Spillover

by David Quammen

  Notwithstanding the quip by Peter Medawar, not every virus is “a piece of bad news wrapped up in a protein”—or at least, it’s not bad news for every host infected. Sometimes the news is merely neutral. Sometimes it’s even good; certain viruses perform salubrious services for their hosts. “Infection” need not always entail any significant damage; the word merely means an established presence of some microbe. A virus doesn’t necessarily achieve anything by making its host sick. Its self-interest requires just replication and transmission. The virus enters cells, yes, and subverts their physiological machinery to make copies of itself, yes, and often destroys those cells as it exits, yes; but maybe not so many cells as to cause real harm. It may inhabit a host rather quietly, benignly, replicating at modest levels and getting transmitted from one individual to another without producing any symptoms. The relationship between a virus and its reservoir host, for instance, tends to involve such a truce, sometimes reached after long association and many generations of mutual evolutionary adjustment, the virus becoming less virulent, the host becoming more tolerant. That’s in part what defines a reservoir: no symptoms. Not every virus-host relationship evolves toward such amicable relations. It’s a special form of ecological equilibrium.

  And like all forms of ecological equilibrium, it’s temporary, provisional, contingent. When spillover occurs, sending a virus into a new kind of host, the truce is canceled. The tolerance is nontransferable. The equilibrium is ruptured. An entirely new relationship occurs. Freshly established in an unfamiliar host, the virus may prove to be an innocuous passenger, or a moderate nuisance, or a scourge. It all depends.

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  The virus known informally as herpes B (and more precisely now as Macacine herpesvirus 1, referring to its natural reservoirs, macaques) sprang from obscurity to medical attention in 1932, after a laboratory mishap at New York University. A young scientist named William Brebner was doing research toward a polio vaccine. Monkeys were important for such work, and the animal of choice was the rhesus macaque (Macaca mulatta), which belongs to the cercopithecine family. Because poliovirus hadn’t yet been cultured in glass (that would eventually be possible, but only when living cells could be maintained in the medium as viral hosts), rhesus macaques typically served both as incubators of the virus and as test subjects. Poliomyelitis is not a zoonosis; it doesn’t naturally affect any animals other than humans; but with the help of a hypodermic needle, it could be made to grow in monkeys. An experimenter would take the poliovirus from one animal, which had been artificially infected, and inject that into the brain or the spinal cord of another, keeping the chain of infection continuous and observing effects on the monkeys along the way. One day, handling a monkey, William Brebner got bitten.

  It wasn’t a bad bite, just a nip across the ring finger and the pinkie of his left hand. Brebner dosed the wounds with iodine, then with alcohol, and kept working. The monkey seemed normal and healthy, though understandably cantankerous, and if it was already carrying polio, that doesn’t seem to have concerned Brebner. Soon afterward the monkey died (under ether, during another experimental procedure), and it wasn’t necropsied.

  Three days later, Brebner noticed “pain, redness, and slight swelling” around the bite. Another three days passed and he was admitted to Bellevue Hospital. His symptoms developed slowly—tender lymph nodes, abdominal cramps, paralysis of his legs, inability to urinate, tingling numbness in his arms, and then a high fever and hiccupping—until, after two weeks, he was very sick indeed. His breathing became labored and he turned blue. Put into a respirator, he convulsed and lost consciousness. Frothy liquid came wheezing out of his mouth and nostrils. Five hours later, William Brebner was dead at the age of twenty-nine.

  What killed him? Was it polio? Was it rabies? A fellow researcher in the same NYU lab, just out of medical school but bright and ambitious, assisted at Brebner’s autopsy and then made a further investigation, using bits of Brebner’s brain, spinal cord, lymph nodes, and spleen. This man was Albert B. Sabin, decades before his fame as creator of an oral polio vaccine. Sabin and a colleague injected an emulsion from Brebner’s brain back into monkeys; they also injected some mice, guinea pigs, and dogs. None of those animals showed signs of what Brebner had suffered. But rabbits, likewise injected, did. Their legs went limp, they died of respiratory failure, their spleens and livers were damaged. From the rabbits, Sabin and his partner extracted a filtered essence capable of causing the same course of infection again. They called it simply “the B virus,” after Brebner. Other work showed that it was a herpesvirus.

  Herpes B is a very rare infection in humans but a nasty one, with a case fatality rate of almost 70 percent among those few dozen people infected during the twentieth century (before recent breakthroughs in antiviral pharmaceutics) and almost 50 percent even since then. When it doesn’t kill, it often leaves survivors with neurological damage. It’s an occupational hazard of scientists and technicians who work with laboratory macaques. Among the macaques themselves it’s common, but merely an annoyance. It abides within nerve ganglia and emerges intermittently to cause mild lesions, usually in or around the monkey’s mouth, like cold sores or canker sores from herpes simplex in humans. The monkey sores come and go. Not so with herpes B in people. In the decades since Brebner’s death, forty-two other human cases have been diagnosed, all involving scientists or laboratory technicians or other animal-handlers who had contact with macaques in captivity.

  The number of human cases rose quickly during the era of fervid research toward a polio vaccine, in the 1950s, probably because those efforts entailed such a sharp increase in the use of rhesus macaques. Conditions of caging and handling were primitive, compared with standards for medical research on primates today. Between 1949 and 1951, a single project within the overall effort financed by the National Foundation for Infantile Paralysis (aka the March of Dimes) consumed seventeen thousand monkeys. The foundation maintained a sort of clearinghouse for imported monkeys in South Carolina, from which one leading researcher had a standing order of fifty macaques per month, at $26 apiece, delivered. Nobody knows exactly how many macaques were “sacrificed” in the labs of Albert Sabin and Jonas Salk, let alone other researchers, but the incidence of herpes B infections peaked in 1957–1958, just as the polio vaccine quest came to its crescendo. Most of those cases occurred in the United States, the rest in Canada and Britain, places where rhesus macaques were thousands of miles removed from their natural habitat but medical research was intensive.

  From that 1950s peak, the rate of accidental infections declined, possibly because lab techs began taking better precautions, such as wearing gloves and masks, and tranquilizing monkeys before handling them. In the 1980s came a small second uptick in herpes B incidents, correlated with another increase in the use of macaques, this time for research on AIDS.

  The most recent case occurred at the Yerkes National Primate Research Center, in Atlanta, in late 1997. On October 29, a young woman working among the captive monkeys was splashed in the eye with some sort of bodily gook from a rhesus macaque. It may have been urine, or feces, or spit; nobody seems to know. She wiped her eye with a paper towel, soldiering on through her chores, and almost an hour later found time to rinse the eye briefly with water. That wasn’t enough. She filed no incident report, but ten days later the eye was red and swollen. She went to an ER, where the physician on duty prescribed antibiotic eyedrops. Thanks a lot. When the eye inflammation worsened, she saw an ophthalmologist. More days passed, and another ophthalmologist examined her, before she was hospitalized for suspected herpes B. Now they put her on strong antiviral drugs. Meanwhile, cultures taken from swabbing her eyes were quietly retrieved from the commercial laboratories to which they had been sent for analysis—um, never mind, we’ll just take those back. Her cultures had belatedly been deemed too dangerous for ordinary lab workers to handle.

  The young woman seemed to improve slightly and left the hospital. But she woke the next morning with worsening sympto
ms—abdominal pain, inability to urinate, weakness in her right foot—and went back. At the end of the month, she began having seizures. Then came pneumonia. She died of respiratory failure on December 10, 1997. Despite the fact that her own father was an infectious-disease doctor, her mother was a nurse, and Yerkes was full of people who knew about herpes B, modern medicine hadn’t been able to save her.

  This pathetic mishap put some people on edge. The probability of cross-species transmission might be low—very low, under normal circumstances—but the consequences were high. Several years later, when eleven rhesus macaques at a “safari park” in England tested positive for herpes B antibodies, management decided to exterminate the entire colony. This decision was driven by the fact that Britain’s Advisory Committee on Dangerous Pathogens had lately reclassified herpes B into biohazard level 4, placing it in the elite company of Ebola, Marburg, and the virus that causes Crimean-Congo hemorrhagic fever. National regulations specified that any animals infected with a level-4 agent had to be either handled under BSL-4 containment (meaning space suits, triple gloves, airlock doors, and all the rest, not quite practicable at a tourist attraction for viewing wildlife) or destroyed. Of course, positive results on antibody tests meant only that those eleven monkeys had been exposed to the virus, not that they were presently infected, let alone shedding herpes B. But that scientific distinction didn’t stop the cull. Hired shooters killed all 215 animals at the safari park, using silenced .22 rifles, in a single day. Two weeks later, another animal park in the English countryside followed suit, killing their hundred macaques after some tested positive for herpes B antibodies. The law was the law, and macaques (infected or not) were probably now bad for business. A more sensitive question, raised by primatologists who considered such cullings grotesque and unnecessary, was whether herpes B does or doesn’t belong in level 4. Some arguments suggest that it doesn’t.

  The rhesus macaque isn’t the only monkey that carries herpes B. The same virus has been found in other Asian monkeys, including the long-tailed macaque (Macaca fascicularis) within its native range in Indonesia. In the wild, though, neither rhesus macaques nor the others have passed any known herpes B infections to humans, not even in situations where the monkeys come into close contact with people. For this there’s no easy explanation, because the opportunities do seem to exist. Both rhesus macaques and long-tailed macaques are opportunistic creatures, largely unafraid of humans or human environments. As the chainsaws and machetes of humanity’s advance guard have driven them out of their native forest habitats—in India, Southeast Asia, Indonesia, and the Philippines—they have been only more willing to take their chances scavenging, stealing, and panhandling at the edges of civilization. They live anywhere they can find food and a modicum of tolerance. You can see rhesus macaques lurking along the parapets of government buildings in Delhi. You can glimpse long-tailed macaques scrounging garbage from the corridors of dormitories at a university not far from Kuala Lumpur. And because both the Hindu and Buddhist religions embrace gentle attitudes toward animals in general, toward nonhuman primates in particular, macaques have become abundantly, boldly present at many temples around their native regions, especially where any such temple stands near or within a remnant of forest.

  At Hindu sites, they have the advantage of their resemblance to the monkey god Hanuman. Buddhism, at least as practiced in Japan, China, and India, also carries ancient threads of monkey veneration. You can see it in iconic art and sculpture, such as the famed three-monkeys carving (see no evil, hear no evil, speak no evil) on the Toshogu Shrine, north of Tokyo. Over generations, over centuries, macaques within these landscapes have come in from the wild and habituated themselves to human proximity. Now they’re mascot monkeys at many temples and shrines, indulged like acolytes of Hanuman or the Shinto deity Sanno, living largely on handouts from pilgrims and tourists.

  One such place is the Sangeh Monkey Forest in central Bali, amid the green volcanic slopes and the shapely rice paddies of the world’s most decorous island. There at Sangeh, two hundred long-tailed macaques wait to cadge handouts from the thousands of visitors who traipse through the temple and its little woodland every month. That’s why an anthropologist named Lisa Jones-Engel, of the University of Washington, and her husband, Gregory Engel, a physician, chose Sangeh as a place to study human exposure to monkey-borne herpes B. They knew that the circumstances would be very different from those in a laboratory.

  Bali, with a population of almost 4 million in an area barely larger than Delaware, is one of the more crowded human habitats on Earth—but gracefully crowded, ingeniously built up and terraced and irrigated and partitioned, not so squashed and squalid as other densely populous tropical states. Bali is home to most of the Hindus of Indonesia, otherwise a predominantly Muslim country. The little forest at Sangeh amounts to about fifteen acres of hardwoods, providing shade and cover for the macaques but not much natural food. They live instead on peanuts, bananas, cold rice, flower petals, and other treats and offerings, all supplied by temple workers, tourists, and Hindu worshippers. The lane leading into the forest is lined with shops selling souvenirs, clothes, and monkey food. The monkeys aren’t shy about accepting, even demanding, those handouts. They have lost their wild instincts about personal space. Enterprising local photographers run a brisk trade in photos of tourists posed with macaques. And here’s me in Bali, with a monkey on my head. Cute little guy, just wanted that Snickers bar. But the cute little guys sometimes bite and scratch.

  Engel, Jones-Engel, and their colleagues gathered two interesting sets of data from this place. They surveyed the monkey population, by way of blood samples; and they surveyed the human workforce at Sangeh, by way of interviews and also blood samples. What they found says a lot about the scope of opportunity for virus spillover between Asian monkeys and people.

  The team drew blood from thirty-eight macaques, of which twenty-eight were adults, the rest youngsters. They screened the blood serum for evidence of antibodies to herpes B, the same virus that killed William Brebner and most of the other people ever infected with it. The results of the lab work were chilling: Among adult long-tailed macaques at Sangeh, the prevalence of herpes B antibodies was 100 percent. Every mature animal had been infected. Every mature animal had either once carried the virus or (more likely, because it’s a herpesvirus, capable of long-term latency) still did. Among juveniles the rate was lower, presumably because they are born free of the virus and acquire it, as they get older, by social interaction with adults.

  Matched against that was the human survey, measuring opportunities for the virus to cross between species. The team found that almost a third of the shopkeepers, photographers, and other local people they interviewed had been bitten at least once by a macaque. Almost 40 percent had been scratched. Some people had been bitten or scratched more than once.

  This study, focused on workers, didn’t even attempt to count bites and scratches among the tourists who come and go. The researchers merely estimated that there must be thousands of monkey-bitten tourists walking away from Sangeh each year—and Sangeh is just one such Balinese monkey temple among a handful. The odds of a human contracting herpes B under these circumstances seem vast.

  But it hasn’t happened, so far as anyone knows. Engel, Jones-Engel, and their coauthors wrote that “no case” of human infection with the virus has been reported in Bali, “either in association with monkey forests or in any other nonlaboratory context.” Thousands of bites, thousands of scratches, thousands of opportunities, and zero cases (anyway, zero reported cases) of humans sickened by herpes B. If that sounds like good news, rather than a spooky enigma, you’re more of an optimist than I am. When I finished reading their paper, still puzzled, I wanted to hear more in person.

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  Before I knew it, I was helping Lisa Jones-Engel and Gregory Engel trap monkeys at a shrine in northeastern Bangladesh.

  We had come to a city called Sylhet, along the banks of the Surma River, an area where
the Bangladesh lowlands begin to wrinkle up into hills. The hills rise northward into mountains, beyond which lie Assam, Bhutan, and Tibet. Sylhet is a district capital, home to a half million people and an indeterminate number of other primates. Its streets are flooded with traffic that somehow manages to move despite a near-total absence of stoplights. Hundreds of green motorbike taxis, powered by natural gas, and thousands of brightly decorated bicycle rickshaws, powered by longsuffering men with skinny brown legs, jockey for position alongside the bashed-up busses and creeping cars. In early morning, two-wheeled pushcarts also roll through the streets, moving vegetables to market. At the bigger intersections loom shopping complexes and upscale hotels behind gleaming glass. It’s a thriving city, one of the richest in this poor country, thanks much to investment and spending by emigrant families, with roots here, who have thrived in Great Britain. They often return home, or at least send money back. Many of the curry shops in London, a man told me, are run by expat Bangladeshis from Sylhet.

  Religious tourism also helps fuel the local economy. There are quite a few shrines. And those shrines, besides bringing pilgrims from all over Bangladesh, are what had brought us.

  On our first afternoon in Sylhet, we scouted a holy place known as Chashnipeer Majar. It’s a small domed structure atop a hillock that looms above a crowded neighborhood, surrounded below by concrete walls, small shops, blank-faced houses fronting the street, and sinuous alleys. A long staircase led us to the shrine, which was overarched by five or six scraggly trees, one with dead limbs where monkeys perched, shaking the branches like mad sailors in a ship’s rigging. The hillsides around the shrine were covered with ragged brush, trash, and the graves of Sylhetian ancestors. It wasn’t a verdant spot, this little island of sacred ground at the heart of an urban neighborhood, but the resident wildlife didn’t seem to mind. There were macaques on the shrine roof, macaques in the trees, macaques on rooftops of the houses below, macaques climbing drainpipes, macaques crossing power lines, macaques loitering on the staircase and walking its railings, macaques scampering among the graves. Having scouted the place on that first afternoon, we came back two days later, in early morning, to disturb the peace.