So much for the wave hypothesis. The particle hypothesis embraces much of the same data, construed differently, to arrive at a vision of independent spillovers, not a traveling wave. Eric Leroy’s group also collected more data, including samples of muscle and bone from gorillas, chimps, and duikers found dead near human outbreak sites. In some of the carcasses (especially the gorillas), they detected evidence of Ebola virus infection, with small but significant genetic differences in the virus among individual animals. Likewise they looked at a number of human samples, from the outbreaks in Gabon and the Republic of the Congo during 2001–2003, and identified eight different viral variants. (These were lesser degrees of difference than the gaps among the five ebolaviruses.) Such distinct viruses, they proposed, should be understood in the context that their genetic character is relatively stable. The differences among variants suggest long isolation in separate locales, not a rolling wave of newly arrived, rather uniform virus. “Thus, Ebola outbreaks probably do not occur as a single outbreak spreading throughout the Congo basin as others have proposed,” Leroy’s team wrote, alluding pointedly to Walsh’s hypothesis, “but are due to multiple episodic infection of great apes from the reservoir.”20
This apparent contradiction between Leroy’s particle hypothesis and Walsh’s wave hypothesis reflects an argument at cross-purposes, I think. The confusion may have arisen from back-channel communications and a certain sense of competition as much as from ambiguity in their published papers. What Walsh suggested—to recapitulate in simplest form—is a wave of Ebola virus sweeping across Central Africa by newly infecting some reservoir host or hosts. From its recent establishment in the host, according to Walsh, the virus spilled over, here and there, into ape and human populations. The result of that process is manifest as a sequence of human outbreaks coinciding with clusters of dead chimps and gorillas—almost as though the virus were sweeping through ape populations across Central Africa. Walsh insisted during our Libreville chat, though, that he had never proposed a continental wave of dying gorillas, one group infecting another. His wave of Ebola, he explained, has been traveling mainly through the reservoir populations, not through the apes. Ape deaths have been numerous and widespread, yes, and to some degree amplified by ape-to-ape contagion, but the larger pattern reflects progressive viral establishment in some other group of animals, still unidentified, with which apes frequently come into contact. Leroy, on the other hand, has presented his particle hypothesis of “multiple independent introductions” as a diametric alternative not to Walsh’s idea as here stated but to the notion of a continuous wave among the apes.
In other words, one has cried: Apples! The other has replied: Not oranges, no! Either might be right, or not, but in any case their arguments don’t quite meet nose to nose.
So … is light a wave or a particle? The coy, modern, quantum-mechanical answer is yes. And is Peter Walsh correct about Ebola virus or is Eric Leroy? The best answer again may be yes. Walsh and Leroy eventually coauthored a paper, along with Roman Biek and Les Real as deft reconcilers, offering a logical amalgam of their respective views on the family tree of Ebola virus variants (all descended from Yambuku) and of the hammer-headed bat and those two other kinds of bats as (relatively new) reservoir hosts. But even that paper left certain questions unanswered, including this one: If the bats have just recently become infected with Ebola virus, why don’t they suffer symptoms?
The four coauthors did agree on a couple of other basic points. First, fruit bats might be reservoirs of Ebola virus but not necessarily the only reservoirs. Maybe another animal is involved—a more ancient reservoir, long since adapted to the virus. (If so, where is that creature hiding?) Second, they agreed that too many people have died of Ebola virus disease, but not nearly so many people as gorillas.
15
WHY DO WE share these diseases with wildlife, and why do they seem to be emerging ever more frequently—Ebola one year, bird flu another year, then SARS out of China, then something called MERS from the Arabian peninsula, then something else, and then Ebola again?
“The key is connectivity,” Jon Epstein told me. He’s a veterinary disease ecologist, based in New York and traveling the world for EcoHealth Alliance, the same organization that employs Billy Karesh. Epstein and I were in Bangladesh at the time, where he was trapping giant fruit bats in search of the virus called Nipah, little known outside of Asia but roughly as lethal as Ebola. “The key is to understand how animals and people are interconnected.” You can’t look at a new bug or a reservoir host as though they exist in a vacuum, Epstein said. It’s a matter of contact with humans, interaction, opportunity. “Therein lies the risk of spillover.”
Repeatedly over the next half hour he returned to the word “opportunity.” It kept knocking. “A lot of these viruses, a lot of these pathogens that come out of wildlife into domestic animals or people, have existed in wild animals for a very long time,” he said. They don’t necessarily cause any disease. They have coevolved with their natural hosts over millions of years. They have reached some sort of accommodation, replicating slowly but steadily, passing unobtrusively through the host population, enjoying long-term security—and eschewing short-term success in the form of maximal replication within each host individual. It’s a strategy that works. But when we humans disturb the accommodation—when we encroach upon the host populations, hunting them for meat, dragging or pushing them out of their ecosystems, disrupting or destroying those ecosystems—our action increases the level of risk. “It increases the opportunity for these pathogens to jump from their natural host into a new host,” he said. The new host might be any animal (the chimpanzee or the gorilla, for instance) but often it’s humans, because we are present so intrusively and abundantly. We offer a wealth of opportunity.
“Sometimes nothing happens,” Epstein said. A leap is made but the microbe remains benign in its new host, as it was in the old one. (There is a thing called simian foamy virus, for instance, which gets into people from monkeys but causes no known human disease.) In other cases, the result is very severe disease for a limited number of people, after which the pathogen comes to a dead end. (Hendra virus in Australia kills about half the people it infects, but it infects few, and it hasn’t passed from human to human.) In still other cases, the pathogen achieves great and far-reaching success in its new host. It finds itself well enough suited to get a foothold; it makes itself still better suited by adapting. It evolves, it flourishes, it continues. The history of HIV is the story of a leaping virus that might have come to a dead end but didn’t.
Yes, HIV is a vivid example, I agreed. But is there any particular reason why other viruses shouldn’t have the same potential? For instance, Nipah?
“No reason at all. There’s no reason at all,” Epstein said. “A lot of what determines whether a pathogen becomes successful in a new host, I think, is odds. Chance, to a large degree.” Many of these new pathogens are RNA viruses, carrying their genomes on a single-stranded molecule, not the double-stranded molecule that is DNA. A single-stranded genome tends to yield more mistakes during replication, meaning a high rate of mutation. With their high rates of mutation and replication, RNA viruses are very adaptable, Epstein reminded me, and every spillover presents a new opportunity to adapt and take hold. We’ll probably never know how often that occurs—how many animal viruses spill into people inconspicuously. Some of those viruses cause no disease, or they cause a new disease that—in some parts of the world, because health care is marginal—gets mistaken for an old disease. “The point being,” he said, “that the more opportunity viruses have to jump hosts, the more opportunity they have to mutate when they encounter new immune systems.” Their mutations are random but frequent, combining nucleotide bases (the coding elements of RNA and DNA) in myriad new ways. “And, sooner or later, one of these viruses has the right combination to adapt to its new host.”
This point about opportunity is a crucial idea, more subtle than it might seem. I had heard it from a few o
ther disease scientists. It’s crucial because it captures the randomness of the whole situation, without which we might romanticize the phenomena of emerging diseases, deluding ourselves that these new viruses attack humans with some sort of purposefulness. (Loose talk about “the revenge of the rainforest” is one form of such romanticizing.21 That’s a nice metaphor, granted, but shouldn’t be taken too seriously.) Epstein was talking, in an understated way, about the two distinct but interconnected dimensions of zoonotic transfer: ecology and evolution. Habitat disturbance, bushmeat hunting, the exposure of humans to unfamiliar viruses that lurk in animal hosts—that’s ecology. Those things happen between humans and other kinds of organisms, and are viewed in the moment. Rates of replication and mutation of an RNA virus, differential success for different strains of the virus, adaptation of the virus to a new host—that’s evolution. It happens within a population of some organism, as the population responds to its environment over time. Among the most important things to remember about evolution—and about its primary mechanism, natural selection, as limned by Darwin and his successors—is that it doesn’t have purposes. It only has results. To believe otherwise is to embrace a teleological fallacy that carries emotive appeal but misleads. This is what Jon Epstein was getting at. Don’t imagine that these viruses have a deliberate strategy, he said. Don’t think that they bear some malign onus against humans. “It’s all about opportunity.” They don’t come after us. In one way or another, we go to them. We offer them opportunity to infect us when we mess with their reservoir hosts, whatever those creatures may be.
16
THE SUBJECT OF reservoir hosts has continued to intrigue and puzzle infectious disease scientists generally, not merely veterinary ecologists such as Epstein, and not merely those who study Ebola virus. In their pursuit of understanding, they look for patterns. They note that some kinds of animals are more deeply implicated than others as reservoirs of the zoonotic viruses that jump into humans.
Hantaviruses jump from rodents. Lassa virus too jumps from rodents. Yellow fever virus jumps from monkeys. Monkeypox, despite its name, seems to jump mainly from squirrels. Herpes B jumps from macaques. The influenzas jump from wild birds into domestic poultry and then into people, sometimes after a transformative stopover in pigs. Measles may originally have jumped into us from domesticated sheep and goats. HIV-1 has jumped our way from chimpanzees. So there’s a certain diversity of origins. But a large fraction of all the scary new viruses known to be zoonoses, and for which reservoir hosts have been identified, come jumping at us from bats.
Hendra virus in Australia: from bats. Marburg in Africa: from bats. SARS coronavirus, which came out of China in 2003: from bats. Nipah virus in Malaysia, 1998, and then again in Bangladesh, 2001: from bats. Rabies, when it jumps into people, comes usually from domestic dogs—because mad dogs get more opportunities than mad wildlife to sink their teeth into humans—but bats are among its chief reservoirs. Duvenhage, a rabies cousin, jumps to humans from bats. Kyasanur Forest virus is vectored by ticks, which carry it to people from several kinds of wildlife, including bats. Menangle virus: from bats. Tioman virus: from bats. Melaka virus: from bats. Australian bat lyssavirus, it may not surprise you to learn, has its reservoir in Australian bats. And the evidence on Ebola virus, though not definitive, as I’ve mentioned, suggests that it too very possibly comes: from bats.
Why bats? Before even considering that question, I suppose it’s necessary to remind ourselves that bats are wondrous, valuable, and necessary animals, filling a variety of crucial roles—as insectivores, pollinators, seed dispersers, and otherwise—within the ecosystems of which they are integral parts. But what is it about the chiropteran order of mammals (or about our relations with them) that accounts for their seemingly inordinate role also as reservoir hosts of novel and nasty zoonotic viruses? I’ve put that question to emerging-disease experts around the world. One of them was Charles H. Calisher, an eminent virologist recently retired as professor of microbiology at Colorado State University.
Calisher came out of the Georgetown School of Medicine with a PhD in microbiology in 1964. He made his bones doing classic lab-table virology, which meant growing live viruses, passaging them experimentally through mice and cell cultures, looking at them in electron micrographs, figuring out where to place them on the viral family tree—the kind of work that Karl Johnson had done on Machupo virus, and that traced back before Johnson to other infectious-disease pioneers. Calisher’s career included a long stretch at the CDC as well as academic appointments, during which he had focused on arthropod-borne viruses (such as West Nile, dengue, and La Crosse virus, all carried by mosquitoes) and rodent-borne viruses (notably the hantaviruses). As a scientist who studied viruses in their vectors and in their reservoirs for more than four decades, but with no particular attention to chiropterans, he had eventually found himself wanting to know: Why are so many of these new things emerging from bats?
Charlie Calisher is a smallish man with a dangerous twinkle, famed throughout the profession for his depth of knowledge, his caustic humor, his disdain for pomposity, his brusque manner, and (if you happen to get past those crusts) his big, affable heart. He insisted on buying me lunch, at a favorite Vietnamese restaurant in Fort Collins, before we got down to serious talk. He wore a fisherman’s sweater, chinos, and hiking boots. After the meal I followed his red pickup truck back to a CSU laboratory compound, where he still had a few projects going. He pulled a flat-sided flask from an incubator, put it under a microscope, focused, and said, Look here: La Crosse virus. I saw monkey cells, in a culture medium the color of cherry Kool-Aid, under attack by something so tiny it could only be discerned by the damage it did. People around the world—doctors, veterinarians—send him tissue samples, Calisher explained, asking him to grow a virus from the stuff and identify it. Okay. That sort of thing has been his life’s work, especially with regard to hantaviruses in rodents. And then came this little excursion into bats.
We repaired to his office, now almost empty as he eased into retirement, except for a desk, two chairs, a computer, and some boxes. He tilted back in his chair, set his boots on the desk, and began to talk: arboviruses, the CDC, hantaviruses in rodents, La Crosse virus, mosquitoes, and a congenial group called the Rocky Mountain Virology Club. He ranged widely but, knowing my interest, circled back to a consequential chat he’d had with a colleague about six years earlier, soon after news broke that SARS, the new killer coronavirus, had been traced to a Chinese bat. The colleague was Kathryn V. Holmes, an expert on coronaviruses and their molecular structure, at the University of Colorado Health Sciences Center near Denver, just down the highway from Fort Collins. Charlie told me the story in his own vivid way, complete with dialogue:
“We oughta write a review paper about bats and their viruses,” he said to Kay Holmes. “This bat coronavirus is really interesting.”
She seemed intrigued but a little dubious. “What would we include?”
“Well, this and that, something else,” Charlie said vaguely. The idea was still taking shape. “Maybe immunology.”
“What do we know about immunology?”
Charlie: “I don’t know shit about immunology. Let’s ask Tony.” Tony Schountz, another professional friend, is an immunologist, then at the University of Northern Colorado, in Greeley, who does research on responses to hantaviruses in humans and mice. At that time Schountz, like Calisher, had never studied chiropterans. But he was a burly young guy, a former athlete, who had played college baseball as a catcher.
“Tony, what do you know about bats?”
Schountz thought Charlie meant baseball bats. “They’re made of ash.”
“Hello, Tony? I’m talkin’ about bats.” Wing-flapping gesture. As distinct from: Joe DiMaggio gesture.
“Oh. Uh, nothing.”
“You ever read anything about the immunology of bats?”
“No.”
“Have you ever seen any papers on the immunology of bats?”
&nbs
p; “No.”
Neither had Charlie—nothing beyond the level of finding antibodies that confirmed infection. Nobody seemed to have addressed the deeper question of how chiropteran immune systems respond. “So I said to Kay, ‘Let’s write a review paper,’” Charlie told me. “Tony said, ‘Are you crazy? We don’t know anything.’”
“Well, she doesn’t know anything, you don’t know anything, and I don’t know anything. This is great. We don’t have any biases.”
“Biases?” said Schountz. “We don’t have any information!”
“I said, ‘Tony, that shouldn’t hold us back.’”
Thus the workings of science. But Calisher and his two pals didn’t plan to flaunt their ignorance. If we don’t know anything in this or that area, he proposed, we’ll just get somebody who does. They enlisted James E. Childs, an epidemiologist and rabies expert at the Yale School of Medicine (and an old friend of Charlie’s from CDC days), and Hume Field, an Australian veterinary ecologist, who had played a key role in the identification of the bat reservoirs of both Nipah and Hendra. This five-member team, with their patchwork of expertise and their sublime lack of biases, then wrote a long, wide-ranging paper. Several journal editors voiced interest but wanted the manuscript cut; Charlie refused. It appeared finally, intact, in a more expansive journal, under the title “Bats: Important Reservoir Hosts of Emerging Viruses.” It was a review, as Charlie had envisioned, meaning that the five authors made no claim of presenting original research; they simply summarized what had previously been done, gathered disparate results together (including unpublished data contributed by others), and sought to highlight some broader patterns. That much, it turned out, was a timely service. The paper offered a rich compendium of facts and ideas—and where facts were scarce, directive questions. Other disease scientists noticed. “All of a sudden,” Charlie told me, “the phone’s ringing off the hook.” They met hundreds of requests for reprints, maybe thousands, sending their “Bats: Important Reservoir Hosts” to colleagues worldwide in the form of a PDF. Everybody wanted to know—everybody in that professional universe anyway—about these new viruses and their chiropteran hideouts. Yes, what is the deal with bats?
Ebola: The Natural and Human History of a Deadly Virus Page 9
