An outbreak, like a story, should have a coherent plot.86
In 1993 Oxford University Press published a collection of essays, edited by Rockefeller University’s Stephen Morse, on new and reemergent viruses. Unlike most scholarly anthologies, Morse’s volume combined the indisputable authority of the field’s leading researchers (including influenza’s “emperor” and “pope,” respectively, Edwin Kilbourne and Robert Webster) with an unusual sense of urgency. Written in the shadow of the AIDS pandemic and the Ebola outbreak in Africa, Emerging Viruses warned that global economic and environmental change were speeding the evolution and interspecies transmission of new viruses, some of which might be as deadly as HIV. In his foreword, Richard Krause of the National Institutes of Health pointed to the new ecologies of disease resulting from globalization. “Microbes thrive in these ‘undercurrents of opportunity’ that arise through social economic change, changes in human behavior, and catastrophic events. . . . They may fan a minor outbreak into a widespread epidemic.”87
One such catastrophic event is Third World urbanization, which is shifting the burden of global poverty from the countrysides to the slum peripheries of new megacities. Ninety-five percent of future world population growth will be in the poor cities of the South, with immense consequences for the ecology of disease. This concentration of the world population in deprived conditions, more than global population growth per se, undergirds what William McNeill calls the “Law of the Conservation of Catastrophe.”88
McNeill is a well-known University of Chicago historian of disease ecology. He writes:
It is obvious that as virus host populations (or potential host populations) increase, there is concomitant increase in the probability of major evolutionary changes in virus populations due to increased opportunities for replication, mutation, recombination, and selection. As the world population of humans (and of their domestic animals and plants) increase, the probability for new viral disease outbreaks must inevitably increase as well. AIDS is not the first ‘new’ virus disease of humans, and it will not be the last.89
“From the point of view of a hungry virus,” McNeill writes in another piece, “we offer a magnificent feeding ground with all our billions of human bodies, where, in the very recent past, there were only half as many people.”90 (As we shall see later, this same relationship between population density and viral evolution obviously applies to industrial livestock as well.)
How is McNeill’s gloomy principle actually woven into the complex fabric of a human-influenced biosphere? In one of the rare studies that has actually attempted to conceptualize the vast web of interconnection between urbanization, the world economy, and the natural environment, an international scientific team recently looked at the implications of the soaring bushmeat trade in West Africa. Their 2004 article in Science provides an epistemological model for thinking about influenza emergence in south China and elsewhere.
Explosive city growth in West Africa (where the urban population is expected to reach 60 million by 2025) drives an ever-growing demand for animal protein. Traditionally, West Africans, like many East Asians, have consumed fish as their principal source of protein; fishing, moreover, is a major industry, employing nearly a quarter of the workforce in some countries. But local boats have been unable to compete with the modern, government-subsidized fleets from Europe that now trawl the Gulf of Guinea. These big factory fleets, along with foreign-flag pirate fishers, “illegally extract fish of the highest commercial value, while . . . dumping 70 to 90 percent of their haul as by-catch.” As a result fish biomass has fallen by at least half since 1977, and fish has become scarcer and more expensive in local markets. Increasingly bushmeat (the generic name for the flesh of some 400 different species of terrestrial vertebrates) has been substituted for fish—yearly some 400,000 tons of wild game now end up on West African dinner plates. Like the practices that led to declining fish stocks, this level of hunting is unsustainable, and mammal biomass is now decreasing at a rate that fundamentally threatens wildlife diversity.91
The authors of this fascinating and troubling study, however, fail to connect a few all-important dots in the causal chain, although undoubtedly they are aware of their importance. One is deforestation, as largely foreign logging companies denude West Africa’s remaining coastal rain forests. The bushmeat trade is indissolubly linked to this logging juggernaut and the food needs of its workers, although hunters also poach within official wildlife reserves as well, with the inevitable result being radically increased biological contact between humans and wild animals. The formerly isolated microbiological reservoirs of the rain forests and mountains have been inadvertently integrated into the food economy of the cities—and the result of this “undercurrent of opportunity” has been a series of viral leaps from animals to humans. The most infamous, of course, is HIV/AIDS: researchers believe that HIV-1 arose as a result of humans eating chimpanzees, while HIV-2 (specific to West Africa) has been linked to the consumption of sooty mangabeys. In the fall of 2004 a team headed by Nathan Wolfe of Johns Hopkins raised new fears with the isolation of a novel HIV-like retrovirus (possibly from gorillas) in the bushmeat trade in Cameroon.92
There is every reason to believe that the ecological impact of the recent urban-industrial revolution in south China has been just as profound and far-reaching as urban population growth in West Africa. Guangdong—long considered the epicenter of influenza evolution—has become the world’s leading export-manufacturing platform, a postmodern Manchester whose toys, running shoes, sports clothing, and cheap electronics are consumed in every corner of the earth. From 1978 until 2002, the province’s GDP grew at an astonishing 13.4 percent per year, and the urban population of the Pearl River Delta area increased from 32 percent to 70 percent of the total population. This spectacular regional transformation, crowned by the return of Hong Kong to China in 1997, has been accompanied by a series of socioeconomic developments that are also likely to reinforce Guangdong’s primacy as a viral exporter.
Key parameters of influenza emergence include human and animal population densities, intensity of contact between different species, and the prevalence of chronic respiratory or immune disorders. Population densities are very high in the Delta, with about 1,273 persons per square kilometer. A large segment of the population (indeed, the majority in the industrial boomtown of Shenzhen) are rural immigrants or “floaters” in perpetual motion between city factories and thousands of rural villages. Without permanent residency permits, these workers live in overcrowded dormitories or slums and are less likely than the registered population to have access to modern medicine. Meanwhile, the state’s share of healthcare spending has fallen sharply (from 34 percent in 1978 to less than 20 percent in 2003) since the advent of a market economy. “[A]bout 50 percent of people who are sick,” explains Yanzhong Huang, “do not see a doctor because of the extremely high out-of-pocket payments.”93 And rampant industrialization has increased exposure to all sorts of environmental hazards and toxins. The Delta, for example, has monstrous air pollution: twenty-four times higher than the rest of China. The population accordingly suffers from all the classical respiratory problems (and, probably, cancers) associated with industrial smog and high sulfur dioxide emissions.
Thanks especially to the prevalence of wet markets in the cities, the urbanization of Guangdong has probably intensified rather than decreased microbial traffic between humans and animals. As income has risen with industrial employment, the population is eating more meat and less rice and vegetables. The most dramatic increase has been in the consumption of poultry, which has more than doubled since 1980. Guangdong is one of China’s three largest poultry producers and is home to more than 700 million chickens. An extraordinary concentration of poultry, in other words, coexists with high human densities, large numbers of pigs, and ubiquitous wild birds. Battery chickens, indeed, “are sometimes kept directly above pig pens, depositing their waste right into the pigs’ food troughs.”94 Moreover, as the urban footprint has expanded and farm acreage has contracted, a fractal pattern of garden plots next to dormitories and factories has brought urban population and livestock together in more intimate contact. Finally, Guangdong is also a huge market for wild meat. Unlike West Africa, where subsistence demand drives the bushmeat trade, the Chinese predilection for exotic animals stems from ancient homeopathic beliefs; the demand is inexorable, and Laos (via Vietnam) has become a major supplier of live game.95
From the beginning of the second wave of H5N1 in the fall of 1997, everyone in Hong Kong was looking nervously over their shoulders at Guangdong and the rest of south China. A newspaper in Beijing reported that there were cases of bird flu in Guangdong but then was forced to retract the story.96 At the WHO’s urging, the CDC sent H5N1 diagnostic kits to researchers in Guangzhou (Canton) and Shenzhen to ensure that everyone doing lab work was using the same protocols. In mid-January, after a brief scuffle over visas, a top-level WHO team was allowed to visit Guangdong for a week. Unlike Hong Kong, with its lively press and political opposition, Guangdong (despite a quarter-million private businesses) was still living under the semantic Maoism of press releases that read, “Thanks to the correct line of the Chinese Communist Party there is no avian flu in Guangdong.” Dr. Daniel Lavanchy, at that time the chief influenza expert for WHO, responded in kind with praise for the “high quality of the surveillance activities which had been implemented by the Chinese government.” The clear purpose of the mission was to build bridges with provincial and national authorities, not to overturn rocks (or flocks) where H5N1 might be hiding.97
The WHO visit bore fruit with the adoption in March of an influenza surveillance plan for south China under the administration of the Chinese National Influenza Center; health workers were asked to be particularly vigilant in reporting and monitoring cases of acute respiratory disease. No human cases of H5N1 were found, but Guangdong and the rest of the south were unexpectedly hit by a severe summer epidemic of normal flu: H3N2. It was a dramatic reminder that influenza can circulate all year round in tropical and semitropical latitudes. In the winter the flu moved north, producing one of the most memorable outbreaks since 1968—in Beijing they called 1998 “the year of the flu.”98 Flu, however, meant H3N2, not H5N1. It was almost as if the reigning champion subtype, vintage Hong Kong 1968, had roared back in the face of the brief challenge from the avian usurper.
In a simpler universe, as in some microbiology textbooks, each subtype would patiently await its turn at the helm. But in late winter 1999, the new surveillance system revealed a claim-jumper: Hong Kong scientists were stunned to discover H9N2 in two children in March, with five “officially unconfirmed” cases simultaneously reported from Guangdong. Although none of the cases was life-threatening, the discovery of another hole in the species barrier was unnerving. The new strain was very close to an H9N2 isolated from quail the year before by Guan, Peiris, and Shortridge. But it was not the only H9 in town. Surveillance of pigs in a Hong Kong slaughterhouse found animals with the quail strain as well as some with a distinctive H9N2 derived from ducks. Genetic analysis then implicated the H9 quail strain in the viral ménage à trois that had generated the 1997 killer. The internal proteins in H5N1 were virtually identical with those from H9N2.99
With this double recognition that H9N2 was a precursor of H5N1 reassortment, as well as a human invader in its own right, the story was getting surprisingly messy. Nonlinear complexity now governed the plot. As some theorists had already recognized, the “interactive dynamics” between multiple, coevolving subtypes might “introduce complexities and substantial mathematical challenges” that would make modeling or predicting viral evolution extraordinarily difficult, if not impossible.100 To gain a better understanding of what was actually happening, the University of Hong Kong research team headed by Guan, Peiris, and Shortridge decided to explore the viral underworld of Guangdong in unprecedented detail. They wanted to find out how many subtypes and strains were circulating in the avian population and, most importantly, how they were interacting with one another. For a year, starting in July 2000, researchers carefully isolated viruses from ducks in the live-poultry markets of the Guangdong city of Shantou. The results of their study, published in the summer of 2003, fundamentally revised the standard picture of influenza evolution.
First of all, they discovered extraordinary and unexpected genetic diversity: almost 500 distinct strains of influenza, including fifty-three different iterations of the H9 subtype. “The diversity of genotypes, gene constellations, and host receptor specificities,” they warned, “will provide these viruses and their progeny with options of hosts.” Second, they established that reassortment was a more common event than previously imagined. Gene segments were vigorously being traded throughout the diverse network of influenzas. Previously, “influenza gene flow was usually considered to occur from aquatic birds to other animals.” Now they found ample evidence that viruses were evolving from ducks to poultry and back again: “i.e., there is a two-way transmission between terrestrial and aquatic.” “The species barriers between the birds have become much more permeable than previously anticipated. Increasing the heterogeneity of influenza viruses in these hosts results in an enlarged and dynamic influenza gene pool in continuous flux rather than one that is limited to aquatic birds and therefore in evolutionary stasis.”101 Or, as American virologist Richard Webby pithily put it, “we have a bucket of evolution going on.”102
The bottom-line of the Shantou report was that several subtypes of influenza were traveling on the path toward pandemic potential. The industrialization of south China, perhaps, had altered crucial parameters in an already very complex ecological system, exponentially expanding the surface area of contact between avian and nonavian influenzas. As the rate of interspecies transmission of influenza accelerated, so too did the evolution of protopandemic strains. The Hong Kong research team had discovered, in other words, that contemporary influenza, like a postmodern novel, has no single narrative, but rather disparate storylines racing one another to dictate a bloody conclusion. “The H5N1 virus was in the process of adapting from aquatic to land-based poultry from the duck via the partially aquatic goose to the chicken,” while the H9N2 (and probably H6N1) were “adapting through a mechanism that took them to the quail and probably other minor land-based poultry such as the pheasant.” Alternately, “aquatic migratory or domestic birds could introduce a ‘genetically adaptable’ virus directly into land-based poultry. The intensification of the poultry industry through large-scale commercial operations in East Asia (and elsewhere) could facilitate this.”103
Each of the aspirant subtypes had different assets. If H5N1 was an assassin of unparalleled lethality, the fact that H9N1 strains—according to the Hong Kong team—were “not highly pathogenic for poultry . . . makes them more, rather than less, likely to be of pandemic relevance.” A milder chicken virus was more likely to survive detection and extermination and thus have time to continue to reassort until it found the optimal gene constellation for rapid infection of human populations.104 In 2003 the Hong Kong researchers would find further evidence to corroborate the pandemic potential of H9N2 in a study of viruses in the live-poultry markets of their own city.105
Meanwhile, H5N1 was again laying siege to Hong Kong. Between February and March 2001, the surveillance network found several strains of the virus among market chickens, quail, pheasants, and pigeons. A few months later, South Korean authorities isolated H5N1 in imported Chinese duck meat. Laboratory testing subsequently revealed that these H5N1 genotypes were a separate reassortment from the 1997 strain and had most likely originated sometime in late 2000 from goose viruses that had “crossed to ducks and re-assorted with other unknown influenza viruses of aquatic origin.” Researchers were horrified to discover that the new H5N1 was even more pathogenic than the old: when mice were infected with the 2001 strains, the virus spread to the brain and killed the animals. In May chickens started dying again in the city’s markets, and once more the city government mandated a slaughter of local poultry before the new strains infected humans or reassorted with H9N2.106
With so much heavy genetic traffic between feral avian reservoirs, domestic poultry, and mammals, researchers were becoming pessimistic about the likelihood of successfully containing further outbreaks by local culling of birds. When H5N1 returned again in February 2002, top virologist Yi Guan of the University of Hong Kong told China Daily that truly drastic action was now necessary—live poultry had to go. Guan said, “I believe that we have to get rid of the farms, and the poultry markets, and the import of fresh chickens.” The poultry industry—seemingly oblivious to the nature of the pandemic threat—screamed that the scientists had gone berserk. “Avian influenza is just like any human flu—you just cannot get rid of it. However, it does not make sense to get rid of the poultry industry to get rid of the bird flu. That would be an ignorant act.”107 The authorities seemingly agreed, and they restricted their response to ordering the destruction of another 900,000 chickens.
In December, textbook theory was again confounded as H5N1 began to decimate its natural hosts. Ducks, as well as geese, flamingos, swans, egrets, and herons, started dying in two popular Hong Kong parks; mallards—presumed immune to the pathogenic effects of influenza—developed catastrophic neurological disorders. The dead ducks were incontrovertible proof that a two-way flow of H5N1 mutants now existed between aquatic and terrestrial birds. Researchers who studied the outbreak were troubled by the theoretical implications:
A pathogenic H5N1 outbreak among waterfowl and wild birds is therefore novel and has serious implications. . . . Previous phylogenetic studies had shown low evolutionary rates of avian influenza viruses in waterfowl. Therefore, it was generally accepted that influenza viruses were in evolutionary stasis in wild aquatic birds, with no evidence of clear evolution over the past 60 years. The data presented in this paper raise the possibility that this balance may be changing in ducks or that it has been disrupted by the introduction of novel viruses to ducks from some other avian source.108
Scientists worried that antigenic drift had been accelerated by the illegal use of unregistered poultry vaccines in Guangdong. Other researchers speculated that lethal strains of H5N1 might spread through the wild duck population and follow the annual migration back to Siberian or even Alaskan lakes.109 (In 2004, the United Nations’ Food and Agriculture Organization [FAO] learned that Russian researchers in Novosibirsk had indeed found H5N1—95 percent similar to the Hong Kong strain—the previous year in a wild mallard duck on Lake Chany in western Siberia.)110 In any event, as Shortridge, Peiris, and Guan glumly pointed out in an article, it was now evident that the H5N1 infection in birds had become “non-eradicable.”111 Meanwhile, Hong Kong closed its parks and slaughtered its beloved wild birds.
Two months later, at the beginning of February 2003, a seven-year-old girl died of an acute respiratory disease while visiting a Fujian province in the company of her mother, sister, and brother. She was buried before the exact cause of death could be ascertained. Her father, who rushed from Hong Kong to his dying daughter’s bedside, was also stricken and died in mid-February, nine days after his return to Hong Kong; his eight-year-old son developed critical symptoms of respiratory distress but ultimately recovered.112 Both father and son were confirmed to have been infected with the same strain of H5N1 that was killing ducks in the parks. Genetic sequencing revealed that it was a remote cousin to the original 1997 strain. The hemagglutinin was derived from the same lineage, but the internal proteins and neuraminidase had evolved elsewhere. Some researchers surmised that the influenza had been contracted in Fujian—the family’s relatives kept chickens—and were skeptical of China’s claim that it had not experienced any large-scale outbreaks of avian influenza among ducks or poultry.113 In any event, experts were troubled by further evidence of increasing virulence in the rapidly evolving H5N1 family. WHO went to pandemic alert status, and public-health officials again buckled their seatbelts.