https://bmcgenomdata.biomedcentral.com/articles/10.1186/s12863-024-01290-2

Pre-pandemic artificial MERS analog of polyfunctional SARS-CoV-2 S1/S2 furin cleavage site domain is unique among spike proteins of genus Betacoronavirus

https://jimhaslam.substack.com/p/baric-referenced-a-2017-molecular

Baric referenced a 2017 molecular blueprint for COVID-19

https://youtu.be/EmWt00ak49k?si=sMb8ZWY7Pmp7E2a0

In German. I will create an English translation soon.

Lisewski reveals explosive details about the origin of SARS-CoV-2: Furin cleavage site, PAT7 sequence & genetic anomalies that raise questions. Here is the paper:

https://bmcgenomdata.biomedcentr...

I’m sure this must be wrong…🙄

A reminder that there’s a set of questions on this topic that will actually resolve. I’m not betting on my own markets, but, in my opinion, it’s a good money making opportunity to vote yes.

My reasoning has nothing to do with expecting people to make a coherent case for lab leak and everything to do with the last month of American academia proving it will do whatever the President asks to keep their heads down and avoid becoming a target for spending cuts.

I suspect journal editors will fear being targeted in political witch hunts if they don’t send manuscripts concluding “lab leak” out for review and if they don’t publish them even if reviews are mediocre or worse.

For those not paying attention, scientific societies and universities are banning words and wiping web pages and records of previous programs. Zero reason imo to expect this to stop at language tangentially related to affirmative action and discrimination.

Are people here already familiar with the earlier draft of DEFUSE that provides more details on the plans to make a virus with the same features as COVID?
https://usrtk.org/covid-19-origins/scientists-proposed-making-viruses-with-unique-features-of-sars-cov-2-in-wuhan/

I think that combined with the information that EcoHealth facilitated gain of function research at WIV is pretty strong evidence:
https://oversight.house.gov/release/breaking-hhs-formally-debars-ecohealth-alliance-dr-peter-daszak-after-covid-select-reveals-pandemic-era-wrongdoing/

@DanielNadolny wait till you see the replies from the two usual suspects. 🙄

@DanielNadolny

1. The BsaI/BsmBI theory was disproven a month before the preprint came out in the same Twitter thread where most people learned about it (e.g. the same thread where Alex Washburne, an author of the paper, learned about it). The restriction sites are unambiguously natural. Found in viruses with shared ancestry. The opposite would be true for engineered sites.

2. Authors of the paper completely ignored this and continue to ignore it. They said they would address it once, but then decided to say that their answer is that all the other bat virus genomes (and pangolin virus genomes) must be fake.

3. SARS2 absolutely doesn’t match what’s proposed in this way. The shortest fragment from a BsmBI/BsaI digest is far shorter than any you’ll find in any coronavirus reverse genetics system — I checked them all. Retaining the sites in the construction like this has never been done before (someone might show up with a reference saying otherwise, but they didn’t read closely enough and are wrong).

4. The authors claim this is a perfect reverse genetics system. Yet, all around the world not a single lab used it. Instead, they made new systems. A global conspiracy of virologists to protect WIV? No, it’s just a shitty system. Prior work would suggest it will have problems because one fragment is generally unstable in plasmids in E. coli in previous work (Baric mentions this in his congressional testimony and it went over everyone’s head).

There’s a lot more that’s wrong in that article, but probably good just to focus on the frauds that Kopp and Ebright have promoted as proving a smoking gun.

Two other scientists were duped by the theory. Justin Kinney figured it out and decided to just never talk about it again and hope it goes away. Francois Balloux wrote a whole blog post about how he figured out it was wrong (in itself, kinda sad since he effectively copied someone else’s analysis and said it was a product of his own deep reflection).

@George what you don’t have any more tweeting bigots you can quote to add to the conversation?

@zcoli Thanks for replying, I'll look into that - If I'm understanding correctly, your response is against analyses based on covid and trying to determine natural vs human-mafe origins, rather than how closely covid matches what was in the earlier draft DEFUSE proposal, but please correct me if I've misunderstood.

How about the location of the furin cleavage site at the S1/S2 boundary?

@DanielNadolny My response is that SARS-CoV-2 doesn't closely match what was in the DEFUSE proposal. You've been duped by the fraud of Bruttel et al if you think so. Sorry.

Additionally, DEFUSE doesn't propose to insert random sequences at the S1/S2 site in random viruses. People are misreading this part of DEFUSE:

This part: "where clear mismatches occur, we will introduce appropriate human-specific cleavage sites." This means they'll make point mutations to what doesn't match. It doesn't mean they'll insert 4 new amino acids. For example, if they stumbled on RaTG13, they might've made HTQRNSR^STS to give the RxxR cleavage motif. If they stumbled onto SARS-CoV, they might've made HTVRLLRSTS. See this figure (borrowed from a fraudulent anti-vax paper I'm not going to link):

Here's an example of doing this at S2' for SARS-CoV - https://pubmed.ncbi.nlm.nih.gov/21435673/

A proteolytic cleavage site at S1/S2 isn't surprising. Inserts with similar lengths and compositions occur throughout the pandemic and occasionally increase viral fitness (maybe you've heard of CGG-CGG being suspicious? there've been CGG-CGG-CGG inserts elsewhere).

It's such a small insert that it will probably always be a bit of a mystery where it came from. It could've happened step by step with inserts of a few nucleotides at a time and various mutations. Mutate a single amino acid in RaTG13 and other viruses similar to SARS-CoV-2 and you get a predicted functional cleavage site that's predicted to be as good as the one in SARS-CoV-2 (probably it's not as good; predictions aren't perfect; no one's done the experiment afaik).

If you've ever heard the term "God of the gaps", you're looking at the world's tiniest God of the gaps. If you haven't heard the term, look it up and see how it's applicable to this question.

@zcoli

Look, I don't think you're really debating in good faith here, but this is a prediction market site, not a mathematical proof, and the point here is to reason from a position of uncertainty, not to prove something beyond all reasonable doubt (which we'll probably never get in this particular case anyway).

The point isn't that COVID is exactly what you'd get if you followed Defuse to the letter. The point is that if you tried to predict what researchers that accidentally released COVID would have put in a grant proposal, Defuse is about as close as what you'd conceivably imagine!

-Research labs typically only do about 1/2 of what they promise in grants, and only about 1/2 of what they do is explicitly laid out in the grant.

-Research labs typically begin new areas of research before they apply for and receive grant funding.

-Grant proposals are often rushed, edited incongruously by several people, and are weird mishmashes of different ideas. It's very unsurprising that Defuse would be quite similar to but not identical to the procedure or motivation behind gain of function research that could lead to COVID.

-Moreover, the phase space of lab leak includes cases where the virus is unmodified, in which case Defuse is from a Bayesian perspective even more likely in these worlds to be evidence for the possession of a COVID-like virus.

@DanielNadolny The restrictions sites thing didn't really get discussed in the Rootclaim debate, since Saar didn't think that paper was actually worth introducing as evidence. I did briefly respond in the written section of the debate, starting on slide 32 here:
https://drive.google.com/file/d/1N2IKOelaTz9c1unWGQ2VjXcFSwAPm5Xx/view

Yes, I included some ad hominem attacks. No, I don't regret it. Washburne and Bruttel do not conduct themselves like trustworthy people. Their theory doesn't make sense either, but understanding the science is kind of hard and understanding who's a bullshitter is comparatively easy -- if Bruttel thinks that monkeypox was a lab leak and Omicron was a lab leak, you might not want to also trust his paper on restriction sites.

When scientists did point out an obvious problem with his paper (the same sites were found in other natural viruses), he retreated to, "maybe those other viruses are all fake".

What's happened since the debate is someone found another document on the DEFUSE grant which describes making a virus in 6 pieces. And the Washburne/Bruttel theory also said 6 pieces.

Does that confirm that the theory was right all along?

I think the actual answer is that every paper Baric published before said 6 pieces, so Washburne+Bruttel made a theory with 6. And then when another document from Baric's lab saying 6 came up, they declared it an amazing coincidence.

But I'm not sure. I haven't read every paper on restriction sites, so I don't know how consistent the 6 segments thing is. Maybe @zcoli knows the answer.

I think the WIV didn't actually even use the same methods that Baric did, for making their viruses, but I also haven't dug into that topic enough to say for sure.

@benshindel I'm arguing in good faith. There's nothing in DEFUSE that leads to SARS-CoV-2. The Bruttel et al paper on BsaI/BsmBI is a fraudulent paper.

If DEFUSE happened even though it wasn't funded, that's evidence against an engineered lab leak! Because there's no path through DEFUSE to an engineered SARS-CoV-2.

If you want to argue for an unmodified lab leak, please do. It's far more likely. Just quit it with the intelligent design appeals to how impossibly unique the furin cleavage site is and so on. DEFUSE doesn't lend support for an unmodified lab leak, either. It describes work everyone already knows WIV was doing from their published work when it comes to sampling. It describes work that's less likely to have a lab leak that's successfully covered up than what WIV did previously, because constructing a small number of viruses from reverse genetics is both less risky than trying to isolate viruses from culturing a bunch of samples, it's also impossible to have a lab leak for a sequenced virus without leaving a huge paper trail that's hard to cover up.

@zcoli I appreciate you watching out regarding sources of information, though I'm a little confused - it looks like you're quoting from the submitted DEFUSE proposal, rather than the draft that's linked to in what I had shared, that seems to have some additional details and correspondence related to its development.

To clarify, I am not looking at sources that were examining the structure of covid and based on that, suggesting how plausibly it was to be constructed in part by human influence. From what I understand, the draft version of DEFUSE and surrounding correspondence is more specific there - is that not the case? If so, I really want to understand the discrepancy in what was claimed in the US Right to Know document and the draft proposal of DEFUSE I linked to, versus what is known about the structure of covid.

@PeterMillerc030 Hey Peter, thanks for replying. I'm a little confused, perhaps you can help clarify. From what I understand of this link, the draft proposal of DEFUSE, and correspondence surrounding it, Covid is in six segments, which is what the draft had proposed: https://usrtk.org/covid-19-origins/scientists-proposed-making-viruses-with-unique-features-of-sars-cov-2-in-wuhan/

You mentioned Baric - he is one of the collaborators with correspondence in that draft proposal.

That draft also includes figure C on page 524:

The US Right to Know article (which includes a link to the draft proposal and correspondence I'm talking about), claims that this is showing a furin cleavage site in the same place it's found in Covid.

This draft proposal and documentation seem critical for understanding the potential links between the proposed work involving WIV and Covid - is this document something you haven't yet had the chance to explore?

@zcoli you seem to be overindexing on specific technical details in the Defuse proposal.

DEFUSE proposed that a lab in Wuhan should work on gain-of-function work on bat coronaviruses to make them more transmissible between humans by inserting a furin cleavage site, in 2018-2019

We know that COVID looks like a bat coronavirus that is markedly more transmissible between humans due to a furin cleavage site, and that it emerged in 2019 in Wuhan.

The proposal from Defuse is the closest single grant proposal (that I'm aware of) to what we'd expect a grant proposal to look like at a lab where covid emerged. If you have a counterexample of another grant proposal that would be closer, feel free to share it.

If that isn't massive support from a Bayesian perspective, I don't know what is.

@DanielNadolny It's a confusing subject. I might recommend watching:
https://www.youtube.com/watch?v=FLnXVflOjMo

Download the slides, pursue various links -- read more about what furin cleavage sites are, what they do, read about previous experiments that modified one. Maybe also watch Yuri's presentation and our debate. Read and fact check as much as possible for both sides. That's a rabbit hole that will last you weeks/months, if you really want to get into this -- I was undecided on covid origins until I had spent ~3 months researching it. I gradually realized that almost all of the case for zoonosis holds up, and almost none of the lab leak stuff does.

For a shorter summary:

I think that the Washburne+Bruttel 6 segments paper does not hold up in any way.

The presence of a furin cleavage site in SARS-CoV-2 is actually interesting. That's been found in some bat viruses and other human viruses, but it has not been found specifically in other bat sarbecoviruses (out of about 1,000, I think? or that order of magnitude).

There are basically 3 options here:

1. some bat sarbecoviruses have a FCS, but it's very rare and hard to find a virus like that.

2. bat sarbecoviruses never have a FCS, but that can evolve after the virus has spilled over to an intermediate species (these are intestinal viruses in bats, but they become respiratory viruses in other species, so evolution starts to favor having the FCS)

3. scientists engineered that site into the virus.

I favor explanation 2. Most lab leakers prefer 3, a handful of scientists prefer explanation 1.

I think the FCS is basically 1 of 2 features of the lab leak theory that holds up to scrutiny (the other 1 being that there is a virology lab in Wuhan). Just about everything else about the lab leak theory falls apart, under scrutiny: the timing of the outbreak, the locations of the cases, the "3 sick researchers at WIV", the double CGG, etc.

The location of the FCS at S1/S2 is basically meaningless as evidence. There are only 2 places where you would put a furin cleavage site -- either S1/S2 or S2'. The final DEFUSE grant seems to say they were interested in S2', and some virologists who favor zoonosis said that is evidence that DEFUSE didn't make covid. Some people who favor lab leak read the new draft as interested in either spot. I think both arguments are basically worthless, because you'd be talking about odds of 1 in 2, either way.

There are several reasons why the specific FCS found in SARS-CoV-2 does not look engineered:
1. it's out of frame, when an engineer would prefer to put it in frame

2. it's inefficient (engineers prefer efficient cleavage sites like RKRR or RRSRR, while Covid uses PRRAR).
   No virology experiment in history has used an inefficient choice like that.
   The proline (P) in particular is a bizarre engineering choice that scientists would be unlikely to make. After covid spilled over, the P evolved into better choices like H and R.

3. it's an insertion, not a mutation. No virology experiment in history has added a furin cleavage site via insertion.

And there are other important ways in which SARS-CoV-2 does not match what was written in the DEFUSE grant. The DEFUSE grant says they're going to put novel spikes into known backbones (like WIV1 and SHC014). SARS-CoV-2 does not have one of those backbones. If it did, everyone would agree it's a lab leak.

The lab leak scenario right now is basically:

1. WIV secretly discovers a novel virus with the right RBD, but for some reason does not publish it along with the rest of their sarbecoviruses in 2018 and 2019.

2. The DEFUSE grant is cancelled in the US but happens in Wuhan instead.

3. WIV makes a novel reverse genetics system for that virus, and uses that instead of using the existing backbones that DEFUSE said they would use.

4. WIV adds an inefficient FCS sequence that's never been used before, via insertion which has also never been used before.

5. WIV makes additional modifications like N-glycan changes that simulate natural evolution in an intermediate host

6. WIV finds some way to grow this virus without leaving a genetic trace (most cell cultures would)

7. The virus infects someone at the lab, who immediately goes across town to a wholesale market and coughs on someone in a raccoon dog shop

8. A week later, a second person from the lab also goes across town to the same market and gets someone else at that market sick.

9. The virus causes no other case cluster in Wuhan or at the lab.

10. There's a perfect cover up, and no one ever finds details on that secret starting virus, the sampling trips to find it, the lab worker who got sick, etc.

None of that is impossible, but there are many highly unlikely steps involved, and the competing theory is just: it was sick animals at a market, the same way SARS1 started, and one shop was selling the exact same animals that started SARS1. My money is on the sick animals theory.

@benshindel As of 2020, one of the most popular lab leak theories was that miners caught covid in a cave in 2013, Covid adapted naturally to humans in their lungs, WIV took samples and froze them, then WIV leaked those samples while experimenting with them in 2019.

People said it couldn't be a coincidence that WIV had been to that cave, that those miners had gotten some respiratory illness, and that WIV had discovered a virus 96% similar to Covid in that cave.

Today, most people have moved on from the Mojiang miners theory, and many now say that the DEFUSE grant can't be a coincidence.

It's pretty easy to read too much into the details of various kinds of research, and to note similarities that seem interesting.

If you want examples of people reading too much into different research grants, go read Jim Haslam's work on Twitter or Substack, or buy his book.

He argues that Covid was not made by DEFUSE but by other grants done by guys like Baric and Munster in the US, they created a new virus, then they exported the work to Wuhan via the single foreign scientist who was working over there (Danielle Andersen, at the Wuhan BSL-4). She leaked it by accident and Chinese scientists were never involved in the creation.

He makes it sound just as convincing as the theories where Chinese scientists and the DEFUSE grant are to blame. Steve Hsu recently had Haslam on his podcast, and Steve seemed to find it all plausible.

https://x.com/Devlinside123/status/1892262539373006957?t=XFtEciu3u8FjGMwsGN_ITg&s=19

The old refrain around Covid is there’s no smoking gun that proves Covid was designed in a lab…

Of course not, there’s no gun…but there’s a country that lied again and again, a lab that was set up to engineer Covid viruses, and a virus itself that had all the telltale signs in its construction and genetic hallmarks with an agency that was bragging that creating just this kind of virus was what they did.

No smoking gun, but the bullet that killed the host had the serial number of the Wuhan lab printed on the casing…

@George It would be easier and your argument might be more persuasive if you focused on factual information instead of meaningless prose and regurgitated nonsense.

@Predictor I am quoting someone else. See link if interested, if not then don't. I am not making an argument. I'm linking to commentary by others. Hope that helps.

@George What other rambling bigots do want to cite in lieu of having any evidence to support your position?

@zcoli I had to look it up...

https://www.ojp.gov/ncjrs/virtual-library/abstracts/women-police-use-force-and-against-female-officers?utm_source=chatgpt.com
https://www.ojp.gov/ncjrs/virtual-library/abstracts/findings-role-officer-gender-violent-encounters-citizens?utm_source=chatgpt.com
https://giwps.georgetown.edu/resource/men-women-and-police-excessive-force-a-tale-of-two-genders/?utm_source=chatgpt.com

Maybe someone can double check with Grok to rule out "woke AI lies to favor women".

@PeterMillerc030 the next thing the guy likes to tweet over and over is way worse than that

With the Trump admin in charge, I think we're more likely to see lab leak evidence come out than zoonosis evidence, so I like the asymmetry of buying YES here and holding for a few months-- even if I have no idea where it settles long-term

@aashiq The problem with markets like this is that evidence for zoonosis is likelier to come out in the far-term while evidence for lab leak is more likely to come in the short-term, which creates more people wanting to buy lab leak for better returns

I don't view that as a problem. I just don't think the current price reflects that bias adequately and have taken a decently big position to that effect.

@aashiq Ratcliffe repeatedly demanding that Biden release the evidence. Now he’s been in power for a month and there’s no evidence. David Asher shifted from demanding evidence to saying that, really, the strongest evidence is the open source data.

There is no secret evidence pointing to any lab and you will be disappointed.

Proof of this is that different agencies conclude different labs. If there were evidence pointing to one lab or the other, all agencies concluding “lab leak” would obviously conclude the same lab.

@ShadowyZephyr Evidence for zoonosis comes out every time there‘s a paper reporting more related genomes sampled from animals and every time there’s a paper with more SARS2 genomes sampled from humans. It just doesn’t make the news because it’s boring to report results conform to expectations from previous data.

@zcoli The bar for evidence that is likely to move this market is very low. You only need admissions that certain key people thought it was a lab leak at various points in the past. There are lots of incentives to produce such evidence, such as agitprop against China

@aashiq I agree it’s an irrational market in that respect where the implied probability blips up every time someone exudes confidence without showing any evidence to base it on.

Or perhaps it’s a rational market in that respect since, the last time we heard from the judge, he was on the fence about Lyme disease being a lab leak based on whatever idiotic thing he happened to Google first.

@zcoli I don’t even know what it means for a market to be rational in the sense that I think you mean it. The sense in which I mean it is that it’s a martingale, which it never is (but it might nearly be)

@aashiq Cool it down.

@zcoli it's an irrational market because like 70% of the NO shares are held by one individual who is ideologically invested in the listed probability of this market, Z...

@benshindel pretty easy to profit massively from this market then if it's clearly irrational, no?

What's keeping all the rational profit-driven betters from betting this market up to where you think it should rationally be?

@JonathanMannhart

-Because there’s probably like a 50-80% chance that it never resolves

-even if it does resolve, it’s not likely to resolve within a decade

-the discount rate on this platform is probably between 5 and 10% (See the UFO market for an example of this)

-thus, even if my true probability for this market is at 99% or 1% (it isn’t, I’m probably at like 75-80% lab leak), there’s no incentive for me to bet in this market, because there’s an expected return of like 2% per year.

@benshindel however, if you are in fact interested in making the probability shown on this market seem different than the true probability, that’s a completely different incentive! I’m not really invested in that, whereas Peter is, which is why he is by far the largest shareholder in this market!

@JonathanMannhart for example, this market should not be at 92%, but it’s not worth correcting for a 2% annual return.

This market doesn’t even end in 4 years like that one!!! It could go on indefinitely!