How Bird Flu Became a Human Pandemic Threat

Scientific American

6 days ago

Rachel Feltman: For Scientific American 's Science Quickly, I'm Rachel Feltman.
H5N1 bird flu has been making a lot of headlines since last year, and for good reason: since March 2024 this subtype of bird flu has infected upwards of 1,000 herds of dairy cattle, raising concerns about the virus's ability to pass between mammals.
This week Science Quickly is doing a three-part deep dive to bring you the latest research on bird flu. From visiting dairy farms to touring cutting-edge virology labs we'll explore what scientists have learned about bird flu—and why it poses such a potential risk to humans.
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Today's episode brings us back to the start: the wild flocks where new strains of bird flu evolve and spread. Our host is Lauren Young, associate editor for health and medicine at Scientific American.
[CLIP: Birds cawing.]
Pamela McKenzie: So many red knots—it's unbelievable.
Lauren Young: Out on Norbury's Landing, a small strip of sandy beach at the southern tip of New Jersey on the Delaware Bay, Pamela McKenzie peers through her binoculars at a massive flock of shorebirds.
McKenzie: It's just, like, a sea of red bellies.
Young: A flurry of different migratory birds, including red knots, ruddy turnstones and sanderlings, are making a pit stop on their long migration up to the Arctic Circle.
The birds are just in sight, and Pam desperately wants to get closer without disturbing them. But there's a problem: the high tide has filled a small channel that's blocking our path.
Young (tape): Wow, there's, like, tons of them over there. That's wild.
McKenzie: Of course, right where we need to go.
Young: So most people go to the beach for the cool waves, the salty breeze and the sunshine. Some might go to collect seashells. But Pam is out here collecting bird poop.
Every year in mid-May she hops between the various beaches of Delaware Bay, scooping poop that just might contain avian influenza viruses. By the second day of this year's collection her team had already found samples that came back positive for different bird flu viruses, but not the headline-making H5N1—at least not yet.
McKenzie: What's unique about Delaware Bay is that it's a hotspot for influenza. Every year these birds migrate here, and we find influenza—and different influenza—every year.
Young: Pam is a virus detective. As director of surveillance for the St. Jude Center of Excellence for Influenza Research and Response she and her fellow research scientists take an annual visit to Delaware Bay. They do this to stay on top of the avian influenza viruses actively circulating in the flocks of migrating shorebirds.
Robert Webster: One of the very important contributions that the laboratory here at St. Jude has made was the realization that influenza in aquatic birds replicates mainly in the intestinal tract and the birds poop it out.
Young: That's Robert Webster. He first visited Delaware Bay in 1985. Robert began St. Jude's influenza surveillance research at the bay, which has continued for the last 40 years.
Webster: Vast quantities of virus [were] in the feces. And so going back to Delaware Bay we didn't have to catch the birds; we simply followed them and took fecal samples from the beach when they pooped.
Young: The reason the shorebirds are here, pooping out a lot of influenza, has to do with the full moon—the first full moon in May, to be exact. The moon's gravitational pull causes the high tides to swell, drawing in thousands of horseshoe crabs, tussling in huge mating piles along the waterline. And the birds know this is the start of the crabs' mating season.
[CLIP: Waves crash on the beach, and birds caw.]
Young: Standing on the shore of Norbury's Landing on a blustery mid-May afternoon, I watched this scene unfold.
Young (tape): So that one is attached and mating.
McKenzie: Yeah, so if she was over here laying eggs, it would be trying to fertilize the eggs, and—like right here: see how its claws are attached to her?
Young: The heavily armored crabs look a bit alien, and sometimes a bit silly, as they draw odd tracks in the sand like uncoordinated Roombas. The ancient arthropods burrow into the sand and lay millions of gelatinous eggs. Those eggs provide the perfect buffet for the migrating birds that need to bulk up before their next leg in their journey.
McKenzie: They're pretty thin though, so they'll be around for a while. They're not nice and fat.
Young: And Pam needs the birds to eat because she needs them to poop.
As time passes and the tide retreats, first the birds swoop in to feast, and then Pam comes in, hot on their trail of droppings. After 15 years of doing this work Pam has developed a special eye for bird poop. She can make a pretty good first guess of what poop belongs to the migratory bird she's most interested in.
McKenzie: Here's one. That's one. It's probably a sanderling, like, small—you know, it's small, so probably a small bird. So this right here, this is so crass [laughs], but it's like a little log, and ruddy turnstones tend to drop logs, so.
Young: Fresh poop is best—damp but not drenched from the tide. This increases the odds it'll contain live virus that can be sequenced back at the lab. Once Pam spots a promising, intact poo she'll use a swab to swiftly scoop the sample from the sand and into a vial.
St. Jude's research center holds a library of more than 20,000 viruses, including isolates of various iterations, or subtypes, of avian influenza collected from Delaware Bay and other locations around the world.
Influenza subtypes are generally classified based on two specific surface proteins: hemagglutinin and neuraminidase. They represent the H and the N in flu names you've probably seen, like the common seasonal flu subtypes H1N1 and H3N2.
There are 144 H and N possible combinations of avian influenza. And over the years the St. Jude team has detected nearly every subtype in fecal samples collected at Delaware Bay. That includes the subtype that's been on our minds a lot lately.
Webster: Amongst those was H5N1, indeed, but not from the European or Chinese ones.
Young: The particular shorebirds stopping by Delaware Bay might not be carrying the kind of bird flu that could be dangerous to domestic animals or humans. But with the right genetic mixing we could potentially see outbreaks of a new 'killer' strain like the one currently ripping through U.S. farms.
Since 2022 a deadly new strain of H5N1 has infected more than 170 million domestic poultry, according to the U.S. Department of Agriculture. The virus has raised our egg prices, led to the culling of millions of chickens and infected upwards of 1,000 herds of dairy cattle since March 2024.
But to really understand the high-pathogenic H5N1 in our cows and chickens—and where it might go from here—we have to go back in time and look at wild birds.
Young: Wild birds, particularly aquatic birds, are hosts, or reservoirs, of different influenza viruses. They're categorized as either low-pathogenic or highly pathogenic, depending on how well they cause disease in chickens. A highly pathogenic, or 'high-path,' virus, as many influenza researchers like to call it, can wipe out an entire poultry flock in just a few days.
The earliest records of high-path avian influenza are believed to come from the late 1800s, when what was known at the time as 'fowl plague' ripped through poultry in Europe. Sporadic spillovers from wild to domestic birds have continued ever since.
Keiji Fukuda: In the influenza field it was clear that there was a very large group of influenza viruses, which infected birds and sometimes infected animals, and then there was a much smaller group of human influenza viruses, which infected people.
Young: That's Keiji Fukuda, a retired physician and influenza epidemiologist who worked for various institutions, including the University of Hong Kong, World Health Organization and the U.S. Centers for Disease Control and Prevention.
Fukuda: We thought these were separate groups of viruses and that animal influenza viruses did not infect humans.
Young: That changed in 1997, when a previously healthy three-year-old boy in Hong Kong was hospitalized and developed a severe pneumonia. Six days later the boy died. Influenza researchers around the world were called upon to help identify the exact type of virus. Robert was one of them.
Webster: It couldn't be identified at CDC. It couldn't be identified in London or in Holland, where they sent it, and they applied to me for the whole range of influenza virus reference serum, and they identified this virus as an H5, an H5N1. And no one would quite believe that this virus had killed the child.
Young: That shocked scientists and public health leaders, including molecular virologist Nancy Cox. She's retired now but worked at the CDC from 1975 to 2014 and was leading the agency's influenza branch in 1997.
Nancy Cox: We didn't expect to see high-path avian influenza viruses infecting humans. We just didn't expect that. We hadn't seen it before. It was really quite out of left field.
Young: Questions started flying rapid-fire.
Fukuda: How could this boy have become infected?
Cox: Where'd this virus come from? Could it have been a laboratory contaminant from eggs that had come in from an infected farm?
Fukuda: Was this boy associated with any kind of unusual exposures?
Cox: Were there other cases that had yet to be identified in Hong Kong?
Young: Everyone hoped the child was a tragic one-off case. But a few months later their worst fears became a reality: more people developed H5N1 infections.
Keiji, who was also with the CDC at the time and had worked with local public health officials on the ground on the first case, returned to Hong Kong.
[CLIP: A reporter interviews Keiji Fukuda during a 1997 press conference: '[Is there a] possibility this virus could, could become stronger in, in terms of its efficiency?']
[CLIP: Fukuda responds to the reporter: 'Well, by stronger, you mean it could become more adapted to humans and sort of pass through? Yes, there is that possibility.']
Young: That was younger Keiji back in 1997, talking to a reporter at a press conference in Hong Kong as the outbreak was unfolding.
Fukuda: We're dealing with a virus which has remained persistent for at least some period of time, and we have no idea: 'Is this the beginning of another pandemic?' And the investigations took on a whole different flavor. It was very serious.
Young: Keiji says the team eventually determined that the virus seemingly spread through traditional live bird markets, often referred to as wet markets. As is the case in many Asian cultures it is common for people in Hong Kong to purchase fresh poultry, including chicken, duck and goose, that is often killed on-site.
Guided by public health advisers, government officials ordered that the markets suspend sales and get cleaned—and that farms and markets cull all poultry.
Fukuda: At that time it was a very kind of disquieting decision and implementation. You know, we had never before recommended the culling of such a large number of birds.
Young: Although it was a brutal decision for farmers and sellers the tactic worked, effectively squashing an outbreak that seemed on the verge of taking off. By the end of the outbreak six people had died of the 18 with confirmed infections. Thankfully there was no evidence of human-to-human transmission, which is key to kick-starting a pandemic.
The genetic sequences of the virus also revealed genes tracing back to its likely reservoir: waterfowl, or geese. Here's Nancy.
Cox: What we saw at the very beginning of the H5N1 outbreak back in 1997 is that the viruses that we identified from poultry and from people were really very, very similar.
Young: But she says a lot has happened since the 1997 Hong Kong outbreak.
Cox: Now we've had this virus circulating globally, and what we're seeing is a huge amount of diversity, and what does that mean? It means that we have a lot more opportunities for the virus to develop the ability to infect humans more efficiently and then eventually, potentially, to become transmissible from human to human.
Young: As H5N1 has fanned across the globe over the years its activity has been a bit like a simmering volcano: occasionally waking up in dramatic spurts, only to go quiet again. And each time it flares up the virus gets a new opportunity to tweak itself—ever so slightly.
Wendy Puryear: During that whole 30-year time period there continued to be ongoing evolution and shifts and changes in the virus.
Young: Wendy Puryear is a scientist studying influenza evolution and adaptation at the Cummings School of Veterinary Medicine at Tufts University.
Puryear: It's an RNA virus, and that means that it is sloppy in the way that it replicates, so there's constantly slight changes that are being introduced every time that virus goes through a replication cycle.
Young: Wendy's research at Tufts focuses on the surveillance of different subtypes of influenza and wildlife. She's been watching with increasing unease how changes, or mutations, are creating a vast diversity of H5N1 viruses—including ones that might be better at infecting different animals.
Puryear: Prior to the COVID pandemic the thing that many of us were very concerned would be the next pandemic of large impact on human health was influenza. So this is one that we've been worried about for a long time.
Young: Wendy says H5N1 keeps hitting mutation milestones that are getting too close for comfort.
Puryear: We keep going further down that road of 'at least it hasn't.'
'At least it hadn't gone into a lot of wild animals and was disseminating around the globe.'
Young: Now lineages of the virus have been detected in animals in nearly every continent. H5N1 has established itself in domestic poultry in various countries in Asia, the Middle East, the Americas, Africa and Europe.
And [starting] a few years ago the number of bird species carrying H5N1 has ballooned. More than 500 different avian species, ranging from seabirds to songbirds, have tested positive for H5N1, according to the Food and Agriculture Organization of the United Nations.
Puryear: ' Well, now it is. Well, at least it wasn't going into mammals.'
Young: Then around 2020 and 2021 highly pathogenic H5N1 started to infect different mammals, to date affecting more than 90 different species in total, including coyotes, minks, opossums, skunks and rodents.
The virus had previously been found in the occasional fox or tiger, typically predators that might've eaten an infected wild bird. But the list of newly infected mammal species is growing in a way that hasn't been seen before.
Pruyear: 'At least there wasn't evidence of mammal-to-mammal transmission.' Well, then we had that in marine mammals in South America.
Young: In 2022 and 2023 the virus spread among various marine animals along the coast of Peru and Chile, killing more than 30,000 sea lions. It happened so rapidly that scientists suspected it must have traveled directly between animals.
The virus made its way around to the Atlantic coast. Groups of dolphins, porpoises and otters were also infected.
Puryear: 'Well, at least it's not in a context that we're in close proximity between humans and those mammals.' Well, now it's in dairy cattle.
Young: No one expected the virus to hit U.S. dairy cows. How it got onto farms in the first place is still a bit of a mystery; you'll hear a lot more about that in the next episode of this three-part series. But it's important to say that scientists do have a strong hunch about how the virus made that jump—and you probably guessed it: wild birds.
Louise Moncla: There's this whole diversity of low-path viruses that don't really cause as many problems that circulate endemically in these wild birds in North America.
Young: That's Louise Moncla. She's a pathobiologist leading a lab at the University of Pennsylvania that's building a family tree of avian influenza viruses.
Moncla: Through this process called reassortment this incurring kind of new virus that entered started mixing with those viruses, and so we now have this diverse mixture of viruses sort of circulating in wild birds, resulting in the emergence of these new genotypes ...
Young: New genotypes, or unique genetic profiles, like the high-path H5N1 that scientists think started infecting dairy cows. This genetic mixing, or reassortment of different influenza viruses, occurs when they co-infect one host: a bird, an animal or, worse, a human. That opens up the window for genetic information to be exchanged.
Here's Wendy again to unpack a bit of what Louise said.
Puryear: Not only do you have this regular evolution that happens with the virus being sloppy in how it replicates, but the fact that it has its genome on separate pieces, its genetic information is actually—those genes are on separate chunks of, of RNA, and that means that it can take a whole gene and swap it out with a different form of influenza, so that gives a whole new kinda Frankenstein version of the virus that can then move forward.
Young: And this process of virus info swapping can potentially spiral into something much bigger—and deadlier.
Here's Louise again.
Moncla: Reassortment is a really important process for influenza evolution because it has led to every past pandemic that we know about. So we usually get influenza pandemics when viruses from two different species mix via reassortment and [that] results in a virus for which a host population like humans doesn't have any prior immunity.
Young: But those viral swap meets leave footprints—clues that help researchers like Wendy and Louise track influenza evolution through time and space. Louise's flu family tree models, for instance, allow for real-time tracking of noteworthy genetic changes in H5N1. The tree's branches show small shifts from the virus's sloppy reproduction and the big evolutionary leaps from reassortment.
Moncla: If you sample and sequence those viral genomes, you can use those mutations to link cases together. So these genomes provide this nice little map of how this virus has been moving between different host species or populations or geographic areas.
Young: And wild birds help paint a picture of where the virus might be now and where it might go next. These feathered virus carriers have effectively moved influenza around the world and into our domesticated animals.
But Louise, Wendy, Nancy, Keiji and folks at St. Jude are all quick to say that migrating birds and wildlife shouldn't be blamed for H5N1's current stronghold—it's the way that humans monitor and respond to the situation.
Moncla: Now that these viruses are really being driven by transmission of wild birds we need to understand how these viruses evolve in wild birds a lot better. And so something I'm really hoping continues to happen is surveillance in wild birds. You know, so without this kind of continuous surveillance effort in wild birds we wouldn't have been able to understand the outbreak in dairy cattle or these human spillovers and where they're coming from.
Young: Wild birds can't be stopped, but they can be watched—just like how the St. Jude group is surveying the shorebirds at Delaware Bay, year after year.
[CLIP: Birds caw.]
Young: Back in Delaware Bay, armed with vials of bird poop and a compact scientific camper van, another virus hunter is doing exactly that.
Lisa Kercher: My name is Lisa Kercher. I am the director of laboratory operations for the Webby Lab group at St. Jude Children's Research Hospital, which is a—our lab group is a large influenza research laboratory.
Young (tape): Great, and tell us where we are right now.
Kercher: Yes, we're sitting in a 19-foot toy hauler that is a trailer camper that has been built out to work as a molecular biology lab.
Young: Lisa lives part time in her truck and camper, living and sleeping alongside carefully stored poop samples preserved in cold liquid nitrogen. The space is a cozy fit for the two of us and her sweet English Labrador retriever, Jax.
Like a lot of campers it's got a small kitchen, bathroom and a very comfortable bed, according to Lisa, but she's customized the space with a makeshift lab bench.
Kercher: I have like already shattered the door once and had to have it replaced.
Young (tape): No...!
Young: Her working area is stocked with protective gear, reagents, pipettes, well plates and a variety of miniature equipment, including a PCR machine that can quickly amplify DNA from samples Pam collected the day before.
Kercher: It can then immediately run a PCR for flu and for H5, and I know on my little laptop here if that's positive within about an hour. And so by the time I'm driving home I have the prevalence of the flu that was in these shorebirds for the time I was here. So it's a great first step.
Young: At that point in site collecting she had processed 250 fecal samples. By the end of the week the team will have collected 1,000. Later the samples will be transported to St. Jude's main labs in Tennessee to verify Lisa's initial readings.
Before she started doing this real-time surveillance work two years ago, the team wouldn't know what avian influenza subtypes they had on their hands until about six months after the sample collections.
Kercher: It's very hard to do epidemiology of how the virus is moving and tracking when you spend six months waiting for the sequence to come out of a national lab or any big lab. It's just hard logistically to then backtrack and figure that out. You can do it, but it's usually a year later. And then you are usually faced with a whole different virus by that time. So the point of doing it faster is so that you can do risk assessment in more real time.
Young: But if Lisa wants to be really fast, she needs more data. The poo samples from the beach are valuable sources of viral sequences, but they can't offer the full flu picture.
Kercher: So when you get a flu virus from a fecal sample you have to give it a name, you have to same say the species that it came from. How do you know?
Young: Like solving any mystery the researchers want to answer the big whodunit—or in this case, who- dung -it.
Knowing the exact bird species that pooed the poo requires more testing and more time, and it's not something that she can do from inside the camper lab. That's why Lisa is teaming up with local wildlife ecologists. Enter Larry Niles and his bird-catching cannon.
Larry Niles: Most of those noises are from the sanderling. We caught almost 100 sanderlings.
Young (tape): Wow.
Niles: We caught a handful of [red] knots and ruddy turnstones.
Young: The day before visiting the mobile lab I was on the beach with Lisa and Larry. He co-leads the Delaware Bay Shorebird Project with Wildlife Restoration Partnerships. Larry has been catching shorebirds here as part of his conservation work for the last 29 years. And yes, his group uses something called a cannon net to nab these birds because ...
Niles: See, shorebirds very difficult to catch because they're hard to get close to because they're used to being out on flats like sand flats. Today we used two cannon, and see, the advantage of that is: the net, which is about 40 feet [roughly 12 meters] long, when we hook it up to the cannons, that net goes so fast that it gets over the birds before they have the time to react.
Young: The birds are temporarily corralled in cloth-covered boxes, waiting for Larry and the other researchers and volunteers to gently pull them out to collect various data points. They'll measure the birds' wings and beaks, weigh them and take a blood and feather sample before they're released back to the horseshoe-crab-egg feast on the beach.
And though Larry has his own research to do on the ecology of the birds—their health, their population numbers and what might threaten those things—he says it's a real bonus to have virus detectives like Pam and Lisa to work with, side by side.
Niles: I'm not a virologist; I'm an ecologist. But I understand the ecology of things, and I think melding the ecology of birds with the ecology of these viruses, that's our part—working with the virologists so that together we could figure it out.
Young: For Lisa, getting access to the shorebirds directly unlocks all sorts of crucial information.
Kercher: So, when you're getting the samples straight from the birds then you already know the species, so that just makes it a little bit easier.
Young: And it's along these migratory routes, called flyways, where the birds, the ecologists and the virologists with camper labs need to meet.
Kercher: When the avian virus jumps into a mammal it has the opportunity to mutate into becoming more mammalianlike, and that is why we are so concerned in the flyway.
Young: There are four main flyways, [also] called avian superhighways, that run through North America. Since getting her mobile lab up and running Lisa has driven it thousands of miles up and down these flyways to sites in Alberta, Canada, and northwest Tennessee. But these avian superhighways have also become increasingly concerning for H5N1.
Kercher: Those birds are carrying this virus in greater numbers and in lots more areas where there's potential for spillover into domestic poultry farms. And of course, this happened in the dairy farms—it spilled over into the cattle, so this virus is now very prevalent all over North America. But the flyways are important because the birds that carry it are moving quickly down the flyway in a very short period of time, and you have a lot of opportunity for spillover there.
Young: Lisa says that speed matters for a rapidly changing virus like H5N1. She could imagine her mobile lab getting scaled up into a large biosurveillance network: multiple satellite labs dotted up and down all the flyways, relaying genetic sequences to other influenza trackers like Louise and Wendy but also to farmers on the ground trying to keep their chickens and cows healthy.
Kercher: Wouldn't it be great if the farmer had a way to go on his computer and look at a dashboard and say, 'Wow, I wonder where the flu is?' They need to know where it is circulating in the wild birds. And if they knew where it was ahead of time—or at least where it was coming from—they would have an opportunity, if they chose, to up their biosecurity a little bit.
Young: Until then virus detectors like Pam and Lisa continue to keep a watchful eye on the surprising twists and turns of H5N1, looking to the birds and the clues they leave behind.
Kercher: We'll never catch up with Mother Nature. We're never gonna catch up with the virus and how it mutates. But if we can get closer and approach it more, you can then look for mutations, much quicker things that make the virus resistant to antivirals or things that make it more mammalian adaptable. You would wanna know that sooner rather than later.
Feltman: That's all for today's episode, but there's lots more to come. Tune in on Wednesday for part two of our special series on bird flu, which explores how avian influenza made its unprecedented leap into cattle.
Science Quickly is produced by me, Rachel Feltman, along with Fonda Mwangi, Kelso Harper, Naeem Amarsy and Jeff DelViscio. This episode was reported and hosted by Lauren Young and edited by Alex Sugiura. Shayna Posses and Aaron Shattuck fact-check our show. Our theme music was composed by Dominic Smith. Special thanks to Michael Sheffield at St. Jude; the volunteers and collaborators with Wildlife Restoration Partnerships; and Kimberly Lau, Dean Visser and Jeanna Bryner at Scientific American. Subscribe to Scientific American for more up-to-date and in-depth science news.
For Scientific American' s Science Quickly, I'm Rachel Feltman. See you next time!