Coronavirus: Meet the legend, the Chinese 'Bat Woman'

DUBAI: It’s been a frustrating time for China’s "Bat Woman", Shi Zhengli. For the past five months, she has been caught in the global COVID-19 storm.

Prof. Zhengli certainly has a fascinating persona; she earned her moniker years ago, when she discovered the link between SARS-COV and bats.

Being one of the world's foremost bat virus experts, she is recognised for her contribution to bat virology. Her credentials, scientific endeavors are beyond reproach.

Now, Prof. Zhengli is celebrated and hated, in equal measure, in her home country.

She was on a team of scientists that collected and compared strands of coronavirus. These specimens were kept in a lab, the Wuhan Institute of Virology (WIV), in Wuhan China, "ground zero" of the first infections of the novel coronavirus in late 2019.

Zhengli, along with other clinical researchers, suggested the antiviral remdesivir and anti-malaria drug chloroquine effectively inhibit the recently-emerged novel coronavirus in vitro.

Q: Who is Shi Zhengli?

Prof. Shi Zhengli, 55 (born May 26, 1964) is a Chinese virologist.

Q: How did the novel coronavirus contagion begin?

When the viral outbreak first occurred in Wuhan, central China, in late 2019, samples were collected and sent to the WIV. The contagion was causing atypical pneumonia. Prof Zhengli was quoted by The Scientific American as recalling the director of WIV called her and said, “Drop whatever you are doing and deal with it now.”

The professor hopped on a train from Shanghai, where she was attending a conference at the time, to Wuhan. She was baffled too, she told the publication.

Her studies had shown that the subtropical areas of Guangdong, Guangxi and Yunnan — not Wuhan — posed the greatest risk of a transmission of a coronavirus from an animal to a human.

Back in her Wuhan lab, the whole thing had seemed an unlikely event. She, too, wondered if it came from her lab.

Q: What did Prof Zhengli say that she did upon returning to her lab?

She insisted that she then put her lab to work. Her main objective: sequence the genomes of SARS-CoV-2 from infected patients. Next, compare these with records of the experiments they had conducted on site.

Scientific American quoted the virologist as saying she didn't find a 100% DNA match between the viruses her team was working on and the new infection from patients.

"That really took a load off my mind," she told the magazine. "I had not slept a wink for days."

Q: So what’s the storm all about? 

The Wuhan lab worked with a close relative of SARS-CoV-2 — a bat coronavirus called RaTG13.

That's according to evolutionary virologist Edward Holmes, of the Charles Perkins Center and the Marie Bashir Institute for Infectious Diseases and Biosecurity at the University of Sydney (as quoted by the Australian Media Center).

But Holmes said of the novel coronavirus: "The level of genome sequence divergence between SARS-CoV-2 and RaTG13 is equivalent to an average of 50 years (and at least 20 years) of evolutionary change." (That means that in the wild, it would take about 50 years for these viruses to evolve to be as different as they are.)

Back in 2015, an experiment involving Prof. Zhengli, who worked with a number of collaborators in the US (i.e. University of North Carolina at Chapel Hill, North Carolina, USA, in a study led by Dr. Ralph S Baric and designed/analysed by Dr Vineet D. Menachery), showed the ability of a bat coronavirus surviving and evolving to thrive in a human cell.

Prof. Baric, who works in UNC's Department of Microbiology and Immunology, is known to have also worked in "rewired TRN SARS-CoV mutants" with proceedings published in 2018.

The 2015 paper (accessed 1.89 million times as of April 20, 2020) published in the journal Nature Medicine, the researchers, described it as a "hybrid virus".

Dr Vineet D. Menachery, now works as Assistant Professor at the Department of Microbiology & Immunology of the University of Texas Medical Branch.

In the virology community, their project is known as "chimeric coronavirus", eerily similar to COVID-19. This chimera is created in a petridish, reportedly with the "surface spike protein (S protein) of a coronavirus found in horseshoe bats, called SHC014, and the backbone of a SARS virus that could be grown in mice".

The team refered to the chimeric CoV (coronavirus) as "SHC014-MA15". The study lists the following as authors: Vineet D Menachery, Boyd L Yount Jr, Kari Debbink, Sudhakar Agnihothram, Lisa E Gralinski, Jessica A Plante, Rachel L Graham, Trevor Scobey, Xing-Yi Ge, Eric F Donaldson, Scott H Randell, Antonio Lanzavecchia, Wayne A Marasco, Zhengli-Li Shi & Ralph S Baric.

Menachery designed, coordinated and performed experiments, completed analysis and wrote the manuscript, according to Nature Medicine.

Here's the scary bit about the chimeric CoV: In the lab (not clear which one), researchers said, this new coronavirus was found so potent it could infect and replicate in human airway cells "naturally". It also infected mice lung cells. It's one of the experiments which prompted Prof Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris, to warn that such research is "misleading" and "irrational", stating thus: “The consequence of any accident would be anywhere from a handful of infections to a catastrophic pandemic.”

Q: When did Prof Zhengli say she completed sequencing the DNA of the novel coronavirus?

It was on January 7, 2020, Prof. Zhengli told Scientific American.

During the current (2019–20) coronavirus pandemic, Prof. Zhengli and other WIV scientists formed an expert group on the research of SARS-CoV 2 (SARS-CoV-2).

[Note: In February 2020, her team published an article in Nature titled "A pneumonia outbreak associated with a new coronavirus of probable bat origin" (29 researchers at the WIV were listed as authors of this study, 3 February 2020].

Soon, the report claimed, an email went out from Yanyi Wang, Director of the Wuhan Institute of Virology, to staff members. The email had a stern message: all the recipients were under strict orders not to disclose information on the disease.

Wang's email reportedly came with words of caution, i.e.  that "inappropriate and inaccurate information was causing general panic". "The National Health Commission 'unequivocally requires that any tests, clinical data, test results, conclusions related to the epidemic shall not be posted on social media platforms, nor shall [it] be disclosed to any media outlets including government official media, nor shall [it] be disclosed to partner institutions'," Wang reportedly added.

Zhengli has been vilified by many mainland citizens on social media, blamed for her role in supposedly "releasing" the virus later called SARS-CoV-2. On February 2, as rumors began to circle of an escaped contagion, Zhengli posted on her WeChat account: “I swear with my life (the virus) has nothing to do with the lab.”

Just as the chatter was dying down, however, a notice from the Chinese Ministry of Science and Technology came on February 15, 2020, calling on all labs to enhance its management of viruses, reported Quartz, sparking more suspicion.

Q: What does the journal Nature Medicine  say about Prof. Shi Zhengli-Li credentials?

She is a virology scholar, listed as representing the “Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.”

She came to international prominence as "bat woman" afer Zhengli and her colleague, Cui Jie, found the SARS virus originated in bats.

Zhengli is a member of the Virology Committee of the Chinese Society for Microbiology. She is also sits in the editorial board of Virologica Sinica, the Chinese Journal of Virology, and the Journal of Fishery Sciences of China.

Q: What's the significance of her study on SARS-Cov?

From 2002, Dr. Zhengli and her team of researchers chased the origin of the deadly SARS virus in a remote cave in Yunnan province. In 2005, after years of hunt across China, they finally found their "smoking gun".

The virologists have identified a single population of horseshoe bats that harbours virus strains with all the genetic building blocks of the one that jumped to humans in 2002, killing almost 800 people around the world.

Their results were published in Science in 2005, and the Journal of General Virology in 2006.

Interestingly, in February 2020, her team also published a paper in Cell Research showing that remdesivir, an experimental drug owned by Gilead Sciences, had a "positive effect" in inhibiting the novel coronavirus in vitro, and applied for a patent for the drug in China on behalf of the WIV.

Q: What happened to her "gain-of-function" research on SARS and coronavirus?

Zhengli was involved in an investigation of bat coronaviruses, specifically "gain of function" (GOF) experiments involving both the SARS and bat coronaviruses, a joint research of University of North Carolina and Wuhan Institute of Virology.

In 2014, funding for the project in the US had been paused due to the moratorium on risky virology studies with influenza, MERS & SARS viruses, announced by the US government that year.

Q: What did the results of the 2015 study she conducted with US counterparts say?

In the 2015 study, the abstract states: “The results indicate that group 2b viruses encoding the SHC014 spike in a wild-type backbone can efficiently use multiple orthologs of the SARS receptor human angiotensin converting enzyme II (ACE2), replicate efficiently in primary human airway cells and achieve in vitro titers equivalent to epidemic strains of SARS-CoV.”

“Additionally, in vivo experiments demonstrate replication of the chimeric virus in mouse lung with notable pathogenesis. Evaluation of available SARS-based immune-therapeutic and prophylactic modalities revealed poor efficacy; both monoclonal antibody and vaccine approaches failed to neutralize and protect from infection with CoVs using the novel spike protein.”

“On the basis of these findings, we synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro and in vivo. Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.”

Q: What did the researchers say about the rapid spread of highly pathogenic viruses and the threat they pose to human populations?

“The emergence of SARS-CoV heralded a new era in the cross-species transmission of severe respiratory illness with globalization leading to rapid spread around the world and massive economic impact," they wrote in the introduction.

“Since then, several strains—including influenza A strains H5N1, H1N1 and H7N9 and MERS-CoV — have emerged from animal populations, causing considerable disease, mortality and economic hardship for the afflicted regions5. Although public health measures were able to stop the SARS-CoV outbreak4, recent metagenomics studies have identified sequences of closely related SARS-like viruses circulating in Chinese bat populations that may pose a future threat".

Q: What did they say about building a 'chimeric virus' encoding a new zoonotic CoV spike protein? 

“However, sequence data alone provides minimal insights to identify and prepare for future prepandemic viruses. Therefore, to examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs, we built a chimeric virus encoding a novel, zoonotic CoV spike protein — from the RsSHC014-CoV sequence that was isolated from Chinese horseshoe bats — in the context of the SARS-CoV mouse-adapted backbone."

"The hybrid virus allowed us to evaluate the ability of the novel spike protein to cause disease independently of other necessary adaptive mutations in its natural backbone."

"Using this approach, we characterized CoV infection mediated by the SHC014 spike protein in primary human airway cells and in vivo, and tested the efficacy of available immune therapeutics against SHC014-CoV. Together, the strategy translates metagenomics data to help predict and prepare for future emergent viruses.”

Q: What did the researchers say about viral replication in human lungs (of the “chimeric virus” that they developed)?

[We’re just copying in toto, the main discussion in the story published in Nature “A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence”, https://www.nature.com/articles/nm.3985. Published November 2015. A Corrigendum to this article was published on 06 April 2016).

“The sequences of SHC014 and the related RsWIV1-CoV show that these CoVs are the closest relatives to the epidemic SARS-CoV strains; however, there are important differences in the 14 residues that bind human ACE2, the receptor for SARS-CoV, including the five that are critical for host range: Y442, L472, N479, T487 and Y491.”

“In WIV1, three of these residues vary from the epidemic SARS-CoV Urbani strain, but they were not expected to alter binding to ACE2. This fact is confirmed by both pseudotyping experiments that measured the ability of lentiviruses encoding WIV1 spike proteins to enter cells expressing human ACE2 and by in vitro replication assays of WIV1-CoV."

“In contrast, 7 of 14 ACE2-interaction residues in SHC014 are different from those in SARS-CoV, including all five residues critical for host range."

“These changes, coupled with the failure of pseudotyped lentiviruses expressing the SHC014 spike to enter cells, suggested that the SHC014 spike is unable to bind human ACE2."

“However, similar changes in related SARS-CoV strains had been reported to allow ACE2 binding suggesting that additional functional testing was required for verification.”

Therefore, we synthesized the SHC014 spike in the context of the replication-competent, mouse-adapted SARS-CoV backbone (we hereafter refer to the chimeric CoV as SHC014-MA15) to maximize the opportunity for pathogenesis and vaccine studies in mice.

- https://www.nature.com/articles/nm.3985#change-history

“Therefore, we synthesized the SHC014 spike in the context of the replication-competent, mouse-adapted SARS-CoV backbone (we hereafter refer to the chimeric CoV as SHC014-MA15) to maximize the opportunity for pathogenesis and vaccine studies in mice.”

“Despite predictions from both structure-based modeling and pseudotyping experiments, SHC014-MA15 was viable and replicated to high titers in Vero cells.”

“Similarly to SARS, SHC014-MA15 also required a functional ACE2 molecule for entry and could use human, civet and bat ACE2 orthologs."

“To test the ability of the SHC014 spike to mediate infection of the human airway, we examined the sensitivity of the human epithelial airway cell line Calu-3 2B4 to infection and found robust SHC014-MA15 replication, comparable to that of SARS-CoV Urbani.

“To extend these findings, primary human airway epithelial (HAE) cultures were infected and showed robust replication of both viruses. Together, the data confirm the ability of viruses with the SHC014 spike to infect human airway cells and underscore the potential threat of cross-species transmission of SHC014-CoV.” [https://www.nature.com/articles/nm.3985]Q: 

Q: What honours did she receive?

Shi Zhengli is a multi-awarded scientist. Among her distinctions are:

Q: Did US officials warn about the Wuhan Institute of Virology?

Yes.

In 2018, according to a Washington Post report, US officials sent to the WIV had dispatched two diplomatic cables back to Washington which “warned about the safety and management weaknesses at the WIV lab”.

The cable noted that the US officials met with Prof. Zhengli. The cables also stated: “The researchers also showed that various SARS-like coronaviruses can interact with ACE2, the human receptor identified for SARS-coronavirus. This finding strongly suggests that SARS-like coronaviruses from bats can be transmitted to humans to cause SARS-like diseases.”

Q: What's the takeaway from Prof Shi Zhengli, the Chinese 'Bat Woman'?

It's easy to point fingers at her, though the story about her endorsement of remdesivir to treat COVID-19 (caused by SARS-CoV-2), and WIV's patent application for the antiviral drug, are interesting.

In some of her closely-scrutinised projects, she clearly did not work alone.

Numerous scholars within China, and from around the world, had collaborated with her. The gain-of-function studies she conducted with US scientists enjoyed funding from American taxpayers.

The controversial 2015 experiments on SARS-like "chimeric coronaviruses" by a team including Zhengli, were designed, coordinated and performed by Dr. Vineet D Menachery, an Indian-American scientist who now teaches at University of Texas.

What's clear is that particular study targetted the primary human airway epithelial (HAE) cultures as a route for infection — with results confirming the ability of "viruses with the SHC014 spike to infect human airway cells and underscore the potential threat of cross-species transmission of SHC014-CoV.”

Virology and genetic engineering are highly specialised fields. It's no secret that big powers and big pharma desire to master and use these to their hegemonic or commercial advantage.

POSTSCRIPT

Research on organisms/viruses with pandemic potential is the exclusive domain of the scientific fraternity. There's little known by the public — who are at the receiving end of any major outbreak — about how viral samples are stored, amplified, used and secured.

Given the nature of transcontinental travel (until COVID-19 killed it), GOF studies on viruses certainly need greater oversight, if only to to guard against unintended, horrifyng releases.

No, such specialised knowledge is not up to the experts alone to do with as they wish, or handle with blithe disregard for untold risks.

Scientific knowledge should be kept open. It's part of the common good. This highly pathogenic coronavirus that keeps us confined for weeks now just underscores the need for the world to come together. It highlights the need for a continued global surveillance of zoonotic viruses, including "chimeric", lab-made ones.

It calls for the world's scientific resources to be marshalled for the good of all. That, however, exists in an ideal world.

Now, it's up to the gene sequencing experts to show and re-confirm to the global community the direct link — or lack of it — between the GOF research, or anything like it, and the current SARS-CoV-2 pandemic.

And we can only hope that this orgy of death and the ravaging of economies and jobs across the world end sooner, rather than later.