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Eight years old, wiry and ponytailed, Precious Reynolds bounds from the elevator to the entrance of the pediatric intensive-care unit. She fidgets impatiently as she waits to be buzzed in, eager to return to the clinic where, by the ironclad expectations of 2,000 years of medicine, she should have died. It was nine months ago, here at the UC Davis Medical Center in Sacramento, California, that Precious survived a confirmed bout of rabies—a disease that for most of human history was considered to be fatal in 100 percent of cases.

Today, though, Precious is back just to visit. In the halls of the pediatric ward, where zoo animals cavort in backlit photos, doing their best to dispel the hospital pall, the nurses who treated Precious greet her with delight. She does not remember them at all. But she speaks shyly to each, listening as they recount to her, in turn, their roles in rescuing her. She grows more talkative when describing the life she has resumed back in Willow Creek, in the wilds of California’s Humboldt County. To get in shape for the peewee wrestling season, Precious has been running laps in the long driveway of the farm where she lives with her siblings and grandparents. She also has resumed her pursuit of “mutton bustin’,” a sport in which kids ride rodeo-style on the backs of frantic sheep for as long as they can; at a recent match, she took home the third-place purse of $23.

Precious’ brush with death began with a simple flu-like illness that soon was accompanied by some odd symptoms: head and neck pain, weakness in her legs. At the hospital, a nurse asked her to drink something, but she choked, unable to swallow the fluid. “She looked at me like ‘Grandma, please help,'” her grandmother, Shirlee Roby, recalls. “I could tell this was no damn flu.” Her symptoms were so severe that the local hospital decided to transfer her by helicopter to UC Davis. When the state health department heard the symptoms and the fact that the patient had come from rural Humboldt County, it immediately suspected rabies. Lab tests confirmed the diagnosis: Precious had antibodies against the disease in her blood serum and cerebrospinal fluid, an impossibility in the absence of infection or vaccination. As it turned out, a feral cat had bitten her a few weeks before as she played outside her elementary school. But no one had thought to treat her at the time, and now it was too late for the standard intervention against rabies—a vaccine, administered in multiple shots over the course of two weeks, that allows the body to mount an immune response before the virus reaches the brain. In Precious’ case, it was clear that her brain had already been infected.

Not long ago, the medical response to this grim situation would have been little more than “comfort care”: administration of sedatives and painkillers to ease the suffering. Untreated, this suffering can be unbearable to watch, let alone experience. That telltale difficulty in swallowing, known as hydrophobia, results in desperately thirsty patients whose bodies rebel involuntarily whenever drink is brought to their lips. Soon fevers spike, and the victims are subject to violent convulsions as well as sudden bouts of aggression; their cries of agony, as expressed through a spasming throat, can produce the impression of an almost animal bark. Eventually the part of the brain that controls autonomic functions, like respiration and circulation, stops working, and the patients either suffocate or die in cardiac arrest. A decade ago, the only choice was to sedate them so their deaths would arrive with as little misery as possible.

But today, after millennia of futility, hospitals have an actual treatment to try. It was developed in 2004 by a pediatrician in Milwaukee named Rodney Willoughby, who, like the vast majority of American doctors, had never seen a case of rabies before. (In the US, there are usually fewer than five per year.) Yet Willoughby managed to save a young rabies patient, a girl of 15, by using drugs to induce a deep, week-long coma and then carefully bringing her out of it. It was the first documented case of a human surviving rabies without at least some vaccination before the onset of symptoms. Soon Willoughby posted his regimen online, and he worked with hospitals around the world to repeat and refine its use. Now referred to as the Milwaukee protocol, his methodology has continued to show limited success: Of 41 attempts worldwide, five more patients have pulled through, including Precious, whose recovery has been the most impressive of any victim to date.

Thousands of years of medical history say that Precious should not have survived. And indeed, some of the world’s foremost rabies experts refuse to concede that Willoughby’s theory of the disease is sound—or even that his protocol is actually saving patients. It’s a scientific controversy that underscores just how little we know about neglected diseases like rabies, which still kills humans in numbers that are significant (55,000 a year, by the most recent World Health Organization estimate, most of them in Asia and Africa), but not significant enough to rate much in the way of research funding. The debate also points to something curious about medical history: the subtle ways it can confound us, with time-honored truths that nevertheless conceal some mysterious complications.

When doctors used his regimen on Precious Reynolds last year, she survived as well.

Photo: Lucas Foglia The vast majority of American doctors have never seen a case of rabies. Following a hunch based on unproven science, Milwaukee pediatrician Rodney Willoughby attempted a novel treatment, and his patient, against all expectation, survived.

Photo: Lucas Foglia In 2004, Jeanna Giese was the first documented patient ever to survive rabies without receiving any vaccine.

Photo: Lucas Foglia

Try to conjure up an image of the rogue genius doctor, the man who saves a doomed patient by bucking the medical orthodoxy, and your mental picture is unlikely to look like Rodney Willoughby. Fifty-six and stocky, with small oval spectacles that he pushes atop his graying hair while lost in thought or conversation, Willoughby is the opposite of a hothead physician: unhurried in his manner, thoughtful and earnest in his speech. A specialist in pediatric infectious disease at the Children’s Hospital of Wisconsin, he was dubious when, in October 2004, he heard that a possible case of rabies was being transferred to his care. “I was skeptical it was really rabies,” he says. “That never happens!”

The patient was a 15-year-old girl named Jeanna Giese, a high school athlete suffering from fatigue, vomiting, vision disturbances, slurred speech, and an uncharacteristic loss of coordination. It was clear how she could have become infected with rabies: While at church four weeks earlier, she had been bitten by a bat after she picked it up from the floor of her parish sanctuary. Still, Willoughby considered some other viral encephalitis, or perhaps an autoimmune disease in the brain, to be a more likely cause for her condition. But he made sure that the samples necessary to rule out rabies were collected and sent to the US Centers for Disease Control and Prevention in Atlanta within hours of the girl’s arrival.

Even though his specialty was infectious disease, Willoughby knew almost nothing about rabies. “For the board exams,” he says, “you only needed to know one thing: that it was 100 percent fatal.” He telephoned the CDC to ask if there was any treatment somewhere in the research pipeline—some promising new therapy, perhaps, not yet published in any medical journal. The CDC had nothing. Not one person had ever been shown to survive rabies without having gotten at least partial vaccination before the virus reached the brain.

With less than a day to formulate a plan, Willoughby attacked the problem with quick but deliberate reading, using his limited time to review the basic neuroscience of rabies. On Jeanna’s second day of hospitalization in Milwaukee, her results came back from the CDC: Her blood serum and cerebrospinal fluid contained antibodies against rabies. An hour later, her physicians met at the hospital to discuss what to do next.

At the meeting, Willoughby laid out a last-ditch idea, the surprising result of his day of reading and thinking. The solution, he says in retrospect, had been “hiding in plain sight.” From the literature, he had developed an understanding—though the science remains far from settled on this subject—that rabies does not kill by destroying neurons or causing inflammation in the brain, the two routes by which most other viral encephalitides cause death. Instead, this theory went, rabies primarily affects neurotransmission, the electrochemical communication that takes place between cells in the central nervous system. Through a mechanism called excitotoxicity, the disease sends the brain into overdrive, causing its cells to outstrip their energy supply and eventually die.

Willoughby knew that the human immune system did mount a response to rabies, a counterattack that could, in principle, fight off the infection. Therefore, he reasoned, the battle against rabies might actually be a battle for time. Rabies might not be killing the brain directly, but it was causing the brain to kill the body before the body had time to fight it off. Willoughby put this question to his colleagues at the Children’s Hospital of Wisconsin: What if they induced a coma? By suppressing Jeanna’s brain activity and taking over her vital functions, they might give her immune system the time it needed.

He offered his colleagues an opportunity to object. “I set it up so that any of them could blackball it,” Willoughby recalls. “If we had one blackball then we wouldn’t do it—because it was such a simple idea it had to be wrong. It was just too obvious. Someone had to have tried it before. So if anybody could see a reason why it would clearly cause harm, they could object and we would drop the plan. Instead, 30 minutes later, we didn’t have an objection to it.”

With the consent of Jeanna’s parents, Willoughby induced a medical coma. In the tense days that followed, the young patient lay motionless in a hospital room, animated only by monitors and by the rhythmic whoosh of the mechanical ventilator. An infusion of ketamine, a dissociative anesthetic, maintained her state of unconsciousness. Willoughby chose ketamine for a particular reason: Not only would it keep the brain in a state of coma, it had been shown in a 1992 study on rats to have an antiviral effect against rabies. The action of the ketamine was broadened by the addition of amantadine, another antiviral, and midazolam, a sedative; this was supplemented with barbiturates, to keep the girl perfectly calm. On the third day, under counsel from the CDC, Willoughby added ribavirin, a broad-spectrum antiviral agent often used in treating hepatitis C. After seven days, Jeanna’s blood serum and cerebrospinal fluid showed a marked increase in antibodies: As Willoughby had predicted, her body was fighting back.

Now her doctors began to withdraw the drugs. Jeanna’s return to consciousness was observed anxiously by Willoughby. The only immediate change in Jeanna’s physical exam was that her pupils became more responsive to light. No other reflexes were apparent. Her limbs lay flaccid and unresponsive on the bed. Willoughby worried silently to himself. “Oh God, I created a lock-in,” he thought—meaning someone who is conscious but unable to communicate or respond in any physical way. “It’s like the worst thing you can do.”

The idea that Jeanna might survive rabies only to be left severely disabled was a constant source of worry during the days and weeks that followed. But her steady improvements kept her doctor’s worst-case scenarios at bay. Four days after the anesthesia was withdrawn, Jeanna’s lower leg kicked in response to Willoughby’s reflex hammer. Two days later, she regained eye movement. In two more days, she was raising her eyebrows in response to speech. “Every day was something new, and it was just miraculous,” Willoughby recalls with a shake of his head.

A Medical Mystery—With Teeth Enigmatic and terrifying, rabies has spawned speculation and myth for centuries.—B.W. & M.M. 1,500 BC Babylonians believe that a lunar eclipse in the 12th month of their calendar would make dogs rabid. AD 79 Pliny the Elder includes, in a list of rabies cures, a recipe for inserting the ashes from a biting dog’s tail into the wound—the origin of our hangover cure “hair of the dog.” 1600s Dog-bite victims travel to the basilica of St. Hubert, in present-day Belgium, to get the holy rabies treatment: a cut across the forehead, into which is stuck a thread from the saint’s sacred stole. 1702 Richard Mead, one of England’s most eminent physicians, publishes the opinion that rabies outbreaks are controlled by the moon. 1805 Benjamin Rush, a prominent American physician, writes that dog bites are only one cause of hydrophobia; others include “cold night air” and “eating beech nuts.” 1830 A British lecturer puts forward the theory that rabies is spontaneously generated in male dogs that are kept from having sexual intercourse. 1859 Abraham Lincoln has his son’s dog bite treated with a “mad stone,” or a hairball from the stomach of a deer or farm animal, to prevent rabies. 1906 Scientists remain unaware that bats too can carry rabies. Mysterious cattle infections in Brazil, brought on by biting vampire bats, go unexplained because they aren’t recognized as rabies. 1937 It’s widely believed that rabies patients are driven to bite other people—a plot point in this year’s famous novel Their Eyes Were Watching God. 1971 Doctors thought vaccine failures—cases in which the rabies vaccine does not prevent symptoms—could never be saved. But this year, a 6-year-old boy in Ohio recovers. 1985 As authorities plan the “Chunnel” from France to England, polls near the English entrance find that 88 percent of residents think the tunnel will make rabies “virtually unstoppable.” 2010 The vaccination protocol for rabies falls to just four shots in the arm over two weeks—nothing like the “20 shots in the stomach” that many still fear. Click the arrows to move through the timeline.

Timeline images: Evan Kafka/Getty; Bettmann/CORBIS; Brian E. Kushner/Getty; Jane Burton/Getty; Tambako the Jaguar/Getty; Getty; Felix Behnke/Getty

Jeanna was clearly responding to her environment, but her family and the doctor both craved more definitive evidence of her return. To test her ability to recognize a familiar face, Willoughby and Jeanna’s mother removed their face shields—worn to safeguard against wayward saliva—and stood side by side next to her bed. The girl’s eyes, held open by Willoughby, flickered between them briefly, and then fixed on her mother. Clearly she was in there after all.

From that point on, Jeanna showed gradual, incremental improvement. Only very slowly did she regain governance of her 5’10” frame. Gesture and movement, expression, swallowing, and speech all had to be relearned. After a month in medical isolation, Jeanna was transferred for intensive inpatient rehabilitation that lasted several more weeks.

On January 1, 2005, Jeanna finally left the hospital for her home in Fond du Lac. Facing her were months of intensive physiotherapy to help her relearn all the basic skills of being human: to stand, then to walk, then to run. But a year into her rehabilitation, only a subtle slurring and a rare stumble in her speech remained apparent. She went on, in the spring of 2011, to become the first member of her family to graduate from college. The Milwaukee Journal Sentinel covered the ceremony at Lakeland College in Sheboygan, Wisconsin, and photographed Willoughby embracing the smiling graduate.

No one survives rabies: Such was the final verdict of medicine, not merely in Rodney Willoughby’s board exam but in medical texts dating back to at least the first century AD. “It is not only an acute disease but one that is unremitting,” wrote Soranus of Ephesus, one famed physician in the Greek tradition. Suśruta, a fabled surgeon of ancient India, gestured at 100 percent fatality in his own account of hydrophobia: “If the patient in such a case becomes exceedingly frightened at the sight or mention of the very name of water, he should be understood to have been afflicted with Jala-trása”—literally water-scare—”and be deemed to have been doomed.”

Rabies has never killed humans in great numbers, but it inspires fear far out of proportion to the risks. In part, this is because of the savage, almost supernatural mania that can grip its victims before they die. “Who is there among us,” declared a letter to The Times of London in 1830, in the midst of one citywide bout with rabid dogs, “that can leave his home in the morning, and say that he may not return in a few hours, brought back in a state that would reduce him to the desperation and frenzy of a demon, and from which a horrible death can alone relieve him?” Tales of hydrophobia filled the newspapers of 19th-century London and Paris, even though their residents were far more likely to perish from cholera or even murder; citizens organized “canicides” or “great dog massacres” to thin out the feral curs believed to carry the disease. Our outsize terror also stems at least in part from the horror-movie mode of transmission: It’s a disease of animal aggression that lurks in saliva and spreads through bites that break the skin. Indeed, in their maddened lunges and infectious bites, our cinematic zombies (not to mention werewolves and sometimes even vampires) are nothing less than projections of our timeless fear of rabies.

That peculiar terror was one reason the great Louis Pasteur, whose two initial vaccines addressed veterinary diseases (chicken cholera and bovine anthrax), chose rabies as his first human disease to confront. His collaborator Émile Roux later wrote that rabies was selected not merely because of its medical reputation as “the most subtle and the most mysterious” of all diseases but also because, in the mind of the general public, it was “the most frightening and dreaded malady.” And indeed, in 1885, when Pasteur’s vaccine was complete, he instantly became a worldwide celebrity, winning the front-page accolades outside France that his earlier and equally impressive work (including the pasteurization process that still bears his name) never did. Pasteur’s rabies vaccine—which, because of the long latency period between bite and brain infection, could be administered days after someone was bitten—transformed an arbitrary killer into a preventable disease.

For this reason the rabies vaccine, while an undeniable boon to human health, has nevertheless proved to be a mixed blessing for medical science. As refinement of the vaccine has brought death from rabies down to near nonexistent levels in the developed world, understanding the virus ceased to be much of a priority from either a research or public-health perspective—especially since the incurability of rabies was considered to have been established long ago. Far better to focus on vaccination, both in human bite victims and in dogs. And indeed, it has been far better, bringing us to the point today where the only nations with a serious human rabies problem are those whose scarce health resources are consumed with fighting far more prolific killers like malaria and tuberculosis. But all this success has left us with a poor understanding of how rabies actually works.

The most intriguing question is how cases of human rabies might differ from one another. A fatality rate of 100 percent has encouraged physicians through the ages to consider all these equally doomed cases as equal. And yet each infection is different, in ways that might—at least in theory—make certain patients more likely to survive. Some animal bites deliver tiny quantities of virus, others a great deal. Bites closer to the central nervous system—to the face, for example—pose a greater danger than bites to the foot or leg, because the virus can travel to the brain more quickly. (From the extremities, that trip can take months or even years.) Some patients quickly mount immune responses, while others’ immune systems lag. Perhaps most important, distinct variants of rabies have evolved to circulate in each species of animal host, such that a bite from a bat or a skunk or a dog will each deliver a slightly different infection. If the research budget and energy were available, studies on rabies sufferers, human and animal, could cast light on these distinctions. Until then, though, the controversy over Jeanna Giese and Precious Reynolds will have to play out in shadow.

Following a hunch based on unproven science, Rodney Willoughby attempted a novel treatment of rabies, and his patient, against all expectation, survived. What some of the world’s top rabies experts believe, also on the basis of unproven science, is perhaps even more startling. They do not deny that Jeanna and Precious had rabies. But they refuse to credit the Milwaukee protocol with saving the two girls (and the other four survivors). Instead, these experts believe that throughout history, despite millennia of faith in rabies as a perfectly fatal disease, some people were surviving it all along.

Nestled among the concrete and glass towers of the medical complex at Bangkok’s Chulalongkorn University is a low-slung two-story building of stucco arcades, capped with a red-tile roof and surrounded by a fragrant garden. This elegant structure is home to the Queen Saovabha Memorial Institute, best known to tourists for its snake farm: Visitors can watch as the institute’s handlers extract venom from live snakes in order to create the precious antidotes. But in keeping with the institute’s original mission as an outpost of the Pasteur Institute, funded in 1913 after a dog bite on the palace grounds led to the death of a royal princess, one of its other prominent departments is devoted to the administration of rabies vaccine and the treatment of rabies patients.

Forgoing a white coat in favor of a plaid vest, Henry Wilde strolls through a bright waiting room in the institute and chats in gruff Thai with the smiling white-capped nurses on duty. Although he hails from Juneau, Alaska, the 84-year-old internist has been practicing on and off in Bangkok since 1968. A nurse flips open that morning’s treatment register for him. “Ah,” Wilde exclaims with a grimace as he runs his finger down the list. “The dogs are biting!”

Wilde and Thiravat Hemachudha, a neurologist and colleague at Chulalongkorn University, are well known in scientific circles for their work on rabies. Together and separately they have published on diverse topics related to the virus: vaccinology, detection methods, pathophysiology, transmission, and treatment. Across the table from each other over lunch at the exclusive Royal Bangkok Sports Club, where Hemachudha is a member, the two collaborators’ odd rapport is on display. Wilde, comfortably rumpled with a blunt speaking style and wry sense of humor, seems an unlikely partner for Hemachudha, a dapper, middle-aged Thai with genteel diction and immaculate manners. But once the two latch onto the topic of rabies, and the Milwaukee protocol in particular, they begin to trade case histories and scientific assertions in a rapid-fire barrage.

“The Milwaukee protocol is very dangerous. It, in itself, will cause death,” Wilde declares over dessert. Hemachudha chimes in with a story about one Thai patient who died from rabies. “They learned from the Internet that rabies can be treatable! That is why they didn’t come for the vaccine.”

Like other rabies experts, Wilde and Hemachudha were excited to hear of Jeanna Giese’s survival in 2004. But they became skeptical after they attempted the Milwaukee protocol themselves in 2006: Their dog-bite victim, fully conscious on admission to the hospital, died in just eight days under Willoughby’s regimen, in a decline that seemed no less dismal than the numerous other cases they’d treated over the years. Some of their antipathy to the protocol clearly stems from the financial realities of developing-world medicine, in which the benefits of every therapy must be weighed against its costs with a ruthlessness unknown in Milwaukee. The protocol involves round-the-clock care under multiple specialists, in exchange for a slight chance of survival and an even slighter chance at full recovery. In a paper published afterward, Wilde and Hemachudha acidly note that the price tag of their one unsuccessful protocol case could have funded pre-exposure rabies vaccination for 16,000 slum kids in Bangkok.

On the basic science, too, the two men raise objections that are hard to explain away. First, there is the underlying theory of Willoughby’s protocol: the notion that rabies is a disease affecting neurotransmission, where excessive stimulation of neurons eventually shuts down the brain. A group of scientists at Queen’s University in Ontario explored this theory in mice and found no evidence that excitotoxicity played a role—and it did find, meanwhile, that rabies was killing brain cells directly, contradicting Willoughby’s notion that a waiting game against the virus is the best chance of saving a patient. Wilde and Hemachudha also wonder whether all rabies cases are indeed created equal. Although the majority of human rabies deaths worldwide are caused by canine strains of the virus, three of the six Milwaukee protocol survivors were infected by bats and two by cats, which can often carry bat strains of the virus.

Not only might those versions of the virus be weaker, Wilde and Hemachudha believe, but the surviving patients might also be stronger. Jeanna Giese and Precious Reynolds were both diagnosed on the basis of their early immune response to rabies, but such a rapid response is actually unusual. Moreover, neither girl’s saliva contained RNA from the rabies virus, a test that typically (though not always) turns up positive in rabies cases. This suggests to Wilde and Hemachudha that both girls might have already begun to clear the virus before their treatment even began.

What the detractors of the Milwaukee protocol are asking us to believe sounds, on its face, like an impossible coincidence: that Willoughby dreamed up a new treatment protocol for rabies but then had the singular fortune (or misfortune) to test it on the vanishingly rare patient who would have survived without any treatment at all. But to dismiss the critics on that basis alone is to ignore the classic pitfall of anecdotal evidence. In treating any patient, a doctor is likely to do something—or neglect to do something—that in hindsight can seem like the crucial factor in explaining why the patient beat the odds, even if in reality that action was inconsequential.

The survival rate under the Milwaukee protocol is wildly impressive when compared with that imposing baseline of zero, buttressed by thousands of years of medical history. But what if some fraction of patients have always survived? Tiny glimmers of that possibility have been passed down through decades of case reports: a German woman in 1875, an Italian teenager in 1912, a 73-year-old American in 1913, a Brazilian woman in 1968, all diagnosed with clinical rabies by their physicians but all surviving, despite no treatment with vaccine. But neither the animals that bit them nor the patients themselves were confirmed by contemporary standards to actually have the disease.

Meanwhile, another class of confirmed rabies survivors is closer to hand, in the present day, their status documented in numerous studies. “There are survivors,” Wilde says. “Fourteen percent of dogs survive. Bats survive.” If rabies doesn’t kill 100 percent of its animal victims, and if no other human disease kills 100 percent of people afflicted, then should we really be surprised to discover that a few human rabies cases prove not to be fatal?

Wilde and Hemachudha both point to the most enigmatic case in recent memory, a mystery patient whom some public-health officials have taken to calling the “Texas wild child.” In February 2009, a 17-year-old runaway from Missouri appeared at a Texas hospital complaining of severe headaches, extreme sensitivity to light, neck pain, dizziness, and tingling in the face and arms. After three days, the girl’s symptoms had resolved and she was sent home. But soon her headaches resumed and intensified, and she went to the emergency room at a different hospital.

Prompted by doctors, the girl recalled an incident that suggested a grim explanation for her symptoms. While on a camping trip two months before, she had walked into a cave and then felt, in the dark, a series of percussive blows against her body: a swarm of flying bats. She hadn’t noticed any bites or scratches afterward, and she never received any rabies vaccine. But bat bites are often so subtle that victims fail to notice them. The next day, the CDC ran tests for rabies and, as with Precious and Jeanna, the results came back positive for rabies antibodies—but there was no virus or viral RNA in her saliva or tissues. Unlike with Jeanna and Precious, though, her symptoms never progressed to the point where she needed intensive care. After two weeks in the hospital, the girl was discharged, and soon she disappeared entirely. Her remarkable recovery makes her the first person ever known to survive rabies with no intensive care, but now she has been lost to history.

In the absence of more research interest, survival from humanity’s most fatal disease will languish as a medical mystery, solvable in principle but not in practice. To counter his detractors, Willoughby hopes to simulate his protocol in animal studies, but neither he nor anyone one else has carried out that research yet. Meanwhile, what Wilde and Hemachudha want most is an antibody test that could be performed in a hospital, right at the patient’s bedside. If doctors in the developing world could identify which patients, like Jeanna and Precious and the Texas girl, quickly mount an immune response to rabies, they could try to refine a regimen of intensive care that might save more of those people. Wilde and Hemachudha believe that regimen won’t resemble the Milwaukee protocol in any way. But for now the truth of that belief remains, like the Texas wild child, on the run.

Monica Murphy is a veterinarian; Bill Wasik is a senior editor at Wired. Their book, Rabid: A Cultural History of the World’s Most Diabolical Virus, is out now from Viking.

This piece was originally published on July 23, 2012.