In 1918, the world was struck by the Great Influenza, which killed between 25 and 100 million people over three years. The pandemic took people in the prime of their lives, with most victims

between the ages of 20 and 40. In the United States, where about 675,000 died, some have estimated that it was responsible for shortening life expectancy by up to 12 years. Despite the

havoc wreaked by the Great Influenza, it didn’t take long for people to move on and for memories to fade. Americans especially came to think of such events as things of the past—relics from

the time of tenement living and premodern medicine. Over the rest of the twentieth century, the United States skirted the worst ravages of other pandemics. The 1957–58 Asian flu, the 1968

SARS in 2002–4, the swine flu in 2009, and MERS in 2012. COVID-19 shocked the entire world out of its complacency. Hardly anyone could claim that their lives had not been disrupted in some

way as the pandemic overwhelmed hospitals, shut down schools and cities, sealed off borders, brought economies to a standstill, and, of course, killed so many people—in the United States, so

far, twice as many as the Great Influenza. As of September 2022, the World Health Organization (WHO) has recorded 6.5 million deaths from COVID-19, but the true toll may be two or three

times that number. In a perverse way, however, the scale of the pandemic has invited a sense of resignation and wishful thinking—surely, humanity has earned another long reprieve from such

horror. And the timing of the pandemic, coming as it did almost exactly 100 years after the 1918 pandemic, brought comparisons to a “100-year flood.” This actuarial term suggests a one

percent chance of disaster in any given year, but it is often incorrectly thought to mean that surviving one such event buys 100 years of safety. After all the death and disruption that

COVID-19 has brought about, people naturally want to believe that this outbreak was a once-in-a-century event. Sadly, the real anomaly was not this pandemic; it was the preceding 100 years

of relative calm. All the while, the risk of pandemics had been steadily rising. The causes are numerous, including population growth, urbanization, greater consumption of meat, and

increasing proximity to wildlife. Taken together, these factors increase the risk of animal viruses spilling over to humans. Once novel viruses infect people, other factors make it more

likely that they will quickly spread far beyond their origins. With the rise of long-distance travel, a pathogen can now transit the globe in hours, and the growth of mass gatherings—from

the Olympics to Oktoberfest in Germany to the Hajj pilgrimage in Saudi Arabia—increases the odds of super-spreader events that can infect large numbers of people at one time. A hundred years

ago, a farmer who contracted bird flu while butchering his chickens likely lived a rural life and thus would probably infect only his family or village. Today, that farmer may well work in

an industrial slaughterhouse near a large city, easily board an airplane, and make it halfway across the world before feeling any symptoms. Population growth in both animals and humans,

industrialization, urbanization, and modernization have raised the risk that diseases will jump to humans and spread. But modern advances have also given the world new tools to prevent,

track, and contain infections, allowing us to stop spillover from turning into global chaos. In other words, spillover and outbreaks are inevitable, but pandemics are not. Humanity’s

greatest task now, therefore, is to do everything possible to sever the link between the former and the latter. It is a task made easier than ever by modern science, yet also one that

requires crucial elements sorely lacking in the age of COVID-19—speed, cooperation, and trust. Without overcoming these deficits, the chain will remain unbroken. SPILLOVER HAPPENS It is hard

to say how many viruses are circulating among animals, but the number is staggering—by one estimate, there are more than 300,000 animal viruses that scientists have yet to characterize.

Roughly every minute, somewhere on earth, an animal virus spreads to a human, an event known as a “zoonotic jump.” Maybe it’s a farmer in rural America who catches a new type of swine flu

from his pig farm. Maybe it’s a bushmeat hunter in the Democratic Republic of the Congo who contracts a monkeypox variant while handling a chimpanzee. Or maybe it’s a shopper browsing a

wildlife market in a Chinese city who picks up a novel coronavirus. In most cases, the story ends there, with the person at the receiving end of spillover never infecting anyone else, often

because the virus was initially blood-borne and had never mutated into an easily spreadable respiratory disease. In other cases, the spillover leads to small clusters of disease that quickly

die out. Consider that in the summer of 2021, while the world was focused on COVID-19, the WHO received alerts about more than 5,000 new outbreaks around the world, few of which made global

headlines. Sometimes, however, the world gets unlucky, and a new variant achieves airborne spread in the first few cases. The rate of spillover appears to be increasing, although by how

much remains unclear, since part of the apparent rise may be a result of faster, better detection. Every year, about one to three novel viruses with the potential to start a pandemic are

reported to jump from animals to humans. What is causing the uptick in spillover outbreaks? In a word, modernity. The world’s population has more than tripled from 1950 to the present,

pushing more humans (and their domesticated animals) into contact with the wilderness. As humans have multiplied, they have slashed countless acres of forests not only to harvest timber but

also to make space for new roads, cities, factories, mines, and, above all, farms. The most invasive species of all is us: humans have converted half the planet’s habitable land to

agriculture. Climate change has exacerbated these problems. It has generated yet more habitat loss and pushed wild animals from hotter to cooler climates, where they are more likely to mix

with new animals and more people. It has led to water shortages and crop failures that have driven humans into dense megacities and migrant camps where pathogens spread easily. And it has

lengthened the breeding seasons and expanded the habitats of disease-carrying ticks, mosquitoes, and flies. > Viral spillover is now the way most pandemics begin. Other aspects of

modernity aren’t helping, either. Bushmeat consumption has risen at both ends of the economic spectrum, with the poor resorting to wildlife as an inexpensive protein source and the rich

having developed a taste for the exotic. Some six million tons of bushmeat are harvested every year from the Congo River basin alone. Meanwhile, the trade in exotic pets is thriving, with

more people adopting animals that once lived only in the wild. The growing trend of backyard chickens is bringing domestic livestock into urban settings. Hundreds of years ago, most large

epidemics, such as plague and cholera, were caused by bacteria or by diseases so familiar that they were considered the natural order among humans. Viral spillover is now the way most

pandemics begin. The 1918 influenza may have begun at an American pig farm. The 1957–58 Asian flu and the 1968 Hong Kong flu both came from birds. The 2009 swine flu crossed over from pigs,

which acted as mixing vessels in which porcine, avian, and human influenza strains recombined. In fact, since the advent of antibiotics and modern vaccines, most new contagious diseases of

any kind have begun as viral animal infections that spilled over to humans. The virus that caused the 2002–4 SARS outbreak, SARS-CoV-1, and the one behind the COVID-19 pandemic, SARS-CoV-2,

probably spilled over from bats, as did the Ebola virus. MERS came from camels. HIV traces its origins to chimpanzees. Smallpox may have spilled over from a rodent. LEAKY LABS Even though

natural spillover is the most likely origin of the next pandemic, it could theoretically start in another way: in a laboratory. Even after a 1972 treaty banned biological weapons, the Soviet

Union undertook a $1 billion effort to develop such a capability. One attempt involved combining smallpox and Ebola into a single “chimera” virus. That experiment failed, as did others

involving anthrax and tularemia. But many Soviet workers were accidentally killed in the secret labs where these experiments were conducted. More innocent accidents are much likelier. Labs

are often home to large collections of monkeys, rats, and bats, all of which can infect workers. Infectious agents can also spread via petri dishes or other equipment. That appears to be how

smallpox claimed its last victim: in 1978, just as the disease was on the cusp of eradication, Janet Parker, a medical photographer at a British university, died of smallpox, having somehow

caught it at the lab where she worked. A fierce debate rages about whether SARS-CoV-2 might have escaped from a lab. Nearly everyone agrees that an early epicenter of the COVID-19 pandemic

was the Huanan Seafood Wholesale Market in Wuhan, China, where thousands of live wild animals were sold. What is disputed is whether the market was the site of the original spillover that

kicked off the pandemic or merely its first super-spreader event. Although no wildlife there was found to be infected with SARS-CoV-2, Chinese investigators did detect genetic material from

it in samples collected from surfaces in the market—before the area was quickly scrubbed. Most proponents of the “lab leak” theory contend that SARS-CoV-2 originated at the Wuhan Institute

of Virology, where researchers are thought to have conducted “gain of function” experiments on bat viruses—genetically altering the viruses to make them more transmissible as part of

scientists’ efforts to understand how they spread and can be prevented or treated. Beijing only added fuel to this theory when, in early 2020, it closed the lab to international inspection.

But there is no evidence that the Wuhan Institute of Virology held viruses that closely resemble SARS-CoV-2, while bats in the wild have been found to be infected by viruses that do.

Moreover, the Wuhan Institute of Virology is more than ten miles from the Huanan Seafood Wholesale Market. But a different lab, the Wuhan Center for Disease Control and Prevention, is just

300 yards away—a few minutes’ walk. That lab is also thought to have had an active program for collecting viruses from wildlife, including bats. Given that the 2002–4 SARS outbreak also

likely came from bats, it would be neither unusual nor nefarious for it to have gathered specimens of these animals infected with SARS-CoV-2. If a lab worker caught the virus there, that may

indicate poor lab practices but not criminal intent. The world may never know how the COVID-19 pandemic began, and as the trail grows colder, the odds of determining its origins are

becoming slimmer. One can say with confidence that there is no credible evidence that SARS-CoV-2 was genetically engineered. Even if a mad scientist had wanted to create this virus, many of

the aspects that make it so transmissible were unknown in 2019; the rapid emergence of new variants shows that it needs no engineering help. Beyond that, however, the jury is still out. On

the one hand, the brisk trade in wildlife at the market and the clusters of infection nearby are consistent with the theory that SARS-CoV-2 originated in animals sold there. On the other

hand, one cannot exclude the possibility that the virus escaped from bats in a laboratory close to the market or from bat collectors or that lab workers who became infected brought the virus

to the market. Finding out the source of COVID-19 is important. Ultimately, however, solving the mystery is a lower priority than recognizing that spillover in a lab or a market are both

viable pathways to pandemics. THE NEXT BIG ONE Of the many large outbreaks, epidemics, and pandemics of new diseases in the last 100 years, only the Great Influenza and COVID-19 have been

catastrophic. What will be the next “big one”? Epidemiologists have a good idea of the types of diseases that make the shortlist. It will most likely be a virus that spills over naturally as

a result of human contact with animals, has a short incubation period, and spreads rapidly through the respiratory pathway—all of which adds up to explosive spread. Two families of viruses

stand out. The first are coronaviruses. Spread mostly through the breathing of shared air, they have short incubation periods—sometimes two or three days—and often mutate promiscuously,

splitting readily into variants and types. The most famous coronavirus, of course, is SARS-CoV-2, but other members of the family have much higher fatality rates. SARS-CoV-1, the strain

behind the 2002–4 SARS outbreak, killed somewhere between ten and 60 percent of people infected, depending on age, and MERS-CoV, the coronavirus behind MERS, has an estimated fatality rate

of 35 percent. The difference was that what SARS-CoV-2 lacked in deadliness, it made up for in transmissibility. Yet as devastating as COVID-19 has been, it could have been worse: it was

simply a lucky spin of the genomic roulette wheel that SARS-CoV-1 and MERS-CoV never developed variants as spreadable as SARS-CoV-2. But the lucky streak might not last. Tied for public

enemy number one are highly pathogenic influenza viruses. These are grouped by two proteins on the surface of the virus, hemagglutinin and neuraminidase, which give the variants their names,

such as H1N1 (which caused the 1918 influenza pandemic) and H2N2 (which caused the 1957–58 Asian flu). With 18 hemagglutinin and 11 neuraminidase proteins known, the permutations and

combinations are many, leading to a high number of variants. That is one reason it is so difficult to make seasonal flu vaccines that match each year’s particular H and N combination. It is

worth noting that in the last 100 years, only these two groups of diseases—coronaviruses and influenza viruses—managed to make the leap from animals to humans and demonstrate the combination

of transmissibility and deadliness to become catastrophic pandemics. With more and more human-animal viral exchanges and a few mutations, humanity could get hit with a novel coronavirus or

an influenza virus that spreads like H1N1 and kills like MERS. Such a pandemic would challenge the very survival of our species. THE OTHERS Next on the not-wanted list are vector-borne

diseases. The main concern is infections from a category of viruses called arboviruses, which are viruses transmitted to humans from arthropods—mostly insects such as fleas, ticks, gnats,

and mosquitoes. Some of the most prominent viruses in this category are yellow fever, West Nile, Zika, chikungunya, dengue, and Japanese encephalitis. All spread primarily through

mosquitoes, making this insect the most dangerous animal alive. Although these viruses are not particularly transmissible from one human to another through casual contact, they can spread

through blood transfusions and organ transplants and via sexual contact. Orthopoxviruses, a category that includes smallpox, are another pandemic threat. The reason orthopoxviruses do not

top the list today is that the big killer in this group, _Variola major_, which causes smallpox, was declared eradicated in 1980, following a decades-long campaign. Although no cases have

occurred since then, under a 1979 WHO agreement, infectious viruses are confined to two laboratories—the Centers for Disease Control, in Atlanta, and the Vector Institute, in Siberia—raising

the terrifying possibility of a lab accident or even a deliberate release. But even setting smallpox aside, other orthopoxviruses are worth worrying about, such as rodentpox, horsepox,

camelpox, and monkeypox. Perhaps one of these could mutate over time to become as deadly as smallpox. That is one reason the 2022 outbreak of monkeypox was so concerning. The disease has

long been endemic in African rodents and primates, but only in 1970 was the first human case identified, and throughout the rest of the 1970s, only a handful of cases were reported each

year. But then came the eradication of smallpox, which had an unfortunate consequence with respect to monkeypox. The smallpox vaccine offered excellent protection against monkeypox, and with

the end of smallpox came the end of worldwide compulsory smallpox vaccination. In the decades that followed, as more and more people born after 1980 were left unvaccinated against smallpox,

the incidence of monkeypox rose, reaching around 3,000 annual cases in recent years. Nearly all these cases occurred in unvaccinated people and were confined to Africa, appearing in small

clusters and likely caused by spillovers from rodents to monkeys to humans. That pattern changed in May 2022, when an outbreak began in Europe and spread from person to person, primarily

among men who have sex with men. The disease has now reached more than 90 countries for the first time. Fortunately, of the two known families of monkeypox, the current epidemic is of the

less virulent one. Moreover, preexisting smallpox vaccines and new monkeypox vaccines are excellent, and some even work if given as late as a few days after exposure. Although the monkeypox

case count is decreasing, a dire, if small, risk remains: that people with monkeypox might “spill back” the disease to animals, especially the rodent population of large cities. If monkeypox

were to become endemic in the rats or mice of New York, São Paulo, or Tokyo, given enough time, this slow-mutating virus might come to resemble a lesser form of smallpox: spreading through

the respiratory pathway and killing many people. The next pandemic could be bacterial rather than viral. Indeed, the deadliest pandemic in recorded history—the Black Death—was caused by the

flea-borne bacterium _Yersinia pestis_. The outbreak, which began in 1346, may have killed a third of Europe. Since the advent of anti­biotics in the middle of the twentieth century, plague

and other bacterial diseases with epidemic potential, such as cholera and tuberculosis, have been kept in check. But the bacteria are still out there—in 2021, more than 100 cases of plague

were reported in the United States—and there is always a chance that they could reemerge with a vengeance. That risk has grown as bacteria have developed resistance to existing antibiotics

and as strikingly few new antibiotics have been brought to market. Like viruses, bacteria respond to the evolutionary pressure exerted by immune hosts; nature selects for bacteria with

mutations that allow them to evade existing defenses. The result is hard-to-treat infections, such as multidrug-resistant tuberculosis, methicillin-resistant _Staphylococcus aureus_ (also

known as MRSA), and vancomycin-resistant _Staphylococcus aureus_ (or VRSA). It’s even possible that penicillin and other mainstay antibiotics could lose their power to control sexually

transmitted diseases such as syphilis, returning society to Dickensian times. Last but not least is something entirely new. With hundreds of thousands of viruses that have not yet jumped to

humans now circulating in animals, it is important for scientists to be humble about how much they do not know. To that end, the WHO has undertaken an initiative to identify what it calls

“Pathogen X.” It might be a new outbreak of a long-hidden virus, as was the case with the Zika virus, which, although identified in 1947, did not emerge as a major threat until 2015. It

might be an unknown disease caused by a family of animal viruses that had never been identified before, as HIV/AIDS was initially. Or it might be something else altogether. SEEK, AND YE

SHALL FIND The logical starting point for pandemic prevention is to stop spillover. Because the main drivers of viral jumps are hard-to-reverse long-term trends—population growth, migration,

climate change, habitat encroachment—it may seem as if little can be done. But innovations in animal disease surveillance are allowing scientists to detect zoonotic viruses before they make

the leap to humans. Through mobile apps and hotlines, people can now report unusual sickness in livestock or poultry and unexpected die-offs among wildlife, giving authorities a chance to

identify the disease, cull the infected animals as needed, and quarantine nearby humans. These programs are cost-effective and more practical than ever, given the ubiquity of

Internet-connected phones, and deserve investment. To close off another route for spillover, governments should crack down on the illegal trade in exotic wildlife and their sale in crowded

markets, which not only enable the spread of disease but also contribute to species endangerment. To reduce the risk of lab accidents, governments should establish strong, transparent

international standards requiring careful precautions, especially in labs collecting animal specimens. Realistically, however, for the foreseeable future, some degree of spillover is

inevitable. Much of the work of preventing pandemics will have to wait until the virus infects its first human victim, so time is of the essence. The faster spillover is detected, the sooner

the spread can be contained. Interrupting transmission becomes harder as viruses adapt to humans, since the pathogens become more efficient at reproducing and better at evading our immune

systems—as the nearly 100 combinations and mutations of SARS-CoV-2 make clear. Fortunately, new technology and larger public health workforces have allowed for faster detection. Twenty years

ago, it could take six months for news of an outbreak in a remote region to reach a national health department, an eternity in epidemiological terms. Today, that same outbreak might be

found in a week or two. Some of the most inspiring developments are coming from spillover hotspots in Asia. Animal-to-human transmissions of the bird flu and of coronaviruses are usually

associated with South and Southeast Asia, particularly in and around the Mekong River basin. (The region has a deadly combination of factors: it is a chokepoint for migrating birds, has many

farms where chickens and pigs feed next to one another, and has high population density.) The 1957–58 Asian flu, the 1968 Hong Kong flu, and the 2002–4 SARS outbreak all originated in and

around southern China. But technology can mitigate these risks. In 2016, for example, the Cambodian Ministry of Health partnered with the nonprofit organization Ending Pandemics (which one

of us, Mark Smolinski, heads) to roll out a hotline for reporting outbreaks. Simply by dialing 1-1-5, Cambodians could tell an automated voice system if they had witnessed any illness or

death in poultry or livestock or if they or their family members had fallen ill. The system averaged nearly 600 daily calls during its first four years of operation, resulting in 20 to 30

follow-up actions by the authorities each month. At one point, for example, public health officials responded to a report from a farmer who had dialed the hotline after one of his chickens

died and his daughter became sick. The authorities quickly tested the dead bird and found it to be infected with H5N1, the highly pathogenic avian influenza, and slaughtered his flock of

chickens to contain the outbreak—saving the farms, and perhaps the lives, of the surrounding villagers. STOP THE SPREAD Even if a disease is not contained at its source, there is still time

to prevent the outbreak from going global. As with efforts to detect outbreaks, new technology has vastly enhanced public health officials’ ability to recognize epidemics. Thanks to the

explosion of data collected online, disease detectives can track emerging diseases faster than ever. Albania, Bangladesh, Cambodia, Pakistan, and Tanzania, for example, are working with

Ending Pandemics to build data dashboards that combine feeds from a variety of sources: local news articles, social media posts, digital disease-surveillance systems, wastewater data, and

tips from hotlines. Technological upgrades have been matched by improvements to the global public health system. Just a few decades ago, the WHO could respond to an outbreak only if it had

been reported by the government of the country where it occurred. But since 2005, when the member states of the WHO updated their rules, the organization has been able to respond to an

outbreak no matter how it learns of it. As part of that reform, the WHO also built its own high-tech tool for detecting early signs of potential pandemics. The Epidemic Intelligence from

Open Sources initiative continuously scans 20,000 digital sources for red flags, looking for everything from a local news report of a market closure to a spike in online searches for

pediatric thermometers. Much more investment in such situational awareness is needed. Although wealthy nations can afford the equipment, supplies, and personnel required to identify and

monitor infectious threats, low- and middle-income countries, where these threats often emerge, largely cannot. Cooperation is a key element of surveillance. In a promising sign, countries

are increasingly sharing public health information across borders, helping ensure that local or national spread does not become global spread. Twenty-eight countries regularly report tips

through Connecting Organizations for Regional Disease Surveillance, or CORDS, a group founded in 2009 by the Nuclear Threat Initiative and the Rockefeller Foundation and backed by several un

agencies and various private organizations. Such early sharing of information is crucial because it permits a coordinated response, giving public health officials a better chance of

preventing it from going global. And it builds trust, something that is much harder to generate once a pandemic has begun. VIRUSES ON THE LOOSE By the time an epidemic has escaped national

or regional boundaries to spread worldwide, it is by definition a pandemic and thus too late for prevention. Nonetheless, timely interventions can minimize its impact. Governments will need

to issue and enforce classic public health recommendations: limit travel, isolate, wash your hands, wear a mask, and avoid mass gatherings. And viral sequencing—which is now faster and

cheaper than ever—is essential for developing diagnostic tests and should be made more globally available. Doctors in developing countries need this powerful tool, too. Ultimately, vaccines

are the main pathway out of a pandemic. After COVID-19 broke out, decades of investment in vaccine technology paid off, allowing billions of doses of highly effective vaccines to be produced

in record time. Humanity can do even better, however, as there are still limits to how quickly production can be scaled up and doses can be distributed. It may be possible to expedite the

deployment of vaccines by developing rapid vaccine trials to determine safety and efficacy—speed that will be crucial as the virus learns to evade first-generation vaccines. Also vital will

be a more distributed infrastructure for manufacturing vaccines. One major source of delay in fighting COVID-19 was what some say was the hoarding of vaccines by the countries that developed

and manufactured them. To be defeated, global pandemics of vaccine-preventable diseases require more manufacturing capacity in the global South. For now, vaccine development still takes too

long to stop the most likely type of pandemic: one caused by a novel respiratory virus, such as an influenza virus or a coronavirus. Both are RNA viruses, which mutate much more easily than

DNA viruses—hence the dozens of variants and subvariants spun out of the original version of SARS-CoV-2. RNA viruses’ proclivity for mutation explains how they adapt to new environments and

jump to new species. It also makes them moving targets for vaccine development. This is not to say that vaccines have no value against RNA viruses; they are still marvelous at protecting

people against serious illness and death. But the shapeshifting nature of RNA viruses does call for interventions that retain their potency even as the pathogens evolve. Enter antiviral

drugs. Unlike fungi and most bacteria, which can grow on surfaces, viruses are “obligate parasites,” unable to reproduce without the machinery inside the cells they infect. Antiviral drugs

attack that Achilles’ heel, hitting various stages of a virus’s life cycle as it replicates within cells. Whereas an RNA virus can evolve relatively easily to evade vaccines, the probability

is low that it can simultaneously develop all the mutations required to survive a multipronged attack from an antiviral drug. And because many viruses use the same reproductive strategies,

researchers can develop drugs that will likely work against classes of viruses that haven’t yet emerged. Such drugs will not eliminate the need for vaccines, and they are more expensive to

produce and distribute. But they should form one pillar of pandemic preparedness. THE DEADLIEST CATCH For catastrophic pandemics, modernity is both cause and cure. Like spillover itself, all

these tools for combating its consequences are the product of human advances. Some of these tools are already available; others are far off. But all hold the promise of severing one or more

links in the chain of events that leads a single mutation in a virus in a bat to upend the entire world: from spillover to outbreak, from outbreak to epidemic, from epidemic to moderate

pandemic, and from moderate pandemic to catastrophic pandemic. In this effort, the developed world should accept that it must shoulder the burden—not just out of altruism but also out of

self-interest. As the COVID-19 pandemic made clear, even the richest and supposedly most prepared countries can be overrun by viruses originating in faraway corners of the world. Rich

countries must invest worldwide in surveillance systems and vaccine production. But one thing no amount of money can cure is a lack of trust. The pandemic laid bare the mistrust among

countries, with some governments concealing data and others hoarding vaccines. And it exposed the mistrust between populations and their own public health officials, with tensions erupting

over mask mandates, school closures, and vaccinations. Trust is the difference between calling a hotline and choosing not to, between sharing information internationally and hiding it,

between following quarantine rules and flouting them, and between sharing vaccines and hoarding them. Without trust, even the best public health policies will fail. It is this human element

that will, above all, determine whether the world can use modernity’s gift of science to stave off catastrophe.