Spillover

by David Quammen

  By 1880, they had crossed the Murray River into New South Wales and were still headed north and west, the rabbitty front advancing at about seventy miles per year, a formidable pace, considering that it included occasional pauses to drop and rear offspring. Decades passed, with the situation only getting worse. By 1950 there were about 600 million rabbits in Australia, competing with native wildlife and livestock for food and water, and Australians were desperate for action.

  That year, the government approved introduction of a poxvirus from Brazil, myxoma, which was known to infect but not greatly harm Brazilian rabbits. There, in its native land, in its accustomed host, it caused small sores on the skin, which remained small or gradually healed. But the Brazilian rabbit was an animal of the Americas that belonged to a genus (Sylvilagus) of the Americas, and experimental work suggested that European rabbits might be affected more drastically by this American bug.

  In the European rabbits of Australia, sure enough, myxoma turned out to be pestilential, killing about 99.6 percent of the individuals it infected, at least during the first outbreak. In them too it caused sores—not just small ones but big ulcerous lesions, and not just on the skin but also on organs throughout the body, severe enough to kill an animal within less than two weeks. It was carried from rabbit to rabbit mainly by mosquitoes, of which Australia had a more than adequate supply, thirsty for blood and quite willing to drink from a new kind of mammal. The transfer of virus seems to have been mechanical, not biological—meaning that virions traveled as a smear on mosquito mouthparts, not as replicating contaminants within a mosquito’s gastric and salivary organs. It’s a clumsier mode of vector transmission, such mechanical transfer, but it’s simple and in some cases effective.

  After a few experimental releases, myxoma caught hold in the Murray River valley, causing what was called a “spectacular epizootic,” which for its speed and its scale “must be almost without parallel in the history of infections.” Thanks to mosquitoes and the breezes they rode, the virus spread quickly. Dead rabbits began piling up by the thousands in Victoria, New South Wales, and Queensland. Everybody was happy except bunny sympathizers and people who made their livings from cheap fur. Within a decade, though, two things happened: The virus became inherently less virulent and the surviving rabbits became more resistant to it. Mortality fell and the rabbit population began climbing back. This is the short, simple version of the story, with its facile lesson: Evolution lowers virulence, tending toward that “more perfect mutual tolerance” between pathogen and host.

  Well, not quite. The real story, teased out through careful experimental work by an Australian microbiologist named Frank Fenner and his colleagues, is that virulence declined quickly from its original extreme, north of 99 percent, and then stabilized at a lower level that was still pretty damn high. Would you consider a kill rate of “just” 90 percent to be mutual tolerance? Me neither. That’s as lethal as Ebola virus, at its most extreme, in a Congolese village. But it’s what Fenner found. He and his co-workers studied the changes in virulence by collecting samples of virus from the wild and testing those samples against naïve, healthy rabbits in captivity, comparing one sample against others. They detected a wide diversity of strains and, for purposes of analysis, they grouped those strains into five distinct grades of Australian myxoma, on a descending scale of lethality. Grade I was the original strain, with its case fatality rate of nearly 100 percent; grade II killed upward of 95 percent; grade III, the intermediate among all five, still killed between 70 and 95 percent of infected rabbits. Grade IV was milder, and grade V milder still (though far from harmless), killing less than 50 percent of the rabbits it infected.

  What was the relative mix of these five grades among infected rabbits? By sampling from the wild, measuring the presence of each grade, and tracing changes in their proportional dominance over time, Fenner and his co-workers hoped to answer some basic questions, chief of which was: Did the virus trend steadily toward becoming innocuous? Did the evolutionary interaction between rabbit and microbe progress toward Zinsser’s “more perfect mutual tolerance,” as represented by grade V, the mildest grade? Did myxoma learn not to kill its host?

  The answer was no. After a decade, Fenner and his partners discovered, grade III myxoma had come to predominate. It was still causing upward of 70 percent mortality among the rabbits, and it constituted more than half of all the samples collected. The most lethal strain (grade I) had nearly disappeared, and the most benign strain (grade V) was still rare. The situation seemed to have stabilized.

  But had it? A ten-year span is an eyeblink in the timescale of evolution, even for creatures that reproduce as quickly as viruses and rabbits. So Frank Fenner kept watching.

  After another twenty years, he saw a significant change. By 1980, grade III myxoma accounted for two-thirds, not just half, of all collected samples. Highly lethal but not always lethal, it was thriving in the wild, an evolutionary success. And the mild strain, grade V, had vanished. It wasn’t competitive. For one reason or another, it seemed to have flunked the Darwinian test; the unfit don’t survive.

  What explains this unexpected result? Frank Fenner guessed astutely that it was the dynamic between virulence and transmission. His tests of one grade versus another, using captive rabbits and captive mosquitoes, revealed that the efficiency of transmission correlated with the amount of virus available on a rabbit’s skin. More lesions, or lesions that lasted longer, meant more available virus. More virus smeared on mosquito mouthparts, more chance of transmission to the next rabbit. But “available virus” assumed that the rabbit was still alive, still pumping warm blood, and therefore still of interest to the vector. Dead, cold rabbits don’t attract mosquitoes. Between the two extreme outcomes of infection—healed rabbits and dead rabbits—Fenner found a point of balance.

  “Laboratory experiments showed that all field strains produced lesions that provided sufficient virus for transmission to occur,” he wrote. But the strains of very high virulence (grades I and II) killed rabbits “so quickly that infectious lesions were only available for a few days.” The milder strains (grades IV and V) produced lesions that tended to heal quickly, he added—and then the payoff, “whereas strains of grade III virulence were highly infectious for the lifetime of the rabbits that died and for a much longer period in those that survived.” Grade III, at that point, was still killing around 67 percent of the rabbits it touched. Myxoma virus, thirty years after its introduction, had found this level of virulence—being pretty damn lethal—to maximize its transmission. It was still capable of killing most of the rabbits it infected, but capable also of assuring its own survival with a continuous chain of infections.

  The first rule of a successful parasite? Myxoma’s success in Australia suggests something different from that nugget of conventional wisdom I mentioned above. It’s not Don’t kill your host. It’s Don’t burn your bridges until after you’ve crossed them.

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  Who makes these rules? Unless you’re a creationist, you’ll likely recognize that the answer is nobody. Where do they come from? Evolution. They are life-history strategies, carved by evolutionary chisels from a broader universe of possibilities. They persist because they work. You can find it in Darwin: descent with modification, natural selection, adaptation. The only surprise, if it is a surprise, is that viruses evolve just as surely as creatures that are unambiguously alive.

  Around the time that Frank Fenner published his thirty-year retrospective on myxoma, two other scientists started developing a theoretical model of parasite-host interactions. They meant to codify not just the first rule but various others. They proposed to do it with mathematics. Their names were Anderson and May.

  Roy M. Anderson is a parasitologist and ecologist of mathematical bent, employed in those days at Imperial College, in London. He did his dissertation on the flatworms that infect bream. Robert M. May is an Australian, like Frank Fenner, like Macfarlane Burnet—but then again, very different. He took a doctorate in
theoretical physics, migrated to Harvard to teach applied mathematics, and somewhere along the way became interested in animal population dynamics. He came under the influence of a brilliant ecologist named Robert MacArthur, then at Princeton, who had applied new levels of mathematical abstraction and manipulation to ecological thinking. MacArthur died young in 1972. May moved to Princeton as his handpicked successor, became a professor of zoology there, and continued the project of applying mathematics to theoretical ecology. His first published paper on parasites was titled “Togetherness among Schistosomes,” describing transmission dynamics in another form of flatworm.

  Brought together by their common interests (ecology, math, flatworms) and their complementing strengths, Robert May and Roy Anderson teamed up, like Watson and Crick, like Martin and Lewis, and presented the earliest form of their disease model in 1978. Over the following dozen years, they elaborated on that and related subjects in a series of papers that were verbally lucid, bestrewn with math, and widely noticed by other scientists. Then in 1991 they put it all, and more, into a thick tome titled Infectious Diseases of Humans. They had built their work on the same sort of conceptual schema used by disease theorists for sixty years, the SIR model, representing a flow of individuals, during the course of an outbreak, through those three classes I mentioned earlier: from susceptible (S) to infected (I) to recovered (R). Anderson and May improved the SIR model in several ways, making it more complex and more realistic. Their most telling improvement involved a fundamental parameter: population size of the hosts.

  Almost all earlier disease theorists, such as Ronald Ross in 1916, Kermack and McKendrick in 1927, and George MacDonald in 1956, had treated population size as a constant. The math was simpler that way, and it seemed a practical shortcut for dealing with real situations. For instance: If the population of a city is two hundred thousand and measles strikes, then as the outbreak progresses the sum of those people still susceptible, plus those now infected, plus those recovered, will always equal two hundred thousand. This assumes that the population is inherently stable, with births balanced by deaths, and that its inherent stability continues despite the epidemic. Epidemiologists and other medical people, even the mathematically adept ones, had generally taken such an approach.

  But that was too simple, too static, for Anderson and May. They came from the realm of ecology, where population sizes are always changing in complex, consequential ways. Let’s treat population size as a dynamic variable, they proposed. Let’s get beyond assuming any artificial, inherent stability and recognize that a disease outbreak itself may affect population size—by killing a large fraction of the populace, say, or by lowering the birth rate, or by increasing societal stresses (such as overcrowding in hospitals) that might raise the rate of death from other causes. Maybe all three of those factors together, plus others. Their aim, wrote Anderson and May, was to “weave together” the two approaches, the medical and the ecological, into a single, savvy method for understanding (and predicting) the course of infectious diseases through populations.

  “That got a whole bunch of ecologists interested in the phenomenon,” one senior member of the guild told me. This was Les Real, of Emory University, whose work on Ebola among gorillas I mentioned earlier. “Ecologists who were looking for what to do in population ecology suddenly got interested in infectious diseases,” he said. As an afterthought, Les qualified his statement: Of course, May and Anderson hadn’t invented the ecological approach to diseases. That had been around for a long time, at least since Macfarlane Burnet. They had done something else. “Bob and Roy mathematized it. And they mathematized it in an interesting way.”

  Math can be correct but boring. It can be elaborate, impeccable, and sophisticated yet at the same time stupid and useless. Anderson and May’s math wasn’t useless. It was nifty and provocative. Don’t take my word for it, but you can trust Les Real on this point. Or consult Science Citation Index, the authoritative scoreboard of scientific influence, and see how frequently the papers of Anderson and May (or May and Anderson, as they occasionally signed) have been cited by other scientists down through the years.

  Some of those papers appeared in august journals such as Nature, Science, and Philosophical Transactions of the Royal Society of London. My own favorite saw print in a more specialized organ called Parasitology. This one, titled “Coevolution of Hosts and Parasites,” appeared in 1982. It began by dismissing those “unsupported statements” in medical and ecological textbooks “to the effect that ‘successful’ parasite species evolve to be harmless to their hosts.” Bosh and nonsense, said Anderson and May. In reality the virulence of a parasite “is usually coupled with the transmission rate and with the time taken to recover by those hosts for whom the infection is not lethal.” Transmission rate and recovery rate were two variables that Anderson and May included in their model. They noted three others: virulence (defined as deaths caused by the infectious agent), deaths from all other causes, and the ever-changing population size of the host. The best measure of evolutionary success, they figured, was the basic reproductive rate of the infection—that cardinal parameter, R0.

  So they had five crucial variables and they wanted to understand the net effect. They wanted to trace the dynamics. This led them to a simple equation. There will be no math questions in the quiz at the end of this book, but I thought you might like to cast your eyes upon it. Ready? Don’t flinch, don’t worry, don’t blink:

  R0 = βN/(α + b + v)

  In English: The evolutionary success of a bug is directly related to its rate of transmission through the host population and inversely but intricately related to its lethality, the rate of recovery from it, and the normal death rate from all other causes. (The clunky imprecision of that sentence is why ecologists prefer math.) So the first rule of a successful parasite is slightly more complicated than Don’t kill your host. It’s more complicated even than Don’t burn your bridges until after you’ve crossed them. The first rule of a successful parasite is βN/(α + b + v).

  The other thing that makes Anderson and May’s 1982 paper vivid is its discussion of myxoma in Australian rabbits. That brought their modeling to an empirical case and allowed them to test theory against fact. They described Frank Fenner’s five grades of virulence. They saluted his methodical combination of field sampling and lab experiments. They mentioned the mosquitoes and the open sores. Then, using Fenner’s data and their own equation, they plotted a relationship between virulence and success. Their result was a model-generated prediction: Given this rate of transmission, given that rate of recovery, given those unrelated mortalities, then . . . an intermediate grade of virulence should come to predominate.

  Son of a gun, it matched what had happened.

  The match showed that their model, though still crude and approximate, might help predict and explain the course of other disease outbreaks. “Our major conclusion,” wrote Anderson and May, “is that a ‘well-balanced’ host-parasite association is not necessarily one in which the parasite does little harm to its host.” Their italics: not necessarily. On the contrary, it depends. It depends on the specifics of the linkage between transmission and virulence, they explained. It depends on ecology and evolution.

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  Anderson and May were theoreticians who worked much with other people’s data. So is Edward C. Holmes. Unlike them, he’s a specialist in viral evolution, one of the world’s leading experts. He sits in a bare office at the Center for Infectious Disease Dynamics, which is part of Pennsylvania State University, in a town called State College, amid the rolling hills and hardwoods of central Pennsylvania, and discerns patterns of viral change by scrutinizing sequences of genetic code. That is, he looks at long runs of those five letters, A, C, T, G, and U, strung out in unpronounceable streaks as though typed by a manic chimpanzee. Holmes’s office is tidy and comfortable, furnished sparsely with a desk, a table, and several chairs. There are few bookshelves, few books, few files or papers. A thinker’s room. On the desk is a compu
ter with a large monitor. That’s how it all looked when I visited, anyway.

  Above the computer hung a poster celebrating “the Virosphere,” meaning the unplumbable totality of viral diversity on Earth. Beside that, another poster showed Homer Simpson as a character in Edward Hopper’s famous painting “Nighthawks.” I’m not sure what that one was celebrating, unless perhaps donuts.

  Edward C. Holmes is an Englishman, transplanted to central Pennsylvania from London and Cambridge. His eyes bug out slightly when he discusses a crucial fact or an edgy idea, because good facts and ideas impassion him. His head is round and, where not already bald, shaved austerely. He wears wiry glasses with a thick metal brow, as in old pictures of Yuri Andropov. Though shaved, though brilliant, though Andropovian at first glance, Edward C. Holmes isn’t austere. He’s lively and humorous, a generous soul who loves conversation about what matters: viruses. Everyone calls him Eddie.

  “Most emerging pathogens are RNA viruses,” he told me, as we sat beneath the two posters. RNA as opposed to DNA viruses, he meant, or to bacteria, or to any other type of parasite. He didn’t need to cite the particulars about RNA viruses because I already had that list in my mind: Hendra and Nipah, Ebola and Marburg, West Nile, Machupo, Junin, the influenzas, the hantas, dengue and yellow fever, rabies and its cousins, chikungunya, SARS-CoV, and Lassa, not to mention HIV-1 and HIV-2. All of them carry their genomes as RNA. The category does seem to encompass much more than its share of dastardly zoonoses, including most of the newest and the worst. Some scientists have begun asking why. To say Eddie Holmes wrote the book on this subject wouldn’t be metaphorical. It’s titled The Evolution and Emergence of RNA Viruses, published by Oxford in 2009, and that’s what had brought me to his door. Now he was summarizing some of the highlights.