Spillover: Animal Infections and the Next Human Pandemic (63 page)

112

T
wo years passed, but then schedules came into alignment and I called on Greg Dwyer at the University of Chicago. His office, on the ground floor of a biology building just off East 57th Street, was cheerily decorated with the usual posters and cartoons and, along the left wall, a long whiteboard. Dwyer was fifty at the time and seemed young, like an amiable grad student whose beard had gone gray. He wore round tortoiseshell glasses and a black T-shirt printed with a grotesquely complex integral equation. Above and below the equation, the shirt asked in large letters: WHAT PART OF [this gobbledygook] DON’T YOU UNDERSTAND? The shirt was a metajoke, he explained to me. The gobbledygook was one of Maxwell’s equations; the joke part, of course, was that no average person would understand the thing at all; the meta part, I think, was that Maxwell’s equations are famous but so notoriously abstruse that even a mathematician might not recognize this one. Get it?

We seated ourselves on opposite sides of his desk but then, as soon as the conversation got rolling, Dwyer jumped up and began drawing on the whiteboard. So I stood too, as though being closer to his scribblings would help me comprehend them. He drew a set of coordinate axes, one axis for the number of gypsy moth eggs in a forest, the other axis for time, and explained how scientists measure an outbreak. Between outbreaks, the gypsy moth is so scarce it’s undetectable. During an outbreak, in contrast, you find thousands of egg masses per acre. With about 250 eggs in each egg mass, that yields a lot of moths. He drew a graph depicting the rise and fall of a gypsy moth population over successive years. It looked like a Chinese dragon, the line of its back arching way up and then dropping way down, way up again, then again way down. He drew a sketch of NPV particles and described how they package themselves for protection against sunlight and other environmental stresses. Each packet is a solid lump of protein, polyhedral in shape (hence the name) and containing dozens of virions embedded like bits of cherry in a fruitcake. Dwyer drew more graphs and, while drawing, explained to me how this nefarious virus works.

The packets of virus lay besmeared on a leaf, left there after the death of a previous caterpillar victim. A healthy caterpillar comes munching along and swallows packets with the leaf tissue. Once inside the caterpillar, a packet unfolds, sinister and orderly, like a MIRV warhead releasing its little nukes over a city. The virions disperse, attacking cells in the caterpillar’s gut. Each virion goes to the cell nucleus (again, hence the name), replicates abundantly, generating new virions that exit the cell and proceed to attack others. “They go from cell to cell, and infect lots and lots of cells,” Dwyer said. Before long the caterpillar is essentially just a crawling and eating bag of virus. Still, it doesn’t act sick. It doesn’t seem to know how sick it is. “If it has eaten a big enough dose,” he said, “then it will continue to wander around on leaves and continue to feed—but after maybe ten days, maybe two weeks, sometimes even as long as three weeks, it will melt onto a leaf.” There was that word again, the same one he had used in Atlanta, exquisitely vivid: melt.

Other caterpillars meanwhile are suffering the same fate. “The virus has almost completely consumed them before they really stop functioning.” Late in this process, as the virions within each caterpillar begin crowding one another, running short of food, they get themselves bundled together again within protective packets. Time to emerge. Time to move on. The caterpillar at this point is filled with virus, consumed by virus, held together only by its skin. But the skin, made of protein and carbohydrates, is tough and flexible. Then the virus releases certain enzymes, which dissolve the skin, and the caterpillar splits open like a water balloon. “They pick up the virus,” Dwyer said, and “they go
splat
on a leaf.” Each caterpillar disintegrates, leaving little more than a viral smudge—a smudge that, in the crowded conditions of an outbreak population of gypsy moths, is soon gobbled by the next hungry caterpillar. And so on. “Another insect comes along, feeds on that leaf, a week or two later,” Dwyer said, then repeated: “It goes
splat
.”

There might be five or six generations of
splat
in the course of the summer, five or six waves of transmission, with the virus progressively increasing its prevalence within the caterpillar population. From a starting point of low prevalence—say, 5 percent of the caterpillars are infected—it might grow to 40 percent by the first autumn. After the surviving caterpillars have metamorphosed to moths, and then mated, in a habitat still cluttered with NPV, some packets of the virus are left besmeared not just on foliage but on the egg masses laid by the female moths. So a large portion of the new caterpillars become infected the following spring as they hatch. The prevalence of the infection rises steeply. And that rise, beyond the preceding year’s level, “translates into an even higher percentage the following year,” Dwyer said. Within two or three years, such ratcheting “basically wipes out the entire population.”

The moths disappear and all that remains is the virus. Sometimes there’s so much of it, he added, that “you’ll see this kind of gray fluid trickling down the bark.” Rains come, and the trees weep with a slurry of dissolved caterpillars and virus. I was duly impressed.

It sounds like Ebola, I said.

“Yeah, right.” He had sat through some of the same meetings and read some of the same books and papers that I had.

Except not Ebola in reality, I said. The sensationalized Ebola, the popularized nightmare of Ebola, the hyped version of victims “bleeding out” like a sack of liquid guts.

He agreed. And the same distinction between degrees of gruesomeness, the real versus the exaggerated, applies to NPV. “With our virus, people like to say, they’ll say, ‘Oh, you study that virus that causes the insect to explode!’ Like, the virus
doesn’t
cause the insect to
explode
,” he insisted. “It causes it to
melt
.”

Having heard this scenario, and seen his graphs, and appreciated the directness of his language, and admired Maxwell’s equation on his T-shirt, I came to the point of my visit: what I called The Analogy. As of last week, I said, we’ve got 7 billion humans on this planet. It seems like an outbreak population. We live at high densities. Look at Hong Kong, look at Mumbai. We’re closely interconnected. We fly around. The 7 million people in Hong Kong are only three hours away from the 12 million people in Beijing. No other large animal has ever been as abundant. And we’ve also got our share of potentially devastating viruses. Some of those might be as nasty as NPV. So . . . what’s the prognosis? Is it valid, The Analogy? Should we expect to crash like a population of gypsy moths?

Dwyer couldn’t be rushed into saying yes. Judiciously empirical, wary of easy extrapolations, he wanted to pause and think. He did. And then we found ourselves talking about influenza.

113

I
haven’t said much about influenza in this book, but not because it isn’t important. On the contrary, it’s vastly important, vastly complicated, and still potentially devastating in the form of a global influenza pandemic. The Next Big One could very well be flu. Greg Dwyer knew this, which is why he mentioned it. I’m sure you don’t need reminding that the 1918–1919 flu killed about 50 million people; and there’s still no magical defense, no universal vaccine, no foolproof and widely available treatment, to guarantee that such death and misery don’t occur again. Even during an average year, seasonal flu causes at least 3 million cases and more than 250,000 fatalities worldwide. So influenza is hugely dangerous, at best. At worst, it would be apocalyptic. I’ve left it for now only because it’s well suited to suggest some closing thoughts on the whole subject of zoonotic disease.

First, the basics. Influenza is caused by three types of viruses, of which the most worrisome and widespread is influenza A. Viruses of that type all share certain genetic traits: a single-stranded RNA genome, which is partitioned into eight segments, which serve as templates for eleven different proteins. In other words, they have eight discrete stretches of RNA coding, linked together like eight railroad cars, with eleven different deliverable cargoes. The eleven deliverables are the molecules that comprise the structure and functional machinery of the virus. They are what the genes make. Two of those molecules become spiky protuberances from the outer surface of the viral envelope: hemagglutinin and neuraminidase. Those two, recognizable by an immune system, and crucial for penetrating and exiting cells of a host, give the various subtypes of influenza A their definitive labels: H5N1, H1N1, and so on. The term “H5N1” indicates a virus featuring subtype 5 of the hemagglutinin protein combined with subtype 1 of the neuraminidase protein. Sixteen different kinds of hemagglutinin, plus nine kinds of neuraminidase, have been detected in the natural world. Hemagglutinin is the key that unlocks a cell membrane so that the virus can get in, and neuraminidase is the key for getting back out. Okay so far? Having absorbed this simple paragraph, you understand more about influenza than 99.9 percent of the people on Earth. Pat yourself on the back and get a flu shot in November.

At the time of the 1918–1919 pandemic, no one knew what was causing it (though there were plenty of guesses). No one could find the guilty bug, no one could see it, no one could name it or comprehend it, because virology itself had scarcely begun to exist. Techniques of viral isolation hadn’t yet been developed. Electron microscopes hadn’t yet been invented. The virus responsible, which turned out to be a variant of H1N1, wasn’t precisely identified until . . . 2005! During the intervening decades there were other flu pandemics, including one in 1957, which killed roughly 2 million people, and another in 1968, which became known as the Hong Kong flu (for where it began) and killed a million. By the end of the 1950s, scientists had recognized the influenza viruses as a somewhat mystifying group, highly diverse and variously capable of infecting pigs, horses, ferrets, cats, domestic ducks, and chickens as well as people. But no one knew where these things lived in the wild.

Were they zoonoses? Did they have reservoir hosts? One hint appeared in 1961, when a number of common terns (
Sterna hirundo
, a kind of seabird) died in South Africa and were found to contain influenza. If the flu virus had killed them, then by definition the terns weren’t its reservoir; but maybe their life histories put them
in contact
with the reservoir. Soon after that, a young biologist from New Zealand went for a walk along the coast of New South Wales with a young Australian biochemist. They saw some dead birds.

These two men were great pals, sharing a love for the outdoors. Their beach walk, in fact, was part of a fishing trip. The New Zealander was Robert G. Webster, transplanted to Australia to do his PhD, and the Australian was William Graeme Laver, educated in Melbourne and London, inspired to a research career by Macfarlane Burnet. Laver was such an adventurous soul that, when he finished his doctoral work in London, he and his wife
drove
home to Australia rather than fly. Several years later he and Webster took their historic stroll, found the beach littered with carcasses of wedge-tailed shearwaters (another seabird, of the species
Puffinus pacificus
), and wondered—with the South African terns in mind—whether these birds too might have been killed by influenza. Laver suggested, almost as a lark, that it would be good to go up to the Great Barrier Reef and sample some birds there for influenza. The Great Barrier Reef is not generally perceived as a hardship venue. They might get a bit of fishing, bake in the sun, enjoy the clear blue-green waters, and do the science. Laver asked his boss at the Australian National University, in Canberra, to fund Webster and him for such a study. You must be hallucinating, said the boss. Not on my dollar, you’re not. So they appealed to the World Health Organization, in Geneva, where a trusting officer gave them $500, a substantial bit of money at the time. Laver and Webster went to a place called Tryon Island, fifty miles off the coast of Queensland, and found influenza virus in wedge-tailed shearwaters.

“So we have flu, related to human flu, in the wild migratory birds of the world,” Robert Webster told me, forty years later. In the scientific literature he had been rather unassuming about this work but in conversation he laid it out: Sure, Graeme Laver made the discovery that waterfowl are the reservoirs of influenza, with my help. Laver by now was dead, but fondly remembered by Dr. Webster.

Robert Webster today is arguably the most eminent influenza scientist in the world. He grew up on a New Zealand farm, studied microbiology, did his doctorate at Canberra, worked and cavorted with Laver, then moved to the United States in 1969, taking a post at St. Jude Children’s Research Hospital in Memphis, and has been there (apart from his frequent travels) ever since. He was almost eighty when I met him but still on the job, still robust, and still at the forefront of influenza research as it responds daily to viral news from all over the world. We spoke in his office, upstairs in a sleek building at St. Jude’s, after he had bought me a cup of strong coffee in the hospital cafeteria. On the office wall hung two mounted fish—a large green grouper and a handsome red snapper—as though in tribute to Graeme Laver. One of the things that makes influenza so problematic, Webster said, is its propensity to change.

He explained. First of all there’s the high rate of mutation, as in any RNA virus. No quality control as it replicates, he said, echoing what I’d heard from Eddie Holmes. Continual copying errors at the level of individual letters of code. But that’s not the half of it. Even more important is the reassortment. (“Reassortment” means the accidental swapping of entire genomic segments between virions of two different subtypes. It’s similar to recombination, as occurs sometimes between crossed chromosomes in dividing cells, except that reassortment is somewhat more facile and orderly. It happens often among influenza viruses because the segmentation allows their RNA to snap apart neatly at the points of demarcation between genes: those eight railroad cars in a switching yard.) Sixteen available kinds of hemagglutinin, Webster reminded me. Nine kinds of neuraminidase. “You can do the arithmetic,” he said. (I did: 144 possible pairings.) The changes are random and most yield bad combinations, making the virus less viable. But random changes do constitute variation, and variation is the exploration of possibilities. It’s the raw material of natural selection, adaptation, evolution. That’s why influenza is such a protean sort of bug, always full of surprises, full of newness, full of menace: so much mutation and reassortment.