How do pandemics begin? There's a new theory — and a new strategy to thwart them

The illness struck the little baby suddenly.

It was a hot, sticky day late in the summer of 2017. Only 5 months old at the time, her little boy was a peaceful infant, his mother recalls. "He didn't make much of a fuss."

The family lives in a small fishing town near the South China Sea in Sarawak, Malaysia, at the mouth of the Rajang River. Their tidy home sits atop stilts, above a maze of canals and families' rowboats tied to piers.

She has six children now; the baby was her fifth. We aren't using their names to protect the family from stigma around the son's illness.

On that humid August day, something was terribly wrong with her child. First, he became feverish. The mother thought he might have the flu or a cold. "The fever went away quickly," she says. But by evening, the child began coughing and struggled to catch his breath. "He was breathing very fast," she remembers.

She took the baby to the nearest clinic, but his condition deteriorated. Doctors rushed them to the nearest city, Sibu. It's three hours away by ambulance, depending on how the ferries are running.

At the hospital, doctors admitted the infant to the intensive care unit. By then, the baby's lungs had begun to fail. They were filled with mucus. He couldn't absorb enough oxygen, his mother says, and doctors connected him to a machine to help him breathe.

For three long days, the child didn't get better. His mother worried for his life. "I was so concerned," she says.

He had pneumonia. "But doctors didn't know why," she says. They ran tests looking for a cause — a bacterium or virus. All the tests for the usual culprits came back negative.

But one pediatrician at the hospital had the foresight to know that scientists might one day have the tools to figure out the cause of the child's life-threatening pneumonia and that perhaps he had a pathogen that no one had detected before. "We are looking for novel infections, even types of viruses that we might not be aware of," says Dr. Teck-Hock Toh, who teaches at SEGi University and heads the Clinical Research Centre at Sibu Hospital.

Toh's team took a little white swab, like the ones in COVID-19 testing kits, and scraped inside the infant's nose. They took the sample to the laboratory, extracted the genetic material from the possible pathogens present and stored the sample in a freezer. In 2016 and 2017, Toh and his team collected about 600 samples like this one.

What doctors eventually found inside the sample — inside the baby's respiratory tract — has fueled a shift in scientists' understanding of how pandemics begin and made them reconsider the way they search for new threatening viruses. It has made them realize there could be an easier, more efficient way to find viruses like SARS-CoV-2 before they evolve into a global nightmare.

Spillover theories, old and revamped

For decades, scientists pretty much thought they understood how pandemics, such as COVID-19, began. It centers on this idea of what's called spillover.

Most new pathogens, up to 75%, come from animals. They're often viruses that have been circulating in animals for decades, even centuries. At some point, they jump — or "spill over" — into people.

For the past 10 years, I've been a global health reporter at NPR. That whole time, I've heard the same idea repeated over and over again about spillovers: They are extremely rare. Animal viruses tend to stay in their animal host. One way scientists have described it is that a virus spilling over is, in a way, winning the lottery: The virus is in the right place at the right time, and on top of that, it has special, rare characteristics that allow it to infect people. For all these events to coincide is remarkably rare, the thinking went.

This theory has shaped how scientists look for new deadly pathogens — or try to predict which ones could cause future pandemics. In particular, it led scientists to focus on searching for new viruses in wild animals. Since 2009, the U.S. government has spent hundreds of millions of dollars trapping wild animals, such as bats and rodents, cataloging all the viruses circulating in their bodies and then trying to predict which of these viruses will most likely spill over into people and cause a costly outbreak or pandemic. Unfortunately, this effort failed to detect SARS-CoV-2 before the virus could spread to multiple continents.

Over the past few years, a growing number of virologists and epidemiologists have begun to question whether this approach is feasible. Some have blatantly said it won't work.

"I think like projects cataloging viruses, doing virus discovery [in wild animals] is interesting from a scientific standpoint," says evolutionary biologist Stephen Goldstein at the University of Utah. "But from the standpoint of predicting pandemics, I think it's a ridiculous concept." The numbers just don't make sense, Goldstein says. Animals contain more than a million viruses, and only a tiny, tiny fraction of those will ever be able to infect people.

But what if the tiny fraction of animal viruses that do infect people actually jump into people way more frequently than scientists thought? What if spillovers aren't extremely rare but are common enough that scientists can actually detect them inside people?

Over the past few decades, few studies have actually looked for spillovers inside people to see how common they are.

In fact, scientists really haven't had the tools — or funding — to detect new viruses inside people, says Dr. Gregory Gray, who's an infectious disease epidemiologist at the University of Texas Medical Branch at Galveston.

"We probably have novel viruses in North America infecting people who work a lot with animals, especially domestic animals," Gray says. "We're just missing them because we don't often have the tools to pick them up."

Take that 5-month-old's illness in 2017, for instance. When a person comes to a hospital with a severe respiratory infection, it doesn't matter whether they're in Sarawak, Malaysia, or San Francisco, Calif. Doctors run tests to see what's causing the infection. But this panel of tests identifies the source of an infection only about 40% of the time, says virologist John Lednicky at the University of Florida. "I like to think about it as 60% of the time doctors have absolutely no idea what is causing the respiratory illness."

The problem is that the current panel of tests can detect only specific — and known — pathogens. "We test for about four to seven viruses and maybe a handful, or more, other organisms," Toh says. Doctors can't pick up new viruses that scientists haven't discovered yet.

Some scientists have been wondering: What are these other, unknown pathogens? Could some of them be new viruses spilling over from animals that scientists have never detected because nobody has really looked inside people?

A few years ago, Toh decided to try answering those questions. He teamed up with Gray at UTMB, who for 30 years has been studying respiratory infections in people who have worked with animals. Together, they focused their attention on one important family of viruses: coronaviruses.

Coronaviruses under investigation

When SARS-CoV-2 emerged in Wuhan, China, in 2019, scientists knew of six coronaviruses that could infect humans: SARS-CoV-1, which most likely jumps from civet cats into people; MERS, which jumps from camels into people; and four other coronaviruses that generally cause a common cold and have uncertain animal origins.

Outside humans, though, there may be about 1,200 unique coronaviruses, Gray says, infecting everything from waterfowl and rodents to monkeys and bats.

He thought that perhaps some of these animal coronaviruses are spilling over into people, making them sick and even putting them in the hospital. "So I asked postdoctoral fellow Leshan Xiu if he could develop a diagnostic tool that would capture all coronaviruses inside the respiratory tracts of pneumonia patients," Gray says. "That's what he designed. It's a very sensitive assay. It gives a signal if any coronavirus is present, and then you can sequence the signal to see what coronavirus is present" — and whether it's one that's been seen before in humans.

When Gray and Xiu were ready to test the tool, Toh over in Malaysia already had the perfect samples to try: the ones taken from pneumonia patients in 2017, including the sample from the baby boy's respiratory tract.

Toh mailed Gray's team about 300 of the patient samples, frozen on liquid nitrogen. And then with Xiu's new tool, they tested each sample one by one for signs of infections with a new coronavirus.

Right away, the team caught a signal, and not just in one or two patients but in eight, including the child. "The tool suggested nearly 3% of the patients were infected with animal coronaviruses that were not previously known to be human pathogens," Gray says. "That's a remarkable percentage." And it suggests this new coronavirus isn't extremely rare but could actually be relatively common in several parts of the world.

The results were so remarkable, in fact, that Gray initially thought perhaps they were due to contamination or a defect in the tool. "It was hard to believe. I even wondered if maybe we had some sort of problem with the lab."

At this point, Gray and his team didn't know exactly which coronavirus they were dealing with. They picked up a hint the virus might come from dogs. But that hypothesis didn't make sense at the time, says virologist Anastasia Vlasova, who's a world expert on coronaviruses and has a specialized lab devoted to studying them at Ohio State University. "Dog and cat coronaviruses were not thought to infect people," Vlasova says.

Nevertheless, Gray sent Vlasova eight of the patients' samples, including the 5-month-old baby's. Vlasova went to work, trying to figure out if indeed these patients had caught a new coronavirus.

Vlasova took a little bit of each sample and added it to a broth that contains dog cells. If indeed a dog virus infected their respiratory tracts, then the virus should be able to infect these cells and grow in the broth.

After three days, Vlasova checked the cells. She saw no signs of virus in any of them, except for one: that little baby. "Luckily, the virus grew very well," she says. The virus quickly multiplied inside the dog cells.

Now, with a bunch of virus particles at hand, she could finally figure out exactly what was inside the child's respiratory tract by sequencing the virus's genes. She found that indeed he had caught a dog coronavirus that scientists had never seen before.

The virus had another surprise, she says: Its genes suggested it could have come from pigs or cats as well. "We were able to see the evidence that the virus exchanged parts of its genome, in the past, with some feline and pig coronaviruses." (No one knows exactly how the baby was infected in 2017; his family does not keep pet dogs.)

Those findings were striking and suggested that the infant was likely the first known case of the seventh coronavirus known to infect people. But he wasn't the only one — not in the least.

Unbeknownst to Vlasova, another virologist 900 miles away was working to solve the exact same coronavirus puzzle. But the person infected wasn't in Malaysia. He lived in Florida.

Meanwhile, in Florida ...

In 2017, while Toh was collecting nasal swabs from people with pneumonia in Sarawak, Malaysia, John Lednicky at the University of Florida was looking for Zika virus in Floridians who had just returned home from traveling. One person, back from a trip to Haiti, had a scratchy throat and fever. Lednicky had stumbled upon the same dog coronavirus that was found inside the little boy.

And so, this new dog coronavirus, which scientists had thought couldn't jump into people, had spilled over both in Malaysia and 12,000 miles away in Haiti.

But its spillovers didn't stop there.

An analysis this past summer found that scientists had actually detected the dog virus two other times before inside sick people. In 2007, Thai scientists identified the dog virus in 8 of 226, or 3.5%, of children tested with respiratory infections. (At the time, the scientists mistakenly identified this virus as another coronavirus known to cause the common cold.) In Arizona, scientists found this dog-linked coronavirus in about 1.5% of people who had flu-like symptoms but tested negative for the flu.

"These spillover events [of the dog coronavirus] are likely happening all the time," says Gray at UTMB. "Unless you have the right tools, such as the diagnostics we have here, you wouldn't know about it."

A case in point: the recent studies from John Lednicky and his colleagues. In the past few years, they not only detected a new dog coronavirus inside a person, they also uncovered a pig coronavirus in not one, but three sick children in Haiti. And just like Gray and Toh, they found the virus quite easily.

"We were just looking at a random sample of children from Haiti — a very small sample at that — and we just casually found two spillover events," says Marco Salemi at the University of Florida, who helped lead the study. "If these spillover events were extremely or exceedingly rare, we would not have seen that."

In 2014 and 2015, Salemi and his colleagues collected blood samples from about 350 schoolkids in Gressier, Haiti, who fell ill for an unknown reason. They had fevers but never tested positive for known pathogens.

In three of the children, or nearly 1% of those tested, Salemi and his colleagues detected pig coronavirus, which normally attacks the intestines of the animals.

As with the dog coronavirus, scientists thought this virus couldn't infect people, Salemi says. "But in fact, while evolving in pigs, some of these viral strains acquired extra mutations that made the virus capable of replicating efficiently in human cells."

In their study, which appeared in Nature in November 2021, Salemi and his colleagues documented at least two spillovers from pigs into the Haitian children. But he suspects there were many, many more, given how easily they identified these two.

"Just to be clear, that's my guess," he says of the possibility of additional spillovers. "But considering that we weren't even looking for this virus and we casually found two spillover events, I think that there were probably many more."

Over in Kenya, an epidemiologist recently came to the same conclusion about another coronavirus: MERS. The virus circulates in camels and has infected herds repeatedly. Since doctors first detected MERS in people in 2012, the thinking has been that it rarely jumps into humans. But when Isaac Ngere of Washington State University in Nairobi, Kenya, took a closer look — and actually tried to detect MERS spillovers in people — he easily found them.

"Our study was unique because we followed these camels for two years, seeing them every week and also visiting the people who take care of them," Ngere says.

Throughout the study, many camels caught MERS. "There were a lot of camels coughing and having discharge from their mouths, eyes and nose," Ngere explains. "At the same time, quite a number of people who had been in contact with those camels also had symptoms of respiratory illness."

Indeed, Ngere and his team detected MERS virus inside three people who handle camels or in the handlers' relatives. At least 75% of these people had signs of previous MERS infections, the team found.

"So if you are handling camels in Kenya, you're at high risk of becoming infected," Ngere says. "And if you're older or have an underlying disease, like diabetes or hypertension, then you may be at high risk of having symptoms and possible severe disease."

Altogether, these clusters of studies paint a clear and striking picture of spillovers: Spillovers aren't like needles in a haystack. They're more like a rake sticking out of the side of the haystack. Once you start looking, you find them — everywhere. The barriers for some animal viruses to jump into humans are likely much lower than previously thought.

"I don't think spillovers are extremely rare because when people actually started looking for spillovers, they found them," says Goldstein, at the University of Utah. And they didn't just find them, they found them easily.

In fact, right now in the world, there's a group of animal viruses that are likely jumping into people every day, perhaps several times a day.

One study, published in August, estimated that more than 60,000 SARS-like viruses spill over from bats into people each year in Southeast Asia alone. "Like snowflakes during a nice winter snow, spillovers are trickling across our population every day," says Peter Daszak, who's president of the nonprofit EcoHealth Alliance and led the study.

"In any environment, even in our homes, every time we take a breath, we breathe in probably thousands of different bacterial and virus strains," says Salemi at the University of Florida. "We catch viruses by touching surfaces, by breathing, by petting our pets. Animal viruses are everywhere."

When I first heard Salemi say this — and read all of the studies with spillovers popping up easily — I have to admit it freaked me out a bit. I would hug my dog at night and imagine all of the dog coronaviruses flowing from her breath. Did a dog virus just spill over from her to me? What about my mom's cat or the neighbors' chickens I held the other day? Every animal seemed to be teeming with new viruses.

On top of that, if spillovers aren't rare, then why don't we have more outbreaks and pandemics? What's holding these viruses back?

But over the course of reporting this story, my view of spillovers switched 180 degrees.

First off, the vast majority of these spillovers don't harm anyone, Salemi says. Most people's immune systems fight off the pathogen without having symptoms at all. When a virus does trigger symptoms, the illness masquerades as a cold, flu or stomach bug.

On top of that, the virus rarely spreads to another person, or only to a few people. Outbreaks are small.

"The virus jumps into humans, infects a few people, and then the pathogen essentially does not have the capacity to really infect a large number of people," Salemi says. That's because the animal viruses, in the vast majority of cases, aren't adapted to live in humans or jump between us, he says.

Second, I began to realize that frequent spillovers may actually help scientists stop the next pandemic, and illnesses like the Malaysian infant's are central to this new strategy.

Epilogue: The case of the baby and the mystery virus

When I visited Malaysia in the fall to talk to the mother about her son's devastating illness, I was anxious to see how the child was doing — and to meet the boy. During our chat, a little boy wearing a Cookie Monster T-shirt walked shyly out of a bedroom, then hid behind his mother. She introduced him to me and said, "He is 5 years old now."

She told me that her baby spent five days in the ICU. "Then he took months to recover," she says. Similar to people with long COVID, he experienced shortness of breath, on and off, for two years. And he is small for his age.

"But now he is healthy and in kindergarten," she says, as he takes his mom's phone from her lap and starts playing a video game.

Despite all their pain and suffering, the mother says she is proud to have helped scientists, in some small way, identify this new coronavirus. But her baby's illness did more than that. It also helped point scientists to a more efficient and easier way to find potentially dangerous viruses.

To learn about this approach firsthand, I traveled inland about 150 miles from her house to the town of Kapit. Nestled between a river as wide as the great Mississippi and the mountains of lush Borneo rainforest, Kapit is a vibrant town filled with colorful buildings painted lime, pink and pale yellow.

In an open-air market, you can find freshwater fish, black olives, red star fruit and wild deer. Up on a hillside, inside a five-story building, you can find a glimpse of the future — the future of pandemic surveillance.

The building contains the town's hospital. Inside, Dr. Toh is busy at the pediatric ward, discussing patients with several of the hospital's doctors. They are currently caring for about a dozen children and babies who are sick with pneumonia and respiratory infections. Many of these children are struggling to breathe and absorb enough oxygen, Toh says.

Each year, this tiny hospital saves the lives of hundreds of kids with these types of infections. But it's part of a global mission as well. It's the site of an innovative project trying to detect the next dangerous coronavirus before it spreads around the world.

What scientists don't always realize, says Dr. Gray at UTMB, is that viruses don't jump from an animal into people and then trigger a pandemic right away. "It takes time — many years — for pathogens to adapt to humans," he says.

A virus needs to spill over many, many times before it evolves the ability to have transmission between people, he explains. "And then only rarely, over long time periods, does a pathogen become highly efficient in transmission," Gray adds. And that's when it becomes a global problem like SARS-CoV-2.

"So if we focus on pathogens that are beginning to take hold in people, such as the dog coronavirus that infected the 5-month-old in 2017, we're not looking at every animal for every possible pathogen. And we can catch these spillover viruses before they fully adapt and become highly transmissible," he says.

That approach would be much less expensive, he says. But that's not the sole advantage. It also gives the world time to study these new pathogens and prepare tests, treatments and even vaccines.

In Kapit, Toh explains how this alternative approach to new virus hunting works on a practical level.

In one small room of the hospital, he says, there's a little boy about 4 or 5 years old lying still in a crib. He's shirtless. Toh can see his chest rise and fall quickly. "He's breathing very rapidly," Toh tells me. Doctors tested him with a panel of known viruses and bacteria, but nothing has come back positive.

"We don't know what he has," Toh says. "And so I said to the team of doctors, 'Take a sample from his nose. Send it to Sibu Hospital and see what might be there' " — what new coronaviruses might be there.

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