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Review 2: "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 onSep 25, 2020
Review 2: "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:

The main issue with this manuscript is that it is not “scientific.” In presentation, it reads like an opinion piece. The authors tie various threads together into a story. However, they are only able to do this by focusing on the most sinister interpretation of just a subset of evidence. Much data is ignored or discounted. Perhaps most important, the argument or hypothesis made by the authors is neither provable nor falsifiable. This falsification principle is a key tenet of science.

Additional questions posed by the editorial office:

1. Does the manuscript confirm previous work or refute current understanding?

It does not. The manuscript attempts to refute our current understanding of the origins of SARS-CoV-2. Briefly, the consensus is that SARS-CoV-2 is a zoonosis and originated in bats with perhaps an intermediate host before spilling over into humans. The authors of this manuscript argue instead that SARS-CoV-2 was engineered in a laboratory starting from a bat coronavirus sequence. They are selective in their citation of the literature. They discount several peer reviewed studies that have provided evidence for the natural origins of SARS-CoV-2. They claim that some of these are not worthy of consideration, because of conflicts of interest from the authors. It is not clear what those conflicts of interest are and why those studies should not stand. They also offer “evidence” that calls these papers into doubt. However, the citations do not appear to substantially call these papers into question. Some appear to be preprints that are more opinion pieces or conjecture, much like this one. To put it another way, the authors don’t contest the natural origin hypothesis with data. Instead, they offer ideas and opinions.

2. How well does the manuscript position the work within the current literature/understanding?

As above, citations are selective and the authors dismiss available data and literature without trying to work within it. The evidence for a remote or recent bat origin of SARS-CoV-2 is supported by the following manuscripts:

Andersen et al. Nature Medicine, 10.1038/s41591-020-0820-9
Lam et al. Nature 2020, 10.1038/s41586-020-2169-0
Latinne et al. Nature Communications doi.org/10.1038/s41467-020-17687-3
Xiao et al. Nature doi.org/10.1038/s41586-020-2313-x
Yan et al. Current Biology doi.org/10.1016/j.cub.2020.05.023
Boni et al. Nature Microbiology doi.org/10.1038/s41564-020-0771-4

Additional areas in which the work does not fit with the current science.

(a) The authors speculate - without evidence - that SARS-CoV-2 was engineered from the backbone of ZC45 or ZXC21 bat coronaviruses. This appears to be convenient for their argument, as these viruses have some linkage, per the authors, to the Chinese government or military. As others have pointed out, using these as starting points for genetic engineering makes little sense. These viruses differ from SARS-CoV-2 at approximately 10% of the positions in the genome. If someone were to engineer a virus like SARS-CoV-2, they would start with a more closely related virus. It is much simpler.

(b) The authors attach inordinate significance to a restriction enzyme site near the receptor binding domain. They consider it something of a smoking gun as it will allow for sub cloning of receptor binding domains during the engineering process. This site is a 6 nucleotide recognition sequence and would occur by chance once every 4096 bases in a genome sequence. In SARS-CoV-2, which is approximately 30,000 bases, one would expect to find this particular sequence 7-8 times by chance. Therefore, attaching significance to its existence in the genome does not make a lot of scientific sense.

(c) The furin-like cleavage site is also considered highly suspicious to the authors. It should be noted that many viruses have these cleavage sites. In and of itself, its existence is not evidence for an engineered origin for SARS-CoV-2. See for example Yan et al. Current Biology (doi above)

(d) The proposed route to engineering SARS-CoV-2 as diagrammed in Figure 8 is simply not credible. If there were a sophisticated effort to engineer SARS-CoV-2 in a laboratory, this would not be the route. Entire viral and bacterial genomes have been created by gene synthesis. That would be the route, as opposed to the multistep restriction enzyme cloning strategy outlined by the authors (see also the significance attached to EcoRI restriction site in my comment above).

(e) A complete review of the many issues with this manuscript can be found here. I concur with the assessments of these authors. https://www.centerforhealthsecurity.org/our-work/publications/in-response-yan-et-al-preprint-examinations-of-the-origin-of-sars-cov-2

3. Is there clarity regarding the recommended actions the result from the findings?

In this reviewer’s opinion, no. The manuscript does not make its case from the foundation of sound scientific argument. It is therefore not accurately presented and does not speak to key audiences.

4. Do the authors pay attention to ethics, diversity, and inclusion?

A key aspect of research ethics and the responsible conduct of research is to include information on who supported the work - financially or otherwise. The authors’ affiliation is the “Rule of Law Society & Rule of Law Foundation.” It is not clear who supports this Foundation or what its purpose is. It is important for there to be transparency regarding research support, especially for a manuscript that is based on conjecture as opposed to data or empiricism. It is also unethical to promote what are essentially conspiracy theories that are not founded in fact.

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