As human civilizations flourished, so did infectious disease. Large numbers of people living in close proximity to each other and to animals, often with poor sanitation and nutrition, provided fertile breeding grounds for disease. And new overseas trading routes spread the novel infections far and wide, creating the first global pandemics.

Here’s how five of the world’s worst pandemics finally ended.

1. Plague of Justinian—No One Left to Die

Yersinia pestis, formerly pasteurella pestis, was the bacteria responsible for the plague. Here it's seen under optical microscopy X 1000.

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Three of the deadliest pandemics in recorded history were caused by a single bacterium, Yersinia pestis, a fatal infection otherwise known as the plague.

The Plague of Justinian arrived in Constantinople, the capital of the Byzantine Empire, in 541 CE. It was carried over the Mediterranean Sea from Egypt, a recently conquered land paying tribute to Emperor Justinian in grain. Plague-ridden fleas hitched a ride on the black rats that snacked on the grain.

The plague decimated Constantinople and spread like wildfire across Europe, Asia, North Africa and Arabia killing an estimated 30 to 50 million people, perhaps half of the world’s population.

“People had no real understanding of how to fight it other than trying to avoid sick people,” says Thomas Mockaitis, a history professor at DePaul University. “As to how the plague ended, the best guess is that the majority of people in a pandemic somehow survive, and those who survive have immunity.”

2. Black Death—The Invention of Quarantine

A couple suffering from the blisters of the Black Death, the bubonic plague that swept through Europe in the Middle Ages. From the Swiss manuscript the Toggenburg Bible, 1411. 

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The plague never really went away, and when it returned 800 years later, it killed with reckless abandon. The Black Death, which hit Europe in 1347, claimed an astonishing 200 million lives in just four years.

As for how to stop the disease, people still had no scientific understanding of contagion, says Mockaitis, but they knew that it had something to do with proximity. That’s why forward-thinking officials in Venetian-controlled port city of Ragusa decided to keep newly arrived sailors in isolation until they could prove they weren’t sick.

At first, sailors were held on their ships for 30 days, which became known in Venetian law as a trentino. As time went on, the Venetians increased the forced isolation to 40 days or a quarantino, the origin of the word quarantine and the start of its practice in the Western world.

“That definitely had an effect,” says Mockaitis.

READ MORE: How Rats and Fleas Spread the Black Death

3. The Great Plague of London—Sealing Up the Sick

Scenes in the streets of London during the Great Plague of 1665.

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London never really caught a break after the Black Death. The plague resurfaced roughly every 10 years from 1348 to 1665—40 outbreaks in just over 300 years. And with each new plague epidemic, 20 percent of the men, women and children living in the British capital were killed.

By the early 1500s, England imposed the first laws to separate and isolate the sick. Homes stricken by plague were marked with a bale of hay strung to a pole outside. If you had infected family members, you had to carry a white pole when you went out in public. Cats and dogs were believed to carry the disease, so there was a wholesale massacre of hundreds of thousands of animals.

The Great Plague of 1665 was the last and one of the worst of the centuries-long outbreaks, killing 100,000 Londoners in just seven months. All public entertainment was banned and victims were forcibly shut into their homes to prevent the spread of the disease. Red crosses were painted on their doors along with a plea for forgiveness: “Lord have mercy upon us.”

As cruel as it was to shut up the sick in their homes and bury the dead in mass graves, it may have been the only way to bring the last great plague outbreak to an end.