According to conventional wisdom, our genes and lifestyles are the most important causes of the most deadly ailments of our time. Conventional wisdom may be wrong. In this controversial book, the eminent biologist Paul W. Ewald offers some startling arguments:
-Germs appear to be at the root of heart disease, Alzheimer's, schizophrenia, many forms of cancer, and other chronic diseases.
-The greatest threats to our health come not from sensational killers such as Ebola, West Nile virus, and super-virulent strains of influenza, but from agents that are already here causing long-term infections, which eventually lead to debilitation and death.
-The medical establishment has largely ignored the evidence that implicates these germs, to the detriment of our public health.
-New evolutionary theories are available, which explain how germs function and offer opportunities for controlling these modern plagues -- if we are willing to listen to them.
Plague Time is an eye-opening exploration of the revolutionary new understanding of disease that may set the course of medical research for the twenty-first century.

Paul W. Ewald, professor of biology at Amherst College, is the author of Evolution of Infectious Disease and the first recipient of the George E. Burch fellowship in Theoretic Medicine. He lives in Shutesbury, Massachusetts.

CHAPTER ONE

The Virulence of Acute Infections

WE ARE THEIR FOOD. THOSE GERMS OF THE PAST THAT BEST converted our bodies into their own propagation are the germs of the present. Those germs of the present that best convert our bodies into their own propagation will be the germs of the future. Why should we care about the prospects of one particular germ over another? Aren't they all just plain bad? The simple answer is no. We can never get rid of them all. Their future is our future. If their future goes one way, we will be relatively healthy; if it goes another, we will be sick or even dead. So the question is, how will they survive? Or rather, how will they evolve?

Surprisingly, neglect of the germ's-eye view of the world is not restricted to the average person; it extends to medicine as a whole for most of its history. Only during the past twenty years have researchers emphasized the importance of looking at a germ's evolutionary scorecard. This scrutiny is suggesting solutions to the most damaging problems of medicine as well as the most irritating. Both categories of problems are important. AIDS, tuberculosis, and malaria are important because they are so damaging; though most of the people reading this book will not suffer from these diseases, they are common enough that our lives are affected indirectly. On the other hand, the common cold is not life-threatening, but it is important because it is such a pervasive nuisance.

Disease from the germ's perspective has been best worked out for the acute infectious diseases. These are the diseases most of us picture when someone mentions infectious diseases--the common cold, strep throat, pneumonia. They typically arise suddenly, within a week or two after the germ has invaded, and are generally controlled by our immune system within a few weeks.

Typically, acute infectious diseases turn quick profits for short-term gain. The pathogens that cause them are corporate raiders, out to get rich quick rather than maintain the health of their targets. If they depend on their host company's well-being, they may have a fairly benign effect. But if the chance to exploit and move on arises, they take it, and the host company suffers and may even be destroyed. Biological parasites take food rather than money, and they spend the food on reproduction rather than material goods. For either kind of parasite-- microbial or human--exploitative propensity depends on whether a relatively healthy host is needed for the leap to the next host. When a sick host suffices, the most damaging parasites can prosper.

The germs cannot consciously plan their moves in the way a corporate raider does. But natural selection molds the pathogens so that they act strategically, almost as if they were making plans. The strategic options can be envisioned as a competition that is played out in two contests. The first contest occurs within the host, where the favored competitors are those that most effectively use the host as food for their own reproduction. The second contest is played out in the transmission of pathogens to new hosts; those pathogens that have been successful at growing within hosts are now in competition to reach the remaining uninfected members of the society. A pathogen that never gets transmitted to a new host is doomed; if it is not destroyed by the immune system, its finite future is guaranteed by the inevitable death of the host in which it resides.

These two contests require different talents. The best competitors are those that do well enough at both events to generate the most progeny--thus dominating the next round of the cycle. Natural selection assesses the strengths and weaknesses of competing pathogens much as judges of a decathlon assess the strengths and weaknesses of competitors in different arenas. With natural selection, however, the "points" are copies of genetic instructions. Pathogens earn these points only by propagating through time. A pathogen that takes so much from a host that it compromises its ability to get to the next host may leave fewer descendants than a less gluttonous pathogen. The more frugal competitor may produce fewer progeny within a host but by keeping the host relatively healthy, it may be better transmitted to the next host if, for example, being terribly sick hinders transmission. If a pathogen relies on some well-placed sneeze in an office or a classroom for transport, a person sick in bed would be a disaster. But the converse could also be true. If a pathogen does not rely on a mobile host, then the more gluttonous competitor may have the higher score in the decathlon of evolution. In other words, because the genetically encoded characteristics of a germ that help it win the competition at one stage of the process might hinder it at another, evolutionary biologists consider the trade-offs that are associated with each characteristic. Growing rapidly inside a person typically involves an evolutionary trade-off: the benefit of generating more progeny within a person is weighed against the reduced chances of contacting a susceptible person if the infected person is too sick to move around. Evolutionary biologists are efficiency experts, always assessing benefits relative to costs.

The basic evolutionary principles underlying such analyses have transformed the modern understanding of infectious disease and promise to transform medicine itself because they reveal a fundamental misconception about disease. Throughout the twentieth century, leading authorities in the health sciences believed that coevolution of pathogens with their hosts would inevitably lead to benign coexistence. They arrived at this mistaken conclusion because they did not consider the trade-offs that were a part of the competition. They focused on the long-term survival of particular parasite species as a whole, rather than the success of particular competitors within the species. The mistake is partly attributable to the catchiness of the phrase "survival of the species." With this phrase jingling around the brain like a pop-song refrain, many medical authorities decided that natural selection somehow directly favored the survival of a species. It does not. Rather, natural selection operates through differences in the rate at which certain genetic instructions are passed on relative to different genetic instructions that occur in other individuals of the same species. The eventual survival of the species may be favored or disfavored as a result, but species extinction, if it eventually occurs, is powerless to influence the course of any competition that occurs prior to the extinction. Natural selection obtains its power from the differences in the survival and reproduction of the competitors within a species, which in turn determine differences in the passing on of the genetic instructions that individuals house. That is where one must look if one wishes to understand why infectious diseases are the way they are and what we can do to control them, because that is where the strategies of pathogens are being shaped.

BY WINGS AND BY WATER

Host-parasite associations can evolve to any point along a continuum from extremely lethal to so mutually beneficial that neither participant could survive without the other. Trade-off analyses seek to explain the spots along this continuum to which particular associations will evolve, over millions of years or just a few months. The rate depends on many things: what kind of variation exists among the germs, how long it takes to generate variation that would be useful for the germs, the differences in success among the competing germs, and what the host has and can muster as countermeasures. The outcomes may not be stable.

Of particular importance to the outcomes is the dependence of pathogen transmission on host mobility. If a mode of transmission allows pathogens to reach susceptible hosts even when the infected host is entirely immobilized by illness, then we expect natural selection to favor a ravaging disease. Among diseases transmitted by mosquitoes, for example, even very sick individuals can serve as a source of infection because the mosquitoes take care of the transportation. In fact, sick individuals may be even better as sources of infection because they are less able to swat mosquitoes. As expected from this argument, diseases transmitted by mosquitoes, tsetse flies, lice, and sandflies do tend to be more lethal than diseases that rely on person-to-person transmission. This simple trade-off argument explains why the agents of malaria, yellow fever, and sleeping sickness are so much more incapacitating than agents of respiratory diseases, such as the common cold, which typically cause just sneezes, coughs, and runny noses.

Mosquitoes and other organisms that transport pathogens from person to person are called vectors; the diseases they transport are, logically enough, referred to as vector-borne. As a group, vector-borne diseases are particularly well endowed with killers, including malaria, sleeping sickness, and yellow fever. But even those vector-borne pathogens that are not especially lethal tend to be agonizing and immobilizing. The dengue virus belongs in this category. It is a cousin of the yellow fever and West Nile viruses and is transmitted largely by the same mosquito that transmits yellow fever: Aedes aegypti. The dengue virus kills fewer than one of every hundred people it infects, but the low probability of death is little comfort to the dengue patient, as is clear from an account by the tropical-disease expert Alan Spira, describing his own case of dengue, which he acquired in East Africa: "A headache behind the eyes that throbbed and pounded, with a sensation of pressure like a kettle brewing and boiling. A fever, mild at first, but later intense with sweating, came bundled with ferocious muscle aches. These aches were rooted deep in the calves and back, and felt like being punched from the inside-out." Dengue is often called breakbone fever because the pain gives the patient the impression that bones are slowly being broken.

The dengue virus was probably passed to humans from monkeys many centuries ago. Though generally confined to a band within twenty-five degrees latitude from the equator, it has circled the earth within this zone and is found in India, Southeast Asia, Africa, the Caribbean, and Mexico. Using its mosquito transport, it quickiy burns through one village and then travels off to another village, town, or even city, wherever the Aedes mosquitoes--and hence the viruses-- have ready access to their human food. The viruses return to repeat the process when the number of susceptible humans in the group increases sufficiently through new births, new immigrants, or the gradual fading of the immunity conferred by previous infection. Dengue is a terrible experience for the afflicted person, yet the incapacitation serves the dengue virus by making the sufferer a more vulnerable target for mosquitoes.

The dependence of transmission on host mobility also explains why some diarrheal diseases are matters of life or death, whereas others are just an annoyance. People can inadvertently create "cultural vectors" which transport pathogens from immobilized hosts much the way mosquitoes transport malaria and dengue. If water supplies are not adequately protected, the washing of clothes and bedsheets can contaminate the water, thereby infecting hundreds of other people, even if the person who contaminated the materials was entirely immobilized with a case of cholera or dysentery. Waterborne pathogens pay a low transmission price when they exploit a person so intensively that the person is completely immobilized, because they can still be transmitted from immobile hosts; and they gain a big fitness benefit from exploiting infected hosts because contaminated water can contact many more people than an infected person can. Waterborne pathogens are not just limited to an infected person's friends and acquaintances; anyone who drinks contaminated water is a potential victim.

Comparisons of human diarrheal diseases confirm the central prediction of this line of reasoning: the more waterborne the diarrheal bacterium, the more deadly it is. This association explains why cholera, typhoid, and dysentery are so deadly, and the bacteria that infect the intestines of rich countries are generally so mild. This evolutionary perspective also explains why travel to countries without adequate protection of drinking water is so dangerous, even when such countries do not have notorious vector-borne diseases such as malaria, dengue, and yellow fever. The diarrheal pathogen that enters the traveler's body through contaminated food or drink may have had a long evolutionary history of transmission that has not depended on mobile people. The traveler feels this legacy much more intensely than the local residents because the residents have already generated an immunity. These residents typically paid the price of initiation early in life when, as babies or toddlers, their lives depended on the defenses their immune systems could muster. Those youngsters who did not pass this test joined the three million or so children who are buried in poor countries each year, children who died from something as simple and violent as diarrhea. The traveler isn't as likely to die from the infection, largely because travelers usually have access to the simple but life-saving doses of antibiotics and rehydration solution. The traveler lives to ponder this firsthand experience of life as it is lived now in poor countries and as it was lived just a few generations ago in rich countries. In the nineteenth century almost all urban centers had the same nasty diarrheal pathogens. By allowing drinking water to be fecally contaminated, the technology of the time fostered the distribution of deadly agents. The children of rich and poor countries alike experienced the same lottery that is being held in poor countries today. One in ten children typically succumbed to disease in areas with unprotected water. Whenever water supplies were protected, the most dangerous protagonists vanished as predictably as actors at the end of a play.

WHAT PATIENTS GET FROM HOSPITALS

Hospital-acquired infections have their own cultural vectors: doctors, nurses, and other attendants inadvertently transfer pathogens from their patients to their hands and then to other patients, either directly or indirectly through contamination of objects in the hospital. Such attendant-borne transmission is the major route for most serious infections acquired in hospitals, such as staphylococci, streptococci, enterococci, and Clostridium difficile, which can cause life-threatening infections of the skin, lungs, and intestinal tract. Attendants usually do not become infected themselves partly because they are less vulnerable than their patients, partly because they will wash their hands before leaving the hospital, and partly because they may have generated some immunity to the hospital organisms. This history is as old as the hospitals themselves.

In the early l850s the Hungarian physician Ignaz Semmelweis was perplexed by the fact that one out of eight healthy mothers-to-be who were admitted to the University of Vienna hospital to deliver babies were leaving in caskets. The "childbed fever" that killed the mothers shortly after delivery was characterized by sepsis, which in the mid-nineteenth century meant an invasion of the blood by rotten or putrid material. Today it means disease resulting from the presence of microbes or their toxins in the blood, a common consequence of hospital-acquired infections.

Semmelweis's concern turned to horror when he began to understand the reasons for the hospital's alarming statistics. He noticed that the women were dying from the same disease that physicians and medical students had been studying in the morgue in between giving pelvic exams. More important, he noticed that the women who received those pelvic exams were more likely to fall ill than those who did not. He concluded, decades before Pasteur and Koch established the germ theory of disease, that the doctors and medical students were inadvertently killing the mothers-to-be by transmitting some invisible agent of disease during the prenatal exams. After the women were removed to the morgue, the agents that killed them were inadvertently returned to the ward on the hands of medical personnel and then transferred from patient to patient during the pelvic exams. To break this cycle, Semmelweis introduced the practice of having hospital staff wash their hands with a chlorine disinfectant. This treatment was followed by an application of oil to the hands; the oil was intended to serve as a barrier to any organisms remaining on the hands--a mid-nineteenth century version of latex examination gloves.