| > there is zero evidence of a lab leak besides circumstantial. First, there are credible, credentialed virologists saying that the lab leak hypothesis has not been ruled out, and that it has been inadequately investigated [1]. Second, there are real anomalies in the Covid genome [2] that seem unlikely to have occurred naturally: however, several characteristics of SARS-CoV-2 taken together are not easily explained by a natural zoonotic origin hypothesis. These include a low rate of evolution in the early phase of transmission; the lack of evidence for recombination events; a high pre-existing binding to human angiotensin-converting enzyme 2 (ACE2); a novel furin cleavage site (FCS) insert; a flat ganglioside-binding domain (GBD) of the spike protein which conflicts with host evasion survival patterns exhibited by other coronaviruses; and high human and mouse peptide mimicry. In particular, the furin cleavage site is extremely interesting because it's exactly the type of genetic manipulation done in gain of function research that was ongoing at the Wuhan Institute of Virology. More on the FCS: Because the presence and coding sequence of a FCS is important for pathogenesis, host range, and cell tropism (Nagai et al. 1993; Millet et al. 2015), the addition of a FCS into viruses has been an active area of gain-of-function research. A FCS can be easily inserted using seamless technology (Yount et al. 2002; Sirotkin and Sirotkin 2020) without any need for cell passage, as previously performed in experiments on virulence and host tropism (Cheng et al. 2019). Insertions to change the properties of SARS-r CoV viruses are documented by Ren et al. (2008) and Wang et al. (2008). Considering that natural mutations have a very low probability to result in a stretch of 12 amino acids coding for an optimized FCS without any known intermediate form in Sarbecovirus, an artificial insertion of the FCS in SARS-CoV-2 may provide a more parsimonious explanation for its presence than natural evolution. In summary, the FCS confers SARS-CoV-2 enhanced human pathogenicity and has never been identified in another Sarbecovirus. At the same time, FCSs have been routinely inserted into coronaviruses in gain-of-function experiments, and we provide a hypothesis through which the specific amino acid sequence of SARS-CoV-2′s FCS may have been generated through cell culture. [1] https://science.sciencemag.org/content/372/6543/694.1 [2] https://link.springer.com/article/10.1007/s10311-021-01211-0 |