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Review 4: "Unusual Features of the SARS-CoV-2 Genome Suggesting Sophisticated Laboratory Modification Rather Than Natural Evolution and Delineation of Its Probable Synthetic Route"

The manuscript does not demonstrate sufficient scientific evidence to support its claims. Claims are at times baseless and are not supported by the data and methods used. Decision-makers should consider the author's claims in this study misleading.

Published onOct 04, 2020
Review 4: "Unusual Features of the SARS-CoV-2 Genome Suggesting Sophisticated Laboratory Modification Rather Than Natural Evolution and Delineation of Its Probable Synthetic Route"

RR:C19 Evidence Scale rating by reviewer:

  • Misleading. Serious flaws and errors in the methods and data render the study conclusions misinformative. The results and conclusions of the ideal study are at least as likely to conclude the opposite of its results and conclusions than agree. Decision-makers should not consider this evidence in any decision.

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Review:

My thoughts on this report are that it is composed entirely of opinion and innuendo. Yan says she will be coming out with more concrete data later, but I doubt it, especially as this current report has been so long in coming. The timing is suspicious. 

She modulates her description of the RaTG13 sequence from “widely questioned” moves to “spurious” moves to “likely fraudulent”. The old camel nose/tent trick. See the following.

“However, the existence of RaTG13 in nature and the truthfulness of its reported sequence are being widely questioned6-9,19-21.”

“A follow-up report, which summarizes the up-to-date evidence proving the spurious nature of RaTG13, will be submitted soon.”

“What is not thoroughly described in this report is the various evidence indicating that several coronaviruses recently published (RaTG1318, RmYN0230, and several pangolin coronaviruses27-29,31) are highly suspicious and likely fraudulent.”

She requires certain viral sequences (including RaTG13 and the pangolin viruses) that are closely related to SARS-CoV2 to be fraudulent, as it allows her to claim that her candidate virus, ZC45, is the closest relative to SARS-CoV2. Why is this her candidate? The reason is probably it’s connection with military, see below.). RaTG13 is 97% identical at the nucleotide level, ZC45 only 89%. At least one of the sources she quotes for the pangolin sequence being fraudulent does not, in fact, make that claim. It merely says that the pangolins may have gotten the virus from a different species. And even if they were fraudulent, it still would require more than 3,000 nucleotide substitutions to become SARS-CoV2. This is not even slightly credible; it beggars reason.

“Genomic sequence analysis reveals that ZC45, or a closely related bat coronavirus, should be the backbone used for the creation of SARS-CoV-2.”

“The genomic sequence of SARS-CoV-2 is suspiciously similar to that of a bat coronavirus discovered by military laboratories in the Third Military Medical University (Chongqing, China) and the Research Institute for Medicine of Nanjing Command (Nanjing, China) (i.e, ZC45).”

Then she presents a scheme for converting ZC45 to SARS2. Totally unnecessary, all you would have to do is synthesize your desired genome, transfect the DNA into a host cell, and out pops your virus. The larger question is, how would you know what exact genome would have all the characteristics you wanted? 

Her second point is that the RBD is “suspiciously close to that of SARS1. No it’s not. The pangolin sequences are 100% in the RBD. Can’t get much closer than that. That’s why she has to claim the pangolin sequences are fraudulent.

Point 3 is the furin cleavage site. She states that this doesn’t occur in “other viruses of this class”. Not clear what she means by class. Presumably she means SARS-like CoVs. It’s certainly in some other coronaviruses. MERS has 2 of them. infectious bronchitis virus (IBV) Beaudette strain, a chicken coronavirus, has 2. People have presented a credible origin of the furin cleavage site by a simple copy-choice mistake by the viral polymerase. 

Finally, her timing is odd. Why hasn’t she published before. What will she submit soon? Why not now? I doubt anything substantive is coming. 

Her research appears to be funded by the Rule of Law Society and the Rule of Law Foundation. The sister nonprofit organizations are connected to Steve Bannon, a former chief strategist for the Trump administration, and Guo Wengui, a billionaire and political activist who fled China in 2014 in anticipation of corruption charges from the Communist Party. Neither organization has published scientific literature before, according to a Google Scholar search. A website linked to Bannon and Wengui has a history of making inaccurate claims about the coronavirus pandemic.

To more specifically review Yan’s publication, let’s look at her Abstract.

  1. She says the natural origin theory lacks substantial support. No it doesn’t(1-3). This seems deliberately deceptive.

  2. She says papers claiming a man-made origin are strictly censored by peer reviewed journals. As a sometime peer reviewer, I don’t call peer review censorship.

  3. She says the virus shows biological characteristics that are inconsistent with a naturally occurring, zoonotic virus. Dubious claim. 

  4. She postulates a synthetic route that is partly doable but tedious, and is otherwise logically impossible. 

The Introduction

  1. She says it has characteristics that are incompatible with a zoonotic respiratory virus, including being highly transmissible and significantly lethal in high-risk populations. The Incas would be relieved to know that measles, derived from rinderpest in cattle, does not share those characteristics.

  2. She claims that the receptor binding domain of the spike protein binds human ACE2 better than any other species. No it doesn’t; it binds various ACE2 receptors from other species about as well, including pikas and rabbits https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25817 . Her citation is a non-peer reviewed in silico modeling study.

  3. She accuses the reports of the sequence of one of the purported precursors to SARS2, RaTG13, as being probably fraudulent. The references she gives are either weak or don’t claim this at all. In fact, one of them notes that six workers in a cave from which a closely related sample was obtained from bat feces suffered from an atypical viral pneumonia and three of them died in 2013 (https://www.preprints.org/manuscript/202005.0322/v2). This would rather seem to point to the reality of RaTG13.

The Proposed Construction

It is necessary for her to claim that a number of sequences (including RaTG13, 97% identical by nucleotide sequence) are fraudulent, because its absence allows her to use ZC45 (89% identical by nucleotide sequence). She probably chose this because she could link it to the military. Here’s what she suggests. She says you start with ZC45 as a precursor. At 89% identity, you would need about 3,300 nucleotide changes. You engineer in an ACE2 receptor binding domain and furin cleavage sites. OK, although that ACE2 binding site is not optimal for ACE2 binding. Then you engineer in a pol gene that responds well to remdesivir (because this gives you a good antiviral and would make remdesivir profitable). Then you adapt the virus by passage in culture for the ability to better infect human cells.  This step, however, is simply beyond belief. You would need more than 3,000 individual mutations. This probably represents hundreds of millenia of evolution. It’s even more incredible because coronaviruses have RNA proofreading enzymes that make them fairly stable genetically, although they do readily undergo recombination by RNA polymerase template slippage or switching. 

My opinion is that this is an inept attempt to make the case the virus was man-made. There are no concrete facts in this report. I do wonder why this is coming out now. She implies she will be coming out with something more convincing in the future, but I’m willing to bet that if anything comes it will just be more of the same.

  1. K. G. Andersen, A. Rambaut, W. I. Lipkin, E. C. Holmes, R. F. Garry, The proximal origin of SARS-CoV-2. Nat Med 26, 450-452 (2020).

  1. B. Hu et al., Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog 13, e1006698 (2017).

  1. V. D. Menachery et al., A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat Med21, 1508-1513 (2015).

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