Note: This is a freely accessible serialized version of Lab Leak Fever. Audio voiceover was AI generated for accessibility. Find an overview of all chapters here or consult the book website for further information.
A river of black drew a line through the darkening sky. Above the silver and gold ornaments on the pagoda’s crimson roofs at Wat Khao Chong Pran, the river flow turned southeast towards the fields. Rationally, I knew that the cave housed around two and a half million horseshoe bats, but observing a seemingly never-ending flood of hectic creatures fly out for more than forty-five minutes, I realized that I never truly appreciated just how many bats share the world with us.
How little did we know about them? Physiologically, bats are extraordinary; they can speed up their metabolism 16 times, creating immense heat that would denature our proteins and fry our cells. A bat’s heart can beat up to 1,000 beats per minute, but it can also slow down to 6 beats per minute during torpor, a type of short-term hibernation. During a nighttime flight, its body temperature can rise to 42°C (107.6°F). Some species tend to live up to 40 years in vast, dense, and diverse colonies, which makes them uniquely suited as hosts to almost all viral families that befall mammals. However, bats do not appear to get visibly sick, and scientists cannot tell their age past adolescence. They have unique immune systems, which we do not yet understand, that do not overreact to viral infections.
There are around 1,500 described bat species that have emerged from their last common ancestor over 60 million years ago. Because they are the only flying mammals, we conceptualize them all together under the umbrella term “bats,” as we do with “fish” in the sea. But based on genetic diversity, that simplification is rarely adequate. It feels like the equivalent of lumping giraffes and cows together with dolphins and whales, all of which diverged from a shared common Artiodactyla—even-toed ungulate—ancestor about fifty million years ago. It’s hard to justify thinking of them as the same, so why do we do it for bats?
It is not an exaggeration to claim that bats come in almost all sizes, shapes, and forms, from the thumb-sized Craseonycteris thonglongyai—also known as the bumblebee bat, weighing just 1.5 grams and holding the title of smallest mammal on earth—to various majestic flying foxes with wing spans of over 6 feet, close to two meters. Some fruit bats look almost like dog puppies you’d want to cuddle and take home, while others might appear as if they’ve escaped from a horror movie production.
The black river of horseshoe bats over my head would probably come closer to the latter for most people. We humans tend to be afraid of what we do not understand. These horseshoe bats are smaller insectivores (insect-eating bats) who get their name from the weird horseshoe-shaped disfigurement where their nose should be. Intuitively, we humans find them rather ugly—I was no exception, at least at first. I think this is partly because we assume their faces are weirdly deformed, like a fully cleft palate, rather than what they truly are: optimized. Horseshoe bats belong to a group of bats that echolocate—send out and receive sonar waves—primarily through their nostrils. Other bats rely primarily on their mouths. These varied shapes and forms in the middle of their faces, however, have intricate functionality for shaping their calls, impacting not only orientation but also their feeding and social lives, too.
Given their enormous diversity, maybe it is not a surprise that bats exist in almost all variations of social structures, from eremites who don’t want to bother with others to ones who live in small family groups, villages, or even multicultural megacities. Some like to mingle with other bat species, while others are territorial and of the “get off my lawn” persuasion, with threatening grunts, fletching teeth, and all. These horseshoe bats flying overhead were not only mixing and mingling cosmopolitans; they are also the species we know today to most prominently carry SARS-related coronaviruses, close viral cousins of both SARS-CoV-1 and SARS-CoV-2 that have caused havoc in our human world.
Does this imply that an ancestor of SARS-CoV-2 came from bats, too? Most scientists believe so. Yet ordinary bat viruses usually do not infect humans or transmit well between humans, and they are certainly unable to cause a pandemic. Something seems to be missing from our understanding, and I believe the intricate social lives of bats might hold the first valuable clue. But to get there, we have to understand some rather technical details of what makes SARS-CoV-2 so extraordinary in the first place.
Since its emergence, it has been a confusing virus for a lot of reasons. First, a novel virus is very infectious to humans and spreads effectively between them via the respiratory route. Second, it does not cause severe disease in every patient, is sometimes asymptomatic, and is subsequently hard to track. Third, side-by-side comparisons to known SARS-related viruses seem to show that the SARS-CoV-2 virus is a chimera. It has some parts with very high genetic similarity to other bat coronaviruses and other parts with low genetic similarity. On top of that, the virus has smaller but important genetic oddities, such as a novel human ACE2-receptor binding domain (RBD) and what looks like an insertion of a polybasic cleavage motif in its spike protein gene. In humans, this polybasic motif gets recognized by a protein-cutting enzyme named furin; that’s why it is better known today as the “furin cleavage site,” or FCS for short. Especially the chimeric genome, the occurrence of an FCS, and the seemingly “human-adapted RBD” gave researchers a hard time wrapping their heads around the novel virus in early 2020. Almost nobody had seen this combination of oddities before, albeit Eddie reminded me later that HKU1, a betacoronavirus from animals, also had an FCS and spread quickly among human. But SARS-CoV-2 was odd enough that even experienced virologists such as Kristian Andersen, Robert Garry, and Eddie Holmes would be driven to sound the alarm of suspicion in the murky weeks of early 2020. So, what chance did mere citizens have to make sense of the genetic intricacies of this confusing virus or assess what they mean by its origin? Especially when there is so much misleading information about them.
“It’s like a cow with deer’s head, rabbit’s ear, and monkey hands,” the bioweapon influencer Scarlett had dramatically announced these confusing features of the virus to Fox News anchor Tucker Carlson and his millions of listeners. A very false abstraction, sure, but with a kernel of truth. SARS-CoV-2 was a genetic chimera, as best scientists could tell. Its genome was made up of separate parts, like a mosaic. As the pandemic went into full swing, multiple man-made theories of varied quality were advanced on how SARS-CoV-2—and its odd genome—possibly came to be. From bioweapon development to gain-of-function research, construction from Shi Zhengli’s RaTG13 bat virus or de-novo genetic engineering to the alleged introduction of HIV sequences, from serial passage through human cells or “humanized” mice to arcane vaccine experiments, many asserted that some type of human manipulation was necessary to explain how this dangerous patchwork virus of high and low sequence similarities to other coronaviruses came about. The virus simply looked stitched together. Some of these early Frankenstein virus narratives still resonate today in public discourse and the halls of Congress. What unholy forces shaped SARS-CoV-2 into the pandemic pathogen that plagued the world? Was reckless gain-of-function research on its bat cousins indeed the culprit, or are Nicholson Baker’s “flask monsters” a mirage conjured up by fretful imagination?
As the geopolitical stalemate provoked by elites ground the international search for the origin of the pandemic to a halt, investigative journalists in the US pursued a more human-centered agenda. Believing they were on the trail of something monstrous—a potential gain-of-function virus cover-up at the highest levels—they put “Big Virology” and its government funders under the microscope. Especially the NIH, the NIAID, and its head, Dr. Anthony Fauci, as well as Peter Daszak, EcoHealth Alliance, and their collaboration with WIV—all long marked as targets by conspiracy theorists and anti-science activists—would find their every word questioned, their emails, communications, documents, and records FOIA’d, leaked, demanded by Congress, or otherwise requested.
Leading the charge among them was The Intercept, a news organization covering national security, government secrets, politics, and international affairs founded by journalists that NSA (US National Security Agency) whistleblower Edward Snowden leaked his documents to. Distrustful of the government, The Intercept released documents of a 2014 research grant named “Understanding the Risk of Bat Coronavirus Emergence” in early September 2021, claiming it provided evidence that the NIH and EcoHealth Alliance had funded dangerous gain-of-function research in Wuhan in the past. It was a dramatic allegation, given that Dr. Anthony Fauci had just had a heated exchange with Senator Rand Paul in Congress, who accused the head of NIAID of “financing gain-of-function research” in Wuhan. The Intercept reported that during this multi-year project, Peter Daszak and Shi Zhengli had worked to:
Examine the risk of future coronavirus (CoV) emergence from wildlife using in-depth field investigations across the human-wildlife interface in China, molecular characterization of novel CoVs and host receptor binding domain genes, mathematical models of transmission and evolution, and in vitro and in vivo laboratory studies of host range.
These experiments—especially the last part, some of the in vitro (using cell culture) and in vivo (using model animals like mice) experiments— were retrospectively portrayed as being reckless gain-of-function research of concern by The Intercept. The 2014 work suggested “using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice,” and many of these experiments were conducted and reported to the NIH. Zhengli and Peter also published a 2017 paper in the journal PLOS Pathogens that described the creation of two chimeric viruses—the spike gene from one bat virus was used to replace the spike gene in the genome of another bat virus—that could infect human cells in culture. How was that not damning gain-of-function research?
The NIH definition of gain-of-function research of concern only applied to experiments with viruses known to infect humans, where there was a reasonable concern that the new chimera could show “enhanced function.” This was not the case. Researchers found that, by exchanging the spike gene of these bat viruses with one of an unknown bat virus, a reduced function was to be expected rather than an enhanced one. This is because viruses need a lot more tricks up their sleeves than just a new spike protein to pose a danger to humans; otherwise, every pseudovirus experiment—recombinant backbones that cannot replicate or fulfill other essential pathogenic functions—would pose a pandemic hazard.
But then again, while bat viruses are not covered by gain-of-function rules, they are not pseudoviruses either, so the legal definition has been a subject of controversy with reasonable arguments and disagreements by experts on both sides. The point of the gain-of-function regulation was intended to provide another layer of oversight over potentially dangerous research and avoid recklessness, but guidelines can only cover the general case. Every scientist knows that each experiment must be judged individually based on its risks versus its benefits, no matter if gain-of-function or not. Animal experiments, like infecting mice with a virus, require multiple layers of oversight and feedback from veterinarians, ethics committees, and university offices. No scientist makes these decisions by themselves. Scientific exploration, by definition, often treads into the unknown; that is why there are always discussions about the details, and regulations need to constantly adapt to keep up. There was a moratorium on gain-of-function research of concern between 2014 and 2017, and a new framework covering the enhancement of pathogens with pandemic potential (ePPP) has since provided new rules, albeit hardly any less technical and complicated than the last. Everybody in the field can understand the complexities.
Yet in 2021, the perfectly complicated regulatory history surrounding evolving gain-of-function definitions and guidelines versus scientific exploration proved to be a goldmine for investigative journalists on the hunt for a scoop. It would not take long for The Intercept to unearth a supposed bombshell. In the FOIA’d annual reports that EcoHealth Alliance sent to the NIH, The Intercept discovered an experiment with chimeric bat viruses that seemed to show enhanced function, reporting:
They twice submitted summaries of their work that showed that, when in the lungs of genetically engineered mice, three altered bat coronaviruses at times reproduced far more quickly than the original virus on which they were based. The altered viruses were also somewhat more pathogenic, with one causing the mice to lose significant weight.
The details behind this decontextualized experiment were, of course, not damning at all. Sometimes the mode of infection is not linear, and the chimeric viruses initially grew faster for a day before the original bat virus caught up. That can even happen when running multiple replicates of the same bat virus. Biology is not an exact science. An NIH spokesperson would explain to the reporters that this “didn’t amount to gain-of-function because, by the end of the experiment, the amount of virus produced by the parent and chimeric strains evened out.” Either way, none of these experiments met the legal definition of gain-of-function research, which applies to the enhancement of human pathogens, not bat viruses.
But for reporters on the hunt for something monstrous, those mundane explanations were rejected. They believed they had found damning results, and they were very confident in their own interpretation of the science. Thus, they reported that the NIH was just “shifting definitions” and that there has been a long history of controversy surrounding this type of reckless research, which they now proved substantiated. Nuance and complexity are, of course, the first things to go during a heated moral panic surrounding gain-of-function research.
After months of media frenzy about a gain-of-function virus and the NIH’s alleged role in funding gain-of-function research at WIV, the information sphere was primed to deliver what the powerful wanted to hear, no matter how innocuous on its merits. The Intercept’s allegations and reporting confirmed the fears of many believers that something untoward happens in virology labs all around the world, and the vehement denial of the NIH just served as evidence that there was a concerted effort from “above” to hide this reality from the public. The conspiracy myth-entertainment complex, drunk from their recent victories in public discourse, was, of course, already three steps ahead of the evidence. If Anthony Fauci and the NIH were willing to “blatantly lie” about funding gain-of-function research, they publicly pondered, what else would they lie about? Did they know that gain-of-function research created the virus after all? Were they also involved in the cover-up?
The plot for a gain-of-function research accident seemed to thicken. “Your house of cards is collapsing, Fauci and Daszak. The reckoning is near,” DRASTIC co-founder and narrative pulse giver Yuri Deigin would proclaim on Twitter. Even mainstream discourse shapers such as the Public Affairs Professor and popular NYT columnist Zeynep Tufekci, with hundreds of thousands of followers on Twitter, got away with writing: “Working hypothesis should be that there is an extensive and sustained cover-up.” All without a shred of substantiating evidence but merely to satisfy the vibes of the moment. The only reason that no evidence for the lab leak hypothesis could be found, as she and others insinuated, is because all evidence has been covered up, and the WHO investigation was a farce.
In fact, the continued lack of evidence for a lab leak would just be considered by fervent believers to be more evidence for the alleged extensiveness of the conspiracy. But what about scientific evidence pointing in the other direction? Well, virologists had a clear conflict of interest, they alleged. Of course, these scientists could not be trusted. If science itself is to blame for the pandemic, then any scientific voice uttering protest is to be treated with suspicion! This self-sealing logic, dismissive of inconvenient scientific evidence, became the dominant opinion among popular discourse shapers, from influencers to pundits to politicians. It had the added bonus that these discourse shapers did not need to understand anything about virology to talk about it. Never let the truth get in the way of a good story, I guess.
In contrast, the scientific resistance to prevailing suspicions and accusations of a genetically engineered virus is not a sexy story but a confusing and unsatisfying one. It started small, messy, and piecemeal. More informed suggestions about how this chimeric genome came about were always available, as we learned, for example, from Jeremy Farrar’s arranged conference call in a previous chapter. While Dr. Kristian Andersen, confused and worried, laid out what he perceived as genetic oddities, Dr. Marion Koopmans and Dr. Ron Fouchier in the Netherlands, as well as Dr. Christian Drosten in Germany, would disagree. They certainly saw nothing unusual in the novel genome. In parallel, other coronavirus veterans, such as Dr. Susan Weiss from the US or SARS veterans in Hong Kong with decades of experience with that particular viral sub-family, also rejected popular notions of engineering. As more evidence emerged, their veteran assessments would ultimately be proven correct and become the dominant position in science. Yet, in the very beginning, it was a difficult argument to make against a novel virus with genetic elements nobody had previously seen. The biggest obstacle researchers faced in making the case for a natural virus was the lack of reference points, namely informative viral cousins of SARS-CoV-2. Those only gradually trickled in once the outbreak’s severity turned into a global pandemic, jolting more and more scientists into urgent action. Scientific research tends to be much slower than the news cycle. Rather than speculate on inconclusive data, many researchers set out to find related coronaviruses to assess how unusual SARS-CoV-2 really was, either by discovering neglected genomes in large biomedical databases or by directly sampling bats in nature.
The majority of researchers soon discovered (or, more appropriately, rediscovered from the pioneering work of the coronavirus experts now under general suspicion) that other SARS-related betacoronaviruses, not just SARS-CoV-2, all looked a bit weird and stitched together. For example, we previously learned about Tommy Lam’s discovery of a pangolin coronavirus sequence in a database that had an ACE2 receptor binding domain (RBD) very closely related to SARS-CoV-2’s. This is remarkable because, as Linfa Wang puts it:
The spike protein of SARS-CoV is a door knocker on human cell surface, they then have to use the CORRECT key to open the locker (the ACE2 receptor) to gain entry into human cells. Just like any other key-locker pair, it is highly specific. Remarkably, the pangolin virus also seemed equally able to bind and infect human cells like SARS-CoV-2.
We also learned from bat researcher Alice Hughes about another bat sarbecovirus—RmYN02, discovered in Mengla County, China—that had what looked like an ancestral genome to SARS-CoV-2, at least for about the first two-thirds of its entire span. The bat virus from Mengla County also contained an insertion reminiscent of the furin cleavage site at the S1/S2 boundary. If the FCS in SARS-CoV-2 stood out like a llama in a flock of sheep, Alice had somehow discovered an alpaca. Supaporn Wacharapluesadee, whose viral sampling trip with the Thai forestry department I was now on, had found another close cousin of SARS-CoV-2 with another reminiscent insertion at this critical S1/S2 boundary. Let’s call it the guanaco in the supposed flock of sheep, which looked more and more like a heterogeneous herd of related varieties.
Then a bombshell arrived in 2021. Laotian and French researchers affiliated with the Institut Pasteur in France discovered a perfect match for the human ACE2-binding RBD of SARS-CoV-2 in bat viruses in Laos; matter-of-factly christened BANAL-52 and BANAL-236 after the - bat anal - sampling method. What was going on?
Genetic engineering is not a plausible explanation for these genetic elements since they have all been discovered in wild animals. Their natural existence, first confirmed by Tommy Lam and Alice Hughes’s efforts, seemingly changed the minds of the “proximal origin” authors, including Kristian Andersen. But why? What could these diverse animal viruses that seem so closely related in one part but so distant in another tell us about the origin of SARS-CoV-2?
Here is what I learned. CoV genomes might just seem confusing or unintuitive because they are shaped by a process called viral recombination. Recombination is a mechanism for genetic exchange between two different parental viruses that creates a new viral genome containing genetic information from both original viruses. It requires two (usually distinct) viruses to be present in the same host cell.
As a useful but very imprecise abstraction, I like to think of recombination as a form of odd “virus sex” that produces unique offspring sharing a mix of parental genomic regions. Offspring that comes about by recombination is almost always a dud, meaning it cannot fulfill all essential functions necessary for the virus to replicate and infect new hosts, or is worse than the parental lineages at doing so. However, on extremely rare occasions, “virus sex” can bring forth recombinant offspring that is in some aspect better—more suited to its current or new environment—than the parental lineages. Any virus needs to constantly spread and adapt to persist; those viruses that are worse than the competition will perish. Natural selection is unforgiving. In fast-changing environments, recombination might be a good survival strategy for viruses. Gradual adaptation processes via single mutations can take a very long time to increase fitness and may be too slow to keep up with changing environmental conditions. In contrast, recombination can be considered a shot in the dark or an “evolutionary fast-forward,” where a lot of genetic changes (compared to the parental genome) happen all at once and can be put to the survival test. Extreme risk, extreme reward.
In principle, all RNA viruses can undergo recombination. But how often they actually have “virus sex” can vary from the promiscuous to the prudent, depending on the viral family and environment. Filoviridae, such as Ebola, Flaviviridae, such as Zika, and even Paramyxoviridae, like Nipah, tend to be on the prudent side, as best we can tell. Recombination does not seem to play an important role in their evolution. In contrast, HIV and coronaviruses seem to fall on the more promiscuous spectrum, and I mean freaky. Recombination, as a mechanism for genetic exchange, is not particularly picky when it comes to partner choice. From long-estranged cousins and viral strangers to incestuous siblings and even their own offspring, seemingly anything goes. Sometimes, even host RNA seems to be thrown into the mix, albeit very rarely producing viable viral progeny. While our human analogies do break down at some point, scientists can observe direct evidence for this promiscuous mingling by finding chimeric viruses with mosaic genomes. These viral genomes consist of multiple parental genetic segments from the generations that came before it; ergo, they had virus sex in the past.
Just as in humans, the genetic code in viruses is as much an instruction manual for protein production as it can be used to build family trees. While we might inherit our grandmother’s eyes or have facial features resembling our father’s forebears, chimeric viruses might inherit a gene or genomic feature that clearly comes from one side of a parental lineage but not the other. This brings us back to SARS-CoV-2. The discoveries of Alice Hughes, Supaporn Wacharapluesadee, Shi Zhengli, and Tommy Lam were the first to open our eyes to the chimeric nature of the new menace. The reason why parts of SARS-CoV-2 had patches of high similarity to these natural bat viruses found in China, Thailand, and later Laos, Cambodia, and Vietnam is simple: they are all cousins sharing partially overlapping ancestries. Sarbecoviruses belong to a big, promiscuous, partially incestuous family (technically a sub-genus), like the Habsburg dynasty that ruled various nations in Europe for centuries through a complicated web of marriages, incest, and inheritance. Both genetic family trees provide evidence for shared ancestors, historical sexual encounters, and the occasional indiscretion leading to newly acquired genetic segments.
The discovery of multiple sarbecovirus cousins in nature dispels naive notions that SARS-CoV-2 is a “unique” Frankenvirus. Because of their shared recombinant ancestry, all discovered viral relatives of SARS-CoV-2 looked equally stitched together from separate parts. Being a chimera with a mosaic genome runs in their family, so to speak, like the Habsburg jaw. I believe this basic observation is critical to understand because this type of genetic family history cannot be faked or recreated in a laboratory. It requires a colorful mingling of many natural sarbecoviruses, most of them undiscovered, whose promiscuous excesses go back and leave a genomic record for decades. Scientists know for certain that SARS-CoV-2 was not stitched together artificially because nobody had all the segments to stitch it together; even today, we have not discovered every required relative to do so.
The recombinant sarbecovirus dynasty found in nature also makes unequivocally clear that at some point in its very recent history, a naturally evolved, immediate bat ancestor to SARS-CoV-2 must have existed. This particular deadly chimera did not spring from a computer sequence, was not dreamt up by a mad scientist, or was not recklessly assembled from disparate parts in a lab. The bat ancestor evolved in nature. Technically, this fact does not exclude the possibility that this bat ancestor could have been found by researchers, brought into the lab, and tinkered with. Recombination has a limited resolution; it cannot see if single mutations were artificially introduced. But on the larger genetic makeup, the recombinant mosaic genome tells us that the SARS-CoV-2 bat ancestor already must have looked a lot like the virus that emerged in Wuhan and that this ancestor came about as naturally as all of its countless cousins still out there, yet to be discovered.
The black river of bats over my head now stretched over kilometers from the cave exit towards the distance, with no end in sight. With so many hosts in this single cave, just how many bat-borne viruses are out there? How many recombinant cousins of SARS-CoV-2 are still awaiting discovery?
“This sight just makes clear how plentiful nature is and how small labs are in comparison”
A voice next to me uttered. It belonged to Linfa Wang from the Duke-NUS Medical University in Singapore, who also watched the fly-out at Ratchaburi in awe. If Shi Zhengli’s research at WIV has endowed her with the moniker “the Batwoman,” Linfa Wang was the original Batman. The timid-looking and unassuming researcher was a true pioneer, an explorer. He took a scientific gamble 30 years ago on studying bat-borne viruses that would come to shake the world at an ever-accelerating pace. A shot in the dark at the time has hit the nail on the head of our current conundrum.
We started chatting about how he fell into this mess. “Funnily enough, it’s the viruses that led me to the bats,” he chuckled. Growing up in communist China during and after the Cultural Revolution, in a family that did not even own a book, he originally wanted to pursue his dream of engineering because engineers could build something useful. Yet, when he reached university age, he was assigned to the biology program at a first-tier school, the East China Normal University in Shanghai, due to his test scores. He didn’t really like biology, so he specialized in biochemistry because it was the furthest away from zoology and living things. For his PhD in California, he studied transcription regulation in bacteria, a very mechanistic topic and the basis for what one might consider modern-day biological engineering. Biology repurposed to build something useful, one might say. Because he was very good at molecular cloning—a way to construct smallish genetic segments such as bacterial or viral genomes—other departments came around asking him for assistance. In a collaborative spirit, he would also construct some of their test organisms, including viruses that infected animals. With that coincidental virus cloning expertise, he suddenly found himself headhunted to work at the Australian Animal Health Laboratory, which was concerned about viral threats to livestock and pathogens that could jump into animals. The Australian laboratory had a remarkable, cutting-edge biosafety facility for research that enticed the young scientist to stay and specialize in virology. There, his curiosity for viruses would be ignited.
Just a few years later, in 1994, the Australian Hendra virus outbreak happened, and his team was on the case, which ultimately led them on an origins hunt from sick horses to Hendra’s host reservoir, large fruit bats. He keeps joking that he does not believe in fate, but his research trajectory certainly seems driven by serendipity. Linfa’s team would soon be dealing with some of the most dangerous bat-borne viruses in the world, including Nipah (Malaysia and Bangladesh variants), Ebola, and Marburg viruses, then SARS and MERS, all at Australia’s BSL-4 laboratory in Geelong, Victoria (at the time, the world’s largest). The first SARS outbreak in November 2002 specifically brought Linfa on a quest to understand where these dangerous zoonotic viruses originated and spilled over. This is when he started approaching Zhengli in China and Peter from EcoHealth Alliance for his quest. A quest that would ultimately lead to all of them being unjustly blamed for a danger they had recognized earlier and warned people about. What were the three of them doing all these years? Why would Zhengli’s lab be mired in gain-of-function allegations and fears of having created the virus?
Initially, Linfa had a hunch to look at bats as a potential host reservoir for SARS. To do that, he needed someone in China who would be willing to go out and sample bats for viruses. That someone was Shi Zhengli. “In the beginning, we did not know where to get started,” Zhengli would later reveal to me. Soon after the pandemic started and Zhengli was blamed, the Batwoman seemingly disappeared behind a wall of silence. “Every time she gives interviews, she gets into trouble,” Linfa offered as an explanation to why Zhengli had become very selective in speaking up. After a few initial email exchanges with reporters early on, where many of her words were twisted and where they wanted her to defend against allegations, Zhengli completely gave up. For years, she has not left China or given interviews to outsiders.
Yet, I believed it was important to learn how she became involved in Linfa’s SARS host search and what drove her research that was now being portrayed as so controversial. After I wrote a very thorough blog post on recombination, I sent it to her, asking if maybe we could chat about her work. I believe my scientific writing created some trust for an honest conversation, and the warm virologist opened up to me for an interview. She explained that when they started, all they had to go on were previous experiences. “Nipah, Hendra, all these viruses are carried by fruit bats. So, our first journey went to the Southwest of China, Guangxi Province, these warm regions that have fruit bats.” They sampled the fruit bats for eight months and took the samples to the laboratory to do PCR testing. “But nothing,” Zhengli exclaimed, throwing her hands in the air. Again and again, they continued to try with the same approach and failed. “That was a mistake,” she recounted lightheartedly. Contrary to Dr. Gao, the Batwoman seemed to have no face-saving issues by being so explicit about past naiveté or errors. It’s just science; doing something that nobody has tried before often fails before it works. Zhengli had to change strategy, going for serological testing that would not only discover acute infection but also evidence of past infections. Viral infections are short-lived; they rampage through a population and burn out. Serology gave Zhengli a bigger time window to catch these transient viruses. They also needed to expand what bat species they explored.
Yet, the magnitude of the task still seemed crazy to me. There are billions of bats in China; how would they ever find the right ones? At this point, her face began brightening up, and while emphasizing every syllable with her hands, she started laughing about their desperation after months of failure. “It is completely random sampling,” Zhengli explained. She was delighted in the fact I understood what a shot in the dark it truely was. It was too ambitious and maybe too overly hopeful. Yet serendipity would intervene. Upon testing the new experimental setup and catching a few local insectivorous horseshoe bats in Hubei Province—Zhengli’s home turf—she finally got a signal. They found three bats that tested positive in their serological test. They took the samples for PCR analysis, and they got one short sequence of the RdRp gene out of one of the samples. A sensation: these bats had encountered a SARS-related virus, albeit a very, very distantly related one. Zhengli had found a target—a candidate host species. Over the next years, she and her team would travel to all of China’s dozens of provinces to catch horseshoe bats, and in many of them, other distant SARS-related CoVs would turn up. No province had closer matches to the original SARS virus than Yunnan in southern China, so she strengthened her efforts there.
Then, just on the outskirts of Kunming, Zhengli narrowed in on one particular site called the Shitou cave. Over the next five years, she would collect bat droppings from there and PCR test them. A longitudinal survey. Then she would begin sequencing promising samples. This way, she would discover evidence of many novel chimeric sarbecoviruses circulating in bats, all of them harmless to humans. She never found a virus quite like SARS-CoV-1. Yet, collectively, the Shitou cave would constitute a sort of natural library for genetic segments closely matching the original SARS virus found in civets in Guangdong that caused the 2002 outbreak. After more painstaking work, Zhengli would eventually discover that all the genetic elements of the dangerous SARS virus were around in this cave, ready to mingle with each other. This region was the birthplace of the viral ancestor that would become SARS.
This brings us back to “virus sex”—recombination—and how it might pose a danger to human health. In sarbecoviruses, the spike gene, a medium-sized genomic segment responsible for cell entry into host cells, shows a high diversity of sequences. The spike gene also has recombination breakpoints within and surrounding it, making this segment very susceptible for genetic exchange. High sequence diversity means that viruses might have a wide range of possible functions that can arise from them.
If we think of general genetic diversity as “potential for new functionalities” and recombination as a mechanism to “shuffle varied genome segments” around, some alarm bells should be ringing. These are the requirements for some pretty reckless and chaotic “gain-of-function” experiments conducted within bat hosts by nature on a daily basis. With the discovery of more and more chimeric sarbecovirus genomes over the years, Zhengli and other scientists became increasingly worried. In essence, they were observing direct evidence of countless potential “gain-of-function” experiments that must have happened in the past. The Shitou cave and places like it are genetic cauldrons that facilitate the (re)combinatorial mixing of diverse “evolutionary fast-forwards” while applying selection pressures where only the fittest offspring genomes survive. The true scale of these gain-of-function experiments is mostly hidden from our observation within the remoteness of these bat caves. Is it millions? Billions? Trillions? How likely was it for these natural “gain-of-function” experiments to bring forth elaborate traits, such as the skill to infect humans?
This is what the bat pioneers surrounding Linfa Wang, Peter Daszak, and Shi Zhengli wanted to find out. Zhengli and her team were the first and only ones to ever isolate a live bat sarbecovirus from fecal pellets in the Shitou cave. They named it WIV1 in honor of the institute. WIV1 stood out because it had a 95.6% identity to SARS and was an almost perfect match to the amino acid sequence for the S1 region of the spike gene. Subsequent cell culture experiments would show that, just like SARS, WIV1 had a broad species tropism and could use human, civet, and bat ACE2 receptors for entry. It had unlocked the door to cross-species infection. A sensational—and worrying—discovery. While Zhengli never found a bat virus closer than 96.8% to SARS-CoV-1, her discoveries still concluded the decade-long search for the natural reservoir and origin of SARS. It was horseshoe bats from the Karst region of southern China.
After that impactful discovery in 2013, Shi Zhengli, Linfa Wang, and Peter Daszak began to warn the world. Bat viruses like WIV1, while not causing human pathology and not shown to infect humans, could, at a minimum, infect human cells in culture. Collaborators from the Baric Lab at the University of North Carolina—working with the WIV1 virus and Zhengli—would later argue that this makes bat viruses like WIV1 potentially poised for emergence. But how exactly would that work?
For a long time, nobody knew. Even today, not all the mysteries of emergence have been solved. That’s why Shi Zhengli and Peter Daszak were so keen on studying wild spike gene sequences in pseudovirus systems; to perform binding assays with RBDs they discovered in the wild and orthologues of various ACE2 receptors, even create simple chimeras, and test their pathogenicity in mice carrying a human ACE2 receptor. None of these experiments are considered “gain-of-function” by the NIH after review, nor are they reckless or dangerous to humans, as scientifically ignorant reporters at The Intercept and pundits pretty much everywhere else were now suggesting. These types of experiments on bat viruses, such as RaTG13 or other close cousins, could never have created SARS-CoV-2. It’s hard to see why these unrelated and irrelevant experiments suddenly needed to be re-litigated on the world stage in 2021. Virology is not magic, and a human pandemic pathogen is very different from a bat virus. Details matter, especially on technical topics. Maybe reporters were not driven by ignorance but rather active lack of curiosity in what the “conflict of interest”-ridden virologists were trying to explain when they had a scoop to sell?
To uphold the pretense of journalistic neutrality, The Intercept would quote an expert accurately denying that there was any reason for concern with Zhengli’s experiments but then frame the story to be damning against this type of research either way, often with the help of contrarian “experts.” First and foremost, of course, was the credentialed lab leak influencer and now resurgent media darling Dr. Alina Chan. “The contents of the grants raise serious questions about the review processes and oversight relating to risky pathogen research,” she would readily supply whatever quotes the journalists likely wanted to hear. That Dr. Chan has no experience or expertise in biosafety regulation, risky pathogen research, or even just virology was conveniently ignored by the amplifiers.
Everybody loved to weigh in on the topic that seemed so intuitively bad to us: scientists supposedly tinkering with dangerous viruses that can infect human cells. Whenever there is a demand for popular sentiment, the information sphere will deliver. Soon, even more established biosafety advocates, who had an axe to grind with virology for a long time, finally saw an opportunity to have the world see it their way. The British-French virologist Simon Wain Hobson believes that “virologists are making the world more dangerous” and that gain-of-function research has inexcusable risks while offering little benefits. “GOF influenza research may well be just one small step for virology; the problem is it’s a giant risk for mankind,” he has dramatically argued since 2013. “The only impact of this work is the creation, in a lab, of a new, non-natural risk,” Richard Ebright, another advocate affiliated with Rutgers University, agreed with him. Zhengli’s work has been a thorn in their eyes since 2015, and now that the contrarians had the public’s attention, they would not waste their chance. Especially Richard Ebright, a bacterial microbiologist with in my eyes no discernible expertise, publications, or understanding in virology, bizarrely became one of the most quoted supposed “experts” in the COVID-19 origins debate, with dozens, if not hundreds, of newspaper articles featuring his commentary.
No “mainstream” virologist who actually published on the topic of viral emergence or SARS-CoV-2 specifically would ever be given the same media exposure. “I had gotten one op-ed in NYT and two in The Guardian, I think, talking about the danger of ecosystem destruction and zoonoses,” Peter Daszak recalled. But now, “nobody wants me to talk about this stuff anymore,” he told me. “What changed?” I asked. Everybody just wants him to defend “his side of the story” when it comes to an alleged lab leak and gain-of-function research. After more than a year of unsatisfying repetition from experts that this was most likely a natural virus, there was a much greater hunger in the information sphere for “new experts”, people like Simon Wain Hobson or credentialed contrarians like Alina Chan and Richard Ebright, or even the conspiracy theorists from the DRASTIC amateur collective. Their relentless advocacy and amplification in the media led to tangible impacts on popular discourse. Gain-of-function became a dirty phrase, a moral panic, and any type of related virology research allegedly posed unjustifiable high risks while not providing any tangible benefits. It needs to be shut down for good, even banned worldwide, as tabloids like the Daily Mail would suggest. But do these tabloids, influencers, contrarians, and pundits really understand the risks, benefits, and stakes of these experiments better than the whole field of virology?
In reality, there is little factual support for contrarian notions, as best I can tell. Zhengli’s exploratory experiments with bat viruses had negligible risk while offering some critically important knowledge. Her research team provided evidence that it was possible for some natural bat viruses to jump species and directly infect human or other mammal cells, sometimes very efficiently. She provided mechanistic details about the role of the spike protein that would later come in handy for designing vaccines and testing new therapies against COVID-19. She also showed that sarbecoviruses were masters at switching genetic elements. In fact, once the genetic keys to human infections were circulating in a bat population, Zhengli, Peter, and Linfa had responsibly warned the world that viral recombination would facilitate the creation of new dangerous chimeras and make their spillover into humanity likely. But how likely exactly?
This question, more than any other, is what drove me away from the heated media frenzies and moral panics of the West into the calm heart of the Southeast Asian Karst region. A biodiverse Wild-Wild East, two and a half times the size of Germany and spanning parts of southern China, Myanmar, Laos, Vietnam, Cambodia, and Thailand, even bits of Malaysia. Karst mountains are created by erosion of soluble carbonate rocks over time. However, it is truly the power of water that, over eons, has shaped the landscape to include spiky spires, enormous sinkholes, underground rivers, and intricate cave systems below the old-growth subtropical forests and rainforests. In other words, this was bat country, and each valley and limestone formation can not only house millions of bats but is a microcosm in itself. “Each isolated limestone hill can host more than 12 unique species found nowhere else on earth, with up to 100 micro-snails, endemic begonias, orchids, and geckos, and yet an estimated 90% of cave-dependent species are undescribed,” conservation biologist, bat researcher, and real-life nature encyclopedia Prof. Alice Hughes had explained to me. “Cave scorpions, snakes, parasites, glow worms,” to her, caves were still a terra incognita for scientific exploration.
Queasy, I now looked up at the wall, wary of scorpions, spiders, and other critters. Despite the romance of exploration, caving was certainly not my favorite activity. Peter Daszak, Chinese journalist Jane Qiu, and I had gotten up at five in the morning to go visit the main entrance to Ratchaburi cave, which is where, on this Saturday, the guano collectors arrived. Once a week, they would go in to collect the nitrogen- and phosphorus-rich bat excrements. It was a potent fertilizer that sold well. Researchers from the Thai forestry department handed me a full-body Tyvek suit—those that resemble white plastic bags and have become all too common during the pandemic. I put the Tyvek’s hoodie over my hat, protective glasses, and PPE mask before zipping it tight. I had no interest in leaving any Achilles heel open for potential contamination.
When we climbed into the cave, a wave of heat and slippery rocks covered in bat excrement awaited us. I ventured in farther, accompanied only by a mixture of light and darkness, as well as the eerie sound of thousands of bats flying, disturbed by our human presence. Peter and Jane, similarly protected, were not far behind. The stench of bat urine and excrement burned up my nostrils in a violent fashion, making me think twice about this endeavor.
We went all the way into what Peter called the “reactor core,” a natural cave pillar where disturbed bats kept circling around. Within the gigantic antechamber, I had to climb up a few meters of steep slope to get as close as possible to the bat reactor, right next to where a guano farmer was filling up his sizable cotton container with a tiny shuffle. Four other containers were already filled and awaiting transport in the middle of the antechamber. The chamber’s roof was broken in on one side, and the sunrise outside illuminated the cave, making me realize that a constant drip of liquids had accompanied me like rain. How much of that was moisture condensation from the cave walls, and how much came from the disturbed bat swarm circling above me? I would rather not contemplate that too deeply. Many bat viruses are shed via urine and excrement; even coronaviruses in bats are thought to be mostly adapted to gut- and gastrointestinal microenvironments, not the respiratory system. A bat coughing in your face is possibly much less of a risk than you touching your nose or eyes with excrement-sullied hands. Pulling my head cover even closer over my masked face, I was certainly very happy for my full protection gear.
Viral recombination always seems abstract, almost like a freak accident, when two different viruses happen to come together in the same host to infect the same cell. But just standing for a minute in the “reactor core,” under the hectic buzzing of their rhinolophid host reservoir, I got the visceral impression that this specific type of genetic exchange is potentially much more common in sarbecoviruses than we might appreciate today. We underestimate the vastness of nature at our own peril.
Maybe the extent and evolutionary role of “virus sex” is one of the most important clues to the puzzle of SARS-CoV-2’s confusing genome and biology—the one piece of knowledge that our public understanding has been missing. We do not get to visit those remote caves; we do not observe millions of bats mingling with one another. We do not intuitively comprehend the environment they live in. There is growing evidence that the lives of sarbecoviruses’ primary hosts, the rhinolophids—horseshoe bats with these nightmarish odd nostrils—are not only a lot more cosmopolitan than the average bat, but they are also a lot more socially intricate. Horseshoe bats vary in nostril shapes because that allows them to specialize in echolocation at very wide ranges of frequencies. Researchers have found that bat echolocation is not only used for orientation and hunting but also for communication and vocal learning. Some of the bat’s extensive vocal repertoire is needed to create specialized social calls used either for parent-offspring reunions, territorial defense, or maintaining group integration. Rhinolophids not only tend to speak a lot, but they also have many different dialects and even different languages, which have a profound impact on their social lives and mating behavior. Some speculate that the evolution and observed differentiation of vocal frequencies over time within a species leads to mating preferences and exclusions, driving genetic niche formation and ultimate species separation into species complexes.
This constant genetic stratification of their host reservoir is a challenge for viruses. Some sarbecoviruses will be driven to specialize in a small niche or subgroup of the species complex by selection forces, whereas other viruses might develop or maintain broad affinity to multiple bat species that might inhabit the same spaces. Specializing in a niche gives viruses a competitive advantage in that niche, but having a broad affinity allows viruses to jump between different hosts in their physical environment. Broad affinity might not be strictly limited to different horseshoe bat species; in fact, host-jumping into other bat species might, in turn, create more viral diversity. Recombination only requires two viruses to infect the same cell; parental viruses cannot create offspring if they never meet, but their offspring might also not be as diverse if they never meet very distinct others.
“So how do these hypersocial rhinolophids do on the ‘meeting new people’ front?” I had asked Prof. Alice Hughes back in Zurich. The bat researcher had seen it all. She responded:
Some of those different species will roost together, especially when it is cooler or during hibernation. So, when we have done work in various cooler caves, we will see clusters. Rhinolophus [horseshoe bats] cuddled up to Miniopterus [long-winged bats], and the next one is Myotis [mouse-eared bats]. Now, these are lineages that diverged 50 million years ago.
Soon after, Alice was involved in a paper discovering a new SARS-CoV-1 relative in a myotis bat, substantiating her point that SARS-like viruses can jump to other bat species hosts and circulate there.
Beyond mere cuddling with strangers, bats are also known to switch roosts constantly. There are maternity-only roosts, summer and winter locations, and roosts that are calm or have special geographic features. Some bats like to stay and guard the house cave; others cycle outside but come back periodically over the year (maybe kids going to college would be a social analogy, if only we could tell bat age, that is); and many bats do food tourism with the seasons. All of this leads to constant turnover, with various bat species mixing and mingling with each other. No matter how one looks at it, it seems that there is a colorful and complex social, seasonal, and geographic mixing of various bat species, even when just studying single locations, like a specific cave or a forest. Zhengli had found dozens of SARS-CoV-1-related viruses in the Shitou cave. And Alice? Her “home cave” in Xishuangbanna botanical garden, where she did longitudinal sampling, had housed many different bat species that changed over time. She assumed some of the cave characteristics, like a long, high chimney-like exit, were very attractive to multiple species, so they competed for the space. In early 2020, Alice discovered four additional SARS-CoV-2-related viruses in her institute’s backyard before her work was shut down by the authorities and the cave walled off. Where are those bats now?
Bats tend to move and mingle. Some of this has always been a natural part of bat life. More recently, however, human encroachment on bat territory—urbanization, deforestation, hunting, tourism, mining, etc.—is considered the biggest factor in displacing bats from their traditional roost sites and forcing species together that might not have ordinarily met. If some bat species that diverged millions of years ago often tend to huddle together—and we already learned that the sequence diversity in spike genes is very high—do the diverse viruses they carry infect each other and influence recombination patterns as well?
This is one question researchers were able to answer recently with a resounding yes. Using a meta-transcriptomics approach (taking a sample and sequencing every single piece of genetic information in it), they discovered that many of the bats they sampled carried more than one virus. On top of that, the study found that some of the discovered viruses were shared between different bat species, suggesting frequent spillover events distributed the virome over multiple hosts. This represents a dramatic opportunity for virus sex (recombination) and the diversification of the viral gene pool with new genetic elements. A chaotic genetic cauldron.
It is reasonable to assume that the intricate population structures, broad social interactions, and geographic migrations of rhinolophids all come together to exert strong evolutionary pressures for sarbecoviruses to constantly adapt to new environmental niches. Recombination, as an “evolutionary fast-forward,” is the only mechanism by which sarbecoviruses can survive in such a chaotic and fast-paced environment, which is why this is such a prominent and critical feature in their evolution. In other words, we should not be surprised to find a complex mosaic within the genomes of sarbecoviruses because it reflects the complex mosaic of bat and virus co-evolution. A constant fight for niche survival against the merciless competition of ever-changing circumstances, one where only the most opportune genetic elements and fittest chimeric viruses will persist. These biodiverse caves and social bats are nature’s vast “gain-of-function” laboratory that we should worry about when it comes to birthing dangerous new viruses. Nature can create diversity we can hardly fathom. On top of that, our human encroachment on bat territory is stirring that particular genetic cauldron ever faster, enabling the spillover and emergence of these diverse and dangerous viruses in us.
In our current discourse, concerns about these natural gain-of-function labs are completely absent. No online crowd, hungry influencer, or populist politician has figured out how to profit from their existence. In fact, many ignore or deny that they exist to make the laboratory “gain-of-function research” idea more salient. Yet, should we somehow worry less about dangerous viruses created by our human mingling with natural ecosystems? Do biosafety risks magically evaporate outside of research labs? Why does the persistent danger of zoonoses not factor in when assessing the real risk versus benefit of Zhengli’s work trying to understand what happens in the wild?
The guano harvesters next to me had only a simple towel wrapped around their heads; many had no mask or, at most, a simple cotton sheet over their mouths and noses; nobody next to me wore any glasses, gloves, or other protective gear. They were barefoot or with sandals, T-shirts, and some light pants. One started carrying out bags of guano over his head, some of its finer dust falling down on his face as he stumbled along the rocky climb in the semi-darkness. Outside, the guano kept piling up into separate little hills in a small marketplace. It seems many more people were involved in judging the quality, assessing the yield, and filling the guano with little shuffles and even bare hands into smaller bags to be sold to farmers as well as bigger distributors. Some negotiations about price seemed to happen right there, outside the cave. The monks were also involved in the guano business.
Asking how many of the participants have antibodies against various CoVs in the blood is a tricky and controversial question. We were told that the scientists studying it, like Supaporn Wacharapluesadee, had to sample these guano collectors quietly to not raise too much awareness and ill will from authorities. Of course, there are medical privacy issues, public relations concerns for the Thai government, and the economic prospect of the allegedly corrupt monks who charged thousands of dollars to rent out collecting patches to the guano collectors. Nobody wants scientists to make a fuss about the potential dangers of this lucrative arrangement between religious worship, economic windfall, tourism, and cultural tradition. Especially not on such a politically sensitive topic. We were the intruders to be eyed skeptically. None of us came to lecture, but rather to understand, experience, and take to heart the lived reality of millions of humans who rely on the biodiverse Karst region for livelihood, community, or intellectual sustenance. All human-animal interfaces can be observed from two sides: the human and the animal. We do no one justice by downplaying one in favor of the other. “From my point of view, we should focus on some hot spots,” Zhengli said, explaining why she believed a more comprehensive approach towards risky animal-human interfaces was necessary. She continued:
We should do surveillance not just of wildlife but also domestic animals and the people that are highly exposed to domestic animals. I think the whole ecological change we should pay attention to. I am trying to persuade the policymakers to pay attention.
“It’s not the bat’s fault. They have been with these viruses for millions of years,” Linfa Wang elaborated on our tendency to focus blame on the wrong culprits. In recent years, the pioneer had ventured into another unchartered territory: bat immunology. His colleagues had asked if he was crazy; said he would tank his career and not make any progress; there just are no tools around to even study immunology in the flying mammals. However, Linfa needed to understand. “Bats did not evolve to carry viruses,” he reasoned. Something made their immune systems special to deal with them—defend but not overreact. He speculated that the adaptation to flight is what made bats’ immune systems so hardened. “Flight is a very stressful activity. If bats had the same system as us, they would get sick every night after flight.” Most mammals, including humans, are different. “We need inflammation for defense, but out of control, it is bad for us. The human immune system kills yourself.” Linfa believes that if we can learn lessons from bat immune systems, it will help us temper and modulate our overreacting immune system in the long run. Our immune system is involved in almost all diseases; if we find ways to better regulate it, medical benefits could be large. “We believe it has everything to do with a long life, less cancer, and better dealing with viral infections,” he offered an optimistic vision of where better knowledge of our distant flying cousins could lead us. We should shed the idea that only bad and evil can come from the only flying mammals just because they carry these deadly viruses—at least deadly for us humans with our subpar immune systems. Why blame them for our weaknesses?
“It’s really us, the disturbing of habitats, the recent farming practices, climate change…” Linfa Wang would trail off. “Bats and humans don’t have very close contact... until recently,” he added after a short pause.
Scientific studies, including some conducted by EcoHealth Alliance, estimate that tens of thousands of spillover events happen every year, most of them from bat coronaviruses that have yet to be discovered and that do not cause an outbreak for a variety of reasons. “The spillover from bats to humans is always very, very low frequency for two reasons. First, bats don’t shed high levels of virus, and second, most are viruses that are not ready to jump.” Linfa Wang would explain this paradox. He offered the Hendra virus as an example. Bats transmit it through urine, so prevalence can be assessed easily by laying out plastic sheets for collection. He found that only 1-3% of bats had detectable levels of virus shedding, always with very low titers. “But if you do serology, you can go all the way to 45% prevalence” in the population. It seemed that, in bats, “viruses don’t need to replicate to high levels because they can propagate” even with very low amounts around. That is why bats do not appear sick even when infected; their special immune system has a good grip on viral infections. Low viral titers in turn reduce risks of spillover to other mammals, including humans. The bat immunologist offered his take on this uncomfortable reality, saying, “If bats would carry high levels of viruses, like we do in our nose, I always say the human population would have been wiped out by now.”
This also implies that we better not stress the bats too much. Stress reduces immune defenses, which seems to be universal for bats, our farmed animals, and humans alike. When bat immunity drops, viral titers—and with it, shedding and spillover risk—rise. In the end, we create our own misery by creating risky animal-human interfaces that are so conducive to spillover and transmission. “Retrospectively, when they sampled the Nipah outbreak in Malaysia, it was also two lineages,” Linfa recalled. Meaning there were at least two distinct introduction events that would ultimately be responsible for the Malaysian Nipah outbreak, possibly many more that did not cause onward transmission chains. The combination of bats, attracted by human-made continuous food source, right in proximity to susceptible pigs that are rapidly bred, weaned off and sold at high frequency, provided a fertile ground for the emergence of Nipah. Today, Linfa and others have every reason to believe that our displacements of horseshoe bats in the Karst region, together with human encroachment into bat territory, might exert a similar pressure on the sarbecovirus hosts, leading to more and more spillover events in the region.
So why do we see so few outbreaks of novel coronaviruses if serological surveys already provide evidence for thousands of spillovers every year? “Most are viruses that are not ready to jump,” Linfa had said before. These are not human pathogens. I think we laymen have a bit of a naive understanding of all the obstacles viruses have to surpass in order to cause an outbreak in humans. There are a series of barriers and filters that have to be overcome. The vast majority of bat coronaviruses that spill over just might not be able to enter human cells very efficiently. Even those that can enter efficiently might not replicate well in the host cell or get shut down by our innate human host defense, such as the interferon pathway, without humans ever being the wiser. Even well-infecting and replicating viruses, such as WIV1, which Zhengli discovered and that can partially evade the interferon pathway and therefore might potentially make humans sick, still cannot spread between their novel hosts.
Transmission is extremely complex—something scientists do not yet understand sufficiently on a mechanistic and molecular level, and they certainly cannot yet design for it. Only nature has figured that part out so far. Even if some genetic jackpot viruses somehow manage to surmount all the prior obstacles and succeed with human-to-human transmission, they might still be unable to spread effectively enough to cause a sustained outbreak. A potential pandemic pathogen would need to be infectious enough to infect fresh hosts quicker than it runs out of steam. On top of that, outbreaks are also always social phenomena. Even a perfectly capable pandemic virus—like the SARS-CoV-2—would have died out by itself with a very high likelihood if it had spilled over in a remote village rather than in a Chinese megacity that supplied countless immune-naive hosts.
Whether these sarbecovirus spillovers happen directly from the bats, or rather via an intermediate animal, like the pigs for Nipah, is also an open question. Both routes are possible and plausible, with outbreaks of novel viruses in farm animals being even more common than in humans and some evidence suggesting intermediate animal hosts being necessary incubators for bat viruses to become human pathogens. Most spillover events are not observed or documented. Scientists only know about their presence from bat sampling efforts and seroprevalence studies in humans, such as the guano harvesters or locals in contact with wildlife, in certain regions where such spillovers are assumed. However, even geographically, we have gigantic blank spots on the map. Regions like the remote, forest-covered, and mountainous areas of northern Thailand, which borders Myanmar and Laos, are all mostly uncharted territory.
“If you give me a billion dollars to find the origin, I would spend 90% of that looking outside of China in Southeast Asia,” Linfa offered his estimate. According to him, there is just so little known about bat diversity here compared to China, where Zhengli, Alice Hughes, the Chinese Academy of Science, the Institut Pasteur, and others have done much more sampling work. The discovery of the Laotian BANAL viruses, the closest bat relatives to SARS-CoV-2 until today, certainly argue for increasing efforts in this region. Today, the Karst region’s unique and biodiverse ecosystem is, in considerable parts, still relatively untouched by humans. This has been changing fast in recent years, especially with deforestation, slash-and-burn cash crop agriculture, and economic development leading to the degradation of the old forests and more human-animal interactions. Even outside of disease prevention, the Karst region’s importance to the global climate and biodiversity conservation is probably second only to the Amazon rainforest, with projections suggesting around 40% loss by the end of the century. A worrying development. Our human encroachment and disruption of bat ecosystems here make the whole region one of the prime hotspots for zoonotic spillover, as scientists like Linfa Wang, Shi Zhengli, Peter Daszak, Supaporn Wacharapluesadee, Alice Hughes, and their many regional and international collaborators have found. They argue that we need more bat sampling and domestic animal surveillance, not less, to better approximate disease risks and guard against them in the future. I agree.
It has been said that science can be a humbling experience. How little we know about the true scope of viral diversity out there seemed conceptually clear to me before I came to meet the virus hunters in Thailand. Yet somehow—even after reading the relevant papers, studies, and estimates—the reality and complexity of that effort did not fully sink in until I was standing at Ratchaburi. That black river in the sky still continued to fly out, twisting and turning like a pencil stroke during a bizarre calligraphy exercise. Meanwhile, after multiple hours of painstaking work capturing some of the bats flying out, the field researchers’ most demanding tasks were still ahead of them. Setting up a nearby field lab to work into the night, the young researchers from Supaporn Wacharapluesadee’s and Linfa Wang’s group, together with the Thai forestry department, had to process the captured bats. Taking them gently but with an experienced grip out of their cotton bags, they measured their weight, size, and wingspan. Busy students were shouting numbers, protocoling measurements, labeling Eppendorf tubes, and passing the bats along, almost like on an assembly line. The virology students were taking various samples, especially wing clips—tiny biopsies taken from wing tissue that would regenerate within days for the bats—to create primary bat cell cultures that were on the agenda for the Singaporean team. These cell cultures might come in handy to study the molecular mechanisms underlying the special immune system in bats. In between workstations, the bats were always put back into their airy cotton bags to relax them. The whole ordeal took about 30 minutes per bat, and then they were released back into the dark night.
All in all, the more than 12-hour workday would yield data from around 50 bats. Fifty. Only a small fraction of them will carry viruses. A drop in the ocean of the total viral diversity out there. Ratchaburi alone housed millions of bats; even if researchers sampled every day, it would take years to test just 1% of all the bats in this single cave. According to Alice Hughes, it is estimated that 90% of caves in Southeast Asia remain scientifically undescribed and uninventoried, while some estimate around 60% of bat species still remain to be discovered, with a staggering number of the bat species we know about having never been sequenced. These numbers can make one’s head swirl. Metaphorically, scientists only get to throw a small bucket into that endless ocean of viral diversity, and every time they catch a fish, it is a new species that is often related to a known one, sometimes completely unknown, but never the same thing. Viruses are not stable; they evolve, adapt, and burn out. To say scientists are merely “under-sampling” bats and viruses is almost a misleading euphemism. In reality, humanity is mostly flying blind in a viral universe, with only a handful of scientists even capable of catching glimpses of the true scope of our ignorance. For me, the visceral experience of our limitations in front of the vastness of nature belied the popular belief that the confusing SARS-CoV-2 chimera must somehow be man-made. Who truly understands what unique and dangerous viruses nature can come up with?
“We are very limited in knowing nature,” Zhengli told me. “That is a problem. We are not ready.” Unfortunately, our ignorance cannot protect us from the Frankenviruses coming out of nature’s neglected gain-of-function laboratories. Zhengli was pessimistic about whether we know enough to stop other novel sarbecoviruses from causing an epidemic or even a pandemic. This is a scary reality. Zhengli, Peter, and Linfa had been sounding the alarm for years because they could see a bit beyond our current blindness to these risks.
Yet, in stark contrast to our underappreciation of nature’s creativity, genetic engineering today is surrounded by scary myths of scientists’ supposed omnipotence. “Doctors in white coats doing things we would not even understand even if they made everything public,” Peter Daszak would say. He has a point. Virology is complicated and unintuitive. But as somebody who spent years trying to assemble a moderately complex viral vector—a traffic-light splicing sensor with two alternating reading frames—let me tell you: scientists working in virology have a very good idea about the type and complexity of “flask monsters” genetic engineers supposedly can conjure up in a lab. They do not compare to nature. Just because we can scribble with the language of biology does not mean we can speak it or understand its many nuances. A virus, birthed through countless trials and errors, evolutionary fast-forwards, and merciless competition against a trillion foes in a fast-paced niche environment, is like a perfect symphony. We can try to listen to it and learn from it; genetic engineers might even be able to copy-paste its genome into a lab to study it. But no genetic engineer in the world can yet come up with something even remotely like it.
“I always say that making a recombinant virus is easy. But to make a virus like SARS-CoV-2 before nature came up with it is impossible.”
Linfa Wang was very clear about this. Over the years, other virologists had told me the same thing. Viruses are complex biological machines that only show their true colors in action and interaction with their niche environment. SARS-CoV-2, as painstaking mechanistic research has uncovered over the years, has a lot more intricacies and tricks up its sleeves than the few oddities Prof. Kristian Andersen identified as potentially engineered in the early days. No engineer could have dreamt these hitherto unknown feats into SARS-CoV-2 before nature invented them. Everything we know about virology, evolution, genetic engineering, recombination, and bat ecosystems screams that this is a natural virus that was not tinkered with in a lab.
This insight into the nature of the virus is something we can be confident about, given the knowledge and evidence we have today. All the questions, moral outrage, and media panic about gain-of-function research and genetic engineering in virology labs, no matter where one stands on these issues, are irrelevant to understanding the true origins of SARS-CoV-2. They are an emotional distraction to the scientific question of its emergence.
That being said, a natural genome does not entirely preclude the possibility that SARS-CoV-2 was brought to Wuhan by researchers, wittingly or unwittingly. After all, wasn’t Zhengli and her team collecting samples for years in Yunnan? Zhengli need not have created the virus to still be guilty of bringing it into the world, as her detractors would immediately pivot their accusations when I challenged them on their engineering fantasies. What if Zhengli secretly collected and cultivated a naturally evolved bat virus (to a level that could infect lab workers and subsequently escape)? A killer virus that was already “pandemic-ready” before it ever saw the inside of a lab? Or what if one of her researchers acquired an asymptomatic infection in the field working with bats, who then brought the “pandemic-ready” virus back to the city without notice? A natural virus does little to dispel these hard-to-refute allegations against her. Proving a negative—that something did not happen—is often impossible scientifically.
With the Chinese authorities stonewalling any further investigations in Wuhan, what hope did Shi Zhengli or researchers in her lab ever have of clearing these accusations against them?
Adapted from Lab Leak Fever: The COVID-19 Origin Theory that Sabotaged Science and Society by Philipp Markolin.
Copyright © 2025 by Philipp Markolin. All rights reserved.
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