Chapter One The Delicate balance between life and death The Venice of the Amazon Belen, a shantytown suburb of the city of Iquitos, lies on the banks of the Amazon River in eastern Peru, not far from the Brazilian border. Population pressure has forced it to expand in all directions, so that some of its palmetto-thatched huts have even been built out on pontoons that extend into a quiet eddy of the river itself. The river flowing past Belen has gathered its water from a great network of rivers and streams that all snake their way eastward through the lowland rainforest. Already, during the season when it is at flood, the young Amazon is three kilometres wide, even though it still has a full three thousand kilometres to flow before it reaches the Atlantic. Indeed, it is quite possible for oceangoing ships to travel from the mouth of the Amazon to Iquitos and Belen and even beyond, having passed through almost the entire length of the Amazon basin. In the nineteenth century, Iquitos was an important port for the vicious and exploitative rubber trade, but the city has since fallen into a kind of dreamlike tropical existence, with a little tourism, a good deal of logging and subsistence agriculture, some mining, and the inevitable drug trade. The centre of Iquitos, which is all the tourists see, has a cheerfully raffish air. Crowds of girls swarm the streets, giggling whenever exotic visitors come into view. There is a pervasive throbbing mixture of tropical and Andean music. Children swarm everywhere, begging and offering small services. A permanent cloud of vultures adds a Graham Greene touch as they circle above the rusty tin roofs. But it is in the surrounding shantytowns like Belen that the real dynamic of this exploding Third World population centre becomes apparent. Typically, the weather during the rainy season is hot, overcast and breathlessly humid. On just such a morning in March 1991, nurse Wilma Casanova de Caspia took a detour through the shantytown's crowded and cheerful street market on her way to work. The market is not in the floating part of the town, but fills the streets of several nearby square blocks on dry land next to the shore. Displays of tropical fruit vie for the browser's attention with piles of meat and many different species of freshly caught fish, some exhibiting fearsome sets of teeth. Shy Indian women from the surrounding villages display mounds of peppers in a dazzling variety of colours, sizes and shapes. You can buy anything you might want in the market, from river turtles to astonishingly cheap Casio watches. As Wilma strolled through the noise and bustle, she suddenly saw the people in front of her draw away. The shoppers had recoiled from a man in the middle of the street who was acting strangely. A fearful whisper ran through the crowd as it pulled back. The stricken man, his trousers soaked and glistening with fluid, weaved unsteadily, and at first she thought he was drunk. He staggered for one final time and collapsed almost at Wilma's feet. It was then she realized that the word the crowd was whispering, a word that suddenly filled the air, was cholera. She was seeing, for the first time in her life, the devastating effects of one of the most dreaded of all human diseases. It is clear in retrospect that Belen is ideally situated to form the focus for an outbreak of cholera, and the wonder is that it did not happen sooner. An astonishing one hundred and twenty shantytowns like Belen are grouped around the city of Iquitos. They draw people like magnets from the two thousand tiny communities that dot the banks of the thousand or so rivers threading through the vast surrounding region of jungle that is known as Loreto. Most of the shantytowns consist of rows of huts lining unpaved roads that soon peter out in the forest. Each hut has a small cleared area behind it, no bigger than a few square metres, with enough room for a few vegetables, chickens, and a pig or two. Shanties closest to the centre of town are connected by slender threads of electric wires. Many of these glitter with newness, testimony to the frantic efforts of the Iquitos city government as it tries to catch up with the city's ever-expanding periphery. But none of the huts has water, except for shallow wells scooped down a few feet to the water table below. Belen, the most unusual of these shantytowns, is known to local promoters as the Venice of the Amazon. Like Venice it has plentiful supplies of both water and garbage, but there the resemblance ends. Belen's equivalent of Venetian palazzi are its strings of palmetto-thatched shanties, all without water and most without electricity. In the wet season these shanties float in the river and boats can ply the canal-like stretches between them. In the dry season, from June to October, when the river can drop several metres below its maximum level, most of the shanties are stranded in rows on the shore, surrounded by a festering sea of mud. At the driest part of the year, a visitor must climb ten metres up the mud bank of the river to the street above, past rotting piles of offal scattered among the huts. The river, that essential cloaca maxima, eventually sweeps all this downstream, but at the time I visited Belen and talked to Wilma about her experiences with cholera the rains were two months away and the flies swarmed in great clouds. Wilma told me how, when she was confronted with her first victim in the market, she shouted vainly for help. Even though she radiated authority and was dressed in her blue-and-white public health nurse's uniform, nobody moved among the fearful crowd that packed the market. Then a porter, a friend of the stricken man, came forward. He picked up the victim like a bundle of bananas and followed Wilma towards the nearby main street. Here they found a continuous traffic of motocars, motorcycles with narrow back seats covered by brightly-coloured little canopies. These tiny vehicles are free to swarm everywhere in Iquitos and its shantytowns, since there is no connection by road to the rest of the world. Wilma and the porter hired two of them and took the victim to Iquitos' main hospital. The emergency room personnel had no idea what to do. But this case of cholera was hardly a surprise. Beginning two months before, there had been a devastating outbreak of cholera on the Peruvian coast, making its appearance in several cities almost simultaneously. News of the epidemic had spurred the establishment of a cholera unit at the hospital, and Wilma immediately found the doctor in charge. He was familiar with the disease, and knew that cholera kills by dehydration as the body's fluids rush unimpeded through the intestinal wall. The victim, now comatose, was put on a bed in the cholera unit and four plastic bags containing a physiological salt solution were attached to him, one for each arm and each leg. Within a few hours he had recovered sufficiently to be able to recognize and smile at his rescuers. Wilma learned the location of the man's village from his friend the porter, and was soon on her way there in a dugout canoe. In the village she found that the victim's wife and children had also become violently ill with diarrhoea during the day, although the symptoms were not as dramatic. She added packets containing a mixture of rehydration salts and glucose to water, and forced them to drink copious amounts. They too recovered quickly. Cholera can strike with appalling suddenness. The man had been in perfect health when he left his family at five o'clock that morning to travel to the Belen market. By eight, when Wilma saw him, he was in such a state of violent dehydration brought on by the disease that one more hour without treatment would have produced irreversible brain and kidney damage. The Walrus and the Carpenter `I weep for you,' the Walrus said; `I deeply sympathize.' With sobs and tears he sorted out Those of the largest size, Holding his pocket-handkerchief Before his streaming eyes. `Oysters,' said the Carpenter, `You've had a pleasant run! Shall we be getting home again?' But answer came there none-- And this was scarcely odd because They'd eaten every one. Lewis Carroll, Through the Looking Glass, 1872 Iquitos has exploded suddenly like an ecological bomb in the middle of the Andean rainforest, a highly diverse and extremely stable ecosystem. We look at Iquitos and are hardly surprised that a plague of cholera broke out there. It is after all a truism that the plagues that afflict us do so because we have upset the balance of nature. We have been upsetting this balance for a very long time. Fossil bones of our remotest ancestors found in East Africa provide evidence that those ancestors were already beginning to modify their environment. The discovery by Donald Johanson of the `First Family', that astonishing collection of Australopithecines that has been dated to 3.2 million years ago, was remarkable for many things. Among them was the striking fact that no other animal bones were found among the remains of these hominids, so animals were not present when the disaster that killed them struck. This suggests that our ancestors were already finding ways to band together and live apart from the natural world, and to alter that world in order to make it safer for them. Such alterations can be extensive. Waves of extinctions of large animals, and dramatic changes in entire ecosystems, have always accompanied our own spread across the planet. Fifty thousand years ago, newly-arrived Aboriginals changed the entire ecology of Australia when they began to burn off huge regions of that continent. Ten thousand years ago hunters from Asia, working their way slowly down the coast of North America, wiped out the last of the great herds of animals living in California's Central Valley. And the first humans to arrive on the island of Madagascar, a thousand years ago, soon drove to extinction the largest birds that ever lived, Aepyornis. All that we have left of this mighty bird is the legend of Sinbad's Roc in the Thousand and One Nights. Unfortunately, upsetting the balance of nature just happens to be what our species has been selected to do well - although we hate to admit it. Like the Walrus in Lewis Carroll's poem, we shed hypocritical tears over the diminishing supply of oysters, white gulping them down as quickly as ever. In this book I would like to explore with you a biologist's view of just how and why such disturbances of the ecological balance can give rise to plagues. Here I define plagues as great epidemic or pandemic disasters. These include not just the bubonic plague or Black Death with which you are already familiar, but a wide variety of diseases which given the right conditions can spread rapidly and cause high mortality. The terms epidemic, pandemic and plague tend to be used rather loosely and to have overlapping meanings. Strictly speaking, an epidemic is confined in time and space - it is derived from the Greek for `visit'. A pandemic is an epidemic of great extent, sweeping across whole continents or the entire planet. The influenza outbreak following World War One was a pandemic, and it could also justifiably be considered a plague - it was responsible for at least twenty million deaths. More recent disease outbreaks, while they can often travel swiftly around the world, usually cause far less mortality - they are epidemics or pandemics, but nobody would call them plagues. This is because we have largely learned to control the worst manifestations of such diseases. If a cholera outbreak as extensive as the 1991 outbreak in Peru had happened in 1850, it would have been a plague, because it would have resulted in mortality of up to fifty per cent. But the 1991 epidemic, although it was part of a larger pandemic of cholera that has been slowly spreading around the planet for decades, had a mortality rate of only one per cent. It was not a plague, thanks to our growing expertise in fighting the disease, though in an earlier time it could easily have been. The plagues that result from ecological disturbance make up only a small part of the story that we will trace here. The majority of diseases are endemic, rather than epidemics or pandemics or plagues. They afflict every species of animal and plant, and it turns out that they have a very important role to play in the natural world. At the end of the book we will explore how these endemic diseases have contributed greatly to the diversity of life on our planet, including our own diversity. A surprising amount of the evolution of living organisms has been driven by such diseases. And we will see that this is not a one way street. At the same time that many different host species have been driven in the direction of greater genetic diversity in order to survive their diseases, the disease organisms that afflict them have not stood still. They have themselves evolved towards greater diversity. Much of this evolution has happened in undisturbed ecosystems, like the rainforest that still surrounds Iquitos. The full dimensions of this remarkable story, combining ecology and evolution, are only just beginning to emerge. As we explore the interaction between ecology and disease, we will also find that our own activities are not entirely to blame for creating plagues. Although we are the most effective disturbers of ecosystems who have ever lived, and also happen to be the first inhabitants of the planet who can write down the history of our diseases, we now know that plagues have afflicted most species of animals and plants for most of the time that life has existed on our planet. The Fourth Horseman We are not quite ready to examine this ecological story, however. First we must try to understand the dynamics of the diseases that afflict our own species. We have thrown up an astounding variety of defences against our diseases, particularly the endemic ones, and they have in turn responded in very complex ways. Of course, our defences against these endemic diseases can be overwhelmed by the disasters of plagues, for we cannot defend ourselves against the unexpected. We have evolved to be very good at defending ourselves against a multitude of disease organisms as long as each is rare, but it is as hard to adapt to surviving plagues as it is to adapt to surviving earthquakes or volcanic eruptions. Surprisingly, the organisms that cause plagues are themselves often ill-adapted. We are lucky that, despite their apparently fearsome nature, these plague organisms have weaknesses that we can exploit. They do not appear weak, of course, to people caught up in the disastrous events that spawn them. Although plagues and threats of plagues have always existed, they have never seemed so immediate as today, thanks to television. In July 1994, over a million terrified Hutu refugees poured out of the mountainous land of Rwanda into the town of Goma and the surrounding countryside just across the border in eastern Zaire. They had been driven there by fear of the Tutsi, a tribe of generally taller people who had provided the kings of Rwanda for centuries, and who had jealously hoarded much of Rwanda's political and social power. Earlier in the year the latest in a series of Hutu rebellions had released hatreds that had been building up during all that time. These culminated in massacres of many of the Tutsi. Soon, however, the Hutu rebellion fell apart as the better-armed and organized Tutsi struck back. Now immense numbers of the Hutu were fleeing what they fully expected would be a fearful revenge. The minority who were guilty of the atrocities blended easily into the stream of innocent refugees. The world's television screens were suddenly filled with apocalyptic landscapes strewn with the limp figures of tens of thousands of exhausted refugees, starving and desperate for water. Members of the defeated Hutu army stalked the camps, threatening and stealing from the innocent and readily killing their own tribespeople if they resisted. The sky was darkened by ash from nearby Mount Nyiragongo, which had chosen this dreadful moment to erupt. Relief agencies were overwhelmed. At their peak, the refugee areas near Goma and elsewhere may have held as many as two million people, with little food and no shelter. Half of the refugees were children, many of whom had been separated from their families. Any sort of sanitation was impossible - the nearby lake, the only source of water, was polluted by corpses and sewage. Even if tools had been available to dig latrines, the hard lava that lay just beneath the camps' thin soil would have made it impossible. The first cases of cholera appeared within two or three days of the refugees' arrival. The severity of the outbreak increased by the hour, and soon at least 250 refugees were dying each day. The corpses, shrouded in pitiful rags, began to pile up unburied by the side of the road that led into the camp. Cholera was closely followed by Shigella dysentery. The world was stunned by the astonishing speed with which these diseases had appeared and spread through the camps. The threat of uncontrolled plagues finally jarred governments into action, belatedly reinforcing the efforts of Medecins sans Frontieres and other private relief organizations. Within weeks, the US Army managed to get water purification equipment into place. Clinics were set up to treat the thousands of wounded and starving and to administer rehydration therapy. The epidemics were brought under control with surprising speed, and the ragtag camps slowly began to shrink as people tentatively and fearfully drifted back to their towns and villages. The situation had gone from apocalyptic to merely desperate. The world's attention shifted elsewhere. That elsewhere turned out to be India, and the disease that broke out there was a startling echo of the medieval world - bubonic plague. The first probable appearances of plague in India are recorded in the ancient chronicle of the Bhagvata Purana, dating from as long ago as 1500 BC. In AD 1031 a new wave of plague swept in from Central Asia with the army of Sultan Mohammed, and in succeeding centuries Tamerlane and other conquerors from the north brought plague along with the other disasters of war. Plague's dreadful toll continued down to the present century. The worst outbreak in modern times took place in 1907. In that year, plague swept through India's cities and 1.3 million people died. But this was only one episode in wave after wave that swept over the subcontinent between 1898 and 1918, during which an astonishing total of twelve and a half million people lost their lives. This is a quarter of the number of people who died in all of Europe during the Black Death of 1348, and it is amazing to realize that this slaughter happened within the memory of people alive today. The last really serious outbreaks of plague before its 1994 reappearance took place during the massive dislocation of populations that had been triggered by the partition of India and Pakistan in 1948. But by the 1970s with only a few possible but unconfirmed cases teeing reported, it seemed that the disease had effectively disappeared. As time went on, India's National Institute for Communicable Diseases discontinued all but three of its plague surveillance units. Then came a series of unusual events. The first happened on 30 September 1993, almost a year before the new appearance of plague. It took the form of a devastating earthquake of magnitude 6.4, centred near the town of Latur some 350 kilometres inland from Bombay. This earthquake was the most deadly ever to have been recorded in any part of the earth's crust far from known fault lines, killing more than 11,000 people. The disaster alerted Indian health authorities. They were very aware of the possibility that wild rats and other animals that harboured the plague bacillus could be displaced from their usual haunts, mixing with domestic rat and human populations and triggering an outbreak of plague. The second event happened in the small town of Beed, over 100 kilometres from Latur. A local doctor reported the finding of numerous dead rats, known as a `ratfall', and of flea bites afflicting the inhabitants of small villages near the town. This took place early in August 1994. Then, starting on 26 August, villagers began to turn up in the local clinics with high fevers. Some had severely swollen lymph nodes in the armpits and groin. On 2 September, K. K. Datta, director of the National Institute of Communicable Diseases in Delhi, got a worried phone call from a health officer in the city of Poona, near Beed. Datta asked him for samples of blood sera from the patients. These were shipped to Delhi and tested over the next few days for antibodies against the plague bacillus Yersinia pestis. Seven out of ten of the samples appeared to be positive, though the test was a crude one dictated by the unavailability of more sophisticated reagents. Datta arranged for a team of entomologists and microbiologists to fly to the area. The number of apparent cases in the villages near Beed continued to increase, eventually totalling 460. Although treatment with the antibiotic tetracycline was only begun several days after the appearance of the first case, there were no deaths. This is surprising because, unless plague is treated very soon after the infection is detected, mortality can be as high as fifty per cent. Even in the US, about fifteen per cent of plague cases die in spite of treatment. Further, there were no instances of the massive lung, brain and intestinal infections that almost always begin to appear as a plague outbreak advances. Then the focus of attention suddenly shifted to the north, to Surat. This grim industrial city, the site of the first British settlement in India in the early seventeenth century, is on the coast some 250 kilometres north of Bombay - and 400 kilometres from the outbreak in Beed. In August, Surat had been hit hard by monsoon rains which had left numerous piles of garbage and dead animals. On 19 September, people began to arrive in the city's hospitals with a frightening set of symptoms. They had high fevers, had great difficulty breathing, were racked with coughs, and showed blood in their sputum. Could this be plague as well? Yes, it could. Plague comes in three forms, depending on how widely the bacterial infection has spread in the body. In the classical bubonic plague the bacteria accumulate in the lymph nodes, with spillover into the bloodstream. The swollen lymph nodes (buboes) are a sign of the frantic response of the patient's overwhelmed immune system. This form of plague can only be spread by fleas, which transfer the infected blood to a new victim. In septicaemic plague, large numbers of the plague bacilli swarm in the bloodstream and can escape into other tissues such as the lungs and the brain. And in pneumonic plague, the most infectious type, the bacteria multiply swiftly in the lungs and are broadcast through the air in tiny droplets. If plague reaches the pneumonic stage it can spread like wildfire, particularly when people are crowded together, for it no longer requires rats or fleas. This is the most dangerous and frightening manifestation of a plague outbreak. And, in contrast to the cases that had been seen in the Beed district, it appeared that those in Surat were pneumonic. Public health authorities in Surat, caught unprepared by this new outbreak, did not at first admit that there was anything wrong. Then, as the number of cases mounted, they overreacted. Radio and television broadcasts announced the presence of plague, and trucks with loudspeakers blared the same message in the poorer parts of the city. Panic ensued. Over the next three or four days Surat essentially shut down. Bus and train stations were besieged by frantic people trying to leave. It is unclear how many succeeded. Early reports suggested that half a million people, one-third of the city's population, managed to flee, but this seems unlikely. India's inadequate train system could never have moved that many people in such a short time. Indeed, train records showed that only about fifteen per cent more tickets than usual were sold during the time of the panic. Other people who were able to do so left by bus and car, and among those who fled, unfortunately, were many of the doctors of Surat. Although the numbers who fled the city were probably not in the hundreds of thousands, there is no doubt that thousands of people from Surat fanned out over India, going for the most part to the homes of relatives. At least fifteen hundred of them are known to have travelled as far as West Bengal, on the other side of the Indian peninsula. After four days, there were some government attempts to seal off the roads and railway lines, though people fleeing by car found no sign of the roadblocks that had been announced. In short, there was utter confusion and wild exaggeration, and the panic quickly spread to the rest of India and the rest of the world. At the panic's height all but two international airlines shut down flights to India. The Gulf states, among India's most important trading partners, banned imports of Indian foodstuffs. At airports around the world, passengers arriving from India were scrutinized for signs of fever In Toronto, airport workers donned gloves and masks. Eleven fever cases arriving in New York from India were quarantined, but all turned out to have something else wrong with them. (Astonishingly, four had malaria and one had typhoid fever, giving a snapshot of the kinds of active diseases that are ferried every day around the planet by the world's airlines.) Reports of plague cases in Bombay and Delhi set off further panics. Hospitals were flooded with people, most of whom were found to be suffering from minor ailments and were quickly discharged. The eventual response of the government, while belated, was dramatic. By 19 September, the area within a fifteen-kilometre radius around Beed had been sprayed with hundreds of tons of DDT and other insecticides. Bombay's Haffkine Institute had 800,000 tetracycline tablets on hand that were immediately available for transport to Surat, and other sources were quickly found. Within days of the Surat outbreak an astonishing eight million tablets had arrived by airlift, and another two million were sent to Beed. These heroic measures quickly contained the disease, but left unanswered the question of whether it had really been plague. When I visited India at the beginning of 1995, controversy still raged, but one thing seems certain. No plague-line outbreak could have withstood the deluge of tetracycline and DDT that descended on it. In this case, the power of twentieth-century technology had proved overwhelming. Navajo Wisdom Technology can not only stamp out plagues in their early stages, but can also permit new diseases to be tracked down and understood with unprecedented speed. The Four Corners virus that recently appeared in the US is a vivid example. The disease's existence was first suspected in the middle of May 1993. Two members of the same New Mexico family, living not far from the Four Corners area where the boundaries of four states touch, died of acute respiratory distress within five days of each other. The apparent coincidence alerted local public health workers, who quickly examined necropsy tissues from the victims' lungs. They were able to rule out any of the obvious bacteria and viruses. Samples of lung tissue from the victims arrived at Atlanta's Centers for Disease Control on 31 May. By 2 June, sensitive immunological assays had yielded a very unusual result. The disease agent in the cells was a virus, which was expected, but it turned out not to be a relative of the known viruses that can cause pneumonia. Instead, it was related to a group called hantaviruses. These are widespread in Asia and Europe, and are responsible for diseases that cause haemorrhaging in the kidneys. The hantavirus connection was unexpected, since the Four Corners virus clearly affected the lungs. Its symptoms were completely different from those of the other hantaviruses. The next step was to use a powerful molecular technique, the polymerase chain reaction, widely known by its abbreviation PCR. Tiny amounts of DNA that had been isolated from the diseased tissues of the infected individuals were added to PCR reaction tubes. Somewhere in this mixture, swamped by the enormous amounts of DNA from the cells of the victims, were a few DNA molecules that had been copied by their cellular machinery from the RNA of the virus. The trick was to amplify this tiny amount of DNA, to make enormous quantities of it that would enable the message that it carried to be read. The PCR reaction itself is extremely simple. Mix short stretches of DNA called primers with a bit of the DNA mixture you want to examine, and add a heat-resistant enzyme that can build new DNA strands using the primers as starting points. Heat and cool this solution repeatedly according to a precise schedule, and after 20 or 30 cycles you will have enormous quantities of the piece of gene that lies between the primers (Figure 1-2 shows how this is done). The result was enormously amplified quantities of a chunk of the hantavirus DNA. These pieces were amplified on 8 June, and the sequence of their bases was determined by 9 June, less than a month from the time that the disease had initially been detected. Once the DNA was available, tissue samples from wild animals that inhabit the region were then rapidly screened for the presence of these sequences, again using PCR. The virus turned out not to be a human disease at all. Rather, it was a natural pathogen of a number of different rodent species, and was particularly common in the charming little white-footed deermouse Peromyscus maniculatus. In a dazzling tour de force of biological detective work, it was soon shown that the Four Corners virus had lived in these rodent populations for a long time, for it was made up of a number of different strains that over many thousands of years had acquired slightly different genetic sequences. The virus, which was found to be responsible for a burst of subsequent cases throughout the western US, turned out to be an old enemy, not a new one. Indeed, it was probably responsible for some of the rare cases of fatal respiratory disease that over the years had occasionally mystified doctors in the rural Southwest. It is ironic that if people had paid attention to local Navajo tradition, which speaks of mice as agents of disease and therefore creatures to be avoided, the outbreak might not have happened. But the ever-increasing numbers of people in the area have probably made this mini-plague inevitable. The Four Corners virus cannot, at least in its present form, be transmitted from one human to another. As a result, the route of infection can easily be blocked. People throughout the region were quickly alerted to the dangers of coming in contact with wild mice and their droppings, and the number of reported cases diminished just as quickly. The speed with which this disease was tracked down, understood, and, at least in the short term, held at bay in the affected population, is remarkable. Luckily, the Four Corners virus is a relatively easy one to control, and since related viruses were already known it could be diagnosed rapidly. A cool look at the hot zone Plagues of various kinds seem to be appearing everywhere. In southern Russia and the Crimea, the end of the hot summer of 1994 brought a wave of cholera cases, with a dozen deaths. And in the depressed and financially ruined cities of Moscow and St Petersburg to the north the resurgent enemy is now diphtheria, a childhood illness that had been thought to be a thing of the past. There were almost 50,000 cases of this choking disease in the first half of 1994, up from 1200 in 1990 and 4000 in 1992. Most were children, and about one in twenty of the victims died. Plagues or threatened plagues of these old diseases are being matched by a horrifying variety of new perils. In Africa, the widespread invasion of the rainforest by the exploding human population has disturbed nests of haemorrhagic viruses with names that sound like a drumbeat of doom: Lassa, Ebola, Marburg. In South America, three other viruses called Junin, Machupo and Guanarito, all related to Lassa, have recently emerged, again apparently as a result of human expansion into the forests. They have caused small but highly lethal clusters of cases in Argentina, Bolivia and Venezuela. No continent and no group of people seem to be immune to such outbreaks. One of the fatalities caused by the recent outbreak of the Four Corners virus was a graduate student in my own department at the University of California, San Diego. She came in contact with it quite unknowingly when she was carrying out field observations on birds in California's Sierra Nevada mountains. She was exposed to the virus while living in a cabin that had been deserted for much of the year and that had become infested with fieldmice. Luckily, so far, the Four Corners virus and most of the other so-called emerging viruses - with one notable exception - have not spread widely. This is because they cannot be transmitted easily from one human to another. The worst of the emerging viruses, of course, and the greatest plague that is facing us at the end of the twentieth century, is HIV, the AIDS virus. Unlike most of the other emerging viruses it is transmitted from one human to another, though not easily, and its rate of spread continues to increase, particularly in the Third World. Especially in sub-Saharan Africa, where it is very widespread, AIDS puts new strains on fragile societies. The very knowledge of the apparent inevitability of the disease has plunged millions of people into numb despair. In that region AIDS is only one part of a grim cycle involving other diseases, poverty, ignorance and warfare, so that cause and effect can no longer be separated. But there is no doubt that its effects on social structures have contributed to the killings in Rwanda and the waves of ethnic slaughter that have taken place elsewhere in Africa. Although a larger fraction of our species is living disease-free lives than ever before, thanks to advances in medicine and public health, the perception in the public mind is that plagues, and the threat of plagues, are ever-present. Recent books such as The Hot Zone and The Coming Plague have painted a truly terrifying picture of these plagues, and of their possible future successors. At any moment, the authors suggest, emerging haemorrhagic viruses might burst forth, be carried around the planet by airline passengers, and quickly turn us all - or at least all but a few resistant survivors - into piles of mush. What are the odds that this will happen? What properties might such a plague need in order to spread so uncontrollably? And what are we doing to ourselves and our planet that might bring on such an apocalyptic event? Where do plagues come from, anyway? Why do they happen? All these diseases are part of a much larger picture. We must understand that picture if we are to face up to them and take the steps needed to conquer them. We must also confront fully the extent to which our own activities trigger the outbreaks we call plagues. Waves of disease have struck the human race many times before. Indeed, many of these waves were a good deal worse than the current surge, since nothing could be done about curing the diseases or about immunizing the people who were likely to be infected. They struck with particularly devastating results when conditions were changing rapidly. For example, populations were undergoing dramatic increases during the Age of Exploration in the fifteenth and sixteenth centuries, just as they are at the present time. New technology allowed people to move long distances with greater ease. Then as now, there was widespread and continual warfare. The invasion of unexplored parts of the world was exposing whole groups of people to new diseases. All these human activities, then as now, were accompanied by disease outbreaks. But is there something unusual in the current outbreaks? Is it possible that they foreshadow the end of our species? Of course, our species was not wiped out by its diseases in the past, and it will not be wiped out by them now. The world is not coming to an end, although there is no doubt that we, both as a species and as individuals, are in for some very unpleasant and dangerous times. This is because there are things about the current wave of plagues that are new. Some of them are obvious and some are not so apparent. First, the obvious. The human race is expanding in numbers at an unprecedented rate. We are spreading into the last unexplored corners of our world, and in consequence we are flushing new diseases from their hiding places. When this expansion is combined with the devastation of war, as in Rwanda, or with economic upheaval, as in Russia, the mix can be particularly deadly. This has always been true, but because of new medical technology and instant communications it has never been so thoroughly documented as now. It is less obvious that our sheer numbers provide an unprecedented opportunity for disease organisms to evolve. In most parts of the planet, so far as these organisms are concerned, we are the largest meal around. As our population multiplies, so do those of the disease organisms that attack us. The human population explosion is also a pathogen population explosion, with all the evolutionary consequences that this implies. Mutations are the feedstock of evolutionary change, and in theory they may happen at any time. The ultimate epidemiological nightmare, always hanging over our heads like the sword of Damocles, is that a disease like AIDS or Ebola will suddenly become highly infectious through mutation. Perhaps these viruses will acquire the ability to travel through the air, or begin to spread with the aid of mosquitoes and other biting insects. There is no doubt that such a horrific event is made much more probable by the presence of huge populations of these pathogens, since the larger the population the more likely it becomes that a rare mutation or some other kind of rare genetic event will occur somewhere within it. More mundanely, pathogens have often borrowed from their relatives genes that can increase their virulence. In Washington State, in January 1993, a consignment of hamburger meat arrived in the kitchens of the Jack-in-the-Box fast-food restaurant chain. It happened to be bacterially contaminated, and was cooked less thoroughly than it should have been. The result was an outbreak of Escherichia coli food poisoning which caused three deaths and more than 500 cases of severe illness. The outbreak was caused by a variant strain, called O157:H7, of this usually mild-mannered bacterium. This strain carries, among a nasty assortment of other genes, a gene for a toxin that is shared widely by a rogues' gallery of E. coli's relatives - Shigella, Yersinia, Campylobacter,and Salmonella. Although most strains of these various bacteria do not have the toxin gene and live relatively benignly in our guts or in the soil, there are a few variant strains of each species that have borrowed this gene and other dangerous genes in the past. Such borrowings happen rarely, but the likelihood is increasing that strains carrying these rare combinations will be found somewhere in the huge mixed populations of bacteria that our activities are creating. A more subtle problem has grown out of our very success at fighting disease. Many of the `easy' diseases, those that are readily susceptible to antibiotics or that we can easily be immunized against, have now been conquered or driven to very low levels. The medical historian Mirko Grmek has suggested that while this has lengthened our lifespans it has also provided an opportunity for rarer, less tractable diseases. AIDS, which takes an average of ten years to kill its victims in industrialized societies, might not have spread so effectively in a world in which people who had been infected with the virus would usually die of something else first. Grmek's example of AIDS may be poorly chosen, since people who have just acquired the virus tend to be the most infective. But it is certainly true that relatively intractable diseases are posing an ever greater danger in many societies. Nowhere is this picture changing more rapidly than in India. A lifetime ago, bubonic plague was a terrible cause of mortality in that teeming country. These days, the greatest danger is far more subtle. As one wanders through the crowded streets of an Indian city or town, it is sobering to realize that over a third of the inhabitants are infected with tuberculosis. Only a few per cent will develop overt signs of the disease during their lifetimes, but these cases still number in the millions. Treatment is difficult, expensive, and lengthy, involving three or even four drugs, taken daily, for a period of six to eight months. Although the cure rate for those who complete this demanding regimen is high, only about half the patients lucky enough to begin the treatment successfully finish it. When the treatment is stopped partway through, the surviving bacilli are those that are the most drug-resistant. As a consequence, drug-resistant strains of the TB bacillus are spreading, making new cases even more difficult to cure. The most encouraging new factor in this litany of disasters is that we are beginning to understand plagues, and to understand them at every level. We cannot give final answers to the question of the nature of future epidemics, but we can formulate the question itself much more sensibly. Epidemiologists have a much clearer idea of how diseases are spread, and can determine the points in their life cycles at which they are best attacked. Our understanding of the cells that make up our bodies and of how they are attacked by pathogens has also grown enormously. Public health officials know the steps that should be taken to limit plagues. Indeed, they are frustrated primarily by a lack of resources and by the prejudice, ignorance, and fear of the public and of their elected officials, particularly when they are faced with an upsurge of sexually transmitted diseases. But whether we can control these diseases or not, we must still confront the most unnerving question of all. What place do plagues and endemic diseases have in the natural world? One of my most searing memories is of being surrounded on a street in Hyderabad by a crowd of lepers, ranging from young people to withered ancients, extending their fingerless hands towards me for alms. The faces of many of them had become collapsed and distorted from the ravages of the disease. Not long before, I had visited a sheltered workshop in the grounds of a hospital in southern India, where similarly crippled lepers were being taught to do simple tasks. In India, leprosy is so prevalent that such programmes are hopelessly inadequate - the leprous beggars who crowded around me on the Hyderabad street had been unable to find a place in them. How is it that diseases as loathsome as leprosy or as deadly as bubonic plague have made a place for themselves in the living world? Generators of diversity Some years ago immunologist Mel Cohn, trying to explain the complexity of the human immune system, drew a box on the blackboard labelled GOD. He explained, deadpan, that this stood for `Generator of Diversity'. Cohn's little joke leads us to a much deeper answer to the question of the existence of plagues and other diseases. They are generators of diversity. Exploring this idea will lead us far beyond our own species, into an examination of the web of ecological interactions that connects us to all the other species with which we share the planet. We will discover that plagues form a part, a small part, of a kind of evolutionary feedback loop that has actually helped to generate the great diversity of the living world. This diversity is one that encompasses both diseases and their hosts. We are challenged with a bewildering variety of diseases - assorted worms, protozoa, bacteria, fungi and viruses that, unchecked, can roister in our bodies in prolific abundance. The same applies to other animals and to plants. One answer to why there are so many diseases is simply that there are so many species on which they can prey. But this immediately raises another question - why should there be so many species of animals and plants in the first place? As we will see, at least part of the answer to this question is that they are so numerous because there are so many diseases. Surely this reasoning is circular! Not quite. As we will see, particularly in the tropics, there are so many pathogens that no host species is capable of defending itself against them all. And at the same time no pathogen, confronted by all these potential host species, is sufficiently versatile to be able to attack all of them. This relationship between pathogens and hosts has actually helped to drive the evolution of the teeming complexity of tropical life, and to a lesser extent life in the temperate zones as well. In the process of becoming very different from each other, host species protect themselves from most of the pathogens that might otherwise be a threat. And because each pathogen must concentrate its efforts on overcoming the defences of a particular type of host, pathogens inevitably become more and more specialized, and thus they too become more and more different from each other. The two processes reinforce each other, and as we will see they have particularly left their mark on the pattern of diversity in the tropical rainforest. Since our species originated in the tropics, we are both the victims and the beneficiaries of this diversity. We are victims because of all the misery and death caused by these diseases. And we are beneficiaries because, even within our own species, this host-parasite competition is operating, helping to drive our own genetic diversity. The competition between ourselves and our pathogens is manifest at every level, and its effects have even dramatically shaped the families of protein molecules that make up our cells. We now know enough about these proteins to measure the consequences of this fierce competition directly. Many different proteins have been sequenced - that is to say, the precise sequence of the smaller molecules called amino acids that are strung together to make up their structure has been determined. Recently, Philip Murphy of the US National Institute of Allergy and Infectious Diseases scanned through the rapidly growing database of such sequenced proteins, looking for those that are found both in humans and in rodents. He arranged these sequences in pairs, one from a human and one from a rodent. Each of these pairs can be traced back to a common ancestral molecule which was probably present in the little insectivore from which humans, rats and mice are descended. The little insectivore lived before the dawn of the Age of Mammals, sixty-five million years ago. Murphy measured how far these pairs of proteins had diverged from each ocher in the course of the separate evolution of humans and rodents (Figure 1-3). He found that proteins involved in defending the hosts against bacteria, viruses and ocher pathogens have diverged three times as quickly as proteins that are not involved in these defences. Something, he thought, must be driving all this accumulation of diversity in our defences. That something seemed very likely to be the very different sets of pathogens that have afflicted humans and rodents in the course of their separate evolution. For tens of millions of years our ancestors have been in a frantic race with their pathogens, trying to keep up as they evolve. At the same time, the ancestors of mice and rats have been in a race of their own, fighting off the continually shifting malign effects of their own sets of pathogens. Such genetic variation has accumulated, not only between species as they have diverged from each other over millions of years, but within species as well. This within-species accumulation, too, has been driven by those furiously evolving pathogens. The immunologist Douglas Green and I have shown thet even though our species is afflicted by a wide assortment of diseases, this diversity tends to spread the burden, so that it is not too onerous for our species to bear. This is because we are so different from each other that no species of pathogen can become too prevalent - the majority of us are resistant to it, even though a few of us may be susceptible. We have called this complex modus vivendi between ourselves and our numerous pathogens, for reasons that will become clear, genetic herd-immunity. We must understand this balance between life and death, and how it can be upset, for the following terribly cogent reason. Human activity not only disturbs ecosystems, it simplifies them. Even though we come in daily contact with at least as many other living organisms as our remote ancestors did, the number of species is far fewer and the mix is very different. We have deliberately surrounded ourselves with creatures that are friendly to us, like dogs and cattle and wheat and corn. And we have also surrounded ourselves with other organisms that we have not meant to. Our activities have inadvertently helped these other organisms to multiply into enormous numbers. These are creatures like rats, fleas, lice, cockroaches, pigeons and seagulls, rarer in the prehuman world but now multiplying enormously. And, although they tend to be overlooked, we have also surrounded ourselves with less obvious creatures, like the teeming micro-organisms that have invaded the estuaries we have polluted, and the new mix of soil bacteria that is now found in the fields we have cultivated and altered with the addition of pesticides and fertilizers. These new combinations of micro-organisms provide new evolutionary opportunities. Pathogens with which we have previously been coexisting can be catapulted into new, short-term but terrible modes of existence. In short, they can become plagues. We are not the only victims Clumsy and genetically awkward as plague organisms are, they have a long evolutionary history. When plagues appear, they do so for a reason. And that reason has to do with the size of the host population and the degree to which it has disturbed its environment. Death, as somebody once said, is Nature's way of telling you to slow down. We must be careful here, however. It is easy, and appears straightforward, to think of plagues as a form of population control, keeping our numbers in check when we have expanded too much for our resources. But this explanation, while it appears superficially to make sense, is redolent of popular views of ecology. Biologists hate this kind of thinking, because it implies that kindly but firm old Mother Evolution exhibits foresight, and that she somehow uses plagues deliberately to keep populations in balance. Indeed, it is obvious that plagues have not evolved simply to control populations. After all, this would run counter to the central point of evolution, which is that successful organisms are successful because they can outbreed their competitors. Population control may be an effect of plagues, but it cannot be their raison d'etre. The end result, however, is the same. When a population of any species - humans, rats, diatoms floating in the ocean - becomes too large for its resources, this provides new opportunities for a small subset of the many diseases that normally afflict it. Among these teeming pathogen populations, the ones that can cause plagues are normally rare. But when the population of hosts happens to explode in numbers, and to modify its environment in the process, the most virulent pathogens can suddenly gain a brief advantage. These dangerous pathogens are able to utilize this new brief ecological niche that is provided by the sudden superabundance of hosts. After the plague, the most virulent strains disappear or fall to low levels, and the host species and its pathogens soon revert to their previous uneasy balance. If plagues really are on the increase in our species, this is telling us something very important about what we are doing to ourselves and our planet, something that we ignore at our peril. But ironically, it is the very plagues we fear so much that have helped to keep the world in balance for so long. And as the world's premier disturbers of ecosystems, we are helping to unleash diseases not only in our own species, but in others. We are justifiably worried about the appearance of new diseases that have emerged from the remnants of the natural world and that threaten us. But we tend to forget or ignore the fact that the flow is not one way. While we may not be contributing many diseases directly to other species, we are none the less causing plagues to spread among them that would not happen otherwise. These plagues threaten the survival of the world of nature at exactly the time at which it is most vulnerable. This book began with the impact of a terrible disease on humans who have invaded and disturbed the rainforest. At the end of the book we will visit the rainforest again, and look at it with new eyes. The world harbours many forms of disease, and when we disturb its balance we are not their only victims.
