The Viral Storm : The Dawn of a New Pandemic Age

Introduction The village of Pang Thruk in the Kanchanaburi province of Thailand is like many in this part of the world—humid, lush, and spilling over with sounds of wildlife. Located in the west of the country near the border of Burma, Pang Thruk is home to about three thousand people whose livelihoods depend on the sugar and rice they grow. In December 2003, it was also home to Kaptan Boonmanuch, a six-year-old boy who would be among the first people to die of a brand-new human virus. Kaptan loved riding his bicycle, climbing trees, and playing with his plastic toy Dalmatian that pulled three puppies in tiny brown wagons as it barked mechanically. Kaptan also enjoyed helping his family on the farm. Nearly every family in Pang Thruk kept egg-laying chickens; some also kept roosters for cock fighting. Kaptan's aunt and uncle lived just down the road on their open-air farm of around three hundred chickens. Each winter in the village a few chickens would die from suspected infections or colds, but in December 2003 chicken deaths increased dramatically. That winter, as on many farms in this region, the chickens in Kaptan's uncle's farm suffered from severe diarrhea, strange behavior, and weakness. All of them either died naturally or were culled as a result of their illness—and Kaptan helped with the dead. A day or two before the New Year, according to reports, the boy carried one of the sick squawking chickens home. That walk home would have lasted no more than a few minutes. A few days later Kaptan grew feverish. A clinic in the village diagnosed him with a cold, but after three days without improvement, his father, Chamnan, a rice farmer who worked part time as a driver, took him to a public hospital. X-rays revealed that the six-year-old had pneumonia, and he was kept in the hospital for observation. A few days more and Kaptan's fever spiked to a dangerous 105 degrees. His father paid the equivalent of thirty-six dollars for an ambulance to speed him to better care at Siriraj Hospital in Bangkok, more than an hour's drive away. Upon arrival, Kaptan presented with shortness of breath and fever. Tests revealed that both lungs were affected with severe pneumonia, and the boy was transferred to the pediatric intensive care unit and put on a ventilator. A series of bacterial cultures tested negative, showing that the infection was likely caused by a virus. More detailed testing using a molecular technique called the polymerase chain reaction, or PCR, revealed that Kaptan was likely infected with an atypical type of influenza—perhaps one not yet seen (or seen widely) in humans. After eleven days of illness, the boy's fever finally began to cool off. However, despite intensive care, his respiratory distress worsened. Just before midnight on January 25, physicians took Kaptan off the respirator. His lungs drowning in fluids, he became Thailand's first known death from H5N1, which would soon become known around the world as "bird flu." As sad as Kaptan's death was—and the reports go on to describe the boy's funeral and the family's mourning in tragic detail—the reality is that children in the developing world die from diseases like this all the time. And infectious diseases, which scientists in the 1960s predicted would be eliminated in short order, remain some of the most important killers today. But when it comes to global risk, all deaths are not equal. Most deaths from infectious diseases are localized events that, while dire for the victims and their families, present limited risk to the planet as a whole. But some, like Kaptan's, signal a potentially world-altering event: the first human infection by an animal virus that may wipe out millions, or hundreds of millions, of people throughout the planet—permanently changing the face of humanity. The main objective of my work is to hunt down these events—the first moments at the birth of a new pandemic—and then work to understand and stop them before they reach a global stage. Because pandemics almost always begin with the transmission of an animal microbe to a human, it's work that takes me all around the globe—from rain forest hunting camps of central Africa to wild animal markets of east Asia. But it also takes me to cutting-edge laboratories at the US Centers for Disease Control and Prevention (CDC) and disease outbreak control centers at the World Health Organization (WHO). Tracking down these potentially devastating bugs has led me to study how, where, and why pandemics are born. I work to create systems that can accurately detect pandemics early, determine their likely importance, and, with any luck, crush those that have the potential to devastate us. As I've lectured on this work around the world and taught undergraduates in my virology seminar at Stanford University, it's hard to ignore a growing general interest in these topics. Everyone recognizes the raw power that pandemics have to sweep through human populations and seemingly kill indiscriminately. Yet, given the importance of these events, large questions remain remarkably opaque: How do pandemics start? Why are we now plagued with so many pandemics? What can we do to prevent pandemics in the future? This book is my attempt to answer these questions—an effort to assemble the pieces of the pandemic puzzle. Part I, "Gathering Clouds," introduces our main character, the microbe, [1] and delves into the history of our relationships with these organisms. It explores the vast world of microbes, putting those that threaten us in their proper perspective. It details some of the most significant events in the evolution of humans and our ancestors and works to develop the often-spotty historical data into a set of hypotheses on how the events influenced our interactions with microbes. Part II, "The Tempest," examines how contemporary human populations have grown so exquisitely susceptible to pandemics and what the future years will hold for pandemic diseases. Part III, "The Forecast," describes the fascinating new world of pandemic prevention and introduces a new crop of scientists eager to help create a virtual global immune system that will stop pandemics before they become planetary nightmares. Along the way, we will journey to remote hunting villages in central Africa, investigate malaria in wild orangutans in Borneo, learn how cutting-edge genetic sequencing tools will change the way that we discover completely novel viruses, and see how Silicon Valley companies may forever transform the way that we conduct surveillance aimed at finding the next major outbreak. At this point you may be asking yourself how someone ends up devoting his career to the study of plagues. Is it a desire to save the world? Or perhaps it's the scientific thrill of discovering completely unknown, invisible beings with the potential to wipe out large swaths of humanity. Maybe it's the desire to understand in detail one part of humans' intricate ecology. Or it's an urge to explore the exotic locations on Earth where these novel viruses often appear. But while my life is now consumed with trying to understand and stop pandemics, that's not how it's always been. My work with microbes actually started as a minor footnote to a study I wanted to conduct among wild chimpanzees in central Africa. As a young child, I acquired what would become a lifelong interest in apes when I watched a National Geographic documentary explaining how humans are more closely related to apes than we are to monkeys. A family tree with humans and apes as siblings (and monkeys as distant cousins) was entirely inconsistent with my memories of seeing these creatures locked up together in the "monkey house" at the Detroit Zoo. We humans were outside the cages, and the rest of them were inside. The idea that apes and humans were closely related certainly struck a chord with me. According to my father, I spent some days after the documentary playing the part: walking around the house on all fours, trying to communicate without language, and otherwise working to bring out my inner ape. My fascination with apes evolved from a childish curiosity to an intellectual interest in what our closest relatives had to tell us about ourselves. What began as a broad interest in apes as animals became a more specific interest in chimpanzees and their less acknowledged brethren, the bonobos—the two ape species that share our own particular branch of the tree of life. How did the years of separation since our last common ancestor with these two kindred ape species shape our minds, our bodies, and our worlds? What features remained the same in all of us? Along with the intellectual interest, I had a growing desire to see these apes living in their natural environment. This desire required tracking them down in the rain forests of central Africa to see for myself what they were really like. So when choosing among doctoral programs, I settled on one at Harvard where I would work with Richard Wrangham and Marc Hauser, two prominent primatologists. I would spend many months during my first year of doctoral work arguing why they should let me study the troops of wild chimpanzees that Wrangham had worked with for years in the Kibale Forest in southwest Uganda. I proposed a study to document self-medicating behavior of the Kibale chimpanzees. The idea that these animals consumed plants with specific medicinal chemicals as a way of fighting against their own infectious diseases was still just an hypothesis at the time, and an intriguing one. I'd explored this idea the previous year while studying at Oxford and working on an exhibit about animal self-medication at the Oxford University Museum of Natural History. The Oxford University Museum is a magnificent nineteenth-century building constructed in the architectural style of a Gothic cathedral but with massive iron supports mimicking the skeleton of a mammal, emphasizing that it was a church of natural history rather than religion. It houses unique collections, including some of the beetles collected by Charles Darwin on his celebrated voyage on the Beagle . It had been home to the famous Huxley-Wilberforce debate on natural selection in 1860 seven months after the publication of Darwin's pivotal book On the Origin of Species . It's a perfect location to ponder the place of humans in the natural world. The work I did under the supervision of the eminent evolutionary biologist W. D. Hamillton and his colleague Dale Clayton, an expert in behaviors animals used to rid themselves of parasites, revealed that self-medication was widespread in the animal kingdom. Animals as disparate as wasps and Kodiak bears utilized the chemical defenses of plants to help rid themselves of their natural pests. As I began my work in Uganda to study chimpanzees, my professors cautioned me that any convincing proof that chimpanzees were medicating themselves with plants would require an understanding of the infectious diseases they were treating. Unless I could show that the use of the purported medicines decreased the burden of disease, my results would be speculative at best. I needed to understand what infectious diseases plagued the chimpanzees. I knew little about microbes, so I approached Andy Spielman, a professor at Harvard's School of Public Health and one of the few people at the time focused on understanding the ecology of microbes in nature. Despite his lab full of fellows and students and his focus on North America rather than the wilds of Africa or Asia, he kindly took me under his wing. Thus began my research on what was known about the infections of chimpanzees. Once I began thinking about microbes I never looked back. And central to my studies would be the viruses. Viruses evolve more rapidly than any organism on the planet, yet we understand less about them than any other form of life. [2] The study of viruses provides a scientist with the opportunity to discover new species and catalog them in a way reminiscent of the world of the nineteenth-century naturalist, which had so fascinated me during my time at Oxford. A scientist can productively spend an entire career looking for new species of primate and never find one, but new viruses are discovered every year. They also have exceedingly short generations, so we can watch them evolve in real time—an ideal system for someone interested in understanding the process of evolution. Perhaps best of all from the perspective of a young scientist, there was important and urgent low-hanging fruit in this discipline: some of these viruses kill us. Thus new discoveries need not only lead to an improved understanding of nature, but they can also have important and rapid applications for controlling human disease. Controlling the spread of human disease was at the forefront of public health efforts in early 2004 when the news broke of Kaptan's death from H5N1. His death was the first confirmed mortality from this virus, the so-called bird flu, in Thailand. The truth is that while they may jump to us via other animals, all human influenza viruses ultimately originate in birds, so the popular designation of the virus as "bird flu" can irritate scientists. Yet within a month that name would become a mainstay of news shows and a topic of discussion for people throughout the world. The scientific name for the virus that killed Kaptan, HPAIA (H5N1), is quite descriptive for virologists. It signifies that the virus is a highly pathogenic avian influenza A-type virus and provides the particular hemagglutinin (H) and neuraminidase (N) protein variants particular to this virus strain. But its true significance is actually much more straightforward. H5N1 is important because it kills remarkably effectively. The virus's case fatality rate, or the percentage of infected individuals that die, is around 60 percent. For a microbe, that's incredibly deadly. As a comparison, we can look back to the devastating 1918 influenza pandemic. While estimates for the 1918 pandemic are imperfect, it is thought around fifty million people died. That's the equivalent of 3 percent of the entire human population at that time, an almost unimaginable catastrophe. To put this in context, more people died from the 1918 influenza pandemic than the total number of soldiers thought to have died in battle during all twentieth-century wars combined . More deaths caused by a simple virus, less than one hundred nanometers in diameter and with only a paltry eleven genes, than were caused by all the battles in WWI, WWII, and all of the other wars in our last war-riddled century. Despite the enormity of the 1918 plague, the highest estimates for its case fatality rate are in the range of 20 percent, and it was almost certainly much lower than that; more careful estimates suggest around 2.5 percent. [3] Recall that H5N1 had a 60 percent fatality rate, far greater than that of the influenza virus that caused the 1918 pandemic. But while deadliness is an important, dramatic, and ongoing obsession of the media, it is only one piece of the puzzle for microbiologists. In fact, some microbes kill virtually all people they infect: a perfect 100 percent mortality rate. And yet such microbes do not necessarily represent critical threats to humanity. Viruses like rabies, which naturally infect a number of mammal species, and the herpes B virus, which naturally infects some species of Asian monkey, will kill all the people they infect. [4] Yet unless you're someone who is exposed to rabid animals or works with Asian monkeys, these microbes do not represent a major concern for you. That's because they don't have the capacity to spread from person to person. In order to be catastrophic, a microbe needs both the potential to harm or kill and the potential to spread. In early 2004 there was no way to know how efficiently H5N1 would spread. Since it comes from a class of viruses that often do spread, the influenza viruses, the possibility was there. And if H5N1 were to spread in the same way that the 1918 influenza virus spread, it would create a calamity unlike any seen before in human history. As impressive as H5N1 is at killing, H1N1, the so-called swine flu, [5] is equally impressive in its capacity to spread. While no one knows exactly when the H1N1 pandemic began, by August 2009, less than a year after it was first recognized, the WHO announced estimates suggesting that the virus could eventually infect over two billion people, roughly a third of the entire human population. The natural drama of this would be hard to overstate. While less visually dramatic than other forms of natural disaster, the ability of this phenomenon to touch people everywhere on the planet made it a powerful force of nature. A virus that likely infected few people in early 2009 moved around the globe to inhabit a sizable percentage of the entire population of the human species in less than a year. This occurred despite the best efforts of global public health infrastructures—structures that we tend to be very proud of and feel protected by. Yet while the case fatality rate of H1N1 is estimated to be well below 1 percent, paling in comparison to H5N1, the sheer number of people it infected has made it a real global killer. One percent of two billion is a lot of lives. To help us understand the real threat of an outbreak, we turn to a concept in epidemiology called R0 , or the basic reproductive number . For any epidemic, R0 is the the average number of subsequent infections that each new case results in (in the context of a population with no prior immunity and no control efforts). If, on average, each case of a new epidemic leads to more than one subsequent infection, the new epidemic has the potential to grow. If, on average, each case leads to less than one subsequent infection, it will peter out. The elegant concept of R0 helps epidemiologists distinguish between epidemics likely to "go viral" and those likely to go extinct. It's basically a measure of scalability. Risk interpretation is not a trivial matter, for either the public or the policy makers. In the case of H1N1 or H5N1, the potential costs of not rushing to develop a vaccine or working to decrease transmission could have been global and catastrophic. Critically, microbes are dynamic—they do not exist in stasis. If H5N1, the deadly bird flu, gains the right combination of genetic mutations it needs to spread effectively, the results will be destructive in a way that, however less visually dramatic, will make even the most deadly earthquakes seem like a walk in the park. And if H1N1, the rapidly spreading swine flu, were to increase in virulence even minimally, its potential to kill would be striking. Neither scenario is implausible. As chapter 1 will explore in detail, influenza and a range of other viruses have an incredible capacity to negotiate the environment of their human hosts. They mutate rapidly, even swapping genes among themselves, a process referred to as reassortment. It is just such reassortment that concerned me, and other scientists, in 2009. As the H1N1 virus spread explosively around the world, there was a nontrivial chance that it would run into H5N1 in people or animals, setting the stage for a potentially cataclysmic series of events. These are the kind of events we work to uncover early before they spread. When infected simultaneously with both of these influenza viruses, a particular human or animal could become a potent mixing vessel, providing the perfect opportunity for the bugs to swap genes. How would this happen? In a sort of sexual reproduction, H5N1 and H1N1 could produce mosaic daughter viruses with some of the genes of one virus and some of the genes of the other. Such reassortment events can occur in individuals infected with multiple similar viruses. In the case of H1N1 and H5N1, if that mosaic daughter virus inherited the potential to spread from its H1N1 parent and the deadliness of its H5N1 parent, the resulting virus would be both highly transmissible and highly fatal—exactly the formula for global impact that we most fear. A mad rush to respond to pandemics has been the mainstay of global public health for the last one hundred years. Now a small but vocal group of scientists and I have begun to argue that we must do better than just respond to pandemics by scrambling for vaccines, developing drugs, and modifying behaviors. This traditional approach has proved a failure for human immunodeficiency virus (HIV), which nearly thirty years after its discovery continues to spread, currently infecting over thirty-three million people at last count. But what if we had been able to catch HIV before it spread? This virus was in humans for over fifty years before it spread widely. It spread for another twenty-five years before French scientists Françoise Barré-Sinoussi and Luc Montagnier, who would go on to win a much-deserved Nobel Prize for their work, finally discovered it. How different would the world be had we stopped it before it left central Africa? The idea that we might one day predict pandemics is a new one. The first time I heard someone discuss it was around ten years ago in the Johns Hopkins office of Don Burke, a retired medical colonel and world-renowned virologist from the Walter Reed Army Institute of Research (WRAIR) who had devoted his life to more traditional approaches to control disease before he took on a professorship at Johns Hopkins University's Bloomberg School of Public Health. Don had hired me as a postdoctoral fellow at Hopkins a few years earlier when I was finishing up my doctoral work in the rain forests of north Borneo studying the ways that mosquitoes and other blood-feeding insects helped microbes move between primate species. Unable to track me down himself, Don had managed to find my mother in Michigan and gave her a call. My mother, whom I would speak to infrequently on trips from our forest research station, scolded me, saying that a "general" from the US military had called her. She asked what kind of trouble I had managed to get myself into. Fortunately, all Don wanted was to see if I'd help him set up a project in central Africa to understand how viruses emerge from animals into human populations. During the years that followed, in addition to the long, slogging work of building research capacity to catch new microbes in central Africa and Asia, Don and I engaged in hours of conversation in the field and in his office in Baltimore. We made numerous beer bets on scientific problems and asked hard questions about the future of our field. I remember the day when I first heard Don suggest that the future would include not only response to pandemics but prediction . It seemed a bold but logical idea, and we quickly moved toward thinking about ways that it could actually happen. Those early conversations formed the foundation of the work my colleagues and I conduct now, setting up and running listening posts at microbial hot spots around the world aimed at catching new microbes locally before they become global pandemics. Among the things we listen for are novel influenza viruses, like H5N1 and H1N1. Unfortunately, the world too easily becomes complacent to threats like H5N1 and H1N1. These and other threats fade quickly from the media's attention. Most of the world doesn't think about either of these viruses seriously. Yet neither virus has gone extinct, and the threat is perhaps as great now as it was when they were each first noticed. Both viruses continue to infect human populations. For example, in 2009, years after the media forgot about the virus, H5N1 caused at least seventy-three laboratory-confirmed cases. This is almost certainly a substantial underestimate of the number of actual cases and does not differ notably from the number of confirmed cases from previous years. H1N1 cases continue to spread as well. We have detected them even in the most remote forest areas where we "listen." Amazingly, in a time when we can sequence an entire human genome for under ten thousand dollars and build massive telecommunications infrastructures that will soon make cell phones available to most people on the planet, we still understand surprisingly little about pandemics and the microbes that cause them. We know even less about how to predict or prevent pandemics before they spread from small towns to cities and the rest of the world. As I'll argue in part II, pandemics will increase in frequency in the coming years as the connections between human populations and the animals in our world continue to grow. Whether it's a mosaic virus with the deadliness of H5N1 and the potential to spread like H1N1, a resurgent SARS, a new retrovirus like HIV, or perhaps most frighteningly, a completely novel microbe that blindsides us, microbial threats will grow in the coming years in their ability to plague us, kill people, destroy regional economies, and threaten humanity in ways more severe than the worst imaginable volcanoes, hurricanes, or earthquakes. A storm is brewing. The objective of this book is to understand this coming storm—to explore the nature of pandemics, to understand where they come from and where they are going. But it will not paint a completely grim picture. In the one hundred years since we first discovered viruses, humans have come a long way in understanding them. Much hard work remains. Yet if we do it well, we will harness the numerous technological advances of our time that provide tools to predict pandemics—just as meteorologists predict the course of hurricanes—and ideally prevent them from occurring in the first place. This is the Holy Grail of modern public health, and in the coming pages, I will argue that it is within our grasp. PART I Gathering Clouds 1 The Viral Planet Martinus Beijerinck was a serious man. In one of the few images that remain of him, he sits in his Delft laboratory in the Netherlands, circa 1921, just a few days before his reluctant retirement. Bespectacled and in a suit, he's presumably as he'd like to be remembered—among his microscopes, filters, and bottles of laboratory reagents. Beijerinck had some peculiar beliefs, including the idea that marriage and science were incompatible. According to at least one account, he was verbally abusive to his students. While rarely remembered in the history of biology, this strange and serious man conducted the pivotal studies that first uncovered the most diverse forms of life on Earth. Among the things that fascinated Beijerinck in the late nineteenth century was a disease that stunted the growth of tobacco plants. Beijerinck was the youngest child of Derk Beijerinck, a tobacco dealer who went bankrupt due to crop losses caused by this blight. Tobacco mosaic disease causes discoloration in young tobacco plants, leading to a unique mosaic pattern on leaves and radically slowing the growth of the adult plants. As a microbiologist, Beijerinck must have been frustrated by the unclear etiology of the disease that had wiped out his father's business. Despite the fact that it spread like other infections, microscopic analysis did not reveal a bacterial cause of disease. Curious, Beijerinck subjected the fluids of one of the diseased plants to intense filtration using a fine-grained porcelain filter. He then demonstrated that even after such filtration the fluids retained their capacity to infect healthy plants. The tiny size of the filter meant that bacteria, the usual suspects for transmissible disease at the time, would be too large to pass through. Something else must have caused the infection—something unknown and considerably smaller than everything else recognized to be alive in his time. Unlike his colleagues, many of whom believed a bacteria would emerge as the cause, Beijerinck concluded that a new form of life must cause tobacco mosaic disease. [6] He named this new organism the virus , a Latin word referring to poison. The word virus had been around since the fourteenth century, but his use was the first to link it to the microbes to which it refers today. [7] Interestingly, Beijerinck referred to viruses as "contagium vivium fluidum," or "soluble living agent," and felt they were likely fluid in nature. That is why he used the term virus —or poison—to denote its "fluidity." It wasn't until later work with the polio and foot-and-mouth-disease viruses that the particulate nature of viruses was confirmed. In Beijerinck's time a new microscopic perspective began revealing itself to scientists. Looking through microscopes and applying gradually smaller filters, these microbiologists realized something that continues to amaze us today: shielded from our human-scaled senses is a wide, teeming, startlingly diverse, unseen world of microbial life. I teach a seminar at Stanford called Viral Lifestyles. The title was meant to evoke curiosity among prospective students but also describe one of the course's objectives: to learn to envision the world from the perspective of a virus. In order to understand viruses and other microbes, including how they cause pandemics, we need to first understand them on their own terms. The thought experiment that I give my students on the first day is this: imagine that you have powerful glasses allowing you to perceive any and all microbes. If you were to put on such magical bug-vision specs, you would instantly see a whole new, and very active, world. The floor would seethe, the walls would throb, and everything would swarm with formerly invisible life. Tiny bugs