EXPERT REACTION: Did COVID-19 come from a lab in Wuhan?
Publicly released: Fri 17 Apr 2020 at 1130 AEST | 1330 NZST
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Nikolai Petrovsky is a Professor in the College of Medicine and Public Health at Flinders University. He is also Research Director, Vaxine Pty Ltd
"An extremely important but still unanswered question is what was the source of COVID-19 virus. While COVID-19 has close similarities to SARS and other bat viruses no natural virus matching to COVID-19 has been found in nature despite an intensive search to find its origins. This raises the very legitimate question of whether the COVID-19 virus might be the result of human intervention.
Certainly, our and other analyses of the genomic sequence of the virus do not reveal any artificial gene inserts that would be the hallmark of a gene jockey, genetic engineers who manipulate or even create viruses by splicing in artificial inserts into their genome. These are generally easily recognisable and hence clear signatures of human intervention in the creation of a virus. The fact that these artificial inserts are not present has been interpreted by some to mean this virus is not the result of human manipulation.
However, this logic is incorrect as there are other ways in which humans can manipulate viruses and that is caused by natural selection. What do I mean? All viruses and bacteria mutate and adapt to their environment over time, with selection of the fittest individuals for survival in that particular environment.
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.
My group in collaboration with other Australian researchers have been using a modelling approach to study the possible evolutionary origins of COVID-19 by modelling interactions between its spike protein and a broad variety of ACE2 receptors from many animals and humans.
This work which we will publish on a prepress server next week shows that the strength of binding of COVID-19 to human ACE2 far exceeds the predicted strength of its binding to the ACE2 of any of the other species. This points to the virus having been selected for its high binding to human ACE2. In the absence of evidence of historic human infections with this virus, which could result in such selection, this either is a remarkable coincidence or a sign of human intervention.
This, plus the fact that no corresponding virus has been found to exist in nature, leads to the possibility that COVID-19 is a human-created virus. It is therefore entirely plausible that the virus was created in the biosecurity facility in Wuhan by selection on cells expressing human ACE2, a laboratory that was known to be cultivating exotic bat coronaviruses at the time. Is so the cultured virus could have escaped the facility either through accidental infection of a staff member who then visited the fish market several blocks away and there infected others, or by inappropriate disposal of waste from the facility that either infected humans outside the facility directly or via a susceptible vector such as a stray cat that then frequented the market and resulted in transmission there to humans.
Whilst the facts cannot be known at this time, the nature of this event and its proximity to a high-risk biosecurity facility at the epicentre of the outbreak demands a full and independent international enquiry to ascertain whether a virus of this kind of COVID-19 was being cultured in the facility and might have been accidentally released."
Last updated: 17 Apr 2020 12:14pm
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Download:(license)
COVID-19 e-print
Important: e-prints posted on arXiv are not peer-reviewed by arXiv; they should not be relied upon without context to guide clinical practice or health-related behavior and should not be reported in news media as established information without consulting multiple experts in the field.
[Submitted on 13 May 2020]
In silico comparison of spike protein-ACE2 binding affinities across species; significance for the possible origin of the SARS-CoV-2 virus
Sakshi Piplani, Puneet Kumar Singh, David A. Winkler, Nikolai Petrovsky
...
Publicly released: Fri 17 Apr 2020 at 1130 AEST | 1330 NZST
...
Nikolai Petrovsky is a Professor in the College of Medicine and Public Health at Flinders University. He is also Research Director, Vaxine Pty Ltd
"An extremely important but still unanswered question is what was the source of COVID-19 virus. While COVID-19 has close similarities to SARS and other bat viruses no natural virus matching to COVID-19 has been found in nature despite an intensive search to find its origins. This raises the very legitimate question of whether the COVID-19 virus might be the result of human intervention.
Certainly, our and other analyses of the genomic sequence of the virus do not reveal any artificial gene inserts that would be the hallmark of a gene jockey, genetic engineers who manipulate or even create viruses by splicing in artificial inserts into their genome. These are generally easily recognisable and hence clear signatures of human intervention in the creation of a virus. The fact that these artificial inserts are not present has been interpreted by some to mean this virus is not the result of human manipulation.
However, this logic is incorrect as there are other ways in which humans can manipulate viruses and that is caused by natural selection. What do I mean? All viruses and bacteria mutate and adapt to their environment over time, with selection of the fittest individuals for survival in that particular environment.
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.
My group in collaboration with other Australian researchers have been using a modelling approach to study the possible evolutionary origins of COVID-19 by modelling interactions between its spike protein and a broad variety of ACE2 receptors from many animals and humans.
This work which we will publish on a prepress server next week shows that the strength of binding of COVID-19 to human ACE2 far exceeds the predicted strength of its binding to the ACE2 of any of the other species. This points to the virus having been selected for its high binding to human ACE2. In the absence of evidence of historic human infections with this virus, which could result in such selection, this either is a remarkable coincidence or a sign of human intervention.
This, plus the fact that no corresponding virus has been found to exist in nature, leads to the possibility that COVID-19 is a human-created virus. It is therefore entirely plausible that the virus was created in the biosecurity facility in Wuhan by selection on cells expressing human ACE2, a laboratory that was known to be cultivating exotic bat coronaviruses at the time. Is so the cultured virus could have escaped the facility either through accidental infection of a staff member who then visited the fish market several blocks away and there infected others, or by inappropriate disposal of waste from the facility that either infected humans outside the facility directly or via a susceptible vector such as a stray cat that then frequented the market and resulted in transmission there to humans.
Whilst the facts cannot be known at this time, the nature of this event and its proximity to a high-risk biosecurity facility at the epicentre of the outbreak demands a full and independent international enquiry to ascertain whether a virus of this kind of COVID-19 was being cultured in the facility and might have been accidentally released."
Last updated: 17 Apr 2020 12:14pm
...
----------------------------------------------------------------------
Download:(license)
COVID-19 e-print
Important: e-prints posted on arXiv are not peer-reviewed by arXiv; they should not be relied upon without context to guide clinical practice or health-related behavior and should not be reported in news media as established information without consulting multiple experts in the field.
[Submitted on 13 May 2020]
In silico comparison of spike protein-ACE2 binding affinities across species; significance for the possible origin of the SARS-CoV-2 virus
Sakshi Piplani, Puneet Kumar Singh, David A. Winkler, Nikolai Petrovsky
The devastating impact of the COVID19 pandemic caused by SARS coronavirus 2 (SARSCoV2) has raised important questions on the origins of this virus, the mechanisms of any zoonotic transfer from exotic animals to humans, whether companion animals or those used for commercial purposes can act as reservoirs for infection, and the reasons for the large variations in susceptibilities across animal species. Traditional lab-based methods will ultimately answer many of these questions but take considerable time. In silico modeling methods provide the opportunity to rapidly generate information on newly emerged pathogens to aid countermeasure development and also to predict potential future behaviors. We used a structural homology modeling approach to characterize the SARSCoV2 spike protein and predict its binding strength to the human ACE2 receptor. We then explored the possible transmission path by which SARSCoV2 might have crossed to humans by constructing models of ACE2 receptors of relevant species, and calculating the binding energy of SARSCoV2 spike protein to each. Notably, SARSCoV2 spike protein had the highest overall binding energy for human ACE2, greater than all the other tested species including bat, the postulated source of the virus. This indicates that SARSCoV2 is a highly adapted human pathogen. Of the species studied, the next highest binding affinity after human was pangolin, which is most likely explained by a process of convergent evolution. Binding of SARSCoV2 for dog and cat ACE2 was similar to affinity for bat ACE2, all being lower than for human ACE2, and is consistent with only occasional observations of infections of these domestic animals. Overall, the data indicates that SARSCoV2 is uniquely adapted to infect humans, raising questions as to whether it arose in nature by a rare chance event or whether its origins lie elsewhere.
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