Kristian G. Andersen

Should we just go ahead and retract our paper?

Slack / Private Message Drop, p.4 · original PDF · in context

Which, I don't know, in combination with wet markets and the like might increase the risk of an outbreak from a bat coronaviruses.We need an actual razor in Occam's razor.

Slack / Private Message Drop, p.5 · original PDF · in context

I also had a pretty heated discussion with him on one of the WH committee calls where I mentioned that the RBD would probably lead to high affinity binding and the furin site being active.

Slack / Private Message Drop, p.6 · original PDF · in context

Speaking of furin - Bob, your old buddy is on the Virological again and it's a pretty nice theory for how the furin site was acquired in bats - just need to add a little extra divergence and there you have it:http://virological.org/t/tackling-rumors-of-a-suspicious-origin-of-ncov2019/384/3

Slack / Private Message Drop, p.7 · original PDF · in context

This cracked me up - from CBS 60 minutes: _"We have been working with Peter Daszak, president of EcoHealth Alliance, and looking at his effort to identify viral threats in the wild.

Slack / Private Message Drop, p.7 · original PDF · in context

Given the recent announcement of their cut in funding, we're looking to speak with someone inthe scientific community *who has used EcoHealth Alliance's data and sequences from samples in their own work* and can speak to the importance of this type of field research"_Hah - what data exactly?

Slack / Private Message Drop, p.7 · original PDF · in context

The furin site is clearly active in tissue culture.

Slack / Private Message Drop, p.23 · original PDF · in context

Typically SARS-like CoVs are cultured in the presence of trypsin (to allow for cleavage of S1/S2), but if trypsin isn't added, there's a *huge* selection pressure for gaining a furin site.

Slack / Private Message Drop, p.23 · original PDF · in context

The example from bovine CoVs (post #6 on the thread on virological) is exactly a 12bp insertion seen in tissue culture creating a furin cleavage site.3.

Slack / Private Message Drop, p.23 · original PDF · in context

They're not furin sites, but there seems to be some affinity specifically for12bp insertions (in T/C) - and of course, the furin cleavage site is exactly 12bp.

Slack / Private Message Drop, p.23 · original PDF · in context

We did, however, get a clear signal for bullshit".I should say though - SARS-CoV-2 RNA _does not_ always remain in nasal secretions - especially in severe cases.We have multiple examples of patients hospitalized with (confirmed) COVID where the tests are repeatedly negative- so I'm not 100% sure he's actually faking it, but knowing it's Fair, well...

Slack / Private Message Drop, p.27 · original PDF · in context

When it comes to the selection argument, what is still most telling to be is the RBD.

Slack / Private Message Drop, p.29 · original PDF · in context

SARS-CoV-2 is already'perfect' for binding, so it doesn't need to - BUT that 'perfect' RBD is found in a pangolin CoV, so clearly it already exists in nature - no further adaptation needed it seems.

Slack / Private Message Drop, p.29 · original PDF · in context

AndersenI read with interest your paper titled, The proximal origin of SARS-CoV-2, in which you conclude this is a natural, zoonotic-sourced infection.

Slack / Private Message Drop, p.37 · original PDF · in context

If you use a map of Wuhan and overlay the first four hospitals that saw cases with a map of the Metro system, you see that the hospitals straddle Line 2, which runs approximately east to west, carries 1,000,000 people a day, and isthe Metro line with stops closest to both the Wuhan Institute of Virology and the original wet market that was considered an early source for the infection.

Slack / Private Message Drop, p.37 · original PDF · in context

Iam not sure why this obvious correlation was not at least pointed out in your paper and then addressed with acogent argument.I look forward to hearing your thoughts.Regards, Steve Steven _MD, PhD

Slack / Private Message Drop, p.37 · original PDF · in context

On to better papers, this is pretty interesting - especially cats: https://science.sciencemag.org/content/sci/368/6494/1016.full.pdf Cat-like intermediate host?

Slack / Private Message Drop, p.44 · original PDF · in context

I'm not sure where he has this from "The novel coronavirus had existed long before", but other than that, seems plausible - I don't really think we have any good reason to believe that all of this started in the seafood market(it could very likely just have been a super spreading event).

Slack / Private Message Drop, p.45 · original PDF · in context

Haven't had time to read this yet, but not quite understanding why I'm not seeing Eddie's name on this... https://advances.sciencemag.org/content/early/2020/05/28/sciadv.abb9153

Slack / Private Message Drop, p.45 · original PDF · in context

And yes, there were (short) delays no doubt - but they were inconsequential in the grand scheme of things (my main issue here is that especially in the US is that people can't uncouple the two - i.e.(1) the delay and (2) the consequences from that delay.

Slack / Private Message Drop, p.49 · original PDF · in context

As to how beneficial the furin site is inhumans, I thought this one was reasonably interesting (although I don't believe we have seen this in our sequences- we'll dig deeper):https://www.biorxiv.org/content/10.1101/2020.06.03.129585v1Between the flu and eLife papers, how about a hypothesis where the virus might have been introduced into (denselypacked) farmed animals and then maybe bouncing back and forth between the animals and humans for a (little) while.

Slack / Private Message Drop, p.58 · original PDF · in context

That'd explain the lack of positive selection in the spike (which really is *highly* unusual IMO) and also the acquisition of the furin site - it clearly seems like some sort of heavy passaging must have been required to gain that site.

Slack / Private Message Drop, p.58 · original PDF · in context

Is it possible that the furin site is advantageous during high passage scenarios (transmission) but maybe not so much within host?

Slack / Private Message Drop, p.59 · original PDF · in context

In that scenario, maybe the furin cleavage site is maintained during exponentially increasing outbreaks (like we have observed up until about a month ago), but might be lost during more low-transmission periods?

Slack / Private Message Drop, p.59 · original PDF · in context

To see ifthere's a link to transmissions, if we look at viruses sequenced in low-transmission places (or during low-transmission times) vs viruses sequenced in high-transmission places (or times), is there an association with the former showing more evidence of furin site loss than the latter?

Slack / Private Message Drop, p.59 · original PDF · in context

We KNOW we can't predict these kind of outcomes with _*any*_ certainty so we shouldn't even try - especially not when it comes to something this important.

Slack / Private Message Drop, p.60 · original PDF · in context

One thing is to report basedon tweets (which is wrong), another is doing it when the person isn't a subject-matter expert - I find that really problematic, especially for something this important.

Slack / Private Message Drop, p.62 · original PDF · in context

_"Clearly, there was some level of social disruption taking place well before what was previously identified as the start of the novel coronavirus pandemic."_ Whatever that was, it wasn't COVID - we know this very specifically from the genetic data.

Slack / Private Message Drop, p.63 · original PDF · in context

While I knew about the furin site insertion experiments, I did know realize this (that the insertion in SARS2 is exactly where they inserted it experimentally in SARS):https://twitter.com/Ayjchan/status/1266805310313967617?s=20

Slack / Private Message Drop, p.68 · original PDF · in context

The furin site in SARS2 is exactly the same as it is in some of the HKU1 sequences.

Slack / Private Message Drop, p.69 · original PDF · in context

When I talked to Farzan way back in the day he mentioned that the one thing he'd be looking for was whether SARS2 would lose the furin site under different conditions - we now know this to be true (primarily in T/C, but there are examples in people too - intrahost).

Slack / Private Message Drop, p.69 · original PDF · in context

The part I'm really struggling with is that at the end of the day, we really don't have any hard evidence one way orthe other - and especially given some of the recent evidence, we also can't rule out that somebody actually put it inthere.

Slack / Private Message Drop, p.69 · original PDF · in context

Our paper was pretty strong insaying "there's no way", but I have less confidence in that statement at this stage.

Slack / Private Message Drop, p.69 · original PDF · in context

People have put furin sites into CoVs previously - here's one example from SARS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111780/

Slack / Private Message Drop, p.70 · original PDF · in context

Nothing has changed in terms of prior risk of lab accident, but the issue is that we're dealing with the fact that WIV has been doing culturing of bat CoVs for over a decade exactly to understand what it takes for these viruses toemerge in humans (in BSL-2).

Slack / Private Message Drop, p.71 · original PDF · in context

We describe this in the paper and say that this work is performed "all of the world", but that isn't true - it has exclusively been going on at WIV.

Slack / Private Message Drop, p.71 · original PDF · in context

A lot of the GOF work on SARS-like CoVs is also from WIV, although there are also other labs that have been doing that (e.g., Baric).

Slack / Private Message Drop, p.71 · original PDF · in context

> But that work isn't exclusively done at the WIV because as you say yourself the Baric lab are doing it No, that work _is_ exclusively at WIV AFAIK.

Slack / Private Message Drop, p.72 · original PDF · in context

All of this is done in BSL-3, so much (much!) less risk of exposure.

Slack / Private Message Drop, p.72 · original PDF · in context

The work in Shi's lab is different - here they are taking bat CoVs and culturing them under BSL-2 in cell lines from different animals - to e.g., understand which ones can infect human cells and what type of mutations that occur inT/C may make them permissive.

Slack / Private Message Drop, p.72 · original PDF · in context

The little details about the furin site - e.g., that it's exactly in the spot where experiments had previously inserted it,the fact that the exact sequence exist in a cat CoV, Shi herself being sketchy with details and considering lab accident, etc.

Slack / Private Message Drop, p.72 · original PDF · in context

I find it peculiar that all these pangolins are showing up sick with all sorts of SARS-like CoVs though - I mean, these guys have been traded_forever_ and only now do we realize they have CoVs?

Slack / Private Message Drop, p.74 · original PDF · in context

I think the data is shifting pretty strongly towards mask wearing being (potentially highly) beneficial.

Slack / Private Message Drop, p.75 · original PDF · in context

Binding isn't everything though, so I wouldn't conclude it's "not as evolved" as previously thought -the binding is still very very strong (but.... so is the pangolin CoV, of course!).

Slack / Private Message Drop, p.81 · original PDF · in context

@Andrew Rambaut have you had a look at the Beijing genomes?

Slack / Private Message Drop, p.81 · original PDF · in context

I have a hard time believing it has been circulating undetected for quite a while inBeijing, so could it be a virus than went human > animal > human?

Slack / Private Message Drop, p.81 · original PDF · in context

Clearly not a separate introduction, but it's again linked to a wet market so I'm wondering if it can bounce back and forth (surely this is possible based on e.g.the Dutch mink farms).

Slack / Private Message Drop, p.81 · original PDF · in context

Is it really possibly Beijing has had an outbreak for quite some time?

Slack / Private Message Drop, p.82 · original PDF · in context

> But there was no coronavirus in Beijing so why would you need to wear masks?

Slack / Private Message Drop, p.83 · original PDF · in context

I think the main problem here is not really how that pangolin sequence ended up having that RBD, but rather whether there's anything sketchy here from a scientific standpoint.

Slack / Private Message Drop, p.86 · original PDF · in context

These studies are presented each as independent evidence of the pangolin virus RBD, but if all those papers are relying on a third data set - and don't actually have _any_ data from this very critical CoV RBD, then that's an issue.

Slack / Private Message Drop, p.86 · original PDF · in context

For the last month, I have been feeling like I'm one of these guys: https://en.wikipedia.org/wiki/Musicians_of_the_RMS_Titanic

Slack / Private Message Drop, p.87 · original PDF · in context

I assume lockdown measures would affect these differently.

Slack / Private Message Drop, p.92 · original PDF · in context

@Andrew Rambaut, great analysis in the COG report: https://www.cogconsortium.uk/wp-content/uploads/2020/07/2 5th-June-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf Question about this part: "As reported in a preliminary analysis of D614G (See COG-UK report #6), a significant association was observed between the age of patients and the probability of the virus carrying D614G, with decreasing odds of carrying the G variant as age increases.

Slack / Private Message Drop, p.93 · original PDF · in context

However, the basis for this association remains unclear and may also result from sampling bias." Are you guys able to isolate the effect of time here?

Slack / Private Message Drop, p.93 · original PDF · in context

And yeah - looks like 1977 was a vaccine trial, which is pretty crazy.

Slack / Private Message Drop, p.101 · original PDF · in context

IMO, this virus is much too dangerous with too many uncertain long-term effects to deliberately infect people - especially given the HUGE number of cases we have in this country.

Slack / Private Message Drop, p.104 · original PDF · in context

Yeah, everything is basically D614G by now, so that's kinda the virus we need to make sure the vaccine works against - but I'm not really concerned there's a difference between Doug and Dougless here.

Slack / Private Message Drop, p.104 · original PDF · in context

I'm super worried this is going to be Trump's next political trick - he would have _no_ hesitation pushing a vaccine through where we have very little or no data on population-wide safety

Slack / Private Message Drop, p.105 · original PDF · in context

"This virus doesn't lurk unobserved" - as is, definitely true - but I _do_ wonder if a pre-furin site virus could.

Slack / Private Message Drop, p.109 · original PDF · in context

I'm SUPER uncomfortable with 30,000 people now getting the Moderna vaccine - can you imagine how detrimental thisis going to be for (COVID and otherwise) vaccine research if this vaccine actually isn't safe?

Slack / Private Message Drop, p.109 · original PDF · in context

We should alert themto the problem, make it clear that they have divulged private and confidential information from the review process (and implicated high-ranking US officials) in a factually wrong narrative about a scientific study on a sensitive subject.

Slack / Private Message Drop, p.117 · original PDF · in context

If Jeremy could mention that the meeting was confidential and the information classified (I believe it was a secure line?) that would be helpful.

Slack / Private Message Drop, p.118 · original PDF · in context

We believe that RB is either Reviewer 2 of our paper, or Reviewer 2shared confidential information with RB.

Slack / Private Message Drop, p.119 · original PDF · in context

There are no other explanations for how RB could have obtained this information, except for a breach of the peer review process - we have not shared any of the peer review details put forward by RB.The libelous accusations put forward by RB includes confidential details about private meetings held via secure lines involving senior US and UK officials/scientists on a topic that is highly sensitive.

Slack / Private Message Drop, p.119 · original PDF · in context

It's the second time I have noticed him being a complete arse - the other time was amplifying that idiotic WaPo WIV story.

Slack / Private Message Drop, p.128 · original PDF · in context

This one about vaccines though is a really serious misstep.

Slack / Private Message Drop, p.128 · original PDF · in context

Whether correct or not, pretty interesting though - especially given the pretty strong political line that this is due toreturn travelers (could be - but I'm also not sure about that...).

Slack / Private Message Drop, p.135 · original PDF · in context

@Eddie Holmes Mostly, I'm just a little confused - because these are big and important questions so we all know that we need to be really careful what we say (especially because of a few prior misfires).

Slack / Private Message Drop, p.136 · original PDF · in context

I love their discussion of the furin site - "This furin cleavage site, *which is poly or multibasic by definition since itscomposed of multiple basic amino acids*".

Slack / Private Message Drop, p.139 · original PDF · in context

Iagree it was mysterious - really mysterious - but then some pangolin viruses came around and mystery solved.Clearly not Bayesians.

Slack / Private Message Drop, p.140 · original PDF · in context

Yeah, I thought it was a pretty interesting article - especially the title.

Slack / Private Message Drop, p.145 · original PDF · in context

Again, we should totally expect reinfections so none of them are surprising - I just get really fucking grumpy when people talk about what we can learn about COVID immunity and vaccines from n=1 studies (some of which might be false positives).

Slack / Private Message Drop, p.147 · original PDF · in context

We need to know frequency and time dependency before we can say *anything* about immunity/vaccines).

Slack / Private Message Drop, p.147 · original PDF · in context

Bob and I are now officially in the same 'Family' as the Grand Wizard of EgoHealth.

Slack / Private Message Drop, p.148 · original PDF · in context

Disappointing to see Helen write about the EgoHealth grant, as opposed to writing about how great it is that NIAIDwill be supporting these centers with an $82 million commitment... https://www.statnews.com/2020/08/27/nih-awards-grant-to-ecohealth-alliance-months-after-uproar-over-political-interference/

Slack / Private Message Drop, p.148 · original PDF · in context

That's the key here - that mouse model is using the human ACE2 receptor, so it'd be a perfect fit - plus the acquisition of furin sites during rapid passage as we discussed in the paper (as is seen for flu).

Slack / Private Message Drop, p.149 · original PDF · in context

Doing that type of work with a novel (bat) CoV would constitute a non-trivial risk for sure - she does not mention whether this isBSL-2 or BSL-3, but likely the former.

Slack / Private Message Drop, p.149 · original PDF · in context

Yeah, very true - actually, maybe we should file a FOIA... :wink:

Slack / Private Message Drop, p.150 · original PDF · in context

Probably the most jarring COVID abstract I have read in a paper I just got for review for Nature Medicine: _"Here, from 273 COVID-19 patients, we identified six cases of reinfection based on clinical, phylogenic, virological, serological, and epidemiological data.

Slack / Private Message Drop, p.151 · original PDF · in context

Yup, common sneaky anti-virus mechanism - it appears SARS2 might be especially good at doing this.

Slack / Private Message Drop, p.153 · original PDF · in context

Trump going to force through an EUA for _any_ vaccine by end of October is going to be the biggest - and by far most consequential - mistake America will do when it comes to COVID-19.

Slack / Private Message Drop, p.154 · original PDF · in context

They can of course refuse to distribute the vaccine, but the crazy thing here is that Trump likely has no or very little interest in actually distributing the vaccine - he just wants itapproved and then leave it to others to figure out what to do.

Slack / Private Message Drop, p.155 · original PDF · in context

The main risk here is that with the EUA, some would demand the vaccine and it'd sideline the clinical trials, causing very significant delays for the development of_actual_ safe and efficacious vaccines.

Slack / Private Message Drop, p.155 · original PDF · in context

Especially the latter point is important when we think about vaccine escape since big and consequential genomic rearrangements can happen really quickly.

Slack / Private Message Drop, p.160 · original PDF · in context

I'm hopeful vaccines will be able to get us to where we need to be immunity wise, just not so sure about natural immunity and how long-lasting it is - but even if it isn't, there's still no doubt that it's already helping to drive down cases in at-risk areas.

Slack / Private Message Drop, p.162 · original PDF · in context

Proposing that all the bat and pangolin sequences are fraudulent and hence SARS-CoV-2 is a lab construct is - well, absurd.

Slack / Private Message Drop, p.163 · original PDF · in context

They put a restriction site INSIDE the furin site so they can follow the viruses over time - it's all very clever.

Slack / Private Message Drop, p.168 · original PDF · in context

I'm not even going to go there - I have no concerns about the bat or pangolin data so simply ignoring all of that is just dumb (well, that data invalidates their findings, so of course, I get it).

Slack / Private Message Drop, p.171 · original PDF · in context

I haven't looked at the pangolin data - I'm not quite sure where the raw data is since I believe it was all uploaded tothe Chinese data portals.

Slack / Private Message Drop, p.178 · original PDF · in context

"the Guangdong pangolin viruses have been sequenced multiple times by multiple groups.

Slack / Private Message Drop, p.179 · original PDF · in context

Plus there are Pangolins from Guangxi that have been sequenced" Yup, I know this - hence I have no concerns about the data.

Slack / Private Message Drop, p.179 · original PDF · in context

Only need to assemble one of the remaining pangolin CoVs, which has a huge dataset.

Slack / Private Message Drop, p.184 · original PDF · in context

E.g., they mention that SARS1 has a furin cleavage site in the spike - that's clearly not true and suggestive of them not looking very closely at the literature.

Slack / Private Message Drop, p.189 · original PDF · in context

Presumably though, if these reads are real surely they must be contamination from other sequencing experiments at WIV.

Slack / Private Message Drop, p.197 · original PDF · in context

> Zhang has now been booted out of China CDC and is now full-time in Shanghai.

Slack / Private Message Drop, p.201 · original PDF · in context

Makes me believe the 'pre-circulation' hypothesis of a furin site-lacking virus in humans a little more (or other animals - maybe cat-like?).

Slack / Private Message Drop, p.206 · original PDF · in context

Good thread summarizing some of the findings: https://twitter.com/influenzal/status/1311959153166954498?s=20[and of course - I want to know if they virus lacking the furin site can actually pick it up after repeated passage inculture on e.g., human lung cells... :wink: ]

Slack / Private Message Drop, p.206 · original PDF · in context

The concern here is that we know that type of work was going on at WIV (the EgoHealth stuff), so we certainly can't dismiss it based on this.

Slack / Private Message Drop, p.208 · original PDF · in context

While there are certainly SS events, it's still not clear to me if events like these are due to a person being particularlyprone to spreading, or whether it's just the event itself (in other words - could any standard patient lead to these events, or does it take something special?).

Slack / Private Message Drop, p.212 · original PDF · in context

When you combine it with this part (from the paper): "we found that bat SARSr-CoV RBDs showed a higher binding affinityto human ACE2 than to R. sinicus ACE2s but did not display obvious differences among the R. sinicus ACE2s" -well, you'll always have a disaster in the waiting....

Slack / Private Message Drop, p.212 · original PDF · in context

I agree it's a little counter-intuitive, but probably the binding to hACE2 is generally speaking more optimized for binding to the RBD (soit's inherently a higher affinity binding - no matter the RBD).

Slack / Private Message Drop, p.212 · original PDF · in context

I especially love the alternative to their declaration "lockdown [...] measures in place until a vaccine is available".

Slack / Private Message Drop, p.213 · original PDF · in context

There is NO significance to this and it's not worth commenting on - ANYBODY who does this type of work knows that sequences get updated every now and again, especially when the sequences are (a) important and (b) had a few low-coverage regions that might have had assembly errors.

Slack / Private Message Drop, p.224 · original PDF · in context

Some of them have the _exact_ same furin site.

Slack / Private Message Drop, p.227 · original PDF · in context

Alina is talking about the pangolin sequences where there's overlap in the data used - as described in Eddie's paper.

Slack / Private Message Drop, p.228 · original PDF · in context

The Huanan market is on Line 2 as well (so is WIV) and where one of these early sequences differ from Hu-1, it is indeed ancestral (as in, the same as RaTG13).I think it's entirely possible these may be some of the very earliest patients and suspected in early December - only later to be sequenced.

Slack / Private Message Drop, p.240 · original PDF · in context

Doesn't really point to lab origins -although the registration dates are a little puzzling and I'm not sure if this particular hospital should raise a flag (ithas a weird name, but don't they all - some hospital bound to be first seeing patients...).

Slack / Private Message Drop, p.240 · original PDF · in context

So if those BioSamples were created on, say 12/25, then that's totally what you'd expect - but we're talking two weeks before there was any (official) realization of a novel coronavirus.

Slack / Private Message Drop, p.242 · original PDF · in context

Eddie, it's your paper... :wink: https://www.thelancet.com/article/S0140-6736(20)30251-8/fulltext I assume this is the same Weijun Chen who's the submitter of the data and is from BGI.

Slack / Private Message Drop, p.242 · original PDF · in context

One thing "Steve" considers a potential hypothesis here is a "vaccine challenge trial" - which isn't totally idiotic.

Slack / Private Message Drop, p.243 · original PDF · in context

(and one pretty critical thing against the bonkers theories in the paper - wouldn't WIV have been mentioned in theBioSample had the virus come from there....? :man-shrugging:)

Slack / Private Message Drop, p.245 · original PDF · in context

I have a TON of DK reporters asking about this, but haven't found anything official.

Slack / Private Message Drop, p.251 · original PDF · in context

Yup, I have been hearing you saying this for years - for Ebola too.

Slack / Private Message Drop, p.260 · original PDF · in context

For SARS we actually got to see some of those mutations because we captured the intermediate host - would be very interesting to see for SARS2 as well, but the mink data is definitely interesting in this regard.

Slack / Private Message Drop, p.260 · original PDF · in context

Yeah, I'm not quite sure what Y453F is about - might just be marginally beneficial.

Slack / Private Message Drop, p.260 · original PDF · in context

A lot of diversity in the size of the various farms- especially in Denmark (not sure about NL - but I think they have more 'mega' farms).

Slack / Private Message Drop, p.261 · original PDF · in context

Yeah, 1977 is definitely an escape - and likely linked to vaccine work.

Slack / Private Message Drop, p.264 · original PDF · in context

And yes, likely vaccine work, although I'd argue that that's just one type of 'escape'.

Slack / Private Message Drop, p.264 · original PDF · in context

As for sterilizing immunity - the animal trials for both the J&J and RNA vaccines were promising on this aspect -the Oxford vaccine, not at all.

Slack / Private Message Drop, p.293 · original PDF · in context