Thread by @wanderer_jasnah

okay, here we go! #COVIDUnknowns livetweet.

George Davey Smith (@mendel_random) is the Session 1 Chair!

https://twitter.com/wanderer_jasnah/status/1446126755341737985

our first speaker is Diego Forni & he'll be talking about how our 4 seasonal HCoVs arose! (a topic i myself have been quite interested in). #COVIDUnknowns

technical difficulties, b/c what would a webinar be w/o technical difficulties...

bit of background overview, two group A β-CoVs (HCoV-OC43, HCoV-HKU1) & two alpha-CoVs. all are endemic, originated in animals...

HCoV-229E: in 2007, a very similar virus was found in alpacas. however, the origin is (unsuprisingly) bats; it jumped to camelids at some point & separated from the camel CoV lineage ~1770.

OC43: as anyone that follows me likely knows, it originates from a bovine CoV making a hop likely somewhere around 1890 (coinciding w/a respiratory pandemic). the original host however is suspected to be RODENTS, w/the hop then to cows.

HCoV-NL63: distantly related to bat alpha-CoVs found in European(!) & American(!!!) bats. intermediate host is unknown, separation from its closest known bat virus is ancient. tMRCA of all known strains is ~1940 - ~1950, emergence date is completely unknown.

HKU1: similarly to OC43, ancient host is again rodents. intermediate host, if any, is unknown. no similar animal β-CoVs to HKU1 have been found. tMRCA of all known strains in circulation is, again, ~1950.

moving on to @bart_haagmans, who will be giving a talk on the origins of SARS Classic & MERS! #COVIDUnknowns.

looking at the MERS-CoV outbreaks, it's apparent that the early outbreaks are due to separate spillovers. this led to the first identification of MERS-CoV in dromedary camels in Qatar, which were not just seropositive but tested +ve for the virus via RT-PCR.

the earliest known camelid sample that was +ve in Africa in 1992, but outbreaks in Africa are unknown. it turns out the picture in Africa & the Middle East is very different due to different virological behaviour.

i'll link my livetweet of Malik Peiris' talk that @bart_haagmans is referencing right now:

https://twitter.com/wanderer_jasnah/status/1402225493856993284

now, onto SARS Classic! here we actually have a good picture of bat -> civet -> human transmission, w/later SARS Classic isolates having a number of genetic differences from the civet ones that was due to human adaptation.

after the initial outbreak, there was a later outbreak in a restaurant from civets in 2004, confirming that civet -> human zoonotic transmission could readily happen.

further research by @Baric_Lab & Dr.Shi Zhengli showed that direct spillover is possible & furthermore from #SARSCoV2, it's been demonstrated that sarbecovirus spillover is possible *back* into animals (in NL mink farms).

so far, an intermediate host for #SARSCoV2 has not been demonstrated.

bringing up the recent Institut Pasteur Laos sarbecovirus preprint, which is again a fascinating read, showing a huge diversity of bat CoVs & massive recombination: researchsquare.com/article/rs-871…

next up, @MarionKoopmans on What We Need To Know to Investigate the Origins of a SARS Outbreak! #COVIDUnknowns.

wrong slideset, lmao...

discussing the summary graphic from the WHO origins likelyhood routes, from most to least likely: zoonotic via intermediate host, zoonotic direct from bats, popsicle origins, lab leak.

going over studies requested in the outbreak, from epidemological studies of respiratory diseases in the timeframe of the early outbreak plus before, virological re-analysis of raw seq. data, etc.

mandate was discussed in Nov. 2020, trip was in July 2021. first two weeks were in hotel quarantine, the next two weeks had the face-to-face meetings & fieldwork.

looking at Wuhan excess mortality data, which doesn't begin to become notable until the second half of January 2020.

conclusion from the epi data: there was widespread circulation in December, but not earlier. Huanan market was a superspreader event, probably not source.

stall-by-stall look at Huanan market vendors is inconclusive due to highly complex supply chains, LACK OF DATA ON FUR ANIMALS(!!!), no detection of #SARSCoV2 in animals other than bats.

re-analysis of genomic data: two clusters, some diversity already. this demonstrates clearly these are not the early cases; tMRCA is as early as mid-November.

adding in early sequences from Sichuan shows intriguing placement wrt these two clusters, more investigation is needed w/early sequences from here!!!

finally, there was a look at WIV, Wuhan CDC, the Agricultural Lab & some hospitals. no evidence from any lab events & no earlier cases found from that, ultimately inconclusive but indeed unlikely.

"zoonotic still ranking highest. other options *are* very difficult to rule out." (i agree fwiw).

next up, Jacques van Helden, on The Importance of Keeping an Open Mind on Origins. #COVIDUnknowns.

talking about the Lancet letter... basically, showing that our current understanding is inconclusive so we should keep an open mind.

claim that the argument that "if #SARSCoV2 is engineered, there'd be a known backbone" is fallacious b/c scientists generally keep sequences secret until published, giving the example of RaTG13 as an example.

hoo boy, the DEFUSE application making an appearance.

also a very... optimistic view of how one might create a consensus sarbecovirus seq. via reverse genetics.

talking about FCS insertions done experimentally (which are consensus sequences), "both origins plausible" (i disagree strongly)...

i can feel my blood pressure rising LOL.

talking about the RBD which *was* highly divergent until recently, w/again the Laos bat sarbecovirus paper showing that BANAL-52 has a highly similar RBD, is able to infect human cells & is within bat flying distance to most of China. still missing ~40 years of evolution.

closing comments about biosafety protocols needing updating b/c labs are making potential pandemic viruses... finally, it's over.

last talk of session#1 by Jonathan Latham & Allison Wilson on the Mojiang Mine Outbreak.

i just heard the phrase "Mojiang mine passage theory" & well... i'm not enthusiastic. #COVIDUnknowns

claim that "there was a concerted effort" to hide links between RaTG13 & #SARSCoV2 b/c the former has been studied since 2013 & got renamed in a paper.

i am less than impressed.

claim that the hospitalization of the miners allowed for human adaptation, & that samples were taken from the miners & taken to WIV, what was done w/the samples.

claim that in the process of sequencing & testing these samples, one of those samples escaped & caused the pandemic.

i promise i will try to be objective but i will admit i am literally facepalming IRL right now.

claim that b/c B.1.1.7 had an accelerated evolutionary trajectory on the order of ~30 mutations, that the same is somehow??? possible??? for RaTG13 on a scale an order of magnitude higher???

this argument is incoherent.

nearest i can tell his argument is that B.1.1.7 occurred via each mutation in a high diversity environment followed by recombination of all of the mutations recombining together??? i genuinely do not understand how this person thinks CoV recombination works.

does this person seriously think S13I & W152C arose *independently* & recombined to remodel the B.1.427 NTD instead of sequential mutation? wtf???

i'm really sorry but literally none of this makes any sense.

finally, it's over, thank fuck. heading straight into session#2 due to lack of time: first up is @angie_rasmussen talking about GoF research: what it is & safety concerns!

defining GoF in general, & more importantly specifically what it means in virology & furthermore what dangerous GoF is.

technically an Adenovirus vaccine is a "gain of function", so even w/o virology it's a wide definition, despite this obviously being not dangerous.

onto specifically what a lot of people think about when they consider GoF, which is "dual use research of concern" GoF, w/the classical example being GoF that looks into improved human transmissibility.

the infamous Fouchier H5N1 serial passaging GoF paper makes an appearance! this would in fact be a prototypical example of DURC GoF, & led to a three-year GoF moratorium in the USA.

there are costs & benefits to such research... the moratorium led to much-needed discussions & regulation, but as a side-effect *did* hamper flu vaccine research for some time.

discussion of the FBI Select Agent program, the strictness of it (for instance, b/c a (+)ssRNA virus is immediately transcriptable into virions, even a CoV genome would fall under this, not just infectious virus) & some history on it.

talking about the P3CO framework, which is talking specifically about GoF research in a PPP (Potential Pandemic Pathogen) that leads to increased transmissibility or pathogenicity *in humans*.

the ***VAST MAJORITY*** of virology experiments DO NOT fall into this category.

finally, an overview on just how much effort & thought goes thru into oversight on any experiments done on potential pandemic pathogens, starting from the PI up to institutions & all the way up to governmental regulations.

closing comments on benefits & risks of not doing this sort of research: on the one hand, not researching this means that we have less risk of lab-related outbreaks but those can be mitigated, & only one pandemic has conclusively been linked to lab work.

conversely, not researching this means that we lack knowledge on dealing w/viruses that have caused... every other pandemic (which have clearly been natural) & unlike the former, these *cannot* be mitigated.

next up, Alison Young on Lab Leaks: Governance & Safety. #COVIDUnknowns.

talking about in 2020, in the USA, there were 134 reported occupational exposure incidents to "select agent" pathogens.

only one of these led to an illness (Q fever).

incident in 2007 of the Pirbright lab leak where a faulty drainage pipe leaked foot-and-mouth disease onto nearby farms... hundreds of cattle had to be culled to contain it.

(lab was confirmed as the source due to the strain being one not in active circulation for decades but widely used in research).

obligatory mention of the 1977 flu pandemic that was from PLA vaccine trials.

talk of the three SARS Classic lab hops, one in Singapore in a WNV researcher, one in Taiwan & one in Beijing, the last of which led to a small outbreak & one death (the mother of one of the grad students involved).

talk of limitations of transparency in a lot of lab safety rules & lab accident disclosure, mostly from this USA today article: usatoday.com/story/news/201…

next up, Johanna Lindahl on Wet Markets: What they Are; Safety & Regulation. #COVIDUnknowns.

talking about how not all wet markets are animal markets, & most of those aren't exotic animal markets.

"where are wet markets" basically it overlaps population centers, unsurprisingly.

this isn't the worst wet market discourse i've heard (not by a longshot) but it's making up for that by being fairly content-free. speaker can't decide on if she wants to discuss wet markets in general or live animal markets in particular & it's just kind of mildly exasperating.

next up, Dilys Roe & Tien Ming Lee on the Wildlife Trade! #COVIDUnknowns.

i feel like i can see @rzhongnotes astral-projecting & facepalming in response to this talk.

most of this talk is going to be similar to the following paper: nature.com/articles/s4189…

huge calls to ban the wildlife trade in the wake of the #COVID19 pandemic from many groups for many reasons.

claim that out of a survey of 5000 scientific articles that discuss wildlife trade & human diseases, only 145 mention at least one case of a human disease in the context of wildlife use & trade.

HOWEVER: risk is not uniform across species, or across conditions (such as species mixing that normally wouldn't occur in the wild, or extremely cramped conditions that lead to animal stress & increase human exposure).

negative consequences of banning wildlife trade completely: negatively affecting FOOD SECURITY for millions of people living in rural conditions in developing countries, affecting livelyhoods of people...

...& if you remove wild meat from diets, this would lead to an increase in agricultural land demand, which would lead to significant habitat conversion, which can lead to extinction of species.

land conversion itsself is a MAJOR risk of zoonotic exposure, so paradoxically a total wildlife trade ban done carelessly likely will *increase* the risk of future zoonotic spillover.

any approach that actually would decrease zoonotic spillover risk needs to treat causes, not symptoms. increased safety, awareness, cooperation w/locals in the trade.

(i very much agree).

next up, Roger Frutos on Studies of Circulating Animal CoVs! #COVIDUnknowns.

talking about how all countries were caught unprepared b/c we caught the disease but this was *after* it had already spilled over. instead, we should look at preventing the emergence of an infectious disease.

LMAO I *HAVE* TO SHARE THIS IMAGE FROM THIS SLIDE:

talking about how species barrier is an illusion, viruses readily jump hosts & all you need is contact & minimal affinity for a receptor.

...while i agree w/the quasispecies model for RNA viruses in general, i don't agree that you can actually consider sarbecoviruses in general a quasispecies. too broad.

rough split of an outbreak into Sylvatic, Societal & Medical phases. not much we can do in the first phase (circulation in the wild) b/c it's just too broad. in the third phase it's too late.

let's focus on the stochastic societal phase *before* when the virus is amplified past the "epidemic threshold". this is the only phase in which we can do anything about preventing a future pandemic.

finally, the last speaker, @SpyrosLytras talking about Lessons from the History of CoV Evolution for the Future! #COVIDUnknowns.

talking about trying to determine phylogenetic relationships between CoVs, trying to find progenitors (for instance, RaTG13 is *not* a prgenitor of #SARSCoV2) & figuring out what the evolutionary history is like.

talking about how recombination makes this difficult (esp. when parts of a CoV genome can be recombined from an unknown lineage) & how we need to treat evolutionary history of recombinant sections on their own carefully.

discussion of the pangolin viruses & how they fit on the evolutionary tree relative to the other SARS2r-CoVs which all have been sampled in horseshoe bats (Rhinolopus spp), many of which have *extensive* geographic ranges.

another mention of the *excellent* Laos bat CoV paper (researchsquare.com/article/rs-871…) & how, allowing for recombination, two of the recently-discovered viruses are the closest relatives to #SARSCoV2.

final takeaways: we've really just scratched the surface of CoV diversity: it's insanely high & the geographic host range is *extremely* broad.

brief mention of the African Swine Fever outbreak in 2019 in China...

lastly: we live in an extremely interconnected world, & all this means that pandemic risks continue to go up over time as a result.

AND WE'RE DONE!!! this wasn't @NIDO20201 but it still was difficult lmao. Q&A now (which i won't be livetweeting).

most of the talks were pretty good, & this was fun as always.