The COVID-19 pandemic has turned out to be one of the biggest threats to human life in more than a century. Contrary to the suggestions of the new coronavirus being man-made, rigorous genetic studies found no evidence that the virus was made in a laboratory or otherwise engineered and showed the new virus SARS-CoV-2 to have originated through natural processes. Surpassing all threats to humanity in recent years has emerged a new scourge that has been spreading its tentacles across the globe steadily since the end of December 2019. First detected in Wuhan city in China, it is a new coronavirus, which has an incubation period of up to 14 days and mainly affects the lungs causing SARS-like symptoms. Initially known as the “2019 novel coronavirus”, it was renamed on 11 February 2020 as “severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)” by the International Committee on Taxonomy of Viruses (ICTV). On the same day, the World Health Organisation (WHO) announced “COVID-19” as the name of the disease it causes. The WHO has declared it as a ‘controllable pandemic’ if countries step up measures to tackle it. While most cases of COVID-19 are mild, the most serious complication of the infection is a type of pneumonia which may be fatal. Since the first cases were detected in China, the number of people infected worldwide has been rising steadily and exceeded 10 million cases, with more than 0.50 million deaths. Coronaviruses are a large family of viruses with single-stranded RNA as the genetic material that can cause illnesses ranging widely in severity. The first known severe illness caused by a coronavirus emerged with the 2003 Severe Acute Respiratory Syndrome or SARS epidemic in China. A second outbreak of severe illness began in 2012 in Saudi Arabia with the Middle East Respiratory Syndrome or MERS. Research is still on to determine the structural characteristics of SARS-CoV-2 that underlie the pathogenetic mechanisms and its high infectivity. Led by researchers in Germany, virologic study of COVID-19 has shown that after infection the virus quickly begins producing high viral burden, sheds RNA efficiently, and multiplies rapidly
in the upper respiratory tract. It may be mentioned here that bats are well known as a reservoir for potential new human diseases. The animals carry dozens, perhaps hundreds, of members of the coronavirus family. Most of those viruses are part of the bats’ normal microbiome, living in harmony with their hosts and causing no harm. But coronaviruses, like all forms of life, accumulate random genetic changes as they reproduce, often turning them into deadly agents.
Two critical mutations that made COVID-19 deadly
According to scientists, two critical mutations in the bat coronavirus set us on the path to the COVID-19 pandemic. The first mutation modified the structure of the spike-like structures that protrude from the virus. Those protrusions give the virus its family name: “Corona” means “crown” in Latin. The altered spikes allow the virus to latch onto an enzyme called ACE2, which lines the respiratory tract in humans. The related virus responsible for the SARS epidemic employs a similar infection mechanism, as does another bat coronavirus that causes common colds in humans.
The second key mutation allowed the coronavirus to grow a protein dagger called a furin, which can slice through other proteins to make the virus bind tightly to throat and lung cells. The furin protein is what made the SARSCoV-2 virus so infectious and deadly to humans. In that sense, COVID-19 is similar to anthrax and various bird flus that also rely on furins to carry out their infection.
According to the scientists, these mutations could have occurred while the virus was circulating
in bats. It is also possible that one or both mutations could have erupted in a person who was infected by an earlier version of the virus but showed no symptoms. One of the most disturbing aspects of the recent pandemic is the plethora of speculative stories appearing in the social media regarding the origin of SARS-CoV-2, some of which describe it as a bioweapon created in the lab and accidentally released. However, rigorous genetic studies of the virus have revealed that the new virus is the product of natural evolution, according to findings published in the journal Nature Medicine. The analysis of public genome sequence data from SARS-CoV-2 and related viruses found no evidence that the virus was made in a laboratory or otherwise engineered. According to scientists, by comparing the available genome sequence data for known coronavirus strains, it can be firmly said that SARSCoV-2 originated through natural processes.
The scientists analysed the genetic template for “spike” proteins (S proteins) — protrusions on the outside of the virus that it uses to grab and penetrate the outer walls of human and animal cells.
More specifically, they focussed on two important features of the spike protein: the receptorbinding domain (RBD) — a kind of grappling hook that grips onto host cells, and the cleavage site — a molecular can opener that allows the virus to crack open and enter host cells.
Evidence for natural evolution
This evidence for natural evolution was supported by data on SARS-CoV-2’s backbone — its overall molecular structure. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known coronaviruses and mostly resembled related viruses found in bats and pangolins. According to them, “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”. Meanwhile, other researchers
who sifted through the genetic sequences of dozens of preserved viral samples found that the new
coronavirus is a distant cousin of the coronavirus that caused the SARS outbreak of 2002 and 2003,
and the coronavirus that gave rise to MERS in 2009. The virus responsible for COVID-19 has distinctive features that separate it from its predecessors by many, many generations, according to their report in the Journal of Virology. But, according to the researchers, none of the genetic mutations looked like the ones “a scientific genius would engineer in a lab to tweak a virus for better performance”. Instead, they have all the hallmarks of the gradual accretion of changes that occur over time as a virus encounters new environments and the immune systems of new organisms. In other words, SARSCoV-2 looks like a virus that has evolved naturally, the team wrote. According to a paper published in the journal National Science Review, coronaviruses are naturally hosted and evolutionarily shaped by bats. Indeed, it has been postulated that most of the coronaviruses in humans are derived from the bat reservoir. Several research teams have confirmed the genetic similarity between SARS-CoV-2 and a bat betacoronavirus (one of four genera of coronaviruses).
The whole-genome sequence of SARS-CoV-2 has 96.2 per cent similarity to that of a bat SARSrelated coronavirus (RaTG13) collected in Yunnan province, China, but has low similarity to that of SARS-CoV (about 79 per cent) or MERS-CoV (about 50 per cent). It has also been confirmed that SARS-CoV-2 uses the same receptor, the angiotensin converting enzyme II (ACE2), as SARS-CoV. Although the specific route of transmission from natural reservoirs to humans remains unclear, several studies have shown that pangolins may have provided a partial spike gene to SARS-CoV-2; the critical functional sites in the spike protein of SARS-CoV-2 are nearly identical to those identified in a virus isolated from a pangolin.
Both SARS-CoV (that causes SARS) and SARS-CoV-2 (that causes COVID-19) bind to ACE2 through the receptor-binding domain of the spike protein in order to initiate membrane fusion and enter human cells. Five out of the six critical amino acid residues in receptor-binding domain were different between SARS-CoV-2 and SARS-CoV, and a 3D structural analysis indicated that the spike of SARS-CoV-2 had a higher binding affinity to ACE2 than SARS-CoV. Intriguingly, these same six critical amino acids are identical between pangolin coronavirus and SARSCoV-2. In contrast, although the genomes of SARS CoV-2 and RaTG13 are more similar overall, only one out of the six functional sites is identical between the two viruses. It has been proposed that the SARS-CoV-2 receptorbinding domain region of the
spike protein might have resulted from recent recombination events in pangolins. Although several ancient recombination events have been described in spike, it also seems likely that the identical functional sites in SARS-CoV-2 and pangolin coronavirus may actually result from coincidental convergent evolution.
Probable routes of evolution
Based on their genomic sequencing analysis, Kristian Andersen, Associate Professor of Immunology and Microbiology at Scripps Research Institute and corresponding author on the Nature Medicine paper, and his collaborators have concluded that the most likely origins for SARS-CoV-2 followed one of two possible routes. The first possible option is that the virus could have evolved to its current pathogenic state through natural selection in a non-human host and then jumped to humans. This is
known to be the route through which previous coronavirus outbreaks had emerged, with humans contracting the virus after direct exposure to civets (SARS) and camels (MERS). Researchers propose bats as the most likely reservoir for SARSCoV 2, as it is remarkably similar to a bat coronavirus. However, since there are no documented cases of direct bat-to-human transmission, an intermediate host was likely involved between bats and humans, say the scientists. In this scenario, both of the distinctive features of SARS-CoV2’s spike protein that binds to cells and the cleavage site that opens the virus up would haveevolved to their current state before entering humans. In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that make it pathogenic and able to spread between people. The second probable route envisions a non-pathogenic version of the virus jumping from an animal host into humans and then evolving to its current pathogenic state within the human population. For instance, some coronaviruses from pangolins (armadillo-like mammals found in Asia and Africa) have a receptor-binding domain structure similar to that of SARS-CoV-2. A coronavirus from a pangolin could possibly have been transmitted to a human, either directly or through an intermediary host such as civets or ferrets.
According to Andersen, after transmission, the other distinct spike protein characteristic of SARS-CoV 2, the cleavage site, could have evolved within a human host, possibly via limited undetected circulation in the human population prior to the beginning of the epidemic. The researchers found that the SARSCoV-2 cleavage site appears similar to the cleavage sites of strains of bird flu that has been
shown to transmit easily between people. SARS-CoV-2 could have evolved such a virulent cleavage site in human cells and soon kicked off the current epidemic, as the coronavirus would possibly have become far more capable of spreading between people, say Andersen. According to the scientists, it is difficult if not impossible to know at this point which of the scenarios is most likely. If the SARS-CoV-2 entered humans in its current pathogenic form from an animal source, it raises the probability of future outbreaks, as the illness-causing strain of the virus could still be circulating in the animal population and might once again jump into humans. But the chances of a non-pathogenic coronavirus entering the human population and then evolving properties similar to SARS-CoV-2 are lower. It must, however, be remembered that despite the recent discoveries, several fundamental issues related to the evolutionary patterns and driving forces behind this outbreak of SARSCoV-2 remain to be fully characterised.