The calamitous global outbreak of COVID-19 has sparked intense scrutiny of its origins. One school of thought holds that the virus emerged naturally, an example of the risks associated with a zoonotic spillover — the transmission of a pathogen from an animal host to a human host.
“We have at least a half-dozen scientific papers in the best scientific journals, including Cell and Science, which convincingly demonstrate how the SARS-2 virus [which causes COVID-19] emerged through zoonotic spillover,” wrote Dr. Peter Hotez, dean of the National School of Tropical Medicine at the Baylor College of Medicine. “In contrast, I’ve not seen a single published scientific paper on lab leak…nor even a serious scientific explanation [of] how that would occur given the scientific evidence to date.”
But the lab leak theory won’t die. Last weekend, the U.S. Central Intelligence Agency (CIA) altered its assessment, concluding – with “low confidence” — that the virus is “more likely” to have come from a lab than a bat or other animal at a wet market. So, although no new evidence has emerged, after a careful re-review of existing but still incomplete data, the CIA now leans toward the lab leak hypothesis.
The CIA’s revised view does not appear politically motivated even though the change occurred in the early days of the new administration. While it’s true that many conservatives have promoted the leak hypothesis, the finding was reached during the final month of the Biden administration after a review under then-CIA chief William Burns, according to reporting by the New York Times. In 2023, the Federal Bureau of Investigation said it favored the lab leak theory, as did a US Congress sub-committee in December 2024.
Let’s take a closer look at the science of the competing hypotheses.
Zoonotic spillovers occur when viruses jump from animal hosts to humans, often facilitated by close contact in settings like wildlife markets or large farms. The Huanan market, located in Wuhan, a city of over 12 million, was home to numerous vendors selling live animals many of them wild — including raccoon dogs, civets, and bamboo rats. Retrospective analysis of early COVID-19 cases revealed that many were linked to this market, either through direct exposure or by proximity to its location.
Among the earliest documented cases, approximately 32% had connections to the Huanan market. Spatial analysis further showed that even those without direct market links lived close to it. This geographic clustering suggests that the market served as an epicenter for the initial spread of SARS-CoV-2. In addition, genomic epidemiology supports this timeline, with the virus’s most recent common ancestor (tMRCA) traced to late November or early December 2019. There is evidence of only a limited number of human infections before the market’s role as an amplification point became apparent.
Early genomic sequences of SARS-CoV-2 fall into two lineages, A and B, which differ by only minor genetic differences. As confirmed by environmental sampling, both lineages were present in the Huanan market. This finding aligns with phylodynamic studies (the use of statistical frameworks to infer pathogen transmission from genetic data) that indicate at least two successful zoonotic spillovers. The presence of these lineages within the market underscores its role in the early transmission dynamics of the virus.
Environmental samples collected in early 2020 from various locations within the market provided critical insights. SARS-CoV-2 genetic material was detected in proximity to wildlife stalls, including those housing raccoon dogs and civets. Notably, DNA from these animals was found in SARS-CoV-2-positive samples, reinforcing the hypothesis that infected animals served as intermediate hosts. Additional animal viruses detected in the same samples highlight the potential for diverse viral spillovers in such settings.
Wildlife trade and viral emergence
Wildlife markets have long been recognized as hotspots for zoonotic spillovers due to the high density and diversity of animals often housed in unsanitary, crowded conditions. Historical precedents, such as the SARS outbreak in the early 2000s, reveal similar patterns. The parallels between these outbreaks emphasize the persistent risks posed by wildlife trade.Studies of the Huanan market’s wildlife stalls identified several species as potential intermediate hosts for SARS-CoV-2. Raccoon dogs, for example, are highly susceptible to the virus, capable of shedding it at high titers and transmitting it to other animals. Similarly, masked palm civets have shown susceptibility to related coronaviruses. While the role of other species, such as bamboo rats and Malayan porcupines, remains less clear, their presence in the market’s SARS-CoV-2-positive stalls warrants further investigation.
Advanced genomic techniques have provided a detailed picture of the market’s role in the pandemic’s origins. Sequencing and phylogenetic analyses have identified the genetic material of potential intermediate hosts and their viruses. These findings support the hypothesis that the Huanan market was not only a site of viral amplification but also a likely point of zoonotic spillover.
Interestingly, the genetic material from raccoon dogs and civets was concentrated in a specific wildlife stall that also tested positive for SARS-CoV-2. Nearby environmental samples, including from drains and animal equipment, showed higher rates of viral positivity, indicating localized shedding of the virus. Although it remains uncertain whether these animals were simply infected or served as conduits for human cases, the detection of genetic material from wildlife and the SARS-CoV-2 virus together strongly supports a zoonotic origin.
Zoonotic spillovers and the future of pandemic research
Although the CIA’s revised but still tentative conclusion ensures that the mystery of the origin of the SARS-CoV-2 virus is unlikely to ever be definitively resolved, it does underscore the need to better understand the risks associated with wildlife trade and zoonotic spillovers. The physical proximity between humans and animals in wildlife markets, particularly those dealing in live animals, creates conditions ripe for cross-species transmission of pathogens. (We have seen a similar phenomenon recently with the spillover of H5N1 avian influenza virus from poultry and cows to people who worked with them.)
The response to the pandemic has included significant policy measures aimed at curbing wildlife trade. In February 2020, China implemented a sweeping ban on the sale of wildlife for human consumption. Similar measures were taken during the SARS-CoV-1 outbreak, reflecting the recurring recognition of the public health risks posed by this practice. However, enforcement and global cooperation are, at best, suboptimal.
The identification of intermediate hosts for the SARS-CoV-2 virus remains an open question. While the Huanan market data provide a shortlist of plausible species, further studies are needed to confirm their roles in the virus’s transmission chain. Serological and virological testing of wildlife species, both in markets and farms, are essential to deepen our understanding of zoonotic pathways.
Policy measures should also extend beyond bans on wildlife trade. Other complementary strategies are needed to mitigate the risks of zoonotic spillovers, including:
- Strengthening biosecurity measures in animal markets and farms.
- Enhancing surveillance of wildlife populations for emerging pathogens.
- Promoting sustainable alternatives to wildlife trade.
- Raising public awareness about the health risks associated with wildlife consumption.
Gain of Function theory gains support
There continues to be speculation about the involvement of gain-of-function (GOF) research causing the pandemic. GOF research involves genetically modifying organisms, typically viruses, to enhance their properties, such as transmissibility, host range, or virulence, often to study potential pandemic threats and develop countermeasures.
The belief that GOF research caused the COVID-19 outbreak stems from concerns that SARS-CoV-2 could have accidentally leaked from the Wuhan Institute of Virology, where research on coronaviruses was being conducted. Proponents of this theory argue that experimental modifications could have made the virus more adaptable to humans, leading to the pandemic. That said, and despite the CIA’s tepid, “low confidence” reversal, definitive evidence proving a lab origin remains elusive, and most scientists appear to support the natural zoonotic spillover hypothesis as more likely.
Some supporters of the lab leak thesis claim that there was a cover-up of that theory because a U.S. research group, EcoHealth Alliance, had been involved with the Wuhan Institute of Virology (WIV) and received U.S. government research funds.
They allege that the WIV, assisted by EcoHealth, engaged in “gain of function” research that involved manipulating coronaviruses to see how they would respond to environmental pressures.
A 2018 grant application submitted by EcoHealth to the U.S. Defense Advanced Research Projects Agency (DARPA) that the group did want to conduct gain-of-function research that included inserting novel cleavage sites into coronaviruses in their lab. However, the application was denied because it was deemed too risky.
Still, and despite the aligned — but “low confidence” — views of the CIA and FBI, most researchers remain unconvinced. Virologist Angela Rasmussen has argued that the intense scrutiny and government oversight of GOF research make it improbable that such research on hard-to-obtain coronaviruses could occur undetected. Additionally, in a 2021 letter published in Science, a group of 18 prominent scientists emphasized the need to consider both natural and laboratory spillover hypotheses seriously until sufficient data are available, implicitly rejecting conclusions drawn without persuasive evidence.
China rejects lab leak hypothesis
Chinese authorities dismissed the CIA report as geopolitically driven. “We firmly oppose the politicization and stigmatization of the source of the virus, and once again call on everyone to respect science and stay away from conspiracy theories,” a spokesperson from China’s US embassy, Liu Pengyu, told Associated Press.
According to the Wall Street Journal, the Trump administration is preparing an executive order that would halt federal funding, at least temporarily, for “gain-of-function” research that involves altering pathogens to make them more dangerous or contagious to better understand their pandemic potential and possible vulnerabilities.
As the world continues to grapple with the consequences of the COVID-19 pandemic (and the threat of a broader outbreak of H5N1 avian influenza virus or other pathogens), addressing the root causes of pandemics will be critical to public health. Prioritizing international collaboration on research and policy — or at the very least, transparent information-sharing — will be essential to’ safeguard global health.
Henry I. Miller, a physician and molecular biologist, is the Glenn Swogger Distinguished Fellow at the American Council on Science and Health. He was the founding director of the FDA’s Office of Biotechnology
