Thread by @Ayjchan

My thoughts about the Yan whistleblower report on SARS2 origins have been percolating over the past few very busy days. I'm ready to share them in this thread:
(1) why+how whistleblowers must be protected
(2) what the report gets right and what it gets wrong

How did this all start? Dr. Limeng Yan arrived in the US at the end of April, escaping China in fears of being disappeared. She is a whistleblower, who has worked for years on vaccines and is co-first author on a Nature paper (July 2020) about SARS2. pubmed.ncbi.nlm.nih.gov/?term=limeng+y…

In fact, Yan blew the whistle on 2 of the senior authors of that Nature paper - claiming that these experts knew about the human-to-human transmissibility of SARS2 but failed to relay this crucial information to the WHO in a timely manner. nature.com/articles/s4158…

It's currently difficult to ascertain what evidence Yan has to support the above claim. She has shown journalists some exchanges. And it seems to be common knowledge now that there were weeks of delay in informing the WHO that SARS2 was a human-transmissible virus.

The lab origins controversy started when Yan claimed that RaTG13, the closest related virus genome to SARS2, published by the WIV was fabricated, and that SARS2 was derived from SARS viruses from Zhoushan - one was successfully isolated in suckling rats. ncbi.nlm.nih.gov/pmc/articles/P…

Before I get into a scientific review of Yan's report, I think it is essential to 1st address a glaring problem in science (and probably other fields): whistleblowers. Why they are rare. Why they can sometimes be incoherent or make unsubstantiated claims. How to get the truth.

Whistleblowers are extremely important people - for the health and sustainability of any organization or field. They're a rare type of people who will risk their lives and careers to make sure no more harm comes to other people... statnews.com/2019/05/01/fro…

Whistleblowers often live in fear and have been abused, gaslit, and traumatized for extended periods by not only their employer (and lawyers), but more importantly by their colleagues (friends) and even spouse/family (such as in the case of Yan). They're often naive/idealistic...

They never envisioned being in a workplace that would turn a blind eye to misconduct, knowingly endanger people's lives or well-being. Suddenly, they have to decide whether to say something and risk everything they've worked for, everything that's safe OR keep quiet and move on.

You can't pick your whistleblower. They're not going to be in the clearest state of mind after abuse. If it's the first time they're blowing the whistle, they're not going to have documented every email and message.

More importantly, the whistleblower cannot pick their savior.

If there is one thing that this entire saga has made clear - it is that whistleblowers (as it pertains to SARS2) have no obvious safe route of sharing their information.

Seriously, who should a SARS2 origins whistleblower go to? Besides this anti-CCP billionaire + Bannon et al.?

I'm just a postdoc in a foreign country. But shouldn't someone in charge be publicizing a safe way for whistleblowers to relay SARS2 origins information? A whistleblower protection program?

This would safeguard against the political manipulation of any forthcoming whistleblower.

The best approach to obtaining the truth from a whistleblower is to remove their dependency on their host/savior. Someone who they now have to rely on for security the rest of their life. Do people seriously think that this is not a consideration for whistleblowers?

So before we get into the scientific discussion of Yan's report, I want this consideration - what it's like to be a whistleblower in a foreign country, you know no one, in a hostage-like situation under powerful political figures - to be at the top of everyone's minds.

Yan's report makes 3 claims:
(1) SARS2 is similar to the Zhoushan viruses isolated and studied by Chinese military labs.
(2) The receptor binding motif of the spike was genetically manipulated.
(3) The infamous S1/S2 furin cleavage site (FCS) was artificially inserted.

The underlying premise of claim (1) is that other more closely related SARS2-like viruses suffer from debilitating integrity issues. RaTG13 - obfuscation of source and links to SARS-like cases, sample processing+sequencing, downstream experiments (?).

GD pangolin CoV - the one virus with a SARS2-like receptor binding domain (RBD) - please see our preprint, which has been under editorial review for 16 weeks, but we think we can see the light at the end of the tunnel now... biorxiv.org/content/10.110…

Due to these issues, Yan et al. refuse to incorporate any of the newly published SARS2-like viruses in her analysis. This is a major weakness of the report that has been pointed out by numerous experts.

I would argue that at least the 4991 RdRp fragment should be considered.

Thus, I would describe the claim that RaTG13 is fabricated and the claim that SARS2 is derived from the Zhoushan viruses (published in 2018) are gut speculations by Yan, who clearly believes that SARS2 is a product of gain of function research by the Chinese government.

My position on this: I don't know. Someone should be looking into the origins of RaTG13 and GD pangolin CoV. What was the sampling+sequencing process? Are there still ways to verify these samples (the former has disintegrated)? Were similar viruses discovered but not reported?

What I do know: claiming SARS2 was derived from the Zhoushan viruses that are >3000 mutations different -- this has destroyed the report's credibility, and, more importantly, diverted attention away from RaTG13, miners, and the missing WIV virus database (the 2nd Zenodo article).

Ok, on to (2). This 2nd claim relies on the 1st claim being true, which is, again, its greatest weakness. Instead of just going with "RBD was copied from another virus", Yan et al. perform enzymatic gymnastics to figure out how it could have gotten into the Zhoushan virus.

What claim (2) kind of gets correct - and I'm paraphrasing here - is that labs (including the WIV) have been codon optimizing spikes and swapping in RBMs to study receptor binding for over a decade. (Actually, this study did introduce an EcoRI site...) jvi.asm.org/content/82/4/1…

But this fixation on cloning sites is irrelevant to determining whether SARS2 was ever manipulated in a lab. Ralph Baric, UNC, long time collaborator of Shi, WIV says as much in his recent interview.

*PLEASE RELEASE THE UNDUBBED VERSION*

huffingtonpost.it/entry/e-possib…

Scientists have been able to clone coronavirus genomes seamlessly for years. They introduce cloning sites to show you that a genome has been manipulated. Another reason to retain a cloning site could be to monitor a feature, e.g. FCS, that tends to be lost during cell passage.

Which leads us to (3) the FCS - the most highly debated feature of SARS2. Why?

SARS2 is the only SARS family virus (out of dozens, maybe 100s, sampled) with an S1/S2 FCS.

The FCS has been actively researched, even in SARS1 & MERS, found to enhance virus tropism and infectivity.

Again, the fixation on whether there is a cloning site surrounding the FCS is unhelpful.

The underlying thought here is that a lab could have been interested enough to follow up on earlier studies of introducing an FCS into SARS virus to see how it enhances pathogenicity.

For more details, please see this earlier thread - it is long and technical:

https://twitter.com/Ayjchan/status/1266805310313967617

The rest of the Yan report delineates a cloning plan for creating the SARS2 genome, which, unfortunately, obscures critical observations with the terrible, terrible restriction cloning strategy and the desperation of somehow deriving SARS2 from the Zhoushan viruses.

The top points:
1. There are likely unpublished virus genomes closely related to SARS2.
2. The spike is generally modified alone before cloning into the larger genomic backbone.
3. Cloning can occur seamlessly. No need for RE site insertions!
4. It can be done in weeks-months.

5. There is a possibility of serial passaging in humanized mice or small animals. The WIV Science Magazine interview says these small animal experiments were conducted at BSL3 using SARS-like viruses. sciencemag.org/news/2020/07/t…

The Yan report ends by emphasizing the dangers of SARS2 and the importance of an independent audit of the WIV - which Peter Daszak, long time friend, collaborator, and funder of the Shi lab has now taken upon himself to lead the charge on.telegraph.co.uk/global-health/…