Thread by @Ayjchan

One question that many people ask me is "how likely is a lab escape vs natural origins of SARS2?"

And everyone complains when I refuse to give some kind of probability estimate. tbh I see this as a trick question because there is no evidence of either scenario at this point.

What we know is that none of the animals from the initially blamed seafood market or even any animals tested in the province of Hubei have been found positive for SARS2. See the interview response from the WIV. sciencemag.org/news/2020/07/t…

Shi Zhengli even says "We have done bat virus surveillance in Hubei Province for many years, but have not found... any coronaviruses that are closely related to SARS-CoV-2. I don't think the spillover from bats to humans occurred in Wuhan or in Hubei Province."

As far as I can tell, the scientists who say natural spillover is most likely rely on 3 things:

1. A large outbreak has never stemmed from a lab escape before (although 1 pandemic came from failed vax)

2. No signs of lab manipulation

3. Possible SARS2 pre-circulation in humans

Re: 1. 1977 H1N1 pandemic
This was the first time a pandemic with lab-based origins had occurred; prior to it, all of the pandemics+outbreaks were, as far as anyone can tell, 100% natural in origin.
ncbi.nlm.nih.gov/pmc/articles/P…

Relying heavily on precedents to calculate risk is, I think, not the correct approach. You need to factor in changes in human activities. As this @JamesMartinCNS guide says, the risk of natural outbreaks and lab accidents are both increasing.
nonproliferation.org/op-49-a-guide-…

If we applied only 1. to calculating the probability of the 1977 pandemic having natural vs lab-based origins. The answer would have been 100% natural - an incorrect answer.

Re: 2. We cannot rule out lab manipulation just by looking at the genome of a virus.

Yes, there are sometimes clear signs of manipulation, but the technology today allows people to build viruses from scratch, seamlessly.

futurehuman.medium.com/how-do-we-know…

Even Ralph Baric, long-time mentor and collaborator of Zhengli Shi says: “You can engineer a virus without leaving any trace . The answers you are looking for, however, can only be found in the archives of the Wuhan laboratory".

huffingtonpost.it/entry/e-possib…

This leaves 3. - that prior to the 2019 outbreak in Wuhan, SARS2 spent months to years "pre-circulating" in the human population, adapting to its human host - which is the type of evidence I would take the most seriously.

A study did look at patient samples banked in Wuhan hospitals but they could only detect SARS2 in samples collected in January, 2020. This alone does not rule out pre-circulation because the virus could have been circulating at a very low level or even outside of Hubei province.

To check for evidence of pre-circulation, populations that travel to Wuhan need to be sampled for SARS2-like viruses and sequenced more extensively. It's difficult for me to imagine that all of the precursors and siblings of such an effective virus would've been snuffed out...

To me, these are the so-called "powerful evidence" for natural origins. The other reason that is often cited, which I think doesn't make sense, is that SARS2-like viruses are found in the wild. To that, I say, all of these published SARS2 viruses were characterized in labs.

So, yes, SARS2 viruses are found in the wild, but they are also found in multiple labs across China since as early as 2013.

Let's switch to look at lab-based origins using the same principles. Lab-based origins, similar to natural origins, encompass diverse scenarios. Most extreme is gain-of-function research to create bioweapons. Least extreme is someone sampling/culturing wild viruses got infected.

1. Are there precedents for lab escape leading to outbreak?

"SARS has not reemerged from the wild since 2003, but it has actually escaped from three different labs, one in Taiwan, one in Singapore, and one at China’s National Institute of Virology"
motherjones.com/politics/2020/…

Even in top labs in the US: "instead of quarantining to wait for signs of infection, the scientist was allowed to go about her life in public for the next 10 days, wearing a surgical mask and reporting her temperature twice daily" propublica.org/article/near-m…

One thing scientists have said in rebuttal is that no lab escape resulted in a massive outbreak. However, many of these lab accidents are known at the moment of infection. This doesn't usually apply to natural spillover - people don't know when a new virus has just spilled over.

Knowing when an infection has occurred, e.g., a SARS mouse bit you, gives people the ability to respond immediately. They know what the pathogen is. They know, hopefully, what the correct quarantine measures are.

With SARS2, you have a very stealthy virus that is infectious even when a patient isn't symptomatic. Produces a range of different symptoms in patients - some do not even develop a fever or cough. It's not like highly lethal viruses like SARS, MERS, that can be detected quickly.

Another type of lab escape that doesn't require a human in the lab to be infected is lab animal escape. People who work in labs know that this happens, not all of the time or even frequently, but it does happen - a mouse escapes and you don't know where it went.

Again, a virus like SARS2 isn't a killer virus even in lab animals. Many lab animals recover from SARS2 infection, even at high initial dose. Infected mice or hamsters could go on living for a while, shedding virus in the environment.

Moving onto 2. are there parts of this virus that could've been the result of lab manipulation?

The answer is: Possible, yes. Definitely, we know for sure that this happened, no.

We know that the S1/S2 FCS occurs in other non-SARS viruses, but it has also been a feature of great interest for virologists, who have repeatedly inserted it into SARS1 to see how it changes the virus' ability to infect different cell types.

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

The two sides of the FCS:

Some scientists say it appears in other natural coronaviruses so it could also appear naturally in SARS2.

Some scientists say that it has not been seen in the dozens of SARS viruses characterized to date, making SARS2 an abnormality.

I don't see how anyone can tell definitively that the S1/S2 FCS is natural or lab-inserted. What I would consider strong evidence for natural origins is if another pair of highly similar spikes (90%+ identity) are discovered, where one has an S1/S2 FCS and one does not...

As it is, the SARS2 spike is 84% and 93% similar at nucleotide level to the GD pangolin CoV and the bat RaTG13 virus - neither of which have an S1/S2 FCS or "natural insertion" in that region.

Other minor points on this topic.

Some have questioned the Proline (P) in the PRRA - being an unexpected choice for the residue in that position. But MERS has a P in the exact same spot and apparently the PRRA FCS motif also exists in feline coronaviruses.

Some have asked, then why is the insertion out-of-frame?
This enters speculation because you're asking why someone would do something a particular way.

I obviously cannot confirm why someone would clone a certain way...

There is a BsaXI cut site that is generated by this out-of-frame insertion. There are several other BsaXI sites across the virus genome. It could be a possible quick way for scientists cloning these genomes to verify if the S1/S2 FCS is still there by doing a quick digest.

Scientists sometimes engineer in RE sites for the purpose of doing quick checks on their constructs. This can involve insertions, moving things out-of-frame while retaining the original protein code.

I'm not saying any of the above happened. It's just a possibility.

Ultimately, the question is, could SARS2 have been cultured and manipulated in a lab before it broke out and caused the pandemic?

And the answer is: Yes, it is possible.

The tech exists. The raw materials (hundreds of wildlife virus samples, many unpublished) exist.

For a better understanding of the research being done in labs that sample wildlife for SARS viruses, please see this thread. Also important to note that all of this work was being done at BSL2/3 on humanized mice and civets, not BSL4 as commonly assumed.

https://twitter.com/Ayjchan/status/1278433585062699008

Actually, I wasn't very skilled at using twitter at that time. I didn't understand the concept of how threads are displayed when there are branches.

So the research pipeline description starts here:

https://twitter.com/Ayjchan/status/1278436519150264328

Finally 3. Does what happened match with a lab escape scenario?

I'd say that this is quite similar to the question: Does what happened match with a natural spillover + pre-circulation scenario?

Plausible, but no evidence.

This answer upsets people on both sides.

Some people, many well-intentioned, have said that I'm fuelling conspiracy theorists.

On the other hand, some people have said that I'm not going far enough in consideration of the obstructions to lab origins investigations.

I think these are both valid POVs.

Some people (including many experts) truly perceive that it is already clear that SARS2 has natural origins.

So, what I'm doing - calling for an investigation and the consideration of circumstantial evidence - looks unscientific and unhinged.

On the other hand, some people (including less experts, at least publicly) perceive that lab origins are clear or at least plausible because of the suspicious behavior surrounding origins. I cover some of it here:

https://twitter.com/Ayjchan/status/1320344055230963712

What I think would be most productive is finding common ground, especially in a situation where evidence is lacking.

People on both sides support an independent international investigation that is not directed or unduly influenced by experts with clear conflicts of interests.

Until an independent team can investigate index cases in Wuhan, sample bat caves & human populations in China (especially Mojiang, Yunnan), go through records, databases, and inventories of labs working on SARS viruses... it's going to be impossible to tell where SARS2 came from.

If, even with joined forces from both sides, an independent investigation just cannot be conducted, then we have to operate as if each pandemic emergence scenario, no matter how unlikely, is a risk that we need to mitigate in the future.

Even if SARS2 came from a lab, it doesn't reduce the risk of pandemics emerging from human activities that destroy natural habitats or create farm reservoirs of disease. This has to be acted on immediately to prevent natural pandemics.

https://twitter.com/GretaThunberg/status/1322458954132316161

Even if SARS2 came from nature sans lab activity, it doesn't reduce the risks of gain-of-function research. We have to talk about "the fallibility of even the most secure laboratories, reinforcing the urgent need for a thorough reassessment of biosafety."
cambridgeworkinggroup.org

Back to the question: "how likely is a lab escape vs natural origins of SARS2?"

The answer to this question, no matter how you calculate it, should not affect the urgency of launching an independent investigation and policies to reduce pandemic emergence from nature or lab.