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How large a part of the corona-virus is coding?

How large a part of the corona-virus is coding?


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If you find an example of a sequenced string of coronavirus it is about 30.000 long. Looking for example here https://nextstrain.org/ncov/europe you'll see that by far the largest part of this is actually coding. But is that because that is the entire strain or is it because they are only showing the ORF-part? If the latter is the case how large is the non-coding part then compared to the coding part?


It is about 92% of the RNA that is protein-coding. ORF10 is not coding according to newer results, see e.g. Jungreis, Sealfon, and Kellis (2021). The article is about identifying protein-coding ORFs and distinguishing them from non-coding ones.


No, the coronavirus wasn’t made in a lab. A genetic analysis shows it’s from nature

The SARS-CoV-2 virus (seen in this transmission electron microscope image of virus isolated from a U.S. patient), which causes COVID-19, was rumored to be human-made, but scientists have now debunked that theory.

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The coronavirus pandemic circling the globe is caused by a natural virus, not one made in a lab, a new study says.

The virus’s genetic makeup reveals that SARS-CoV-2 isn’t a mishmash of known viruses, as might be expected if it were human-made. And it has unusual features that have only recently been identified in scaly anteaters called pangolins, evidence that the virus came from nature, Kristian Andersen and his colleagues report March 17 in Nature Medicine.

When Andersen, an infectious disease researcher at the Scripps Research Institute in La Jolla, Calif., first heard about the coronavirus causing an outbreak in China, he wondered where the virus came from. Initially, researchers thought the virus was being spread by repeated infections jumping from animals in a seafood market in Wuhan, China, into humans and then being passed person to person. Analysis from other researchers has since suggested that the virus probably jumped only once from an animal into a person and has been spread human to human since about mid-November (SN: 3/4/20).

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But shortly after the virus’s genetic makeup was revealed in early January, rumors began bubbling up that maybe the virus was engineered in a lab and either intentionally or accidentally released.

An unfortunate coincidence fueled conspiracy theorists, says Robert Garry, a virologist at Tulane University in New Orleans. The Wuhan Institute of Virology is “in very close proximity to” the seafood market, and has conducted research on viruses, including coronaviruses, found in bats that have potential to cause disease in people. “That led people to think that, oh, it escaped and went down the sewers, or somebody walked out of their lab and went over to the market or something,” Garry says.

Accidental releases of viruses, including SARS, have happened from other labs in the past. So “this is not something you can just dismiss out of hand,” Andersen says. “That would be foolish.”

Looking for clues

Andersen assembled a team of evolutionary biologists and virologists, including Garry, from several countries to analyze the virus for clues that it could have been human-made, or grown in and accidentally released from a lab.

“We said, ‘Let’s take this theory — of which there are multiple different versions — that the virus has a non-natural origin … as a serious potential hypothesis,’ ” Andersen says.

Meeting via Slack and other virtual portals, the researchers analyzed the virus’s genetic makeup, or RNA sequence, for clues about its origin.

It was clear “almost overnight” that the virus wasn’t human-made, Andersen says. Anyone hoping to create a virus would need to work with already known viruses and engineer them to have desired properties.

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But the SARS-CoV-2 virus has components that differ from those of previously known viruses, so they had to come from an unknown virus or viruses in nature. “Genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone,” Andersen and colleagues write in the study.

“This is not a virus somebody would have conceived of and cobbled together. It has too many distinct features, some of which are counterintuitive,” Garry says. “You wouldn’t do this if you were trying to make a more deadly virus.”

Other scientists agree. “We see absolutely no evidence that the virus has been engineered or purposely released,” says Emma Hodcroft, a molecular epidemiologist at the University of Basel in Switzerland. She was not part of Andersen’s group, but is a member of a team of scientists with Nextstrain.org that is tracking small genetic changes in the coronavirus to learn more about how it is spreading around the world.

That finding debunks a widely disputed analysis, posted at bioRxiv.org before peer review, that claimed to find bits of HIV in the coronavirus, Hodcroft says. Other scientists quickly pointed out flaws in the study and the authors retracted the report, but not before it fueled the notion that the virus was engineered.

Some stretches of the virus’s genetic material are similar to HIV, but that’s something that stems from those viruses sharing a common ancestor during evolution, Hodcroft says. “Essentially their claim was the same as me taking a copy of the Odyssey and saying, ‘Oh, this has the word the in it,’ and then opening another book, seeing the word the in it and saying, ‘Oh my gosh, it’s the same word, there must be parts of the Odyssey in this other book,” she says. “It was a really misleading claim and really bad science.”

Finding peculiar features

Andersen’s group next set out to determine whether the virus could have been accidentally released from a lab. That’s a real possibility because researchers in many places are working with coronaviruses that have potential to infect humans, he says. “Stuff comes out of the lab sometimes, almost always accidentally,” he says.

A couple of unexpected features of the virus caught the researchers’ eyes, Andersen says. In particular, the gene encoding the coronavirus’s spike protein has 12 extra RNA building blocks, or nucleotides, stuck in it.

This spike protein protrudes from the virus’ surface and allows the virus to latch onto and enter human cells. That insertion of RNA building blocks adds four amino acids to the spike protein, and creates a site in the protein for an enzyme called furin to cut. Furin is made in human cells, and cleaves proteins only at spots where a particular combination of amino acids is found, like the one created by the insertion. SARS and other SARS-like viruses don’t have those cutting sites.

See all our coverage of the coronavirus outbreak

Finding the furin cutting site was a surprise: “That was an aha moment and an uh-oh moment,” Garry says. When bird influenza viruses acquire the ability to be cut by furin, the viruses often become more easily transmissible. The insertion also created places where sugar molecules could be fastened to the spike protein, creating a shield to protect the virus from the immune system.

The COVID-19 virus’ spike protein also binds more tightly to a protein on human cells called ACE2 than SARS does (SN: 3/10/20). Tighter binding may allow SARS-CoV-2 to more easily infect cells. Together, those features may account for why COVID-19 is so contagious (SN: 3/13/20).

“It’s very peculiar, these two features,” Andersen says. “How do we explain how this came about? I’ve got to be honest. I was skeptical [that it was natural]. This could have happened in tissue culture” in a lab, where viruses may acquire mutations as they replicate many times in lab dishes. In nature, viruses carrying some of those mutations might be weeded out by natural selection but might persist in lab dishes where even feeble viruses don’t have to fight hard for survival.

Clinching the case for nature

But then the researchers compared SARS-CoV-2 with other coronaviruses recently found in nature, including in bats and pangolins. “It looks like SARS-CoV-2 could be a mix of bat and pangolin viruses,” Garry says.

Viruses, especially RNA viruses such as coronaviruses, often swap genes in nature. Finding genes related to the pangolin viruses was especially reassuring because those viruses’ genetic makeup wasn’t known until after SARS-CoV-2’s discovery, making it unlikely anyone was working with them in a lab, he says.

Coronaviruses that infect pangolins gave researchers important clues that the SARS-CoV-2 virus is natural. 2630ben/iStock/Getty Images Plus

In particular, pangolins also have the amino acids that cause the tight binding of the spike protein to ACE2, the team found. “So clearly, this is something that can happen in nature,” Andersen says. “I thought that was very important little clue. It shows there’s no mystery about its tighter binding to the human [protein] because pangolins do it, too.”

The sugar-attachment sites were another clue that the virus is natural, Andersen says. The sugars create a “mucin shield” that protects the virus from an immune system attack. But lab tissue culture dishes don’t have immune systems, making it unlikely that such an adaptation would arise from growing the virus in a lab. “That sort of explained away the tissue-culture hypothesis,” he says.

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Similarity of SARS-CoV-2 to bat and pangolin viruses is some of the best evidence that the virus is natural, Hodcroft says. “This was just another animal spillover into humans,” she says. “It’s really the most simple explanation for what we see.” Researchers still aren’t sure exactly which animal was the source.

Andersen says the analysis probably won’t lay conspiracy theories to rest. Still, he thinks the analysis was worth doing. “I was myself skeptical at the beginning and I kept flipping back and forth,” Andersen says, but he’s now convinced. “All the data show it’s natural.”

Questions or comments on this article? E-mail us at [email protected]

Citations

K. G. Andersen et al. The proximal origin of SARS-CoV-2. Nature Medicine. Published online March 17, 2020. doi: 10.1038/s41591-020-0820-9.


Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2 pro ), the Nsp3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth.

Keywords: Innate immunity Macrodomain Nucleic-acid binding domain Papain-like protease Structural biology Ubiquitin-like domain.

Copyright © 2017 Elsevier B.V. All rights reserved.

Figures

Genome organization of coronaviruses Nsp3…

Genome organization of coronaviruses Nsp3 domains and their functions. (A) The 5′-terminal two…

Structures (in cartoon view) of…

Structures (in cartoon view) of the ubiquitin-like domain 1 (Ubl1) and Ubl2 in…

Crystal structure of the papain-like…

Crystal structure of the papain-like protease domain 1 (PL1 pro ) of TGEV.…

Structure of the MERS-CoV macrodomain…

Structure of the MERS-CoV macrodomain I (Mac1, X domain) in complex with ADP-ribose…

Structures (in cartoon style) of…

Structures (in cartoon style) of the macrodomains II (Mac2) and III (Mac3), of…

Structure of the SARS-CoV papain-like…

Structure of the SARS-CoV papain-like protease 2 (PL2 pro ) in complex with…

Recently described inhibitors of the…

Recently described inhibitors of the CoV PL2 pro . (A) Structural formula of…

NMR structure of the nucleic…

NMR structure of the nucleic acid-binding (NAB) domain in SARS-CoV (cartoon style PDB…

Multiple sequence alignment of the…

Multiple sequence alignment of the 3Ecto and the N-terminal portion of the Y1…


How does COVID-19 spread?

Like other respiratory diseases, COVID-19 primarily spreads through small droplets—saliva or mucus—that an infected person expels when they cough, sneeze, or talk. These droplets can travel three to six feet and remain infectious for anywhere from four to 48 hours, depending on the surface. (The virus may also spread via accidental consumption of fecal matter or aerosols, tiny particles that are mostly a concern in clinical settings.)

You can protect yourself from catching the virus by staying six feet away from others and washing your hands with soap and water for more than 20 seconds.


Genome study reveals East Asian coronavirus epidemic 20,000 years ago

Professor Kirill Alexandrov. Credit: QUT

An international study has discovered a coronavirus epidemic broke out in the East Asia region more than 20,000 years ago, with traces of the outbreak evident in the genetic makeup of people from that area.

Professor Kirill Alexandrov from CSIRO-QUT Synthetic Biology Alliance and QUT's Centre for Genomics and Personalised Health, is part of a team of researchers from the University of Arizona, the University of California San Francisco, and the University of Adelaide who have published their findings in the journal Current Biology.

In the past 20 years, there have been three outbreaks of epidemic severe coronaviruses: SARS-CoV leading to Severe Acute Respiratory Syndrome, which originated in China in 2002 and killed more than 800 people MERS-CoV leading to Middle East Respiratory Syndrome, which killed more than 850 people, and SARS-CoV-2 leading to COVID-19, which has killed 3.8 million people.

But this study of the evolution of the human genome has revealed another large coronavirus epidemic broke out thousands of years earlier.

"The modern human genome contains evolutionary information tracing back tens of thousands of years, like studying the rings of a tree gives us insight into the conditions it experienced as it grew," Professor Alexandrov said.

In the study, the researchers used data from the 1000 Genomes Project, which is the largest public catalog of common human genetic variation, and looked at the changes in the human genes coding for SARS-CoV-2 interacting proteins.

An international study has discovered a coronavirus epidemic broke out in the East Asia region more than 20,000 years ago, with traces of the outbreak evident in the genetic makeup of people from that area. Credit: QUT

They then synthetized both human and SARS-CoV-2 proteins, without using living cells, and showed that these interacted directly and specifically pointed to the conserved nature of the mechanism coronaviruses use for cell invasion.

"Computational scientists on the team applied evolutionary analysis to the human genomic dataset to discover evidence that the ancestors of East Asian people experienced an epidemic of a coronavirus-induced disease similar to COVID-19," Professor Alexandrov said.

East Asian people come from the area that is now China, Japan, Mongolia, North Korea, South Korea, and Taiwan.

"In the course of the epidemic, selection favored variants of pathogenesis-related human genes with adaptive changes presumably leading to a less severe disease," Professor Alexandrov said.

"By developing greater insights into the ancient viral foes, we gain understanding of how genomes of different human populations adapted to the viruses that have been recently recognized as a significant driver of human evolution.

"Another important offshoot of this research is the ability to identify viruses that have caused epidemic in the distant past and may do so in the future.

"This, in principle, enables us to compile a list of potentially dangerous viruses and then develop diagnostics, vaccines and drugs for the event of their return."


COVID: Top 10 current conspiracy theories

As the COVID-19 crisis worsens, the world also faces a global misinformation pandemic. Conspiracy theories that behave like viruses themselves are spreading just as rapidly online as SARS-CoV-2 does offline. Here are the top 10 conspiracy theories making the rounds.

Blaming 5G

This conspiracy theory should be easy to debunk: it is biologically impossible for viruses to spread using the electromagnetic spectrum. The latter are waves/photons, while the former are biological particles composed of proteins and nucleic acids. But that isn’t really the point — conspiracy theories are enticing because they often link two things which at first might appear be correlated in this case, the rapid rollout of 5G networks was taking place at the same time the pandemic hit. Cue a viral meme linking the two, avidly promoted by anti-vaccine activists who have long been spreading fears about electromagnetic radiation, egged on by the Kremlin.

It’s worth repeating, as the World Health Organization (WHO) points out, that viruses cannot travel on mobile networks, and that COVID-19 is spreading rapidly in many countries that do not have 5G networks. Even so, this conspiracy theory — after being spread by celebrities with big social media followings — has led to cellphone towers being set on fire in the UK and elsewhere.

Bill Gates as scapegoat

Most conspiracy theories, like the viruses they resemble, constantly mutate and have several variants circulating at any one time. Many of these plots and subplots seem to involve Bill Gates, who became a new target of disinformation after gently criticizing the defunding of the World Health Organization. According to the New York Times, anti-vaxxers, members of QAnon and right-wing pundits have seized on a video of a 2015 Ted talk given by Gates — where he discussed the Ebola outbreak and warned of a new pandemic — to bolster their claims he had foreknowledge of the COVID pandemic or even purposely caused it.

A recent variant of this conspiracy theory, particularly beloved by anti-vaccination activists, is the idea that COVID is part of a dastardly Gates-led plot to vaccinate the world’s population. There is some truth in this, of course: vaccinating much of the world’s population may well be the only way to avoid an eventual death toll in the tens of millions. But anti-vaxxers don’t believe vaccines work. Instead some have spread the myth that Gates wants to use a vaccination program to implant digital microchips that will somehow track and control people. The spread of misinformation has meant that ID2020, a small non-profit that focuses on establishing digital IDs for poorer people around the world, has had to call in the FBI. (The Cornell Alliance for Science is partly funded by the Bill & Melinda Gates Foundation.)

The virus escaped from a Chinese lab

This one at least has the benefit of being plausible. It is true that the original epicenter of the epidemic, the Chinese city of Wuhan, also hosts a virology institute where researchers have been studying bat coronaviruses for a long time. One of these researchers, Shi Zhengli, a prominent virologist who spent years collecting bat dung samples in caves and was a lead expert on the earlier SARS outbreak, was sufficiently concerned about the prospect that she spent days frantically checking lab records to see if anything had gone wrong. She admits breathing a “sigh of relief” when genetic sequencing showed that the new SARS-CoV-2 coronavirus did not match any of the viruses sampled and studied in the Wuhan Institute of Virology by her team.

However, the sheer coincidence of China’s lead institute studying bat coronaviruses being in the same city as the origin of the COVID outbreak has proven too juicy for conspiracists to resist. The idea was seeded originally via a slick hour-long documentary produced by the Epoch Times, an English-language news outlet based in the United States with links to the Falun Gong religious cult that has long been persecuted by the Chinese Communist Party (CCP). The Epoch Times insists on calling COVID “the CCP virus” in all its coverage. The theory has now tipped into the mainstream, being reported in the Washington Post, the Times (UK) and many other outlets.

COVID was created as a biological weapon

A spicier variant is that COVID not only escaped from a lab, but it was intentionally created by Chinese scientists as a biowarfare weapon. According to Pew Research, “nearly three-in-10 Americans believe that COVID-19 was made in a lab,” either intentionally or accidentally (the former is more popular: specifically, 23 percent believe it was developed intentionally, with only 6 percent believing it was an accident).

This theory that the Chinese somehow created the virus is particularly popular on the US political right. It gained mainstream coverage thanks to US Sen. Tom Cotton (Republican, Arkansas) who amplified theories first aired in the Washington Examiner (a highly conservative media outlet) that the Wuhan Institute of Virology “is linked to Beijing’s covert bio-weapons program.”

This theory can be easily debunked now that there is unambiguous scientific evidence — thanks to genetic sequencing — that the SARS-CoV-2 virus has entirely natural origins as a zoonotic virus originating in bats. The Examiner has since added a correction at the top of the original piece admitting the story is probably false.

The US military imported COVID into China

The Chinese government responded to the anti-China theories with a conspiracy theory of its own that seeks to turn blame back around onto the United States. This idea was spread initially by Chinese foreign ministry spokesman Zhao Lijian, who Tweeted “it’s possible that the US military brought the virus to Wuhan.” These comments, according to Voice of America news, “echoed a rumored conspiracy, widely circulated in China, that US military personnel had brought the virus to China during their participation in the 2019 Military World Games in Wuhan last October.” For China, as the Atlantic reported, this conspiracy theory, and an accompanying attempt to rename COVID the “USA virus,”’ was a transparent “geopolitical ploy” — useful for domestic propaganda but not widely believed internationally.

GMOs are somehow to blame

Genetically modified crops have been a target of conspiracy theorists for years, so it was hardly a surprise to see GMOs blamed in the early stages of the COVID pandemic. In early March, Italian attorney Francesco Billota penned a bizarre article for Il Manifesto, falsely claiming that GM crops cause genetic pollution that allows viruses to proliferate due to the resulting environmental “imbalance.” Anti-GMO activists have also tried to blame modern agriculture, which is strange, since the known path of the virus into the human population — as with Ebola, HIV and many others — was through the very ancient practice of people capturing and killing wildlife.

Ironically, GMOs will almost certainly be part of any vaccine solution. If any of the ongoing 70 vaccine projects work (which is a big if), that would be pretty much the only guaranteed way the world can get out of the COVID mess. Vaccines could be based on either GM attenuated viruses or use antigens produced in GM insect cell lines or plants. If GMOs do help save the world from the curse of COVID, maybe they’ll stop being a dirty word.

COVID-19 doesn’t actually exist

According to professional conspiracy theorists like David Icke and InfoWars’ Alex Jones, COVID-19 doesn’t actually exist, but is a plot by the globalist elite to take away our freedoms. Early weaker versions of this theory were prevalent on the political right in the notion that the novel coronavirus would be “no worse than flu” and later versions are now influencing anti-lockdown protests across several states in the US. Because believers increasingly refuse to observe social distancing measures, they could directly help to spread the epidemic further in their localities and increase the resulting death rate.

The pandemic is being manipulated by the ‘deep state’

Some believe that a “deep state” of America’s elite is plotting to undermine the president — and that Dr. Anthony Fauci, the face of the US coronavirus pandemic response — is a secret member. Fauci’s expression of disbelief when the deep state was mentioned during a press briefing supposedly gave the game away.

COVID is a plot by Big Pharma

Many conspiracy theory promoters are in reality clever actors trying to sell quack products. Alex Jones, between rants about hoaxes and the New World Order, urges viewers to buy expensive miracle pills that he claims can cure all known diseases. Dr. Mercola, a quack anti-vax and anti-GMO medic who has been banned from Google due to peddling misinformation, claims that vitamins (and numerous other products he sells) can cure or prevent COVID. NaturalNews, another conspiracist site, sells all manner of pills, potions and prepper gear. These conspiracists depend for their market on getting people to believe that evidence-based (i.e. conventional) medicine doesn’t work and is a plot by big pharmaceutical companies to make us ill. Big Pharma conspiracies are a staple of anti-vaccination narratives, so it is hardly surprising that they have transmuted into the age of the coronavirus.

COVID death rates are inflated

Another far-right meme is the idea that COVID death rates are being inflated and therefore there is no reason to observe lockdown regulations or other social distancing measures. Prominent in promoting this myth is Dr. Annie Bukacek, whose speech warning that COVID death certificates are being manipulated has been viewed more than a quarter of a million times on YouTube. Bukacek appears in a white lab coat and with a stethoscope around her neck, making her look like an authoritative medical source. Dig a little deeper, however, as Rolling Stone magazine did, and it turns out she’s actually a far-right anti-vaccination and anti-abortion activist, previously noted for bringing tiny plastic fetuses into the Montana state legislature. Her insistence that COVID death rates are inflated has, of course, no basis in fact. More likely the current death toll is a serious under-count. T0 further clarify the issue, the Centers for Disease Control has published information about excess deaths associated with COVID-19.

How to recognize and debunk conspiracy theories

It is important to speak out and combat online misinformation and conspiracist narratives, whether on COVID or climate change or anything else. This handbook (PDF) by John Cook and Stephan Lewandowsky, both of whom have extensive experience in combating climate denialism, is an essential tool.

Note: As in previous coverage, it is our policy to avoid linking directly to websites and social media feeds that promote misinformation and conspiracy theories, so as not to drive traffic to them and give them higher visibility.


Did the SARS-CoV-2 virus arise from a bat coronavirus research program in a Chinese laboratory? Very possibly.

On May 15, the Bulletin of the Atomic Scientists published a short commentary titled, &ldquoLet evidence, not talk radio, determine whether the outbreak started in a lab,&rdquo by Ali Nouri, a biologist and president of the Federation of American Scientists. &ldquoThe outbreak&rdquo referred to the pandemic of SARS-CoV-2 now circling the globe. It is a thin commentary, and it is puzzling why the Bulletin thought it desirable to publish it at all. Only two weeks earlier the journal had published a reasoned and competent appraisal by Kings College London biosecurity expert Filippa Lentzos titled, &ldquoNatural spillover or research lab leak? Why a credible investigation is needed to determine the origin of the coronavirus pandemic.&rdquo

The Nouri article very correctly pilloried the statements by President Donald Trump, Secretary of State Mike Pompeo, presidential legal advisor Rudy Giuliani, and radio personality Rush Limbaugh. These are as notorious a gang of four fabricators as will ever likely be recorded in American history. They were ably assisted by Fox News, which the Nouri critique also mentions. Nouri ended his commentary with these lines: &ldquoOur leaders ought to … take steps to prevent the next pandemic, instead of diverting our attention to unsupported sensationalist theories spread by cable TV and talk radio.&rdquo

Perhaps the most damaging blows to efforts to obtain a certain answer as to the origin of the SARS-CoV-2 &ldquooutbreak&rdquo have been the pronouncements by Trump, Pompeo, and their echo chambers. But they and their remarks are not the measure by which the question of the possibility that a laboratory escape began the pandemic should be examined. Trump&rsquos diversionary ranting comes from a president who did nothing for two months in the face of an oncoming lethal pandemic, actively denied and denigrated intelligence warnings of the imminent danger, and said that SARS-CoV-2 would &ldquojust go away … like a miracle&rdquo and that &ldquowithin a couple of days is going to be down close to zero.&rdquo All this has been widely and thoroughly chronicled. 1

But long before Trump, Pompeo and Co. sought a Chinese scapegoat for the president&rsquos gross and willful incompetence, researchers understood that the possibility of laboratory escape of the pathogen was a plausible, if unproven, possibility. It is most definitely not &ldquoa conspiracy theory.&rdquo

The circumstantial evidence for a lab escape. By way of introduction, there are two virology institutes in Wuhan to consider, not one: The Wuhan Center for Disease Control and Prevention (WHCDC) and the Wuhan Institute of Virology (WIV). Both have conducted large projects on novel bat viruses and maintained large research collections of novel bat viruses, and at least the WIV possessed the virus that is the most closely related known virus in the world to the outbreak virus, bat virus RaTG13. This virus was isolated in 2013 and had its genome published on January 23, 2020. Seven more years of bat coronavirus collection followed the 2013 RaTG13 isolation.

One component of the novel-bat-virus project at the Wuhan Institute of Virology involved infection of laboratory animals with bat viruses. Therefore, the possibility of a lab accident includes scenarios with direct transmission of a bat virus to a lab worker, scenarios with transmission of a bat virus to a laboratory animal and then to a lab worker, and scenarios involving improper disposal of laboratory animals or laboratory waste.

Documentary evidence indicates that the novel-bat-virus projects at Wuhan CDC and the Wuhan Institute of Virology used personal protective equipment and biosafety standards that would pose high risk of accidental infection of a lab worker upon contact with a virus having the transmission properties of the outbreak virus.

In assessing the possibility of a lab accident, one must take into consideration each of the following eight elements of circumstantial evidence:

1. Official Chinese government recognition early in the SARS-CoV-2 outbreak of biosafety inadequacies in China&rsquos high containment facilities. In February 2020, several weeks after the outbreak of the disease in Wuhan, China&rsquos President Xi Jinping stressed the need to ensure &ldquobiosafety and biosecurity of the country.&rdquo 2 This was followed immediately by a China Ministry of Science & Technology announcement of new guidelines for laboratories, especially in handling viruses. 3 Almost at the same time, the Chinese newspaper Global Times published an article on &ldquochronic inadequate management issues at laboratories, including problems of biological wastes.&rdquo 4

A PBS NewHour presentation on May 22, 2020 provided the following information:

On January 1, Wuhan Institute of Virology&rsquos director general, Yanyi Wang, messaged her colleagues, saying the National Health Commission told her the lab&rsquos COVID-19 data shall not be published on social media and shall not be disclosed to the media. And on January 3, the commission sent this document, never posted online, but saved by researchers, telling labs to destroy COVID-19 samples or send them to the depository institutions designated by the state. Late Friday [May 16, 2020] the Chinese government admitted to the destruction &hellip but said it was for public safety.

The Chinese government explanation for the destruction of SARS-CoV-2 samples has no scientific credibility. For purposes of &ldquopublic safety&rdquo any samples would surely be stored and studied, exactly as with the ones that were isolated from patients, and their RNA genomes decoded and published.

2. Recognition by Zhengli Shi, a renowned scientist who leads a research team at the Wuhan Institute of Virology, that a laboratory escape was a possibility. Shi took the possibility of a laboratory escape perfectly seriously. Jonna Mazat of the University of California-Davis, a collaborator with Dr Shi, told Josh Rogin of the Washington Post, &ldquoAbsolutely, accidents can happen.&rdquo In an interview with Scientific American, Shi admitted that her very first thought was &ldquoIf coronaviruses were the culprit, she remembers thinking &lsquoCould they have come from our lab?&rsquo”

Meanwhile she frantically went through her own lab&rsquos records from the past few years to check for any mishandling of experimental materials, especially during disposal. She breathed a sigh of relief when the results came back: none of the sequences matched those of the viruses her team had sampled from bat caves. &lsquoThat really took a load off my mind,&rsquo she says. &lsquoI had not slept a wink for days.&rsquo

3. Questions surrounding Chinese government attribution of the Wuhan&rsquos Huanan South China Seafood Market as the source of the SARS-CoV-2 virus. Many China scholars noted that it was quite unusual for Chinese government authorities to identify Wuhan&rsquos Huanan South China Seafood Market so quickly as the source of the outbreak. They thought this behavior so uncharacteristic that it raised suspicions in their minds. The authors of a newly published paper wrote that

&hellipwe were surprised to find that SARS-CoV-2 resembles SARS-CoV in the late phase of the 2003 epidemic after SARS-CoV had developed several advantageous adaptations for human transmission. Our observations suggest that by the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV. However, no precursors or branches of evolution stemming from a less human-adapted SARS-CoV-2-like virus have been detected&hellip. It would be curious if no precursor or branches of SARS-CoV-2 evolution are discovered in humans or animals&hellip.Even the possibility that a non-genetically-engineered precursor could have adapted to humans while being studied in a laboratory should be considered, regardless of how likely or unlikely. 5

It is important to note that no intermediary host has yet been identified for the SARS-CoV-2 virus. The authors also noted that &ldquo[n]o animal sampling prior to the shutdown and sanitization [of the Wuhan fish market] was done.&rdquo

The question of whether the index case appeared in the Wuhan fish market appears to be moot in any case. Chinese researchers have published data showing that there were 41 cases of SARS-CoV-2 between December 1, 2019 and January 2, 2020. Fourteen of these had no contact with the Huanan seafood market, including the very first recorded case on December 1, 2019. 6 And that supposes that the true index case was December 1, which is doubtful.

On May 26, the Chinese government scrapped the previous official story about the Wuhan fish market:

China&rsquos top epidemiologist said Tuesday that testing of samples from a Wuhan food market, initially suspected as a path for the virus&rsquos spread to humans, failed to show links between animals being sold there and the pathogen. Gao Fu, director of the Chinese Center for Disease Control and Prevention, said in comments carried in China state media. 7

No SARS-CoV-2 isolates were detected in any of the animals or fish sold at the market, only in environmental samples, including sewage. Gao Fu added, &ldquoAt first, we assumed the seafood market might have the virus, but now the market is more like a victim. The novel coronavirus had existed long before.&rdquo 8

4. Suppression of information and individuals by Chinese authorities. A publication by two Chinese university academics discussed both the WHCDC and the WIV and concluded that &ldquothe killer coronavirus probably originated from a laboratory in Wuhan&rdquo the publication was removed from the internet by Chinese government officials. The paper had been posted on Research Gate but was blocked after 24 hours. After being placed on an archive file by internet users, it was again blocked after a week, and the two Chinese authors were pressured to retract the paper. However, it is still available on Web archives. 9

The Chinese government closed the laboratory in Shanghai that first published the genome of COVID-19 on January 10, explaining that it had been shuttered for &ldquorectification&rdquo the closure happened on January 11. The government then permitted the same genome to be published by Shi on January 12. 10 Chinese citizens who reported on the coronavirus were censured and, in some cases, &ldquodisappeared.&rdquo 11 These have included businessman Fang Bin, lawyer Chen Qiushi, former state TV reporter Li Zehua and, most recently, Zhang Zhan, a lawyer. They are reportedly being held in extrajudicial detention centers for speaking out about China&rsquos response to the pandemic. They are usually accused of &ldquopicking quarrels and provoking trouble.&rdquo 12

Another aspect of Chinese government secrecy involved in the SARS-CoV-2 pandemic relates to official reporting by Chinese government officials on the severity of the outbreak in China and on levels of mortality. The number of cases and deaths are suspected of being undercounted by at least an order of magnitude, and possibly two, meaning that the reported figures could be as little as one percent of the actual totals. In the last week of April 2020, Caixin, one of the most reliable publications in China, reported that a serological study had been carried out in Wuhan on 11,000 inhabitants. Extrapolating from its results, which showed that five to six percent of the sample of 11,000 persons carried antibodies for SARS-CoV-2, Caixin estimated that 500,000 people in the city had been infected, or 10 times the level of official Chinese government reporting. The publication was quickly deleted by Chinese government censors. 13

The Chinese government has also attempted to obscure the origins of the pandemic with disinformation. On March 13, Chinese Foreign Ministry spokesperson Zhao Lijian suggested that the United States might have introduced the coronavirus to Wuhan. 14 A month later, Zhao Lijian again posted Russian coronavirus and biowarfare-related disinformation, this time followed by online posts from Chinese ambassadors in 13 countries spread across the world. 15 This was unprecedented diplomatic behavior for China, but not an accident. It was a concerted, deliberate, and preposterous disinformation campaign, repeated in May by CGTN, the China Global Television Network, which reposted the disinformation to the social media sites Weibo, Facebook, and Twitter. 16 The history of Soviet and then Russian government biowarfare disinformation suggests that a country spreading such disinformation has or may have something to hide. 17

5. Laboratory accidents and the escape of highly dangerous pathogens from laboratories are frequent occurrences worldwide. The accidental infection of researchers in the highest containment biosafety facilities&mdashlabelled BSL-2, BSL-3 and BSL-4&mdashoccurs worldwide, as do accidental releases by other means. In an excellent review published in February 2019, Lynn Klotz of the Center for Arms Control and Non-Proliferation noted that three releases of Ebola and Marburg viruses from BSL-4 and lower-containment facilities in the United States had occurred due to incomplete inactivation of cultures. Releases via infection of researchers took place in the highest containment facilities in the United States&mdashat the Centers for Disease Control and Prevention (CDC) in Atlanta and at the US Army Medical Research Institute of Infectious Diseases (USAMRIID)&mdashbut in all cases only the researcher became ill, and there was no further transmission of the pathogen.

&ldquoIn an analysis circulated at the 2017 meeting for the Biological Weapons Convention, a conservative estimate shows that the probability is about 20 percent for a release of a mammalian-airborne-transmissible, highly pathogenic avian influenza virus into the community from at least one of 10 labs over a 10-year period of developing and researching this type of pathogen,&rdquo Klotz wrote. &ldquoThis percentage was calculated from FSAP [US Federal Select Agent Program] data for the years 2004 through 2010. Analysis of the FOIA NIH (National Institutes of Health) data gives a much higher release probability&mdashthat is, a factor five to 10 times higher, based on a smaller number of incident reports.&rdquo 18

Between 2009 and 2015, the FSAP recorded 749 incidents in seven categories&mdashnot solely releases or researcher infections&mdashfrom 276 facilities. In addition, Klotz recorded 11 confirmed releases of select agents that resulted in a laboratory-acquired infection in roughly 280 specifically approved laboratories in the United States between 2003 and 2017, a rate of just under one per year. 19 A second publication in the Bulletin that covered closely-related subject matter and a personal communication from its author suggested that federally reported cases involving select agents were likely to be substantially undercounted: 20

There is a fundamental problem of using the defined select agents as a surrogate for potential pandemic agent releases from research labs. The vast majority of &lsquoclassical BW agents&rsquo that initially defined select agents in the US were selected specifically to be NOT capable of sustained transmission so as to better define the military tactical limits of a military employment and because the establishment of progressive transmission was considered unpredictable and possibly counterproductive in military operations, at least on the US side of offensive development in the 1940s-1960s.

As my historical review of lab escapes that resulted in pandemics or wide area epidemics published in the BAS found, most pandemic, continental or large scale community outbreaks originating from lab escapes came from civilian labs working with public or veterinary pathogens of non-military interest.

It takes only one superspreading graduate student or maintenance worker to start a pandemic.

It is known that a very large percentage of the individuals infected with the SARS-CoV-2 virus show no symptoms and do not become clinically ill, which would facilitate an unrecognized infection of one or more laboratory researchers.

6. There have been laboratory accidents and escapes of highly dangerous pathogens in China in general and biosafety issues at the Wuhan Institute of Virology in particular. After the SARS epidemic in 2002-2003, which originated naturally in China and which China initially kept secret, work on the coronavirus pathogen that was responsible for the outbreak was undertaken in laboratories around the world. This research led to six cases of infection in laboratory workers: four in the National Institute of Virology in Beijing and one each in laboratories in Singapore and Taiwan.

The laboratory-acquired infections of lab workers in Beijing led to short-lived outbreaks of SARS in the Beijing region in 2004. 21

A second case of infected researchers in China resulted in brief outbreaks of disease in early December 2019. An outbreak of brucellosis began in an agricultural laboratory in Lanzhou (Gansu Province, central China) and spread to China&rsquos premier bird flu laboratory in Harbin (Heilongjiang Province, northeast China). It was linked to index cases involving graduate students who were exposed while conducting research and included at least 96 people. 22

7. Under what biosafety conditions was bat coronavirus research carried out at the Wuhan Institute of Virology? Most work&mdashincluding all published work using live bat coronaviruses that were not SARS-CoV and MERS-CoV&mdashwas conducted under BSL-2 conditions. 23 This was consistent with both WHO and CDC recommendations. 24 BSL-2 provides only minimal protection against infection of laboratory researchers, and these regulations were almost certainly too lenient for working with bat coronaviruses. All such work should have been carried out under BSL-3 conditions. However, extremely high-risk gain of function (GoF) studies with bat SARS-related coronaviruses were carried out at BSL-3 or BSL-4. Statements made by various commentators claiming that the WIV worked only with RNA isolates and not with live viruses are untrue (as discussed in further detail in a following section).

In regard to the Wuhan Institute of Virology in particular, relevant information is again available from both Chinese and Western sources. Information from official Chinese government sources appeared in a Voice of America report which noted:

[T]here is Chinese evidence that the lab had safety problems. VOA has located state media reports showing that there were security incidents flagged by national inspections as well as reported accidents that occurred when workers were trying to catch bats for study.

About a year before the corona virus outbreak, a security review conducted by a Chinese national team found the lab did not meet national standards in five categories.

The document on the lab&rsquos official website said after a rigorous and meticulous review, the team gave a high evaluation of the lab&rsquos overall safety management. &ldquoAt the same time, the review team also put forward further rectification opinions on the five non-conformities and two observations found during the review.&rdquo
In addition to problems in the lab, state media also reported that national reviewers found scientists were sloppy when they were handling bats.

One of the researchers working at the Wuhan Center for Disease Control & Prevention described to China&rsquos state media that he was once attacked by bats, and he ended up getting bat blood on his skin.

In another incident, the same researcher forgot to take protective measures, and the urine of a bat dripped &ldquolike rain onto the top of his head,&rdquo reported China&rsquos Xinhua state news agent. 25

Also, information was leaked from the US Department of State and published in the Washington Post on April 14:

Two years before the novel coronavirus pandemic upended the world, U.S. Embassy officials visited a Chinese research facility in the city of Wuhan several times and sent two official warnings back to Washington about inadequate safety at the lab, which was conducting risky studies on corona viruses from bats. The cables have fueled discussions inside the U.S. government about whether this or another Wuhan lab was the source of the virus &ndash even though conclusive proof has yet to emerge.

In January 2018, the U.S. Embassy in Beijing took the unusual step of repeatedly sending U.S. science diplomats to the Wuhan Institute of Virology, which had in 2015 become China&rsquos first laboratory to achieve the highest level of international bioresearch safety (known as BSL-4). WIV issued a news release in English about the last of these visits, which occurred on March 27, 2018. The U.S. delegation was led by Jamison Fouss, the consul general in Wuhan, and Rick Switzer, the embassy&rsquos counselor of environment, science, technology and health. Last week, WIV erased that statement from its website, though it remains archived on the Internet.

What the U.S. officials learned during their visits concerned them so much that they dispatched two diplomatic cables categorized as Sensitive But Unclassified back to Washington. The cables warned about safety and management weaknesses at the WIV lab and proposed more attention and help. The first cable &hellip also warns that the lab&rsquos work on bat coronaviruses and their potential human transmission represented a risk of a new SARS-like pandemic.

&ldquoDuring interactions with scientists at the WIV laboratory, they noted the new lab has a serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory,&rdquo states the Jan. 19, 2018, cable, which was drafted by two officials from the embassy&rsquos environment, science and health sections who met with the WIV scientists.

&ldquoMost importantly,&rdquo the cable states, &ldquothe 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. From a public health perspective, this makes the continued surveillance of SARS-like coronaviruses in bats and study of the animal-human interface critical to future emerging coronavirus outbreak prediction and prevention. 26

The US government had supplied a portion of the funds to build the Wuhan Institute of Virology and these cables were an appeal for funds to support additional training in biosafety and biosecurity. There were similar concerns about the nearby Wuhan Center for Disease Control and Prevention lab, which operates entirely at BSL-2. Chinese government authorities did not provide the US government with samples of the virus obtained from either the earliest cases or from the Wuhan fish market. A US intelligence official commented: &ldquoThe idea that it was just a totally natural occurrence is circumstantial. The evidence it leaked from the lab is circumstantial. Right now, the ledger on the side of it leaking from the lab is packed with bullet points, and there&rsquos almost nothing on the other side.&rdquo 27

8. What is the nature of the research being carried out in Zhengli Shi&rsquos laboratory at the Wuhan Institute of Virology? Details of the most recent National Institute of Allergy and Infectious Diseases (NIAID) grant for WIV bat coronavirus surveillance and WIV bat coronavirus gain of function research are publicly available. The key activity for bat coronavirus surveillance is &ldquoAim 1 &hellip We will sequence receptor binding domains (spike proteins) to identify viruses with the highest potential for spillover which we will include in our experimental investigations (Aim 3).&rdquo The key activity for bat coronavirus gain of function investigation is &ldquoAim 3&hellip. We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments, and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential.&rdquo 28

Translated into something approaching lay language, Aim 3 states that de novo synthesis is to be used to construct a series of novel chimeric viruses, comprising recombinant hybrids using different spike proteins from each of a series of unpublished natural coronaviruses in an otherwise-constant genome of a bat coronavirus. The ability of the resulting novel viruses to infect human cells in culture and to infect laboratory animals would be tested. The underlying hypothesis is that a direct correlation would be found between the receptor-binding affinity of the spike protein and the ability to infect human cells in culture and to infect laboratory animals. This hypothesis would be tested by asking whether novel viruses encoding spike proteins with the highest receptor-binding affinity have the highest ability to infect human cells in culture and laboratory animals.

The WIV began its gain of function research program for bat coronaviruses in 2015. Using a natural virus, institute researchers made &ldquosubstitutions in its RNA coding to make it more transmissible. They took a piece of the original SARS virus and inserted a snippet from a SARS-like bat coronavirus, resulting in a virus that is capable of infecting human cells.&rdquo 29 This meant it could be transmitted from experimental animal to experimental animal by aerosol transmission, which means that it could do the same for humans. In other words, gain of function techniques were used to turn bat coronaviruses into human pathogens capable of causing a global pandemic.

There have been three publications, in 2015, 30 2016 and 2017, describing the WIV gain of function research. The WIV, having learned both basic and traceless infectious-clone technology from joint research with a laboratory at the University of North Carolina (UNC) in 2015, initiated construction of novel chimeric coronaviruses without UNC immediately thereafter. WIV&rsquos first publication on the use of basic infectious-clone technology to construct novel chimeric coronaviruses at WIV appeared in 2016. 31 WIV&rsquos first publication on the use of traceless, signature-free infectious-clone technology also appeared in 2016. 32

As this article was being edited, two excellent publications appeared that provide greater technical detail on WIV&rsquos gain of function research, and readers should certainly examine these with care. 33 The two papers strongly support the argument that the SARS-CoV-2 outbreak was the results of an escape from one of the two Chinese virology laboratories in Wuhan.

The Chinese government has proudly stated that the WIV &ldquopreserves more than 1,500 strains of virus,&rdquo the largest collection in Asia of bat and other coronaviruses. 34 (The government statement probably should have said 1,500 isolates rather than &ldquostrains.&rdquo) The 2019 interview with Shi in Scientific American reports that the WIV had at least hundreds of individual strains. 35 These numbers have been reported by Chinese government authorities, and they are being taken at face value here.

From 2004 on, the WIV published many dozens of partial or full genome sequences of coronaviruses in their collection. On June 1, Daszak and Shi published partial genetic sequences of 781 Chinese bat coronaviruses, more than one-third of which had never been published previously. 36 There are also multiple published records of animal infection research with bat coronaviruses at the WIV. In order to carry out the research program described above, the WIV laboratory needs to use live viruses, and not just RNA fragments. This contradicts two of the assertions, made by some commentators, that Shi worked only with RNA fragments and that her laboratory did not maintain live viruses. On May 24, 2020, the director of the WIV acknowledged that the laboratory did have &ldquothree live strains of bat corona viruses on site,&rdquo but implied only three. 37 Knowledgeable virologists assume that the number must be much higher, probably hundreds of live viral isolates. 38

It is precisely in the course of the kind of gain of function research that the WIV conducted that there would be the greatest likelihood of infection of a laboratory researcher. Many commentators have noted that millions of people in several western Chinese provinces, as well as in other South Asian countries, live their lives in daily proximity to bat caves and that serological testing has shown a fraction of these villagers to have antibodies to bat coronaviruses, showing that natural infection had occurred. The commentators argue therefore that &ldquothe odds&rdquo are in favor of SARS-CoV-2 having arisen in the field, and that a laboratory escape is so implausible that it is out of consideration. The logic of &ldquothe odds&rdquo is specious: It would take only a single laboratory infection to overcome &ldquothe odds,&rdquo if such could in fact be reckoned. That is essentially what happened in the four SARS laboratory infections that occurred in the Beijing laboratory in 2004 &ldquothe odds&rdquo for exposure of villagers in Yunnan province were irrelevant.

Since the SARS-CoV-2 genome was decoded and published, there have been numerous statements from virologists that the genome shows no indication of genetic manipulation, and that this too supports the argument that it arose in the field and did not escape from a laboratory. Although this argument implicitly recognizes that the WIV laboratory was using genetic engineering technology, there is no reason to arbitrarily assume that only a bat coronavirus that was genetically modified might have escaped from the laboratory. Nevertheless, the second portion of the NIAID research grant design made absolutely clear that the WIV would be applying genetic engineering techniques to bat coronaviruses. Using the current standard genetic engineering technology, many alterations of several bases in the RNA genome would be undetectable, including construction of a chimeric coronavirus encoding an unpublished spike protein in an unpublished genome. This would be the equivalent of a natural mutation in several bases that coded for the spike proteins.

An article in Independent Science News by Jonathan Latham and Allison Wilson discusses another mechanism, described by Nikolai Petrovsky of Flinders University in Australia, that could have resulted in the SARS-CoV-2 virus that produced the pandemic:

Take a bat coronavirus that is not infectious to humans, and force its selection by culturing it with cells that express human ACE2 receptor, such cells having been created many years ago to culture SARS coronaviruses and you can force the bat virus to adapt to infect human cells via mutations in its spike protein, which would have the effect of increasing the strength of its binding to human ACE2, and inevitably reducing the strength of its binding to bat ACE2.

Viruses in prolonged culture will also develop other random mutations that do not affect its function. The result of these experiments is a virus that is highly virulent in humans but is sufficiently different that it no longer resembles the original bat virus. Because the mutations are acquired randomly by selection there is no signature of a human gene jockey, but this is clearly a virus still created by human intervention. 39

Final comments. On April 30, Newsweek described a report produced by the US Defense Intelligence Agency which stated that &ldquoin early February, China&rsquos Academy for Military Medical Sciences &lsquoconcluded that it was impossible for them to scientifically determine whether the Covid-19 outbreak was caused naturally or accidentally from a laboratory incident.&rsquo&rdquo The author of a newly published paper analyzing the genome of SARS-COV-2 reported that &ldquothe COVID-19 virus is exquisitely adapted to infect humans&hellip The virus&rsquos ability to bind protein on human cells was far greater than its ability to bind the same protein in bats, which argues against bats being a direct source of the human virus.&rdquo 40

Overall, the data indicates that SARS-CoV-2 is uniquely adapted to infect humans, raising important questions as to whether it arose in nature by a rare chance event or whether its origins might lie elsewhere.

Geng Shuang, a spokesman for the Chinese Ministry of Foreign Affairs, said. &ldquoChina has mentioned many times that the origin of the virus is a scientific question, which should be evaluated by scientists and medical experts, and should not be politicized.&rdquo 41 Essentially the same position on the possibility that a lab leak originated the pandemic was expressed by Xiao Qiang, a research scientist at the School of Information at the University of California, Berkeley. &ldquoI don&rsquot think it is a conspiracy theory. I think it&rsquos a legitimate question that needs to be investigated and answered. To understand exactly how this originated is critical knowledge for preventing this from happening in the future.&rdquo 42

But Chinese officials reacted angrily in April when Australian officials suggested that the World Health Organization should be able to quickly investigate a disease outbreak that could lead to a pandemic, retaliating by instituting trade restrictions on several Australian agricultural exports to China. In early May, the World Health Organization&rsquos representative in China, Gauden Galea, publicly complained that China had refused repeated requests to permit the WHO to participate in whatever investigations the Chinese government was undertaking itself. He said that the WHO had not been given access to laboratory logs at the WIV or the Wuhan Chinese Center for Disease Control and Prevention. 43

On May 18, prior to a meeting of the WHO governing board, the European Union submitted a draft resolution supported by 100 nations that asked the WHO &ldquoto work with other United Nations agencies to &lsquoidentify the zoonotic source of the virus and the route of introduction to the human population, including the possible role of intermediate hosts. &hellip The document does not propose a review to identify missteps in how countries handled the outbreak and is instead forward-looking. It calls on the WHO to potentially arrange &lsquoscientific and collaborative field missions&rsquo to help prevent similar future outbreaks. It also appears to rule out the possibility that the virus was man-made or experimented upon.&rdquo 44

The draft resolution did not mention Wuhan or China. 45

On May 18, China&rsquos President Xi addressed the meeting of the governing body of the WHO via video. Ironically, Xi asked that countries &ldquostep up information sharing&rdquo but declared that China would support a review of the pandemic led by the WHO as long as it was &ldquoobjective and impartial&rdquo and held after the pandemic was under control or over. The operative WHO resolution focuses on identifying &ldquothe zoonotic source of the virus&rdquo and says nothing about any forensic investigation. 46 The Chinese Foreign Ministry spokesman Zhao Lijian declared that &ldquoChina supported an international inquiry all along,&rdquo and China&rsquos Global Times asked: &ldquoWill China oppose scientific research into the virus&rsquo origin? No, because it is a necessary move to fight COVID-19 in a scientific way and conducive to prevention measures and development of vaccines and medicine,&rdquo but added &ldquoNot only China-related factors but also those related to the US and other countries need to be included. Earlier confirmed cases than the previously known first infected case have continuously been found in the US. Among those diagnosed as having flu last winter, how many were coronavirus infections? All these clues shouldn&rsquot be missed.&rdquo 47

What does this all mean at the present time? We have in China:

&bull a record of laboratory escape of the SARS virus in 2004 from a premier Chinese research institute.
&bull a record of poor biosafety in some of its high-containment facilities, including in the Wuhan institutes.
&bull a record of suppression of information in general, and in the case of SARS-CoV-2 in particular.
&bull the initiation of a disinformation campaign in regard to the origin of SARS-CoV-2, targeting US biological laboratories.
&bull a record of gain of function research at the Wuhan Institute of Virology, including passage of a bat coronavirus construct through experimental animals.

Writing in the Bulletin of the Atomic Scientists before the WHO governing board was convened, Filippa Lentzos advocated for a forensic investigation and described what it would entail:

Investigating the range of possible spillover sites&mdashfrom the wet market, to an accidental lab or fieldwork infection, or an unnoticed lab leak&mdashrequires a forensic investigation. Obtaining case histories, epidemiological data, and viral samples from different times and places, including the earliest possible samples from infected individuals and samples from wildlife, is paramount&hellip A forensic investigation would additionally involve auditing and sampling viral collections at relevant labs that had been studying coronaviruses, examining the types of experiments carried out and the viruses used, and reviewing the safety and security practices in place. Key data would also come from documents, including standard operating procedures at the labs and during fieldwork, risk assessments of individual experiments, experiment logs and fieldwork notebooks, training records, waste management logs, accident and infection records, facility maintenance and automated systems records, access logs, security camera footage and communications logs. …A COVID-19 origins investigation will need to be negotiated and begun rapidly before relevant data diminishes or disappears entirely as time passes. 48

There is no semblance of any of this in the WHO resolution, and one can scarcely imagine that any of it would be permitted by the current administration in China. An investigation held after the pandemic &ldquois under control&rdquo cannot possibly be carried out &ldquorapidly,&rdquo and is in fact postponed into the indefinite future. Unfortunately, if there were any documentation in either of the two Wuhan virology institutes that recorded the infection of a laboratory researcher or an escape, or that either had a virus sample that was extremely similar to SARS-CoV-2, one has to assume that such information has already been removed or destroyed.

Others have suggested that an international &ldquocommission, independent of the WHO, needs to be set up with the broad objective of how to ameliorate the next pandemic. Its mandate should go well beyond that of the WHO and part of its work could be to look at how COVID-19 started.&rdquo 49 Unfortunately it is equally difficult to envision such a commission coming to pass.

At present, the origin of SARS-CoV-2 remains unknown. The pros and cons regarding the two alternative possibilities&mdashfirst, that it arose in the field as a natural evolution, as many virologists maintain, or second, that it may have been the consequence of bat coronavirus research in one of the two virology research institutes located in Wuhan that led to the infection of a laboratory researcher and subsequent escape&mdashare equally based on inference and conjecture. The points gathered in this paper can be no more than suggestive. There is no hard scientific evidence to support either position. Both are inferences from circumstantial evidence. The US administration&rsquos political hectoring only assures that it will be very difficult if not impossible to ever find out which is true.

Acknowledgements: The author would like to thank several colleagues with far-better computer skills than he has for supplying many of the electronic references. I would also like to thank several colleagues for reading and commenting on the paper. This manuscript was submitted for publication on May 27, 2020.


Why the Coronavirus Has Been So Successful

We’ve known about SARS-CoV-2 for only three months, but scientists can make some educated guesses about where it came from and why it’s behaving in such an extreme way.

One of the few mercies during this crisis is that, by their nature, individual coronaviruses are easily destroyed. Each virus particle consists of a small set of genes, enclosed by a sphere of fatty lipid molecules, and because lipid shells are easily torn apart by soap, 20 seconds of thorough hand-washing can take one down. Lipid shells are also vulnerable to the elements a recent study shows that the new coronavirus, SARS-CoV-2, survives for no more than a day on cardboard, and about two to three days on steel and plastic. These viruses don’t endure in the world. They need bodies.

But much about coronaviruses is still unclear. Susan Weiss, of the University of Pennsylvania, has been studying them for about 40 years. She says that in the early days, only a few dozen scientists shared her interest—and those numbers swelled only slightly after the SARS epidemic of 2002. “Until then people looked at us as a backward field with not a lot of importance to human health,” she says. But with the emergence of SARS-CoV-2—the cause of the COVID-19 disease—no one is likely to repeat that mistake again.

To be clear, SARS-CoV-2 is not the flu. It causes a disease with different symptoms, spreads and kills more readily, and belongs to a completely different family of viruses. This family, the coronaviruses, includes just six other members that infect humans. Four of them—OC43, HKU1, NL63, and 229E—have been gently annoying humans for more than a century, causing a third of common colds. The other two—MERS and SARS (or “SARS-classic,” as some virologists have started calling it)—both cause far more severe disease. Why was this seventh coronavirus the one to go pandemic? Suddenly, what we do know about coronaviruses becomes a matter of international concern.

The structure of the virus provides some clues about its success. In shape, it’s essentially a spiky ball. Those spikes recognize and stick to a protein called ACE2, which is found on the surface of our cells: This is the first step to an infection. The exact contours of SARS-CoV-2’s spikes allow it to stick far more strongly to ACE2 than SARS-classic did, and “it’s likely that this is really crucial for person-to-person transmission,” says Angela Rasmussen of Columbia University. In general terms, the tighter the bond, the less virus required to start an infection.

There’s another important feature. Coronavirus spikes consist of two connected halves, and the spike activates when those halves are separated only then can the virus enter a host cell. In SARS-classic, this separation happens with some difficulty. But in SARS-CoV-2, the bridge that connects the two halves can be easily cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tissues. “This is probably important for some of the really unusual things we see in this virus,” says Kristian Andersen of Scripps Research Translational Institute.

For example, most respiratory viruses tend to infect either the upper or lower airways. In general, an upper-respiratory infection spreads more easily, but tends to be milder, while a lower-respiratory infection is harder to transmit, but is more severe. SARS-CoV-2 seems to infect both upper and lower airways, perhaps because it can exploit the ubiquitous furin. This double whammy could also conceivably explain why the virus can spread between people before symptoms show up—a trait that has made it so difficult to control. Perhaps it transmits while still confined to the upper airways, before making its way deeper and causing severe symptoms. All of this is plausible but totally hypothetical the virus was only discovered in January, and most of its biology is still a mystery.

The new virus certainly seems to be effective at infecting humans, despite its animal origins. The closest wild relative of SARS-CoV-2 is found in bats, which suggests it originated in a bat, then jumped to humans either directly or through another species. (Another coronavirus found in wild pangolins also resembles SARS-CoV-2, but only in the small part of the spike that recognizes ACE2 the two viruses are otherwise dissimilar, and pangolins are unlikely to be the original reservoir of the new virus.) When SARS-classic first made this leap, a brief period of mutation was necessary for it to recognize ACE2 well. But SARS-CoV-2 could do that from day one. “It had already found its best way of being a [human] virus,” says Matthew Frieman of the University of Maryland School of Medicine.

This uncanny fit will doubtlessly encourage conspiracy theorists: What are the odds that a random bat virus had exactly the right combination of traits to effectively infect human cells from the get-go, and then jump into an unsuspecting person? “Very low,” Andersen says, “but there are millions or billions of these viruses out there. These viruses are so prevalent that things that are really unlikely to happen sometimes do.”

Since the start of the pandemic, the virus hasn’t changed in any obviously important ways. It’s mutating in the way that all viruses do. But of the 100-plus mutations that have been documented, none has risen to dominance, which suggests that none is especially important. “The virus has been remarkably stable given how much transmission we’ve seen,” says Lisa Gralinski of the University of North Carolina. “That makes sense, because there’s no evolutionary pressure on the virus to transmit better. It’s doing a great job of spreading around the world right now.”

There’s one possible exception. A few SARS-CoV-2 viruses that were isolated from Singaporean COVID-19 patients are missing a stretch of genes that also disappeared from SARS-classic during the late stages of its epidemic. This change was thought to make the original virus less virulent, but it’s far too early to know whether the same applies to the new one. Indeed, why some coronaviruses are deadly and some are not is unclear. “There’s really no understanding at all of why SARS or SARS-CoV-2 are so bad but OC43 just gives you a runny nose,” Frieman says.

Researchers can, however, offer a preliminary account of what the new coronavirus does to the people it infects. Once in the body, it likely attacks the ACE2-bearing cells that line our airways. Dying cells slough away, filling the airways with junk and carrying the virus deeper into the body, down toward the lungs. As the infection progresses, the lungs clog with dead cells and fluid, making breathing more difficult. (The virus might also be able to infect ACE2-bearing cells in other organs, including the gut and blood vessels.)

The immune system fights back and attacks the virus this is what causes inflammation and fever. But in extreme cases, the immune system goes berserk, causing more damage than the actual virus. For example, blood vessels might open up to allow defensive cells to reach the site of an infection that’s great, but if the vessels become too leaky, the lungs fill even more with fluid. These damaging overreactions are called cytokine storms. They were historically responsible for many deaths during the 1918 flu pandemic, H5N1 bird flu outbreaks, and the 2003 SARS outbreak. And they’re probably behind the most severe cases of COVID-19. “These viruses need time to adapt to a human host,” says Akiko Iwasaki of the Yale School of Medicine. “When they’re first trying us out, they don’t know what they’re doing, and they tend to elicit these responses.”

During a cytokine storm, the immune system isn’t just going berserk but is also generally off its game, attacking at will without hitting the right targets. When this happens, people become more susceptible to infectious bacteria. The storms can also affect other organs besides the lungs, especially if people already have chronic diseases. This might explain why some COVID-19 patients end up with complications such as heart problems and secondary infections.

But why do some people with COVID-19 get incredibly sick, while others escape with mild or nonexistent symptoms? Age is a factor. Elderly people are at risk of more severe infections possibly because their immune system can’t mount an effective initial defense, while children are less affected because their immune system is less likely to progress to a cytokine storm. But other factors—a person’s genes, the vagaries of their immune system, the amount of virus they’re exposed to, the other microbes in their bodies—might play a role too. In general, “it’s a mystery why some people have mild disease, even within the same age group,” Iwasaki says.

Coronaviruses, much like influenza, tend to be winter viruses. In cold and dry air, the thin layers of liquid that coat our lungs and airways become even thinner, and the beating hairs that rest in those layers struggle to evict viruses and other foreign particles. Dry air also seems to dampen some aspects of the immune response to those trapped viruses. In the heat and humidity of summer, both trends reverse, and respiratory viruses struggle to get a foothold.

Unfortunately, that might not matter for the COVID-19 pandemic. At the moment, the virus is tearing through a world of immunologically naive people, and that vulnerability is likely to swamp any seasonal variations. After all, the new virus is transmitting readily in countries like Singapore (which is in the tropics) and Australia (which is still in summer). And one recent modeling study concluded that “SARS-CoV-2 can proliferate at any time of year.” “I don’t have an immense amount of confidence that the weather is going to have the effect that people hope it will,” Gralinski says. “It may knock things down a little, but there’s so much person-to-person transmission going on that it may take more than that.” Unless people can slow the spread of the virus by sticking to physical-distancing recommendations, the summer alone won’t save us.

“The scary part is we don’t even know how many people get normal coronaviruses every year,” Frieman says. “We don’t have any surveillance networks for coronaviruses like [we do for] flu. We don’t know why they go away in the winter, or where they go. We don’t know how these viruses mutate year on year.” Until now, research has been slow. Ironically, a triennial conference in which the world’s coronavirus experts would have met in a small Dutch village in May has been postponed because of the coronavirus pandemic.

“If we don’t learn from this pandemic that we need to understand these viruses more, then we’re very, very bad at this,” Frieman says.


Doctors keep discovering new ways the coronavirus attacks the body

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Deborah Coughlin was neither short of breath nor coughing. In those first days after she became infected by the novel coronavirus, her fever never spiked above 100 degrees. It was vomiting and diarrhea that brought her to a Hartford, Conn., emergency room on May 1.

“You would have thought it was a stomach virus,” said her daughter, Catherina Coleman. “She was talking and walking and completely coherent.”

But even as Coughlin, 67, chatted with her daughters on her cellphone, the oxygen level in her blood dropped so low that most patients would be near death. She is on a ventilator and in critical condition at St. Francis Hospital, one more patient with a strange constellation of symptoms that physicians are racing to recognize, explain and treat.

At the beginning, we didn’t know what we were dealing with,” said Valentin Fuster, physician-in-chief at Mount Sinai Hospital in New York City, the epicenter of the U.S. outbreak. “We were seeing patients dying in front of us. It was all of a sudden, you’re in a different ballgame, and you don’t know why.”

Today, there is widespread recognition that the novel coronavirus is far more unpredictable than a simple respiratory virus. Often it attacks the lungs, but it can also strike anywhere from the brain to the toes. Many doctors are focused on treating the inflammatory reactions it triggers and its capacity to cause blood clots, even as they struggle to help patients breathe.

They have little solid research to guide them as they learn on the fly about a new disease with more than 78,000 U.S. deaths attributed to it. The World Health Organization’s database already lists more than 14,600 papers on covid-19. Even the world’s premier public health agencies, including the Centers for Disease Control and Prevention, have constantly altered their advice to keep pace with new developments.

“We don’t know why there are so many disease presentations,” said Angela Rasmussen, a virologist at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health. “Bottom line, this is just so new that there’s a lot we don’t know.”

More than four months of clinical experience across Asia, Europe and North America has shown the pathogen does much more than invade the lungs. “No one was expecting a disease that would not fit the pattern of pneumonia and respiratory illness,” said David Reich, a cardiac anesthesiologist and president of Mount Sinai Hospital in New York City.

It attacks the heart, weakening its muscles and disrupting its critical rhythm. It savages kidneys so badly some hospitals have run short of dialysis equipment. It crawls along the nervous system, destroying taste and smell and occasionally reaching the brain. It creates blood clots that can kill with sudden efficiency and inflames blood vessels throughout the body.

It can begin with a few symptoms or none at all, then days later, squeeze the air out of the lungs without warning. It picks on the elderly, people weakened by previous disease, and, disproportionately, the obese. It harms men more than women, but there are also signs it complicates pregnancies.


Global Health Security

An international panel of experts undertook a comprehensive assessment and benchmarking of health security and response capabilities across 195 countries. 5 The purpose of the project was to address risks from infectious disease outbreaks that could lead to international epidemics and pandemics and measure response capabilities for each nation. The hope was that the GHS Index would lead to quantifiable changes in national health security and improve international preparedness.

The GHS Index measured indicators across six broad categories:

  1. Prevention: Prevention of the emergence or release of pathogens.
  2. Detection and Reporting: Early detection and reporting for epidemics of potential international concern.
  3. Rapid Response: Rapid response to and mitigation of the spread of an epidemic.
  4. Health System: Sufficient and robust health system to treat the sick and protect health workers.
  5. Compliance with International Norms: Commitments to improving national capacity, financing plans to address gaps, and adhering to global norms.
  6. Risk Environment: Overall risk environment and country vulnerability to biological threats.

The major GHS Index summary findings were:

  1. Although the United States scored an 83 out of 100 points, health security around the world is very weak and no country is adequately prepared for epidemics or pandemics. The average score was only 40.2 out of 100.
  2. Preparedness is very weak, and capacities have not been tested.
  3. Funding and budgets are inadequate.
  4. Training and coordination are lacking along with foundational health systems' capacities for epidemic and pandemic response.

Unfortunately, the veracity of the GHS Index study is being borne out in real time with the COVID-19 outbreak the world is experiencing now. But there is no time to point fingers and say &ldquoI told you so.&rdquo We need to act, fast and furious.

At this writing, we are about three months into the COVID-19 outbreak. The WHO officially declared it a pandemic on March 11, 2020. Countries experiencing the greatest number of cases include China, Iran, Italy, and the Republic of Korea. Although the United States ranks eighth, currently, with under 2,000 confirmed cases, insufficient testing does not provide a clear and complete picture. Therefore, we need to take immediate and serious actions to: first, protect ourselves, family, loved ones, and others in our communities and second, act to contain the spread by preparing our homes, workplaces, and businesses.

This article is the first of a two-part article series detailing the COVID-19 pandemic. To continue reading the second part of this series discussing the recommended cleaning protocols and transmission prevention, click here.

  • To learn more about the numerous pandemics that have occurred throughout history, up to the most recent pandemic, SARS-CoV-2 (COVID-19), access our complimentary infographic: Pandemics Throughout History