The Viral Storm

by Nathan Wolfe

  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.

  Dr. Martinus Beijerinck. (Undated photo)

  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.1 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.2 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 would blanket every surface—your coffee cup, the pages of the book on your lap, your actual lap. The larger bacteria would themselves teem with still smaller bugs.

  This alien army is everywhere, and some of its most powerful soldiers are its smallest. These smallest of bugs have integrated themselves, quite literally, into every stitch of the fabric of earthly life. They are everywhere, unavoidable, infecting every species of bacterium, every plant, fungus, and animal that makes up our world. They are the same form of life that Beijerinck found in the late days of the nineteenth century, and they are among the most important of the microbial world. They are viruses.

  * * *

  Viruses consist of two basic components, their genetic material—either RNA or DNA—and a protein coat that protects their genes. Because viruses don’t have the mechanisms to grow or reproduce on their own, they are dependent on the cells they infect. In fact, viruses must infect cell-based life forms in order to survive. Viruses infect their host cells, whether they are bacterial or human, through the use of a biological lock-and-key system. The protein coat of each virus includes molecular “keys” that match a molecular “lock” (actually called a receptor) on the wall of a targeted host cell. Once the virus’s key finds a matching cellular lock, the door to that cell’s machinery is opened. The virus then hijacks the machinery of that host cell to grow and propagate itself.

  Viruses are also the smallest known microbes. If a human were blown up to the size of a stadium, a typical bacterium would be the size of a soccer ball on the field. A typical virus would be the size of one of the soccer ball’s hexagonal patches. Though humans have always felt virus’s effects, it’s no wonder it took us so long to find them.

  Microbes, Above: In detail; Below: To scale. (Dusty Deyo)

  Viruses, the most diverse forms of life, remained completely opaque to humans until a meager one hundred years ago with Beijerinck’s discovery. Our very first glimpses of bacteria came a little under four hundred years ago when Antonie van Leeuwenhoek adapted the looking glasses of textile merchants to create the first microscope. With it, he saw bacteria for the first time. This finding represented such an incredible paradigm shift that it took the British Royal Society another four years before it would accept that the unseen life forms were not merely artifacts of his unique apparatus.

  Our scientific understanding of unseen life has proceeded pitifully slowly. Compared to some of the other major scientific breakthroughs over the last few thousand years, our understanding of the dominance of unseen life occurred only recently. By the time of Jesus, for example, we already understood critical elements of how the Earth rotated, its rough size, and its approximate distance to the sun and moon—all fairly advanced elements in understanding our place in the universe. By 1610 Galileo had already made his first observations using a telescope. Van Leeuwenhoek’s microscope came fifty years after that.

  L: Replica of van Leeuwenhoek’s microscope, 17th century; R: van Leeuwenhoek’s microscope in use. (L: Dave King / Getty Images; R: Yale Joel / Getty Images)

  It is hard to overstate the paradigm shift that van Leeuwenhoek’s discovery represents. For thousands of years humans had recognized the existence of planets and stars. Yet our understanding of unseen life and its ubiquity began only a few hundred years ago with the invention of the microscope. The discovery of novel life forms continues to this day. The most recent novel life form to be uncovered is the unusual prion, whose discovery was acknowledged with a Nobel Prize in 1997. Prions are an odd microscopic breed that lack not only cells but also DNA or RNA, the genetic material that all other known forms of life on Earth use as their blueprint. Yet prions persist and can be spread, causing, among other things, mad cow disease. We would be arrogant to assume that there are no other life forms remaining to be discovered here on Earth, and they are most likely to be members of the unseen world.3

  * * *

  We can roughly divide known life on Earth into two groups: noncellular life and cellular life. The major known players in the noncellular game are viruses. The dominant cellular life forms on Earth are the prokaryotes, which include bacteria and their cousins, the archaea. These life forms have lived for at least 3.5 billion years. They have striking diversity and together make up a much larger percentage of the planet’s biomass than the other more recognizable cellular forms of life, the eukaryotes, which include the familiar fungi, plants, and animals.

  Another way of categorizing life is this: seen and unseen. Because our senses detect only the relatively large things on Earth, we are parochial in the way that we think about the richness of life. In fact, unseen life—which combines the worlds of bacteria, archaea, and viruses as well as a number of microscopic eukaryotes—is the truly dominant life on our planet. If some highly advanced extraterrestrial species were to land on Earth and put together an encyclopedia of life based on which things made up most of Earth’s diversity and biomass, the majority of it would be devoted to the unseen world. Only a few slender volumes would be dedicated to the things we normally equate with life: fungi, plants, and animals. For better or worse, humans would make up no more than a footnote in the animal volume—an interesting footnote but a footnote at best.

&nbs
p; Global exploration to chart the diversity of microbes on the planet remains in its infancy. Considering viruses alone gives some sense of the scale of what’s unknown. It’s thought that every form of cellular life hosts at least one type of virus. Essentially—if it has cells, it can have viruses. Every alga, bacterium, plant, insect, mammal. Everything. Viruses inhabit an entire microscopic universe.

  Even if every species of cellular life harbored only one unique virus, that would by definition make viruses the most diverse known life forms on the planet. And many cellular life forms, including humans, harbor a range of distinct viruses. They are found everywhere—in our oceans, on land, deep underground.

  The dominant forms of life on our planet, when measured in terms of diversity, are unambiguously microscopic.

  The largest virus to be discovered is the still microscopic six-hundred-nanometer Mimivirus—viruses are by nature tiny. But the sheer number of viruses in our world leaves a significant biological impression. A groundbreaking paper published in 1989 by Oivind Bergh and his colleagues at the University of Bergen in Norway found up to 250 million virus particles per milliliter of seawater, using electron microscopy to count the viruses. Alternate, more comprehensive measurements of the biomass of viruses on Earth are even more unimaginably outsized. One estimate suggests that if all the viruses on Earth were lined up head to tail the resulting chain would extend 200 million light years, far beyond the edge of the Milky Way. Though often thought of as a pesky irritant or blight, viruses actually serve a role that goes far beyond, and has a much greater impact than, what was previously understood—a role that scientists are only just beginning to comprehend.