9 ms·

Endonuclease fingerprint indicates a synthetic origin of SARS-CoV-2?

274 points by johnwdefeo 4y ago

graeme 4y ago
Popular science summary of paper from one of the authors: https://alexwasburne.substack.com/p/a-synthetic-origin-of-sars-cov-2 https://alexwasburne.substack.com/p/a-synthetic-origin-of-sa...
puffoflogic 4y ago
jgeada 4y ago
So a likely extremely controversial paper being shared publicly to a non-expert audience prior to any peer-review. Is this going to be yet one more of those “will be withdrawn after peer scrutiny but by then it is too late because the false meme has been injected into the public consciousness” things?
- johnwdefeo 4y ago
  I sincerely hope not. From one of the authors: "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!"
  - iso1337 4y ago
    Any publicity is good publicity. Sprinkle in some words about "this needs further study" and hope someone comes along to fund the next few years of your lab.
  - alchemist1e9 4y ago
    Lazy question. Is there a git url for the code?
    - kens 4y ago
      To save you the two clicks, the code is at https://github.com/reptalex/SARS2_Reverse_Genetics https://github.com/reptalex/SARS2_Reverse_Genetics
- graeme 4y ago
  They did share it with scientists. Here’s Francois Balloux saying he replicated the results, tried to find holes, couldn’t https://mobile.twitter.com/BallouxFrancois/status/1583165259799412737 https://mobile.twitter.com/BallouxFrancois/status/1583165259...
  - lamontcg 4y ago
    Here's another blue check immunologist on twitter with a substantially different take: https://twitter.com/K_G_Andersen/status/1583252866394771456 https://twitter.com/K_G_Andersen/status/1583252866394771456
    - mikeyouse 4y ago
      The authors of this paper are confused about the technology they're using... it's not a good sign about their conclusions.. https://twitter.com/matias_kaplan/status/1583235087067336704 https://twitter.com/matias_kaplan/status/1583235087067336704 https://twitter.com/NoahOlsman/status/1583275862442807299 https://twitter.com/NoahOlsman/status/1583275862442807299
      - lamontcg 4y ago
        Oh dear... Yeah, the author affiliations on the title paper made me wonder if they knew what they were doing at all.
        tripletao 4y ago
        Their terminology would indeed seem wrong, but the WIV has apparently used a similar assembly strategy (leaving the sites in the final assembly) before: https://twitter.com/jbkinney/status/1583267221047869441 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.
        4y ago
- spookthesunset 4y ago
  > 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? 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.
Traubenfuchs 4y ago
- KoftaBob 4y ago
  More likely it's academic laboratories doing reckless gain of function research because it keeps the grant money rolling in, and in Wuhan Lab's case, they also half ass the safety precautions.
- ishche 4y ago
  Isn't it enough infections already to sell tons of drugs, why to design the new for this case?
  - Ancapistani 4y ago
    Well, if you own the patent on the only approved drug for the condition, it would make financial sense. NOTE: I am emphatically not asserting that this is the case with SARS-CoV-2. I am only responding to the parent comment's criticism of a possible financial motive for hypothetical biotech companies to purposefully engineer pathogens for profit.
  - funnymony 4y ago
- mrkramer 4y ago
  >So biotech companies secretly manufacturing illnesses.... They are not but they profit from lab leaks liked Covid.
jshaqaw 4y ago
throwawaymaths 4y ago
This is brilliant: it looks at the negative space in restriction enzymes cut patterns to determine the likelihood that these sites have been engineered out. I don't see details on why they picked BSM-B1 to analyze, but the only thing is if they looked at several re sites and only reported the interesting one, that alters the meaning of the statistics to the negative of the hypothesis. (I happen to believe the lab leak hypothesis -- there are receipts if you search hard, but I think we should be careful about our evidence)
jalino23 4y ago
do I understand this correctly? that the paper is saying that covid 19 is highly likely a synthetic virus?
- shadowgovt 4y ago
  It's claiming that there are sequences on the viral code that are unlikely to have occurred naturally, but are really convenient for slicing the genetic sequence in a lab context. Sort of like if you shaved the fur on a hyena and discovered a "THIS END UP" tattoo on its skin.
  - jalino23 4y ago
    oh damn! thats very interesting
  - emsign 4y ago
    Or rather: you have many hyenas without fur, and on the skin you can see scars that suggest the skin has been cut at very specific places, places where you'd normally see operation scars. Now all the discussion has come down to is how likely it is that the positional patterns and the type of scar itself could occur in nature. For example whether Hyena bites and scratches make the same scars as human scalpel.
- entwife 4y ago
  On October 18, these three scientists presented an argument with evidence that Covid-19 was created in a laboratory. Their paper has not been peer reviewed, and it is self-published. The discussion here has a couple of counter-arguments. Non-experts would do well to wait for peer review before accepting these arguments.
callesgg 4y ago
I Honestly thought it was common belief that corona come from that lab in china. 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.
- danbtl 4y ago
  > why play blame games 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?
  - pencilguin 4y ago
    What court would usefully find this? What authority would enforce it?
    - cybertronic 4y ago
      US court?
      - pencilguin 4y ago
        Against China?
    - landswipe 4y ago
      I think you'll find the wheels are already in motion (if the hypothesis is true).
- navhc 4y ago
  I don't think it's all about blame, knowing it came from a lab would also pull into question the practice of engineering viruses and the safety and security standards required.
excalibur 4y ago
Of course the lab leak origin is probably accurate, it appeared right in the vicinity of the lab and is the exact thing they were studying. This shouldn't be controversial, it shouldn't have been politicized to the point where the truth matters far less than whose narrative it supports. We should have taken it as an accident, learned lessons, improved processes, and moved on. Instead we tore ourselves apart, and now we're back to playing nuclear Russian roulette, with maybe half the chambers loaded this time. Good job humans.
fdgsdfogijq 4y ago
True story, in early January of 2020, on an academic virology forum, which I wont link, it was known the virus was synthetic. Before the story hit the mainstream media, professors were sharing data about the virus fingerprint. There were concerns about the integrity of the data shared by the Chinese. One specific comment I will never forget by a Harvard professor when discussing the implications: "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.
- shikshake 4y ago
  > which I wont link Why not? HN promotes logical evidence-backed discussion. The least you can do is link the forum.
  - RichardCNormos 4y ago
  - mikeyouse 4y ago
    He's talking about virological and making up threads that never existed. There was a lot of discussion in the early days about how it seemed possible it was synthetic based on the binding site affinity but as scientists do, they researched the literature, conferred with their colleagues and almost all came around to the virus arising via natural origin. The early threads are super interesting in an anthropological sense: https://virological.org/t/tackling-rumors-of-a-suspicious-origin-of-ncov2019/384 https://virological.org/t/tackling-rumors-of-a-suspicious-or...
    - fdgsdfogijq 4y ago
      You can claim whatever you want, I'm just sharing what I discovered
- Dig1t 4y ago
  Is there a wayback machine archive of that conversation?
m0llusk 4y ago
There are at least a couple of suspicious points in this study: 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.
- Dig1t 4y ago
  I really don't see how saying that the pandemic was a bad thing and that there is value in understanding its origin is "a dangerous level of sloppiness".
  - _jal 4y ago
    The accusation of sloppiness is based on two claims, and you're only responding to a bastardization of one of them.
  - 4y ago
lizardactivist 4y ago
someuser54541 4y ago
Genuinely surprises me that there are people out there who think or have been persuaded the virus is of natural origin. The lab right next to the market was literally studying and experimenting with the exact same type of virus. How can a someone think that that's just a coincidence? 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".
- kelseyfrog 4y ago
  My Occam's razor says that every other virus has a natural origin, why wouldnt this one too? Maybe your razor needs sharpening?
  - MockObject 4y ago
    How can you prove that natural origin is the hypothesis selected by the razor in this particular case?
    - shadowgovt 4y ago
      The point of Occam's Razor is you can't prove the things the Razor leans you to. Not in a way sufficient to remove the need to invoke the Razor. But you can say that one explanation is simpler than another (such as a pandemic virus being more closely patterned to every other pandemic in human history than to a novel mechanism that has never become a pandemic before). 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.
      - MockObject 4y ago
        I wasn't asking for a proof of the phenomenon, but a proof that the razor points to that phenomenon.
adamredwoods 4y ago
Coincidentally, Alex Washburne is also trying to get his startup going: https://selvasci.substack.com/p/coming-soon https://selvasci.substack.com/p/coming-soon
guelo 4y ago
I've seen several papers with the opposite conclusion. Why do we only see the lab leak hypothesis front paged on HN?
- astrange 4y ago
  Cynical engineers are required to believe in it because it's 1. "the opposite of the current thing" 2. contains more rationality than the other leading hypothesis (i.e. more of what happened was planned, rather than an accident) 3. and lets them blame a person rather than a bat. 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"
  - thunky 4y ago
    That's pretty dark. A nicer thing to wish for is that it leads to better safety an accountability protocols.
  - tgv 4y ago
    None of the gain-of-function research has been any help at all in the CoVID pandemic, nor in the SARS outbreaks. I also fail to see how it could have helped. What particularly helpful insight or technique came from that particular lab in Wuhan?
  - z7 4y ago
    Unfalsifiable speculation about the psychological motives of people proposing a hypothesis, a retribution fantasy on the "fitting end" for such cynical deviants, plus an inversion of what side of the investigation was subjected to censorship? Nice combo.
- Shish2k 4y ago
  Now that you mention it, I wonder if there’s any correlation between the startup-mindset (believing that success comes from hard work more than good luck), and the conspiracy-mindset (believing that disaster comes from hard work more than bad luck)...
jpeloquin 4y ago
"To avoid losing power with multiple comparisons, we focus our analysis on the BsaI/BsmBI sites in SARS-CoV-2 and compare the BsaI/BsmBI map in SARS-CoV-2 to all other restriction maps of all other CoVs used in our analysis." 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?
- yellowcake0 4y ago
  > It's important to know whether or not the authors picked BsaI & BmBI blind, before looking at the genome. 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?
  - timr 4y ago
    > To your point however, could someone comment on the suitability of BsaI/BsmBI for the in vitro assembly of synthetic coronaviruses? 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.
photochemsyn 4y ago
Looks interesting: > "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."
XorNot 4y ago
There's a line in this paper which has been cited a few times in this thread which really stands out to me: > 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 https://doi.org/10.1371/journal.ppat.1000896 [2] https://doi.org/10.1371/journal.ppat.0030005 https://doi.org/10.1371/journal.ppat.0030005
puffoflogic 4y ago
I see dang no longer bothers to comment when he editorializes a title with a "?" to indicate a non-narrative headline.
- dang 4y ago
  Sometimes I do and sometimes not. That's nothing new. I don't think it's so unclear why we'd put that up there.
rossdavidh 4y ago
The opening line: "To prevent future pandemics, it is important that we understand whether SARS-CoV-2 spilled over directly from animals to people, or indirectly in a laboratory accident." 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.
- Fomite 4y ago
  I think you have a reasonable point here. 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.
- gary_0 4y ago
  Good point. Arguing about who or what to point the finger at for SARS-CoV-2 seems more like politics than epidemiology. The evidence of a laboratory source is unclear enough, and the chance of a natural source plausible enough, that I'm not sure how the cost/benefit is supposed to work out here. 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.
  - BlueTemplar 4y ago
    Epidemiology doesn't work without taking into account politics. 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 ! https://youtu.be/9WfZuNceFDM?t=504 https://youtu.be/9WfZuNceFDM?t=504
pfisherman 4y ago
The lab leak hypothesis is the “jet fuel can’t melt steel beams” of our day.
- somenameforme 4y ago
  Or the "Iraq doesn't have WMD" of our day.
mariojv 4y ago
.
- emsign 4y ago
  I'm pretty sure the way they did science in the 24th century of a fictional TV show is slightly different from how it's done in reality.
lazyeye 4y ago
If this turns out to be true, how many cumulative man years of media coverage on this issue can we say was complete garbage?
b3nji 4y ago
Wasn't this a conspiracy theory at the start if this? I'm sure this kind of talk might have been squashed, suppressed, and some people might even people got banned for saying such things?
- jonnycomputer 4y ago
  It is a conspiracy theory until you have good data and rigorous analysis. If you cannot see that people resisting jumping on an emotionally appealing bandwagon with racist undertones before careful evidence is collected on it, then I honestly don't know what to do for you.
  - salawat 4y ago
    >If you cannot see that people resisting jumping on an emotionally appealing bandwagon with racist undertones 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.
  - origin_path 4y ago
    It is still a conspiracy theory, because it theorizes the existence of a conspiracy designed to cover up the true origins of SARS-CoV-2, it just happens to be a theory that is almost certainly true. The conflation of the term "conspiracy theory" with an entirely separate meaning of "untrue claim" is a huge problem, exactly because it is used as an excuse to censor people who are pointing out where conspiracies are likely to be hiding - a highly valuable and useful activity that society should encourage! 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.
doener 4y ago
Criticism: https://twitter.com/k_g_andersen/status/1583252858740219906 https://twitter.com/k_g_andersen/status/1583252858740219906

274 points by johnwdefeo 4y ago

Popular science summary of paper from one of the authors: https://alexwasburne.substack.com/p/a-synthetic-origin-of-sars-cov-2 https://alexwasburne.substack.com/p/a-synthetic-origin-of-sa...

puffoflogic 4y ago

jgeada 4y ago

So a likely extremely controversial paper being shared publicly to a non-expert audience prior to any peer-review. 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?

johnwdefeo 4y ago
I sincerely hope not. From one of the authors: "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!"
- iso1337 4y ago
  Any publicity is good publicity. Sprinkle in some words about "this needs further study" and hope someone comes along to fund the next few years of your lab.
- alchemist1e9 4y ago
  Lazy question. Is there a git url for the code?
  - kens 4y ago
    To save you the two clicks, the code is at https://github.com/reptalex/SARS2_Reverse_Genetics https://github.com/reptalex/SARS2_Reverse_Genetics
graeme 4y ago
They did share it with scientists. Here’s Francois Balloux saying he replicated the results, tried to find holes, couldn’t https://mobile.twitter.com/BallouxFrancois/status/1583165259799412737 https://mobile.twitter.com/BallouxFrancois/status/1583165259...
- lamontcg 4y ago
  Here's another blue check immunologist on twitter with a substantially different take: https://twitter.com/K_G_Andersen/status/1583252866394771456 https://twitter.com/K_G_Andersen/status/1583252866394771456
  - mikeyouse 4y ago
    The authors of this paper are confused about the technology they're using... it's not a good sign about their conclusions.. https://twitter.com/matias_kaplan/status/1583235087067336704 https://twitter.com/matias_kaplan/status/1583235087067336704 https://twitter.com/NoahOlsman/status/1583275862442807299 https://twitter.com/NoahOlsman/status/1583275862442807299
    - lamontcg 4y ago
      Oh dear... Yeah, the author affiliations on the title paper made me wonder if they knew what they were doing at all.
      - tripletao 4y ago
        Their terminology would indeed seem wrong, but the WIV has apparently used a similar assembly strategy (leaving the sites in the final assembly) before: https://twitter.com/jbkinney/status/1583267221047869441 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.
        4y ago
spookthesunset 4y ago
> 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? 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.

Traubenfuchs 4y ago

KoftaBob 4y ago
More likely it's academic laboratories doing reckless gain of function research because it keeps the grant money rolling in, and in Wuhan Lab's case, they also half ass the safety precautions.
ishche 4y ago
Isn't it enough infections already to sell tons of drugs, why to design the new for this case?
- Ancapistani 4y ago
  Well, if you own the patent on the only approved drug for the condition, it would make financial sense. NOTE: I am emphatically not asserting that this is the case with SARS-CoV-2. I am only responding to the parent comment's criticism of a possible financial motive for hypothetical biotech companies to purposefully engineer pathogens for profit.
- funnymony 4y ago
mrkramer 4y ago
>So biotech companies secretly manufacturing illnesses.... They are not but they profit from lab leaks liked Covid.

jshaqaw 4y ago

throwawaymaths 4y ago

This is brilliant: it looks at the negative space in restriction enzymes cut patterns to determine the likelihood that these sites have been engineered out. I don't see details on why they picked BSM-B1 to analyze, but the only thing is if they looked at several re sites and only reported the interesting one, that alters the meaning of the statistics to the negative of the hypothesis. (I happen to believe the lab leak hypothesis -- there are receipts if you search hard, but I think we should be careful about our evidence)

jalino23 4y ago

do I understand this correctly? that the paper is saying that covid 19 is highly likely a synthetic virus?

shadowgovt 4y ago
It's claiming that there are sequences on the viral code that are unlikely to have occurred naturally, but are really convenient for slicing the genetic sequence in a lab context. Sort of like if you shaved the fur on a hyena and discovered a "THIS END UP" tattoo on its skin.
- jalino23 4y ago
  oh damn! thats very interesting
- emsign 4y ago
  Or rather: you have many hyenas without fur, and on the skin you can see scars that suggest the skin has been cut at very specific places, places where you'd normally see operation scars. Now all the discussion has come down to is how likely it is that the positional patterns and the type of scar itself could occur in nature. For example whether Hyena bites and scratches make the same scars as human scalpel.
entwife 4y ago
On October 18, these three scientists presented an argument with evidence that Covid-19 was created in a laboratory. Their paper has not been peer reviewed, and it is self-published. The discussion here has a couple of counter-arguments. Non-experts would do well to wait for peer review before accepting these arguments.

callesgg 4y ago

I Honestly thought it was common belief that corona come from that lab in china. 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.

danbtl 4y ago
> why play blame games 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?
- pencilguin 4y ago
  What court would usefully find this? What authority would enforce it?
  - cybertronic 4y ago
    US court?
    - pencilguin 4y ago
      Against China?
  - landswipe 4y ago
    I think you'll find the wheels are already in motion (if the hypothesis is true).
navhc 4y ago
I don't think it's all about blame, knowing it came from a lab would also pull into question the practice of engineering viruses and the safety and security standards required.

excalibur 4y ago

Of course the lab leak origin is probably accurate, it appeared right in the vicinity of the lab and is the exact thing they were studying. This shouldn't be controversial, it shouldn't have been politicized to the point where the truth matters far less than whose narrative it supports. We should have taken it as an accident, learned lessons, improved processes, and moved on. Instead we tore ourselves apart, and now we're back to playing nuclear Russian roulette, with maybe half the chambers loaded this time. Good job humans.

fdgsdfogijq 4y ago

True story, in early January of 2020, on an academic virology forum, which I wont link, it was known the virus was synthetic. Before the story hit the mainstream media, professors were sharing data about the virus fingerprint. There were concerns about the integrity of the data shared by the Chinese. One specific comment I will never forget by a Harvard professor when discussing the implications: "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.

shikshake 4y ago
> which I wont link Why not? HN promotes logical evidence-backed discussion. The least you can do is link the forum.
- RichardCNormos 4y ago
- mikeyouse 4y ago
  He's talking about virological and making up threads that never existed. There was a lot of discussion in the early days about how it seemed possible it was synthetic based on the binding site affinity but as scientists do, they researched the literature, conferred with their colleagues and almost all came around to the virus arising via natural origin. The early threads are super interesting in an anthropological sense: https://virological.org/t/tackling-rumors-of-a-suspicious-origin-of-ncov2019/384 https://virological.org/t/tackling-rumors-of-a-suspicious-or...
  - fdgsdfogijq 4y ago
    You can claim whatever you want, I'm just sharing what I discovered
Dig1t 4y ago
Is there a wayback machine archive of that conversation?

m0llusk 4y ago

There are at least a couple of suspicious points in this study: 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.

Dig1t 4y ago
I really don't see how saying that the pandemic was a bad thing and that there is value in understanding its origin is "a dangerous level of sloppiness".
- _jal 4y ago
  The accusation of sloppiness is based on two claims, and you're only responding to a bastardization of one of them.
- 4y ago

lizardactivist 4y ago

someuser54541 4y ago

Genuinely surprises me that there are people out there who think or have been persuaded the virus is of natural origin. The lab right next to the market was literally studying and experimenting with the exact same type of virus. How can a someone think that that's just a coincidence? 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".

kelseyfrog 4y ago
My Occam's razor says that every other virus has a natural origin, why wouldnt this one too? Maybe your razor needs sharpening?
- MockObject 4y ago
  How can you prove that natural origin is the hypothesis selected by the razor in this particular case?
  - shadowgovt 4y ago
    The point of Occam's Razor is you can't prove the things the Razor leans you to. Not in a way sufficient to remove the need to invoke the Razor. But you can say that one explanation is simpler than another (such as a pandemic virus being more closely patterned to every other pandemic in human history than to a novel mechanism that has never become a pandemic before). 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.
    - MockObject 4y ago
      I wasn't asking for a proof of the phenomenon, but a proof that the razor points to that phenomenon.

adamredwoods 4y ago

Coincidentally, Alex Washburne is also trying to get his startup going: https://selvasci.substack.com/p/coming-soon https://selvasci.substack.com/p/coming-soon

guelo 4y ago

I've seen several papers with the opposite conclusion. Why do we only see the lab leak hypothesis front paged on HN?

astrange 4y ago
Cynical engineers are required to believe in it because it's 1. "the opposite of the current thing" 2. contains more rationality than the other leading hypothesis (i.e. more of what happened was planned, rather than an accident) 3. and lets them blame a person rather than a bat. 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"
- thunky 4y ago
  That's pretty dark. A nicer thing to wish for is that it leads to better safety an accountability protocols.
- tgv 4y ago
  None of the gain-of-function research has been any help at all in the CoVID pandemic, nor in the SARS outbreaks. I also fail to see how it could have helped. What particularly helpful insight or technique came from that particular lab in Wuhan?
- z7 4y ago
  Unfalsifiable speculation about the psychological motives of people proposing a hypothesis, a retribution fantasy on the "fitting end" for such cynical deviants, plus an inversion of what side of the investigation was subjected to censorship? Nice combo.
Shish2k 4y ago
Now that you mention it, I wonder if there’s any correlation between the startup-mindset (believing that success comes from hard work more than good luck), and the conspiracy-mindset (believing that disaster comes from hard work more than bad luck)...

jpeloquin 4y ago

"To avoid losing power with multiple comparisons, we focus our analysis on the BsaI/BsmBI sites in SARS-CoV-2 and compare the BsaI/BsmBI map in SARS-CoV-2 to all other restriction maps of all other CoVs used in our analysis." 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?

yellowcake0 4y ago
> It's important to know whether or not the authors picked BsaI & BmBI blind, before looking at the genome. 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?
- timr 4y ago
  > To your point however, could someone comment on the suitability of BsaI/BsmBI for the in vitro assembly of synthetic coronaviruses? 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.

photochemsyn 4y ago

Looks interesting: > "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."

XorNot 4y ago

There's a line in this paper which has been cited a few times in this thread which really stands out to me: > 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 https://doi.org/10.1371/journal.ppat.1000896 [2] https://doi.org/10.1371/journal.ppat.0030005 https://doi.org/10.1371/journal.ppat.0030005

puffoflogic 4y ago

I see dang no longer bothers to comment when he editorializes a title with a "?" to indicate a non-narrative headline.

dang 4y ago
Sometimes I do and sometimes not. That's nothing new. I don't think it's so unclear why we'd put that up there.

rossdavidh 4y ago

The opening line: "To prevent future pandemics, it is important that we understand whether SARS-CoV-2 spilled over directly from animals to people, or indirectly in a laboratory accident." 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.

Fomite 4y ago
I think you have a reasonable point here. 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.
gary_0 4y ago
Good point. Arguing about who or what to point the finger at for SARS-CoV-2 seems more like politics than epidemiology. The evidence of a laboratory source is unclear enough, and the chance of a natural source plausible enough, that I'm not sure how the cost/benefit is supposed to work out here. 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.
- BlueTemplar 4y ago
  Epidemiology doesn't work without taking into account politics. 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 ! https://youtu.be/9WfZuNceFDM?t=504 https://youtu.be/9WfZuNceFDM?t=504

pfisherman 4y ago

The lab leak hypothesis is the “jet fuel can’t melt steel beams” of our day.

somenameforme 4y ago
Or the "Iraq doesn't have WMD" of our day.

mariojv 4y ago

emsign 4y ago
I'm pretty sure the way they did science in the 24th century of a fictional TV show is slightly different from how it's done in reality.

lazyeye 4y ago

If this turns out to be true, how many cumulative man years of media coverage on this issue can we say was complete garbage?

b3nji 4y ago

Wasn't this a conspiracy theory at the start if this? I'm sure this kind of talk might have been squashed, suppressed, and some people might even people got banned for saying such things?

jonnycomputer 4y ago
It is a conspiracy theory until you have good data and rigorous analysis. If you cannot see that people resisting jumping on an emotionally appealing bandwagon with racist undertones before careful evidence is collected on it, then I honestly don't know what to do for you.
- salawat 4y ago
  >If you cannot see that people resisting jumping on an emotionally appealing bandwagon with racist undertones 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.
- origin_path 4y ago
  It is still a conspiracy theory, because it theorizes the existence of a conspiracy designed to cover up the true origins of SARS-CoV-2, it just happens to be a theory that is almost certainly true. The conflation of the term "conspiracy theory" with an entirely separate meaning of "untrue claim" is a huge problem, exactly because it is used as an excuse to censor people who are pointing out where conspiracies are likely to be hiding - a highly valuable and useful activity that society should encourage! 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.

doener 4y ago

Criticism: https://twitter.com/k_g_andersen/status/1583252858740219906 https://twitter.com/k_g_andersen/status/1583252858740219906