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Scientists "Firmly Determine" That SARS-CoV-2 Was Not Engineered

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The COVID-19 outbreak caused by the spread of the virus SARS-CoV-2 is a product of natural evolution, scientists conclude in a correspondence piece published in Nature Medicine.

The SARS-CoV-2 virus that is causing COVID-19 was first reported to the World Health Organization towards the latter part of 2019. Since then, there has been much discussion, debate and theorizing on the origins of the coronavirus. Where did it come from?

Shortly after the initial outbreak, Chinese scientists endeavored to sequence the genome of SARS-CoV-2. They were successful in their feat and made the data available to researchers across the globe. Now, a collaborative research team have analyzed the sequence to explore the evolution of SARS-CoV-2, concentrating on several distinct features of the virus such as the spike protein (S protein).

Their conclusion? SARS-CoV-2 was not engineered. “By comparing the available genome sequence data for known coronavirus strains, we can firmly determine that SARS-CoV-2 originated through natural processes,” said Kristian Andersen, PhD, an associate professor of immunology and microbiology at Scripps Research and corresponding author on the paper.

Distinct features of SARS-CoV-2

Andersen et al decided to focus on the S protein of SARS-CoV-2. For readers that are unfamiliar, the S protein is a "multifunctional molecular machine" that facilitates coronavirus entry into the cells of the host. Learning more about this molecular machinery can enhance both methods to understand transmission of the virus and efforts to treat it.

The team analyzed the genetic blueprint for the S proteins, focusing on two elements: the receptor-binding domain (RBD) and the cleavage site. The researchers use metaphors to explain the importance of these two sites: the RBD is essentially a "hook" that grips onto host cells, whereas the cleavage site can be likened to a can opener, pulling open the host cell, permitting entry and subsequent infection.

Through their analysis, Andersen and colleagues discovered that the RBD element of the S protein had evolved very specifically to target a receptor known as angiotensin converting enzyme 2, or ACE2. Under normal physiological conditions this receptor is involved in blood pressure regulation and is expressed in the vascular endothelial cells of the kidneys and the hearts, predominantly. The scientists found that SARS-CoV-2 was so effective in binding to ACE2 that it simply must be the result of natural selection.

Epidemics lead at The Wellcome Trust, Josie Golding, PhD, remarked that these findings are "Crucially important to bring an evidence-based view to the rumors that have been circulating about the origins of the virus (SARS-CoV-2) causing COVID-19."

In addition to the specific binding of the S protein to ACE2, a feature of the molecular structure of SARS-CoV-2 also shed some light on its origin. The backbone of SARS-CoV-2 differs substantially from the already known coronaviruses. In fact, it mostly resembles related viruses that are found in bats and pangolins.

A polybasic cleavage site at the junction of two subunits of the S protein exists, and this site enables cleavage by a protein known as furin and other proteases, implicated in determining the infectivity and host range of a virus. A proline, an amino acid that is used in the biosynthesis of proteins, also inserts at this site; this is predicted to subsequently flank the cleavage site. In the paper, the researchers note: "Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans13. Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species." “These two features of the virus, the mutations in the RBD portion of the spike protein and its distinct backbone, rules out laboratory manipulation as a potential origin for SARS-CoV-2” said Andersen.

So, where did SARS-CoV-2 come from?

One scenario is that SARS-CoV-2 evolved to its current form via natural selection in a non-human organism and then jumped to humans. The previous SARS and MERS outbreaks occurred in this fashion, whereby humans contracted the virus after exposure to civets in the SARS outbreak and camels in the MERS outbreak. The non-human host proposed in the instance of SARS-CoV-2 is bats.

If this theory is to be true, it would mean that the two distinctive features of the S protein, the RBD portion and the cleavage site, would have evolved to their current form before entering humans. The scientists say that, in this situation, the epidemic would most likely have emerged as soon as humans were infected as SARS-CoV-2. Why? The virus would possess the features it needs for pathogenicity and to be able to spread between people easily.

Scenario two postulates that a non-pathogenic version of SARS-CoV-2 jumped directly from an animal host to a human, and subsequently evolved into its current pathogenic form within the human host. Some viruses that infect pangolins (commonly found in Asia and Africa) possess an RBD structure that is similar to SARS-CoV-2, so this is conceivable.

The study co-author Andrew Rambaut from the University of Edinburgh says that, at this point, it's difficult to distinguish between the two different scenarios.

Reference: Andersen et al. (2020). The proximal origin of SARS-CoV-2. Nature Medicine. DOI: https://doi.org/10.1038/s41591-020-0820-9.