Spillover

by David Quammen

  One notable implication of their work was stated near the end: “Small increases of the infectivity rate may lead to large epidemics.” This quiet warning has echoed loudly ever since. It’s a cardinal truth, over which public health officials obsess each year during influenza season. Another implication was that epidemics don’t end because all the susceptible individuals are either dead or recovered. They end because susceptible individuals are no longer sufficiently dense within the population. W. H. Hamer had said so in 1906, remember? Ross had made the same point in 1916. But the paper by Kermack and McKendrick turned it into a working principle of mathematical epidemiology.

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  The second bit of landmark disease theory came from George MacDonald. He was another malaria researcher of mathematical bent (is it inevitable that so many of them be Scottish?), who worked in the tropics for years and eventually became director of the Ross Institute of Tropical Hygiene, in London, which had been founded decades earlier for Ronald Ross himself. MacDonald got some of his field experience in Ceylon (now Sri Lanka) during the late 1930s, just after a calamitous malaria epidemic there in 1934–1935, which sickened a third of the Ceylonese populace and killed eighty thousand. The severity of the Ceylon epidemic had been surprising because the disease was familiar, at least in parts of the island, recurring as modest annual outbreaks that mostly affected young children. What happened differently in 1934–1935 was that, after a handful of years with little malaria at all, a drought increased breeding habitat for mosquitoes (standing pools in the rivers, instead of flowing current), whose population then multiplied hugely, carrying malaria into areas where it had been long absent and where most people—especially the young children—possessed no acquired immunity. Back in London, fifteen and twenty years later, George MacDonald tried to understand how and why malaria exploded in occasional epidemics, using math as his method and Ceylon as a case in point.

  That was just about the time, in the mid-1950s, when the World Health Organization began formulating a campaign to eradicate malaria globally, rather than just controlling or reducing it in one country and another. WHO’s vaunting ambition—total victory, no compromise—was partly inspired by the existence of a new weapon, the pesticide DDT, which seemed capable of exterminating mosquito populations and (unlike other insect poisons, which didn’t linger as lethal residue) keeping them dead. The other crucial element of WHO’s strategy was to eliminate malarial parasites from human hosts, also thoroughly, in order to break the human-mosquito-human cycle of infection. This would be achieved by treating every human case with malaria medicine, maintaining careful surveillance to detect any new or relapsing cases, and then treating those too, until the last parasite had been poisoned out of the last human bloodstream. That was the idea, anyway. George MacDonald’s writings were meant to clarify and assist the effort. One of them, published in WHO’s own Bulletin in 1956, was titled “Theory of the Eradication of Malaria.”

  In an earlier paper, MacDonald had made the point that “very small changes in the essential transmission factors” of malaria in any given place could trigger an epidemic. This affirmed Kermack and McKendrick’s point about small increases in “infectivity” leading to large epidemics. But MacDonald was more specific. What were those essential transmission factors? He identified a whole list, including the density of mosquitoes relative to human density, the biting rate of the mosquitoes, the longevity of the mosquitoes, the number of days required for malarial parasites to complete a life cycle, and the number of days during which any infected human remains infectious to a mosquito. Some of these factors were known constants (a life cycle for P. falciparum takes about thirty-six days, a human case can remain infectious for about eighty days) and some were variable, dependent on circumstances such as which kind of Anopheles mosquito was serving as vector and whether pigs were present nearby to distract thirsty mosquitoes away from humans. MacDonald created equations reflecting his reasonable suppositions about how all those factors might interact. Testing his equations against what was known about the Ceylon epidemic, he found that they fit nicely.

  That tended to confirm the accuracy of his suppositions. He concluded that a fivefold increase in the density of Anopheles mosquitoes in relatively disease-free areas of Ceylon, combined with conditions allowing each mosquito relative longevity (sufficient time to bite, become infected, and bite again), had been enough to launch the epidemic. One variable among many, increased by five—and the conflagration was lit.

  The ultimate product of MacDonald’s equations was a single number, which he called the basic reproduction rate. That rate represented, in his words, “the number of infections distributed in a community as the direct result of the presence in it of a single primary non-immune case.” More precisely, it was the average number of secondary infections produced, at the beginning of an outbreak, when one infected individual enters a population where all individuals are nonimmune and therefore susceptible. MacDonald had identified a crucial index—fateful, determinative. If the basic reproduction rate was less than 1, the disease fizzled away. If it was greater than 1 (greater than 1.0, to be more precise), the outbreak grew. And if it was considerably greater than 1.0, then kaboom: an epidemic. The rate in Ceylon, he deduced from available data, had probably been about 10. That’s very high, as disease parameters go. Plenty high enough to yield a severe epidemic. But it was the lower side of the range for circumstances such as those in Ceylon. On the upper side, MacDonald imagined this: that a single infected person, left untreated and remaining infectious for eighty days, exposed to ten mosquitoes each day, if those mosquitoes enjoyed reasonable longevity and reasonable opportunities to bite, could infect 540 other people. Basic reproduction rate: 540.

  WHO’s eradication campaign failed. In fact, by the judgment of one historian: “It all but destroyed malariology. It turned a subtle and vital science dedicated to understanding and managing a complicated natural system—mosquitoes, malarial parasites and people—into a spraygun war.” After years of applying pesticides and treating cases, the healthocrats watched malaria resurge ferociously in those parts of the world, such as India, Sri Lanka (as then known), and Southeast Asia, where so much money and effort had been spent. Apart from the problem (which proved large) of acquired resistance to DDT among Anopheles mosquitoes, the planners and health engineers of WHO probably gave insufficient respect to another consideration—the consideration of small changes and large effects. Humans have an enormous capacity to infect mosquitoes with malaria. Miss one infected person in the surveillance-and-treatment program to eliminate malarial parasites from human hosts, and let that person be bitten by one uninfected mosquito—it all starts again. The infection spreads and, when its basic reproduction rate is greater than 1.0, it spreads quickly.

  If you read the recent scientific literature of disease ecology, which is highly mathematical, and which I do not recommend unless you are deeply interested or troubled with insomnia, you find the basic reproduction rate everywhere. It’s the alpha and omega of the field, the point where infectious disease analysis starts and ends. In the equations, this variable appears as R0, pronounced aloud by the cognoscenti as “R-naught.” (It’s a little confusing, I concede, that they use R0 as the symbol for basic reproduction rate and plain R as the symbol for recovered in an SIR model. That’s just a clumsy coincidence, reflecting the fact that both words begin with the letter R.) R0 explains and, to some limited degree, it predicts. It defines the boundary between a small cluster of weird infections in a tropical village somewhere, flaring up, burning out, and a global pandemic. It came from George MacDonald.

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  Plasmodium falciparum isn’t the only malarial parasite of global concern. Outside of sub-Saharan Africa, most human cases are caused by Plasmodium vivax, the second-worst of the four kinds adapted particularly to infecting people. (The other two, P. ovale and P. malariae, are far more rare and not nearly so virulent, causing infections that usually pass without medical treatment.) P. vivax
is less lethal than P. falciparum but it does create a lot of misery, lost productivity, and inconvenience, accounting for about 80 million cases of mostly nonfatal malaria each year. Its origins have lately been elucidated, again using molecular phylogenetics, and again one of the researchers involved is Ananias A. Escalante, formerly of the CDC, now at Arizona State University. Escalante and his partners have shown that, rather than emerging from Africa along with the earliest humans, as P. falciparum seems to have done, P. vivax may have been waiting for our ancestors when they arrived to colonize Southeast Asia. The evidence suggests that its closest relatives are plasmodia infecting Asian macaques.

  I’m not going to summarize this body of work, because we’re in deep enough already; but I want to alert you to one small aspect that leads off irresistibly on a peculiar tangent. Escalante’s team reported in 2005 that P. vivax shares a recent ancestry with three kinds of macaque malaria. One of those is Plasmodium knowlesi, a parasite known from Borneo and Peninsular Malaysia, where it sometimes infects at least two native primates, the long-tailed macaque and the pig-tailed macaque. P. knowlesi occupies a strange place in medical annals, involving the treatment of neurosyphilis (syphilis of the central nervous system), which for a time in the early twentieth century was done using induced malarial fevers.

  The story goes like this. Dr. Robert Knowles was a lieutenant colonel in the Indian Medical Service, assigned to Calcutta in the 1930s and doing malaria research. In July 1931 he came into possession of an unfamiliar new strain of malarial parasite, derived from an imported monkey. It was a plasmodium, he could see, but not any he recognized. Knowles and a junior colleague, an assistant surgeon named Das Gupta, decided to study it. They injected the bug into several other kinds of monkey and followed the progress of infection. This mystery strain proved devastating to rhesus macaques, causing high fevers and high loads of parasites in the blood, killing the animals quickly. In bonnet macaques, though, it had little effect. Knowles and Gupta also injected it into three human volunteers (that is to say, “volunteers,” their freedom to decline having been a dubious matter), one of whom was a local man who had come to the hospital for treatment of a rat bite on his foot. This poor guy got very sick—not from the rat bite but from the injected malaria. In those experimental subjects (monkey and human) who suffered intermittent fevers, Knowles and Gupta noticed that the period of the fever cycle was one day, as distinct from the two-day or three-day cycles known for human malarias. Knowles and Gupta published a paper on the unusual parasite but didn’t give it a name. Soon afterward another set of scientists did, labeling it Plasmodium knowlesi in honor of its senior discoverer.

  Shift of scene: to Eastern Europe. Reading the literature, a well-connected malaria researcher in Romania named Mihai Ciuca got interested in the properties and potential uses of Plasmodium knowlesi and wrote to one of Knowles’s colleagues in India, asking for a sample. When the monkey blood arrived, Professor Ciuca started injecting doses of P. knowlesi into patients with neurological syphilis. This was not nearly as crazy as it sounds, though even for Romania perhaps a little edgy, since the range of effects of P. knowlesi in humans was so little known. Still, Ciuca was merely following a line of therapy that had not only proven effective but had been scientifically canonized. Back in 1917 a Viennese neurologist named Julius Wagner-Juaregg had begun inoculating advanced syphilis patients with other strains of malaria, and not only had he escaped malpractice prosecution and accusations of criminal goofiness but he had also received a Nobel Prize in medicine. Wagner-Juaregg was a man of unsavory eminence in the old style, a bilious anti-Semite who advocated “racial hygiene,” favored forced sterilization for the mentally ill, and wore a Nietzschean mustache, but his “pyrotherapy” using malaria seems to have helped many neurosyphilis patients, who otherwise would have suffered out their last days in asylums. There was cold logic—revise that, hot logic—to Wagner-Juaregg’s mode of treatment. It worked because the syphilis bug is so sensitive to temperature.

  Syphilis is caused by a spiral bacterium (aka a spirochete) known as Treponema pallidum. The bacterium is usually acquired during sexual contact, whereupon it corkscrews its way across mucous membranes, multiplies in the blood and lymph nodes, and, if a patient is especially unlucky, gets into the central nervous system, including the brain, causing personality change, psychosis, depression, dementia, and death. That’s in the absence of antibiotic treatment, anyway; modern antibiotics cure syphilis easily. But there were no modern antibiotics in 1917, and the early chemical treatment known as Salvarsan (containing arsenic) didn’t work well against late-stage syphilis in the nervous system. Wagner-Juaregg solved that problem after noting that Treponema pallidum didn’t survive in a test tube at temperatures much above 98.6 degrees Fahrenheit. Raise the blood temperature of the infected person a few degrees, he realized, and you might cook the bacterium to death. So he began inoculating patients with Plasmodium vivax.

  He would allow them to cycle through three or four spikes of fever, delivering potent if not terminal setbacks to the Treponema, and then dose them with quinine, bringing the plasmodium under control. “The effect was remarkable; the downward progression of late-stage syphilis was stopped,” by one account, from the late Robert S. Desowitz, who was a prominent parasitologist himself as well as a lively writer. “Institutions for malaria therapy rapidly proliferated throughout Europe and the technique was taken up in several centers in the United States. In this way, tens of thousands of syphilitics were saved from a sure and agonizing death”—saved by malaria.

  One of those European institutions was in Bucharest, with Professor Ciuca its vice-director. Romania had a long history of struggles against malaria, and presumably its share of syphilis too, but Ciuca evidently felt that Plasmodium knowlesi might be a better weapon against neurosyphilis than other kinds of the parasite. He inoculated several hundred patients and, in 1937, reported fairly good success. His program of treatments continued until, almost twenty years later, a problem arose. Repeatedly passaging P. knowlesi through a series of human hosts (injecting infected blood, allowing the merozoites to multiply, and then extracting infected blood) had made Ciuca’s strain increasingly virulent—too virulent for comfort. After 170 such passages, he and his colleagues became concerned with its growing ferocity and stopped using it. That was a first cautionary signal, but still just a laboratory effect. (Passaging was necessary for replenishing a supply of the parasite, since it couldn’t be cultured in a dish or a tube; but passaging it directly through humans liberated the parasite from whatever different evolutionary pressures had been entailed in completing its life cycle within mosquitoes. It became like the protist equivalent of a designated hitter—very capable of batting, and freed from the responsibility to play outfield.) Other evidence would eventually show that P. knowlesi could be dangerous enough to humans in its wild form.

  In March 1965, a thirty-seven-year-old American surveyor employed by the US Army Map Service spent a month in Malaysia, including five days in a forested area northeast of the capital, Kuala Lumpur. For reasons of medical privacy (and possibly other reasons too), the surveyor’s name has been occluded from the scientific literature, but his initials were BW. According to one report, BW did his work by night and slept during daylight. Hmm, stop to think: How odd for a surveyor. This wasn’t the Sahara, where daytime heat was forbidding, nighttime cool, and moonshine more convenient for activity. It was tropical forest. Why the surveyor had arranged his labors that way, or what he could have been surveying (luminescent caterpillars? bat populations? natural resources? radio waves?) has never been explained, though there’s some speculation that he was a spy. Malaysia at that time was struggling through its early years of independence, under pressure from the Communist-supported Sukarno government of nearby Indonesia, which must have made it a focus of US strategic concern; or maybe (as per one rumor) he was monitoring signals traffic from China. Anyway, for whatever political or cadastral reasons, this lone surveyor spent nights enough
in the jungle to be bitten by more than a few Anopheles mosquitoes. He arrived back at Travis Air Force Base, in California, feeling sick—chills, fever, the sweats. What a surprise! Within three days, BW was admitted to the Clinical Center of the National Institutes of Health, in Bethesda, Maryland, and put into treatment for malaria. The NIH doctors diagnosed Plasmodium malariae, based on the look of the parasites in his blood smears under a microscope. But that identification was contradicted by the evidence of his fever cycle, just one day long. Then came the real surprise: Further testing revealed that he was infected with P. knowlesi, the monkey malaria. It wasn’t supposed to be possible. “This occurrence,” wrote a quartet of the doctors involved, “constitutes the first proof that simian malaria is a true zoonosis.”

  It was sometimes a human infection, in other words, as well as a disease of macaques.

  But the case of BW was considered anomalous, just a one-time situation resulting from quirky circumstances. Many people spend nights out in the Malaysian jungle—local villagers while hunting, for instance—but few of them are American visitors, surveying or spying or whatever, and able later to get good medical diagnoses of their feverish ailments. That’s roughly where things stood with Plasmodium knowlesi for thirty-five years, until two microbiologists in Malaysian Borneo, a married couple named Balbir Singh and Janet Cox-Singh, began looking into some peculiar patterns of malaria occurrence around a certain community in the Bornean interior.

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  Singh and Cox-Singh had arrived in Borneo by roundabout routes. He was born in Peninsular Malaysia, into a Sikh family with roots in the Punjab, and went to England for a university education. Eventually he got his PhD in Liverpool. Janet Cox came from Belfast to Liverpool, also to do a doctorate. They met at the Liverpool School of Tropical Medicine, in 1984, and found themselves sharing an interest in malaria, among other things. (The Liverpool School of Tropical Medicine, old and august, was a logical place to nurture such interest; Ronald Ross himself, after leaving the Indian Medical Service and before the Ross Institute was founded in London, had been a professor there.) Some years later, now married and with two young daughters, Singh and Cox-Singh moved back (for him) to the East: specifically, to Kelantan, on the east coast of Peninsular Malaysia. Then in 1999, offered a chance to do research under the auspices of a new medical school, they relocated to Sarawak, one of Malaysia’s two Borneo states, establishing their lab within the University of Malaysia Sarawak, in Kuching, an exotic old city on the Sarawak River. Rajah Brooke had a palace there in the mid-nineteenth century. Alfred Russel Wallace passed through. It’s a charming place if you want little backstreet hotels and riverboat commerce and Bornean jungle out your back door. Kuching means “cat,” hence the nickname “Cat City,” and at the gateway to its Chinatown sits a huge concrete feline. Singh and Cox-Singh, though, didn’t choose it for local color. They were tracking malaria. Soon after settling, they heard about some strange data coming from Kapit, a community along an upper tributary of the Rajang River in Sarawak.