In 1796, English physician Edward Jenner had a hunch. As hundreds of thousands around him succumbed to the blistering agony of smallpox, Jenner’s eye was on the rosy, unblemished complexion of Sarah Nelmes , a local milkmaid. Her skin bore none of the oozing lesions that signaled almost certain death for a third of smallpox sufferers—save for her hands, busily milking a cow named Blossom.

The locals called the unsightly affliction “cowpox.” But apart from a smattering of welts, Sarah and her fellow milkmaids were remarkably free of disease. To Jenner, this wasn’t a coincidence. Acting on little more than sparse observations, Jenner decided to extract a small sample of Sarah’s pus and inject it into the arm of a young boy named James Phipps . To everyone’s amazement—including Jenner’s—when Jenner stuck Phipps with a second needle, this time sporting a hefty dose of smallpox, Phipps remained healthy. Against all odds, the risky treatment had granted the child miraculous immunity.

This revolutionary (and wildly unethical) experiment catapulted the world into the era of what would come to be called “vaccination,” a word whose etymology contains a reverent nod to the Latin vacca, for “cow.” Smallpox would become the first disease officially conquered by human medicine.

“[Smallpox eradication] shows what we can really achieve when we have the proper tools to fight a disease,” says Sabrina Sholts , a curator of anthropology at the National Museum of Natural History, where she developed the infectious-disease-centric “Outbreak” exhibit. “But knowing about the disease also shows us how many people were killed… and we realize there’s no reason it couldn’t happen again.”

Not only is there the potential for smallpox (or at the very least, something very similar) to resurge, but unbeknownst to most, the very origins of this revolutionary vaccine are in question. For decades, scientists have thought t he legend of cowpox as the savior—first, of James Phipps, then, of the world— may very well be wrong. That cryptic crack in medical history could leave humanity vulnerable to a future outbreak—however unlikely it may be.

***********

By the end of the 18th century, smallpox, caused by variola virus, was a worldwide terror , claiming hundreds of thousands of lives each year. The disease was an ancient one, plaguing populations at least as far back as the third century B.C ., and infected indiscriminately, sparing neither rich nor poor and felling men, women and children alike.

So, when Jenner’s “vaccine” (really just pus teeming with virus) hit the scene, it literally went viral. By 1813, it was widely accessible in Europe, Asia and the Americas. Because poxviruses like smallpox are most easily passed from animal to animal, scientists first created new reserves of the vaccine by collecting pus from infected livestock. Each time stocks ran low, scientists rounded up a fresh herd of naturally infected animals and consolidated their secretions.

“The vaccine evolved,” says Inger Damon , who leads the poxvirus and rabies branch at the United States Centers for Disease Control and Prevention. “The way it was propagated—either on the sides of cows or in rabbits—changed and introduced related viruses into the pool… [so] a swarm of viruses was used in various vaccines.”

In 1939, a researcher at the University of Liverpool named Allan Watt Downie became curious about how the smallpox vaccine might have changed over time. Nowadays, vaccines are meticulously produced en masse and most (including some modern versions of smallpox vaccine) contain severely weakened versions of infectious microbes or small, incomplete bits of the pathogens—the bare minimum required to jolt the immune system into action. This circumvents the possibility of causing a real infection or spreading a new agent of disease within the human population. But the early smallpox vaccine was based on a virus fully capable of causing disease—one less severe than smallpox, but disease all the same. And active viruses are still subject to the pressures of evolution.

When Downie compared the viral contents of a smallpox vaccine, still known to this day as a lineage called “vaccinia virus,” to a sample of cowpox isolated directly from cattle, he was surprised to find that they were different . Related, yes—but certainly not identical.

This, unfortunately, opened quite the can of worms. The two samples were divergent enough that it seemed highly improbable that vaccinia, the current smallpox vaccine, was descended from cowpox. This left Downie and his colleagues with an unsettling question: What on earth had they been injecting into the arms of millions of people for the past 150 years?

Sleuthing through historical records led some scientists to speculate that another virus called horsepox, known to infect both horses and cows, may have been vaccinia virus’ ancestor. Even Jenner himself mused about the equine origins of his miracle drug in his original publication, speculating that the most protective route of vaccine transmission might be horse to cow to human.

As far as science had progressed, the field of virology did not yet have the right set of tools to fully suss out the answers. In the meantime, vaccinia—despite its murky ancestry—had been working miracles. And so, with a wary shrug, scientists put an exceptionally large pin in the mysterious origins of the millennium’s medical marvel and moved on. Soon, it seemed humanity, with the help of vaccinia, had won its centuries-long battle with smallpox. In May of 1980, the World Health Organization triumphantly proclaimed, “ Smallpox is dead .”

The world’s memory is brief. As smallpox disappeared from hospital wards, so did it from the minds of the public. Eventually, technology advanced to the point where it was finally feasible to reopen medicine’s greatest cold case and discover the true roots of the smallpox vaccine. But why not let sleeping pox lie? The scourge of smallpox had been wiped from the face of the earth—whatever was in that vaccine, be it derived of cow or horse or confetti—did it even matter?

But the era of smallpox is far from over. Although smallpox is technically eradicated, at least two laboratories —one in Russia and one at CDC headquarters in Atlanta, Georgia—still harbor samples of variola virus. And concerns of a future outbreak go far beyond a hapless laboratory accident: Modern gene-editing techniques have made it possible to build a lethal lookalike from scratch. Now more than ever, the threat of bioterrorism looms large.

Since routine vaccination efforts ceased nearly four decades ago, the vast majority of the modern global population would be completely vulnerable to an unexpected pandemic. Anywhere from 30 to 88 percent of people exposed to the virus can be infected, and nearly a third of those who contract the disease will die. It was only in July of 2018 that the FDA approved the first drug to treat smallpox. Vaccination remains the only other tool at our disposal—and if an outbreak were to occur, millions of Americans, including pregnant women and people with HIV or eczema, would be precluded from vaccination.

Creating a new or improved vaccine could help, but working with the world’s limited stores of smallpox (like those at the CDC or in Russia) is both impractical and extremely dangerous. Tooling instead with a less virulent close relative could help researchers safely and effectively hit pay dirt. So if horsepox was the virus that kicked off vaccination in the 18th century, modern research should trend equine—but first, the world needs proof.

Some researchers have taken steps in that direction. In the 1970s, a small handful of scientists decided to once again probe the relationship between the vaccinia vaccine strain and horsepox. One group was able to show an encouraging degree of relatedness between horsepox and an old Brazilian vaccine strain, supposedly sourced from France in the mid-1800s. But this finding was but a blip on the scientific radar, and little progress was made in the decades that followed.

Recent advances in technology have reinvigorated the investigation, however. Scientists like Damon at the CDC, along with an independent team led by virologist Jose Esparza at the University of Maryland, have begun collecting old smallpox vaccines from museums and laboratories from around the world to analyze the genetic sequences contained within. With viral genomes, researchers may be able to trace vaccine ancestry backwards in time and eventually pinpoint the source—or likely, sources—of these protective artifacts.

The work is ongoing, says Esparza, but he is confident that horsepox entered the mix at some point. His team has compiled 15 vaccine samples and counting, most from the early 1900s, and recently published a genetic analysis of a 1902 vaccine that bears a striking resemblance to horsepox. The resemblance is imperfect, says Esparza, but together, these findings provide strong evidence that horsepox played a role in smallpox vaccine production.

Esparza calls these new findings “a lesson in humility.” Jenner, for all his genius, was likely shooting in the dark. (Although it's possible he had a few more hints than the oft-told story of his discovery implies.) He couldn’t possibly have understood the intricacies of vaccination as we do today—but often, Esparza says, we must develop solutions without knowing every scientific detail. Now, it’s time to play catch-up: Technology finally has the power to find the answers to a medical problem that only claims to be solved.

“There’s nothing more interesting to me, as a scientist, than solving a problem,” Esparza says. “I just want to find the truth.”

Importantly, Esparza adds, even if the world doesn’t have much to fear from smallpox itself, plenty of other viruses in the “pox” family could still be cause for concern for humans and wildlife alike. Many animals have their own flavor of poxvirus, including monkeys, pigs and even mollusks. Several—though not all—of these diseases have been known to be zoonotic, hopping from wildlife into human populations. Protecting both animals and humans requires an intimate knowledge of the viruses in question. According to Esparza, better understanding the smallpox vaccine, down to its murky four-legged roots, may be one of our most powerful tools to forestall an entire family of known diseases.

What’s more, it’s unlikely humans are done encountering all the poxviruses that may trouble us in the future. “Some people estimate we’ve discovered less than 1 percent of the existing viruses in nature,” says Esparza. “Smallpox is eradicated. But the world is full of viruses waiting to be discovered .”

In the meantime, the jury is still out on the relative contributions of horses, cows and their respective poxviruses to the eradication of smallpox—but horsepox was certainly, well, the dark horse of this race. As the debate continues, though, should we start making the verbal switch from “vaccines” to “equines”? Not just yet, says Damon. Cows and milkmaids, regardless of the exact strain they carried, were still an integral piece of Jenner’s discovery. Blossom’s legacy remains intact—for now.