When a dozen merchant ships from the Black Sea docked in Messina, Sicily, in October 1347, they carried a deadly cargo that would change the course of history.

Most of the sailors onboard were dead. The few survivors were covered in oozing, black pustules. Though authorities quickly ordered all people to remain onboard the “death ships,” rats had already disembarked. They and the fleas they carried were infected with Yersinia pestis, the bacterium that causes bubonic plague.

Over the next five years, the Black Death swept Europe, killing 34 to 50 million people—between a third and a half of the population at the time. Scholars at the University of Paris blamed the contagion on a dangerous "triple [astrological] conjunction of Saturn, Jupiter and Mars."

Nearly seven centuries after the Black Plague hit Europe, yet another pandemic is raging. This time scientists know it’s caused by a virus, and modern germ theory coupled with advanced gene sequencing mean we have the tools to study its weaknesses and curb its spread. Nevertheless, the current recorded death toll from COVID-19 has surpassed 4.8 million, and experts say true numbers are far higher.

Deadly outbreaks and novel diseases have challenged human existence throughout history, profoundly impacting economics, culture, and commerce, killing world leaders and bringing down empires, says David Morens, a zoonotic disease expert at the National Institute of Allergy and Infectious Diseases. Many of the viruses and bacteria behind these outbreaks existed for millennia without causing widespread harm. Human behavior has changed that. “Few people realize that measles, plague, and other diseases go back thousands of years, with Neolithic origins,” he says.

The growing human population, increasing globalization, and environmental damage are all accelerating the process, says William Karesh, an executive vice president at EcoHealth Alliance, a New York-based nonprofit that studies zoonoses, or diseases that spread between animals and humans. “The laws of biology haven’t changed, but the playing field has changed dramatically,” he says.

The result: Dangerous new human diseases are emerging at unprecedented rates, including Marburg virus, avian flu, AIDS, severe acute respiratory syndrome (SARS), Nipah virus, swine flu, Ebola, Lyme disease, chikungunya, Zika, dengue, Lassa fever, yellow fever, and now COVID-19. Some 2.5 billion people are infected with zoonotic diseases each year, and because many of these ailments have no cure, they kill about 2.7 million annually, according to the U.S. Centers for Disease Control and Prevention.

Unlike previous centuries when diseases took time to spread, the infected can now board a plane and disseminate their germs worldwide before they even show symptoms. COVID-19 emerged in China just 21 months ago, and cases have since been reported in 223 countries and territories. Humans have also enabled disease-carrying ticks and mosquitoes to expand their ranges by altering the climate. As the planet warms, these insects move into new territory.

Part of the problem is that forgetting the lessons from past disease outbreaks has become a recurring theme in human history, Morens says. “Almost all the experts I know think that this will keep happening again and again because the problem is not the germs. The problem is our behavior, right?”

The Neolithic revolution
From a pathogen’s perspective, the bonanza of vulnerable hosts began 12,000 years ago during the Neolithic Revolution. Small bands of nomads that rarely came in contact with others couldn’t spawn a pandemic. But once hunter-gatherers transitioned to farming and congregated in large, crowded settlements, infectious microbes flourished.

There were many opportunities for infection. Settlers shared the land with wild species. They domesticated wolves as companions, and later, tamed and lived with wild sheep, goats, and cows they used as livestock. Grain stores attracted flea- and tick-infected rodents. Standing water in wells and irrigation systems allowed mosquitoes to flourish.

In close contact, all of them swapped pathogens and parasites, allowing zoonotic diseases to jump the Darwinian divide between animals and humans. Some 60 percent of humankind’s deadliest killers originated in animals, including smallpox, cholera, and influenza. “Some may have jumped multiple times before successfully infecting people,” says Timothy Newfield, a historical epidemiologist at Georgetown University.

Some diseases use “middlemen” as part of their jump between species. Livestock often fill that role, acting as an intermediary host between wildlife and humans. One example is Nipah virus, which jumped from wild fruit bats to domesticated pigs to humans in Malaysia in 1998. Livestock sometimes becomes reservoirs for diseases: for example, people transmitted tuberculosis to cows, some of which now harbor the bacterium that causes it, allowing the disease to keep moving between species.

Still, it’s a roll of the dice what happens once pathogens find a new host, Morens says. Factors such as contagion level, how a disease is spread, and the availability of appropriate hosts dictate whether an emerging disease becomes a dead-end infection, as most do, or explodes into a serious outbreak.

The rise of outbreaks
Historical accounts offer glimpses into ancient pandemics. Mesopotamian cuneiform tablets, the world’s oldest surviving writings, describe plague and pestilence that raged in 2000 B.C. These writings blame angry gods for illnesses, or sometimes, the demons they enlisted, which were known as “the hand of a ghost,” says Troels Pank Arbøll, an Assyrian historian at the University of Oxford. Celestial conjunctions involving the planet Mars, which was linked to the Assyrian god of death, could portend an epidemic.

The cuneiform texts describe how venerated healers diagnosed patients. Male exorcists or physicians combined physical examination with environmental observations, which could be anything from a creaking door in the house to animals that appeared. How those animals moved was indicative of their impact: from the right, propitious, from the left, not good, Troels says.

The healers would then consult written “omens” to concoct and administer herbal remedies, which they applied as poultices or poured into the appropriate orifice. They chanted incantations and prayers to appease the deities and ritually dispelled symptoms by melting a figurine of the patient in a fire or tossing it in a river.

Warnings about rabid dogs are the tablets’ only mention of zoonotic disease. But other ancient evidence exists. Smallpox is described in early Indian, Chinese, and Egyptian writings. When archaeologists discovered the mummy of ancient Egyptian Pharaoh Ramses V in 1898, they found his skin pocked with scars. He, along with two other mummies, revealed that smallpox has existed for at least 3,000 years. Researchers note that it may have jumped from a rodent pox virus; rodents are also a reservoir for closely related cowpox and camelpox.

One of history’s first documented plagues—the virulent Plague of Athens—ravaged ancient Greece from 430 to 425 B.C. As growing settlements and rising cities facilitated infection, people evolved resistance to local diseases. Then they began to travel, unwittingly spreading germs across the ancient world in a process Morens calls “pathogen pollution.”

The Athens plague is thought to have arrived by sea, ravaging a city ripe for contagion. At the time, Athens was embroiled in war with neighboring Sparta and the city was crowded with refugees.

The historian Thucydides lived in Athens during the plague and vividly detailed the symptoms. People’s heads burned with fever, their mouths bled, eyes turned red, they coughed, vomited, had dysentery, and developed an unquenchable thirst. Their reddened skin erupted in ulcers. Most were dead within a week. The suffering “seemed almost beyond the capacity of human nature to endure,” Thucydides wrote in the History of the Peloponnesian War.

Scavenger animals avoided the unburied dead. Enveloped in a specter of death, the city descended into “unprecedented lawlessness ... the catastrophe was so overwhelming that men, not knowing what would happen next to them, became indifferent to every rule of religion or of law,” Thucydides wrote.

This mysterious pestilence still has not been identified, though experts suggest it could have been anthrax, smallpox, typhus, or any of two dozen other infectious candidates. Whatever it was, the plague killed tens of thousands, and a weakened Athens fell to Sparta in 404 B.C.

Altering history with waves of disease
Over the next few centuries, devastating waves of bubonic plague, measles, and smallpox annihilated huge numbers of people across three continents.

“It shows how interconnected the world was 2,000 years ago,” says Lucie Laumonier, a historian at Montreal’s Concordia University. The Silk Road and trading ships connected Europe with North Africa and Asia, creating big opportunities for microbes, with each outbreak altering human history in its own way.

A pandemic may have sped the demise of the Han Empire in A.D. 160. Just five years later, Roman armies returning home from Western Asia imported an unknown disease that caused the Plague of Antonius. It killed emperor Marcus Aurelius as well as five million Romans and devastated the empire, impacting both the military and agriculture and emptying state coffers.

The Justinianic Plague struck Constantinople, now Istanbul, during the sixth century, the first of three pandemics of bubonic and pneumonic plague. They rank among humanity’s most fatal biological events, says Georgetown’s Timothy Newfield.

The historian Procopius, who carefully chronicled Emperor Justinian’s reign, wrote that “there was a pestilence, by which the whole human race came near to being annihilated.” He claimed it came from Egypt, which shipped wheat to Constantinople. That’s feasible: Grain shipments back then could have carried plague-bearing rodents and fleas.

Mongol armies may have been responsible for the next bubonic plague pandemic by unwittingly bringing flea-infested rats from Central Asia to Ukraine in 1346 during the siege of Kaffa. Some historians have suggested that the Mongols used biological warfare and catapulted diseased corpses over the city walls to infect those inside—however, evidence is limited, and critics have since called that idea into question.

Either way, the survivors fled, sailing from the Black Sea to Genoa and Messina and bringing the Black Death with them. Within three years the disease had spread to England, Germany, and Russia.

In 1348, Italian poet Giovanni Boccaccio described the bubonic plague as a disease that “would rush upon its victims with the speed of a fire racing through dry or oily substances ... Swellings, either on the groin or under the armpits … waxed to the bigness of a common apple, others to the size of an egg.” These buboes turned black and purple, seeping blood and pus. Victims shook with fever, aches, and digestive distress.

To try to cure them, doctors often used bloodletting or induced vomiting. Most of the infected quickly succumbed. “The scale of mortality was unlike anything that we can even imagine,” says Newfield.

Superstition ruled. Some people believed planetary movements, bad air, or poisoned water caused this deadly pestilence. Many thought it was a punishment from God. Other people blamed outsiders. Various minority groups were driven away, tortured, or killed. “The desire to scapegoat is very, very old,” Newfield says.

Meanwhile, rats and fleas thrived in cities without regular garbage collection. They burrowed into rugs made from wetland rushes and nibbled leftovers that were thrown to pet cats and dogs. Their role in the pandemic went unnoticed, along with lice that may also have been carriers.

Back in Asia, the plague killed some 16 million people. Since pandemics limit travel and trade, this plague caused the Mongols to lose control of Persia and China, and that ultimately dissembled their empire.

Ancient roots of prevention
Fear of contagion during this second plague outbreak sparked countermeasures that are still in use today.

In 1377, in the Venetian-controlled port of Ragusa (now Dubrovnik, Croatia), officials set up a place outside the city to treat the town’s sick residents. They also isolated all ships and overland caravans for 30 days before allowing travelers entry to the city. That later stretched to 40 days—or quarantino in Italian. These measures created the cornerstone of Medieval preventative social distancing.

Still, the plague ebbed and recurred for the next 400 years. A ferocious 1664 outbreak in London is famous for ''dead carts'' that clattered along cobblestone streets with drivers shouting, ''Bring out your dead,'' immortalized by Monty Python. The last of the three bubonic plague pandemics began in the Chinese province of Yunan around 1855 and lasted until 1960.

It was during this episode that Swiss scientist Alexandre Yersin discovered the bacterial cause in 1894. Four years later, Jean-Paul Simond traced transmission from rodents to fleas to humans. When bubonic plague crossed the Pacific and reached San Francisco in 1900, officials rejected the accumulated science, instead quarantining Asian immigrants.

In 1897, scientists developed a preliminary vaccine; a better version emerged in 1931, and antibiotic treatment proved effective in 1947. With these tools in hand, plague in humans can be controlled and large outbreaks are far less likely. However, the bacteria are still circulating in the wild. Plague was in the headlines just this August after it was detected in chipmunks in Lake Tahoe, California, forcing some tourist destinations to shut down.

Various viruses have also haunted humankind, and smallpox was among the deadliest. From the time of ancient Egypt onward, “the speckled monster” infected the Old World, often leaving survivors horribly scarred or blind. It killed 25 to 40 percent of victims, including pharaohs, nobles and royalty: China’s Shunzi Emperor (1661), Queen Mary II of England (1694), Habsburg Emperor Joseph I (1711) , Russia’s Czar Peter II (1730), and Louis XV of France (1774), among others. It’s thought that Japan’s Emperor Komei died of smallpox in 1867. Queen Elizabeth I of England and U.S. President Abraham Lincoln barely survived infection.

By contrast, the New World had been comparatively free of pandemic disease, possibly because indigenous peoples domesticated fewer animal species, offering fewer opportunities for germs to jump to humans. That ended when the conquistadors carried Eurasian germs across the Atlantic. The hueyzahautal—or “great eruption”—of smallpox exploded in Mexico in 1520 and spread into South America, slaying some 3.5 million people, including Aztec emperor Cuitláhuac and Incan emperor Huayna Capac. It crippled both empires and facilitated Spanish conquests.

“The age of exploration might more appropriately be called the age of global microbial devastation,” says Morens.

Notably, an exponential rise in human population that also started around the 1500s brought with it a sharp increase in dangerous epidemics and pandemics.

In 1793 U.S. President George Washington was confronted by the “American plague” of yellow fever, which would burn its way across the country for the next six years. In 1832 a cholera pandemic spread from India into Europe, killing more than 18,000. And the devastating 1918 influenza pandemic erupted near the end of World War I, killing at least 50 million worldwide. From 1900 to today, the world has been introduced to microbial killers ranging from HIV, the H1N1 swine flu, Zika virus, and infectious coronaviruses that are still wreaking havoc.

Still, there is no global pandemic prevention strategy. Morens notes that since COVID-19 emerged in late 2019, there has been growing discussion of the need for greater surveillance, international communication, and vaccine development. But there has been little mention of mitigating the human activities that boost the risk of dangerous disease, he says. That includes deforesting land, encroaching into wild ecosystems and selling and consuming wild animals, actions that bring wildlife, livestock, and humans into close contact.

Global cooperation in a unified “one health” effort is needed to prevent the next pandemic, says Steve Osofsky, director of the Cornell Wildlife Health Center in Ithaca, New York. It's an approach that “recognizes the relationships between our own health, the health of our domestic animals, and the health of wildlife and how all that's underpinned by environmental stewardship,” he says. This framework will protect both humanity and nature, but, he adds, it requires collaborations between a wide spectrum of experts, from medical doctors, veterinarians, epidemiologists, zoologists, business leaders and Indigenous peoples to agriculture, public health, and environment professionals. “How we treat the natural world has direct bearing on our future,” Osofsky says.