Walking the streets of Manhattan, one encounters spitting, staggering, and convulsing on a daily basis, but the offenders generally perambulate on two legs, not four. In July 2009, though, a suspiciously erratic animal was spotted on Payson Avenue, just outside Inwood Hill Park at the island’s northern tip. It tested positive for rabies: not an unprecedented occurrence in the borough, but one that officials at the health department felt they should monitor closely. Later that summer, on August 27, 2009, a second case was found, this time along the northern border of Central Park. Then, in December, after more than four months of quiet, ten more were found to be infected, eight of them in Central Park. As 2010 began, the situation started to spiral out of control: twenty-two gone mad in January, twenty-nine in February, with two people bitten. New York’s favorite dog-walking destination had quite suddenly become infested with rabies. Yet all the beloved poodles and French bulldogs and bichons frises were not vectors but potential victims.
The perpetrator was a wild animal, but one that nevertheless lives nearly as close among us as our dogs do. Most North Americans, upon being awoken by the characteristic rattle and crash of a trash can lid, will guess the culprit immediately. It is Procyon lotor, or the common raccoon, identifiable by its masked face, its shuffling gait, its light- and dark-ringed tuft of tail. During the past twenty years, raccoons have become the U.S. species most frequently found to be infected with rabies. And although their range covers nearly the whole continent, from Canada to Panama, raccoons thrive more today in urban and suburban locales than they do in pristine forests; the highest density of raccoons in New York State is not in the Catskills or the Adirondacks but in New York City. They come, like many human visitors to New York, for the food. One of the most omnivorous animals on earth, the raccoon eats everything—earthworms and acorns, minnows and bluebird nestlings—but it especially enjoys trash, from corncobs to cat chow to cheesecakes. Urban environments, inhospitable to much of the wild kingdom, offer up tons of delectable food for raccoons every day, conveniently presented to them in plastic bags or in cylindrical serving containers that their nimble hands can pry open easily. Sated at this buffet, raccoons can bunk down just about anyplace, whether an abandoned burrow or a sewer, a treetop or a fire escape.
The spread of rabies among raccoons has been described by the CDC as “one of the most intensive wildlife rabies outbreaks in history,” and a human blunder seems to have been at least partly to blame. Before the mid-1970s, raccoon rabies—a strain adapted to the raccoon, such that the animal is generally able to survive infection long enough to transmit the virus to another—was confined to Florida and neighboring states, spreading very slowly through the Deep South at a rate of eighteen to twenty-four miles per year. But starting in 1977, more than thirty-five hundred raccoons were legally trapped in Florida and shipped to private hunting clubs in Virginia, where they were released as prospective game. Seeing as how raccoons do not respect the lines of private property, the creatures were effectively being released into the wild. The mid-Atlantic saw its first case of raccoon rabies in 1977, near the Virginia–West Virginia line, far from the existing margins of the southern outbreak. Now there were two loci of infection: one emanating out from Florida, another from the Virginias. Within three decades, rabid raccoons had been observed throughout the entire eastern United States, with a few cases sighted as far west as Ohio.
By 2009, raccoon rabies had already hunkered down in the New York suburbs; it even kept a semipermanent residence in the Bronx. Now, finally, it had swept furiously into Manhattan. Every week, as the city made updates to its online rabies map, the red dots—denoting spots where afflicted raccoons were found—sprayed across Central Park and the vicinity like bullet wounds from a tommy gun. On February 16, 2010, with a total of forty cases identified, the city health department announced a daring plan. It was a scheme that involved, as one rabies expert puts it, “thinking like a raccoon.” Based on an understanding of their habitats and behaviors, teams would set collapsible cage traps around the affected areas at night, baiting them with food. The traps would then be checked at dawn and the rabid animals destroyed; those that appeared healthy would be sedated, tagged, vaccinated, and released, on the principle (just as with feral dogs in Bali and elsewhere) that moving or killing healthy animals only invites the population to fill out again with potentially sick ones. Central Park being one of the most popular parks in the world, traps needed to be kept away from the curious hands of children and noses of dogs. Thus the teams had to set traps in out-of-the-way locales, working quickly under cover of darkness: set, sedate, vaccinate, collapse the traps, and go.
Even as this heroic undertaking got under way, rabid raccoons were staggering out with frightening regularity through the green spaces of upper Manhattan, even venturing into the tony neighborhoods nearby. March saw nearly as many cases as February, and April saw nearly as many as March. But by that summer, the reported cases had slowed to a coon-like creep. In the eight months beginning on December 1, 2009, there had been 124 rabid raccoons confirmed, but in July, August, and September 2010 there were only 6; since then, as of the fall of 2011, only 1 more case has been reported. For all the arduousness of trapping and vaccination, the effort seems to have paid off, with the urban jungle of Manhattan left to its more customary ravages.
How, then, to understand the great Manhattan Rabies Outbreak of 2009–10? It was a far cry from the rabies paranoias that racked New York and the great cities of Europe near the end of the nineteenth century. All the way into the twentieth, with Pasteur’s cure on the march, rabies lurked as a constant menace in streets and lanes, even in the developed world. The agent of infection was the familiar—the all-too-friendly dog, sometimes even one’s own pet—and the consequence of a bite was routinely a horrible death. By contrast, at the beginning of the twenty-first, our dogs are largely vaccinated, our bites are nearly always treated; the threat, meanwhile, lingers among creatures not adapted to our companionship, such as raccoons and foxes, skunks and bats. Rabies has receded to become a sort of spectral presence, a ghost story. It’s gone until it isn’t.
As we saw in the last two chapters, the struggle of science against rabies seems to have arrived at a frustrating stalemate. Through his innovative, last-ditch protocol for human cases, Rodney Willoughby has broken the 100 percent fatality rate of the world’s deadliest virus. But reliable rescue of patients through his methods has proven elusive. By the same token, in the fight to control the exposure rate, the path for government health agencies is clear: with diligent and mandatory vaccination of dogs, human cases can be brought down to near-negligible levels, even in poorer countries where strays are a problem. And yet as the tale of Bali makes clear, beating back the virus can be extremely costly, in both capital and effort, and gains can be quickly reversed if government vigilance flags.
Despite the terrible manner in which it kills, and despite the fact that prevention through dog vaccination is far more cost-effective than treating bites after they happen (to say nothing of managing the fatal cases)—despite all this, the small number of human deaths from rabies means that money for prevention is hard to come by. Charles Rupprecht, chief of the rabies unit at the CDC and still arguably the world’s preeminent expert on the virus, calls this the “cycle of neglected diseases.” Rupprecht is an odd combination of a soft speaker and a tough talker, rarely conversing for more than ten minutes without touting his New Jersey roots. Growing up in Trenton, he cultivated a deep love for animals, but also for science fiction, and so he sees the course of his career as having been in some sense inevitable. “When you put the two together—reality and fantasy, animals and monsters—you can’t get much closer than rabies,” he says with a chuckle. One particularly vivid childhood memory is a face-to-face encounter with a bat, which his brother had inadvertently scared out into view by throwing a basketball against the side of their house. While in graduate school in zoology at the University of Wisconsin, he studied bat ecology; that took him to a summer fellowship in Panama, where he studied bats at the Smithsonian Tropical Research Institute. While he was in veterinary school at the University of Pennsylvania, his interest in bat-borne disease brought him to the Wistar Institute, a biomedical research group on campus, where—his curiosity piqued by the garish medical oddities in the building’s front windows—Rupprecht knocked on the door of Tad Wiktor, head of the institute’s rabies unit, and introduced himself as a bat specialist. “Ah, bats,” Wiktor replied gravely, sucking on his pipe. “I’ve always wanted bats. How do you grow them?”
Since then, Rupprecht has had a hand in nearly every important advance in rabies management during the past twenty-five years. At Wistar, he played a role in developing a recombinant oral rabies vaccine for wildlife, which helped beat back a nasty outbreak among Texas coyotes in the 1990s. He was involved with the first trap-vaccinate-release campaigns among raccoons, on the mid-Atlantic’s Delmarva Peninsula and in Philadelphia’s Fairmount Park. It was Rupprecht, after moving to the CDC, who consulted with Willoughby when he was scheming a rescue plan for Jeanna; he also was one of the experts that Janice Girardi consulted in devising BAWA’s vaccination plan. (“The CDC is a service organization,” explains Rupprecht. “It’s like The X-Files.”) It’s charming to talk to a virus hunter who speaks with such deep respect for his quarry. An “exquisite parasite,” Rupprecht calls rabies, citing all the ways that it has perfectly adapted to its mammalian hosts. “We love to lick, we love to suck, we love to bite,” he points out, and so rabies “exploits what mammals do naturally.”
Like many other rabies experts, Rupprecht believes that dog rabies—the type responsible for the vast majority of human deaths worldwide—can be eradicated during his lifetime. Unfortunately, though, any concerted effort to do so would require a fairly precise understanding of what the rabies “burden” is: an epidemiologically sound tally of canine infection (which often goes unnoticed or unreported) and human death from rabies (which, if counted at all, often get misclassified as some other encephalitis). This census never gets made, precisely because the number of definitive infections and deaths doesn’t seem to justify the spending. “We don’t have an effective surveillance system, because there are no resources,” Rupprecht says with exasperation. “And there are no resources because there are no cases!” Together with his peers at other health departments worldwide, along with a nonprofit called Global Alliance for Rabies Control, Rupprecht has helped to popularize World Rabies Day, an annual affair designed to build awareness and keep health officials informed about strategies against the disease. If you’d like to mark your calendar, the date each year is September 28—in honor of Louis Pasteur, who died that day in 1895.
There is one realm in which one might say rabies has been conquered during the past ten years—even, in a strange way, enslaved. If this most ancient of viruses can never be eradicated from animals, molecular biologists have hit upon the next best outcome: they are harnessing its uniquely diabolical properties in an attempt to resolve one of our thorniest medical problems. Rabies still knows how to infect us, but at the molecular level we have learned how to infect it.
To see how this is possible, we need to understand what neuroscientists call the “blood-brain barrier.” This barrier is not, as the word might imply, a solid wall or even a discrete membrane. Capillaries, just as they do elsewhere in the body, feed every cell in the brain with blood directly; there are nearly four hundred miles of capillaries in the brain alone, each lying less than two-hundredths of an inch from one another. These brain capillaries, however, prohibit most types of molecules from passing through their walls. Oxygen, carbon dioxide, and hormones make it in and out, but larger bodies—including, thankfully, most pathogens—are unable to enter easily.
The existence of the blood-brain barrier was first hinted at by the work of Paul Ehrlich, a German biologist best known for discovering a cure for syphilis. (An unlikely 1940 Hollywood film about that feat, Dr. Ehrlich’s Magic Bullet, starred Edward G. Robinson as the good doctor.) In dyeing experiments on animals, Ehrlich showed that certain pigments, introduced into the bloodstream, would soon stain all the internal organs—except the brain. Soon, one of his students thought to carry out the opposite side of the equation: injecting the same dye directly into the brain. What he discovered was that the dye stained the whole brain but nothing else. Something unique was happening at the boundary between brain and body.
From the perspective of contemporary medicine, the great irony of the blood-brain barrier is that its parsimony—which, in most cases, protects the brain admirably from infection—becomes a choke hold when the brain falls ill. The barrier does loosen somewhat in situations of infection, but most of the body’s own immune responders still have trouble getting in. So, too, do most of the pharmaceutical innovations that have saved untold millions from infectious disease. Antibiotics cannot cross the border, meaning that bacteria such as streptococci, easily snuffed out elsewhere in the body, become fatal meningitis in those uncommon cases when they slip into the brain’s membrane. The same is true for antivirals: for example, the herpes virus, a common culprit in viral encephalitis, responds well to antiviral drugs for bodily infections, but these drugs do not pass readily to the brain.
A tremendous focus of pharmaceutical research today is on finding ways to deliver drug therapies through the barrier. Most of the approaches are in their infancy at this point, so it’s hard to say which will prove effective at delivering which therapies, or whether any will wind up being practical to manufacture at the necessary scale to become a regular tool in medicine. One promising vehicle is nanoparticles—meaning particles less than one ten-thousandth of a centimeter in diameter, or less than a quarter the size of the smallest bacteria—which entirely by dint of their diminutive form can slip through the barrier’s defenses. Barring that under-the-radar approach, drugs would essentially have to fool the barrier, by arriving while attached to some other molecule that naturally passes through the vigilant vessels. That is, they need to hitch a ride with something that itself knows, deep down in its molecular structure, how to slip across the border.
Of all the mechanisms for crossing the blood-brain divide, by far the most surprising—the use of rabies—was dreamed up by a research team led by Priti Kumar, currently an assistant professor at Yale Medical School. Kumar became an innovative biochemist only after a comical series of bureaucratic snafus during her school years. As an undergraduate in Bombay, she intended to study physics but could only get a spot in chemistry. She pursued a concentration in physical chemistry, even finishing two years of a three-year program—only to be told that she hadn’t taken enough mathematics in the first year, and so she had to finish her concentration in organic chemistry. When her family moved back to Bangalore (her father worked for the Life Insurance Corporation of India in a “transferable” job, which means they moved him frequently), and Kumar tried to pursue a master’s degree there, the local university told her that spots in organic chemistry were full. She would have to shift her focus once again, this time to biochemistry.
It was an involuntary switch, but it turned out to be a happy one. When Kumar went on for her Ph.D. at Bangalore’s Indian Institute of Science, she concentrated on the biochemistry of infectious disease. For her dissertation, she focused not on rabies but on another fascinating zoonosis: Japanese encephalitis, which is carried to humans by mosquitoes from its reservoirs in pigs and birds. The disease infects some thirty thousand to fifty thousand people each year, most of them in a band of oceanic Asia that arcs counterclockwise from Japan through Southeast Asia and comes to rest over the Indian subcontinent. Like rabies, Japanese encephalitis—along with the other, similar viruses in the same class, called flaviviruses, which also include West Nile virus—is a disease that infects the brain, though unlike rabies it travels through the blood rather than the nerves. For ten to fifteen days after exposure, the virus attempts to cross the barrier; when it succeeds, it takes a devastating course, inflaming and often killing regions of the brain responsible for memory and even locomotion. The casefatality rate after infection, while not approaching that of rabies, nevertheless sits at a formidable 30 percent, and many survivors wind up brain-damaged or even paralyzed.
In her thesis, Kumar studied the immune response of humans to Japanese encephalitis, looking for specific T cells that might help some hosts fight off the virus more effectively than others. At her Yale office—a sparsely appointed room that she accesses through a bewildering warren of tunnels and stairs—she reminisces fondly on her training in India. Kumar feels that even though her university didn’t have access to the incredible technology that the best American research institutions do, she nevertheless got a world-class education—in part, because of that fact. “Here in the United States, when you want to do an experiment, you can buy a kit for it,” she explains. “But in India, we had to do everything from scratch, whether it was plating E. coli or growing some other bacterium. You start making solutions by weighing out components. You want sodium chloride, you want LB agar? You weigh out everything and autoclave it. So in terms of raw biological knowledge, Ph.D.’s coming out of places like the Indian Institute of Science know an incredible amount.”
After graduation, Kumar hoped to find a research team where she could continue working on flaviviruses. She found a group at Harvard that was studying the way that gene therapies, specifically a technique called RNA interference (RNAi), might help to treat flaviviral infections in mice. RNAi uses specially created chunks of RNA that can suppress, or turn off, the harmful effects of certain genes, including those in viruses. It’s no exaggeration to say that RNAi, two pioneers of which were awarded the 2006 Nobel Prize in Medicine, is one of the two or three most promising pharmaceutical innovations in a generation. The technique could prove valuable for treating what Kumar calls “undruggable” diseases, particularly in the brain, where the threat of side effects makes most drugs unworkable; RNAi’s cardinal virtue is its incredible specificity, because it can (at least in theory) target the harmful effects of disease at the molecular level while leaving the rest of the brain untouched. Kumar and her team readily found an interfering strand of RNA that reduced the fatality rate in mice infected with Japanese encephalitis—when the therapy was delivered by direct injection into the brain.
For human patients, though, the FDA isn’t likely to approve brain injections anytime soon. Drugs can’t reach the brain through the temples; Kumar says that the only way to deliver these therapies through direct injection would essentially involve brain surgery, and the complication rates of that approach are prohibitively high. And even if those could be brought down to acceptable levels, one imagines that Western patients today would be put off by the prospect of frequent trepanation, which we tend to associate with the medical ideas of the fifteenth century, not the twenty-first. For RNAi to become workable in the brain, then, it needs to find a way in; it needs, that is, to cross the same blood-brain barrier that confounds so many promising brain therapies.
Kumar and her collaborators started with the idea of attaching their treatment to transferrin, a protein that carries iron through the bloodstream. But then they stumbled across a twenty-five-year-old paper that suggested an even more radical idea. Back in 1982, a Yale researcher named Thomas Lentz, in collaboration with three colleagues, showed that rabies took a very particular path into the nervous system: it bound to a specific molecule in peripheral nerves, something called the nicotinic acetylcholine receptor. The receptor is called nicotinic because it serves as the mode by which nicotine makes its way to the brain; it’s also the path taken by cobra venom in killing its victim. By linking rabies to this receptor as well, Lentz’s work demonstrated for the first time, at a molecular level, the way that rabies so efficiently worked itself into the nerves. More than that, though, in a subsequent paper eight years later, Lentz went so far as to isolate which part of the rabies virus accomplished this trick: a particular peptide, made of twenty-nine amino acids, that bound the virus to the receptor.
If this rabies peptide used the receptor in the peripheral nerves, Kumar and her team reasoned, it might be able to exploit the same receptor at the boundary to the brain. They started with Lentz’s peptide and then refined it. They attached it to fluorescents in order to show that it could penetrate the brain; sections of mouse brain showed that the peptide did, in fact, carry the dye into the entire brain. Finally, they assembled a treatment molecule to deliver the RNA therapy, with this crucial section of the rabies virus—a key, as it were, to unlocking the door to the brain—out in front. What they found was impressive: after treatment with the molecule, 80 percent of the mice fought off the infection of Japanese encephalitis, compared with none of the control group. And this success has been replicated: three years later, in March 2011, a team at Oxford further refined their carrier molecule and thereby delivered large quantities of an anti-Alzheimer’s RNAi to the brains of mouse subjects.
It’s far too early, of course, to declare victory against the blood-brain barrier, or to declare rabies the agent of its conquest. After all, countless thousands of mice are “saved” every year by drugs that will never see the inside of a person, let alone preserve a human life. There is not yet even a single FDA-approved drug that employs RNAi technology; the closest to market is probably a drug to fight macular edema (that is, swelling) in diabetics, which lingered in Phase II trials as of March 2011.
But Kumar’s triumph in the laboratory, besides giving hope for treatment of brain illnesses in general, presents two grand, historical ironies—not noteworthy, perhaps, in the context of contemporary science, but germane to the four-thousand-year acquaintance of humans with rabies. The first is that rabies, for so long our most visible and intractable animal-to-human infection, could be harnessed in the treatment of another deadly zoonosis, namely Japanese encephalitis. After we have spent millennia weathering maladies derived from pigs and fowl, it is sweet revenge to think that we might use rabies to combat some of these diseases in the twenty-first century.
The second and even more gratifying irony is the method by which rabies has been exploited: the hollowing out of the virus for the use of its shell—the possession of it, one might say. As we have seen, rabies itself is our most ancient possessor, devouring the brains of its victims, transforming them into slavering vehicles for its own malign spread. Its evolutionary strategy, maximally fatal, must also be maximally manipulative: given only a brief window to replicate itself, the virus must incite its hosts to stalk and to salivate, to obsess and to attack. That humans die, and die terribly—with the otherworldly aversion to water, the hallucinations, the foaming and gulping, and worse—is just a senseless side effect.
If we can never completely eradicate rabies, we can at least take some comfort in the fact that we now have turned this cruel gambit back on itself. Just as rabies exploited the sociability of dogs in aiding its spread, humanity has now taken rabies’ own defining characteristic—its efficient binding into the nervous system—and seized control over it, in the hopes of saving human lives. We have charmed the beast, mesmerized it, forced it to do our bidding. One is reminded of Orpheus, who, in search of his dead love Eurydice, employed his beautiful music to retrieve her from the underworld. “Cerberus stood agape,” records the poet, “and his triple jaws forgot to bark.”