From nature or from a laboratory? Science, health, and politics in the dispute over the origin of SARS-CoV-2

Abstract

This paper examines the current scientific and sociopolitical discourse on the origins of SARS-CoV-2, focusing on Viral by Alina Chan and Matt Ridley and Breathless by David Quammen. These books present contrasting narratives, highlighting competition within the scientific community and conflicts of interest. Central to the debate are the Huanan Seafood Market and Wuhan Institute of Virology, with discussions that involve zoonotic spillover and high-containment lab research. Both sources stress the need to identify the origins of the novel coronavirus to prevent future pandemics, but they diverge on key aspects, particularly regarding the importance and risks associated with laboratory research on potentially pandemic pathogens.

Keywords
Origin; SARS-CoV-2; Lab leak; Natural spillover; Politics

Resumo

Este artigo analisa a discussão científica e sociopolítica acerca das origens do SARS-CoV-2, concentrando-se nas obras Viral, de Alina Chan e Matt Ridley, e Sem fôlego, de David Quammen. Esses livros apresentam versões contrastantes, salientando conflitos de interesse e competição dentro da comunidade científica. O Mercado Atacadista de Frutos do Mar de Huanan e o Instituto de Virologia de Wuhan estão no centro do debate, gerando discussões que envolvem transbordamento zoonótico e pesquisas em laboratórios de alta contenção. Ambas as fontes ressaltam a necessidade de identificar as origens do novo coronavírus para evitar futuras pandemias, mas divergem em aspectos-chave, sobretudo quanto à importância e aos riscos associados à pesquisa laboratorial de patógenos com potencial pandêmico.

Palavras-chave
Origem; SARS-CoV-2; Vazamento de laboratório; Transbordamento natural; Política

It is an idea that may provoke laughter, but the only way to fight the plague is honesty (Camus, 1947, p.151).

“I used to watch for it,” he said. “I used to think about the countries on the other side of the ocean, wonder if any of them had somehow been spared. If I ever saw an airplane, that meant that somewhere planes still took off. For a whole decade after the pandemic, I kept looking at the sky” (Mandel, 2014, p.128).

When the covid-19 pandemic was first reported in January 2020, it immediately sparked two competing hypotheses about the origin of the virus responsible, SARS-CoV-2. These theories, which were primarily explored in scientific articles and on social media, suggested that the pandemic resulted from either a natural spillover at a live animal market in central China or a leak during an experiment at a virology laboratory in China. The debate quickly expanded to the geopolitical arena. Accusations intensified (particularly between the United States and China) as time went on without clear answers regarding the origin of the virus, centering around transparency issues related to live animal markets and virology laboratories.

In November 2021, Alina Chan and Matt Ridley published Viral: the search for the origin of covid-19. Chan, a Chinese-Canadian molecular biologist specializing in gene therapy and cell engineering, has numerous publications in prestigious journals; at the time of the book’s release, she was a postdoctoral fellow with limited experience in virology. Despite the validity of her claims, some viewed her as unorthodox and lacking strong evidence (Honigsbaum, 15 Nov. 2021). Ridley, a British author with a doctorate in biology, is also a journalist and businessman best known for his work on biology, the environment, and economics. Viral offers extensive scientific references from an unconventional perspective, suggesting – controversially for some – that covid-19 may have originated from a laboratory leak of a SARS-like coronavirus. Chan and Ridley point to the Wuhan Institute of Virology (hereafter, WIV), led by virologist Zhengli Shi, as the likely source of the leak. The WIV is located in Wuhan, a city of approximately eleven million people that was the epicenter of the pandemic, and collaborates with other researchers, including virologist Peter Daszak, who chairs the US-based non-profit EcoHealth Alliance. The mission of EcoHealth Alliance is to protect humans, animals, and the environment from emerging infectious diseases, and reportedly collaborates with Chinese researchers to understand why this region is a hotspot for diseases such as SARS, H5N1 avian flu, and covid-19. The organization, which plays a key role in the One Health movement, promotes an interdisciplinary approach that links human, animal, and environmental health. This framework has been instrumental in guiding global responses to zoonotic diseases.¹

Viral discusses the significance, relevance, limitations, and risks of research on pathogens with pandemic potential. In over four hundred pages, Chan and Ridley compile a substantial body of information (scientific, economic, as well as political) to present historical events they consider relevant to covid-19 and explain molecular and genetic methods used in research on coronaviruses and other viruses. They emphasize the role of non-experts who have raised questions about the origins of the pandemic on platforms like Twitter, WeChat, and Weibo. Utilizing the US Freedom of Information Act (Foia), Viral reveals public and private emails between scientists, administrators, and politicians, offering insights into the uncertainties surrounding the pandemic’s origin. In some cases, emails from researchers at the National Institutes of Health and the Centers for Disease Control and Prevention were disclosed, igniting debates about transparency and political interference in science.

Nearly a year later, in October 2022, David Quammen published Breathless: the scientific race to defeat a deadly virus. Quammen, a renowned American journalist and writer on biology and human health, captures the intense scientific and public health response to the covid-19 pandemic. The book contextualizes the novel coronavirus using knowledge from past pandemics, highlighting research on bats and SARS-like coronaviruses. The book also sheds light on the complex impact of both the legal and illegal wildlife trades (which drive live animal markets) in facilitating zoonotic spillover, highlighting the connections between biodiversity loss, human encroachment on wildlife habitats, and emerging infectious diseases. Although the title suggests a broader focus, Breathless delves deeply into the origins of SARS-CoV-2, and even offers a critical perspective on Alina Chan and Matt Ridley.

The authors of Viral highlight that during the early months of the covid-19 pandemic, the genetic material of the SARS-CoV-2 virus did not undergo significant mutations and showed no accumulation of changes that would suggest adaptation to the human host. The concept of adaptation here refers to the evolutionary process involving random mutations and natural selection by which a structure, capacity, or behavior confers an advantage in a specific environment (Caponi, 2014a). In other words, while the “new coronavirus” changed, it did not evolve in the expected evolutionary sense. In a widely discussed May 2020 preprint, Shing Hei Zhan, Benjamin Deverman, and Alina Chan argued that, from the start of the pandemic, SARS-CoV-2 appeared “pre-adapted” to humans, since it was already capable of entering human cells, replicating, and transmitting to new hosts. Zhan and his colleagues compared SARS-CoV-2 with the 2002-2003 SARS virus, which infected around eight thousand people and caused eight hundred deaths, noting that SARS-CoV-2 exhibited greater genetic stability early in the pandemic. This led them to suggest that SARS-CoV-2 may have undergone serial passage experiments, a common virology technique in which repeated infections are performed to accumulate mutations leading to key adaptations. Molecular biologist Rosana Segreto (who was cited in Viral) supported this theory, arguing that the genetic stability of SARS-CoV-2, despite its global spread, warranted serious consideration of the lab leak hypothesis (Segreto, Deigin, 2020; Segreto et al., 2021). Viral provides this analysis as part of its broader case for a more open investigation into all possible scenarios for the emergence of covid-19.

Before addressing the origin of SARS-CoV-2, Breathless establishes a broad foundation on pandemics in general, zoonotic viruses, and the intricate relationship between the natural world and humanity. In the initial chapters, Quammen examines the context of coronaviruses, how they circulate among species, and the dynamics of infectious disease outbreaks that reveal recurring patterns and associated risks despite appearing to be isolated events. Quammen also dedicates substantial attention to introducing scientists, their research, and their hypotheses, constructing a framework that clarifies how and why SARS-CoV-2 was anticipated by numerous experts. He details previous outbreaks related to 2002-2003 SARS and 2012 MERS, illustrating how these events contributed to an understanding of the nature of coronaviruses and the way in which these lessons were applied (or neglected) when SARS-CoV-2 emerged. This detailed introduction underscores that the issue of origin is not limited to just where the virus came from, but rather the scientific and ecological context that facilitates these transmissions. In Breathless, the pandemic’s emergence concurrent with SARS-related research taking place in Wuhan is considered a coincidence, while Viral contends that a lab leak from the WIV presents a plausible origin scenario. Chan and Ridley dismiss conspiracy theories, instead suggesting an accidental release of either a modified or natural coronavirus. Quammen, meanwhile, highlights contradictions within the lab leak theory and focuses on scientific efforts to mitigate pandemics (Frutos, Gavotte, Devaux, 2021; Gavotte, Gaucherel, Frutos, 2023).

Both narratives were written while the pandemic was in full swing, and vaccines had yet to be introduced. Together, they reflect scientific debates and other relevant discussions that unfolded on digital platforms. With the rise of social media, individuals and profiles became key players in disseminating information and were recognized as sources in both scientific and social debates. Chan and Ridley incorporated the voices of social actors into their book: despite not being scientists, they participated in rigorous debates about the origin of the virus, particularly on Twitter. Breathless similarly highlights the role of digital communication, as Quammen conducted interviews through online platforms, including one with Alina Chan herself. The pandemic hindered Quammen’s usual research method, traveling internationally to interview researchers in person (for example, see Quammen, 2012).

In this work, we focus on what we consider the most relevant points of the scientific dispute: (1) the minimal variation of the virus at the onset of the pandemic, contrasting with expectations from the 2002-2003 SARS outbreak; (2) the 2012 case of guano scrapers in a copper mine in Mojiang, in southeastern China, who developed a severe respiratory syndrome; (3) gain-of-function experiments, which allow virologists to increase the virulence and transmissibility of pathogens for scientific research; (4) the evolution of the ACE2 receptor-binding domain in the Spike protein of SARS-CoV-2, which enables the virus to bind more effectively to target cells; and (5) the origin of the furin cleavage site in the same SARS-CoV-2 Spike protein, which is absent in its closest relatives. This site is cleaved by the enzyme furin, causing a conformational change that facilitates viral entry into host cells. Naturally, due to the length and scope of Viral and Breathless these points are discussed in much greater detail, and there are additional areas of disagreement that we will not address here due to space constraints.

Recent studies highlight a broader issue: how environmental and climatic disruptions in the Anthropocene (a new geological epoch defined by humanity’s unprecedented influence on Earth’s ecosystems) affect viral evolution and pandemic emergence (Holmes, 2024; Domingo, 2024). The defining characteristics of the Anthropocene era – global warming, habitat destruction, biodiversity loss – disrupt natural balances and bring humans into closer contact with wildlife, in turn facilitating zoonotic spillovers. Human-driven changes like deforestation, urbanization, and global trade have accelerated ecological disturbances, disturbing natural habitats and increasing human-wildlife interactions (Rohr et al., 2019; Worster, 2020). Pandemics like covid-19 serve as potent indicators of humanity’s profound, intertwined impact on natural evolutionary processes and global health risks, reflecting the direct and indirect roles that anthropogenic changes play in shaping viral dynamics and enhancing pandemic potential. These processes are intensified by climate change, which not only alters habitats and animal migration patterns but also forces species into closer contact with human populations, increasing opportunities for zoonotic transmissions (Rohr et al., 2019; Bernstein et al., 2022; Gavotte, Gaucherel, Frutos, 2023; Natterson-Horowitz et al., 2023; Silva, 2024; Pfenning-Butterworth et al., 2024; Waizbort, 2024).

The scientific problem

Virtually all scientific articles on this topic agree that identifying the origin of SARS-CoV-2 is a crucial scientific challenge. Viral and Breathless align on this point. According to Chan and Ridley (2021, p.4):

How the covid-19 pandemic started may be the keenest mystery of our lifetime. The saga will forever punctuate the history of humanity. It has led to the deaths of millions of people, sickened hundreds of millions and dramatically changed the lives of almost every person on the planet. The impact of this invisible virus can also be measured in weddings and gatherings cancelled, jobs lost and businesses bankrupted, schools closed and parents balancing childcare and work, clinical visits missed and treatments put on hold, and innumerable people living more isolated lives than before. If we do not find out how this pandemic began, we are ill equipped to know when, where and how the next pandemic may start.

We would add that if we fail to understand how this pandemic started, we will be even less prepared to understand why future pandemics threaten us. In the field of philosophy of the biological sciences, questions about the “why” of a phenomenon or process often pertain to its evolutionary causes (Caponi, 2014b). Viral and Breathless do not claim to provide the reader with narratives concerning the evolutionary causes of the virus and the pandemic (Waizbort, 2024), but rather offer a comprehensive discussion on the proximate origin of SARS-CoV-2, as Quammen (2022, p.231) notes:

When a novel virus appears suddenly as an infection among humans, one of the first questions is always: appeared from where? Everything comes from somewhere, including viruses. The origin of an unfamiliar, dangerous virus is a matter of urgent interest for several reasons, including prevention of further such surprises and understanding the biology of the thing. Understanding the biology of the thing, and its evolutionary history, can be crucial to the development of therapeutic drugs and vaccines. But tracing it to that origin is often difficult and takes time.

At this time, the animal species responsible for the initial transmission of SARS-CoV-2 to human(s) has not been identified to an extent that would permit the scientific community to confirm the origin of this virus (Alwine et al., 2023, 2024; Domingo, 2024; Holmes, 2024). The closest related viruses, which diverged approximately forty years ago, were discovered in bats from copper mines in Yunnan (RaTG13, 96.3% genetic identity) and Laos (BANAL-52, 96.8% genetic identity) (Garry, 2022; Teemmam et al., 2023). Both of these locations are hundreds of kilometers from Wuhan, where covid-19 first emerged. Along with other Chinese laboratories, Shi Zhengli’s laboratory at the WIV conducts research on coronaviruses from these regions in collaboration with international scientific groups, particularly those from the United States (Chan, Ridley, 2021, p.19; Chan, June 2024). Viral emphasizes the relationship between the WIV and EcoHealth Alliance, focusing on allegations that Peter Daszak funded gain-of-function research on SARS-like coronaviruses (Chan, Ridley, 2021, p.117-118).

The EcoHealth Alliance, a multidisciplinary consortium comprising scientists, veterinarians, epidemiologists, biologists, and public health experts, maintains robust institutional partnerships that support its global health initiatives.² Its research activities, especially those involving international collaborations, have become a central topic in the discourse on SARS-CoV-2’s origins, raising particular scrutiny over its funding for research in Chinese laboratories. By facilitating and funding research on zoonotic diseases, the EcoHealth Alliance works closely with laboratories and researchers worldwide to understand pathogen spillover risks. This cooperation has come under intense public and academic examination amid concerns about the origins of SARS-CoV-2, most notably high-profile collaborations with institutions that study coronaviruses in wildlife, including bats. These include extensive cooperation with international scientists to understand the ecology of this virus family in bats and other wildlife reservoirs. One prominent figure in this research, doctor Zhengli Shi, has received support from the EcoHealth Alliance in partnership with various organizations and funding bodies to enhance the capacity to study bat coronaviruses. The EcoHealth Alliance also leads Project Predict, an initiative funded by the US Agency for International Development (Usaid) to identify emerging viruses in wildlife before potential human transmission.

Quammen has been warning about the risks of a respiratory virus pandemic since at least 2012, in his best-selling book Spillover: animal infections and the next human pandemic. In this work, he explored the transmission pathways of diseases with pandemic potential, emphasizing both the legal and illegal trade in exotic animals as well as increasing “points of contact” between humans and animals driven by deforestation, urbanization, and intensive animal farming. Spillover underscored the importance of epidemiological surveillance and disease control as key strategies for mitigating zoonotic risks (Quammen, 2012). In Breathless, Quammen reaffirms the significant role played by the commercial trade in animals (both wild and domesticated) for food and traditional Chinese medicine. He notes that between 1975 and 2000, over 170 thousand pangolins were traded legally (Quammen, 2022, p.96). An article published in 2021 lists species such as snakes, chickens, ducks, badgers, and raccoon dogs as being traded in Wuhan markets, with some sold alive in precarious conditions (Xiao et al., 2021). Although bats and pangolins were not explicitly listed, species like raccoon dogs and civets are known to be susceptible to SARS-like coronaviruses (Xiao et al., 2021; Holmes, 2024). It is therefore unsurprising that the covid-19 pandemic emerged in Wuhan, where the Institute of Virology and the Huanan Seafood Market are located just 24 kilometers apart. Numerous other markets in Wuhan and across Asia engage in the trade of wild mammals, heightening concerns about virus transmission. Research into SARS-like viruses conducted in laboratories in the city further underscores the region’s epidemiological significance.

Viral presents the problem of the origin of SARS-CoV-2 as a “mystery,” and as early as the Prologue refers to the 2012 case of six guano scrapers who worked in a copper mine and subsequently contracted an acute respiratory disease. Guano (the accumulated excrement of seabirds, bats, or seals) is used as a fertilizer due to its high content of nitrogen, phosphate, and potassium; workers typically remove the guano from caves, mines, or areas where these animals roost, sometimes in difficult or hazardous environments. Historically, guano was highly valued for its agricultural benefits and was a major export from certain regions. The information regarding the six workers who fell ill after working in the Mojiang mine was initially uncovered by an anonymous Twitter user, as Chan and Ridley (2021, p.7) report:

One of the most tantalising pieces of the puzzle was a medical thesis unearthed in May 2020 by an anonymous Twitter user called the Seeker, a former science teacher in India. It was around this once obscure thesis that numerous sleuths, journalists and scientists began to coalesce to trace the origin of covid-19. The thesis carefully chronicled the story of miners in Yunnan province who had sickened with a mysterious pneumonia after working in a bat-infested mine in 2012. In the years afterwards, scientists from top laboratories, including the Wuhan Institute of Virology (WIV), home of China’s most high-security virus laboratory, had repeatedly made the long journey to visit the mine to find the virus that could have infected the miners. By their accounts, they did not succeed, but in 2013 the WIV team did collect a virus that would later prove to be the closest genetic match to SARS-CoV-2. Perhaps a clue to the origin of covid-19 lies in that distant mine in south-west China.

The medical thesis that was uncovered was written by a Chinese medical student named Li Xu, who conducted a comprehensive study on the illness that emerged in these miners as part of his medical degree at Kunming Medical University and defended the thesis in 2013. The miners were admitted to a hospital in Kunming, the capital of Yunnan province in southwest China, and three died (Chan, Ridley, 2021; Quammen, 2022). There is considerable literature on this case (Rahalkar, Bahulikar, 2020; Frutos, Gavotte, Devaux, 2021). Chan and Ridley demonstrate that the copper mine has been the subject of numerous restrictions, and several journalistic teams were prevented from accessing the site. In 2020, Rahalkar and Bahulikar sought to establish a relationship between the symptoms manifested by these guano scrapers; they argued, with support from respiratory disease experts, that the symptoms were consistent with those of covid-19, and suggested that the pandemic could have originated from samples collected in the mines where these men worked. However, other authors maintain that the clinical presentation of these workers was incompatible with the symptoms of SARS-CoV-2 infection (Frutos et al., 2022a; Domingo, 2024). In another paper published in 2022, Rahalkar and Bahulikar clarified that their previous article did not propose that the Mojiang miners were infected with SARS-CoV-2. They instead highlighted the similarities between the symptoms of the pandemic disease and those that affected the six guano miners, emphasizing the importance of a transnational investigation with access to the biological material collected by the WIV, such as serum samples and throat swabs (Rahalkar, Bahulikar, 2022). Viral and Breathless both address this case, with the former suggesting a link between the pandemic and the 2012 disease and the latter denying this correlation.

The WIV group, led by Zhengli Shi, had access to the copper mine in question to collect biological material. From these samples, Shi and her collaborators derived the RaTG13 coronavirus, which according to Viral was involved in a controversial name change (it was previously identified as BtCoV/4991) and the WIV group’s puzzling silence during the early months of the pandemic regarding RaTG13’s genetic similarity to SARS-CoV-2 (Chan, Ridley, 2021; Quammen, 2022; Chan, 2024; for a recent review, see Domingo, 2024). Chan and Ridley also describe past incidents where pathogens escaped from laboratories, causing illness and death, although none reached pandemic levels. This information, which they present in detail, is cited as evidence supporting the plausibility of the lab-origin theory. The evidence remains circumstantial, however, and has not convinced many other scientists who have extensively studied SARS-CoV-2 and the covid-19 pandemic (Frutos et al., 2022b; Garry, 2022; Quammen, 2022; Holmes, 2024; Domingo, 2024).

One method used to study viruses with pandemic potential involves altering their genomes to enhance their characteristics in terms of virulence and transmission, in experiments known as gain-of-function research (Berche, 2023; Sharpless et al., 2015). The term “gain-of-function” typically refers to experiments that result in a pathogen acquiring a new or enhanced ability, such as the capacity to infect a new cell type or host species (Chan, Ridley, 2021, p.176; Quammen, 2022, p.263). Motives for this risky research include prevention, scientific explanation, drug development (including vaccines), and expanding knowledge of virulence, transmission, and pathogen evolution. Interest in these experiments dates back to the 2002-2003 SARS pandemic and grew during the 2012 MERS pandemic, and coronaviruses (particularly those originating from bats) were recognized as posing a significant pandemic threat. Other respiratory viruses like those involved in avian and swine flu, along with their many variants, are also studied in this context (Berche, 2023; Gaviria, Martin, 2023). Gain-of-function experiments with SARS-like coronaviruses have been conducted at the WIV and other research centers located within a few kilometers of the Huanan Seafood Market. The process of passing viruses through laboratory cells (serial passage), as previously mentioned, is considered a gain-of-function experiment. Viral argues that such experiments may have introduced genetic material into the genome of a SARS-like coronavirus, which then accidentally escaped from the laboratory and initiated the pandemic, potentially infecting individuals at the Huanan Market. It further suggests that laboratories in Wuhan were working with SARS-CoV-2 samples collected directly from bats inhabiting caves in southwestern China or Laos, or even from the cave where the guano workers were infected. However, Quammen contends that there is no concrete evidence these viruses were present in the laboratory, although he acknowledges the importance of discussing the relevance of such experiments and the safety levels of laboratories that handle these pathogens. Frutos and collaborators argue that the conjectures surrounding the lab leak of coronaviruses collected from the Mojiang mine (whether engineered or not) contradict one another: if the virus is engineered, it cannot be an accidental leak of a natural virus, and vice versa (Frutos et al., 2022a).

There are two key structural features in the envelope of SARS-CoV-2, encoded by mutations in its genome, that distinguish it from SARS and other sarbecoviruses (a subgenus within betacoronaviruses): the ACE2 receptor-binding domain and the furin cleavage site. The receptor-binding domain (RBD) is a critical component of the virus’s Spike protein (also known as the S protein), enabling it to bind to the target cell. This binding is essential for viral entry, as it allows the virus to attach to the host cell’s surface. The high affinity of SARS-CoV-2’s RBD for human ACE2 receptors significantly enhances its efficiency in infecting human cells.

Research has identified coronaviruses in pangolins containing RBDs closely resembling that of SARS-CoV-2 (Lam et al., 2020; Xiao et al., 2020; Andersen et al., 2020). The high sequence identity between these RBDs and the RBD of SARS-CoV-2 suggests that pangolin coronaviruses may exhibit a comparable binding affinity to the ACE2 receptor, underscoring their potential role in the evolutionary pathway of the virus. This similarity indicates that genetic recombination between different coronaviruses in intermediate hosts like pangolins may have occurred prior to the emergence of SARS-CoV-2. Pangolins could have served as a bridge between bats (likely the original hosts of sarbecoviruses) and humans, facilitating the exchange of genetic material that contributed to the creation of SARS-CoV-2. However, while some pangolin coronaviruses exhibit high similarity to SARS-CoV-2 in specific regions of the genome, their overall genetic similarity is not as close. This suggests that although parts of the genome may have undergone recombination, the complete pangolin coronavirus is not the direct ancestor of SARS-CoV-2. Genetic recombination is common in coronaviruses, making it difficult to pinpoint a clear origin (Boni et al., 2020). It is possible that pangolin coronaviruses acquired parts of their genome through recombination with coronaviruses from bats or other animals, which may explain the similarities in the RBD. Furthermore, there is no direct evidence that infected pangolins transmitted the virus to humans: the zoonotic jump of SARS-CoV-2 from pangolins to humans has not been demonstrated, and other species may have been involved. Other animals, particularly bats, remain more likely candidates as natural reservoirs of SARS-CoV-2, with pangolins possibly acting as secondary or incidental hosts. While Viral and Breathless discuss the potential transmission of coronaviruses from pangolins to humans, both books consider this route of transmission improbable.

The furin cleavage site represents the most significant mutation in the Spike protein of SARS-CoV-2 (Andersen et al., 2020; Holmes et al., 2021; Garry, 2022). Furin, an enzyme present in all mammals including humans, cleaves proteins at specific sites, playing a crucial role in regulating and processing various cellular proteins. In the SARS-CoV-2 Spike protein, there is a region encoded in the virus’s RNA that is cleaved by furin. This site induces a conformational change in the Spike protein that facilitates viral entry into the host cell, a critical step in infection. Even the coronaviruses most closely related to SARS-CoV-2, including RaTG13, BANAL-52, and the virus responsible for the 2002-2003 SARS pandemic, lack this furin cleavage site (Andersen et al., 2020; Segreto et al., 2021; Garry, 2022; Teemman et al., 2023). Similarly, pangolin coronaviruses do not possess this site, significantly reducing the likelihood that they were directly involved in the transmission of SARS-CoV-2 to humans. The furin cleavage site in SARS-CoV-2 may have evolved independently through genetic mutations or recombination in an unknown host, suggesting that while pangolin coronaviruses could have contributed to the virus’s formation, they are not its direct source. The furin cleavage site is also present in other viruses, such as MERS-related coronaviruses, H5N1 bird flu, and the Ebola virus. Since the beginning of the pandemic, the origin of this genomic region has been a major point of controversy.

In a correspondence article (Letter) to Nature in March 2020, Andersen and collaborators compared the genome of the SARS-CoV-2 Spike protein with those of other evolutionarily related coronaviruses (Andersen et al., 2020). This work became a central point of contention in the debate over the origin of SARS-CoV-2 after the authors made a categorical statement: “Our analyses clearly show that SARS-CoV-2 is not a laboratory-built or intentionally manipulated virus” (Andersen et al., 2020, p.450) and “We don’t believe that any kind of lab-based scenario is plausible” (p.452). They argue that it would not make scientific or biological sense for two of the most prominent features of the virus’s genome – the ACE2 receptor-binding site and the furin cleavage site – to have been artificially inserted into the genetic structure of a SARS-like coronavirus that had never been previously identified and remains undiscovered. Furthermore, they explain that lab-based virus studies like gain-of-function experiments typically focus on manipulating known viruses, altering the genome to better understand and control viral behavior and to develop vaccines and other treatments.

As noted, numerous non-scientists have become engaged with the question of SARS-CoV-2’s origins, likely due to the influence of social media. Nicholas Wade, a British-American science writer and former editor for the New York Times, Science, and Nature, became a significant figure in this debate in 2021 with a widely read essay on the Medium web platform. “Origin of covid: following the clues” critically examines the origins of SARS-CoV-2, considering both natural and laboratory-based hypotheses. Wade maintained it was possible SARS-CoV-2 could have originated from a laboratory incident at the WIV in China, arguing that specific viral features (particularly the furin cleavage site in the Spike protein) might suggest laboratory manipulation rather than natural zoonotic evolution. Drawing from scientific studies and reports, Wade pointed to gaps in transparency at Chinese laboratories and questioned the broader scientific community’s response to investigating the virus’s origins. His involvement illustrates the complexities faced by journalists and scientists in discussing sensitive scientific questions with global public health implications.

In an article published in 2024, Edward Holmes, an Australian virologist and co-author of “Proximal origin of SARS-CoV-2,” reinforces the arguments from the 2020 study: “It would be puzzling to genetically engineer a bat virus using a furin cleavage site with no precedent and one that is not found in any human coronavirus” (Holmes, 2024, p.11). Holmes argues that SARS-CoV-2 is a generalist virus, capable of infecting any mammal with ACE2 receptors in the cells of their respiratory tracts. After crossing the species barrier from bats to humans, the virus was transmitted from humans to at least twenty other animal species across diverse geographic regions, with more than 3,400 reported cases of infection or exposure. This list includes lions, tigers, dogs, cats, hamsters, various rodents, primates, and notably, mink and white-tailed deer (Holmes, 2024, p.15). It would have been crucial to determine whether the virus underwent significant variation after spilling over from humans to other species (supporting the lab leak hypothesis) or remained relatively unchanged (supporting the natural spillover hypothesis); however, as far as we have been able to determine, no such studies have been conducted. Holmes also revisits the argument regarding the limited variation of SARS-CoV-2 at the beginning of the pandemic, expanding on it further:

Another argument presented as evidence of the theory of experimental manipulation in a laboratory as the origin of SARS-CoV-2 is that the virus did not undergo extensive adaptive evolution during its early spread, as might be expected for a virus that has newly emerged in humans … Such a lack of adaptation is suggested to indicate that the virus was laboratory-adapted to humans, perhaps following the insertion of the furin cleavage site … and subsequent passage in humanized mice (Holmes, 2024, p.10).

In Viral, Chan and Ridley devote considerable attention to documenting a notable shift in stance by Kristian Andersen and several other scientists between January and February 2020. Initially inclined to consider the possibility of a laboratory origin for SARS-CoV-2, these scientists transitioned to supporting the natural spillover theory. Chan and Ridley highlight that, in an email to Anthony Fauci on January 31, 2020, Andersen expressed that “some of the features look (potentially) like engineered” (Chan, Ridley, 2021, p.152). This shift has drawn scrutiny and has been central to discussions on the factors influencing early scientific consensus regarding the origins of SARS-CoV-2. The authors of Viral examine numerous emails between scientists, administrators, and politicians obtained through the Foia and US Right to Know. They report that Andersen had fully reversed his position by February 4, 2020, stating: “‘The main crackpot theories going around at the moment relate to this virus being somehow engineered with intent and that is demonstrably not the case’ and ‘the data conclusively show that neither [engineering for basic research or nefarious reasons] was done’” (Chan, Ridley, 2021, p.152). Chan and Ridley also explore other contradictions among scientists, including Edward Holmes, who initially considered the possibility of a lab leak before moving to support the natural spillover hypothesis. Quammen interprets these shifts as typical when dealing with a novel disease caused by a rapidly spreading, deadly virus, emphasizing that scientific progress often follows non-linear paths. Epistemologically, Quammen is correct; historically, the pursuit of scientific truth is marked by back-and-forths, changes in positions, and even complete reversals.

“The proximal origin of SARS-CoV-2” predicted that “given the level of genetic variation in the Spike protein, it is likely that a SARS-CoV-2-like virus, with partial or complete polybasic [furin] cleavage sites, will be discovered in other species” (Andersen et al., 2020, p.450). This prediction, based on the high variation and recombination in the sarbecovirus genome and ordinary evolutionary processes like natural selection and convergent evolution, has not been confirmed to date. It is important to emphasize that so far no virus has been found in bats or other mammals with sufficient genetic similarity to SARS-CoV-2 to definitively resolve the mystery of its origin. Additionally, there is no direct evidence that SARS-CoV-2 leaked from Shi’s laboratory or any other laboratory in Wuhan.

Entangled threads of geopolitics and science

As Alex de Waal notes, referencing the prominent German physician and political activist Rudolph Virchow (1821-1902): “‘Medicine is a social science, and politics is nothing but medicine at scale’” (Waal, 2021, p.50). By understanding medicine as inherently intertwined with social structures and political forces, this perspective emphasizes that health crises like the covid-19 pandemic are not solely biological events but are deeply influenced by social determinants and political choices. Virchow’s perspective suggests that these social and political dimensions are not secondary but integral to understanding the pandemic’s origin and subsequent impact on global health governance.

In Viral, Chan and Ridley take a direct and assertive stance on how the pandemic has shaped and intensified geopolitical tensions, particularly between the United States and China. One of the book’s main arguments is that China’s handling of the early stages of the pandemic, especially its secrecy about research at the WIV, exacerbated global mistrust. Chan and Ridley highlight how the Chinese government’s refusal to provide full access to data and its control over scientific narratives not only undermined international cooperation but also heightened geopolitical conflicts. They assert that this lack of transparency from China allowed the lab leak theory to become a focal point in international relations, with the US leading the charge in demanding more investigations. In this context, the lab leak hypothesis becomes not just a scientific question, but a geopolitical tool. Viral presents the origin dispute as one of the key battlegrounds in a broader struggle for influence, where China is perceived as manipulating both scientific and political narratives to avoid accountability (see also Liu, Fakhruddin, 2023). The implications are clear: if the virus did indeed originate from a lab, China’s actions would be seen as a direct threat to global health and stability. Additionally, Chan and Ridley use evidence of email communications between scientists, including Kristian Andersen, Edward Holmes and Anthony Fauci, to suggest that there was an early reluctance to consider the lab leak theory due to political pressures. This focus on internal scientific communication reveals how even within the scientific community, the debate over the virus’s origins became entangled with geopolitical concerns. The authors imply that this reluctance to pursue the lab leak hypothesis served only to further divide global powers, since it became a symbol of larger questions about accountability, transparency, and the role of international organizations like the WHO, which some argue were too reliant on Chinese cooperation.

In contrast, Breathless adopts a more nuanced and global perspective. Quammen focuses less on assigning blame or emphasizing geopolitical fault lines and more on understanding how the pandemic fits into broader patterns of zoonotic disease and planetary health. While he does not entirely dismiss the lab leak theory, Quammen leans toward the natural spillover hypothesis, placing the pandemic within the context of other zoonotic diseases such as Ebola, MERS, and SARS. Quammen argues that the uncertainty and reversals in scientific consensus – such as shifts in opinion by scientists like Kristian Andersen and Edward Holmes – are part of the scientific process, which is often messy and non-linear. This contrasts with Viral, which tends to portray these shifts as part of a broader geopolitical strategy. Quammen emphasizes that the focus should be on improving international cooperation and understanding the environmental, ecological, and evolutionary factors that lead to pandemics, rather than solely on the political and nationalistic elements of the origin debate. Breathless explores how the pandemic exposed weaknesses in global health systems and the limitations of international organizations like WHO (Delardas et al., 2022). Quammen highlights how the pandemic laid bare the fragility of global health infrastructures and inequities in vaccine distribution, which were shaped not only by geopolitics but also broader issues of global inequality. Quammen views this as symptomatic of deeper systemic issues, where the pandemic highlighted disparities between wealthy and developing nations and the challenges of ensuring global public health cooperation (see also Naseer et al., 2023).

The scientific dispute over the origin of SARS-CoV-2 remains open. Alwine et al. (2023), in an editorial published in the prestigious Journal of Virology, summarize the types of evidence that would be necessary to definitively refute either the lab leak hypothesis or the natural spillover hypothesis, emphasizing that these forms of evidence are fundamentally different in nature:

Establishing the lab leak hypothesis would require evidence that the WIV was working on a CoV [coronavirus] very closely related to the original Wuhan strain, and such evidence would have to come from laboratory records. Had the WIV been working on such a virus, evidence of a laboratory accident and/or that some of the initial cases had come from individuals at the WIV would strongly support the possibility of a lab leak. While the Chinese government has denied that such work was being done by the WIV, transparency is lacking. Unless such evidence is forthcoming, the laboratory leak hypothesis cannot be confirmed. Conclusively establishing the zoonotic hypothesis requires finding evidence of the original animal-to-human infection event(s). This is difficult because these events likely occurred unnoticed, and there may be no record of their eventuality. However, the recovery of a CoV that is closely related to SARS-CoV-2 from bats and/or intermediate hosts would support the hypothesis that the coronavirus disease 2019 (covid-19) pandemic was initiated by a zoonotic event. As discussed below, however, the needed exploration of multiple species for CoV prevalence and diversity will take time to achieve (Alwine et al., 2023, p.2).

While conclusive evidence has yet to emerge, texts continue to be published that reinforce the lab leak hypothesis, many rooted in conspiracy theories (Butter, Knight, 2023). Chan and Ridley make it clear that they reject conspiracy theories: despite exploring the possibility of a lab leak origin for SARS-CoV-2, they differentiate their analysis from unfounded claims that lack scientific basis. The authors focus on evidence-based arguments and call for transparency and thorough investigation, distancing themselves from narratives that rely on speculation rather than credible data. Several other respected scientists within the expert community including Richard Ebright, David Relman, Michael Worobey, and Jesse Bloom maintain that the lab leak hypothesis is plausible. However, Alina Chan is certainly the most vocal advocate of the lab accident conjecture. In her June 2024 article published in the New York Times, “Why the pandemic probably started in a lab, in 5 key points,” Chan presents a compelling argument for the lab leak hypothesis as the origin of SARS-CoV-2. First, Chan emphasizes the unique genetic features of the virus, such as the furin cleavage site, which she suggests could have been inserted during gain-of-function research in laboratories. Second, she points to the WIV, which was conducting experiments on coronaviruses closely related to SARS-CoV-2. These experiments, in her opinion, raise the possibility of an accidental leak. Third, she criticizes the Chinese government for failing to provide crucial data and samples from the early days of the pandemic, hindering a thorough investigation. Fourth, she points to internal communications among scientists, revealing that initial doubts about the virus’s natural origin were dismissed due to political and reputational pressures. Finally, Chan calls for an open and transparent investigation into the origins of the virus, insisting that all hypotheses (including the lab leak theory) must be thoroughly examined.

Chan’s article did not go unanswered for long. In September 2024, Alwine and over forty collaborators published a critical commentary in the Journal of Virology. They began by observing that Chan’s article in the New York Times appeared on the same day Anthony Fauci testified voluntarily before the House subcommittee investigating the covid-19 pandemic. During this session, Fauci addressed the origins of SARS-CoV-2, affirming that after thorough scientific review, most experts concluded that the virus had most likely emerged as a zoonosis (Alwine et al., 2024, p.1). The commentary by Alwine et al. (2024), entitled “The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence,” emphasizes that “while biosafety standards are critically important for research, the anxiety evoked by the lab leak hypothesis has resulted in policy proposals that, if adopted, would unnecessarily restrict essential research for vaccine and antiviral development in the US” (p.3). The authors offer a robust critique of Alina Chan’s position, asserting that despite extensive investigation, no conclusive evidence supports the lab leak hypothesis. They argue that promoting this hypothesis without substantiation risks serious harm to public health and scientific progress, potentially undermining public trust in science and health authorities. Public perception that scientists or governments may be concealing the virus’s true origins could foster skepticism toward public health directives including vaccination and preventive measures, in turn diminishing compliance and potentially exacerbating the pandemic’s impact. Furthermore, the lab leak narrative threatens to strain international relations, diverting attention and resources from critical research into zoonotic spillovers, which is crucial for preventing future outbreaks. The authors also caution that the politicization of the lab leak theory risks stifling open and objective scientific inquiry; researchers may avoid politically sensitive topics due to fear of backlash, potentially hindering advancements in pandemic prevention and preparedness (Alwine et al., 2024).

Final considerations

At this point, there is no definitive scientific conclusion regarding the origin of SARS-CoV-2. Some researchers even suggest that we may never definitely determine its origin in scientific terms due to intense genetic recombination among bat viruses, considering the possibility that the direct ancestor of this coronavirus disappeared amid numerous mutations and exchanges of genetic material (Boni et al., 2020; Mallapaty, May 2022; Teemman et al., 2023; Alwine et al., 2024). The scientific consensus leans in favor of the natural spillover hypothesis (Alwine et al., 2024; Holmes, 2024; Domingo, 2024). Extensive research (experimental as well as theoretical) has been conducted on SARS-CoV-2 since the onset of the pandemic, including computer simulations. Yet the proximate origins of a pandemic remain unclear, and the exact mechanisms through which virus populations evolve to become both prevalent and transmissible among humans are still unknown.

While the natural spillover model posits a unique transmission event, recent discussions underscore the need for a more nuanced understanding of “spillover” and the development of refined models to elucidate the origins of pandemics. The research team led by French scientist Roger Frutos argues that the concept of pathogen spillover to humans, which is widely referenced in the literature on emerging infectious diseases, is often treated as if it were scientifically substantiated. However, their systematic review reveals a profound polysemy within this term, encompassing ten distinct definitions of spillover. Moreover, most studies do not provide a clear definition of spillover, and none document a specific spillover mechanism. Only ten articles propose hypothetical models for spillover events, which remain largely conceptual (Gavotte, Gaucherel, Frutos, 2023). Frutos and colleagues propose the “circulation model,” positing that pandemic emergence stems from the convergence of two events: a genetic mutation that enhances pathogen transmissibility among mammals, and social conditions that amplify this transmissibility. Together, these conditions enable the pathogen to reach a critical infection threshold, affect a substantial number of hosts, and achieve pandemic status (Frutos, Gavotte, Devaux, 2021; Quammen, 2022; Gavotte, Gaucherel, Frutos, 2023). This model diverges from the simplistic view of direct virus transmission from animal to human populations. Quammen sheds light on this complexity in his summary:

Viruses with relatively high mutation rates and evolutionary flexibility do not generally abide in just one reservoir host. If they are animal viruses, they aren’t limited to one kind of animal. They generate a welter of genetic diversity among their viral populations, by mutation, so that swarms of loosely related viral strains can surge this way and that, exploring various niches and strategies. Such viruses circulate broadly within the animal kingdom, crossing species boundaries, infecting a range of hosts, coming to a dead end in one animal, succeeding temporarily in another animal and its contacts, probing possibilities, evolving, ready for opportunities. They are multihost viruses. In areas of the world where humans live in close contact with wild animals – rural areas, edge areas, places where people are making incursions into natural landscapes, causing outsized disturbance to ecosystems – humans will be among the variety of hosts within which such a virus circulates. What leads to an epidemic or a pandemic, the Frutos group wrote, is no single incident of an animal virus spilling over into a human, finding itself well adapted, and roaring of to infect millions more humans, but rather ‘the occurrence of a double accident.’ They meant something far different from a laboratory accident: a genetic mutation or cluster of mutations or recombination event that yields potential advantage, followed by a societal circumstance within which the advantage is well rewarded. Once that double accident happens, the chains of infection do not come to dead ends – not all of them, anyway. The prevalence of the virus rises to a critical threshold within some aggregation of people. The circulation of a restless virus within multiple hosts, including humans, plus one accident, plus a second accident, yields a new human virus – a new disease emergency. Maybe it’s an outbreak. Maybe it’s an epidemic. Maybe it becomes a pandemic (Quammen, 2022, p.291; emphasis in the original).

There is no singular origin for SARS-CoV-2. According to Frutos et al. (2022b), viruses (like all living organisms) are born from the intertwined forces of evolution and chance and shaped by the environments they inhabit. For viruses, the environment is far from a static backdrop. In Frutos’s dual circulation model, viruses do not merely inhabit hosts; they circulate across different species and ecological contexts, evolving and adapting through selective pressures unique to each environment. The interplay between virus and host thus creates a dynamic ecosystem of adaptation and mutation, where small and often imperceptible changes can have profound consequences. Pandemics arise when two forces converge: a genetic mutation that enhances pathogen transmissibility, and social conditions that amplify its spread. In the case of SARS-CoV-2, the initial jump from animals to humans represented only the beginning of a longer evolutionary pathway. Its rapid adaptation to human hosts – evidenced by high transmissibility and global spread – mirrors patterns observed in previous pandemics. For instance, the 1918 influenza virus circulated within local populations before mutating into a strain capable of precipitating a global health crisis, while human immunodeficiency virus (HIV) crossed from primates to humans and remained latent for decades until conditions favored the outbreak of the acquired immune deficiency syndrome pandemic.

The journey of SARS-CoV-2 is far from over; even now it evolves, giving rise to new variants that are ever more attuned to their hosts. As with other viruses, such as influenza or HIV, the evolutionary trajectory of SARS-CoV-2 is shaped by its interactions with diverse human populations, immune responses, and environmental and social pressures. Each new variant represents an evolutionary experiment, a test of how effectively the virus can navigate and exploit its host. The virus’s ability to adapt so swiftly to different human environments (geographical, immunological, and social) reminds us of the continuous nature of viral evolution.

The haunting question is not merely how such a virus emerged, but why it escalated into a pandemic of global proportions. Understanding pandemics requires us to move beyond biology alone. Globalization, urbanization, deforestation, and increased human-wildlife interactions have cultivated conditions where zoonotic viruses like SARS-CoV-2 are more likely to spill over into human populations. In this context, pandemics can be seen as not only the product of viral mutation but also of “social accidents,” circumstances in which human behaviors and environments create pathways for rapid transmission. Factors such as frequent international travel and dense urban settings intensify viral reach, turning isolated outbreaks into global threats. Climate change also exerts pressure, as shifting ecosystems drive animals (and the pathogens they harbor) closer to human populations, creating new opportunities for transmission. Together, these socio-environmental conditions serve as catalysts, allowing a virus with pandemic potential to flourish and spread. Covid-19’s impact consequently reflects a perfect storm of biological and social elements, revealing that pandemics are as much a product of our social structures as they are of evolutionary processes.

What actions can society take to prevent the future emergence of such viruses? Solutions extend beyond reactive measures or “magic bullets” like the development of vaccines and treatments only after a pandemic has taken hold; while these tools are essential, they alone are insufficient to address the broader environmental and socio-ecological drivers of pandemics.

Proactive strategies are, thus, imperative. Such strategies include strengthening global surveillance systems for early detection of viral threats, increasing investments in public health infrastructure, and fostering robust international cooperation. Furthermore, addressing the root causes of pandemics is crucial. Anthropogenic pressures, such as habitat destruction, wildlife trafficking, and the intensification of agricultural practices, exacerbate human-wildlife interactions, creating more opportunities for zoonotic spillover.

In the context of biological evolution, these conditions accelerate the potential for viruses to adapt and thrive in new hosts, including humans, underscoring the need for interventions that recognize the interconnectedness of ecological, biological, and societal factors. By tackling these foundational drivers, society can mitigate the emergence of future zoonotic pathogens, contributing to a more resilient and sustainable public health landscape.

Acknowledgments

Funding received from FIOTEC (PAEF III/projeto IOC-008-FIO-22).

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NOTES

• 1
  These details were obtained directly from the EcoHealth Alliance website (EcoHealth..., 3 June 2024).
• 2
  These details were obtained directly from the EcoHealth Alliance website (EcoHealth..., 3 June 2024).
• Preprint:
  Not previously published on a preprint server.
• Research data:
  Not deposited in a data repository.
• Peer review:
  Double-blind peer review.

Data availability

Not deposited in a data repository.

Publication Dates

• Publication in this collection
  09 Jan 2026
• Date of issue
  2025

History

• Received
  13 Aug 2024
• Accepted
  14 Jan 2025