HAVE ESCAPED FROM A LABORATORY? There are precedents for laboratory incidents leading to isolated infections and transient transmission chains, including SARSCoV (Parry, 2004). However, with the exception of Marburg virus (Ristanovic et al., 2020 ), all documented laboratory escapes have been of readily identifiable viruses capable of human infection and associated with sustained work in high titer cultures (Geddes, 2006; Lim et al., 2004; Senior, 2003). The 1977 A/ H1N1 influenza pandemic, that most likely originated from a large-scale vaccine challenge trial (Rozo and Gronvall, 2015), is the only documented example of a human epidemic or pandemic resulting from research activity. No epidemic has been caused by the escape of a novel virus, and there is no data to suggest that the WIV—or any other laboratory—was working on SARS-CoV-2, or any virus close enough to be the progenitor, prior to the COVID-19 pandemic. Viral genomic sequencing without cell culture, which was routinely performed at the WIV, represents a negligible risk because viruses are inactivated during RNA extraction (Blow et al., 2004). No case of laboratory escape has been documented following the sequencing of viral samples. Known laboratory outbreaks have been traced to both workplace and family contacts of index cases and to the laboratory of origin (Geddes, 2006; Lim et al., 2004; Ristanovic et al., 2020; Senior, 2003). Despite extensive contact tracing of early cases during the COVID-19 pandemic, there have been no reported cases related to any laboratory staff at the WIV, and all staff in the laboratory of Dr. Shi Zhengli were said to be seronegative for SARS-CoV-2 when tested in March 2020 (World Health Organization, 2021), with the laboratory reportedly following the appropriate biosafety protocols during their coronavirus work (Cohen, 2020). During a period of high influenza transmission and other respiratory virus circulation (Liu et al., 2020a), reports of illnesses would need to be confirmed as caused by SARSCoV-2 to be relevant. Epidemiological modeling suggests that the number of hypothetical cases needed to result in multiple hospitalized COVID-19 patients prior to December 2019 is incompatible with observed clinical, genomic, and epidemiological data (Pekar et al., 2021). ll OPEN ACCESS 4850 Cell 184, September 16, 2021 Review The WIV possesses an extensive catalog of samples derived from bats (Latinne et al., 2020) and has reportedly successfully cultured three SARSr-CoVs from bats—WIV1, WIV16, and Rs4874 (Ge et al., 2013; Hu et al., 2017; Yang et al., 2015). Importantly, all three viruses are more closely related to SARS-CoV than to SARS-CoV-2 (Ge et al., 2013; Hu et al., 2017; Yang et al., 2015). In contrast, bat virus RaTG13 from the WIV has reportedly never been isolated or cultured and only exists as a nucleotide sequence assembled from short sequencing reads (Cohen, 2020). The three cultured viruses were isolated from fecal samples through serial amplification in Vero E6 cells, a process that consistently results in the loss of the SARS-CoV-2 furin cleavage site (Davidson et al., 2020; Klimstra et al., 2020; Liu et al., 2020b; Ogando et al., 2020; Sasaki et al., 2021; Wong et al., 2021; Zhu et al., 2021b). It is therefore highly unlikely that these techniques would result in the isolation of a SARSCoV-2 progenitor with an intact furin cleavage site. No published work indicates that other methods, including the generation of novel reverse genetics systems, were used at the WIV to propagate infectious SARSr-CoVs based on sequence data from bats. Gain-of-function research would be expected to utilize an established SARSr-CoV genomic backbone, or at a minimum a virus previously identified via sequencing. However, past experimental research using recombinant coronaviruses at the WIV has used a genetic backbone (WIV1) unrelated to SARS-CoV-2 (Hu et al., 2017), and SARS-CoV-2 carries no evidence of genetic markers one might expect from laboratory experiments (Andersen et al., 2020). There is no rational experimental reason why a new genetic system would be developed using an unknown and unpublished virus, with no evidence nor mention of a SARS-CoV-2-like virus in any prior publication or study from the WIV (Ge et al., 2012; Hu et al., 2017; Menachery et al., 2015), no evidence that the WIV sequenced a virus that is closer to SARS-CoV-2 than RaTG13, and no reason to hide research on a SARS-CoV-2-like virus prior to the COVID-19 pandemic. Under any laboratory escape scenario, SARS-CoV-2 would have to have been present in a laboratory prior to the pandemic, yet no evidence exists to support such a notion and no sequence has been identified that could have served as a precursor. A specific laboratory escape scenario involves accidental infection in the course of serial passage of a SARSr-CoV in common laboratory animals such as mice. However, early SARSCoV-2 isolates were unable to infect wild-type mice (Wan et al., 2020). Although murine models are useful for studying infection in vivo and testing vaccines, they often result in mild or atypical disease in hACE2 transgenic mice (Bao et al., 2020; Hassan et al., 2020; Israelow et al., 2020; Rathnasinghe et al., 2020; Sun et al., 2020b). These findings are inconsistent with a virus selected for increased pathogenicity and transmissibility through serial passage