Thread by @janeqiuchina

Meet China’s bat woman: She’s spent 18 years studying coronaviruses. She’s traced both SARS and covid to bats. Did she cause the pandemic? Is she the victim of a witch hunt? I spent 14 months trying to find answers. Join me in Wuhan and at a bat cave. 1/n
bit.ly/3oDC1sK

A long story, a long🧵:@techreview

1️⃣ What’s new & surprising?
2️⃣ What makes 🦇research incredibly painstaking and difficult that goes on at snail’s pace?
3️⃣ Did a coronavirus killed the miners in 2012?
4️⃣ What’s so dangerously fascinating about a🦇relative of SARS virus?

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A long story,a long🧵:@techreview

5️⃣ How should work on viruses of🦇origins be regulated?
6️⃣ How did a @washingtonpost op-ed launch lab leak claims?
7️⃣ What happens when mistrust is left unchecked?
8️⃣ How have the past two years marked China’s🦇woman?

Bonus: trip to a🦇cave

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The story is not about providing answers. You’ll have to make up your own minds. It’s for sophisticated readers open to new perspectives & appreciate the world in 50 shades of grey.

It’s about how this deeply entrenched controversy has come about & how we can move forward

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I visited Wuhan institute several times, often on the spur of the moment, and talked to Shi Zhengli’s team for >40 hours

My experience interacting with them was no different from labs in other parts of the world: no minder, no submitted question, no review before publication

5/

Shi has a collection of >20,000 🦇 samples from across China.Does it mean she has 20,000 🦇 viruses?

Only 10% contain coronaviruses & 10% of those are closely related to SARS-CoV-1.She’s identified only 220 such viruses. It’s RNA sequences I’m talking about, not live viruses

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Shi’s laser focus before covid: to look for🦇viruses that were closely related to SARS-CoV-1. Whenever she found one,she asked the same questions:

How threatening is it to other species,including humans?

What would it take for the virus to cause major epidemics like SARS?

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A safe way to test if a coronavirus can infect humans: using pseudoviruses—viruses whose ability to copy their genomes is disabled—to test if its spikes could help it enter cells.

It doesn’t involving working with nasty live viruses, and can be done at biosafety level 2.

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But what pseudoviruses can address is limited because:

Spikes are not the only factor that determines a virus’ ability to infect cells

The approach also can’t show how a virus makes cells sick, how it spreads from one cell to another, or how it might evade immune responses

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Those questions, which are critical for the development of drugs and vaccines, can be addressed only by using the real thing—a fully functional virus 🦠 🦠

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I didn’t realise how hard it was to isolate coronaviruses from🦇samples

🦇harbor lots of viruses but their immune system, very different from human’s,can keep them at low levels, so—contrary of patients specimens—only a small % of samples contain even a whiff of the viruses

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Until Jan 2021, Shi’s team was the only one that had managed to isolate live CoVs from 🦇samples. It’d managed to isolate only 3 🦇 CoVs

It’d also synthesized another 3 from genomic sequences

All 6 are close relatives of SARS-CoV-1. None could have been the source of covid

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But some regard RaTG13—a 🦠 in Shi’s🦇sample—a prime suspect because it was found in a mine in Mojiang in Yunnan,where 6 miners fell ill with pneumonia after cleaning up🦇guano (3 died) in 2012. It’s 96% identical to SARS-CoV-2

Were the miners infected with a SARS-like CoV?

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Local doctors blamed it on fungus infection, not uncommon in the region. Zhong Nanshan, China’s top respiratory clinician, suspected it might be caused by a virus and asked Shi to run a few tests

Shi couldn’t find evidence of infection by known viruses, including SARS-CoV-1

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After covid struck, Shi went back to Mojiang samples to look for traces of SARS-CoV-2 proteins and found none

Zhong has never reached any conclusion regarding what had sickened the miners. “It remains a mystery to this day,” he told me during our two-hour chat in his office

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Even though Shi couldn’t figure out what had sickened the miners, her instinct told her that something interesting might be going on in the cave

So she kept going back to sample 🦇 in Mojiang mine

But why—if her tests showed that miners were not infected with a SARS virus?

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This is related to an approach known as longitudinal surveillance that scientists use to find interesting viruses in 🦇, in which they sample the same cave at different seasons for years

This was how Shi found the origins of SARS in 🦇cave after 5 years of such surveillance

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Longitudinal surveillance is labor intensive. For caves 1,000 miles away, it’s expensive & logistically challenging. So Shi has to be strategic & focus on caves that are more likely to give interesting results.

Mojiang mine was a much more promising site than a random cave.

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Shi’s team didn’t think they had got anything interesting.Nine of the 300 or so coronaviruses they found in🦇samples in Mojiang mine belonged to the same group of viruses as SARS-CoV-1

They are only distant cousins—based on comparison of certain genes

Only RNA. No live 🦠

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One of 9 distant cousins of SARS-CoV-1 was sequenced in 2018. In 2020, it turned out to be 96% identical to the covid virus. It was named RaTG13.

The other 8 were sequenced after pandemic. They’re about 75% identical to both SARS and covid viruses.

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bit.ly/3MjQB2P

The overall similarity between RaTG13 & SARS-CoV-2 is not indicative of a source: RaTG13 couldn’t have naturally morphed into SARS-CoV-2.

Neither could anybody have used the 🦇 virus as the backbone to engineering the new contagion.

But how about Shi’s chimeric viruses?

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Scientists don’t create chimeric viruses for fun. Genetics is a powerful way to understand how viruses work and how to counter them.

They would start with a well characterized virus and change the viral genome one bit at a time to see how that might change its function.

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A genome is like a Lego strand consisting of different pieces strung together.

In viral genetics, you basically change one Lego piece at a time, so you can try to understand its function (eg, whether it makes the virus more infectious or better at evading immune responses)

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You can also replace a Lego piece from one virus with another lego piece from another virus, creating a chimeric virus.

This kind of genetic mixing matching is nothing new. It’s been a key workhorse of modern medicine for decades.

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Example of SHC014: a fascinating 🦇 virus that Shi discovered a decade ago in Yunnan at the birthplace of the original SARS virus.

It’s 95% identical to SARS virus, but its spike is totally different. Pseudoviruses coated with the SHC014 spikes couldn’t enter human cells.

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Does this mean that it’s unable to infect humans? Shi couldn’t test this directly because her team didn’t manage to isolate the virus.

How could we study the function of a virus when you don’t have the real thing? 🦠🦠

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Two possibilities: To synthesize the virus from its genomic sequence.

Alternatively, to test if SARS-CoV-1 could still cause disease if its spike was replaced with that of SHC014. In effect, you’d create a chimeric virus consisting SHC014’s spike in the SARS-CoV-1 backbone.

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The team led by Ralph Baric,a towering figure in virus genetics @UNC,conducted those experiments—using Shi’s genomic sequence—and the results were astounding

It turned out both synthesized SHC014 & SARS-CoV-1-SHC014 chimera were able to infect humans cells & make mice sick

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Neither was as lethal as SARS-CoV-1, but—worryingly—existing drugs and vaccines that worked against SARS were unable to counter their effects.

We are vulnerable to SHC014 and possibly many similar viruses in 🦇.

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go.nature.com/3MjMSlO

Shi’s team did similar tinkering to probe genetic ingredients that could allow🦇viruses to cause SARS-like diseases in humans

A big difference: Baric used a human pathogen; Shi used🦇virus called WIV1, the 1st they isolated, as the backbone, whose real-world risk is unknown

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Shi replaced WIV1’s spike with that from newly identified sequences of🦇coronaviruses

Again, the results were astounding: the chimera that was most pathogenic was WIV-1-SHC014, whose spike was most dissimilar to SARS-CoV-1. The one whose spike was most similar had no effect

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Conclusions:spikes are not the only factor that determines if a virus can make an animal sick

We can’t asses emergent potential of viruses using only pseudovirus assays or predictions based on genomic sequences & molecular modeling

We need live viruses & use genetics tools

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Before the pandemic, Shi’s team had created a dozen or so chimeras using close🦇relatives of SARS-CoV-1—mostly WIV1—as the backbone, only a handful of which could infect human cells

None of them was closely related to SARS-CoV-2, and so none could have caused the pandemic.

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⚠️ But working with live viruses & genetic tinkering are inherently risky

Accidents can happen: scientists might get infected in the lab; genetic tinkering might unexpectedly create a superbug whose ability to escape overmatches biosafety designation of its parental strains

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Even though none of the viruses in Shi’s bat samples or the chimera her team created could have caused the pandemic, there are concerns whether biosafety standards at the Wuhan institute are rigorous enough.

How does China regulate the research of 🦇 coronaviruses?

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China’s biosafety designations of coronaviruses:

- SARS-CoV-1, SARS-CoV-2 & MERS-CoV: BSL3
- Human CoVs that cause common cold: BSL2
- 🦇CoVs: BSL2 for molecular and culture work; BSL3 for animal work

Critics like @R_H_Ebright regard it unsafe to culture 🦇viruses at BSL2

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Is that a sign Shi’s lab has lax BSL standards?

Until recently, the dominant view was 🦇viruses would have to evolve in an intermediate animal first before they could infect humans even though some were ~96% identical to SARS-CoV-1 & could infect humans cells in Petri dish.

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It’s not uncommon for labs🌎 to grow animal viruses of🦇origins in BSL2

Porcine epidemic diarrhea virus (PEDV) & swine acute diarrhea syndrome CoV (SADS) are CoVs of bat origins.They’ve caused deadly outbreaks in 🐖 & can infect humans cells

They’re cultured in BSL-2 in US

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PEDV and SADS are potentially more dangerous to humans than Shi’s 🦇viruses because they have already been adapted in 🐖.

Pigs & humans have very similar immune systems, which is why 🐖 are used as a model system for immunology research and organ transplantation in humans.

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Based on what was known at the time,BSL2 designation for molecular & culture work of 🦇viruses was reasonable,says @angie_rasmussen

But covid should force us to reevaluate the BSL standards for viruses with unknown risks.“The pandemic has changed that risk-benefit equation”

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China’s BSL labs face other challenges:shortage of funding to train workers means that scientists can’t make the most out of the cutting-edge facilities

Managers of Wuhan BSL4 lab lamented about it in academic articles & to visiting US embassy staff

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bit.ly/3IHajmH

Some paint such challenges as clear sign of lax standards

A @washingtonpost op-ed by @joshrogin says two cables sent after US officials’ visit of Wuhan lab in 2018 meant to sound alarm & provide one more piece of evidence to support lab leak claims.

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wapo.st/3HDgvee

The op-ed marked a turning point in the debate,catapulting lab leak theory into the mainstream

@fredguterl @Newsweek: “a record of shoddy [biosafety] practices” bit.ly/3Hxgb0F

@natashaloder @TheEconomist: biosafety “was known to be spotty” econ.st/3Kg7clZ

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What did the cables really say?

Lack of trained workers could “impede research”, but “opens up even more opportunities for expert change”, noting Wuhan lab’s ability “to undertake productive research despite limitations.”

bit.ly/3Mf5TWB

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wapo.st/3tu7vmr

Scientists are appalled by misrepresentation of the embassy cables:

The cables “did not appear to focus on any specific safety concerns or egregious activities within the laboratory,” @KindrachukJason

Neither do they shed any light on covid origins debate, says @BillHanage

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Many scientists are dismayed by the way Shi and Wuhan institute are portrayed in Western media:

It’s shockingly biased, driven partly by geopolitical motive and deep-rooted prejudice, says @angie_rasmussen @robertson_lab, who have no connection to Shi or Wuhan institute.

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It’s hard to separate allegations against Shi from general suspicion of China:“Shi is a victim of the Western mistrust of China & Chinese science,”says @DrJoyZhang

Some think that everything in Wuhan institute’s freezers would have been cleared out and data records scrubbed

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Shi finds such allegations “baseless and appalling”:“If that’s what they think,then there is nothing we can do to convince them otherwise”

Some in the West agree:“I’m quite distressed by people throwing this kind of extremely serious allegations around,” says Nancy Connell

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But to be fair to those who don’t trust Chinese institutions, China’s questionable credibility and curious missteps haven’t helped:

- Massive coverup during SARS
- Obfuscation about early covid cases
- Ministry rules: scientists have to seek approval to publish covid work

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Now the fun part: A trip to a 🦇cave in Hubei province (where Wuhan sits)!

The cave is Shi’s home base, where the team goes regularly. It’s damp and smelly. But 🦇 are gentle and lovely. They provide important ecological services by eating insects and pollinating flowers.

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In addition to taking swabs, Shi’s team also banded dozens of🦇and fixed satellite tags to a handful—very much in the same ways birds are studied

The goal is to trace their movement & the pathogens they carry and to see how their range might overlap with human populations.

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It’s crucial to determine the exposure risks of rural people, especially in regions teeming with SARS-like viruses

Shi’s team found 4% of people living close to🦇& working with wildlife—9% among butchers—in southern China were infected with dangerous viruses, including CoVs

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It’s worrying considering that viruses closely related to SARS-CoV-2 spread over a massive geographic range, from Japan to Cambodia.

“It’s quite terrifying really to think how we can fuck this up by not finding where those viruses are and risk more spillover, @robertson_lab

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Solution? Long-term surveillance of wildlife,farmed animals,people who live close to wildlife & work in animal trade

“It can help strengthen capacity building in neglected rural regions. It should be a concerned global effort,”says Fabian Leendertz

We need to work together

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But Chinese scientists are increasingly wary of international collaboration.

Trained in France, Shi cherishes critical thinking, independent-mindedness, and not following the crowd: “I used to admire the West. I used to think it was a just and meritocratic society.”

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What does Shi think now?

“Now I think if you are Chinese then it doesn’t matter how good you are at your job—because you are tried by nationality”

“I’ve now realised that Western democracy is hypocritical,and that much of its media is driven by lies, prejudices & politics”

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“They’ve lost the moral high ground as far as I’m concerned,” says China’s 🦇 woman.

If politics trumps science, “then there will be no basis for any cooperation.”

It will be a lose-lose scenario. It’s sobering—and real.

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Excited to talk to @PeaseRoland about the time I spent with China’s🦇woman,about her work on CoVs,what she’s like as a person,her international outlook, and how past 2 years had marked her: 22-32 min. @amsterdammed @BBCRadio4

bit.ly/3JEYy0o

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bbc.in/3CgXugq

Thrilled to be featured as the lead in @bbcworldservice Science in Action. @PeaseRoland

Did Shi Zhengli run a clandenstine coronavirus factory?

Was it painstaking work carried out at snail’s pace under international norms?

bit.ly/3JEYy0o

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bbc.in/3hDMKQ1

Thanks @jonsawyer for highlighting my @techreview story in @pulitzercenter newsletter.Thanks for supporting quality journalism that matters

“Qiu’s deeply reported,fair-minded presentation of a controversial,complex subject is illustrative of the Pulitzer Center at its best”

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https://twitter.com/janeqiuchina/status/1491445332089384960

“This story by former @KSJatMIT fellow and acclaimed science writer @janeqiuchina is fascinating. But it's also meticulous, fair-minded, insightful - and wholly worth your time”

— Deborah Blum: Pulitzer-winning journalist and director of
@KSJatMIT

bit.ly/3JEYy0o

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https://twitter.com/deborahblum/status/1491473226282815490

“I am jealous of @janeqiuchina. She has written the masterpiece I wish I'd been able to do. This is an absolute must-read.”

— Laurie Garrett: Pulitzer-winning journalist, author of The Coming Plague: Newly Emerging Diseases in a World Out of Balance

bit.ly/3JEYy0o

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https://twitter.com/laurie_garrett/status/1491583632548507653

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