The famous question about whether the world as we know it arose from evolution or creation was settled long ago in favour of evolution and against religious bigotry. But the old debate resurfaced, only in a different garb, during the pandemic. The question is posed thus: did the SARS-CoV-2 virus, which causes COVID-19, naturally evolve from bats through an intermediary to humans or was it engineered in a laboratory in Wuhan, the capital of Hubei Province, and leaked accidentally or intentionally?

COVID-19, perhaps one of the most virulent pandemics in the past 100 years, has exposed the frailties of public health systems in many countries, as evidenced by the massive loss of lives and livelihoods across the world. But it has also shown the power of science and technology, especially the open and quick sharing of data and results. Obversely, the ensuing infodemic has brought with it a tide of misinformation, chiefly the manufactured controversies on whether the SARS-CoV-2 virus evolved naturally or was deliberately or artificially created by Chinese scientists who then caused its spread intentionally or otherwise.

Here, we argue that the virus, which appears so perfect and complexly suited to infecting humans and for transmission amongst them, is most likely of natural evolutionary origin. Various statements and articles speculating that the virus was created by design and released through laboratory leaks appear to lack scientific credibility and border on conspiracy theories. The push by some scientists and governments for investigations, in the name of biosafety monitoring, into a possible laboratory leak from the Wuhan Institute of Virology (WIV) appear to be driven by paranoia or a Chinaphobia.

Nearly two centuries ago, Charles Darwin said in his Origin of Species: To suppose that the eye with all its inimitable contrivances .could have been formed by natural selection, seems, I freely confess, absurd in the highest degree. When it was first said that the sun stood still and the world turned round, the common sense of mankind declared the doctrine false .Reason tells me, that if numerous gradations from a simple and imperfect eye to one complex and perfect can be shown to exist, ...then the difficulty of believing that a perfect and complex eye could be formed by natural selection, though insuperable by our imagination, should not be considered as subversive of the theory.

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Viruses are opportunistic and take advantage of unusual situations and the weaknesses of their hosts. In most cases, humans invite viral pathogens upon themselves by invading and occupying biological spaces to the detriment of other animals, thereby also presenting viruses with greater opportunities to infect them. The precise path that leads a particular virus jumping from its reservoir population to humans is mostly fortuitous, difficult to determine and, in some instances, has remained inconclusive.

The influenza pandemic that started in 1918, which was popularly called the Spanish flu though the origin was not in Spain but in Haskell County, Kansas, United States, infected about 500 million people and resulted in the death of possibly 50 million. It is now known to have been caused by the virus H1N1 with genes of avian origin, although the exact origin has still not been conclusively established. It is thought to be of zoonotic origin from birds because since then there have been several similar influenza virus pandemics: in 1958 (H2N2), 1968 (H3N2) and 2009 (H1N1 pdm09). Interestingly, H1N1 pdm09 was also called swine flu because it contained a sequence segment similar to the Eurasian swine influenza virus from 1992. It is estimated that 0.001 per cent to 0.007 per cent of the worlds population died of respiratory complications associated with the H1N1 pdm09 virus infection in the first 12 months of the virus circulation. Where did that virus jump from? No intermediate host has been identified. Thankfully, there was no laboratory leak conspiracy theory for that episode.

A highly pathogenic avian influenza (HPAI), A(H5N1) was first detected in humans in 1997 during an outbreak among poultry in Hong Kong. H5N1 has continued to circulate and been detected at various times, for instance in 2003 and 2014. It has been found that low pathogenicity avian influenza viruses (LPAIVs) are generally asymptomatic in their natural avian hosts. LPAIVs can evolve into highly pathogenic forms, which can affect avian and human populations with devastating consequences. The acquisition of multiple amino acids with positively chargeable side chains such as lysine (K) and arginine (R) in the haemagglutinin cleavage site creates what is called a polybasic motif because of the presence of exchangeable hydrogens in the side chains. Thus, for example, the polybasic motif (RERRRKKR) can be cleaved by proteases such as furin in the human host. This leads to the switch to a HPAI virus from LPAIV precursors facilitating viral entry into cells. Proteolytic cleavage regulates numerous processes in health and disease.

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The ubiquitously expressed protease furin cleaves a plethora of proteins at polybasic recognition motifs. Mammalian substrates of furin include cytokines, hormones, growth factors and receptors. A viral pathogen generally needs to bind to a receptor in human cells in order to make its entry. The receptor binding decides the type of cells the virus infects. Receptor binding is often enhanced by proteolytic cleavage of the viral protein that binds. Since the virus can reproduce and make the proteins it needs only after entry into cells, it makes use of the proteases in the host. So, not surprisingly, numerous viral pathogens exploit the ubiquitous nature of furin to enhance their virulence and spread. A furin cleavage site occurs in SARS-CoV-2, and its occurrence is the centrepiece of the conspiracy theories, the so-called smoking gun if you will.

Acquired immune deficiency syndrome (AIDS), which was first reported in 1981 from New York City, has killed about 35 million plus people so far. A retrovirus, now termed human immunodeficiency virus type 1 (HIV-1), was subsequently identified as the causative agent of what has since become one of the most devastating infectious diseases to have emerged in recent history. The zoonotic origin of HIV-1 was unclear for more than a decade and was discovered by pure luck and some hard work.

The HIV-1 is similar in sequence and genomic organisation to viruses found in chimpanzees (simian immunodeficiency virus, or SIVcpz). However, there was a low prevalence of SIVcpz infection in wild-living animals. Moreover, chimpanzees were present in geographic regions of Africa, but AIDS was not initially seen there. This along with the differences between HIV-1 and SIVcpz cast doubts on chimpanzees as a natural host and reservoir for HIV-1. It was then suggested that another, as yet unidentified, primate species could be the natural host for SIVcpz and HIV-1. The link was finally established in 1999. A chimpanzee (named Marilyn) of the subspecies Pan troglodytes troglodytes had been caught in the wild in Africa and then exported as an infant to the U.S. for research. She had not received any blood contaminated with HIV. But, during a sero-survey in 1985 amongst 98 chimpanzees, Marilyn showed a high level of antibodies to HIV-1. She died shortly afterwards giving birth to stillborn twins. A polymerase chain reaction analysis in 1999 of the spleen and lymph node tissues retrieved from frozen samples showed the presence of the virus now called SIVchzptt, which is the closest relation to HIV-1, and confirmed its zoonotic origin.

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Interestingly, the HIV-1 envelope protein initiates infection by mediating the fusion of the viral envelope with the cell membrane. For this to occur, the envelope protein has to be cleaved by host proteases such as furin at a polybasic motif in a loop connecting two regions. In fact, in an attempt to bolster the conspiracy theory that SARS-CoV-2 was man-made, claims have been made that Dr Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), holds patents of an HIV component used to create COVID-19.

The severe acute respiratory syndrome (SARS) pandemic of November 2002 to July 2003, which was caused by a coronavirus now called SARS-CoV, affected about 8,000 people in more than 30 countries. In May 2003, sampling of 25 animals in a wet market in Hong Kong showed the presence of a coronavirus in three masked palm civets, one racoon dog and two Chinese ferret badgers with 99.8 per cent of its sequence identical to the human SARS-CoV. Subsequently, serological and epidemiological surveys pointed to traders of palm civets having been infected with SARS-like viruses earlier. Studies in 2004 suggested that a small proportion of healthy individuals in Hong Kong had been exposed to SARS-CoV-related viruses at least two years before the SARS outbreak reached Hong Kong in mid February 2003.

In 2005, two groups of researchers demonstrated that bats were natural reservoirs of SARS-like viruses. There is now evidence to suggest that there are four possible routes of transmission of SARS-CoV: animal-to-human, animal-to-animal, human-to-human and human-to-animal. Studies with animals showing infectivity to SARS-CoV have shown that inter-species contact and cross-species virus transmission (i.e. spillover) are essential and sufficient to cause epidemic emergence. Sustained transmission and virus adaptation within the spillover species determine the magnitude and scope of subsequent disease outbreaks. For example, SARS-CoV uses the angiotensin-converting enzyme (ACE2) as a receptor for its spike protein to bind to and gain entry into human cells. The spike protein also gets cleaved by a host protease (not furin), which enables the binding and fusion of the viral envelope with the cell membrane. It was found that the spike protein in the virus isolated from human patients in the 2002-03 outbreak bound more efficiently to the ACE2 receptor than the virus isolated from palm civets or from humans with mild cases in 2004. It took about three years after the outbreak of SARS-CoV to establish all this.

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However, a study in 2012 isolated a SARS-like coronavirus that was able to utilise ACE2 in humans, civets and in Chinese horseshoe bats for cell entry. This virus (bat SL-CoV-WIV1) offers strong evidence that SARS-CoV originated from a bat reservoir and suggests that an intermediate host may not have been required to facilitate adaptation to human ACE2. Curiously, in 2009 an article in the journal Proceedings of National Academy of Sciences of the United States of America revealed that a group at Cornell University engineered SARS-CoV to introduce a furin cleavage polybasic site to study the proteolytic activation of SARS-CoV.

In November 2012 came the first case of the disease that since May 2013 has been called the Middle East respiratory syndromes (MERS), which is caused by the MERS coronavirus (MERS-CoV). The outbreak started in the Middle East and has now spread to about 24 countries, affecting people and causing deaths, albeit in comparatively smaller numbers than COVID-19. In June 2014, it was found that the sequence of the virus from a man who became sick with MERS and that isolated from the camel he was tending were nearly identical. It was concluded that the camel was the intermediate host from which the virus could have jumped to humans. But a 2015 study showed that transmission from camels to humans is rare. This raises questions about whether the camel was really the intermediate animal for transmission. MERS-CoV does not use ACE2 as the receptor but binds to dipeptidyl peptidase 4 (DPP4). However, it has a furin cleavage site similar to that in SARS-CoV-2, which helps in its infection.

In China, on December 29, 2019, local hospitals in Wuhan using the surveillance mechanism for a pneumonia of an unknown aetiology that was established in the wake of the 2003 SARS outbreak identified the first four cases of COVID-19, which were all associated with the seafood wholesale market in Wuhan. On December 31, the Chinese Centre for Disease Control and Prevention dispatched a rapid response team to Wuhan to accompany the Hubei provincial and Wuhan city health authorities who were conducting an epidemiological and aetiological investigation. Scientists of the WIV made the sequence of the virus available to the international community through a manuscript that was submitted to the journal Nature on January 20, 2020. The paper was published online on February 3. It showed that the sequence of the virus from human patients was 94.4 per cent identical to SARS-CoV and 96.2 per cent identical to the virus from bat samples (RaTG13) collected previously from caves in Yunan.

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On February 11, the International Committee on Taxonomy of Viruses named the virus SARS-CoV-2 because of its close relationship to SARS-CoV. The World Health Organisation (WHO) called the disease COVID-19 to distinguish it from the earlier SARS. The disease rapidly spread to many countries, and the WHO declared it a pandemic on March 11. The virus was shown to use the ACE2 receptor for binding and cell entry and was aided by cleavage by protease transmembrane serine protease 2 (TMPRSS2). A furin protease cleavage site not seen in SARS-CoV was found in this virus, and the cleavage at this site enables the entry of the virus into the cell.

To date, the disease has caused 177.5 million cases and 3.8 million deaths worldwide, and 1.99 million sequences from infected cases have been made publicly available. These sequences have shown the evolutionary changes that are happening in the virus. No other virus or disease in history has been subject to such close scrutiny and public discussion, thanks to the sharing of data and findings facilitated by modern communication, including social media channels. The first reports of the virus and disease were from China, which is becoming a major player in the world economy and is threatening to surpass existing powerhouses. The fact that the WIV specialises in coronaviruses, and has allegedly been engaged in collaborative work with U.S. institutions on gain of function research because of the prevalence of these viruses in the region, gave rise to conspiracy theories spread by right-wing governments and scientists.

At the beginning of 2020, several scientists/virologists were of the opinion that the question of whether the virus was the result of natural evolution should be answered in the affirmative. But because of the elections in the U.S., President Donald Trump needed an enemy to blame and attack in order to distract attention from his poor handling of the pandemic despite prior warnings from the U.S. Centres for Disease Control and Prevention. When the horrifying images of people being buried in New York were splashed in the media, he chose to call the virus a China virus. He even declared that he had found the cure in the form of hydroxychloroquine. But in the beginning, a few reputed scientists even declared the disease an ordinary influenza. Later, the vicious nature of the pandemic became clear, and the whole world had to look for solutions that would work in the temporary short term as well as the permanent long term.

Once the U.S. elections were over, the new President brought in measures to help the vulnerable sections and to ramp up vaccinations. Now the question about the origin of the virus, which scientists were working on anyhow, became politicised to align with the new policy to challenge the emerging force of China. The discredited conspiracy theory that the virus was a bioweapon engineered at a laboratory in Wuhan is now brought out as new wine in old bottles with the claim it leaked from that same laboratory.

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So what evidence has been marshalled in support of the contending conjectures and what should be done now? Coronaviruses are not new. They have been around for at least a few decades. Jemma Geoghegan, the well-known virologist from New Zealand who was prominent in her countrys prompt COVID-19 response, said: SARS-CoV-2, the virus that causes the COVID-19, is closely related to other viruses that exist in nature. This virus is likely to have taken a path similar to SARS in 2003, viz., from animals to humans. Jemma Geoghegan explores the role that size, structure and mode of transmission of viruses play in the prediction of whether a virus will infect humans and cause a pandemic. She explained that prediction was difficult because of the vast number of viruses and said it was simply impossible to predict... whether a newly discovered animal virus could jump into humans and cause a pandemic. She also mentioned that five coronaviruses have emerged in the past and the intermediary animal responsible for COVID-19 remains unclear. Farm animals such as rabbits could be a possible intermediary for many viruses, but more studies are required to establish this conclusively. Ninety-six per cent of the genome sequence of SARS-CoV-2 is common to that found in bat coronaviruses. That the spike protein of SARS-CoV-2 can bind effectively to human cells is most likely a result of natural selection rather than manipulation in a laboratory. The backbone of the virus seems to be linked to bats and pangolins and is quite different from anything available in laboratories.

The genome of SARS-CoV-2 shows thousands of differences from its closest relative, according to Jonathan Stoye, group leader of the Retrovirus-Host Interactions Laboratory at the Francis Crick Institute in the United Kingdom. Now the changes that have been observed in the nucleotide sequence of the SARS-CoV-2 genomes sequenced so far clearly indicate that it is highly improbable for modifications that span such a large evolutionary distance to have taken place in a laboratory. This therefore suggests that the variations happened in animals, either bats, which form the reservoir for coronaviruses, or an intermediary animal in the wild, which is yet to be discovered.

The most important supposed villain in this is said to be the spike glycoprotein, which helps the virus bind to the specific ACE2 receptor. A cleavage of the spike protein by the host proteases, one of which is furin, helps facilitate the entry. This was the smoking gun the science correspondent Nicholas Wade attributed to the Noble laureate David Baltimore. While Wade used this information and spun stories beyond what is known, Baltimore himself withdrew from Wades surmises. In an article in Current Science (June 10, 2021), Prof. P. Balaram developed Wades arguments and gave further impetus to the improbable thesis that the virus was manipulated/engineered in the WIV and leaked. This scenario was also the favourite among the conspiracy theorists initially. However, U.S. scientists immediately responded that nature was responsible for the virus reaching humans through an intermediary via slow evolutionary processes. Moreover, many viruses use the furin cleavage site, and it is not unique to SARS-CoV-2. An analysis of all coronavirus sequences published in the journal Stem Cell Research in December 2020 showed that furin cleavage sites in spike proteins naturally occurred independently multiple times in coronaviruses.

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A recent report in the journal Cell showed the great diversity of viruses in least horseshoe bats, or Rhinolophus pusillus (https://doi.org/10.1016/j.cell.2021.06.008 ). It showed that apart from the previously reported coronavirus sample, RaTG13, two others, RpYN06 and RmYN02, had similarities over the whole genome. A bioRxiv reprint in March 2021 used the available 1,58,118 public seasonal genome sequences of hCoV, SARS-CoV-1, SARS-CoV-2 and MERS-CoV and noted that the current sampled diversity of seasonal coronaviruses had emerged over a 70-year-period, punctuated by the emergence of new lineages at intervals ranging from 5 to 20 years.

Interestingly, in July 2020, a group published an analysis of the more than 45,000 SARS-CoV-2 sequences from infected people then available, which showed the mutations and deletions that happened in the furin cleavage site, and concluded that the furin cleavage site might not be essential for SARS-CoV-2 to enter human cells in vivo. This shows that the virus in its passage through human cells is capable of losing the furin cleavage site. So it is not a site that is essential to virus infection, and this makes the case for the artificial insertion of this sequence to create a new virus much less appealing. A study published in PLOS Biology in March 2021 showed that the bat virus closest to SARS-CoV-2, RmYN02 (sharing an ancestor from about 1976), arose from a recombination within coronaviruses in bats and shares genetic features similar to SARS-CoV-2. This suggests the possibility that SARS-CoV-2 could have evolved in bats and directly jumped to humans without the need for an intermediate animal.

Although it is possible to conclude that there may be an undiscovered facilitating intermediate species, the results support the premise that the progenitor of SARS-CoV-2 was capable of efficient human-to-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, that created a relatively generalist virus capable of infecting many hosts. Thus, finding the closest relative to SARS-CoV-2 could then be a matter of screening diverse bat populations. This really warns us against jumping the gun, whether it is smoking or not, and concluding that SARS-CoV-2 does not have a natural origin. A letter published in Science on May 14 said: We must take hypotheses about both natural and laboratory spillovers seriously until we have sufficient data. A proper investigation should be transparent, objective, data-driven, inclusive of broad expertise, subject to independent oversight, and responsibly managed to minimise the impact of conflicts of interest.

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But a couple of months earlier, The Lancet published a letter emphatically dismissing conspiracy theories and saying that sharing of data is being threatened by disinformation and rumours. This issue of sharing data and information has become more about political sloganeering, in which some scientists too have joined in, than about science. Scientists from various countries have analysed the genomes of SARS-CoV-2 and come to the conclusion that this virus originated in the wild as did many other pathogens. The presidents of the U.S. national academies of sciences, engineering and medicine have backed this and warned that conspiracy theories create only fear, rumours and prejudice and jeopardise the global fight against the virus. They said they supported the call from the WHO Director General to promote scientific evidence and unity over misinformation and conjecture.

The problem with conspiracy theories is that they usually provide one point of speculative evidence that forms the basis for further speculative theorising. Essentially, they all turn to one final definitive source to rest their case. In this case, Nicholas Wades publication of his speculative thesis in Bulletin of the Atomic Scientists has been used to spread the canard that the pandemic was caused by negligence or deliberate action in Wuhan.

Incidentally, Wades book A Troublesome Inheritance: Genes, Race and Human History (2014) drew sharp criticism from 130 scientists for its racist overtones. They said in a letter to The New York Times: Wade juxtaposes an incomplete and inaccurate account of our research on human genetic differences with speculation that recent natural selection has led to worldwide differences in I.Q. test results, political institutions and economic development. We reject Wades implication that our findings substantiate his guesswork. They do not. We are in full agreement that there is no support from the field of population genetics for Wades conjectures. In the past, many people have criticised him for misreporting their remarks in his articles.

No doubt more data is needed on the nature of studies at the WIV. The institute is one of international standing where research work is carried out in collaboration with scientists from the U.S., Europe, Australia, Japan and India (the National Centre for Biological Sciences, or NCBS) with funding from these countries. It is one of the two laboratories in China to have a biosafety level of 4 (the highest level). Even the U.S. Department of Defence has funded programmes at the institute. It is only natural that researchers from these countries would demand a high degree of transparency about safety procedures at the WIV, including the recording of accidents and the corrections undertaken. The WIV has a high level safety procedures that is not matched even by the Indian Department of Atomic Energyfunded NCBS. There has even been a collaboration on the bat viruses from Nagaland involving scientists from the NCBS. A needless controversy has now been created about whether proper approvals were obtained from the Indian Council of Medical Research, the Ministry of External Affairs, and so on, for such studies. This is because the issue has deliberately been politicised with the intention of derailing international scientific collaborations with entities based in China.

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To this end, conspiracy theorists have attempted to link Dr Fauci, the face of the COVID-19 response in the U.S., to the laboratory leak theory. His office provided a research grant of $6,00,000 for five years (which the NIH eventually halted) to an American organisation, EcoHealth Alliance, working with the WIV. Dr Fauci received an email on April 18, 2020, from the zoologist Peter Daszak thanking him on behalf of the staff of EcoHealth Alliance for rejecting the laboratory leak theory. Actually, Dr Fauci did not reject it but only claimed it was less likely compared with the zoonotic origins theory. Republican senators in the U.S. introduced a Bill to remove Dr Fauci, who has advised several Presidents across parties, from his post.

Harping on conspiracies vitiates the atmosphere to the point where research involving international collaboration, particularly on virus mutations and the required responses, becomes increasingly difficult. In an article in Forbes magazine, Ethan Siegel lists out the strident remarks that have been made about the virus, which cannot, in the language of the scientific method, even be termed hypotheses: 1. It was a bioweapon developed in Wuhan. 2. Dr Fauci was directly involved in funding the programme in the laboratory that created the virus 3. Dr Shi Zhengli, the bat woman, was the brains behind the research to unleash the virus 4. Some kind of banned/unregulated research in gain of function was being done to modify a coronavirus, which resulted in the virus that causes COVID-19. All these are extraordinarily improbable compared with the hypothesis that the disease has zoonotic origins.

But the international collaboration the pandemic has brought about among scientists, virologists, medical professionals and public health administrators is extraordinary. They will eventually agree that Darwin still rules the world of cell biology.

S. Krishnaswamy is a retired professor of biotechnology earlier from Madurai Kamaraj University, Tamil Nadu. T.R. Govindarajan is a retired professor of physics from the Institute of Mathematical Sciences, Chennai.

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The controversy being created about the origins of the virus that causes COVID-19 - Frontline