Is considering a genetic-manipulation origin for SARS-CoV-2 a conspiracy theory that must be censored?
https://www.researchgate.net/publication/340924249_Is_considering_a_genetic-manipulation_origin_for_SARS-CoV-2_a_conspiracy_theory_that_must_be_censored?fbclid=IwAR0x8AQ4xEmRdGr-Aw8m9Mx06Kn9LXTg8TZ8yOD0bvXJcwEbFUWK_6m37ms
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Como biólogo molecular con experiencia en manipulación genética
(hongos), no excluyo un origen sintético para el SARS-CoV-2. En mi
manuscrito no acuso a ninguna nación o grupo de investigación por la
posible manipulación genética del virus. Hice una amplia investigación
bibliográfica sobre el tema y sugiero un posible diseño experimental que
podría haber originado el SARS-CoV-2, conocido por ser quimérico.
Además, expreso un análisis crítico del artículo de Andersen y colegas
recientemente publicado en Nature on the Proximal Origin of SARS-CoV-2.
As molecular biologist with expertise in genetical manipulation (fungi) I
do not exclude a synthetic origin for SARS-CoV-2. In my manuscript I do
not accuse any nation or research group for possible genetic
manipulation of the virus. I did a wide literature research on the topic
and I suggest a possible experimental design that could have originated
SARS-CoV-2, known to be chimeric.
Moreover, I express a critical analysis of the paper of Andersen and
colleagues recently published in Nature on the Proximal Origin of
SARS-CoV-2.
Abstract
The origin of SARS-CoV-2 is still controversial. Comparative genomic analyses have shown that SARS-CoV-2 is likely to be chimeric, most of its sequence being very close to the CoV detected from a bat,whereas its receptor binding domain is almost identical to that of CoV obtained from pangolins. Thefurin cleavage site in the spike protein of SARS-CoV-2 was previously not identified in other SARS-likeCoVs and might have conferred ability to cross species and tissue barriers. Chimeric viruses can bethe product of natural recombination or genetic manipulations. The latter could have aimed toidentify pangolins as possible intermediate hosts for bat-CoV potentially pathogenic for humans.
Theories that consider a possible artificial origin for SARS-CoV-2 are censored as they seem to
support conspiracy theories. Researchers have the responsibility to carry out a thorough analysis,
beyond any personal research interests, of all possible causes for SARS-CoV-2 emergence for
preventing this from happening in the future.
Several months have passed since the outbreak of SARS-CoV-2 in Wuhan, China, and its origin is stillcontroversial. The theory that the Wuhan’s Huanan Seafood Wholesale Market was the first sourcefor animal–human virus transmission has lost credibility. During the first phase of the epidemic inWuhan, several hospitalized patients with confirmed SARS-CoV-2 infections had no link with the
market.
The closest relatives to SARS-CoV-2 are bat and pangolin coronaviruses
Zhou and colleagues2 from the Wuhan Institute of Virology (WIV) first identified and characterized
the new coronavirus (CoV), recently named SARS-CoV-2. The genomic sequences obtained from earlycases shared 79% sequence identity to the CoVs that caused Severe Acute Respiratory Syndrome(SARS-CoV) in 2002-2003 and 96·2 % sequence identity to RaTG13, a total genomic sequence of aCoV detected from a Rhinolophus affinis bat. This sample was collected in the Yunnan province(China) by the same group of researchers in 2013. Zhou and colleagues2 found a short region of RNA-dependent RNA polymerase (RdRp) in their data and then fully sequenced the original sample. Thissequence is currently the closest phylogenetic relative for SARS-CoV-2 found3 and it has not beenpublished before the outbreak of SARS-CoV-2.
The RdRp of RaTG13 has 100 % identity with the sequence BtCoV/4991 (KP876546) identified by Geand colleagues4 in a Rhinolophus affinis bat in the Yunnan province in 2013 as RaTG13. Based on thephylogenetic analysis carried out by Ge and colleagues4, BtCoV/4991 is a novel beta-CoV, clearly
separated from all known alpha- and beta-CoVs at that time. Spike genes were amplified as well, and
made available upon request to Ge and colleagues.4 BtCoV/4991 clearly differentiates from other bat
CoVs also in the phylogenetic analysis carried out by Wang and colleagues.5 Chen and colleagues6
identified BtCoV/4991 as the closest sequence to SARS-CoV-2 because RaTG13 had not yet been
published at that time. How BtCoV/4991 and RaTG13 relate to each other remains unclear.
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The second non-human RdRp sequence closest to BtCoV/4991 (91·89%) is the CoV sequence MP789isolated in 2019 in a Malaysian pangolin (Manis javanica) in the Guangdong province, China
(MT084071).Bat CoVs have been studied intensely and genetically manipulated
Several studies point out that bats are reservoirs for a broad diversity of potentially pathogenic SARS-like CoV.4,7,8 Some of these viruses can directly infect humans9, whereas others need to mutate theirspike protein in order to effectively bind to the human angiotensin 1-converting enzyme 2 (hACE2)receptor and mediate virus entry.10 In order to evaluate the emergence potential of novel CoVs,receptor and mediate virus entry.10 In order to evaluate the emergence potential of novel CoVs,chimeric CoVs with Bat CoV backbones not able to infect human cells were fused to spike proteins ofCoVs compatible with human ACE2, simulating recombination events that occur naturally.7,11,12 These experiments with gain of function have raised biosafety concerns and controversy amongresearchers and the public
Key difference between SARS-CoV-2 and its closest relative RaTG13SARS-CoV-2 differs from its closest relative RaTG13 by few key characteristics. The most striking oneis the acquisition in the spike protein of SARS-CoV-2 of a cleavage site activated by the host-cellenzyme furin, previously not identified in other beta-CoVs of lineage b15 and similar to that of Middle
East Respiratory Syndrome Coronavirus (MERS-CoV).16 Host protease processing plays a pivotal roleas species and tissue barrier. Engineering of the cleavage sites of CoV spike proteins modifies virustropism and virulence.17 The ubiquitous expression of furin in different organs and tissues may have conferred to SARS-CoV-2 the ability to infect body parts insensitive to other CoVs, leading to
systematic infection in the body.18 Cell-cultured SARS-CoV-2 that was missing the above-mentioned
cleavage site caused attenuated symptoms in infected hamsters.19
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Pangolin or not pangolin, that is the question
The possibility that pangolins could be the intermediate host for SARS-CoV-2 is still under
discussion.20,21 SARS-CoV-2 and RaTG13 mostly diverge because of the RBD of their spike protein.3
Although the average genome similarity is lower compared to RaTG13, CoV isolated from pangolins
has RBDs almost identical to that of SARS-CoV-2. Indeed, pangolin CoVs and SARS-CoV-2 possess
identical amino acids at the five critical residues of the RBD, whereas RaTG13 only shares one amino acid with SARS-CoV-2.16 ACE2 sequence similarity is higher between humans and pangolins thanbetween humans and bats. Before the SARS-CoV-2 outbreak, pangolins were the only mammals
other than bats documented to carry a SARS-CoV-2 related CoV.22 Recombination events between
the RBD of CoV from pangolins and RaTG13-like backbone could have originated SARS-CoV-2 as
chimeric strain. For recombination to occur, the two viruses must have infected the same cell in the
same organism simultaneously.16
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Is a lab origin for SARS-CoV-2 a baseless conspiracy theory?
Due to the broad-spectrum of research conducted over almost 20 years on bat SARS-CoV justified by
their potential to spill over from animal to human23, a possible synthetic origin by laboratory
engineering of SARS-CoV-2 is a reasonable hypothesis. Andersen and colleagues24 stated that strong
evidence that SARS-CoV-2 did not result from genetic manipulation is that the high-affinity binding ofthe SARS-CoV-2 spike protein to human ACE2 could not have been predicted by models based on theRBD of SARS-CoV. As described above, creation of chimeric viruses has been carried out over theyears with the purpose to study the potential pathogenicity of bat CoVs for humans. In this context,SARS-CoV-2 could have been synthetized by combining a backbone similar to RaTG13 with the RBD ofCoV similar to the one recently isolated from pangolins20, because the latter is characterized by ahigher affinity with the hACE2 receptor. Such research could have aimed to identify pangolins aspossible intermediate hosts for bat-CoV potentially pathogenic for humans
Regarding the furin cleavage site, Andersen and colleagues24 state that “The functional consequence
of the polybasic cleavage site in SARS-CoV-2 is unknown”. New studies from several groups have
lately identified this activation site as possibly enabling the virus to spread efficiently between
humans and attack multiple organs.25
Andersen and colleagues24 also state, based on the work of Almazan and colleagues26 that “the
genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus
backbone”. In the last six years before the outbreak of SARS-CoV-2 the number of potential bat
backbones has been undeniably increased by several bat CoV screenings, last but not least bringing
RaTG13 to scientific attention in January 2020. Other possible backbones could, as well, still wait for
publicationndersen and colleagues24 also state that “The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios”. Methods for insertion of apolybasic cleavage site in infectious bronchitis CoV are given in Cheng and colleagues27 and resultedin increased pathogenicity. The addition of O-linked glycans typically occurs under immune selectionand could have arisen during in vivo experiments. To overcome problems of bat CoV isolation,experiments based on direct inoculation of bat CoV in suckling rats have been carried out 28.
Pangolins or other animals with similar ACE2 conformation could have been used as experimental
animals as well. The authors also state that “Subsequent generation of a polybasic cleavage site
would have then required repeated passage in cell culture or animals with ACE2 receptors similar to
those of humans, but such work has also not previously been described.” It should not be excluded
that such experiments could have been aborted due to the SARS-CoV-2 outbreak, before a possible
publication of the results or that the results were never intended to be published.
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Conclusion
Due to the gravity of SARS-CoV-2 impact on humanity, researchers have the responsibility to carry
out a thorough analysis, beyond any personal research interests, of all possible causes for SARS-CoV-2 emergence. Unfortunately, theories that consider a possible artificial origin for SARS-CoV-2 arecensored by international scientific journals as they seem to support conspiracy theories. Genetic
manipulation of SARS-CoV-2 may have been carried out in any laboratory in the world with access tothe backbone sequence and the necessary equipment
Xiao Qiang, a research scientist at the School of Information at the University of California at
Berkeley, recently stated “To understand exactly how this virus has originated is critical knowledge
for preventing this from happening in the future” (Washington Post, April 14, 2020).
Conclusion
La manipulación del SARS-CoV-2 puede haberse realizado en cualquier laboratorio del mundo con acceso a la secuencia de la columna vertebral y el equipo necesario
Xiao Qiang, un científico investigador de la Escuela de Información de la Universidad de California en Berkeley, recientemente declaró "Entender exactamente cómo se ha originado este virus es un conocimiento crítico para evitar que esto ocurra en el futuro" (Washington Post, 14 de abril de 2020).
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