by Aksel Fridstrøm
July 13, 2020 - 16:47
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In the article “The Evidence which Suggests that This Is No Naturally Evolved Virus” by Sørensen, Dalgleish and Susrud, uploaded by Minerva today, Sørensen and his co-authors present several arguments for why they consider a non-natural origin for the novel coronavirus to be the most logical explanation on how the virus evolved.
It is observations on the spike protein of the Sars-Cov-2 virus that leads Sørensen and his co-authors to believe that the virus has originated in a laboratory.
FACTBOX – Spike Protein
A spike protein is a part of the virus attached to the surface of the virus. The spike protein is used by the virus when it enters cells, enabling it to stick in humans. The properties of the spike determine which receptors a virus can utilise and thus which cells the virus can enter to create illness.
“There are several factors that point towards this”, Sørensen told Minerva in an interview last week. “Firstly, this part of the virus is very stable; it mutates very little. That points to this virus as a fully developed, almost perfected virus for infecting humans.
“Secondly, this indicates that the structure of the virus cannot have evolved naturally. When we compare the novel coronavirus with the one that caused SARS, we see that there are altogether six inserts in this virus that stand out compared to other known SARS viruses”, he goes on explaining.
Sørensen says that several of these changes in the virus are unique, and that they do not exist in other known SARS coronaviruses.
“Four of these six changes have the property that they are suited to infect humans. This kind of aggregation of a type of property can be done simply in a laboratory, and helps to substantiate such an origin”, Sørensen argues.
Sørensen was also quoted saying that he is quite confident that the virus originated in a laboratory. “I think it’s more than 90 percent certain. It’s at least a far more probable explanation than it having developed this way in nature”, Sørensen said.
Sørensen also highlights other data than those related to the virus’ properties:
“The properties that we now see in the virus, we have yet to discover anywhere in nature. We know that these properties make the virus very infectious, so if it came from nature, there should also be many animals infected with this, but we have still not been able to trace the virus in nature”, Sørensen also elaborated in last week's interview.
Chimera
In the article Sørensen and his co-authors add additional context to how they believe the virus evolved through experiments in laboratories.
The authors do this by pointing to earlier and open articles by Chinese and American researchers, where the researchers demonstrate and discuss how they have manipulated new chimeraviruses into existence, with SARS-coronavirus as a starting point.
FACTBOX – Chimeravirus
Chimeravirus is defined by U.S. Department of Agriculture's Animal and Plant Health Inspection Service as a hybrid micro-organism which is created by combining fragments from two or more micro-organisms where at least one of the two fragments contain the necessary genes for replication.
The word chimera derives from Greek mythology and refers to a fable being which was a third dragon, a third lion and a third goat.
Sørensen and his co-authors point to four different research projects where the chronology of the creation of a new chimeravirus is documented.
The first of these is the research project led by the world-famous Chinese scientist Dr. Zheng-Li Shi and her colleagues at Wuhan Virology Institute in 2008, which “successfully demonstrated technical capabilities to interchange RBD’s between bat SARS-like and human SARS viruses”.
These findings made the exchange of properties between SARS-coronavirus possible, Sørensen and his co-authors argue.
Furthermore, Sørensen’s article points to the fact that Wuhan’s Virology Institute again in 2010 took part in gain-of-function experiments with international collaborators, where SARS-coronavirus was provided with additional properties that increase the virus’s ability to infect humans: “In 2010 scientists from the ‘Special Viruses’ section of the Wuhan Institute of Virology were engaged in ‘gain of function’ experiments, jointly with international collaborators, to increase SARS-CoV infectiousness for humans. They used an HIV pseudovirus to express seven bat ACE2 receptors and compared their binding properties to human ACE2 receptors in order to pick the best for further optimizing a SARS-like coronavirus’s ability to bind to human cells”, they write.
FACTBOX – gain-of-function-research
Gain-of-function studies are according to the US Department Health and Human Services research which involves increasing the capacity of a pathogen to cause illness. The method is controversial because it can also risk new viruses leaking out of laboratories and into the population.
In the period 2014 to 2018 this type of research was prohibited in the US, but in December 2017 American authorities announced that these kinds of studies would again be allowed.
Chimerica
In order to build further on this research, Shi and her colleagues sought help from American researchers.
“The Chinese originally lacked the technology and competence to grow and measure the development of the virus”, Sørensen argues.
However, according to Sørensen, Shi and her colleagues received help from the University of North Carolina at Chapel Hill in the US, where a human cell culture was made available for further research on SARS-coronavirus.
In the article, Sørensen and his co-authors write: “In 2015 scientists from the ‘Special Viruses’ section of the Wuhan Institute of Virology were engaged in ‘gain of function’ experiments jointly with a majority team from the University of North Carolina Chapel Hill. Together, they manipulated bat viruses to create a mouse adapted chimeric virus SHC014-MA15 which binds to and can proliferate on human upper airway cells (2B4 Calu-3 – a cell line contributed by Chapel Hill).”
Sørensen and his co-authors write that this work created “a chimeric virus with very high infectivity potential targeted to the human upper respiratory tract” and that what is being described is “in fact, precisely SARS-CoV-2 properties”, which is the virus that causes Covid-19.
Sørensen and his co-authors writes that “the 2015 authors were well aware that the chimeric virus which they had created was very dangerous because they discussed this fact”, but also explains that the creation of the chimeric virus of increased pathogenicity was not intentional. “In vivo experiments at Chapel Hill replicated the chimeric virus in mouse lung which showed significant pathogenesis which was the opposite of what the team had expected (“the creation of chimeric viruses like SHC014-MA15 was not expected to increase pathogenicity”).
The chimeric virus SHC014-MA15 that was created as a part of the collaboration between the Wuhan Institute of Virology and University of North Carolina at Chapel Hill is however according to an article published Shan-Lu Liu et al still different from the Sars-Cov-2 virus with a “divergence in the genetic sequence of this construct with the new SARS-CoV-2 (>5,000 nucleotides)”, Shan-Lu Liu writes.
Professor Kristian Andersen at the department of immunology and microbiology at Scripps Research again refers to the study conducted by Shan-Lu Liu when he writes that “the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone”.
Sørensen and his co-authors is however not convinced that the divergence between the chimeric SHC014-MA15 virus created in 2015 and the novel coronavirus Sars-Cov-2 is enough to eliminate the possibility of Sars-Cov-2 being another chimeric virus that builds on this research.
To establish a connection between the chimeric viruses engineered by the Wuhan Institute of Virology and the Sars-CoV-2 virus Sørensen and his co-authors points to events back in 2016 when a new coronavirus started to infect pigs in China. This disease named SADS ended up killing approximately 25,000 piglets. The epidemic was investigated by the researcher at the Wuhan Institute of Virology, and tested against all known receptors used by coronaviruses, but none of these worked.
Sørensen and his co-authors therefore draws the conclusion that “SADS is a CoV infection utilising new tissue-specific binding domains”, and argues that the Sars-CoV-2 coronavirus has attained directly or indirectly properties from the SADS virus that makes it possible for the virus to use new receptors to attach to human cells in the upper airways.
Hence the evolution of the Sars-Cov-2 virus is summarized by Sørensen and his co-authors as follows: “In 2008, Dr Zheng-Li Si and WIV colleagues successfully demonstrated technical capabilities to interchange RBD’s between bat SARS-like and human SARS viruses. Building upon this, the 2010 work (Hou et al, 2010) perfected the ability to express receptors on human cells. On these foundations, the central Gain of Function work that underpins the functionalities of SARS-CoV-2 took place, carrying the WIV spike and plasmid materials to bond successfully to a UNC Chapel Hill human epithelial cell-line.
This work produced a highly infectious chimeric virus optimised to the human upper respiratory tract. In convergent support of this hypothesis, both Lu and Jia have now, in January and April 2020, shown that SARS-CoV-2 has a bat SARS-like backbone but is carrying an RBD from a human SARS and Zhan et al have, like us, noted unusual adaption to humans from the first isolate.
In the 2015 Chapel Hill work it was only ACE2 receptors that were discussed. However, in 2018 Zhou P. et al demonstrated capabilities to clone other receptors like APN and DPP4 and to test and compare these against the (intestine) tissue specific SADS-CoV identified. Then, in the 2019-20 Covid-19 pandemic, profuse symptoms indicating compromise of the bitter/sweet receptors are reported. Taken all together, this implies that by employing insights gained after 2015, as just deduced, a further optimization of the 2015 chimeric virus for additional binding to receptors/co-receptors such as bitter/sweet specific upper airway epithelia receptors occurred. That would help to explain the otherwise puzzling high infectivity and pathology associated with SARS-CoV-2 and hence also help to explain the social epidemiology of its spread”.
Thinking the unthinkable
The release of a potential pandemic pathogen from a laboratory is by many viewed as a too catastrophic event to even be considered.
However many scientists now argue that it has already happened. In 1977 the H1N1 influenza virus caused an epidemic in the Soviet Union and China. This rapidly spreading epidemic was almost entirely restricted to persons younger than 26 years of age. A common explanation for this oddity is that the epidemic was caused by a frozen version of the virus that circulated in the 1950s, and in some way or another escaped laboratory containment.
It is also a known fact that the SARS-coronavirus that caused the SARS epidemic in 2003 has escaped laboratories in South-East Asia on at least four occasions. In 2003 WHO issued a statement calling for increased safety measures in laboratories that handle SARS-coronaviruses highlighting the risk of lab accidents: “The possibility that a SARS outbreak could occur following a laboratory accident is a risk of considerable importance, given the relatively large number of laboratories currently conducting research using the SARS-CoV or retaining specimens from SARS patients. These laboratories currently represent the greatest threat for renewed SARS-CoV transmission through accidental exposure associated with breaches in laboratory biosafety”, the WHO stated.
The laboratory operated by the Wuhan Institute of Virology was however built to adhere to far stricter security protocols than the ones criticized by the WHO back in 2003, and became the first Chinese laboratory that operated at the highest level of biosafety (level 4), when it was inaugurated in 2015.
At the Wuhan Institute of Virology lead scientist Dr. Shi Zhengli ferociously denies any possibility that the Sars-cov-2 virus is a lab escapee. In a rare interview with the Scientific American, Zhengli explains that “she frantically went through her own lab’s records from the past few years to check for any mishandling of experimental materials, especially during disposal. Shi 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”.
“That really took a load off my mind”, she is quoted saying.
Dr. Zhengli has also published the genomic sequence of a new virus that her team had sampled in an abandoned mine shaft seven years ago that shares an overall genome sequence identity of 96.2% with the Sars-Cov-2 virus, the closest match so far according to her article.
The hypothesis that SARS-CoV-2 evolved in the Mojiang miner’s lungs potentially resolves many scientific questions about the origin of the pandemic. But it raises others having to do with why this information has not come to light hitherto. The most obvious of these concern the actions of the Shi lab at the WIV.
Why did the Shi lab not acknowledge the miners’ deaths in any paper describing samples taken from the mine (Ge et al., 2016 and P. Zhou et al., 2020)? Why in the title of the Ge at al. 2016 paper did the Shi lab call it an “abandoned” mine? When they published the sequence of RaTG13 in Feb. 2020, why did the Shi lab provide a new name (RaTG13) for BtCoV/4991 when they had by then cited BtCoV/4991 twice in publications and once in a genome sequence database and when their sequences were from the same sample and 100% identical (P. Zhou et al., 2020)? If it was just a name change, why no acknowledgement of this in their 2020 paper describing RaTG13 (Bengston, 2020)? These strange and unscientific actions have obscured the origins of the closest viral relatives of SARS-CoV-2, viruses that are suspected to have caused a COVID-like illness in 2012 and which may be key to understanding not just the origin of the COVID-19 pandemic but the future behaviour of SARS-CoV-2.
These are not the only questionable actions associated with the provenance of samples from the mine. There were five scientific publications that very early in the pandemic reported whole genome sequences for SARS-CoV-2 (Chan et al., 2020; Chen et al., 2020; Wu et al., 2020; P. Zhou et al., 2020; Zhu et al., 2020). Despite three of them having experienced viral evolutionary biologists as authors (George Gao, Zheng-li Shi and Edward Holmes) only one of these (Chen et al., 2020) succeeded in identifying the most closely related viral sequence by far: BtCoV/4991 a viral sequence in the possession of the Shi lab at the WIV that differed from SARS-CoV-2 by just 5 nucleotides.
-- A Proposed Origin for SARS-CoV-2 and the COVID-19 Pandemic, by Jonathan Latham, PhD and Allison Wilson, PhD
However, concerns about the operational safety at the Wuhan Institute of Virology persist. In an article written by Josh Rogin at The Washington Post, Rogin refers to a leak embassy cable sent from the American Embassy in Beijing that raised on concerns about the safety routines at the Wuhan laboratory
“During 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”, states the Jan. 19, 2018, cable, which was drafted by two officials from the embassy’s environment, science and health sections who met with the scientists at the Wuhan Institute of Virology.
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 coronaviruses 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 — 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 (WIV), which had in 2015 become China’s 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’s 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, which I obtained, also warns that the lab’s work on bat coronaviruses and their potential human transmission represented a risk of a new SARS-like pandemic.
“During 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,” states the Jan. 19, 2018, cable, which was drafted by two officials from the embassy’s environment, science and health sections who met with the WIV scientists. (The State Department declined to comment on this and other details of the story.)
The Chinese researchers at WIV were receiving assistance from the Galveston National Laboratory at the University of Texas Medical Branch and other U.S. organizations, but the Chinese requested additional help. The cables argued that the United States should give the Wuhan lab further support, mainly because its research on bat coronaviruses was important but also dangerous.
As the cable noted, the U.S. visitors met with Shi Zhengli, the head of the research project, who had been publishing studies related to bat coronaviruses for many years. In November 2017, just before the U.S. officials’ visit, Shi’s team had published research showing that horseshoe bats they had collected from a cave in Yunnan province were very likely from the same bat population that spawned the SARS coronavirus in 2003.
“Most importantly,” the cable states, “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. 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.”
The research was designed to prevent the next SARS-like pandemic by anticipating how it might emerge. But even in 2015, other scientists questioned whether Shi’s team was taking unnecessary risks. In October 2014, the U.S. government had imposed a moratorium on funding of any research that makes a virus more deadly or contagious, known as “gain-of-function” experiments.
As many have pointed out, there is no evidence that the virus now plaguing the world was engineered; scientists largely agree it came from animals. But that is not the same as saying it didn’t come from the lab, which spent years testing bat coronaviruses in animals, said Xiao Qiang, a research scientist at the School of Information at the University of California at Berkeley.
“The cable tells us that there have long been concerns about the possibility of the threat to public health that came from this lab’s research, if it was not being adequately conducted and protected,” he said.
There are similar concerns about the nearby Wuhan Center for Disease Control and Prevention lab, which operates at biosecurity level 2, a level significantly less secure than the level-4 standard claimed by the Wuhan Insititute of Virology lab, Xiao said. That’s important because the Chinese government still refuses to answer basic questions about the origin of the novel coronavirus while suppressing any attempts to examine whether either lab was involved.
Sources familiar with the cables said they were meant to sound an alarm about the grave safety concerns at the WIV lab, especially regarding its work with bat coronaviruses. The embassy officials were calling for more U.S. attention to this lab and more support for it, to help it fix its problems.
“The cable was a warning shot,” one U.S. official said. “They were begging people to pay attention to what was going on.”
No extra assistance to the labs was provided by the U.S. government in response to these cables. The cables began to circulate again inside the administration over the past two months as officials debated whether the lab could be the origin of the pandemic and what the implications would be for the U.S. pandemic response and relations with China.
Inside the Trump administration, many national security officials have long suspected either the WIV or the Wuhan Center for Disease Control and Prevention lab was the source of the novel coronavirus outbreak. According to the New York Times, the intelligence community has provided no evidence to confirm this. But one senior administration official told me that the cables provide one more piece of evidence to support the possibility that the pandemic is the result of a lab accident in Wuhan.
“The 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’s almost nothing on the other side,” the official said.
As my colleague David Ignatius noted, the Chinese government’s original story — that the virus emerged from a seafood market in Wuhan — is shaky. Research by Chinese experts published in the Lancet in January showed the first known patient, identified on Dec. 1, had no connection to the market, nor did more than one-third of the cases in the first large cluster. Also, the market didn’t sell bats.
Shi and other WIV researchers have categorically denied this lab was the origin for the novel coronavirus. On Feb. 3, her team was the first to publicly report the virus known as 2019-nCoV was a bat-derived coronavirus.
The Chinese government, meanwhile, has put a total lockdown on information related to the virus origins. Beijing has yet to provide U.S. experts with samples of the novel coronavirus collected from the earliest cases. The Shanghai lab that published the novel coronavirus genome on Jan. 11 was quickly shut down by authorities for “rectification.” Several of the doctors and journalists who reported on the spread early on have disappeared.
On Feb. 14, Chinese President Xi Jinping called for a new biosecurity law to be accelerated. On Wednesday, CNN reported the Chinese government has placed severe restrictions requiring approval before any research institution publishes anything on the origin of the novel coronavirus.
The origin story is not just about blame. It’s crucial to understanding how the novel coronavirus pandemic started because that informs how to prevent the next one. The Chinese government must be transparent and answer the questions about the Wuhan labs because they are vital to our scientific understanding of the virus, said Xiao.
We don’t know whether the novel coronavirus originated in the Wuhan lab, but the cable pointed to the danger there and increases the impetus to find out, he said.
“I don’t think it’s a conspiracy theory. I think it’s a legitimate question that needs to be investigated and answered,” he said. “To understand exactly how this originated is critical knowledge for preventing this from happening in the future.”
-- State Department cables warned of safety issues at Wuhan lab studying bat coronaviruses, by Josh Rogin, The Washington Post, April 14, 2020
WHO to investigate
On the 18-19th of May the WHO conducted its 73rd general assembly, and passed a resolution that “requests the Director-General, working with other organizations and countries, to identify the zoonotic source of the virus and the route of introduction to the human population”.
Sørensen and his co-authors argue that this investigation should not be limited to examining the origin of the Sars-Cov-2 virus solely based on the assumption of a zoonotic source.
The WHO investigation commenced on the 7th of July.