That is, to be frank, even as an epidemiologist who is very skeptical of the lab leak hypothesis, a comforting thought.
2) It's a popular topic in the Substack/Medium set, because it moves the pandemic back into their wheelhouse of expertise, international relations, policy, etc. It becomes a human problem with human solutions.
3) It appeals to the contrarian mindset.
4) All of the lab leak papers at least attempt to show definitive proof. In contrast, actually finding the source of spillover events is the work of decades (and isn't always or even often successful). "Science is slow and uncertain" is a less compelling narrative.
"Bad lab security means an outbreak" is also stochastic though?
Of course if you go down that rabbithole then you might wind up concluding that the vegans have been right all along, which certain groups might find an unpalatable result.
I'm still on the fence, BTW.
Yes, much more comforting to believe that the virus originated in a lab, that a successful (so far) conspiracy has been carried out to conceal its origins, and that there will be no transparency or accountability for any of the people involved, who are likely continuing similar research today.
Is it beyond reasonable doubt that a virus created as part of a gain-of-function research programme escaped? We simply don't know definitively one way or the other, and it's rather unscientific to make blanket statements about these things one way or the other in the absence of evidence to validate the claim. (I'm an immunologist, by the way.)
The more pressing matter is the conspiracies between some top level specialists and some governments that seem to have effectively pushed public opinion away from the lab leak hypothesis (where they both can take a lot of blame) to the zoonotic hypothesis (less blame) - even though actual specialist opinion was (and still is) pretty split... (Not so much if you remove the specialists with a conflict of interest and the pressure they and the governments might have been able to exert ?)
From my perspective inside the field, a small number of specialists and a very enthusiastic lay readership have pushed the lab leak hypothesis in a way that presents far more disagreement than there actually is.
Especially when the CNRS - (which would be partially guilty in the case of a lab leak !) - published the claim that the lab leak hypothesis could not be dismissed.
But you know how paradigms work, you have to be an anti-conformist to support what is going to become the new paradigm...
And sure, there most certainly is a very enthusiastic lay readership on the lab leak side... but why do you think there isn't one on the zoonosis side ?
And especially an even bigger fraction of specialists and lay readership that aren't rejecting either ?
(It bears repeating : I'm not anti-zoonosis, since I am not competent to judge either way anyway, I just find it very worrying that there seemed to be a campaign from quite early on, when social pressure wouldn't have had as much effect yet, to outright dismiss the lab leak theory, even though among the specialists gathered at the WHO in January 2020, there was no such consensus.)
I guess it only goes to show how bubbly the Internet (and your specific sub-field bubble ?) can be...
Because showing a zoonotic origin of a disease like SARS-CoV-2 is the work of years, if not decades, and with the disruption of the pandemic to research + the political ramifications of that work, it may well already be beyond us.
I think the reason there isn't an enthusiastic readership on the zoonotic side is simply because that's how people are conditioned to think about these diseases. Everything from movies like Outbreak to Contagion, the current fuss about the emu YouTube woman, etc. primes people to think about that. It's hard to foster an enthusiastic readership for what people think they already know.
It's also not particularly...sensational. There's no smoking gun. No shadowy conspiracy. The problems that emerge from zoonoses are hard and dispersed. It makes for very bad SubStack material.
As if epidemiologists are the only profession studying stochastic phenomena. What does deterministic vs stochastic have to do with it? Every phenomena has stochastic effects.
Bad lab security is stochastic too: consider experimental security protocols; imagine them being set in year X, no protocol results in 100% security, we can only make attempts to drive down probability. Say a certain step requires tubes to be UVC sterilized with a certain fluence dose per cm^2. This was deemed suitable in year X during which experiments happened at rate R_x. This implicitly corresponds to some unknown rate of lab leaks world wide (perhaps once in a century for example). As education and automation progresses, such experiments are occurring at higher and higher rates. A possible lesson from a conclusion that it was a lab leak, and that people again underestimated the exponential curve of scientific growth could be that that security protocols be formulated in terms of the global rate of research. If theres 100x the rate of experiments compared to 20 years ago, perhaps the protocols should be tighter so that the scurity lapse rate decreases 100x as well, in order to maintain the constant tolerable global rate of lab leaks. The electrons in a flip flop may individually behave stochastically, but collectively very deterministically. The misconception -that it is safe enough if lab security protocols meet a constant per single execution safety bar- will deterministically be violated with constant growth of rate of experiments. (EDIT/ADDITION: In a world that includes the global rate of experiments, a current researcher, reading the securiy protocols of the past will find the current protocols unfairly absurd, when he realizes they are 100x more stringent, but thats because there was perhaps 10x fewer researchers in the past and 10x higher troughput of experiments; similarily a researcher at the end of his career will find the security measures to be say 100x more stringent compared to the start of his career)
> 2) It's a popular topic in the Substack/Medium set, because it moves the pandemic back into their wheelhouse of expertise, international relations, policy, etc. It becomes a human problem with human solutions.
Why does humanity like to install lightning rods? because it moves the 'act of god' lighting phenomena (and resulting fires etc.) back into their wheelhouse of expertise, policy, etc. It becomes a human problem with human solutions.
> 3) It appeals to the contrarian mindset.
There exists no such thing as the contrarian mindset. That's an epidemic idea used to silence criticism.
> 4) All of the lab leak papers at least attempt to show definitive proof. In contrast, actually finding the source of spillover events is the work of decades (and isn't always or even often successful). "Science is slow and uncertain" is a less compelling narrative.
For the average cold coronavirus (not sars cov), its very easy to detect and trace the path of a virus, its just that nobody bothers.
When a new potential epidemic is detected (just a few death and a few sick people, as the likelihood punctures the noise-floor), it was quickly traced to the cooling towers nearby the city where I live. Turns out there was negligence which allowed a microbe to prosper and infect people. Initially there was doubt about which cooling tower of which company caused the infections, but by genetic sequencing it was quickly identified which tower caused the issues. It didn't take decades, just weeks.
I'm sure this kind of talk might have been squashed, suppressed, and some people might even people got banned for saying such things?
It wasn't that back then, especially if you were following trends in that vein of research. We just had a cheeto in office, so people reached for the first shoe to dismiss it/discredit the cheeto instead of actually grappling with an intrinsically frightening, destabilizing possibility.
Also, treating anything as a conspiracy theory (a phrase coined, popularized, and cultivated during the Cold War/Vietnam era to discredit activists/leakers) by default is perhaps not the best starting point of a proper investigator. You should be going in with as few notions as can be supported by facts you can prove, or that can't be otherwise immediately disproven. The disprovable ones should only be thrown out if you are handed evidence that disproves it. Something you can't prove, bit you can't get cooperation to disprove is still on the table.
Once you have eliminated the impossible, whatever remains, no matter how improbable, must within it contain the truth. And you won't ever get there if you're putting out your eyes in the beginning.
At any rate, this particular conspiracy theory was obviously very likely to be true right from the moment it was first proposed. The analysis and data was always rigorous. This new genetic evidence is good, but the extraordinarily tiny probability of a very unusual new virus emerging right next to one of the only labs in the world doing research on that exact type of thing, already rendered it irrational to adopt the natural origin theory right from day one. You don't even need to study the RNA at all to know that SARS-CoV-2 is a very unusual event, having CoV virus labs in a city is also very unusual, that lab leaks are common, that public databases being pulled offline due to "hacking" right before such a virus emerges is very unusual, and that these things intersecting followed by suspiciously immediate and vehement denial on the back of no evidence at all is also very unusual. Estimate those probabilities and then multiply them together. The number you get is astronomically low.
But now after reading this, I searched a bit and read up on it and I guess it is still a somewhat honest debate on the topic.
Even if it was lab made, it would be sort of stupid to dig in to it, due to the political nature of the matter. What happened happened, most likely the release would have been accidental, so why play blame games.
That said, the blame game would still be there, and people would pull that card...
It’s all about blame. Blame is a useful geopolitical tool.
Because of the question of liability: If it was lab made and accidentally released, was it due to recklessness or criminal negligence? Is someone guilty of involuntary mass-manslaughter? Or if this was state-sponsored research, could they be found liable for the damage caused?
With ~7M deaths and a ~$1-10M value of human life [1], that's $7-70T in losses in lives alone, before lost productivity and economic value.
[1] https://en.wikipedia.org/wiki/Value_of_life#:~:text=In%20Wes....
A lot of countries would probably really not want to have the kind of public in-depth examination of their pandemic responses that would be necessary to figure damages.
https://www.science.org/content/article/do-three-new-studies...
>> Still, Worobey and his co-authors concede, even that evidence might not be enough to end this polarizing debate. “With the way that people have been able to just push aside any and all evidence that points away from a lab leak, I do fear that even if there were evidence from one of these samples that was full of red fox DNA and SARS-CoV-2 that people might say, ‘We still think it actually came from the handler of that red fox,’” Worobey says.
They initially claimed their evidence was "dispositive" but their peer reviewers (correctly, IMHO) made them take it out.
https://ayjchan.medium.com/evidence-for-a-natural-origin-of-...
Add that to the fact that the funding for that research lab was approved by the same guy who become the de facto thought leader on the virus in the U.S., AND funded by the foundation of one of the most recognizable American billionaires. To put the cherry on top, even suggesting a synthetic origin resulted in bans on most social platforms!
This stuff is common sense...Occam's razor comes to mind. No wonder there were so many "conspiracy theories".
I see a bright glow on the eastern horizon about 7AM and it's probably the sun coming up. It could be the first strike in a world-ending nuclear exchange. I can't prove it isn't.
... but it's probably not.
I see nothing needlessly complex here, and certainly not extraordinary.
On one hand you have the market which housed animals that throughout its history some have had and spread different coronaviruses naturally. Every prior pandemic has been believed to have been from animal to human transmission, it’s seemingly the simplest explanation.
The lab leak theory of course assumes a lab accident. Biolab accidents are fairly rare, some years have no recorded accidents, others a handful. They’ve all been successfully contained with no more than a couple fatalities each.
It’s not that it’s needlessly complex. It’s that you have a market with animals who have coronaviruses and you have a lab that studies coronaviruses. Both are reasonable explanations, but a pandemic similar to all other prior pandemics and lots of humans being exposed to lots of potential virus carriers with no protection _is_ a simpler explanation.
Having said that, I’ve remained open minded and willing to consider both reasonable and unproven. Some pandemic will be the first from a lab leak, this may have been it. We will probably never definitively know.
Put another way, the simplest explanation that fits the available evidence is most likely to be correct.
At this point it seems to me that a lab origin that superspreads at a market looks rather simpler than a market origin with double zoonosis and no trace of an intermediate host.
Double zoonosis? The virus jumped to us and then to dogs, cats, tigers, hippos, pigs, etc. 29 known species! An unfathomable triple zoonosis that happened many, many times (thousands?) over the years. I’d say double zoonosis isn’t too uncommon.
The initial SARS presumably passed from bat to intermediate host to humans in a wet market. This exact type of event happened in China just 20 years ago.
And there isn’t “no trace” of an intermediate host. There are suspected intermediate hosts but none confirmed. Similarly SARS had a couple potential intermediate hosts, and MERS had a potential intermediate host but unanswered questions around that, too. Scientists had more confidence in those theories, but still uncertainties.
Again, I think both theories are plausible. But being a repeat to what we’ve seen before _is_ simpler. When you hear hooves, think horses not zebras.
The likelihood a lab accident is independent of "all other prior pandemics", because it is not adjusted by whether there have been two natural pandemics, or two million of them. Rather, it's adjusted by the safety practices at the lab.
It's still not obvious that the wet market explanation is simpler than the lab leak. I don't see Occam's Razor making a selection here.
All throughout history viruses have spread from close animal contact with humans. Including—and I cannot stress this enough—a novel coronavirus circa 2002 that spread from bat to intermediary host to humans in a wet market in the very same country.
In comparison, for the lab leak you’re assuming a lab accident (rare), that it wasn’t noticed and quarantined immediately (even rarer), and that the wet market still randomly became the epicenter of early cases despite at that point the transmission being human to human (rare, there’d be no reason for it to be any more significant than any other place people gather).
So when we’ve never seen a significant outbreak from a lab accident (zebras) and throughout all of human history we’ve seen viruses spread to humans from close contact with animals (horses)… yes when there is ambiguity to what the cause is, defaulting to what we’ve always seen before—including literally just 20 years ago—is simpler.
The horse/zebra analogy is not so convincing within miles of a zebra breeding farm, with fences reported to be weak. Near this place, such assumptions don't carry their normal weight.
[0] https://www.voanews.com/a/covid-19-pandemic_chinese-lab-chec...
That's simply not true. There's an entire branch of virology dedicated to synthetic viruses; the first was made over 20 years ago.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113851/
>> In most bat families, both alpha- and betacoronaviruses are known, and these detections have originated from both frugivorous and insectivorous bat hosts. Lack of detection in the remaining bat families is likely due to non-exhaustive sampling of the almost 1200 extant bat species (Schipper et al., 2008, Simmons, 2005, Teeling et al., 2005). This void may be filled in future studies.
All three of these are possible. And all are compatible with your Occam's razor (and mine).
My bet is with option C.
Lab leak of a natural-origin, but tweaked, virus.
Yes, it can be both natural origin and tweaked. When you tweak something, you have to start with a something, and that something can have a natural origin.
The evidence against the lab leak appears cooked up based on data provided by interested authorities in China, and was assembled and presented by compromised people (people in the field with an active interest in protecting their own field) who actively promoted the false claim that they had no conflict of interest.
Extraordinary claims require extraordinary evidence. This is why people are skeptical.
If you’re at home and you hear loud booms, then look at the calendar and see it’s July 4, the date “explains away” the thousands of other explanations for why you are hearing loud booms.
The bats don’t need to be at all near the market, the theory is an intermediate host was in the market. A bat could infect the host population days prior or years prior. A long potential span of time.
It might be illustrative to look at MERS. They found camel populations >3,000 miles away from the outbreak with antibodies to MERS. One potential explanation is the virus doesn’t sicken camels and had been spreading in their population for a long time prior to transmission to humans.
Or we look to SARS. They did not find SARS in a bat population, but after 5 years of searching they did find a cave where all the building blocks existed. It was a couple provinces away from the outbreak. >500 miles.
So despite your beliefs, how many bats freely roaming the neighborhood may not actually be a much better probability analysis than flu viruses in Antarctica. /s
For people in the Bay Area, this is roughly equivalent distance-wise to a conspiracy theory about an outbreak at Twitter's HQ started by an "adjacent" lab in the Upper Mission that actually turned out to be in Jack London Square in Oakland instead.
But "This happening" needs to be defined for Bayes to be of any use. State clearly what you think happened and it can be judged, because as has been proven over and over again, the virus is of natural origin. So the proximity to a lab studying Coronaviruses isn't nearly as interesting given China's history with these viruses.
This is long but in my opinion, worth reading regarding the Bayesian probabilities that actually matter here: https://protagonistfuture.substack.com/p/natures-neglected-g...
What if they’d done that multiple times?
“Bias” isn’t relevant when it comes to calling out bad actors.
It is by far the simplest and most obvious explanation.
The very first synthetic virus created in 2002 and was modeled after polio, which is fairly transmissible and affects humans. That virus was made 20 years ago; synthetic biology has come a very long way since then.
Does that fact alter your opinion?
Synthetic biology (the actual synthesis of DNA) has come a long way, we don't understand all the components yet though.
As a corollary, there are unhappy accidents, and with respect to life forms in a chaotic system, such accidents can perpetuate and endure without human recognition.
This is basically the reason we can't get rid of it. Even if we had a perfect human vaccine that blocked transmission, it wouldn't help.
The existence of gain of function research shows that you are wrong.
It seems plausible, at least, that it leaked from the lab, in the sense that labs aren't magically impenetrable and leaks could happen.
> Add that to the fact that the funding for that research lab was approved by the same guy who become the de facto thought leader on the virus in the U.S., AND funded by the foundation of one of the most recognizable American billionaires. To put the cherry on top, even suggesting a synthetic origin resulted in bans on most social platforms!
I don't understand what this is supposed to mean. How does the fact that this guy (Fauci?) approved some funding make COVID seem more likely to have been leaked from a lab? It seems natural that somebody who's been working in government on medical topics at a high level for a long time would have approved funding on lots of things, and also likely that they'd become a figurehead in a pandemic, but I don't see any deeper links.
Exactly nothing in your post supports a synthetic origin over a sample from nature that got studied in a lab.
Jumping to these kinds of one sided conclusions should be a red flag.
Of course. But saying "It was studied in a lab, therefore it must be synthetic" is just idiotic and pretty much derails the entire conversation.
It derails the conversation because it conflates a number of issues that have to be assessed seperately: lab safety, mucking about with deadly deseases, and the intent to set deadly deseases free.
If you start conflating any one of these, it becomes more easy to deride the entire conversation as tinfoil hattery. If just one of those components is an easy target for derision or is seen as unlikely, everyone who dares to pick up any of the other points gets painted in the same colour in the public eye. There doesn't even need to be any evil intent behind it. It's just how people are.
And this is precisely what happened when people started pointing out the existence of a lab next to ground zero. A lot of scientists retracted their speculation on this because they were immediately put into the same category as the crowd shouting "tHe cHiNeSe made iT!!".
If they built the lab next to the viruses that were already there, then it would be reverse causation, which isn't a coincidence, but also kind of is one.
That's the meaning of "correlation is not causation".
First outbreak of SARS1: Foshan
Distance from cave containing progenitor virus in Yunnan to Foshan: 1,400 km
Doesn't anyone ask themselves why Foshan? Why not Qujing or Hanoi?
People don't take the location as some dispositive point proving the conspiracy because 15 years prior, a bat coronavirus from nearly 1,500km away infected an animal in the wildlife trade that started a pandemic in busy metropolitan area. So it doesn't seem especially unlikely for that to have happened again.
I don't think it's so unclear why we'd put that up there.
"Should we turn on the bat signal"
Which I always interpreted it to mean should we alert the authorities. A week later all posts were deleted and nothing could be found.
Why not? HN promotes logical evidence-backed discussion. The least you can do is link the forum.
The early threads are super interesting in an anthropological sense:
https://virological.org/t/tackling-rumors-of-a-suspicious-or...
Known by whom? Why? Based on what evidence? Can we know it, too?
I would truly love to hear more.