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.”
ACKNOWLEDGMENTS
First, we must acknowledge the great debt we owe to the historians and scientists who have written extensively during the past fifty years on different aspects of rabies: Jean Théodoridès, Patrice Debré, Neil Pemberton and Michael Worboys, Kathleen Kete, Harriet Ritvo, Alan C. Jackson, John D. Blaisdell, Wu Yuhong, Merritt Clifton, Bert Hansen, George M. Baer, Charles Rupprecht, and others.
We are also enormously indebted to Neil Henry and the Berkeley Graduate School of Journalism for their generous appointment of us as visiting scholars, which allowed us to use the world-class resources of the University of California at Berkeley to complete our research on this book. Many thanks, too, to the UC libraries and their staff.
Thanks are due, as well, to friends and colleagues who helped us with research and inspiration during the writing of this book. Jon Lackman, Gideon Lewis-Kraus, and Henrik Kuhlmann gave indispensable translation advice. Ellen Silbergeld’s lab at the Johns Hopkins School of Public Health provided an early sounding board for the book’s basic structure. Wired gave Bill leave to finish this project; thanks in particular to Thomas Goetz, Jake Young, and Chris Anderson. Also, many thanks to Rafil Kroll-Zaidi, Meghan Davis, and Jess Benko, all of whom read early drafts of the book and gave valuable feedback.
On a personal note, we’d like to thank our family: Bob and Mary Wasik, Emmett L. Murphy, Jean Austin, Dave and Jen Wasik, Becca Hurley, Emmett J. and Anne Murphy, and Janet Wasik.
We’re tremendously grateful to our agent, Tina Bennett, for encouraging us in this project and helping to see it through. Thanks, too, to the brilliant team at Viking who made this book crisp and beautiful: Maggie Riggs, Wendy Wolf, Bruce Giffords, Ingrid Sterner, Jim Tierney, Carolyn Coleburn, Rebecca Lang, Yen Cheong, Kevin Doughten, and all the rest.
Finally, we can’t say enough about our editor and friend Josh Kendall, who championed this book and improved it at every step of the process. From his deep interest in Greek myth to his obsession with cheap horror, Josh’s enthusiasm for this project has been nothing short of rabid.
NOTES
INTRODUCTION: LOOKING THE DEVIL IN THE EYE
Page
1 Consider the kamikaze bobcat in Cottonwood: John Faherty, “No Tall Tale: Rabid Bobcat Invades Cottonwood Bar,” Arizona Republic, March 27, 2009.
1 Or the frenzied otter in Vero Beach: Associated Press, May 27, 2007.
1 Or the enraged beaver in the Loch Raven Reservoir: Bob Allen, North County News, Aug. 22, 2007.
2 one young couple in the Adirondack hamlet: Bob Condon, “Man Bitten in Attack by Rabid Fox,” Glens Falls Post-Star, April 9, 2008.
2 “What disturbs me,” remarked one Connecticut man: NBC Connecticut, Aug. 18, 2010.
2 For one victim in Putnam County: This American Life, Oct. 27, 2006.
2 the red fox in South Carolina: Jill Coley, “Deadly, Grisly Rabies Still Threat in Lowcountry,” Charleston Post and Courier, Nov. 20, 2008.
3 a dog was attacked by a mad peccary: KPHO.com, Feb. 18, 2011.
3 a skunk that beset the pet Pekingese: ThePilot.com, Nov. 24, 2010.
3 a donkey fell prey to the madness: Brennan Leathers, “Donkey Bite Prompts Rabies Warning,” Post-Searchlight, Jan. 12, 2011.
3 In Imperial, Nebraska, the afflicted animal: Russ Pankonin, “Rabid Sheep Causes Stir at the Fair,” Imperial Republican, Sept. 3, 2010.
4 “the lethal gift of livestock”: Jared Diamond, Guns, Germs, and Steel (New York: W. W. Norton, 2003), 195.
4 “breathed out nastier germs”: Ibid., 195.
5 Susan Sontag noted that even as late as: Illness as Metaphor and AIDS and Its Metaphors (New York: Picador, 2001), 126–27. Illness as Metaphor was originally published in 1978; AIDS and Its Metaphors, from which this particular insight was drawn, was originally published in 1988.
6 King of the Hill: “To Kill a Ladybird,” December 12, 1999.
6 Beavis and Butt-Head: “Rabies Scare,” March 18, 1994.
6 Scrubs: “My Lunch,” April 25, 2006.
6 The Office: “Fun Run,” September 27, 2007.
6 fifty-five thousand, in the estimate: World Health Organization, September 2011.
7 a portrait of Lennox as a boy: George Romney, Charles Lennox, 4th Duke of Richmond, Duke of Lennox, and of Aubigny (ca. 1776–77).
7 so named in honor of Gebhard Leberecht von Blücher: Rosemary Baird, Goodwood: Art and Architecture, Sport and Family (London: Frances Lincoln, 2007), 170.
8 it began one day with shoulder pains: Alan C. Jackson, “The Fatal Neurologic Illness of the Fourth Duke of Richmond in Canada: Rabies,” Annals of the RCPSC 27, no. 1 (Feb. 1994).
8 On YouTube one can find video: http://www.youtube.com/watch?v=OtiytblJzQc.
8 “I don’t know how it is”: Frederic Tolfrey, The Sportsman in Canada, Vol. 2 (London: T. C. Newby, 1845), 228.
9 The next day, the duke ate and drank: Jackson, “Fatal Neurologic Illness.”
9 so repelled was he by the water in the basin: Baird, Goodwood, 170.
9 “the patient is seized with sudden
terror”: Armand Trousseau, Lectures on Clinical Medicine (Philadelphia: Lindsay & Blakiston, 1873), 2:85.
9 sometimes occurring at a rate of once per hour: Morbidity and Mortality Weekly Report 59, no. 38 (2010): 1236–38.
9 an unfortunate porter who suffered such emissions: Armand Trousseau, Lectures on Clinical Medicine (Philadelphia: Lindsay & Blakiston, 1867), 1:686.
10 the duke dictated a lengthy letter: Baird, Goodwood, 171.
10 once saw Pasteur perform this trick: Axel Munthe, The Story of San Michele (New York: Dutton, 1930), 51.
10 “At the beginning of each session” : Patrice Debré, Louis Pasteur, trans. Elborg Forster (Baltimore: Johns Hopkins University Press, 1998), 430.
Chapter 1: In the Beginning
15 “Mix us stronger drink”: The Iliad of Homer, trans. Richmond Lattimore (Chicago: University of Chicago Press, 1997), 9.203.
15 “I have learned to be valiant”: Ibid., 6.444.
16 “a hunting hound in the speed of his feet”: Ibid., 8.338–39.
16 his pitch to Achilles: Ibid., 9.238–39.
16 no fewer than nine terms: Thomas Walsh, Fighting Words and Feuding Words: Anger and the Homeric Poems (Lanham, Md.: Lexington Books, 2005), 1–3.
16 It has not been invoked anywhere in the poem: The definitive accounting of lyssa in Homer is Bruce Lincoln’s essay “Homeric Lyssa: ‘Wolfish Rage,’” in Death, War, and Sacrifice: Studies in Ideology and Practice (Chicago: University of Chicago Press, 1991), 131–37.
16 goading Heracles to slay his family: Euripides, Heracles.
16 Pentheus’s own mother and aunt: Euripides, The Bacchae.
16 a feminine form wearing a dog’s head: One such image is here: http://www.theoi.com/Gallery/N17.1.html.
17 “as a snake waits for a man by his hole”: Iliad of Homer, trans. Lattimore, 22.93.
17 “powerful lyssa unrelentingly possesses”: Iliad 21:242–43; translated in Lincoln, “Homeric Lyssa: ‘Wolfish Rage.’”
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