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Showing posts with label Research. Show all posts
Showing posts with label Research. Show all posts

Saturday, 6 June 2020

Unveiling Covid-19 research scandal - hydroxychloroquine

Questions swirl around small health care company as authors of major studies retract their work



The hydroxychloroquine paper caused the World Health Organization, Britain and France to suspend clinical trials. Photo: AFP
The first research scandal of the coronavirus pandemic has created unnecessary distraction around the politically divisive drug hydroxychloroquine, scientists say, as questions swirl around the tiny health care company at the center of the affair.
On Thursday, most of the authors of major studies that appeared in The Lancet and the New England Journal of Medicine (NEJM) retracted their work and issued apologies, saying they could no longer vouch for their data after the firm that supplied it – Chicago-based Surgisphere – refused to be audited.
At any other time the matter might have led to hang-wringing within academia, but it has taken on a new dimension as the world grapples with a virus that has claimed some 400,000 lives.
Of particular interest was the paper in The Lancet that claimed to have analyzed the records of 96,032 patients admitted to 671 hospitals across six continents, finding that hydroxychloroquine showed no benefit and even increased the risk of death.
Its withdrawal is seen as a boost to backers of the decades-old anti-malarial drug, who include US President Donald Trump and his Brazilian counterpart Jair Bolsonaro.
“It’s very politicized – there is a group, probably not particularly small, who have learned to mistrust science and scientists, and this just feeds into that narrative,” Gabe Kelen, a professor of emergency medicine at Johns Hopkins University, told AFP.
This is despite the fact that even without The Lancet paper, evidence has been building against hydroxychloroquine’s use against Covid-19.
On Friday, results from a fourth randomized controlled trial – carefully designed human experiments considered the most robust form of clinical investigation – showed it had no impact against the virus.

Mystery company

The Lancet, which first published in 1823, is one of the world’s most trusted medical journals.
As a result, the hydroxychloroquine paper had an outsized impact: the World Health Organization, Britain and France all suspended ongoing clinical trials.
But things soon began unravelling after researchers noticed numerous red flags, from the huge number of patients involved to the unusual level of detail about the doses they had received.
Both The Lancet and the equally prestigious NEJM, which had published a paper on whether blood thinners elevated the risk of Covid-19 that relied on the same company, issued expressions of concern – before the authors themselves pulled both papers.
Surgisphere, founded in 2007 by vascular surgeon Sapan Desai, had refused to share data with third-party reviewers, saying it would violate privacy agreements with hospitals.
However, when science news site The Scientist began reaching out to hospitals throughout the US to ask whether they had participated, it found none.
Surgisphere’s internet profile has also raised numerous questions. Only a handful of employees could be found on LinkedIn, and most have now deactivated their accounts.
According to the Guardian newspaper, its employees included an adult model and until last week the contact page on its website redirected to a WordPress template for a cryptocurrency website, leaving it unclear how hospitals could have reached out to them.
Meanwhile Desai, who according to court records has three outstanding medical malpractice suits against him, has written extensively in the past on research misconduct.
“The most serious cause of fraud in medical publishing is manufactured data that authors use to support high impact conclusions,” he said in a 2013 paper.

Systemic issues

For Ivan Oransky, who founded Retraction Watch in 2010, the affair is far from surprising, serving instead to highlight systemic issues in science publishing and the way science is reported to the public.
“No one took a hard look at the data,” said Oransky. “But we’ve known about these issues for literally decades.”
Policymakers should get away from the idea of using the results of a single study to inform their decisions, he added, as was the case for the WHO – and the media has a responsibility to place papers in context instead of hyping them up.
The problem also stems from the fact that even leading journals rely too heavily on an honor system, but “you never know when a catastrophe is going to happen, if you’re not willing to put into place some reasonable safeguards,” added Oransky.
As to the future, the current episode is unlikely to serve as a wake-up call, he said. If one journal increases its diligence, more blockbuster papers will start appearing in its competitors.
– AFP

Wednesday, 3 June 2020

Explained: Scientific indications that show SARS-CoV-2 virus is man-made

Retired US army colonel slams attempts to control the public narrative on SARS-CoV-2's origin
Published: 22 May 2020
GM Watch
Coronavirus in green
Views supporting the possibility that the SARS-CoV-2 virus that causes COVID-19 is genetically engineered are proliferating, despite concerted attempts by some scientists and journalists to shut them down.
One example is the article below, which is written by a retired US army colonel, evidently with the benefit of good scientific advice. He has also written a followup piece, which we'll put out in a separate email.
The article has a distinct anti-China and anti-Communist tone, but the facts presented are solidly based, to the best of our knowledge. GMWatch readers will know by now that there was strong US involvement – and thus culpability – in China's gain-of-function research with coronaviruses that is believed by some to have led to an accidental lab release of the SARS-CoV-2 virus. All the involved parties, whatever their country of origin, must be investigated and held accountable for their actions.
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Explained: Scientific indications that show COVID-19 is man-made

The Chinese Communist Party (CCP), some Western scientists sympathetic to China and the obsequious media have expended enormous efforts to convince the public that the COVID-19 pandemic is a naturally-occurring outbreak of disease.
Included in that effort are restrictions imposed by the Chinese government on academic research related to the origins of COVID-19, in what is likely part of a wider attempt to control the narrative surrounding the origin of the pandemic.
There are now rumours swirling within the global scientific community that Western professional journals are submitting to pressure from Beijing and refusing to publish data that do not conform to the naturally-occurring interpretation of the origin of COVID-19.
The narrative promoted by the CCP is that COVID-19, while circulating in a bat population mutated, acquiring the ability to infect humans, which was then transmitted to people either visiting or working in the Wuhan Seafood Market.
First of all, it was already known by the end of January 2020, that the initial patients hospitalised between December 1-10, 2019 had not visited the market and bats were not sold there.
Despite the extraordinary propaganda campaign mounted by the Chinese government and its sycophants in the West, the origin of COVID-19 remains unknown and all of the structurally close bat coronaviruses so far identified to explain its origin have only raised more doubts.
In the February 3, 2020 Nature article, scientists from the Wuhan Institute of Virology, led by Zheng-Li Shi, claimed that the coronavirus RaTG13, isolated from bats in Yunnan Province, China, showed a 96.2% sequence identity with COVID-19 and, therefore, “RaTG13 is the closest relative” of COVID-19 and forms a distinct lineage from other coronaviruses.
A month later on March 17, 2020, the article, “The proximal origin of SARS-CoV-2”, widely-cited by scientists and the media, supported the conclusion that RaTG13 is CoVid-19’s closest relative, which likely “jumped” from animals to humans in the Wuhan Seafood Market.
It was later revealed that RaTG13 only existed on paper and was actually a duplicate of another bat coronavirus, BtCoV/4991, about which very little experimental data have been published.
Nevertheless, if we use the RaTG13 sequence, which has provided the basis of China’s naturally-occurring theory for the origin of COVID-19, holes begin to appear in its argument.
COVID-19’s receptor binding domain, which allows the attachment of the virus to a human cell, is structurally closer in its amino acid sequence to that of pangolins (scaly anteaters) than to bat RaTG13.
COVID-19
N S N N L D S K V G G N Y N Y L Y R L F R K S N L K P F E R D I S T E I Y Q A G S T P C
N G V E G F N C Y F P L Q S Y G F Q P T N G V G Y Q P Y
Pangolin
N S N N L D S K V G G N Y N Y L Y R L F R K S N L K P F E R D I S T E I Y Q A G S T P C
N G V E G F N C Y F P L Q S Y G F H P T N G V G Y Q P Y
RaTG13
N S K H I D A K E G G N F N Y L Y R L F R K A N L K P F E R D I S T E I Y Q A G S K P C
N G Q T G L N C Y Y P L Y R Y G F Y P T D G V G H Q P Y
As you can see, the pangolin sequence differs from COVID-19 by only one amino acid, while RaTG13 differs in seventeen positions.
Within the receptor-binding domain there are fourteen specific amino acids that were previously shown to be critical for coronaviruses to bind to the angiotensin-converting enzyme-2 receptor that initiates the COVID-19 infection in humans.
At least two pangolin species match those critical COVID-19 amino acids in thirteen out of fourteen positions, whereas RaTG13 matches only seven out of fourteen and other bat coronaviruses do so to an even lesser extent.
Chinese scientists suggest that the pangolin receptor binding domain was “donated” to COVID-19, presumably through some type of recombinant event occurring between a bat coronavirus and a pangolin coronavirus inside a pangolin host.
Their naturally-occurring explanation for the presence of a pangolin-like receptor binding domain is highly speculative and no evidence exists to support such a contention.
A far more likely scenario is that the native receptor binding domain within a bat coronavirus “backbone” was artificially replaced with one from a pangolin strain.
After that, came the insertion of the furin polybasic cleavage site, found in COVID-19 and none of the close bat coronaviruses relatives yet identified and a distinctive feature is widely known for its ability to enhance pathogenicity and transmissibility in coronaviruses.
There is additional information now being discussed on virology blogs indicating that COVID-19 is not naturally-occurring because its differential ratio of synonymous to non-synonymous substitution is vastly different compared to that which occurs in nature among bat populations as well as natural factors that would select against the presence of a furin polybasic cleavage site.
China’s ongoing propaganda campaign and its associated Western censorship will not stop honest scientific inquiry from discovering the true origin of COVID-19.
(Disclaimer: The opinions expressed above are the personal views of the author and do not reflect the views of ZMCL)
https://www.gmwatch.org/en/news/latest-news/19406-explained-scientific-indications-that-show-sars-cov-2-virus-is-man-made

The case is building that COVID-19 had a lab origin

Various researchers and news media have drawn up a prima facie case that a laboratory origin is a strong possibility
This is a great article that's best read at the original URL in order to follow up links to sources.

The case is building that COVID-19 had a lab origin

By Jonathan Latham, PhD and Allison Wilson, PhD
Independent Science News, 2 June 2020
Scientist in protective overall
If the public has learned a lesson from the COVID-19 pandemic it is that science does not generate certainty. Do homemade face masks work? What is the death rate of COVID-19? How accurate are the tests? How many people have no symptoms? And so on. Practically the lone undisputed assertion made so far is that all the nearest known genetic relatives of its cause, the Sars-CoV-2 virus, are found in horseshoe bats (Zhou et al., 2020). Therefore, the likely viral reservoir was a bat.
However, most of these ancestor-like bat coronaviruses cannot infect humans (Ge et al., 2013). In consequence, from its beginning, a key question hanging over the pandemic has been: How did a bat RNA virus evolve into a human pathogen that is both virulent and deadly?
The answer almost universally seized upon is that there was an intermediate species. Some animal, perhaps a snake, perhaps a palm civet, perhaps a pangolin, served as a temporary host. This bridging animal would probably have had an ACE2 cellular receptor (the molecule which allows cellular entry of the virus) intermediate in protein sequence (or at least structure) between the bat and the human one (Wan et al., 2020).
In the press and in the scientific literature, scenarios by which this natural zoonotic transfer might have occurred have been endlessly mulled. Most were fuelled by early findings that many of the earliest COVID-19 cases seem to have occurred in and around Wuhan’s Huanan live animal market. [The latest data are that 14 of the 41 earliest cases, including the first, had no connection to the animal market (Huang et al. 2020)].
Since the two previous coronavirus near-pandemics of SARS (2002-3) and MERS (2012) both probably came from bats and both are thought (but not proven) to have transitioned to humans via intermediate animals (civets and dromedaries respectively), a natural zoonotic pathway is a reasonable first assumption (Andersen et al., 2020).
The idea, as it applied to the original (2002) SARS outbreak, is that the original bat virus infected a civet. The virus then evolved briefly in this animal species, but not enough to cause a civet pandemic, and then was picked up by a human before it died out in civets. In this first human (patient zero) the virus survived, perhaps only barely, but was passed on, marking the first case of human to human transmission. As it was successively passed on in its first few human hosts the virus rapidly evolved, adapting to better infect its new hosts. After a few such tentative transmissions the pandemic proper began.
Perhaps this scenario is approximately how the current COVID-19 pandemic began.
But one other troubling possibility must be dispensed with. It follows from the fact that the epicentre city, Wuhan (pop. 11 million), happens to be the global epicentre of bat coronavirus research (e.g. Hu et al., 2017).
Prompted by this proximity, various researchers and news media, prominently the Washington Post, and with much more data Newsweek, have drawn up a prima facie case that a laboratory origin is a strong possibility (Zhan et al., 2020; Piplani et al., 2020). That is, one of the two labs in Wuhan that has worked on coronaviruses accidentally let a natural virus escape; or, the lab was genetically engineering (or otherwise manipulating) a Sars-CoV-2-like virus which then escaped.
Unfortunately, in the US at least, the question of the pandemic’s origin has become a political football; either an opportunity for Sinophobia or a partisan “blame game“.
But the potential of a catastrophic lab release is not a game and systemic problems of competence and opacity are certainly not limited to China (Lipsitch, 2018). The US Department of Homeland Security (DHS) is currently constructing a new and expanded national Bio and Agro-defense facility in Manhattan, Kansas. DHS has estimated that the 50-year risk (defined as having an economic impact of $9-50 billion) of a release from its lab at 70%.
When a National Research Council committee inspected these DHS estimates they concluded, “The committee finds that the risks and costs could well be significantly higher than that“.
A subsequent committee report (NAP, 2012) continued:
“the committee was instructed to judge the adequacy and validity of the uSSRA [updated Site-Specific Risk Assessment]. The committee has identified serious concerns about 
(1) the misapplication of methods used to assess risk, 
(2) the failure to make clear whether and how the evidence used to support risk assessment assumptions had been thoroughly reviewed and adequately evaluated, 
(3) the limited breadth of literature cited and the misinterpretation of some of the significant supporting literature, 
(4) the failure to explain the criteria used to select assumptions when supporting literature is conflicting, 
(5) the failure to consider important risk pathways, and 
(6) the inadequate treatment of uncertainty. 
Those deficiencies are not equally problematic, but they occur with sufficient frequency to raise doubts about the adequacy and validity of the risk results presented. 
In most instances (e.g., operational activities at the NBAF), the identified problems lead to an underestimation of risk; in other instances (e.g., catastrophic natural hazards), the risks may be overestimated. 
As a result, the committee concludes that the uSSRA is technically inadequate in critical respects and is an insufficient basis on which to judge the risks associated with the proposed NBAF in Manhattan, Kansas.”
China, meanwhile, having opened its first in Wuhan in 2018, is planning to roll out a national network of BSL-4 labs (Zhiming, 2019). Like many other countries, it is investing significantly in disease surveillance and collection of viruses from wild animal populations and in high-risk recombinant virus research with Potential Pandemic Pathogens (PPPs).
On May 4th, nations and global philanthropies, meeting in Brussels, committed $7.4 billion to future pandemic preparedness. But the question hanging over all such investments is this: the remit of the Wuhan lab at the centre of the accidental release claims is pandemic preparedness. 
If the COVID-19 pandemic began there then we need to radically rethink current ideas for pandemic preparation globally. Many researchers already believe we should, for the sake of both safety and effectiveness (Lipsitch and Galvani, 2014; Weiss et al., 2015; Lipsitch, 2018). The worst possible outcome would be for those donated billions to accelerate the arrival of the next pandemic.
Historical lab releases, a brief history
An accidental lab release is not merely a theoretical possibility. In 1977 a laboratory in Russia (or possibly China), most likely while developing a flu vaccine, accidentally released the extinct H1N1 influenza virus (Nakajima et al., 1978). H1N1 went on to become a global pandemic virus. A large proportion of the global population became infected. In this case, deaths were few because the population aged over 20 yrs old had historic immunity to the virus. 
This episode is not widely known because only recently has this conclusion been formally acknowledged in the scientific literature and the virology community has been reluctant to discuss such incidents (Zimmer and Burke, 2009; Wertheim, 2010). 
Still, laboratory pathogen escapes leading to human and animal deaths (e.g. smallpox in Britain; equine encephalitis in South America) are common enough that they ought to be much better known (summarised in Furmanski, 2014). Only rarely have these broken out into actual pandemics on the scale of H1N1, which, incidentally, broke out again in 2009/2010 as “Swine flu” causing 3,000 or so deaths on that occasion (Duggal et al., 2016).
Many scientists have warned that experiments with PPPs, like the smallpox and Ebola and influenza viruses, are inherently dangerous and should be subject to strict limits and oversight (Lipsitch and Galvani, 2014; Klotz and Sylvester, 2014). Even in the limited case of SARS-like coronaviruses, since the quelling of the original SARS outbreak in 2003, there have been six documented SARS disease outbreaks originating from research laboratories, including four in China. These outbreaks caused 13 individual infections and one death (Furmanski, 2014). In response to such concerns the US banned certain classes of experiments, called gain of function (GOF) experiments, with PPPs in 2014, but the ban was lifted in 2017.
For these reasons, and also to ensure the effectiveness of future pandemic preparedness efforts­, it is a matter of vital international importance to establish whether the laboratory escape hypothesis has credible evidence to support it. This must be done regardless of the problem–in the US–of toxic partisan politics and nationalism.
The COVID-19 Wuhan lab escape thesis
The essence of the lab escape theory is that Wuhan is the site of the Wuhan Institute of Virology (WIV), China’s first and only Biosafety Level 4 (BSL-4) facility. (BSL-4 is the highest pathogen security level). The WIV, which added a BSL-4 lab only in 2018, has been collecting large numbers of coronaviruses from bat samples ever since the original SARS outbreak of 2002-2003; including collecting more in 2016 (Hu, et al., 2017; Zhou et al., 2018).
Led by researcher Zheng-Li Shi, WIV scientists have also published experiments in which live bat coronaviruses were introduced into human cells (Hu et al., 2017). Moreover, according to an April 14 article in the Washington Post, US Embassy staff visited the WIV in 2018 and “had grave safety concerns” about biosecurity there. The WIV is just eight miles from the Huanan live animal market that was initially thought to be the site of origin of the COVID-19 pandemic.
Wuhan is also home to a lab called the Wuhan Centers for Disease Prevention and Control (WCDPC). It is a BSL-2 lab that is just 250 metres away from the Huanan market. Bat coronaviruses have in the past been kept at the Wuhan WCDPC lab.
Thus the lab escape theory is that researchers from one or both of these labs may have picked up a Sars-CoV-2-like bat coronavirus on one of their many collecting (aka ‘”virus surveillance”) trips. Or, alternatively, a virus they were studying, passaging, engineering, or otherwise manipulating, escaped.
Scientific assessments of the lab escape theory
On April 17 the Australian Science Media Centre asked four Australian virologists, “Did COVID-19 come from a lab in Wuhan?“
Three (Edward Holmes, Nigel McMillan and Hassan Vally) dismissed the lab escape suggestion and Vally simply labeled it, without elaboration, a “conspiracy”.
The fourth virologist interviewed was Nikolai Petrovsky of Flinders University. Petrovsky first addressed the question of whether the natural zoonosis pathway was viable.
He told the Media Centre, “no natural virus matching to COVID-19 has been found in nature despite an intensive search to find its origins.”
That is to say, the idea of an animal intermediate is speculation. Indeed, no credible viral or animal host intermediaries, either in the form of a confirmed animal host or a plausible virus intermediate, has to-date emerged to explain the natural zoonotic transfer of Sars-CoV-2 to humans (e.g. Zhan et al., 2020).
In addition to Petrovsky’s point, there are two further difficulties with the natural zoonotic transfer thesis (apart from the weak epidemiological association between early cases and the Huanan “wet” market).
The first is that researchers from the Wuhan lab travelled to caves in Yunnan (1,500 Km away) to find horseshoe bats containing SARS-like coronaviruses. To-date, the closest living relative of Sars-CoV-2 yet found comes from Yunnan (Ge et al., 2016). Why would an outbreak of a bat virus therefore occur in Wuhan?
Moreover, China has a population of 1.3 billion. If spillover from the wildlife trade was the explanation, then, other things being equal, the probability of a pandemic starting in Wuhan (pop. 11 million) is less than 1%.
Zheng-Li Shi, the head of bat coronavirus research at WIV, told Scientific American as much:
“I had never expected this kind of thing to happen in Wuhan, in central China.” Her studies had shown that the southern, subtropical provinces of Guangdong, Guangxi and Yunnan have the greatest risk of coronaviruses jumping to humans from animals—particularly bats, a known reservoir. If coronaviruses were the culprit, she remembers thinking, “Could they have come from our lab?”
Wuhan, in short, is a rather unlikely epicentre for a natural zoonotic transfer. In contrast, to suspect that Sars-CoV-2 might have come from the WIV is both reasonable and obvious.
Was Sars-CoV-2 created in a lab?
In his statement, Petrovsky goes on to describe the kind of experiment that, in principle, if done in a lab, would obtain the same result as the hypothesised natural zoonotic transfer–rapid adaptation of a bat coronavirus to a human host.
“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.”
In other words, Petrovsky believes that current experimental methods could have led to an altered virus that escaped.
Passaging, GOF research, and lab escapes
The experiment mentioned by Petrovsky represents a class of experiments called passaging. Passaging is the placing of a live virus into an animal or cell culture to which it is not adapted and then, before the virus dies out, transferring it to another animal or cell of the same type. Passaging is often done iteratively. The theory is that the virus will rapidly evolve (since viruses have high mutation rates) and become adapted to the new animal or cell type. Passaging a virus, by allowing it to become adapted to its new situation, creates a new pathogen.
The most famous such experiment was conducted in the lab of Dutch researcher Ron Fouchier. Fouchier took an avian influenza virus (H5N1) that did not infect ferrets (or other mammals) and serially passaged it in ferrets. The intention of the experiment was specifically to evolve a PPP. After ten passages the researchers found that the virus had indeed evolved, to not only infect ferrets but to transmit to others in neighbouring cages (Herfst et al., 2012). They had created an airborne ferret virus, a Potential Pandemic Pathogen, and a storm in the international scientific community.
The second class of experiments that have frequently been the recipients of criticism are GOF experiments. In GOF research, a novel virus is deliberately created, either by in vitro mutation or by cutting and pasting together two (or more) viruses. The intention of such reconfigurations is to make viruses more infectious by adding new functions such as increased infectivity or pathogenicity. These novel viruses are then experimented on, either in cell cultures or in whole animals. These are the class of experiments banned in the US from 2014 to 2017.
Some researchers have even combined GOF and passaging experiments by using recombinant viruses in passaging experiments (e.g. Sheahan et al., 2008).
Such experiments all require recombinant DNA techniques and animal or cell culture experiments. But the very simplest hypothesis of how Sars-CoV-2 might have been caused by research is simply to suppose that a researcher from the WIV or the WCDCP became infected during a collecting expedition and passed their bat virus on to their colleagues or family. The natural virus then evolved, in these early cases, into Sars-CoV-2. For this reason, even collecting trips have their critics. Epidemiologist Richard Ebright called them “the definition of insanity“. Handling animals and samples exposes collectors to multiple pathogens and returning to their labs then brings those pathogens back to densely crowded locations.
Was the WIV doing experiments that might release PPPs?
Since 2004, shortly after the original SARS outbreak, researchers from the WIV have been collecting bat coronaviruses in an intensive search for SARS-like pathogens (Li et al., 2005). Since the original collecting trip, many more have been conducted (Ge et al., 2013; Ge et al., 2016; Hu et al., 2017; Zhou et al., 2018).
Petrovsky does not mention it but Zheng-Li Shi’s group at the WIV has already performed experiments very similar to those he describes, using those collected viruses. In 2013 the Shi lab reported isolating an infectious clone of a bat coronavirus that they called WIV-1 (Ge et al., 2013). WIV-1 was obtained by introducing a bat coronavirus into monkey cells, passaging it, and then testing its infectivity in human (HeLa) cell lines engineered to express the human ACE2 receptor (Ge et al., 2013).
In 2014, just before the US GOF research ban went into effect, Zheng-Li Shi of WIV co-authored a paper with the lab of Ralph Baric in North Carolina that performed GOF research on bat coronaviruses (Menachery et al., 2015).
In this particular set of experiments the researchers combined “the spike of bat coronavirus SHC014 in a mouse-adapted SARS-CoV backbone” into a single engineered live virus. The spike was supplied by the Shi lab. They put this bat/human/mouse virus into cultured human airway cells and also into live mice. The researchers observed “notable pathogenesis” in the infected mice (Menachery et al. 2015). The mouse-adapted part of this virus comes from a 2007 experiment in which the Baric lab created a virus called rMA15 through passaging (Roberts et al., 2007). This rMA15 was “highly virulent and lethal” to the mice. According to this paper, mice succumbed to “overwhelming viral infection”.
In 2017, again with the intent of identifying bat viruses with ACE2 binding capabilities, the Shi lab at WIV reported successfully infecting human (HeLa) cell lines engineered to express the human ACE2 receptor with four different bat coronaviruses. Two of these were lab-made recombinant (chimaeric) bat viruses. Both the wild and the recombinant viruses were briefly passaged in monkey cells (Hu et al., 2017).
Together, what these papers show is that, 1) The Shi lab collected numerous bat samples with an emphasis on collecting SARS-like coronavirus strains, 2) they cultured live viruses and conducted passaging experiments on them, 3) members of Zheng-Li Shi’s laboratory participated in GOF experiments carried out in North Carolina on bat coronaviruses, 4) the Shi laboratory produced recombinant bat coronaviruses and placed these in human cells and monkey cells. All these experiments were conducted in cells containing human or monkey ACE2 receptors.
The overarching purpose of such work was to see whether an enhanced pathogen could emerge from the wild by creating one in the lab. (For a very informative technical summary of WIV research into bat coronaviruses and that of their collaborators we recommend this post, written by biotech entrepreneur Yuri Deigin).
It also seems that the Shi lab at WIV intended to do more of such research. In 2013 and again in 2017 Zheng-Li Shi (with the assistance of a non-profit called the EcoHealth Alliance) obtained a grant from the US National Institutes of Health (NIH).
The most recent such grant proposed that “host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice” (NIH project #5R01Al110964-04).
It is hard to overemphasize that the central logic of this grant was to test the pandemic potential of SARS-related bat coronaviruses by making ones with pandemic potential, either through genetic engineering or passaging, or both.
Apart from descriptions in their publications we do not yet know exactly which viruses the WIV was experimenting with but it is certainly intriguing that numerous publications since Sars-CoV-2 first appeared have puzzled over the fact that the SARS-CoV-2 spike protein binds with exceptionally high affinity to the human ACE2 receptor “at least ten times more tightly” than the original SARS (Zhou et al., 2020; Wrapp et al., 2020; Wan et al., 2020; Walls et al., 2020; Letko et al., 2020).
This affinity is all the more remarkable because of the relative lack of fit in modelling studies of the SARS-CoV-2 spike to other species, including the postulated intermediates like snakes, civets and pangolins (Piplani et al., 2020). In this preprint these modellers concluded, “This indicates that SARS-CoV-2 is a highly adapted human pathogen.”
Given the research and collection history of the Shi lab at WIV it is therefore entirely plausible that a bat SARS-like cornavirus ancestor of Sars-CoV-2 was trained up on the human ACE2 receptor by passaging it in cells expressing that receptor.
How do viruses escape from high security laboratories?
Pathogen lab escapes take various forms. According to the US Government Accountability Office, a US defense Department laboratory once “inadvertently sent live Bacillus anthracis, the bacterium that causes anthrax, to almost 200 laboratories worldwide over the course of 12 years. The laboratory believed that the samples had been inactivated.” In 2007, Britain experienced a foot and mouth disease outbreak. Its’ origin was a malfunctioning waste disposal system of a BSL-4 laboratory leaking into a stream from which neighbouring cows drank. The disposal system had not been properly maintained (Furmanski, 2014). In 2004 an outbreak of SARS originating from the National Institute of Virology (NIV) in Beijing, China, began, again, with the inadequate inactivation of a viral sample that was then distributed to non-secure parts of the building (Weiss et al., 2015).
Writing for the Bulletin of The Atomic Scientists in February 2019, Lynn Klotz concluded that human error was behind most laboratory incidents causing exposures to pathogens in US high security laboratories. While equipment failure was also a factor, of the 749 incidents reported to the US Federal Select Agent Programme between 2009-2015, Klotz concluded that 79% resulted from human error.
But arguably the biggest worry is incidents that go entirely unreported because escape of the pathogen goes undetected. It is truly alarming that a significant number of pathogen escape events were uncovered only because investigators were in the process of examining a completely different incident (Furmanski, 2014). Such discoveries represent strong evidence that pathogen escapes are under-reported and that important lessons still need to be learned (Weiss et al., 2015).
The safety record of the WIV
The final important data point is the biosafety history of the WIV. The WIV was built in 2015 and became a commissioned BSL-4 lab in 2018. According to Josh Rogin of the Washington Post, US embassy officials visited the WIV in 2018. They subsequently warned their superiors in Washington of a “serious shortage of appropriately trained technicians and investigators needed to safely operate this high-containment laboratory”.
And according to VOA News, a year before the outbreak, “a security review conducted by a Chinese national team found the lab did not meet national standards in five categories”.
Credible reports from within China also question lab biosafety and its management. In 2019, Yuan Zhiming, biosecurity specialist at the WIV, cited the “challenges” of biosafety in China. According to Zhiming: “several high-level BSLs have insufficient operational funds for routine yet vital processes” and “Currently, most laboratories lack specialized biosafety managers and engineers.” He recommends that, “We should promptly revise the existing regulations, guidelines, norms, and standards of biosafety and biosecurity.” Nevertheless, he also notes that China intends to soon build “5-7” more BSL-4 laboratories (Zhiming, 2019).
And in February 2020, Scientific American interviewed Zheng-Li Shi. Accompanying the interview was a photograph of her releasing a captured bat. In the photo she is wearing a casual pink unzipped top layer, thin gloves, and no face mask or other protection. Yet this is the same researcher whose talks give “chilling” warnings about the dire risks of human contact with bats.
All of which tends to confirm the original State Department assessment. As one anonymous “senior administration official” told Rogin:
“The idea that it was just a totally natural occurrence is circumstantial. The evidence it leaked from a 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 leading hypothesis is a lab outbreak
For all these reasons, a lab escape is by far the leading hypothesis to explain the origins of Sars-CoV-2 and the COVID-19 pandemic. The sheer proximity of the WIV and WCDCP labs to the outbreak and the nature of their work represents evidence that can hardly be ignored. The long international history of lab escapes and the biosafety concerns from all directions about the labs in Wuhan greatly strengthen the case. Especially since evidence for the alternative hypothesis, in the form of a link to wild animal exposure or the wildlife trade, remains extremely weak, being based primarily on analogy with SARS one (Bell et al,. 2004; Andersen et al., 2020).
Nevertheless, on April 16th Peter Daszak, who is the President of the EcoHealth Alliance, told Democracy Now! in a lengthy interview that the lab escape thesis was “Pure baloney”. He told listeners:
“There was no viral isolate in the lab. There was no cultured virus that’s anything related to SARS coronavirus 2. So it’s just not possible.”
Daszak made very similar claims on CNN’s Sixty Minutes, “There is zero evidence that this virus came out of a lab in China.” Instead, Daszak encouraged viewers to blame “hunting and eating wildlife”.
Daszak’s certainty is highly problematic on several counts. The closest related known coronaviruses to Sars-CoV-2 are to be found at the WIV so a lot depends on what he means by “related to”. But it is also dishonest in the sense that Daszak must know that culturing in the lab is not the only way that WIV researchers could have caused an outbreak. Third, and this is not Daszak’s fault, the media are asking the right question to the wrong person.
As alluded to above, Daszak is the named principal investigator on multiple US grants that went to the Shi lab at WIV. He is also a co-author on numerous papers with Zheng-Li Shi, including the 2013 Nature paper announcing the isolation of coronavirus WIV-1 through passaging (Ge et al., 2013). One of his co-authorships is on the collecting paper in which his WIV colleagues placed the four fully functional bat coronaviruses into human cells containing the ACE2 receptor (Hu et al. 2017). That is, Daszak and Shi together are collaborators and co-responsible for most of the published high-risk collecting and experimentation at the WIV.
An investigation is needed, but who will do it?
If the Shi lab has anything to hide, it is not only the Chinese Government that will be reluctant to see an impartial investigation proceed. Much of the work was funded by the US taxpayer, channeled there by Peter Daszak and the EcoHealth Alliance. Virtually every credible international organisation that might in principle carry out such an investigation, the WHO, the US CDC, the FAO, the US NIH, including the Gates Foundation, is either an advisor to, or a partner of, the EcoHealth Alliance. If the Sars-CoV-2 outbreak originated from the bat coronavirus work at the WIV then just about every major institution in the global public health community is implicated.
But to solve many of these questions does not necessarily require an expensive investigation. It would probably be enough to inspect the lab notebooks of WIV researchers. All research scientists keep detailed notes, for intellectual property and other reasons, but especially in BSL-4 labs. As Yuan Zhiming told Nature magazine in an article marking the opening of the facility in Wuhan, “We tell them [staff] the most important thing is that they report what they have or haven’t done.”
Meticulous lab records plus staff health records and incident reports of accidents and near-accidents are all essential components (or should be) of BSL work. Their main purpose is to enable the tracking of actual incidents. Much speculation could be ended with the public release of that information. But the WIV has not provided it.
This is puzzling since the Chinese government has a very strong incentive to produce those records. Complete transparency would potentially dispel the gales of blame coming its way; especially on the question of whether Sars-CoV-2 has an engineered or passaged origin. If Zheng-Li Shi and Peter Daszak are correct that nothing similar to Sars-CoV-2 was being studied there, then those notebooks should definitively exonerate the lab from having knowingly made an Actual Pandemic Pathogen.
Given the simplicity and utility of this step this lack of transparency suggests that there is something to hide. If so, it must be important. But then the question is: What?
A thorough investigation of the WIV and its bat coronavirus research is an important first step. But the true questions are not the specific mishaps and dissemblings of Drs Shi or Daszak, nor of the WIV, nor even of the Chinese government.
Rather, the bigger question concerns the current philosophy of pandemic prediction and prevention. Deep enquiries should be made about the overarching wisdom of plucking and counting viruses from the wild and then performing dangerous ‘what if’ recombinant research in high tech but fallible biosafety labs. This is a reductionistic approach, we also note, that has so far failed to predict pandemics and may never do so.
https://www.gmwatch.org/en/news/latest-news/19417-the-case-is-building-that-covid-19-had-a-lab-origin

Tuesday, 2 June 2020

Chinese and US scientists genetically engineered bat coronaviruses in dangerous gain-of-function research stretching back years

Chinese and US scientists have been collaborating for years in dangerous gain-of-function experiments that involve genetically engineering coronaviruses from bats and other animals, as revealed by a series of scientific publications.

Coronavirus in green
Research was omitted from landmark paper claiming natural origin of SARS-CoV-2. Report: Claire Robinson
 The coronaviruses are related to the SARS viruses that cause severe respiratory diseases in humans. The scientists were based at the Wuhan Institute of Virology (WIV) in China, the lab suspected by some of accidentally releasing the SARS-CoV-2 virus that caused the COVID-19 pandemic, and at the University of North Carolina (UNC) in the US.

Oddly, however, this long and high-profile research history was entirely omitted from the scientific paper, published in Nature in February this year, in which Shi Zhengli and her team at the WIV claimed to have identified a natural origin for SARS-CoV-2. The origin, according to the WIV scientists, was a bat virus, RaTG13, that was thought to have jumped from an animal to a human at a Wuhan seafood and wildlife market (the “zoonotic” theory – that is, coming from animals by a natural spillover event).

Why the omission? To understand the possible reason, we need to first understand the nature of the research work that was done by the WIV scientists and their US collaborators.

The purported benign aim of this line of research was to investigate the potential of bat coronaviruses to infect humans, to improve scientists’ ability to predict pandemics, and to develop vaccines or other therapies.

However, this is also gain-of-function research, which aims to make viruses more infective or transmissible. Such research has come under increasing criticism by scientists for many years, due to its tendency to pose huge risks for little benefit.

This fear is borne out by the results of a particularly risky gain-of-function experiment carried out in the US and published in 2015 by scientists from the UNC in collaboration with WIV scientists, including Shi Zhengli, dubbed China’s “bat woman” for her work with bat coronaviruses. The work was funded by:
* The National Institute of Allergy & Infectious Disease (NIAID) of the US National Institutes of Health (NIH). The director of the NIAID is Dr Anthony Fauci, who currently heads up the US COVID-19 response. The NIH’s money was directed through the US-based Eco-Health Alliance, headed by Dr Peter Daszak;
* USAID; and
* Chinese institutions.

In the published paper reporting the risky experiment, the scientists state that they began their work before the 2014 US temporary moratorium on virus gain-of-function studies, which was prompted by several high-profile biosafety failures at US labs. But in spite of the moratorium, as stated in the paper, the NIH gave permission for the study to continue. Dr Fauci of the NIAID “outsourced” the research to the WIV in China, in the words of one media article.

Alarming finding

In the experiment, the scientists took a mouse coronavirus and exchanged its spike protein – the part on the surface of the virus that determines infectivity – for one from a bat coronavirus that was similar to the virus that causes the human epidemic disease SARS. They kept the mouse virus “backbone” – its basic RNA and protein molecular structure. The bat coronavirus, in its natural state, was unable to infect humans as its spike protein was inadequate – it was not able to dock onto the ACE2 receptor on human cells.

Infectivity is supposed to be determined just by the spike protein. So joining the bat spike protein with the mouse virus backbone should have resulted in a virus that was non-infectious to humans.  

But the resulting genetically engineered chimeric virus unexpectedly turned out to be highly infectious to humans. In fact, its infectivity, tested in human airway cells, was comparable to the human epidemic-causing virus strain SARS-CoV Urbani.

The scientists were clearly surprised and alarmed by this finding. As they state, “based on previous models of emergence”, the creation of this chimeric virus “was not expected to increase pathogenicity”. They deduced that the nature of the spike protein alone was not enough to determine infectivity – the backbone of other protein components is also important.

The researchers then tried – but failed – to develop a vaccine or antibody therapy. The antibodies were unable to block the receptor binding domain (RBD – the part of the spike protein that binds to the human ACE2 receptor, resulting in infection) of the bat-mouse chimeric virus.

The researchers conclude their publication with a caution and a question left hanging in the air. They write that their findings “represent a crossroads of GOF [gain-of-function] research concerns; the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens. In developing policies moving forward, it is important to consider the value of the data generated by these studies and whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved.”

In short, the very research that is claimed by some to be necessary to develop vaccines and other interventions risks creating a pandemic.

Guide to making a bioweapon

While there are serious risks involved in carrying out such research, there are also risks involved in publishing it. In this case the researchers examined the amino acid sequences of the bat virus spike protein and identified the sequences required for human infectivity – and published information on them in their paper.

The London-based molecular geneticist Dr Michael Antoniou commented, “The information on amino acid sequences provided in this paper is crucial to designing a virus that is infective in humans. Anyone with access to a standard laboratory would be able to use the information to estimate the amino acid sequence needed to engineer an RBD that would be highly likely to infect human cells.”

In other words, the researchers have provided a guide to making a bioweapon.

Dr Antoniou explained how their data makes what would otherwise have been a laborious process far quicker and more efficient. If you start with no information, you could engineer a human-infective virus like SARS-CoV-2 by using a “directed iterative evolutionary selection process”. This would involve using genetic engineering in a mutagenesis procedure to generate a large number of randomly mutated versions of the SARS-CoV spike protein RBD, which would then be selected for strong binding to the human ACE2 receptor and consequently high infectivity of human cells.

However, using the information provided by the UNC and WIV researchers, Dr Antoniou says, “You don’t have to go in blind using a total ‘saturation’ mutagenesis of the RBD amino acid sequence. You don’t have to start from a black box of unknowns. You already have an insight into which amino acid sequence is needed for human infectivity, so that guides you as to how to engineer the virus.”

This raises the ethical question of whether gain-of-function research is ever worth the risk. Dr Antoniou believes that it is not: “Research of this type is not necessary to identify new targets for therapeutic intervention. An investigation of the basic mechanisms of how virus infection takes place and progresses is sufficient for this. Thus gain-of-function research with known dangerous pathogens such as coronaviruses should be banned.”

More gain-of-function research

In spite of the dangers highlighted in the 2015 paper, and in the wake of the US temporary moratorium on virus gain-of-function work, the research with bat coronaviruses continued – this time in China. In 2017 WIV scientists, including Shi Zhengli, published a study with funding shared between Chinese and US institutions, the latter including the US NIH and USAID.

The researchers report the findings from virus infectivity experiments where genetic material was combined from different SARS-related coronaviruses to form novel chimeric versions. They were trying to find out which mutations were needed to allow certain bat coronaviruses to bind to the human ACE2 receptor. They found that two genetically engineered chimeric viruses replicated “efficiently” in human cells. The consequences of escape of such viruses could be serious.

Then, only this month, WIV scientists led by Shi Zhengli published a pre-print reporting work in which they investigated the ability of spike proteins from bat SARS-related coronavirus (SARSr-CoV), among other coronaviruses, to bind to bat and human ACE2 receptors. In other words, they examined how efficiently these coronaviruses infect humans and how human infectivity can be optimised. 

Mystery of the missing research

The three papers examined above show that over a period of several years, Chinese and US scientists were using genetic engineering techniques for gain-of-function experiments with coronaviruses, resulting in the generation of viruses better adapted to infect humans.

Against this background Shi Zhengli published her landmark paper in the journal Nature in February this year, after the COVID-19 pandemic had spread across the globe. In this paper, Shi and her co-authors claimed to have identified the closest relative to SARS-CoV-2 and its “probable” origin, a natural bat coronavirus, which she called RaTG13. The paper highlights the natural origin zoonotic theory for SARS-CoV-2 – that it jumped from an animal into humans at the Huanan seafood and wildlife market. This theory has not subsequently been supported by emerging evidence.

All publications arguing for a natural origin for SARS-CoV-2 rely heavily on this one paper by Shi Zhengli and colleagues, describing the sequence of a purported natural bat coronavirus named RaTG13. But notably absent from the paper is any reference at all to Shi and her collaborators’ long history of gain-of-function genetic engineering research with bat coronaviruses, described above. That includes the important paper by UNC and WIV scientists of 2015, which had the alarming result of turning a harmless bat virus into a human pathogen.

Vested interests

It is as if this research background simply didn’t exist. Why? Could it be because drawing attention to it might raise the suspicion in people’s minds that SARS-CoV-2 might also have been intentionally or accidentally optimised in the lab during gain-of-function research?

After all, if the belief gained traction that the virus might have escaped from a lab, virologists could expect their research to be “impacted adversely by tighter laboratory controls”, as the leading vaccine researcher Professor Nikolai Petrovsky has pointed out in explaining why the majority of scientists seem to be supporting the idea that the virus originated in a wet market rather than a lab.

It would also, of course, almost certainly bring the “gravy train” of virus gain-of-function research to an abrupt halt, quite apart from causing a massive political storm. It might even awaken public doubts about the safety of other risky applications of genetic engineering.

But despite this array of vested interests, a forensic investigation needs to begin as soon as possible into the exact origins of a pandemic virus that, in the words of Professor Petrovsky, seems “like it was designed to infect humans”.
https://www.gmwatch.org/en/news/latest-news/19410-chinese-and-us-scientists-genetically-engineered-bat-coronaviruses-in-dangerous-gain-of-function-research-stretching-back-years