Why Do Researchers Claim That SARS-CoV-2 Is Not Developed in the Laboratory?
Through comparative genomic analysis, researchers have explained that SARS-CoV-2 is not a laboratory construct or a deliberately engineered virus.
Since the first case was identified in China in November 2019, about 724K people worldwide have died of coronavirus disease. While health workers and scientists throughout the world are striving to control its transmission and develop a vaccine, a group of people strongly suspect that the virus has been created as a biological weapon in the laboratory. Besides, the presence of a Level 4 Biosafety Laboratory (BL4) in the Wuhan region of China, the epicenter of the epidemic, has fuelled the fire of this conspiracy theory.
However, most of the researchers who have investigated the virus have ruled out this possibility, claiming that it has evolved naturally. You may wonder exactly how scientists know that SARS-CoV-2 is not artificially constructed in the lab? All the answers are in the genetic material and the evolutionary connections of the virus.
Kristian G. Andersen, Director of Infectious Disease Genomics at Scripps Research Institute, and his team published a correspondence article on a nature journal where they suggested two possible theories about the origin of SARS-CoV-2 from the comparative analysis of genomic data. They also reported two significant genomic features of SARS-CoV-2:
a. Mutations in the Receptor Binding Domain (RBD)
The infection of SARS-CoV-2 begins with the attachment of its spike protein (S) with the ACE2 receptor found on the surface of certain types of human cells. This S protein contains a receptor-binding domain or section (RBD) consisting of six amino acids that are essential for binding to ACE2 receptors. Andersen et al. noticed that five of these six amino acid residues vary between SARS-CoV-2 and SARS-CoV.
According to several experimental studies, SARS-CoV-2 appears to have an RBD that binds with a high affinity to the ACE2 receptor of humans and some other species that have receptor homology. Therefore, the high-affinity binding of the SARS-CoV-2 S protein to human or human-like ACE2 is most likely the result of natural selection.
Natural selection, process that results in the adaptation of an organism to its environment by means of selectively reproducing changes in its genotype, or genetic constitution. -Encyclopaedia Britannica
b. Polybasic furin cleavage site
The spike protein of SARS-CoV-2 has two subunits (S1 and S2) and contains a polybasic furin cleavage site at the junction of these subunits. The betacoronavirus genus has four lineages: A, B, C, D, and SARS-CoV-2 is from linage B. Other related coronaviruses from this linage do not seem to have this polybasic cleavage site, although beta coronaviruses of different lineages (such as HKU1 from lineage A) appear to contain these sites. Observing such genetic variation in spike protein, researchers believe that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites may be found in other species.
Theories of SARS-CoV-2 origins
Experts claim that SARS-CoV-2 does not emerge from the manipulation of any SARS-CoV-like coronavirus. If the virus were genetically modified in the laboratory, there would be indications of alteration in the genome data. There have been several reverse genetic systems available for betacoronavirus, but none of them was used in this case. In simpler words, this virus does not include any residual vector-related sequences conventionally used for genetic engineering. Alternatively, Andersen et al. suggested two theoretical perspectives that can feasibly explain the origin of SARS-CoV-2:
1. Natural selection in animal before zoonotic transfer
When a disease or disease-causing agent transfers from an animal host to human, it is called zoonotic transmission. Huanan market in Wuhan is known for trading several types of wild animals, and many early cases of SARS-CoV-2 were linked to this market.
SARS-CoV-2 shows close similarities with many other bat SARS-CoV-like coronaviruses, such as RaTG13, another type of betacoronavirus isolated from Rhinolophus affinis bat, is ~96% identical overall to SARS-CoV-2. But its spike protein diverges in the receptor-binding domain (RBD), which suggests that it may not bind efficiently to human ACE2.
On the other hand, certain coronaviruses from Malayan pangolins (Manis javanica) seem to be very similar to SARS-CoV-2 in the RBD. This explicitly shows that the SARS-CoV-2 spike protein adapted for binding to human-like ACE2 is perhaps the result of natural selection.
Now you may ask, “What’s about polybasic cleavage site?” No polybasic cleavage site has been identified in beta coronaviruses sampled from bats and pangolins so far. That’s why scientists assume that this site can be acquired in SARS-CoV-2 through a natural evolutionary mechanism such as mutations, insertions, or deletions.
2. Natural selection in human after zoonotic transfer
It is possible that progenitor of SARS-CoV-2 first jumped into humans and then during undetected human to human transmission acquired above mentioned genomic features through adaptation. As coronaviruses from pangolins have SARS-CoV-2 like RBD, scientists believe this special RBD was also probably in the progenitor that jumped to humans.
In this case too, the question may arise that how the cleavage site inserted during transmission? Based on current sequencing data, it is estimated that the virus may have emerged in between late November 2019 to early December 2019.
So it may be that several undetected previous zoonotic events have created short chains of human to human transmission over a prolonged period, and the virus acquired polybasic cleavage during these transmissions. This essentially resembles the situation of MERS-CoV outbreak in 2012.
Accidental release from the laboratory
Andersen and his colleagues have also investigated the chances of unintentional leakage of SARS-CoV-2 from laboratory, as there are instances of such incidents in case of SARS-CoV.
An ancestor with very high genetic similarity would have required to develop SARS-CoV-2 via cell culture or animal passage. However, such work has not been reported in any journal before. So it does seem that there is almost no possibility of accidental release of SARS-CoV-2 from the lab.
Although the shreds of evidence discussed here indicate that the coronavirus was not intentionally created or manipulated, it is difficult to prove or disprove other theories in such a short time because it requires more rigorous analysis from both a structural and an evolutionary point of view. However, with the presence of notable features such as optimized RBD and polybasic cleavage site, related coronaviruses in nature, scientists firmly believe that SARS-CoV-2 is unlikely to originate from any laboratory-based scenario.
