In 2020, the world was engulfed by a global pandemic of unprecedented scale; we were all caught off guard by the emergence of a highly infectious and contagious disease termed today as COVID-19. COVID-19 is a respiratory illness that can cause severe health complications such as pneumonia and acute respiratory distress syndrome(1). The causative agent of COVID-19 is SARS-CoV-2 virus, which is a member of the family of coronaviruses (CoVs). CoVs are RNA viruses that have unique uniformly-arranged surface glycoproteins that give it an appearance of a crown, and crown in Latin is corona (Figure 1A). Today, more than 214 million people worldwide have contracted COVID-19 and the disease has claimed more than 4 million lives(2).
This is, however, not the first time the world had to face a global pandemic caused by CoVs. The severe acute respiratory syndrome (SARS) pandemic back in 2003 was caused by the SARS-CoV virus. According to the WHO, over 8000 people globally had SARS and about 700 of them died(3). Then, in 2012, there was the Middle East Respiratory Syndrome (MERS), caused by the MERS-CoV virus. There was an estimate of 845 MERS-related deaths(4). Just by looking at these statistics, we can appreciate the magnitude of the COVID-19 pandemic, which reflects the highly virulent nature of SARS-CoV-2.
As soon as the first cases of COVID-19 were reported, investigations were conducted to uncover the epidemiology of COVID-19 and the source of the outbreak(5). The emergence of SARS, MERS, and now COVID-19 serve as apt reminders about the continual battle the world has against pathogenic viruses. Therefore, it is exceptionally important for us to understand the origin of COVID-19 to predict, mitigate, and even prevent the emergence of new viral strains.
There is currently an ongoing heated debate on the origin of COVID-19, segregating people into two schools of thought – COVID-19 originated by natural means (natural theory) and COVID-19 was a result of artificial means (lab-leak theory). While a majority of the scientific community is in consensus about the natural theory(6) and results from investigations spearheaded by WHO favor the natural theory(7), a survey showed that about half of the U.S. population believe in the lab-leak theory(8). Why do the majority of the public subscribe to the lab-leak theory? And where did COVID-19 originate from? Herein, I share my thoughts on the origin of COVID-19. In this article, I seek to understand and approach the ongoing debate on the origin of COVID-19 primarily from a scientific perspective.
I highly recommend this video posted by a YouTube channel ‘Insights’ entitled ‘COVID-19 Origin: The Where and the Who’. It echoes some of my opinions on these questions, with sharp insights from world-renowned scientists, media professionals, and psychologists, including Dennis Carroll, Jonna Mazet, Justin Ling, Adrian Frank Furnham, Eric Merkley etc.
The first cluster of COVID-19 cases
Several cases of viral pneumonia of unknown cause emerged in Wuhan, China in December 2019 and the relevant health authorities were immediately notified. The first cluster of COVID-19 cases was associated with the Huanan Wholesale Seafood Market, a local market where seafood, wild, and farmed animals were sold(5,9). It is, however, difficult to determine if the SARS-CoV-2 virus was transmitted to humans from a particular animal in the market or by an already-infected individual who happened to visit the market.
The ongoing debate on the origin of COVID-19
There is an ongoing, heated debate on the origin of COVID-19 - the natural v.s. lab-leak theory. In essence, the natural theory states that the SARS-CoV-2 virus has natural origins (i.e. the virus emerged naturally), while the lab-leak theory states that the SARS-CoV-2 virus is man-made and has accidentally escaped from a laboratory that was working on coronaviruses. In a similar vein, some believed that the virus was a by-product of a gain-of-function experiment that had gone wrong in the laboratory. Others have subscribed to a more extreme thought that is that the virus was engineered in the laboratory and was meant to be utilized as a bioweapon.
The lab-leak theory was supported by one Dr. James Lyons-Weiler, who wrote an online article claiming that the genome of the SARS-CoV-2 virus contains a unique genetic sequence that was similar to the sequence of an expression vector (plasmid) that was commonly used in a research laboratory(10). Another group of researchers claimed that the SARS-CoV-2 virus contains HIV genetic sequences. While it is not impossible for SARS-CoV-2 to be a laboratory construct that has evolved and adapted to infect human cells in vitro and was then accidentally/ intentionally released from the laboratory(11), there is no evidence available that supports this hypothesis(12,13). Aside from the non-peer-reviewed articles and the convenient geographical association between the research institution and the first cluster of COVID-19 cases, there has yet to be any other evidence-based reasoning supporting lab-leak theory.
The structure and biology of SARS-CoV-2
In order to begin understanding the process by which scientists are attempting to define the origin of COVID-19 and approaching the natural v.s. lab-leak theory debate, it is necessary for us to take a few steps back to understand the structure and biology of the SARS-CoV-2 virus. This is because the biological properties of the virus particles, including both protein and genetic information, holds valuable information about not only disease pathology but also the origin of the virus.
The SARS-CoV-2 is an enveloped virus. Within the virus particle lies a single strand of RNA (29,881 bp long) which contains genetic information for making all components of the virus. The surface of the viral particle is covered with the Spike protein (S protein), which is essential for viral entry into host cells (Figure 1A). The viral S protein recognizes and binds to the ACE2 receptors expressed on the surface of target cells. Then, the TM protease serine 2 (TMPRSS2) enzyme activates the S protein, allowing viral entry into the cell. Once inside the cell, viral RNA is released and undergoes replication and transcription to produce more virus particles (Figure 1B)(14).
Figure 1 – A simplified diagram illustrating the structure of the SARS-CoV-2 virus as well as the life cycle of the virus (created using biorender.com)
An illustration of the structure of a single SARS-CoV-2 virus
The life cycle of the SARS-CoV-2 virus
CoVs are zoonotic; this means that they are transmitted between animals and people and they are able to transmit across species barriers. Bats are known to be reservoirs for CoVs(15). SARS-CoV virus which caused the 2003 SARS pandemic, was found to likely be transmitted to humans from their intermediate hosts, palm civets (Paguma larvata)(16,17). Due to genetic similarities to a bat CoV (RaTG13), SARS-CoV-2 is thought to also have originated from bats(18). However, it is unlikely that RaTG13 CoV is the direct source of SARS-CoV-2. There are some suggestions about the involvement of pangolins, as a potential intermediate host animal (19–21). The fact that the COVID-19 outbreak began at the Huanan Wholesale Seafood Market supports the idea that the virus spillover from bats directly or indirectly through intermediate animals to humans. Nonetheless, it is difficult to know if this spillover process took place within the market.
Biological data holds the key to resolving the debate
A virus’s genetic sequence contains more information than you will expect – it provides some hints into the source or origin of the virus. Viruses that are genetically similar tend to come from a similar source or geographical area. Today, with powerful genetic sequencing tools at our disposal, the whole genome of SARS-CoV-2 can be further scrutinized.
Genetic comparisons show that SARS-CoV-2 is about 79% similar to SARS-CoV. Both viruses share about 72% similarity in the nucleotide sequence for the S protein. Both viruses bind to ACE2 receptors on target cells. Although SARS-CoV-2 is highly similar to RaTG13, as mentioned earlier, phylogenetic analyses show that SARS-CoV-2 viruses have undergone complex genetic recombination events during their evolution, placing them genetically more distant from RaTG13. It is known that the S proteins of CoVs undergo frequent genetic changes naturally. Studies that compared CoVs show that SARS-CoV-2 exhibited strong purifying selection, with evidence of site-specific positive selection especially on the S protein(22). This can occur when different viral strains recombine when residing in different non-human animal host species. The rapid emergence of SARS-CoV-2 variants (caused by variations in the gene coding for the S protein) all over the world further illustrates the propensity of the S protein for mutation and recombination. Collectively, this biological evidence firstly, suggests that SARS-CoV-2 is genetically similar to SARS-CoV, which could suggest similar zoonotic origins. Secondly, the high rates of recombination and purifying selection of SARS-CoV-2 S protein highlight the profound molecular evolution of the virus.
Why the lab-leak theory is highly improbable
Considering the zoonotic origin and molecular evolution of CoVs, as well as the genetic comparisons presented by several scientific publications, the lab-leak theory appears to be relatively improbable when compared to the natural theory. This is because:
The articles that claimed that there were plasmid or HIV genetic sequences in the SARS-CoV-2 genome, indicating laboratory origins have been refuted(10,23).
Viruses that have caused global pandemics in the past are known to be zoonotic and were transmitted to humans from animals.
The constant contact between humans and animals is common in the farming, animal trade, and live-animal trafficking industries where virus spillover can occur; these industries are connected to the sources of wildlife sold at the Huanan market(24).
The affinity of SARS-CoV-2 to the human ACE2 receptor is incredibly high, which suggests that the virus that undergone a tremendous amount of natural selection and adaptation in animal hosts before the spillover to humans(25). This is something that, although not impossible, is extremely technically challenging to perform in the lab in secret.
Genetic analyses have provided convincing evidence on the molecular evolution of SARS-CoV-2 comprising of genetic recombination and purifying selection events.
‘Principle of Parsimony’, one of the fundamental rules of Science states that the simplest explanation is generally the most likely. The lab-leak theory is convoluted, far-fetched, and is as not straightforward as the natural theory.
Factors facilitating the propagation of the lab-leak theory
Although this article is written with the goal of focuses on scientific aspects of the debate, it is also paramount to recognize and highlight the other non-scientific factors perpetuating the lab-leak theory:
The rampant spread of fake news/ misinformation
In today’s era of the Internet, unfiltered and unpoliced information can spread rapidly, causing confusion and doubt amongst the public. This has led to an erosion of the public’s trust towards both scientific and governmental bodies.
Political agenda, cultural wars
As mentioned earlier, in a politically divisive country such as the U.S., the lab-leak theory has been utilized as a tool for political propaganda to rally support and misguide the public(26).
Poor science communication
Poor science communication from scientists and scientific organizations may be one of the contributing factors. Communicating complex sciences to the public has always been a challenge. The popularity of the lab-leak theory could be a result of poor or rather the lack of proper science communication campaigns.
Human coping mechanism
Psychologists propose that perhaps, the subscription to the lab-leak theory is one of the coping mechanisms used by people to reconcile with the stresses and uncertainties brought about by the pandemic.
Exploitation by the media
The sensationalizing nature of the debate is perhaps exploited by the media in the bid to increase viewership. Media outlets may be exploiting the ongoing debate by creating more content surrounding the attention-grabbing, ‘mysterious’ lab-leak theory.
Limitations of scientific research are amplified by the media
The media emphasizes and over-amplifies the limitations of scientific research. Contrary to popular belief, scientific research is never a flawless process; there are limitations to every study, and statistics used to understand scientific data have intrinsic shortcomings. Also, conclusions that can be made from scientific studies (such as investigations into the origin of COVID-19) depends on the quality of the data used.
Concluding thoughts
The COVID-19 global pandemic is truly unexpected and to say that the world was ill-prepared to cope with a highly rampant viral infection is an absolute understatement. Knowing how COVID-19 came to be is not just an endeavor to satisfy our curiosity; comprehending the emergence of the SARS-CoV-2 virus will accelerate our knowledge about zoonotic viruses and their relationships with humans, which will, in one way or another, equip us better with the know-how to manage or even prevent another global pandemic in the future. This is why the WHO and many scientists around the world are committed to this project.
While having multiple theories or alternative hypotheses are healthy for scientific engagements, the lab-leak theory in explaining the origins of COVID-19 insofar remains to be lacking scientific evidence to corroborate the hypothesis. In addition, the theory seems improbably and relatively far-fetched. This is in contrast to the natural theory which provides a more logical and simpler explanation that is backed up by sound biological evidence. There is a sense of frustration amongst the scientific community because despite being the more unlikely of scenarios (by way of scientific reasoning), the lab-leak theory has gathered a sizeable group of fans.
Will the debate ever end? The short answer to the question is no. Today, we are equipped with powerful scientific tools that facilitate the discovery of the origin of the SARS-CoV-2 virus. I am confident that ongoing studies on the origin of COVID-19 will yield promising results that will strengthen the natural theory. However, it is important to acknowledge that the debate is likely to continue indefinitely if other mitigating strategies such as science communication campaigns, collaboration between the scientific and media communities, public science education projects, better policing of ‘fake news’ etc., are not executed.
References
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