Spillover: Animal Infections and the Next Human Pandemic (32 page)

52

O
stfeld is sensitive to the human toll, not just to the wondrous intricacy of
Borrelia burgdorferi
dynamics in American forests. He showed me some figures from Dutchess County, New York, which includes Millbrook and the Cary Institute, between 1986 and 2005. The twenty-year trend of human infections was steeply upward, with especially high peaks in 1996 and 2002. People were suffering. In 1996 there were 1,838 reported cases of Lyme disease. After that came a sizable decline until, in 2002, again almost two thousand new cases were reported.

Still, it’s best understood as an ecological phenomenon, not just a medical problem. “Lyme disease in humans exists because we are sort of unwitting victims of a wildlife-tick interaction,” Ostfeld said. “We’re interlopers into this system where ticks and these hosts—the reservoir hosts—pass bacterial infections back and forth.” One way of construing those peaks in 1996 and 2002, he explained, is that they reflect autumns of bounteous production in the local forests. White-footed mice love acorns and, because the mice reproduce quickly and mature quickly, responding to food abundance with bursts of heightened fecundity, big masting events are often followed (after a two-year lag) by big increases in the mouse population. One pair of mice, given circumstances of plentiful food, could produce a net gain of fifty to seventy-five mice within a year. More acorns, more mice, more infected ticks, more Lyme.

Dutchess County is a halcyon Yankee getaway just east of the Catskills and only two hours from Manhattan via the Taconic State Parkway. It’s a landscape of rolling hills, stone fences, small towns, old roadhouses, little gullies and streams carrying rain to the Hudson River, golf courses, and suburban neighborhoods, including some graceful homes with sizable yards shaded by hardwood trees and bordered by hedges or feral brush. The residential areas, even the commercial districts and malls, are well garnished with greenery. Scattered between and around the zones of concentrated human presence are parks, woodlots, and forest patches, dominated not by people
but by oak and maple. The understory of those patches is rife with mosses, leaf litter, barberry, chickweed, acorn scraps, poison ivy, wild mushrooms, rotting logs, soggy swales, and the newts, frogs, salamanders, crickets, pill bugs, earthworms, spiders, and garter snakes that thrive in such places. Ticks too, of course—manymanymany ticks. During the year before my visit, Dutchess County health authorities had recorded another 1,244 cases of Lyme disease within a resident population of less than three hundred thousand people. It was enough to make you think twice about a stroll through the woods.

Ostfeld and his team can’t afford to be squeamish, though, because those forest patches are where they gather their data. I had tagged along earlier that day, walking trap lines with him and some of his young colleagues. One of them was Jesse Brunner, a postdoc from Helena, Montana, bearded and balding, who was engaged in a multiyear study exploring the correlation, if any, between Lyme prevalence and species diversity on forest patches of various sizes. Another teammate was Shannon Duerr, a tech assistant employed in Ostfeld’s lab, presently suffering a case of Lyme disease herself and under treatment with amoxicillin. Ostfeld, I noticed, wore his jeans tucked into his socks as we moved through the forest, and he worked in latex gloves while handling a captured animal. Jesse Brunner showed me his own technique with a white-footed mouse, and then handed the creature to me.

I held the mouse, as instructed, with a gentle pinch of the skin over its shoulders. Its eyes were dark and huge, protrusive with fear, gleaming like steel BBs. Its ears were large and velvety. Its fur was a soft brownish gray. Attached to one ear I could see several dark dots, each no bigger than a period. Those were larval ticks, Brunner explained; they had recently come aboard and scarcely begun to drink. In the other ear was a larger black lump, big as a pinhead. That larva had been attached longer and was now engorged with blood. At this time of the season, Brunner told me, the mouse was probably already infected with
B. burgdorferi
from the bite of a nymphal tick. The engorged larva had probably just become infected, in turn, from the mouse. So I was holding, most likely, two infected carriers. As I listened raptly to Brunner, the mouse sensed my lapse of attention, sprang free of my grip, hit the ground running, and disappeared in the undergrowth. And so the cycle continued.

That afternoon, during our chat in his office, I asked Ostfeld a practical question: Say you’re a parent with young children, living here in your Millbrook dream house on three acres of beautiful lawn and shrubbery—what do you want for protection against Lyme disease? There might be a whole range of desperate options. Pesticide spraying by the county? Deer eradication by the state? Thousands of mousetraps (not Shermans but the lethal kind), deployed in the forest and baited with cheese, snapping away like brushfire? Do you pave your yard and ring it with an oil-filled moat? Do you put flea-and-tick collars on your kids’ ankles before they go out to play?

No, none of those. “I would feel a lot more comfortable,” Ostfeld answered, “if I knew that the landscape would support healthy populations of owls, foxes, hawks, weasels, squirrels of various kinds—the components of the community that could regulate mouse populations.” In other words, biological diversity.

This was his offhand way of expressing the most notable conclusion that has emerged from twenty years of research: Risk of Lyme disease seems to go up as the roster of native animals, in a given area, goes down. Why? Probably because of the differences in reservoir competence between mice and shrews (both with high competence) and almost all other vertebrate hosts (low competence) that may share habitat with them. The effect of the most competent reservoirs is diluted by the presence, when there is such presence, of less-competent alternatives. In forest patches containing a full cast of ecological players—medium-sized predators such as hawks, owls, foxes, weasels, and possums, as well as smallish competitors such as squirrels and chipmunks—the populations of white-footed mice and shrews are relatively small, held in check by predation and competition. The average reservoir competence is therefore low. In forest patches with little diversity, on the other hand, white-footed mice and shrews are almost certainly there, flourishing inordinately. And where they flourish, transmitting infection efficiently to the ticks that bite them,
Borrelia burgdorferi
flourishes also.

This insight had led Ostfeld to another interesting question, one with direct implications for public health. Which forest patches contain less species diversity than others? In practical terms: Which woodlots and green zones and parks harbor the greatest risk of exposure to Lyme disease?

Bear in mind that any patch of forest, surrounded by pavement and buildings and other forms of human impact, is to some degree an ecological island. Its community of land animals is insularized because, when individuals try to leave or to enter, they get squashed. (Birds are a special case, though they tend to conform to the same pattern.) Be aware too that big islands generally support more diversity than small islands do. Madagascar is more richly diverse than Fiji, which in turn is more richly diverse than Pohnpei. Why? The simple answer is that greater land area and greater habitat diversity allow the survival of more kinds of creatures. (The complicated details behind that simple answer are addressed by a field of science called island biogeography, familiar to Rick Ostfeld because it so heavily influenced ecological thinking during the 1970s and 1980s, and familiar to me because I wrote a book about it in the 1990s.) Apply that principle to Dutchess County, New York, and it yields a prediction that small forest patches, postage-stamp woodlands, contain fewer kinds of animal than larger forest tracts. That’s what Rick Ostfeld did—applied the prediction of area-related diversity as a rough hypothesis and then studied real sites to test it. By the time of my visit to Millbrook, he could say that the pattern did seem to hold true, while Jesse Brunner’s postdoctoral work probed further into the same topic.

Then time passed. Five years after I spoke with him, Rick Ostfeld could state the matter more confidently based on two decades’ worth of continuous investigation. It became an important theme in his
Lyme Disease
book. With his increasing confidence in the general principles has come increasing appreciation for the various ways those principles play out in differing circumstances. All his conclusions are now carefully modified with conditionals. But the basic findings are clear.

A tiny patch of woodland in a place such as Dutchess County is likely to harbor only a few kinds of mammal, one of which is the white-footed mouse. The mouse is a good colonizer, a good survivor, a fecund breeder, an opportunist; it is there to stay. Restrained by few predators and few competitors, its population fluctuates around a relatively high average level and, in summers following a big acorn crop, goes much higher still. A plague of mice will infest the little woodland, like rats on the road out of Hamelin. There will also be plenty of ticks. The ticks drink heartily of mouse blood and have a high rate of survival, because white-footed mice (unlike possums, catbirds, or even chipmunks) are not very good at grooming themselves clear of larvae. And because the mouse is such a competent reservoir of
Borrelia burgdorferi
—so efficient at harboring and transmitting it—most ticks carry the infection.

In a larger area of forest, with a more richly diverse community of animals and plants, the dynamics are different. Facing a dozen or more kinds of predators and competitors, the white-footed mouse is less numerous; the other mammals are less competent as hosts for the spirochete and less tolerant of thirsty tick larvae; the net effect is fewer infected ticks.

Although it’s an intricate system, as Ostfeld warned in his title, certain points about Lyme disease emerge plainly. “
We know that walking into a small woodlot
,” he wrote, “is riskier than walking into a nearby large, extensive forest. We know that hiking in the oak woods two summers after a big acorn year is much riskier than hiking in those same woods after an acorn failure. We know that forests that house many kinds of mammals and birds are safer than those that support fewer kinds. We know that the more opossums and squirrels there are in the woods, the lower the risk of Lyme disease, and we suspect that the same is true of owls, hawks, and weasels.” As for white-tailed deer: They’re involved, yes, but far from paramount, so don’t believe everything you’ve heard.

Some people take “All life is connected” to be
the central truth of ecology, Ostfeld added. It’s not. It’s just a vague truism. The real point of the science is understanding which creatures are more intimately connected than others, and how, and to what result when change or disturbance occurs.

53

O
ne of the signal lessons of Lyme disease, as Rick Ostfeld and his colleagues have shown, is that a zoonosis may spill over more readily within a disrupted, fragmented ecosystem than within an intact, diverse ecosystem. Another lesson, though, has little to do with Ostfeld’s work and can’t be addressed at the scale of Sherman traps baited with oats. This one derives from a more basic fact—the fact that
Borrelia burgdorferi
is a bacterium.

It’s a bacterium, admittedly, with some peculiar traits. When assaulted with antibiotics, for instance,
B. burgdorferi
seems to retreat into a defensive, impervious form,
a sort of cystlike stage known as a
“round body.” Round bodies are resistant to destruction and very difficult to detect. A patient who seems cured of Lyme disease by the standard two-to-four-week course of amoxicillin or doxycycline might still be harboring round bodies and therefore subject to relapse. Round bodies might even explain the “chronic Lyme disease” syndrome so hotly contested by suffering patients, maverick physicians, and the IDSA. Or not.

Don’t confuse the round bodies of
Borrelia burgdorferi
with the small form of
Coxiella burnetii
, the agent of Q fever, also cystlike but found adrift on the Dutch breezes, carrying infection downwind from a birthing goat. Nobody is claiming, not so far, anyway, that Lyme disease can likewise travel on the wind. Both the round bodies of
B. burgdorferi
and the small form of
C. burnetii
merely illustrate that, even in the age of antibiotics, bacteria can be sneaky and tough. These microbes remind us that you don’t have to be a virus to cause severe, intractable, mystifying outbreaks of zoonotic disease in the twenty-first century. Although it helps.

VI

GOING VIRAL

54

V
iruses were an invisible mystery, like dark matter and Planet X, until well into the twentieth century. They were momentously consequential but undetectable, like the neutron. Anton van Leeuwenhoek’s microbial discoveries hadn’t encompassed them, nor had the bacteriological breakthroughs of Pasteur and Koch, two hundred years later. Pasteur worked on rabies as a disease, true, and even developed a vaccine, but he never laid eyes on the rabies virus itself nor quite understood what it was. Likewise, in 1902, William C. Gorgas eliminated yellow fever from Cuba, by a program of mosquito eradication, without ever knowing just what infectious agent those mosquitoes carried. It was like a blindfolded hunter shooting ducks by the sound of their quacking. Even the influenza virus of 1918–1919, having killed up to 50 million people around the world, remained a ghostly cipher, unseen and unidentified at the time. Viruses couldn’t be viewed with an optical microscope; they couldn’t be grown in a culture of chemical nutrients; they couldn’t be captured, as bacteria could, with a porcelain filter. They could only be inferred.

Why so elusive? Because viruses are vanishingly minuscule, simple but ingenious, anomalous, economical, and in some cases fiendishly subtle. Expert opinion even divides on the conundrum of whether viruses are alive. If they aren’t, then at the very least they’re mechanistic shortcuts on the principle of life itself. They parasitize. They compete. They attack, they evade. They struggle. They obey the same basic imperatives as all living creatures—to survive, to multiply, to perpetuate their lineage—and they do it using intricate strategies shaped by Darwinian natural selection. They evolve. The viruses on Earth today are well fit for what they do because only the fittest have survived.

The word “virus” has a much longer history than the study of what we now call by that name. It comes directly from the Latin
virus
,
a term meaning “poison, sap of plants, slimy liquid.” You can even find the Latin word rendered as “poisonous slime.” Its earliest known use in English to denote a disease-causing agent was in 1728, though for the rest of the eighteenth century, throughout the nineteenth, and for several decades beyond, there was no clear distinction between “virus” as a vague term, applicable to any
infectious microbe, and the very particular group of entities we know as viral today. As late as 1940, even Macfarlane Burnet sometimes called the Q fever microbe a “virus” in casual usage, though by then he knew perfectly well it was a bacterium.

The effects of viruses were detected long before viruses themselves. Smallpox and rabies and measles were excruciatingly familiar at the clinical level for centuries, millennia, although their causal agents weren’t. Acute disease and epidemic outbreaks were understood in a variety of inventive ways—as caused by miasmal vapors and “effluvia,” by decaying matter and filth, by poverty, by the whim of God, by bad magic, by cold air or wet feet—but the recognition of infectious microbes came slowly. Around 1840, a German anatomist named Jakob Henle began to suspect the existence of noxious particles—creatures or things—that were too small to be seen with a light microscope and yet able to transmit specific diseases. Henle had no evidence, and the idea didn’t immediately take hold. In 1846, a Danish physician named Peter Panum witnessed a measles epidemic on the Faroe Islands, a remote archipelago north of Scotland, and drew some keen inferences about how the ailment seemed to pass from person to person, with a delay of about two weeks (what we’d now call an incubation period) between exposure and symptoms. Robert Koch, who had been a student of Jakob Henle’s at Göttingen, advanced beyond observation and supposition with his experimental work of the 1870s and 1880s, identifying the microbial causes of anthrax, tuberculosis, and cholera. Koch’s discoveries, along with those of Pasteur and Joseph Lister and William Roberts and John Burdon Sanderson and others, provided the empirical bases for a swirl of late-nineteenth-century ideas that commonly get lumped as “the germ theory” of disease, which marked a movement away from older notions of malign vapors, transmissible poisons, imbalanced humors, contagious putrefaction, and magic. But the germs with which Koch, Pasteur, and Lister mainly concerned themselves (apart from Pasteur’s brilliant guesswork on rabies) were bacteria.

And bacteria weren’t quite so ineffable. They could be seen with a normal microscope. They could be cultured in a Petri dish (the invention of Julius Petri, Koch’s assistant) containing a nutrient-rich medium of agar. They were bigger and easier to grasp than viruses.

The next crucial insight came from agronomy, not medicine. During the early 1890s, a Russian scientist named Dmitri Ivanofsky, in St. Petersburg, studied tobacco mosaic disease, a problem on plantations within the empire. The “mosaic” spots on the leaves led eventually to stunting and shriveling, which lowered productivity and cost growers money. Earlier work had shown that this disease was infectious—it could be transferred experimentally from one plant to another by applying sap drawn from infected leaves. Ivanofsky repeated the transmission experiment, with one added step. He put the juice through a Chamberland filter, a device made from unglazed porcelain, with tiny pores, for purifying water by screening out bacteria. Ivanofsky’s report, that “
the sap of leaves infected with tobacco mosaic disease
retains its infectious properties even after filtration,” constituted the first operational definition of viruses: infectious but “filterable,” meaning so small they would pass through where bacteria wouldn’t. Soon afterward, a Dutch researcher named Martinus Beijerinck arrived independently at the same result and then pushed one step farther. By diluting the filtered sap from an infected plant and using that tincture to infect another plant, Beijerinck found that the infectious stuff, whatever it was, regained its full strength even after dilution. That meant it was reproducing itself in the second plant’s living tissues, which meant in turn that it wasn’t a toxin, a poisonous excretion, of the sort that some bacteria produce. A toxin, diluted in volume, is reduced in effect—and it doesn’t spontaneously recover its strength. This stuff did. But in a container of filtered sap alone, it wouldn’t grow. It needed something else. It needed the plant.

So the cumulative work of Martinus Beijerinck, Dmitri Ivanofsky, and a few colleagues showed that tobacco mosaic disease is caused by an entity smaller than a bacterium, invisible by microscope, and capable of multiplication within—only within—living cells. That was the basic profile of a virus, though still nobody had seen one. Beijerinck guessed that the tobacco-mosaic agent was liquid and labeled it
contagium vivum fluidum
, a contagious living fluid. Later work, including the invention of the electron microscope in the 1930s, proved him wrong on that point. A virus is not liquid but solid: minute particles.

This was all about plants. The first animal virus discovered was the one causing foot-and-mouth disease, another sore problem to agriculture. Cattle and swine passed it to one another, like a sneeze on the breeze, and died from it or else had to be culled. Friedrich Loeffler and Paul Froesch, at a university in northern Germany, using the same techniques of filtering and dilution as Beijerinck, proved in 1898 that the foot-and-mouth agent is also a filter-passing entity capable of replication only in living cells. Loeffler and Froesch even noted that it might be just one of a whole class of disease agents, so far undiscovered, possibly including some that infected people, causing phenomena such as smallpox. But the first viral infection recognized in humans wasn’t smallpox; it was yellow fever, in 1901. Around the time William Gorgas was solving the practical problem of yellow fever in Cuba, by killing off all those mosquitoes, Walter Reed and his little team of microbiologists showed that the causative agent was indeed mosquito-transmitted. Still, they couldn’t see it.

Scientists then began using the label “filterable virus,” which was a clumsy but more precise application of the old poisonous-slime word. Hans Zinsser, for example, in his 1934 book
Rats, Lice and History
, a classic chronicle of medical groping and discovery, declared himself “
encouraged by the study of the so-called ‘filterable virus’ agents
.” Many epidemic diseases, Zinsser wrote, “are caused by these mysterious ‘somethings’—for example, smallpox, chicken pox, measles, mumps, infantile paralysis, encephalitis, yellow fever, dengue fever, rabies, and influenza, to say nothing of a large number of the most important afflictions of the animal kingdom.” Zinsser realized, too, that some of those animal afflictions might overlap with the first category, human epidemics. He added a crucial point: “
Here, as in bacterial disease
, there is a lively interchange of parasites between man and the animal world.” Zinsser was a panoramic thinker as well as an acutely trained microbiologist. Eight decades ago he sensed that viruses, only lately discovered, might be among the most nefarious of zoonoses.

55

T
he difficulty of cultivating viruses
in vitro
made them obscure to early researchers, elusive in the laboratory, but it was also a clue to their essence. A virus won’t grow in a medium of chemical nutrients because it can only replicate inside a living cell. In the technical parlance, it’s an “obligate intracellular parasite.” Its size is small and so is its genome, simplified down to the bare necessities for an opportunistic, dependent existence. It doesn’t contain its own reproductive machinery. It mooches. It steals.

How small is small? The average virus is about one-tenth the size of the average bacterium. In metric terms, which are how science measures them, roundish viruses range from around fifteen nanometers (that’s fifteen
billionths
of a meter) in diameter to around three hundred nanometers. But viruses aren’t all roundish. Some are cylindrical, some are stringy, some look like bad futuristic buildings or lunar landing modules. Whatever the shape, the interior volume is minuscule. The genomes packed within such small containers are correspondingly limited, ranging from 2,000 nucleotides up to about 1.2 million. The genome of a mouse, by contrast, is about 3
billion
nucleotides. It takes three nucleotide bases to specify an amino acid and on average about 250 amino acids to make a protein (though some proteins are much larger). Making proteins is what genes do; everything else in a cell or a virus results from secondary reactions. So a genome of just two thousand code letters, or even thirteen thousand (as for the influenzas) or thirty thousand (the SARS virus), is a very sketchy set of engineering specs. Even with such a small genome, though, coding for just eight or ten proteins, a virus can be wily and effective.

Viruses face four basic challenges: how to get from one host to another, how to penetrate a cell within that host, how to commandeer the cell’s equipment and resources for producing multiple copies of itself, and how to get back out—out of the cell, out of the host, on to the next. A virus’s structure and genetic capabilities are shaped parsimoniously to those tasks.

Sir Peter Medawar, an eminent British biologist who received a Nobel Prize the same year as Macfarlane Burnet, defined a virus as “
a piece of bad news wrapped up in a protein
.” The “bad news” Medawar had in mind is the genetic material, which so often (but not always) inflicts damage on the host creature while exploiting its cells for refuge and reproduction. The protein wrap is known as a capsid. The capsid serves two purposes: It protects the viral innards when they need protection and it helps the virus lever its way into cells. The individual viral unit, one particle, standing intact outside a cell, is called a virion. The capsid also defines the exterior shape of a virus. Virions of Ebola and Marburg, for instance, are long filaments, which is why they’ve been placed in a group known as filoviruses. Other viruses have particles that are spherical, or ovoid, or helical, or icosahedral (twenty-sided, like a soccer ball designed by Buckminster Fuller). HIV-1 particles are globular. Rabies virions are shaped like bullets. A plate of Ebola virions mixed with Hendra virions would resemble capellini in a light sauce of capers.

Many viruses are wrapped with an additional layer, known as an envelope, comprising not only protein but also lipid molecules drawn from the host cell—in some cases, pulled from the wall of the cell when the virion made its exit. Across the outer surface of the envelope, the virion may be festooned with a large number of spiky molecular protuberances, like the detonator stubs on an old-fashioned naval mine. Those spikes serve a crucial function. They’re specific to each kind of virus, with a keylike structure that fits molecular locks on the outer surface of a target cell; they allow the virion to attach itself, docking like one spaceship to another, and they open the way in. The specificity of the spikes not only constrains which kinds of host a given virus can infect but also which sorts of cell—nerve cells, stomach cells, cells of the respiratory lining—the virus can most effectively penetrate, and therefore what sort of disease it may cause. Useful as they are to a virus, though, the spikes also represent points of vulnerability. They are the primary targets of immune response by an infected host. Antibodies, produced by white blood cells, are molecules that glom onto the spikes and prevent a virion from grabbing a cell.

The capsid shouldn’t be mistaken for a cell wall or a cell membrane. It’s merely analogous. Viruses, from the beginning of virology, have been defined in the negative (
not
captured by a filter,
not
cultivable in chemical nutrients,
not
quite alive), and the most fundamental negative axiom is that a virion is not a cell. It doesn’t function the way a cell functions; it doesn’t share the same capacities or frailties. That’s reflected in the fact that viruses are impervious to antibiotics—chemicals valued for their ability to kill bacteria (which are cells) or at least impede their growth. Penicillin works by preventing bacteria from building their cell walls. So do its synthetic alternatives, such as amoxicillin. Tetracycline works by interfering with the internal metabolic processes by which bacteria manufacture new proteins for cell growth and replication. Viruses, lacking cell walls, lacking internal metabolic processes, are oblivious to the effects of such killer drugs.