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Tag: genetic material

  • Deer Are Beta-Testing a Nightmare Disease

    Deer Are Beta-Testing a Nightmare Disease

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    Scott Napper, a biochemist and vaccinologist at the University of Saskatchewan, can easily envision humanity’s ultimate doomsday disease. The scourge would spread fast, but the progression of illness would be slow and subtle. With no immunity, treatments, or vaccines to halt its progress, the disease would eventually find just about every single one of us, spreading via all manner of body fluids. In time, it would kill everyone it infected. Even our food and drink would not be safe, because the infectious agent would be hardy enough to survive common disinfectants and the heat of cooking; it would be pervasive enough to infest our livestock and our crops. “Imagine if consuming a plant could cause a fatal, untreatable neurodegenerative disorder,” Napper told me. “Any food grown within North America would be potentially deadly to humans.”

    This nightmare illness doesn’t yet exist. But for inspiration, Napper needs to look only at the very real contagion in his own lab: chronic wasting disease (CWD), a highly lethal, highly contagious neurodegenerative disease that is devastating North America’s deer, elk, and other cervids.

    Read: An incurable disease is coming for deer

    In the half century since it was discovered in a captive deer colony in Colorado, CWD has worked its way into more than 30 U.S. states and four Canadian provinces, as well as South Korea and several countries in Europe. In some captive herds, the disease has been detected in more than 90 percent of individuals; in the wild, Debbie McKenzie, a biologist at the University of Alberta, told me, “we have areas now where more than 50 percent of the bucks are infected.” And CWD kills indiscriminately, gnawing away at deer’s brains until the tissue is riddled with holes. “The disease is out of control,” Dalia Abdelaziz, a biochemist at the University of Calgary, told me.

    What makes CWD so formidable is its cause: infectious misfolded proteins called prions. Prion diseases, which include mad cow disease, have long been known as terrifying and poorly understood threats. And CWD is, in many ways, “the most difficult” among them to contend with—more transmissible and widespread than any other known, Marcelo Jorge, a wildlife biologist at the University of Georgia, told me. Scientists are quite certain that CWD will be impossible to eradicate; even limiting its damage will be a challenge, especially if it spills into other species, which could include us. CWD is already a perfect example of how dangerous a prion disease can be. And it has not yet hit the ceiling of its destructive potential.

    Among the world’s known infectious agents, prions are an anomaly, more like zombies than living entities. Unlike standard-issue microbes—viruses, bacteria, parasites, fungi—prions are just improperly folded proteins, devoid of genetic material, unable to build more of themselves from scratch, or cleave themselves in two. To reproduce, they simply find properly formed proteins that share their base composition and convert those to their aberrant shape, through mostly mysterious means. And because prions are slightly malformed versions of molecules that our bodies naturally make, they’re difficult to defend against. The immune system codes them as benign and ignores them, even as disease rapidly unfolds. “This is an entirely new paradigm of infectious disease,” Napper told me. “It’s a part of your own body that’s turning against you.”

    And yet, we’ve managed to keep many prion diseases in check. Kuru, once common in the highlands of Papua New Guinea, was transmitted through local rituals of funerary cannibalism; the disease fizzled out after people stopped those practices. Mad cow disease (more formally known as bovine spongiform encephalopathy) was contained by culling infected animals and eliminating the suspected source, cow feed made with infected tissues. Even scrapie, a highly contagious prion disease of sheep and goats, is limited to livestock, making it feasible to pare down infected populations, or breed them toward genetic resistance.

    Read: Insomnia that kills

    CWD, meanwhile, is a fixture of wild animals, many of them migratory. And whereas most other prion diseases primarily keep quarters in the central nervous system, CWD “gets in pretty much every part of the body,” Jorge told me. Deer then pass on the molecules, often through direct contact; they’ll shed prions in their saliva, urine, feces, reproductive fluids, and even antler velvet long before they start to show symptoms. Candace Mathiason, a pathobiologist at Colorado State University, and her colleagues have found that as little as 100 nanograms of saliva can seed an infection. Her studies suggest that deer can also pass prions in utero from doe to growing fawn.

    Deer also ingest prions from their environment, where the molecules can linger in soil, on trees, and on hunting bait for years or decades. A team led by Sandra Pritzkow, a biochemist at UTHealth Houston, has found that plants can take up prions from the soil, too. And unlike the multitude of microbes that are easily done in by UV, alcohol, heat, or low humidity, prions are so structurally sound that they can survive nearly any standard environmental assault. In laboratories, scientists must blast their equipment with temperatures of about 275 degrees Fahrenheit for 60 to 90 minutes, under extreme pressure, to rid it of prions—or drench their workspaces with bleach or sodium hydroxide, at concentrations high enough to rapidly corrode flesh.

    Infected deer are also frustratingly difficult to detect. The disease typically takes years to fully manifest, while the prions infiltrate the brain and steadily destroy neural tissue. The molecules kill insidiously: “This isn’t the kind of disease where you might get a group of deer that are all dead around this watering hole,” Jorge told me. Deer drift away from the herd; they forage at odd times. They become braver around us. They drool and urinate more, stumble about, and begin to lose weight. Eventually, a predator picks them off, or a cold snap freezes them, or they simply starve; in all cases, though, the disease is fatal. Because of CWD, deer populations in many parts of North America are declining; “there is definitely some concern that local populations will disappear,” McKenzie told me. Researchers worry the disease will soon overwhelm caribou in Canada, imperiling the Indigenous communities who rely on them for food. Hunters and farmers, too, are losing vital income. Deer are unlikely to go extinct, but the disease is depriving their habitats of key grazers, and their predators of food.

    Read: America needs hunting more than it knows

    In laboratory experiments, CWD has proved capable of infecting rodents, sheep, goats, cattle, raccoons, ferrets, and primates. But so far, jumps into non-cervid species don’t seem to be happening in the wild—and although people eat an estimated 10,000 CWD-infected cervids each year, no human cases have been documented. Still, lab experiments indicate that human proteins, at least when expressed by mice, could be susceptible to CWD too, Sabine Gilch, a molecular biologist at the University of Calgary, told me.

    And the more prions transmit, and the more hosts they find themselves in, the more opportunities they may have to infect creatures in new ways. Prions don’t seem to evolve as quickly as many viruses or bacteria, Gilch told me. But “they’re not as static as we would like them to be.” She, McKenzie, and other researchers have detected a multitude of CWD strains bopping around in the wild—each with its own propensity for interspecies spread. With transmission so unchecked, and hosts so numerous, “this is kind of like a ticking time bomb,” Surachai Suppattapone, a biochemist at Dartmouth, told me.

    The world is unlikely to ever be fully rid of CWD; even the options to slow its advance are so far limited. Efforts to survey for infection depend on funding and researchers’ time, or the generosity of local hunters for samples; environmental decontamination is still largely experimental and tricky to do at scale; treatments—which don’t yet exist—would be nearly impossible to administer en masse. And culling campaigns, although sometimes quite effective, especially at the edges of the disease’s reach, often spark public backlash.

    Deer that carry certain genetic variants do seem less susceptible to prions, and progress more slowly to full-blown disease and death. But because none so far seems able to fully block infection, or completely curb shedding, prolonging life may simply prolong transmission. “Once an animal gets infected,” Abdelaziz told me, there’s almost a “hope it dies right away.” Even if sturdier prion resistance is someday found, “it’s probably just a matter of time until prions start to adapt to that as well,” Gilch said.

    Vaccines, in theory, could help, and in recent years, several research groups—including Napper’s and Abdelaziz’s—have made breakthroughs in overcoming the immune system’s inertia in attacking proteins that look like the body’s own. Some strategies try to target the problematic, invasive prions only; others are going after both the prion and the native, properly folded protein, so that the vaccine can do double duty, waylaying the infectious invader and starving it of reproductive fodder. (So far, lab animals seem to do mostly fine even when they’re bred to lack the native prion protein, whose function is still mostly mysterious.) In early trials, both teams’ vaccines have produced promising immune responses in cervids. But neither team yet fully knows how effective their vaccines are at cutting down on shedding, how long that protection might last, or whether these strategies will work across cervid species. One of Napper’s vaccine candidates, for instance, seemed to hasten the progression of disease in elk.

    Vaccines for wildlife are also tough to deliver, especially the multiple doses likely needed in this case. “It’s not like you can just run around injecting every elk and deer,” Napper told me. Instead, he and other researchers plan to compound their formula with a salty apple-cider slurry that he hopes wild cervids might eat with some regularity. “The deer absolutely love it,” he said.

    Should any CWD vaccines come to market, though, they will almost certainly be the first prion vaccines that clear the experimental stage. That could be a boon for more than just deer. Another prion disease may spill over from one species to another; others may arise spontaneously. CWD is not, and may never be, the prion disease that most directly affects us. But it is, for now, the most urgent—and the one from which we have the most to lose, and maybe gain.

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    Katherine J. Wu

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  • The Other Group of Viruses That Could Cause the Next Pandemic

    The Other Group of Viruses That Could Cause the Next Pandemic

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    Whether it begins next week, next year, or next decade, another pandemic is on its way. Researchers can’t predict precisely when or how the outbreak might begin. Some 1.6 million viruses are estimated to lurk in the world’s mammalian and avian wildlife, up to half of which could spill into humans; an untold number are attempting exactly that, at this very moment, bumping up against the people hunting, eating, and encroaching on those creatures. (And that’s just viruses: Parasites, fungi, and bacteria represent major infectious dangers too.) The only true certainty in the pandemic forecast is that the next threat will be here sooner than anyone would like.

    But scientists can at least make an educated guess about what might catalyze the next Big One. Three main families of viruses, more than most others, keep scientists up at night: flu viruses, coronaviruses, and paramyxoviruses, in descending order of threat. Together, those groups make up “the trifecta of respiratory death,” Sara Cherry, a virologist at the University of Pennsylvania, told me.

    Flu and coronavirus have a recent track record of trouble: Since 1918, flu viruses have sparked four pandemics, all the while continuing to pester us on a seasonal basis; some scientists worry that another major human outbreak may be brewing now, as multiple H5 flu viruses continue to spread from birds to mammals. The past two decades have also featured three major and deadly coronavirus outbreaks: the original SARS epidemic that began in late 2002; MERS, which spilled into humans—likely from camels—in 2012; and SARS-CoV-2, the pandemic pathogen that’s been plaguing us since the end of 2019. Common-cold-causing coronaviruses, too, remain a fixture of daily living—likely relics of ancient animal-to-human spillovers that we kept transmitting amongst ourselves.

    Read: Bird flu has never done this before

    Paramyxoviruses, meanwhile, have mostly been “simmering in the background,” says Raina Plowright, a disease ecologist at Cornell. Unlike flu viruses and coronaviruses, which have already clearly “proven themselves” as tier-one outbreak risks, paramyxoviruses haven’t yet been caught causing a bona fide pandemic. But they seem poised to do so, and they likely have managed the feat in the past. Like flu viruses and coronaviruses, paramyxoviruses can spread through the air, sometimes very rapidly. That’s certainly been the case with measles, a paramyxovirus that is “literally the most transmissible human virus on the planet,” says Paul Duprex, a virologist at the University of Pittsburgh. And, like flu viruses and coronaviruses, paramyxoviruses are found in a wide range of animals; more are being discovered wherever researchers look. Consider canine distemper virus, which has been found in, yes, canines, but also in raccoons, skunks, ferrets, otters, badgers, tigers, and seals. Paramyxoviruses, like flu viruses and coronaviruses, have also repeatedly shown their potential to hopscotch from those wild creatures into us. Since 1994, Hendra virus has caused multiple highly lethal outbreaks in horses, killing four humans along the way; the closely related Nipah virus has, since 1998, spread repeatedly among both pigs and people, carrying fatality rates that can soar upwards of 50 percent.

    The human versions of those past few outbreaks have petered out. But that may not always be the case—for Nipah, or for another paramyxovirus that’s yet to emerge. It’s entirely possible, Plowright told me, that the world may soon encounter a new paramyxovirus that’s both highly transmissible and ultra deadly—an “absolutely catastrophic” scenario, she said, that could dwarf the death toll of any epidemic in recent memory. (In the past four years, COVID-19, a disease with a fatality rate well below Nipah’s, has killed an estimated 7 million people.)

    All that said, though, paramyxoviruses are a third-place contender for several good reasons. Whereas flu viruses and coronaviruses are speedy shape-shifters—they frequently tweak their own genomes and exchange genetic material with others of their own kind—paramyxoviruses have historically been a bit more reluctant to change. “That takes them down a level,” says Danielle Anderson, a virologist at the Doherty Institute, in Melbourne. For one, these viruses’ sluggishness could make it much tougher for them to acquire transmission-boosting traits or adapt rapidly to spread among new hosts. Nipah virus, for instance, can spread among people via respiratory droplets at close contact. But even though it’s had many chances to do so, “it still hasn’t gotten very good at transmitting among humans,” Patricia Thibault, a biologist at the University of Saskatchewan who studied paramyxoviruses for years, told me.

    The genetic stability of paramyxoviruses can also make them straightforward to vaccinate against. Our flu and coronavirus shots need regular updates—as often as annually—to keep our immune system apace with viral evolution. But we’ve been using essentially the same measles vaccine for more than half a century, Duprex told me, and immunity to the virus seems to last for decades. Strong, durable vaccines are one of the main reasons that several countries have managed to eliminate measles—and why a paramyxovirus called rinderpest, once a major scourge of cattle, is one of the only infectious diseases we’ve ever managed to eradicate. In both cases, it helped that the paramyxovirus at play wasn’t great at infecting a ton of different animals: Measles is almost exclusive to us; rinderpest primarily troubled cows and their close kin. Most flu viruses and SARS-CoV-2, meanwhile, can spread widely across the tree of animal life; “I don’t know how you can eradicate that,” Anderson told me.

    The problem with all of these trends, though, is that they represent only what researchers know of the paramyxoviruses they’ve studied—which is, inevitably, a paltry subset of what exists, says Benhur Lee, a virologist at Mount Sinai’s Icahn School of Medicine. “The devil we don’t know can be just as frightening,” if not more, Lee told me. A pattern-defying paramyxovirus may already be readying itself to jump.

    Researchers are keyed into these looming threats. The World Health Organization highlights Nipah virus and its close cousins as some of its top-priority pathogens; in the U.S., paramyxoviruses recently made a National Institute of Allergy and Infectious Diseases list of pathogens essential to study for pandemic preparedness. Last year, the Bill & Melinda Gates Foundation announced a hefty initiative to fund paramyxovirus antiviral drugs. Several new paramyxovirus vaccines—many of them targeting Nipah viruses and their close relatives—may soon be ready to debut.

    Read: We have a mink problem

    At the same time, though, paramyxoviruses remain neglected—at least relative to the sheer perils they pose, experts told me. “Influenza has been sequenced to death,” Lee said. (That’s now pretty true for SARS-CoV-2 as well.) Paramyxoviruses, meanwhile, aren’t regularly surveilled for; development of their treatments and vaccines also commands less attention, especially outside of Nipah and its kin. And although the family has been plaguing us for countless generations, researchers still don’t know exactly how paramyxoviruses move into new species, or what mutations they would need to become more transmissible among us; they don’t know why some paramyxoviruses spark only minor respiratory infections, whereas others run amok through the body until the host is dead.

    Even the paramyxoviruses that feel somewhat familiar are still surprising us. In recent years, scientists have begun to realize that immunity to the paramyxovirus mumps, once thought to be pretty long-lasting and robust, wanes in the first few decades after vaccination; a version of the virus, once thought to be a problem only for humans and a few other primates, has also been detected in bats. For these and other reasons, rubulaviruses—the paramyxovirus subfamily that includes mumps—are among the potential pandemic agents that most concern Duprex. Emmie de Wit, the chief of the molecular-pathogenesis unit at Rocky Mountain Laboratories, told me that the world could also become more vulnerable to morbilliviruses, the subfamily that includes measles. If measles is ever eradicated, some regulators may push for an end to measles shots. But in the same way that the end of smallpox vaccination left the world vulnerable to mpox, the fall of measles immunity could leave an opening for a close cousin to rise.

    The next pandemic won’t necessarily be a paramyxovirus, or even a flu virus or a coronavirus. But it has an excellent chance of starting as so many other known pandemics have—with a spillover from animals, in parts of the world where we’ve invaded wild habitats. We may not be able to predict which pathogen or creature might be involved in our next big outbreak, but the common denominator will always be us.

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    Katherine J. Wu

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  • An Adorable Way to Study How Kids Get Each Other Sick

    An Adorable Way to Study How Kids Get Each Other Sick

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    At the start of 2022, as the Omicron variant of the coronavirus blazed across the United States, Seema Lakdawala was in Pittsburgh, finalizing plans to open a brand-new day care. She had found the perfect facility and signed the stack of paperwork; she had assembled a hodgepodge of plushies, puzzles, and toys. It was the perfect setup, one that “I’ve been dreaming about for years,” Lakdawala, a virologist at Emory University, told me. She couldn’t help but swell with pride, later that spring, when she ushered in her establishments’ first attendees: five young ferrets—including one deliberately infected with the flu.

    Over the next several months, Lakdawala and her colleagues watched several cohorts of ferrets ping-pong flu viruses back and forth as they romped and wrestled and frolicked inside of a shared playpen. The researchers meticulously logged the ferrets’ movements; they took note of the surfaces and other animals that each one touched. Their early findings, now being prepared for publication in a scientific journal, could help researchers figure out how flu viruses most efficiently spread in group settings—not just among ferrets, but among human kids.

    Aerosols, droplets, face-to-face contact, contaminated surfaces—there are plenty of ways for flu viruses to spread. But the nitty-gritty of flu transmission remains “pretty much a black box,” says Aubree Gordon, an epidemiologist at the University of Michigan. Despite decades of research, “we really don’t know the relative importance of each potential route.” Now, though, ferrets in playpens could help researchers to tease out those dynamics—and even, someday, to design flu-blocking measures for bona fide day cares.

    Ferrets have long been the “gold standard for influenza infection and transmission,” says Nicole Rockey, an environmental engineer at Duke University who led the experiments with Lakdawala. The animals’ airway architecture is uncannily similar to ours, and unlike most lab mice, ferrets are vulnerable to catching and passing on flu viruses—even developing the same coughy, sniffly symptoms that so many humans do. But most flu-transmission experiments in ferrets remain limited to artificial circumstances: pairs of animals in tiny cages with dividers between them, where scientists ogle them inhaling each other’s air for days or even weeks. That’s not how animals catch one another’s infections in the wild, and it’s certainly not how human outbreaks unfold. “We don’t interact with each other for 48 hours straight through a perforated wall,” Rockey told me.

    A giant playpen outfitted with toys, air samplers, and video cameras isn’t exactly a natural habitat for a ferret. But the setup does tap into many of the animals’ impish instincts. Domesticated by humans over thousands of years, ferrets “are a very playful species, and they love to be social,” says Alice Dancer, an animal-welfare researcher at the University of London’s Royal Veterinary College. That makes them great models for not just flu transmission, but flu transmission among kids, who are thought to be major drivers of outbreaks. In their day care, the ferrets squabble over toys, clamber up play structures, and canoodle plush snakes; they chase one another around, and nap in big piles when they get tuckered out; they exchange affectionate nuzzles, bonks, and little play bites. Every interaction represents a potential transmission event; so, too, do the surfaces they touch, and the shared pockets of air from which they all breathe.

    Read: The flu may never be the same

    Already, the researchers have collected some results that, Lakdawala told me, are “changing the way I think about transmission a little bit.” In one early experiment, involving an infected animal cavorting with four uninfected ones, they were surprised to find that the ferret with the least direct contact with the flu “donor” was the only “recipient” in the room who got sick. It seemed counterintuitive, Lakdawala told me, until video footage revealed that the newly sickened recipient had been copying everything that the donor did—chewing the toys it chewed, rolling the balls it rolled, swiping the surfaces it swiped. It was as if the first ferret was leaving a trail of infectious breadcrumbs for the second one to snarf. If that finding holds up in other experiments, which the researchers are analyzing now, it could suggest that contaminated surfaces, or fomites, are playing a larger-than-expected role in passing the virus around, Rockey told me.

    Another of the team’s early findings points to a similar notion. When the researchers cranked up the ventilation in their ferret day cares, hoping to clear virus particles out of the air, they found that the same proportion of uninfected ferrets ended up catching the virus. This was disappointing, but not a total shock given how paws-on ferrets—and kids, for that matter—are with one another and their surroundings. It didn’t matter if the air in the room was being exchanged more than once every three minutes. Whenever the ferrets had their run of the room, the researchers would find virus particles smeared on the toys, the snack station, and the playpen walls.

    Ventilation wasn’t totally useless: More air exchanges, the team found, did seem to reduce the concentration of flu genetic material in the air, and the ferrets who got infected under those conditions were slower to start shedding the virus—a hint, Lakdawala thinks, that they might have taken in a lower infectious dose. Among humans, that might translate into less severe cases of disease, Gordon told me, though that would need to be confirmed.

    Whatever upshots Rockey and Lakdawala’s ferret findings might have for human day cares won’t necessarily apply to other venues. In offices, hospitals, and even schools for older kids, people are generally a lot less tactile with one another, and a lot better versed on hygiene. Plus, adult bodies just aren’t built like kids’, says Cécile Viboud, an epidemiologist at the Fogarty International Center at the National Institutes of Health. Their airways are bigger, stronger, and more developed—and some experiments suggest that, for at least some respiratory viruses, the older and larger people are, the more infectious aerosols they might expel. For adults, ventilation may matter all the more.

    Lakdawala and her colleagues are still mulling some other interventions that might work better for ferrets, and eventually kids: humidifiers, air purifiers, targeted cleaning, maybe even keeping individuals from crowding too closely into a portion of the playpen. (They don’t plan to experiment with handwashing or masking; imagine the difficulty of strapping an N95 to a ferret’s face.) Lakdawala is also mulling whether surfaces made of copper—which her team has shown can render flu viruses inactive within minutes—could play a protective role.

    But everything that happens in the ferrets’ playpens will still come with caveats. “It’s still an animal model, at the end of the day,” Viboud told me. For all the similarities between the ferret airway and ours, the way their little noses and snouts are shaped could affect how they cough and sneeze. And the researchers haven’t yet studied spread among ferrets with preexisting immunity to flu, which some day-care attendees will have. Ferrets are also more inclined to bite, wrestle, and defecate wherever they please than the average (potty-trained) kid.

    Still, for the most part, Lakdawala delights in how childlike the ferrets can be. They’re affectionate and mischievous; they seem to bubble with energy and glee. After discovering that the air-sampling robot stationed in the center of their day care was mobile, several of the ferrets began to take it for rides. In watching and sharing the footage at conferences, Lakdawala has received one piece of feedback, over and over again: Oh yeah, parents tell her. My kids do that too.

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    Katherine J. Wu

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  • A Major Clue to COVID’s Origins Is Just Out of Reach

    A Major Clue to COVID’s Origins Is Just Out of Reach

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    Updated at 2:45 p.m. on March 21, 2023

    Last week, the ongoing debate about COVID-19’s origins acquired a new plot twist. A French evolutionary biologist stumbled across a trove of genetic sequences extracted from swabs collected from surfaces at a wet market in Wuhan, China, shortly after the pandemic began; she and an international team of colleagues downloaded the data in hopes of understanding who—or what—might have ferried the virus into the venue. What they found, as The Atlantic first reported on Thursday, bolsters the case for the pandemic having purely natural roots: The genetic data suggest that live mammals illegally for sale at the Huanan Seafood Wholesale Market—among them, raccoon dogs, a foxlike species known to be susceptible to the virus—may have been carrying the coronavirus at the end of 2019.

    But what might otherwise have been a straightforward story on new evidence has rapidly morphed into a mystery centered on the origins debate’s data gaps. Within a day or so of nabbing the sequences off a database called GISAID, the researchers told me, they reached out to the Chinese scientists who had uploaded the data to share some preliminary results. The next day, public access to the sequences was locked—according to GISAID, at the request of the Chinese researchers, who had previously analyzed the data and drawn distinctly different conclusions about what they contained.

    Read: The strongest evidence yet that an animal started the pandemic

    Yesterday evening, the international team behind the new Huanan-market analysis released a report on its findings—but did not post the underlying data. The write-up confirms that genetic material from raccoon dogs and several other mammals was found in some of the same spots at the wet market, as were bits of SARS-CoV-2’s genome around the time the outbreak began. Some of that animal genetic material, which was collected just days or weeks after the market was shut down, appears to be RNA—a particularly fast-degrading molecule. That strongly suggests that the mammals were present at the market not long before the samples were collected, making them a plausible channel for the virus to travel on its way to us. “I think we’re moving toward more and more evidence that this was an animal spillover at the market,” says Ravindra Gupta, a virologist at the University of Cambridge, who was not involved in the new research. “A year and a half ago, my confidence in the animal origin was 80 percent, something like that. Now it’s 95 percent or above.”

    For now, the report is just that: a report, not yet formally reviewed by other scientists or even submitted for publication to the journal—and that will remain the case as long as this team continues to leave space for the researchers who originally collected the market samples, many of them based at the Chinese Center for Disease Control and Prevention, to prepare a paper of their own. And still missing are the raw sequence files that sparked the reanalysis in the first place—before vanishing from the public eye.

    Every researcher I asked emphasized just how important the release of that evidence is to the origins investigation: Without data, there’s no base-level proof—nothing for the broader scientific community to independently scrutinize to confirm or refute the international team’s results. Absent raw data, “some people will say that this isn’t real,” says Gigi Gronvall, a senior scholar at the Johns Hopkins Center for Health Security, who wasn’t involved in the new analysis. Data that flicker on and off publicly accessible parts of the internet also raise questions about other clues on the pandemic’s origins. Still more evidence might be out there, yet undisclosed.

    Transparency is always an essential facet of research, but all the more so when the stakes are so high. SARS-CoV-2 has already killed nearly 7 million people, at least, and saddled countless people with chronic illness; it will kill and debilitate many more in the decades to come. Every investigation into how it began to spread among humans must be “conducted as openly as possible,” says Sarah Cobey, an infectious-disease modeler at the University of Chicago, who wasn’t involved in the new analysis.

    The team behind the reanalysis still has copies of the genetic sequences its members downloaded earlier this month. But they’ve decided that they won’t be the ones to share them, several of them told me. For one, they don’t have sequences from the complete set of samples that the Chinese team collected in early 2020—just the fraction that they spotted and grabbed off GISAID. Even if they did have all of the data, the researchers contend that it’s not their place to post them publicly. That’s up to the China CDC team that originally collected and generated the data.

    Part of the international team’s reasoning is rooted in academic decorum. There isn’t a set-in-stone guidebook among scientists, but adhering to unofficial rules on etiquette smooths successful collaborations across disciplines and international borders—especially during a global crisis such as this one. Releasing someone else’s data, the product of another team’s hard work, is a faux pas. It risks misattribution of credit, and opens the door to the Chinese researchers’ findings getting scooped before they publish a high-profile paper in a prestigious journal. “It isn’t right to share the original authors’ data without their consent,” says Niema Moshiri, a computational biologist at UC San Diego and one of the authors of the new report. “They produced the data, so it’s their data to share with the world.”

    If the international team released what data it has, it could potentially stoke the fracas in other ways. The World Health Organization has publicly indicated that the data should come from the researchers who collected them first: On Friday, at a press briefing, Tedros Adhanom Ghebreyesus, the WHO’s director-general, admonished the Chinese researchers for keeping their data under wraps for so long, and called on them to release the sequences again. “These data could have and should have been shared three years ago,” he said. And the fact that it wasn’t is “disturbing,” given just how much it might have aided investigations early on, says Gregory Koblentz, a biodefense expert at George Mason University, who wasn’t involved in the new analysis.

    Publishing the current report has already gotten the researchers into trouble with GISAID, the database where they found the genetic sequences. During the pandemic, the database has been a crucial hub for researchers sharing viral genome data; founded to provide open access to avian influenza genomes, it is also where researchers from the China CDC published the first whole-genome sequences of SARS-CoV-2, back in January 2020. A few days after the researchers downloaded the sequences, they told me, several of them were contacted by a GISAID administrator who chastised them about not being sufficiently collaborative with the China CDC team and warned them against publishing a paper using the China CDC data. They were in danger, the email said, of violating the site’s terms of use and would risk getting their database access revoked. Distributing the data to any non-GISAID users—including the broader research community—would also be a breach.

    This morning, hours after the researchers released their report online, many of them found that they could no longer log in to GISAID—they received an error message when they input their username and password. “They may indeed be accusing us of having violated their terms,” Moshiri told me, though he can’t be sure. The ban was instated with absolutely no warning. Moshiri and his colleagues maintain that they did act in good faith and haven’t violated any of the database’s terms—that, contrary to GISAID’s accusations, they reached out multiple times with offers to collaborate with the China CDC, which has “thus far declined,” per the international team’s report.

    GISAID didn’t respond when I reached out about the data’s disappearing act, its emails to the international team, and the group-wide ban. But in a statement released shortly after I contacted the database—one that echoes language in the emails sent to researchers—GISAID doubled down on accusing the international team of violating its terms of use by posting “an analysis report in direct contravention of the terms they agreed to as a condition to accessing the data, and despite having knowledge that the data generators are undergoing peer review assessment of their own publication.”

    Maria Van Kerkhove, the WHO’s COVID-19 technical lead, told me that she’s learned that the China CDC researchers recently provided a fuller data set to GISAID—more complete than the one the international team downloaded earlier this month. “It’s ready to go,” she told me. GISAID just needs permission, she said, from the Chinese researchers to make the sequences publicly available. “I reach out to them every day, asking them for a status update,” she added, but she hasn’t yet heard back on a definitive timeline. In its statement, GISAID also “strongly” suggested “that the complete and updated dataset will be made available as soon as possible,” but gave no timeline. I asked Van Kerkhove if there was a hypothetical deadline for the China CDC team to restore access, at which point the international team might be asked to publicize the data instead. “This hypothetical deadline you’re talking about? We’re way past that,” she said, though she didn’t comment specifically on whether the international team would be asked to step in. “Data has been uploaded. It is available. It just needs to be accessible, immediately.”

    Why, exactly, the sequences were first made public only so recently, and why they have yet to reappear publicly, remain unclear. In a recent statement, the WHO said that access to the data was withdrawn “apparently to allow further data updates by China CDC” to its original analysis on the market samples, which went under review for publication at the journal Nature last week. There’s no clarity, however, on what will happen if the paper is not published at all. When I reached out to three of the Chinese researchers—George Gao, William Liu, and Guizhen Wu—to ask about their intentions for the data, I didn’t receive a response.

    “We want the data to come out more than anybody,” says Saskia Popescu, an infectious-disease epidemiologist at George Mason University and one of the authors on the new analysis. Until then, the international team will be fielding accusations, already flooding in, that it falsified its analyses and overstated its conclusions.

    Researchers around the world have been raising questions about these particular genetic sequences for at least a year. In February 2022, the Chinese researchers and their close collaborators released their analysis of the same market samples probed in the new report, as well as other bits of genetic data that haven’t yet been made public. But their interpretations deviate pretty drastically from the international team’s. The Chinese team contended that any shreds of virus found at the market had most likely been brought in by infected humans. “No animal host of SARS-CoV-2 can be deduced,” the researchers asserted at the time. Although the market had perhaps been an “amplifier” of the outbreak, their analysis read, “more work involving international coordination” would be needed to determine the “real origins of SARS-CoV-2.” When reached by Jon Cohen of Science magazine last week, Gao described the sequences that fleetingly appeared on GISAID as “[n]othing new. It had been known there was illegal animal dealing and this is why the market was immediately shut down.”

    There is, then, a clear divergence between the two reports. Gao’s assessment indicates that finding animal genetic material in the market swabs merely confirms that live mammals were being illegally traded at the venue prior to January 2020. The researchers behind the new report insist that the narrative can now go a step further—they suggest not just that the animals were there, but that the animals, several of which are already known to be vulnerable to SARS-CoV-2, were there, in parts of the market where the virus was also found. That proximity, coupled with the virus’s inability to persist without a viable host, points to the possibility of an existing infection among animals, which could spark several more.

    The Chinese researchers used this same logic of location—multiple types of genetic material pulled out of the same swab—to conclude that humans were carrying around the virus at Huanan. The reanalysis confirms that there probably were infected people at the market at some point before it closed. But they were unlikely to be the virus’s only chauffeurs: Across several samples, the amount of raccoon-dog genetic material dwarfs that of humans. At one stall in particular—located in the sector of the market where the most virus-positive swabs were found—the researchers discovered at least one sample that contained SARS-CoV-2 RNA, and was also overflowing with raccoon-dog genetic material, while containing very little DNA or RNA material matching the human genome. That same stall was photographically documented housing raccoon dogs in 2014. The case is not a slam dunk: No one has yet, for instance, identified a viral sample taken from a live animal that was swabbed at the market in 2019 before the venue was closed. Still, JHU’s Gronvall told me, the situation feels clearer than ever. “All of the science is pointed” in the direction of Huanan being the pandemic’s epicenter, she said.

    To further untangle the significance of the sequences will require—you guessed it—the now-vanished genetic data. Some researchers are still withholding their judgment on the significance of the new analysis, because they haven’t gotten their hands on the genetic sequences themselves. “That’s the whole scientific process,” Van Kerkhove told me: data transparency that allows analyses to be “done and redone.”

    Van Kerkhove and others are also wondering whether more data could yet emerge, given how long this particular set went unshared. “This is an indication to me in recent days that there is more data that exists,” she said. Which means that she and her colleagues haven’t yet gotten the fullest picture of the pandemic’s early days that they could—and that they won’t be able to deliver much of a verdict until more information emerges. The new analysis does bolster the case for market animals acting as a conduit for the virus between bats (SARS-CoV-2’s likeliest original host, based on several studies on this coronavirus and others) and people; it doesn’t, however, “tell us that the other hypotheses didn’t happen. We can’t remove any of them,” Van Kerkhove told me.

    More surveillance for the virus needs to be done in wild-animal populations, she said. Having the data from the market swabs could help with that, perhaps leading back to a population of mammals that might have caught the virus from bats or another intermediary in a particular part of China. At the same time, to further investigate the idea that SARS-CoV-2 first emerged out of a laboratory mishap, officials need to conduct intensive audits and investigations of virology laboratories in Wuhan and elsewhere. Last month, the U.S. Department of Energy ruled that such an accident was the likelier catalyst of the coronavirus outbreak than a natural spillover from wild animals to humans. The ruling echoed earlier judgments from the FBI and a Senate minority report. But it contrasted with the views of four other agencies, plus the National Intelligence Council, and it was made with “low confidence” and based on “new” evidence that has yet to be declassified.

    Read: The lab leak will haunt us forever

    The longer the investigation into the virus’s origins drags on, and the more distant the autumn of 2019 grows in our rearview, “the harder it becomes,” Van Kerkhove told me. Many in the research community were surprised that new information from market samples collected in early 2020 emerged at all, three years later. Settling the squabbles over SARS-CoV-2 will be especially tough because the Huanan market was so swiftly shut down after the outbreak began, and the traded animals at the venue rapidly culled, says Angela Rasmussen, a virologist at the University of Saskatchewan and one of the researchers behind the new analysis. Raccoon dogs, one of the most prominent potential hosts to have emerged from the new analysis, are not even known to have been sampled live at the market. “That evidence is gone now,” if it ever existed, Koblentz, of George Mason University, told me. For months, Chinese officials were even adamant that no mammals were being illegally sold at the region’s wet markets at all.

    So researchers continue to work with what they have: swabs from surfaces that can, at the very least, point to a susceptible animal being in the right place, at the right time, with the virus potentially inside it. “Right now, to the best of my knowledge, this data is the only way that we can actually look,” Rasmussen told me. It may never be enough to fully settle this debate. But right now, the world doesn’t even know the extent of the evidence available—or what could, or should, still emerge.

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    Katherine J. Wu

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  • The Strongest Evidence Yet That an Animal Started the Pandemic

    The Strongest Evidence Yet That an Animal Started the Pandemic

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    For three years now, the debate over the origins of the coronavirus pandemic has ping-ponged between two big ideas: that SARS-CoV-2 spilled into human populations directly from a wild-animal source, and that the pathogen leaked from a lab. Through a swirl of data obfuscation by Chinese authorities and politicalization within the United States, and rampant speculation from all corners of the world, many scientists have stood by the notion that this outbreak—like most others—had purely natural roots. But that hypothesis has been missing a key piece of proof: genetic evidence from the Huanan Seafood Wholesale Market in Wuhan, China, showing that the virus had infected creatures for sale there.

    This week, an international team of virologists, genomicists, and evolutionary biologists may have finally found crucial data to help fill that knowledge gap. A new analysis of genetic sequences collected from the market shows that raccoon dogs being illegally sold at the venue could have been carrying and possibly shedding the virus at the end of 2019. It’s some of the strongest support yet, experts told me, that the pandemic began when SARS-CoV-2 hopped from animals into humans, rather than in an accident among scientists experimenting with viruses.

    “This really strengthens the case for a natural origin,” says Seema Lakdawala, a virologist at Emory who wasn’t involved in the research. Angela Rasmussen, a virologist involved in the research, told me, “This is a really strong indication that animals at the market were infected. There’s really no other explanation that makes any sense.”

    The findings won’t fully silence the entrenched voices on either side of the origins debate. But the new analysis may offer some of the clearest and most compelling evidence that the world will ever get in support of an animal origin for the virus that, in just over three years, has killed nearly 7 million people worldwide.

    Read: The lab leak will haunt us forever

    The genetic sequences were pulled out of swabs taken in and near market stalls around the pandemic’s start. They represent the first bits of raw data that researchers outside of China’s academic institutions and their direct collaborators have had access to. Late last week, the data were quietly posted by researchers affiliated with the country’s Center for Disease Control and Prevention, on an open-access genomic database called GISAID. By almost pure happenstance, scientists in Europe, North America, and Australia spotted the sequences, downloaded them, and began an analysis.

    The samples were already known to be positive for the coronavirus, and had been scrutinized before by the same group of Chinese researchers who uploaded the data to GISAID. But that prior analysis, released as a preprint publication in February 2022, asserted that “no animal host of SARS-CoV-2 can be deduced.” Any motes of coronavirus at the market, the study suggested, had most likely been chauffeured in by infected humans, rather than wild creatures for sale.

    The new analysis, led by Kristian Andersen, Edward Holmes, and Michael Worobey—three prominent researchers who have been looking into the virus’s roots—shows that that may not be the case. Within about half a day of downloading the data from GISAID, the trio and their collaborators discovered that several market samples that tested positive for SARS-CoV-2 were also coming back chock-full of animal genetic material—much of which was a match for the common raccoon dog. Because of how the samples were gathered, and because viruses can’t persist by themselves in the environment, the scientists think that their findings could indicate the presence of a coronavirus-infected raccoon dog in the spots where the swabs were taken. Unlike many of the other points of discussion that have been volleyed about in the origins debate, the genetic data are “tangible,” Alex Crits-Christoph, a computational biologist and one of the scientists who worked on the new analysis, told me. “And this is the species that everyone has been talking about.”

    Finding the genetic material of virus and mammal so closely co-mingled—enough to be extracted out of a single swab—isn’t perfect proof, Lakdawala told me. “It’s an important step, I’m not going to diminish that,” she said. Still, the evidence falls short of, say, isolating SARS-CoV-2 from a free-ranging raccoon dog or, even better, uncovering a viral sample swabbed from a mammal for sale at Huanan from the time of the outbreak’s onset. That would be the virological equivalent of catching a culprit red-handed. But “you can never go back in time and capture those animals,” says Gigi Gronvall, a senior scholar at the Johns Hopkins Center for Health Security. And to researchers’ knowledge, “raccoon dogs were not tested at the market and had likely been removed prior to the authorities coming in,” Andersen wrote to me in an email. He underscored that the findings, while an important addition, are still not “direct evidence of infected raccoon dogs at the market.”

    Still, the findings don’t stand alone. “Do I believe there were infected animals at the market? Yes, I do,” Andersen told me. “Does this new data add to that evidence base? Yes.” The new analysis builds on extensive previous research that points to the market as the source of the earliest major outbreak of SARS-CoV-2: Many of the earliest known COVID-19 cases of the pandemic were clustered roughly in the market’s vicinity. And the virus’s genetic material was found in many samples swabbed from carts and animal processing equipment at the venue, as well as parts of nearby infrastructure, such as storehouses, sewage wells, and water drains. Raccoon dogs, creatures commonly bred for sale in China, are also already known to be one of many mammal species that can easily catch and spread the coronavirus. All of this left one main hole in the puzzle to fill: clear-cut evidence that raccoon dogs and the virus were in the exact same spot at the market, close enough that the creatures might have been infected and, possibly, infectious. That’s what the new analysis provides. Think of it as finding the DNA of an investigation’s main suspect at the scene of the crime.

    The findings don’t rule out the possibility that other animals may have been carrying SARS-CoV-2 at Huanan. Raccoon dogs, if they were infected, may not even be the creatures who passed the pathogen on to us. Which means the search for the virus’s many wild hosts will need to plod on. “Do we know the intermediate host was raccoon dogs? No,” Andersen wrote to me, using the term for an animal that can ferry a pathogen between other species. “Is it high up on my list of potential hosts? Yes, but it’s definitely not the only one.”

    On Tuesday, the researchers presented their findings at a hastily scheduled meeting of the World Health Organization’s Scientific Advisory Group for the Origins of Novel Pathogens, which was also attended by several of the Chinese researchers responsible for the original analysis, according to multiple researchers who were not present but were briefed about it before and after by multiple people who were there.

    Shortly after the meeting, the Chinese team’s preprint went into review at a Nature Research journal—suggesting that a new version was being prepared for publication. (I reached out to the WHO for comment and will update the story when I have more information.)

    At this point, it’s still unclear why the sequences were posted to GISAID last week. They also vanished from the database shortly after appearing, without explanation. When I emailed George Gao, the former China CDC director-general and the lead author on the original Chinese analysis, asking for his team’s rationale, I didn’t immediately receive a response. Given what was in the GISAID data, it does seem that raccoon dogs could have been introduced into and clarified the origins narrative far sooner—at least a year ago, and likely more.

    China has, for years, been keen on pushing the narrative that the pandemic didn’t start within its borders. In early 2020, a Chinese official suggested that the novel coronavirus may have emerged from a U.S. Army lab in Maryland. The notion that a dangerous virus sprang out from wet-market mammals echoed the beginnings of the SARS-CoV-1 epidemic two decades ago—and this time, officials immediately shut down the Huanan market, and vehemently pushed back against assertions that live animals being sold illegally in the the country were to blame; a WHO investigation in March 2021 took the same line. “No verified reports of live mammals being sold around 2019 were found,” the report stated. But just three months later, in June 2021, a team of researchers published a study documenting tens of thousands of mammals for sale in wet markets in Wuhan between 2017 and late 2019, including at Huanan. The animals were kept in largely illegal, cramped, and unhygienic settings—conditions conducive to viral transmission—and among them were more than 1,000 raccoon dogs. Holmes himself had been at the market in 2014 and snapped a photo at Stall 29, clearly showing a raccoon dog in a cage; another set of images from the venue, captured by a local in December 2019 and later shared on Weibo, caught the animals on film as well—right around the time that the first recorded SARS-CoV-2 infections in humans occurred.

    And yet, Chinese researchers maintained their stance. As Jon Cohen reported for Science magazine last year, scientists from several of China’s largest academic institutions posted a preprint in September 2021 concluding that a massive nationwide survey of bats—the likeliest original source of the coronavirus before it jumped into an intermediate host, such as raccoon dogs, and then into us—had turned up no relatives of SARS-CoV-2. The implication, the team behind the paper asserted, was that relatives of the coronavirus were “extremely rare” in the region, making it unlikely that the pandemic had started there. The findings directly contradicted others showing that cousins of SARS-CoV-2 were indeed circulating in China’s bats. (Local bats have also been found to harbor viruses related to SARS-CoV-1.)

    The original Chinese analysis of the Huanan market swabs, from February 2022, also stuck with China’s party line on the pandemic. One of the report’s graphs suggested that viral material at the market had been mixed up with genetic material of multiple animal species—a data trail that should have led to further inquiry or conclusions, but which the Chinese researchers appear to have ignored. Their report noted only humans as being linked to SARS-CoV-2, stating that its findings “highly” suggested that any viral material at the market came from people (at least one of whom, presumably, picked it up elsewhere and ferried it into the venue). The Huanan market, the study’s authors wrote, “might have acted as an amplifier” for the epidemic. But “more work involving international coordination” would be needed to suss out the “real origins of SARS-CoV-2.”

    The wording of that report baffled many scientists in Europe, North America, and Australia, several of whom had, almost exactly 24 hours after the release of the China CDC preprint, published early versions of their own studies, concluding that the Huanan market was the pandemic’s probable epicenter—and that SARS-CoV-2 might have made its hop into humans from the venue twice at the end of 2019. Itching to get their hands on China CDC’s raw data, some of the researchers took to regularly trawling GISAID, occasionally at odd hours—the only reason that Florence Débarre, an evolutionary biologist at the French National Centre for Scientific Research, spotted the sequences pinging onto the server late last Thursday night with no warning or fanfare.

    Within hours of downloading the data and starting their own analysis, the researchers found their suspicions confirmed. Several surfaces in and around one stall at the market, including a cart and a defeathering machine, produced virus-positive samples that also contained genetic material from raccoon dogs—in a couple of cases, at higher concentrations than of human genomes. It was Stall 29—the same spot where Holmes had snapped the photo of the raccoon dog, nearly a decade before.

    Slam-dunk evidence for a raccoon-dog host—or another animal—could still emerge. In the hunt for the wild source of MERS, another coronavirus that caused a deadly outbreak in 2012, researchers were eventually able to identify the pathogen in camels, which are thought to have caught their initial infection from bats—and which still harbor the virus today; a similar story has played out for Nipah virus, which hopscotched from bats to pigs to us.

    Read: Bird flu leaves the world with an existential choice

    Proof of that caliber, though, may never turn up for SARS-CoV-2. (Nailing wild origins is rarely simple: Despite a years-long search, the wild host for Ebola still has not been definitively pinpointed.) Which leaves just enough ambiguity to keep debate about the pandemic’s origins running, potentially indefinitely. Skeptics will likely be eager to poke holes in the team’s new findings—pointing out, for instance, that it’s technically possible for genetic material from viruses and animals to end up sloshed together in the environment even if an infection didn’t take place. Maybe an infected human visited the market and inadvertently deposited viral RNA near an animal’s crate.

    But an infected animal, with no third-party contamination, still seems by far the most plausible explanation for the samples’ genetic contents, several experts told me; other scenarios require contortions of logic and, more important, additional proof. Even prior to the reveal of the new data, Gronvall told me, “I think the evidence is actually more sturdy for COVID than it is for many others.” The strength of the data might even, in at least one way, best what’s available for SARS-CoV-1: Although scientists have isolated SARS-CoV-1-like viruses from a wet-market-traded mammal host, the palm civet, those samples were taken months after the outbreak began—and the viral variants found weren’t exactly identical to the ones in human patients. The versions of SARS-CoV-2 tugged out of several Huanan-market samples, meanwhile, are a dead ringer for the ones that sickened humans with COVID early on.

    The debate over SARS-CoV-2’s origins has raged for nearly as long as the pandemic itself—outlasting lockdowns, widespread masking, even the first version of the COVID vaccines. And as long as there is murkiness to cling to, it may never fully resolve. While evidence for an animal spillover has mounted over time, so too have questions about the possibility that the virus escaped from a laboratory. When President Biden asked the U.S. intelligence community to review the matter, four government agencies and the National Intelligence Council pointed to a natural origin, while two others guessed that it was a lab leak. (None of these assessments were made with high confidence; a bill passed in both the House and Senate would, 90 days after it becomes a law, require the Biden administration to declassify underlying intelligence.)

    If this new level of scientific evidence does conclusively tip the origins debate toward the animal route, it will be, in one way, a major letdown. It will mean that SARS-CoV-2 breached our borders because we once again mismanaged our relationship with wildlife—that we failed to prevent this epidemic for the same reason we failed, and could fail again, to prevent so many of the rest.

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    Katherine J. Wu

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  • What Happened to Hand-Washing?

    What Happened to Hand-Washing?

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    Way back in the early, whirlwind days of the pandemic, surfaces were the thing to worry about. The prevailing scientific wisdom was that the coronavirus spread mainly via large droplets, which fell onto surfaces, which we then touched with our hands, with which we then touched our faces. (Masks, back then, were said by public health authorities to be unnecessary for the general public.) So we washed our hands until they were raw. We contorted ourselves to avoid touching doorknobs. We went through industrial quantities of hand sanitizer, and pressed elevator buttons with keys and pens, and disinfected our groceries and takeout orders and mail.

    And then we learned we’d had it all backwards. The virus didn’t spread much via surfaces; it spread through the air. We came to understand the danger of indoor spaces, the importance of ventilation, and the difference between a cloth mask and an N95. Meanwhile, we mostly stopped talking about hand-washing. The days when you could hear people humming “Happy Birthday” in public restrooms quickly disappeared. And wiping down packages and ostentatious workplace-disinfection protocols became a matter of lingering hygiene theater.

    This whole episode was among the stranger and more disorienting shifts of the pandemic. Sanitization, that great bastion of public health, saved lives; actually, no, it didn’t matter that much for COVID. On one level, this about-face should be seen as a marker of good scientific progress, but it also raises a question about the sorts of acts we briefly thought were our best available defense against the virus. If hand-washing isn’t as important as we thought it was in March 2020, how important is it?

    Read: Don’t worry, it’s not COVID

    Any public-health expert will be quick to tell you that, please, yes, you should still wash your hands. Emanuel Goldman, a microbiologist at Rutgers New Jersey Medical School, considers it “commonsense hygiene” for protecting us against a range of viruses spread through close contact and touch, such as gastrointestinal viruses. Also, let’s be honest: It’s gross to use the bathroom and then refuse to wash, whether or not you’re going to give someone COVID.

    Even so, the pandemic has piled on evidence that the transmission of the coronavirus via fomites—that is, inanimate contaminated objects or surfaces—plays a much smaller role, and airborne transmission a much larger one, than we once thought. And the same likely goes for other respiratory pathogens, such as influenza and the coronaviruses that cause the common cold, Linsey Marr, an environmental engineer and aerosols expert at Virginia Tech, told me.

    This realization is not an entirely new one: A 1987 study by researchers at the University of Wisconsin found that a group of men playing poker with “soggy,” rhinovirus-contaminated cards were not infected, while a group playing with other sick players were. Now Goldman intends to push this point even further. At a conference in December, he is going to present a paper arguing that, with rare exceptions, such as RSV, all respiratory pathogens are transmitted predominantly through the air. The reason we’ve long thought otherwise, he told me, is that our understanding has been founded on faulty assumptions. Generally speaking, the studies pointing toward fomite-centric theories of transmission were virus-survival studies, which measure how long a virus can survive on a surface. Many of them either used unrealistically large amounts of virus or measured only the presence of the virus’s genetic material, not whether it remained infectious. “The design” of these experiments, he said, “was not appropriate for being able to extrapolate to real-life conditions.”

    The upshot, for Goldman, is that surface transmission of respiratory pathogens is “negligible,” probably accounting for less than .01 percent of all infections. If correct, this would mean that your chance of catching the flu or a cold by touching something in the course of daily life is virtually nonexistent. Goldman acknowledged that there’s a “spectrum of opinion” on the matter. Marr, for one, would not go quite so far: She’s confident that more than half of respiratory-pathogen transmission is airborne, though she said she wouldn’t be surprised if the proportion is much, much higher—the only number she would rule out is 100 percent.

    Read: The very real lessons America has learned from COVID

    For now, it’s important to avoid binary thinking on the matter, Saskia Popescu, an epidemiologist at George Mason University, told me. Fomites, airborne droplets, smaller aerosol particles—all modes of transmission are possible. And the proportional breakdown will not be the same in every setting, Seema Lakdawa, a flu-transmission expert at Emory University, told me. Fomite transmission might be negligible at a grocery store, but that doesn’t mean it’s negligible at a day care, where kids are constantly touching things and sneezing on things and sticking things in their mouths. The corollary to this idea is that certain infection-prevention strategies prove highly effective in one context but not in another: Frequently disinfecting a table in a preschool classroom might make a lot of sense; frequently disinfecting the desk in your own private cubicle, less so.

    Much of the conspicuous cleaning we did early in the pandemic was excessive, Popescu said, but she worries that we may have slightly overcorrected, lumping some useful behaviors—targeted disinfection, even hand-washing in some cases—into the category of hygiene theater. Whatever the setting, the experts I spoke with all agreed that these behaviors remain important for contending with non-respiratory pathogens. Recently, when several members of Marr’s family came down with norovirus, an extremely unpleasant stomach bug that causes vomiting, diarrhea, and stomach cramping, she disinfected a number of high-touch surfaces around the house. Picture that: one of the country’s foremost experts on airborne transmission wiping down doorknobs and light switches.

    Marr isn’t convinced we’ve overcorrected. Hand sanitizer still abounds, businesses still tout their surface-cleaning protocols, and air quality still gets comparatively little attention. Recently, she watched a person use their shirt to open the door of a visitor center without touching the handle … then proceed inside unmasked. There’s nothing wrong with taking certain precautions to prevent fomite transmission, she said—these should not all be dismissed en masse as hygiene theater—as long as they don’t come at the expense of efforts to block airborne transmission. “If you’re doing extra hand washing … then you should also be wearing a good mask in crowded indoor environments,” Marr said. “If you’re bothering to clean the surfaces, then you should be bothering to clean the air.”

    On Friday, with respiratory-virus season looming, CDC Director Rochelle Walensky tweeted out three pieces of advice for staying healthy: “Get an updated COVID-19 vaccine & get your annual flu vaccine,” “Stay home if you are sick,” and—not to be forgotten—“Practice good hand hygiene.” She made no mention of masks or ventilation.

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    Jacob Stern

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  • The Fatal Error of an Ancient, HIV-Like Virus

    The Fatal Error of an Ancient, HIV-Like Virus

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    Many, many millions of years ago, an HIV-like virus wriggled its way into the genome of a floofy, bulgy-eyed lemur, and got permanently stuck.

    Trapped in a cage of primate DNA, the virus could no longer properly copy itself or cause life-threatening disease. It became a tame captive, passed down by the lemur to its offspring, and by them down to theirs. Today, the benign remains of that microbe are still wedged among a fleet of lemur genes—all that is left of a virus that may have once been as deadly as HIV is today.

    Lentiviruses, the viral group that includes HIV, are an undeniable scourge. The viruses set up chronic, slow-brewing infections in mammals, typically crippling a subset of immune cells essential to keeping dangerous pathogens at bay. And as far as scientists know, these viruses are pretty uniformly devastating to their hosts—or at least, that’s true of “all the lentiviruses that we know of,” says Aris Katzourakis, an evolutionary virologist at the University of Oxford. Which means, a long time ago, that lemur lentivirus was likely devastating too. But somewhere along the way, the strife between lemur and lentivirus dissipated enough that their genomes were able to mix. It’s proof, says Andrea Kirmaier, an evolutionary virologist at Boston College, that lentivirus and host “can coexist, that peace can be made.”

    Détentes such as these have been a fixture of mammals’ genomic history for countless millennia. Scientists have stumbled across lentiviruses embedded in the DNA of not just lemurs, but rabbits, ferrets, gliding mammals called colugos, and most recently, rodents—all of them ancient, all of them quiescent, all of them seemingly stripped of their most onerous traits. The infectious versions of those viruses are now extinct. But the fact that they posed an infectious threat in the past can inform the strategies we take against wild lentiviruses now. Finding these defunct lentiviruses tells us which animals once harbored, or might still harbor, active ones and could potentially pass them to us. Their existence also suggests that, in the tussle between lentivirus and host, the mammal can gain the upper hand. Lemurs, rabbits, ferrets, colugos, and rodents, after all, are still here; the ancient lentiviruses are not. Perhaps humans could leverage these strange genetic alliances to negotiate similar terms with HIV—or even extinguish the modern virus for good.

    When viruses assimilate themselves into animal genomes in a heritable way, a process called endogenization, scientists generally see it as “kind of a mistake,” says Daniel Blanco-Melo, a virologist at the Fred Hutchinson Cancer Center. Once cemented into one host, the virus can no longer infect others; much of its genome may even end up degrading over time, which is “certainly not what it evolved to do.” The blunders usually happen with retroviruses, which have RNA-based genomes that they convert into DNA once they enter cells. The flip allows the viruses to plug their genetic material into that of their host, which is then forced to manufacture its pathogen’s proteins alongside its own. Sometimes, a retrovirus will inadvertently stitch itself into the genome of a sperm or an egg, and its blueprints end up passed to its host’s progeny. If the melding doesn’t kill the animal, the once-pathogen can become a permanent fixture of the creature’s DNA.

    Over time, the human genome has amassed a horde of these viral hitchhikers. Our DNA is so riddled with endogenous retroviruses, ERVs for short, that they technically occupy more space in our genomes than bona fide, protein-manufacturing genes do. But on the long list of ERVs that have breached our borders, lentiviruses are conspicuously absent, in both our genomes and those of other animals; up until the mid-aughts, some scientists thought lentiviruses might not endogenize at all. It wasn’t a totally wonky idea: Lentiviruses have complex genomes, and are extremely picky about the tissues they invade; they’re also quite dangerous, not exactly the kind of tenant that most creatures want occupying their cellular real estate. Or perhaps, some researchers posited, lentiviruses were endogi-capable, but simply too young. If they had only begun infecting mammals within the past few hundreds of thousands of years, there might not have been time for such accidents to occur.

    Then, some 15 years ago, a team led by Katzourakis and Rob Gifford, an evolutionary virologist at the University of Glasgow, discovered an endogenous lentivirus called RELIK in the genomes of rabbits and then in hares, a hint that it had lodged itself in the animals’ mutual ancestor at least 12 million years before. In an instant, the lentivirus timeline stretched, and in the years since has kept growing. Scientists have now identified endogenous lentiviruses in a wide enough array of mammals, Gifford told me, to suspect that lentiviruses may have been a part of our history for at least 100 million years—entering our very distant ancestors’ genomes before the demise of the dinosaurs, before the rise of primates, before the land masses of North and South America kissed. “That tells us just how long virus and host have been connected,” Katzourakis told me. Through those eons, lentiviruses and the mammals they afflict have been evolving in concert—the pathogen always trying to infect better, the animal always trying to more efficiently head its enemy off.

    Knowing that lentiviruses are so deeply laced into our past can help us understand how other mammals are faring against the ones that are still around today. Two species of monkeys, sooty mangabeys and African green monkeys, have spent so much evolutionary time with a lentivirus called SIV—the simian version of HIV—that they’ve grown tolerant of it. Even when chock-full of virus, the monkeys don’t seem to suffer the severe, immunocompromising disease that the pathogen induces in other primates, says Nikki Klatt, a microbiologist and an immunologist at the University of Minnesota. The key seems to be in the monkeys’ ultra-resilient, fast-healing guts, as well as their immune systems, which launch more muted attacks on SIV, keeping the body from destroying itself as it fights. Such immunological shrugs could enable certain retroviruses to eventually endogenize, says Lucie Etienne, an evolutionary virologist at the International Center for Infectiology Research, in Lyon, France.

    Many mammals have also developed powerful tools to prevent lentiviruses from reproducing in their bodies in the first place—proteins that can, for instance, mess with viral entry or replication, or prevent new viral particles from busting out of already infected cells. Viruses, too, can mutate and evolve, far faster than animals can. That’s given the pathogens plenty of chances to counteract these defenses; HIV, for instance, has no trouble sidestepping or punching through many of the shields that human cells raise against it.

    Read: Could genetics be the key to never getting the coronavirus?

    But take the equivalent immune-defense protein from a monkey, and HIV “cannot degrade that,” says Michael Emerman, a virologist at the Fred Hutchinson Cancer Center. Other primates have had different infectious histories from ours, which have shaped their immune evolution in distinct ways. Studying those primates’ genomes—or maybe even the genomes of mammals that are carrying lentiviruses as neutered genetic cargo—might eventually inspire therapies that “augment our immunity,” Emerman told me. At the very least, such experiments could point scientists to lentiviruses’ common weak spots: the parts of the virus that ancient immune systems once targeted successfully enough that their hosts survived to tell the tale. “Evolution has already taught us the best places to target retroviruses,” says Maria Tokuyama, a virologist at the University of British Columbia. “Why not push for the types of interactions that we already know have worked?”

    Another, perhaps more radical idea might yet give way to an HIV cure: speeding the path toward endogenization—allowing lentiviruses to tangle themselves into our genomes, in the hopes that they’ll stay permanently, benignly put. “We could figure out a way to silence the virus, such that it’s there but we don’t care about it,” says Oliver Fregoso, a virologist at UCLA. One of the holy grails of HIV research has always been cooking up a vaccine that could prevent infection—an extraordinarily difficult thing to do. But if some sort of gentle armistice can be reached, Boston College’s Kirmaier told me, “maybe we don’t need to go that far.”

    Cedric Feschotte and Sabrina Leddy, virologists at Cornell, are among those pushing for such an intervention. They’re capitalizing on HIV’s tendency to go dormant inside cells, where it can hide from some of our most powerful antiretroviral drugs. The virus essentially “plays dead,” Leddy told me, then reawakens when the coast is clear. But if HIV could be silenced stably, its rampage would end when it jammed itself into the genome. “We’re hoping to emulate this natural path that ERVs have taken,” where they’re effectively locked in place, Leddy said. The imprisoned viruses could then be excised from cells with gene editing.

    The idea’s ambitious and still a way off from yielding usable treatments. But if it works, it could produce an additional perk. After setting up shop inside us, our viral tenants can start to offer their landlord benefits—such as fighting off their own active kin. In recent years, researchers have found that some animals, including cats, chickens, mice, primates, sheep, and even humans, have been able to co-opt proteins from certain endogenous retroviruses to create blockades against incoming viruses of similar ilk. Blanco-Melo and Gifford were part of a team that made one such discovery in 2017, describing an ERV that ancient monkeys and apes might have used to strip viral entryways off the surfaces of their cells. When encountering an ERV-ed-up host, the infectious, still-pathogenic version of that ERV would no longer have been able to get in.

    Eventually, the active retrovirus “just went extinct,” Blanco-Melo told me—an outcome that he thinks could be attributable to the antics of its endogenous counterpart. It’s a devious move, essentially a way to “turn the virus against itself,” Kirmaier said. This sort of friendly-fire tactic may already be at work among lentiviruses, duking it out inside and outside host genomes: Species with endogenous lentiviruses usually aren’t bedeviled by active lentiviruses, at least none that has been identified yet, Fregoso told me. With any luck, the same could someday be true for HIV, the virus little more than a memory—or an idle fragment in our cells.

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    Katherine J. Wu

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  • A Simple Rule for Planning Your Fall Booster Shot

    A Simple Rule for Planning Your Fall Booster Shot

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    In less than two weeks, you could walk out of a pharmacy with a next-generation COVID booster in your arm. Just a few days ago, the Biden administration indicated that the first updated COVID-19 vaccines would be available shortly after Labor Day to Americans 12 and older who have already had their primary series. Unlike the shots the U.S. has now, the new doses from Pfizer and Moderna will be bivalent, which means they’ll contain genetic material based both on the ancestral strain of the coronavirus and on two newer Omicron subvariants that are circulating in the U.S.

    These shots’ new formulation promises some level of protection that simply hasn’t been possible with the original vaccines. “A bivalent vaccine will have some benefit for almost everybody who gets it,” Rishi Goel, an immunologist at the University of Pennsylvania, told me. “How much benefit that is, we’re still not exactly sure.” People who aren’t at high risk could end up only marginally more protected against severe outcomes, and no one thinks the shots will banish COVID infections for good. There is, however, a simple rule of thumb that nearly everyone can follow to maximize the uncertain gains from a shot: Wait three to six months from your last COVID infection or vaccination.

    Put that rule into action, and it plays out a little differently, depending on your circumstances.

    If you haven’t had an Omicron infection:

    If you haven’t had COVID since about November 2021, the advantage of a bivalent booster over the original formula is obvious, and as long as you haven’t gotten boosted recently, there’s every reason to get the new one right away. (If you have been boosted in the past few months, your antibody levels are probably still too high for a new shot to do much for you.) Marion Pepper, an immunologist at the University of Washington, told me that Americans who have already gotten three or more doses “have probably maxed out the protective capacity” of the original shots. By contrast, the bivalent vaccines offer something new to those who have so far escaped Omicron: a lesson on the spike proteins of the BA.4 and BA.5 subvariants, which will help the immune system fight the real thing should it get into your body. “I’m just super excited to get the bivalent vaccine,” says Jenna Guthmiller, an immunologist at the University of Colorado who has not yet had COVID. “I think it’ll be really nice and ease my mind a little bit.”

    Read: The pandemic’s soft closing

    If you have had an Omicron infection:

    Veterans of Omicron infections might still have something to gain from seeing the BA.4 and BA.5 spike proteins—especially if your goal is to avoid getting sick with COVID at all. Past a certain number of shots, boosters’ impact on your long-term protection against severe disease is unclear, Goel told me. Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia, told me he doesn’t plan on getting a booster at all this fall because, after three vaccine doses and an infection, “I think I’m protected against serious illness.” But if you want to stave off infection, Goel said, “the bivalent vaccines, or really any variant-containing vaccines, have real value.” That’s because formulas based on a given variant have been shown to temporarily increase your stock of antibodies that target that variant.

    How long that extra-protective state lasts, or whether it’s sufficient to prevent any infection whatsoever, is still a scientific puzzle. The original boosters were shown to increase antibody levels to a peak about two weeks after the shot, then decay steadily over the following three months. We don’t know yet whether a bivalent formula will change that timeline, Goel said.

    But you can still use it to estimate approximately when your protection will be at its highest. You might, for example, choose to err on the early side of that three-to-six-month timeline if you have a particularly high-risk event coming up in the next few weeks. “If all we had was the original booster and I was going to an indoor wedding or something, I think it would be reasonable to get that booster,” Pepper said.

    Read: The BA.5 wave is what COVID normal looks like

    If you had an Omicron infection this summer:

    “You’re still riding the wave of antibodies that you generated as a result of that infection,” Guthmiller told me, so a shot won’t do much for you yet. That’s true regardless of which Omicron subvariant you might have been infected with, she said, because BA.2 infections have been shown to protect fairly well against today’s dominant strains, BA.4 and BA.5. (BA.2 became dominant in the United States back in March.) The severity of your illness doesn’t really matter either, Goel said. A higher fever and more intense cough might indicate that your immune system got extra revved up, he said, but they could just as easily mean that your body needs more help responding to the coronavirus. In either case, once a little more time has passed, getting the bivalent vaccine could help extend your body’s memory of its last COVID encounter, and keep infection at bay.

    If you’re at high risk:

    Certain groups of people should get any booster as soon as it’s available to them, the experts I spoke with emphasized to me: immunocompromised people, people over the age of 50 or so, and people with medical conditions that put them at high risk of severe disease. If you fall in one of these categories and haven’t received all the boosters you’re eligible for, “I wouldn’t wait for the bivalent,” Offit said. For people in these high-risk categories who have already gotten the recommended number of boosters, you should get the new one as soon as it’s available to you. (The FDA and CDC have not yet indicated whether they will recommend a waiting period between your most recent shot and the bivalent booster.) Goel recommended waiting at least a month after your most recent infection or shot, but if you’re very worried about your risk, you don’t need to stretch the delay to three months. Your body might still have extra antibodies floating around, but with no practical way to check at scale, “I’m honestly in favor of recommending boosting as a way to maximize individual benefit,” he said.

    Read: America’s fall booster plan has a fatal paradox

    If you want to wait and see:

    Waiting is always an option if you want to know more about how the bivalent vaccines perform. The FDA and CDC are set to green-light the shots based on human data from the existing boosters and other experimental bivalent boosters that didn’t make it to market in the U.S.—plus trials on the new formula in mice. Pfizer and Moderna simply haven’t progressed very far in their human trials. While there’s no reason to suspect that the new shots won’t be safe, Offit recommended opting for the original boosters until more safety and efficacy data are available, which could be as soon as a couple of months after the rollout—as long as the vaccine makers or the government collects that information and makes it public. But Guthmiller and Goel said they weren’t concerned about the lack of human data, and the bivalent shot is almost certainly the better bet.

    There is one significant reason to avoid waiting too long for the bivalent shot: It offers the greatest protection against infection from the subvariants it’s actually designed around. BA.4 and BA.5 might be with us through the fall and winter—or they might give way to a different branch of Omicron, or even a variant that’s entirely unlike Omicron. You’d certainly be better off against this new variant with a bivalent booster than no booster at all. But if you want to maximize your anti-infection shield while you have it, consider putting it up against the enemy you know.

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    Rachel Gutman-Wei

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