“We are looking at it” – said former US President Donald Trump in April 2020, referring to the possibility of SARS-CoV-2 — the virus causing COVID-19 — having been engineered in a Chinese laboratory, and adding: “It seems to make sense”.

Conspiracy theories are owing their existence to rational flaws. If it makes sense, it must be true, and if it’s true, somebody must be lying and hiding the truth. This is how every conspiracy theory is built. Take flat Earthers for example — our planet seems flat to the eye, it must be flat. Everything else must therefore be a lie. Following the same logic, if there is a virology institute in Wuhan researching coronaviruses, it this must be the origin of the pandemic.

On May 3, 2020, US secretary of state Pompeo said there is “enormous evidence [the virus] is manmade or genetically modified”. The “enormous evidence” turned out to be the presence of a virology institute in Wuhan, and nothing else — a gross miresepresentation.

Besides Pompeo’s improper use of this term, evidence is something that needs to be built upon several observations, utilizing different methodological approaches, replicated by independent researchers.

That said, there’s a clear distinction between theory and conspiracy theory.

A theory means something specific

Take the theory of evolution as an example. Despite certain aspects of this theory still debated among scientists, we and other animals (including insects or reptiles) originate from common ancestors. Viruses and bacteria follow the same rules, too. Therefore, despite being called a theory for historical reasons, biological evolution is no longer a theory, it is essentially an established truth.

Now take the “flat Earth theory”. This is disproven by evidence of any kind. For example, there is an incredible amount of video footage from space, coming from various sources. This would all have to be fake, for the theory to hold true. Then there is day and night – and we know the planet rotates around its axis. There are seasons, because the planet rotates around the Sun. If you organize a meeting with a friend overseas, you will need to take into account their time zone – it may be dark there! There’s obviously much more than just this. We can therefore conclude the flat Earth theory is not only a theory, but rather a conspiracy theory. In fact, despite the evidence and the information available for everybody, conspiracy theorists still support the idea.

So we have proven theories, conspiracy theories, and finally, we have theories. Just theories. They can be far-fetched, ridiculous, and verging on the impossible, but as long as there is no evidence of the opposite, there is still a chance they can be true.

Theories built on anecdotal evidence, not supported by previous evidence, shared by people with a lack of expertise, and deemed inappropriate by experts are generally false. Despite this, there is still a chance, albeit remote, the theory is actually correct. To debunk a theory and put it in the folder with other conspiracy theories, there needs to be evidence supporting another line of thought, with this second theory being in logical contradiction with our theory of interest. Alternatively, there ought to be substantial evidence of the groundlessness of the theory. Practically, the theory needs to be disproven.

Fighting an infodemic

So what does this mean for the pandemic? Scientists and health professionals — including myself — have immediately flagged the theory that SARS-CoV-2 was engineered in a laboratory, or that an undesired spillover from a laboratory took place, as a conspiracy theory.

After all, these ideas have all the ingredients to suggest their skewed and potentially conspirative nature: they support the idea that unknown elites with obscure powers are controlling the future of mankind (say, the Chinese government), or that multiple organizations are involved in covering up the origin of the pandemic (take the World Health Organization as an example).

In the first months of the pandemic, despite China’s claim that the virus originated at the Huanan Seafood Wholesale Market, there was no evidence of how the virus originated and transmitted to humans, and from which source. For scientists, the idea of a zoonotic transmission at the market sounded plausible, especially in light of the similar dynamics of previous coronavirus outbreaks causing SARS and MERS. Scientists and the World Health Organization flagged other views on this topic as misinformation, despite them constituting an actual, albeit remote, possibility.

To explain why this has happened we need to understand how the role of scientists within global society has changed over time. Scientists, besides their research, also have to fight rampant misinformation, fake news and public mistrust. “We’re not just fighting an epidemic”, WHO’s General-Director Tedros Adhanom Ghebreyesus said at the United Nations Department of Global Communication. “We are fighting an infodemic”.

Constantly faced with conspiracy theories and myths that damage their precious work, scientists have grown increasingly skeptical about every unverified piece of information circulating online. “Fighting the infodemic” is challenging, and as this is a new threat for everybody, even scientists go to battle with biases and strategic flaws.

While the WHO is currently conducting a difficult investigation on the origin of the pandemic, here we try to understand all possible scenarios, from the most probable to the most arcane – debunking all myths, whether they come from the world of conspirators or from the academic world. So let’s dive in.

The multiple origins of the pandemic

1. The Huanan Seafood Wholesale Market

The most supported hypothesis based on phylogenetic reconstructions – which are computational operations that predict common genetic ancestry based on genomic sequences – is that SARS-CoV-2 originated from other coronaviruses circulating among bats and pangolins. The hypothesis is therefore of an animal origin (also referred to as proximal origin) of the virus.

The Huanan Seafood Wholesale Market has long been thought to be the place where the first zoonotic transmission of SARS-CoV-2 took place, especially considering the market was an easy point of contact between wild animals and humans. The market came under the spotlight predominantly because the activity of 28 out of 41 patients hospitalized in the early days of the pandemic was linked to the market in the days before hospitalization. However, 19 of the initial pool of patients did not have established contacts with the market, as well as the first confirmed COVID-19 patient, who didn’t seem to have had contact with either the market nor the other 40 patients.

Animal and environmental samples were taken from the market, and a fraction of them resulted to be contaminated with SARS-CoV-2, but no evidence of the initial animal source could be found. So based on this information, it is more likely that the market was an initial super-spreading event of the virus, but almost certainly not the place where the first zoonotic transmission took place. It remains possible, but unlikely, for this to be the origin.

Another incongruence that underscores the probability of this theory to be correct concerns time. It has been thought for months that the first zoonotic transmission to humans occurred in late November 2019. The first COVID-19 patient was reported to have the first symptoms on December 1^st, 2019. As most readers certainly remember, it took some time before COVID-19 outbreaks appeared in various countries, such as Italy, Iran and Spain. However, over the course of the last few months, a posteriori analyses of various biological and environmental samples demonstrated COVID-19 was circulating in various countries already in late 2019.

When the first study showing that COVID-19 was circulating earlier than expected was published, it was suggested that detection of SARS-CoV-2 in old samples was potentially due to contamination with more recent sources of the virus. However, in addition to the reported case of the patient that was retrospectively tested positive for COVID-19 in France in late December 2019, there have been numerous other studies in recent months drawing similar conclusions.

The increasing number of studies from independent groups and different institutions is now constituting convincing evidence that the virus was circulating earlier than expected. For example, in a recent study from Brazil, researchers analyzed two independent samples from human sewage and detected the presence of SARS-CoV-2 already on the 27^th of November 2019, long before the first official COVID-19 case in the Americas (only on January 21^st, 2020 in the United States). A fresh Italian study demonstrated the presence of SARS-CoV-2 in an oropharyngeal swab specimen from early December 2019 taken from a child with suspected measles. Another study from January 2021 showed the presence of the virus in sewage across several Italian cities on December 18^th, 2019.

So the virus was already circulating before the wet market transmission happened.

Considering these overwhelming results, the first zoonotic transmission likely took place earlier than initially thought, possibly between late October and the beginning of November 2019. The place of origin, despite also being not certain, is still very likely to be Wuhan, China, due to rampant infection cases reported from December 2019 to January 2020.

2. The proximal origin

“Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus”.

This is the conclusive sentence of the abstract of a letter published in Nature Medicine in March 2020 and entitled “The proximal origin of SARS-CoV-2”. This letter from various experts aimed to debunk various myths about the origin of SARS-CoV-2, and in particular claims that the virus was the result of experiments conducted at the Wuhan Institute of Virology in the lab of Shi Zhengli, a leading researcher who works on mechanisms of emerging viruses of wildlife origin, and in particular with coronaviruses and bats. The Nature Medicine paper in question provided convincing evidence for the proximal origin of SARS-CoV-2. At the time of writing, it has been cited more than a thousand times in just a few months, and the paper has been read more than 5 million times.

The first of the two main arguments for the proximal origin in this paper concerns the structure of the viral receptor-binding domain of the spike protein. This is of fundamental importance for the infection, as its structure determines the binding of the virus to the ACE2 human and animal receptors on cells, which allow viral entry. In simple words, if the virus is unable to properly attach to our cells, it won’t be able to infect them.

According to structural analyses, the receptor-binding domain structure of SARS-CoV-2 has affinity with the ACE2 receptor in humans, but the binding is not ideal. In fact, new variants of the virus that seem to have better affinity to the ACE2 receptors have emerged in the past months and have been associated with higher infectivity of the virus. The main argument is that, if the virus was man-made, it would likely have had a receptor-binding domain that was ideal for binding human ACE2 receptors in the first place. Authors conclude that “this is evidence that SARS-CoV-2 is not the product of purposeful manipulation”.

Despite being reasonable, the conclusion is inadequate. The authors only prove the receptor-binding domain of the SARS-CoV-2 spike protein is not ideal for binding to human ACE2 receptors. This doesn’t tell us anything about whether the virus was actually manipulated, or for which purpose.

Let’s consider a scenario in which the virus was in fact manipulated to study what structural changes would allow coronaviruses to infect humans. The result of this investigative manipulation would likely not result in the “generation” of an ideal virus for human infection, rather in one with potential for human infection. This also doesn’t exclude that the researchers have willingly chosen that particular structure, despite not being the ideal one for binding ACE2 receptor – after all this resulted in a pandemic, so in such a case it would have been considered as “good enough”.

The second argument from the aforementioned paper concerns genetic engineering. For a virus to be manipulated in a laboratory, traces of genetic engineering would need to be left, and would be consequently detected. The authors cited a review paper from 2014 describing the main techniques used in the field to achieve this. Based on these techniques, the authors excluded that any of these “backbones” was used and concluded that SARS-CoV-2 was not engineered in a laboratory.

This however doesn’t take into consideration more recent literature — new techniques to engineer coronaviruses have emerged after 2014 – or even the possibility that unpublished techniques could have been used to engineer SARS-CoV-2. The authors conclude “the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone” but to support this very claim they cite a review article published by Shi Zhengli and coauthors in Nature Reviews Microbiology which offers an in-depth analysis on the origin and evolution of pathogenic coronaviruses, without any reference to genetic engineering approaches for coronaviruses. Overall, this argument, despite reasonably suggesting a proximal origin of the virus, remains weak and does not exclude many alternatives.

3. Evolutionary placement of SARS-CoV-2

More convincing evidence on the natural origin of SARS-CoV-2 was provided by a study published in Nature Microbiology in July 2020, entitled “Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic”. The authors showed that this type of coronavirus has a broad genetic diversity in bats due to frequent recombination events. Basically, RNA viruses, and in particular the family of coronaviruses (sarbecoviruses) which include SARS-CoV-2, may infect the same cellular host and recombine – which consists of the exchange of genetic information between two different viruses, thus producing a new virus with mixed genetic features.

Based on a phylogenetic reconstruction, SARS-CoV-2 and the virus causing SARS diverged between 1932 and 1988, whereas SARS-CoV-2 diverged from RaTG1 – the most closely known related virus in bats – between 1930 and 2000. In another study, authors at the Institute of Zoology, Chinese Academy of Science, identified RmYN02, the closest virus to SARS-CoV-2 known to date, showing the extent of recombination events in its genetic history and large differences with SARS-CoV-2, again suggesting a proximal origin for SARS-CoV-2 and also pointing out to the fact that a large number of viruses circulating in wild animals have not yet been characterized.

As mentioned above, the natural origin of SARS-CoV-2 is certainly the most likely scenario, but these studies cannot exclude with certainty whether the virus was genetically created in a laboratory.

For example, the extent of recombination in coronaviruses and the lack of information about closer relatives to SARS-CoV-2, leave us with a large uncertainty about the hypothesis for a natural evolution of SARS-CoV-2. Furthermore, phylogenetic analyses are known for their intrinsic imprecision (they are models after all) and even more when many assumptions need to be made, such as in the case of viruses that are so prone to recombination. Second, a proximal origin of the virus does not exclude that humans involuntarily or unwittingly releasing the virus initiated the pandemic, as we will discuss in the next section.

4. The man-made virus

Let’s now assume the virus was voluntarily released by humans, and see whether this is a possible scenario, or whether there’s enough evidence to flag this as a “myth”. A conspiracy theorist would find this one the most probable and intriguing scenario. As scientists, we would rather classify it as the least likely one. Nonetheless, let’s have a look at it.

Let’s say the virus was engineered in a Chinese laboratory to purposefully cause a pandemic. If a state like China was planning on creating a biological weapon to set a stage for their rise as the hegemon of the world, it would likely do so in secrecy and using a weapon with no signature on it. In order to achieve this, years of research would have likely been conducted with the help of experts.

The Wuhan Institute of Virology, and in particular the lab of Shi Zhengli, would have been the appropriate institutions to start creating a coronavirus-based bioweapon. Top notch, unpublished engineering techniques would have likely been used – to avoid being unveiled after the first genomic analysis by a laboratory outside of China (see the aforementioned Nature Medicine paper). Further, the spread of the virus from inside China, the presence of the market in Wuhan to provide an excuse and the unpreparedness of the West to face this kind of threat would have constituted the perfect plan.

More than one year into the COVID-19 pandemic, China has nearly eradicated SARS-CoV-2 and its economy has started to grow as before the pandemic, whereas Americans and Europeans are nowhere close to an end of the tunnel, with their economies expected to suffer for years to come. Corruption of a few key figures occupying relevant positions in global health institutions, such as the WHO, would have been the perfect recipe for disaster of the West, and for the growth and prosperity of China. For example, Bruce Aylward’s infamous interview offers highlights of the political role the WHO has been playing since the early outbreak of COVID-19, also in consideration of the essential role China plays in funding the organization. Owing to the COVID-19 pandemic, Chinese economy will surpass American economy by 2028, instead of the expected 2032 before the pandemic. By then, China will become the largest economic powerhouse worldwide.

Despite this conspiracy theory-like scenario being extremely unlikely and the fact that there is no real evidence to point in this direction, it nonetheless remains a possibility that cannot be fully ruled out just yet — and countries worldwide should ensure this is not the case. The WHO, supported by all its member countries, should be allowed to investigate in various directions, without excluding this one.

Given the extent of this unprecedented crisis, we should leave room for any option. Old weapons and old wars are for the past – humanity has always been able to produce new monsters, and surprise the world. All conclusions, however, should be based on real evidence, not proximity and speculation.

5. The research origin

A second possibility is that research on coronaviruses caused the pandemic in the first place, by accident. As we know, human activities cause environmental changes including wildlife erosion, and place us and wild animals in closer proximity, thus increasing the likelihood of zoonotic transmissions occurring.

Especially since the outbreak of SARS in 2002, much research, especially in China, has focused on coronaviruses and on the identification of reservoirs of this type of virus in bats. For this type of research, scientists need to collect samples of animals in the wild and analyze them in the laboratory. With this approach researchers aim to identify different coronaviruses already present in nature, gathering information about their evolution and infectivity, thus anticipating strategies of prevention for potential outbreaks or suggesting recommendations for health organizations and governments. In fact, as previously discussed, humanity remains extremely ignorant about the diversity of coronaviruses circulating in wild animals. Research in this field is in fact important to be prepared for new viruses to infect humans and thus prevent pandemics.

Authors of the aforementioned paper identifying the closest relative of SARS-CoV-2 describe in the methods section that “between May and October 2019 [they] collected a total of 302 samples from 227 bats from Mengla County, Yunnan Province in China. […] These samples included patagium (a skin membrane between the limbs of bats), lung, liver, and feces. All but three bats were sampled alive and subsequently released”. A similar description of the fieldwork can be found in two papers from Shi Zhengli and colleagues (here and here), in which it is additionally stated that “all sampling procedures were performed by veterinarians, with approval of the Ethics Committee of the Wuhan Institute of Virology”.

Safety procedures to collect samples may simply have been inappropriate or may have been neglected – and precise methodological description of the safety measures utilized to conduct the research is not necessary nor requested by editors and reviewers for publication. Those who have laboratory work experience among the readers know mistakes can be made, and negligence by less experienced researchers is common (see the example of the SARS outbreak in Singapore in late May 2003 caused by a non-trained student working with viruses in a biosafety level 3 laboratory). Supposedly this isn’t different for fieldwork with bats. As a matter of fact, YouTube is filled with plenty of videos of researchers handling live bats with bare hands and no protection at all. In fact, it has been generally believed a rabies vaccine is all you need to work with these animals.

Therefore, we cannot exclude that the first zoonotic transmission occurred because of investigative research conducted on coronaviruses. However, it is needless to say that from a probabilistic perspective, it is more likely that the vicinity of animals and humans could have been due to the use of bats as food sources.

6. Proximal for proximal origin

We previously mentioned those papers suggesting the proximal origin of SARS-CoV-2 based on phylogenetic analyses (here and here). Besides the issues we discussed before, a major problem with their approach is that, in order to demonstrate proximal origin, authors must have assumed proximal origin.

Here we try to untangle this seemingly circular argument. The phylogenetic distance between two viruses is a measure of how different two species are, based on their genetics. Based on the similarity and differences between multiple viruses, researchers can infer and predict how far in time two viruses diverged, until a point in time when there was a common ancestral virus. As mentioned above, they calculated a temporal distance between SARS-CoV-2 and its closest known virus and determined this is too long for any genetic manipulation to have occurred. This is however true only if they assumed natural evolution occurred – without human intervention.

Humans can push natural evolution to their advantage, and they have been doing so for a very long time. For example, the evolution of maize has been pushed by selecting corn with specific characteristics, including resistance to pests, ability to grow on different soils, etc. This has allowed this crop to become a staple of the modern human diet. In this process, humans haven’t genetically manipulated maize directly, but they nonetheless acted as selective forces that naturally led to the creation of a crop with desired characteristics. An animal example is the evolution of dogs from wolves, the first and very successful example of domestication.

Therefore, despite our ancestors knowing nothing about genetics, they were aware of the concept of selective breeding. This concept can potentially be used for pushing viral evolution, too. Basically, we can speed up the natural process of evolution if we wish to. For instance, among many other research groups using this concept in their research, of note a group of scientists managed to reproduce natural evolution of a RNA virus in cell culture.

In principle, using available SARS-like viral strains, researchers could have selected viruses for their ability to infect human cells. This does not exclude the proximal origin of the virus, as in this case humans could have simply assisted the process, and the two hypotheses are not mutually exclusive. This very possibility demonstrates the inherent logical inaccuracy of phylogenetic analyses to demonstrate proximal origins.

As natural evolution in the lab can be pushed to occur at much faster rates than in nature, a temporal analysis of the divergence between two viruses in this specific context is nonsense. Furthermore, selection during passage in cell culture could also explain the “imperfect” binding of SARS-CoV-2 to human ACE2 and the lack of evidence for backbones used to genetically engineer the virus.

Authors of the famous Nature Medicine paper discussed this issue in their manuscript, and concluded they “do not believe that any type of laboratory-based scenario is plausible”. Their belief — this choice of words is questionable at best — stems from the observation that recombination events involving viruses in pangolins provides a valid explanation for retaining sequences with affinity to the human ACE2 receptor. This however does not exclude that samples of viruses closely related to SARS-CoV-2 have been obtained from the environment after natural events of recombination occurred, or that this natural process has been simulated in a “laboratory” environment.

On this point, the authors say that “a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described”. In this line, authors are substantially suggesting that if something hasn’t been published, it cannot have happened and cannot be true.

Furthermore, the authors claimed that the presence of a polybasic cleavage site is evidence that passage in cell culture didn’t occur. Also on this point, they use the same logic, claiming “Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described”.

Conclusion: moderating instead of canceling

Here we comprehensively listed all possible scenarios concerning the origin of SARS-CoV-2 and of the ongoing pandemic. As we have seen, a proximal origin is very likely, albeit this doesn’t exclude the possibility that humans may have played a part in this process, willingly or not. As one paper puts it:

“Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here.”

More than one year into this pandemic, we still know very little about the origin of SARS-CoV-2. Following Socrates’ famous quote “I know that I know nothing”, scientists should remember to be fully committed to scientific reasoning and logic, even during a time in which scientific misinformation is rampant and the consequences of it are tangible.

Scientists should focus on identifying the early events of the pandemic, solving it and preventing future – foreseeable – disasters. They should also focus on debunking scientific misinformation and conspiracy theories, of course. And they should find viable strategies to halt the ongoing infodemic.

That said, canceling more or less unlikely theories prior to having proved them wrong is not what a scientist should do. Scientific hypotheses have always generated debate among scientists, and nowadays the general public is inevitably part of this process. Despite most theories coming from people lacking expertise ending up in the trash, scientists should not silence them, but rather find a way to moderate them. They should explain why these theories are not so likely to be true, their flaws, and lack of evidence. For theories supportive of a laboratory spillover, for example, scientists should underline these theories lack substantial evidence, albeit they may still end up being correct. These theories should be challenged with a rigorous method, rather than being silenced.

In conclusion: We should highlight and challenge theories having precursor traits of conspiracy theories, and challenge language that is not scientific and precise. But again, we should not discredit them prior to having conducted proper and comprehensive analyses.

Scientism should not prevail over science. The ongoing infodemic is challenging the scientific movement in multiple ways, and this is one of those we should not neglect.