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A New Germ Theory
Evolutionary biology
The dictates of evolution virtually demand that the causes of some of humanity's chronic and most baffling "noninfectious" illnesses will turn out to be pathogens -- that is the radical view of a prominent evolutionary biologist

by Judith Hooper

(The online version of this article appears in three parts. Click here to go to part two. Click here to go to part three.)

A LATE-SEPTEMBER heat wave enveloped Amherst College, and young people milled about in shorts or sleeveless summer frocks, or read books on the grass. Inside the red-brick buildings framing the leafy quadrangle students listened to lectures on Ellison and Emerson, on Paul Verlaine and the Holy Roman Empire. Few suspected that strains of the organism that causes cholera were growing nearby, in the Life Sciences Building. If they had known, they would probably not have grasped the implications. But these particular strains of cholera make Paul Ewald smile; they are strong evidence that he is on the right track. Knowing the rules of evolutionary biology, he believes, can change the course of infectious disease.
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  • In a hallway of the Life Sciences Building an anonymous student has scrawled above a display of glossy photographs and vitae of the faculty, "We are the water; you are but the sponge." This is the home of Amherst's biology department, where Paul Ewald is a professor. He is also the author of the seminal book Evolution of Infectious Disease and of a long list of influential papers. Sandy-haired, trim, and handsome in an all-American way, he looks considerably younger than his forty-five years. Conspicuously outdoorsy for an academic, he would not seem out of place in an L. L. Bean catalogue, with a golden retriever by his side. Ewald rides his bike to the campus every day in decent weather -- and in weather one might not consider decent -- from the nearby hill village of Shutesbury, where he lives with his wife, Chris, and two teenage children in a restored eighteenth-century house.

    As far as Ewald is concerned, Darwin's legacy is the most interesting thing on the planet. The appeal of evolutionary theory is that it is a grand unifying principle, linking all organisms, from protozoa to Presidents, and yet its essence is simple and transparent. "Darwin only had a couple of basic tenets," Ewald observed recently in his office. "You have heritable variation, and you've got differences in survival and reproduction among the variants. That's the beauty of it. It has to be true -- it's like arithmetic. And if there is life on other planets, natural selection has to be the fundamental organizing principle there, too."

    These Darwinian laws have led Ewald to a new theory: that diseases we have long ascribed to genetic or environmental factors -- including some forms of heart disease, cancer, and mental illness -- are in many cases actually caused by infections. Before we take up this theory, we need to spend a moment with Ewald's earlier work.

    Paul Ewald
    Paul Ewald
    Ewald began in typical evolutionary terrain, studying hummingbirds and other creatures visible to the naked eye. It was on a 1977 field trip to study a species called Harris's sparrow in Kansas that a bad case of diarrhea laid him up for a few days and changed the course of his career. The more he meditated on how Darwinian principles might apply to the organisms responsible for his distress -- asking himself, for instance, what impact treating the diarrhea would have on the vast populations of bacteria evolving within his intestine -- the more obsessed he became. Was his diarrhea a strategy used by the pathogen to spread itself, he wondered, or was it a defense employed by the host -- his body -- to flush out the invader? If he curbed the diarrhea with medication, would he be benefiting the invader or the host? Ewald's paper outlining his speculations about diarrhea was published in 1980, in the Journal of Theoretical Biology. By then Ewald was on his way to becoming the Darwin of the microworld.

    "Ironically," he says, "natural selection was first recognized as operating in large organisms, and ignored in the very organisms in which it is especially powerful -- the microorganisms that cause disease. The time scale is so much shorter and the selective pressures so much more intense. You can get evolutionary change in disease organisms in months or weeks. In something like zebras you'd have to wait many centuries to see it."

    For decades medical science was dominated by the doctrine of "commensalism" -- the notion that the pathogen-host relationship inevitably evolves toward peaceful coexistence, and the pathogen itself toward mildness, because it is in the germ's interest to keep its host alive. This sounds plausible, but it happens to be wrong. The Darwinian struggle of people and germs is not necessarily so benign. Evolutionary change in germs can go either way, as parasitologists and population geneticists have realized -- toward mildness or toward virulence. It was Ewald's insight to realize what we might do about it.

    Manipulating the Enemy

    SAY you're a disease organism -- a rhinovirus, perhaps, the cause of one of the many varieties of the common cold; or the mycobacterium that causes tuberculosis; or perhaps the pathogen that immobilized Ewald with diarrhea. Your best bet is to multiply inside your host as fast as you can. However, if you produce too many copies of yourself, you'll risk killing or immobilizing your host before you can spread. If you're the average airborne respiratory virus, it's best if your host is well enough to go to work and sneeze on people in the subway.

    Now imagine that host mobility is unnecessary for transmission. If you're a germ that can travel from person to person by way of a "vector," or carrier, such as a mosquito or a tsetse fly, you can afford to become very harmful. This is why, Ewald argues, insect-borne diseases such as yellow fever, malaria, and sleeping sickness get so ugly. Cholera uses another kind of vector for transmission: it is generally waterborne, traveling easily by way of fecal matter shed into the water supply. And it, too, is very ugly.

    "Here's the [safety] hood where we handle the cholera," Jill Saunders explained as we toured the basement lab in Amherst's Life Sciences Building where cholera strains are stored in industrial refrigerators after their arrival from hospitals in Peru, Chile, and Guatemala. "We always wear gloves." A medical-school-bound senior from the Boston suburbs, Saunders is one of Ewald's honor students. As she guided me around, pointing out centrifuges, -80 degree freezers, and doors with BIOHAZARD warnings, we passed a closet-sized room as hot and steamy as the tropical zones where hemorrhagic fevers thrive. She said, "This is the incubation room, where we grow the cholera."

    Cholera invaded Peru in 1991 and quickly spread throughout South and Central America, in the process providing a ready-made experiment for Ewald. On the day of my tour Saunders had presented to the assembled biology department her honors project, "Geographical Variations in the Virulence of Vibrio cholerae in Latin America." The data compressed in her tables and bar graphs were evidence for Ewald's central thesis: it is possible to influence a disease organism's evolution to your advantage. Saunders used a standard assay, called ELISA, to measure the amount of toxin produced by different strains of cholera, thus inferring the virulence of V. cholerae variants from several Latin American regions. Then she and Ewald looked at figures for water quality -- what percentage of the population had potable water, for example -- and looked for correlations. If virulent strains correlated with a contaminated water supply, and if, conversely, mild strains took over where the water was clean, the implication would be that V. cholerae becomes increasingly mild when it cannot use water as a vector. When the pathogen is denied easy access to new hosts through fecal matter in the water system, its transmission depends on infected people moving into contact with healthy ones. In this scenario the less-toxic variants would prevail, because these strains do not incapacitate or kill the host before they can be spread to others. If this turned out to be true, it would constitute the kind of evidence that Ewald expected to find.

    The dots on Saunders's graphs made it plain that cholera strains are virulent in Guatemala, where the water is bad, and mild in Chile, where water quality is good. "The Chilean data show how quickly it can become mild in response to different selective pressures," Ewald explained. "Public-health people try to keep a disease from spreading in a population, and they don't realize that we can also change the organism itself. If you can make an organism very mild, it works like a natural vaccine against the virulent strains. That's the most preventive of preventive medicine: when you can change the organism so it doesn't make you sick." Strains of the cholera agent isolated from Texas and Louisiana produce such small amounts of toxin that almost no one who is infected with them will come down with cholera.

    Virulence Joseph Schall, a professor of biology at the University of Vermont, offers a comment on Ewald's work: "If Paul is right, it may be that the application of an evolutionary theory to public health could save millions of lives. It's a stunning idea. If we're able to manipulate the evolutionary trajectory of our friends -- domestic animals and crops -- why not do the same with our enemies, with cholera, malaria, and HIV? As Thomas Huxley said when he read Darwin, "How stupid of me not to have thought of that before." I thought when I heard Paul's idea, "Gee, why didn't I think of that?"

    Ewald put forward his virulence theories in Evolution of Infectious Disease. Today his book is on the syllabus for just about every college course in Darwinian medicine or its equivalent. "I regard him as a major figure in the field," says Robert Trivers, a prominent evolutionary biologist who holds professorships in anthropology and biology at Rutgers University. "It is a shame his work isn't better known to the public-health and medical establishments, who are willfully ignorant of evolutionary logic throughout their training." While praising Ewald's boldness and originality, some of his peers caution that his data need to be independently corroborated, and others object that his hypotheses are too crude to capture the teeming complexity of microbial evolution. "Evolutionary biologists have had very poor success in explaining how an organism evolves in response to its environment," says James Bull, an evolutionary geneticist at the University of Texas. "Trying to understand a two-species interaction should be even more complicated."

    Recently, in any case, Ewald has adopted a new cause, far more radical but equally rooted in evolution. Let's call it Germ Theory, Part II. It offers a new way to think about the causes of some of humanity's chronic and most baffling illnesses. Ewald's view, to put it simply, is that the culprits will often turn out to be pathogens -- that the dictates of evolution virtually demand that this be so.

    The Case for Infection

    GERM Theory, Part I, the edifice built by men like Louis Pasteur, Edward Jenner, and Robert Koch, took medicine out of the Dark Ages. It wasn't "bad air" or "bad blood" that caused diseases like malaria and yellow fever but pathogens transmitted by mosquitoes. Tuberculosis was famously tracked to an airborne pathogen, Mycobacterium tuberculosis, by Robert Koch, the great German scientist who in 1905 won a Nobel Prize for his work. Koch also revolutionized medical epidemiology by laying out his famous four postulates, which have set the standard for proof of infectivity up to the present day. The postulates dictate that a microbe must be (a) found in an animal (or person) with the disease; (b) isolated and grown in culture; (c) injected into a healthy experimental animal, producing the disease in question; and then (d) recovered from the experimentally diseased animal and shown to be the same pathogen as the original.

    By the early twentieth century the whole landscape had changed. Most of the common killer diseases, including smallpox, diphtheria, bubonic plague, flu, whooping cough, yellow fever, and TB, were understood to be caused by pathogens. Vaccines were devised against some, and by the 1950s antibiotics could easily cure many others. Smallpox was actually wiped off the face of the earth (if you don't count a few strains preserved in laboratories in the United States and Russia).

    By the 1960s and 1970s the prevailing mood was one of optimism. Ewald is fond of quoting from a 1972 edition of a classic medical textbook: "The most likely forecast about the future of infectious disease is that it will be very dull." At least in the developed world, infectious diseases no longer seemed very threatening. Far scarier were the diseases that the medical world said were not infectious: heart disease, cancer, diabetes, and so on. No one foresaw the devastation of AIDS, or the serial outbreaks of deadly new infections such as Legionnaire's disease, Ebola and Marburg hemorrhagic fevers, antibiotic-resistant tuberculosis, "flesh-eating" staph infections, hepatitis C, and Rift Valley fever.

    The infectious age is, we now know, far from over. Furthermore, it appears that many diseases we didn't think were infectious may be caused by infectious agents after all. Ewald observes,"By guiding researchers down one path, Koch's postulates directed them away from alternate ones. Researchers were guided away from diseases that might have been infectious but had little chance of fulfilling the postulates." That is, just because we couldn't readily discover their cause, we rather arbitrarily decided that the so-called chronic diseases of the late twentieth century must be hereditary or environmental or "multifactorial." And, Ewald contends, we have frequently been wrong.

    Germ Theory, Part II, as conceived by Ewald and his collaborator, Gregory M. Cochran, flows from the timeless logic of evolutionary fitness. Coined by Darwin to refer to the fit between an organism and its environment, the term has come to mean the evolutionary success of an organism relative to competing organisms. Genetic traits that may be unfavorable to an organism's survival or reproduction do not persist in the gene pool for very long. Natural selection, by its very definition, weeds them out in short order. By this logic, any inherited disease or trait that has a serious impact on fitness must fade over time, because the genes that spell out that disease or trait will be passed on to fewer and fewer individuals in future generations. Therefore, in considering common illnesses with severe fitness costs, we may presume that they are unlikely to have a genetic cause. If we cannot track them to some hostile environmental element (including lifestyle), Ewald argues, then we must look elsewhere for the explanation. "When diseases have been present in human populations for many generations and still have a substantial negative impact on people's fitness," he says, "they are likely to have infectious causes."

    Although its fitness-reducing dimensions are difficult to calculate, the ordinary stomach ulcer is the best recent example of a common ailment for which an infectious agent -- to the surprise of almost everyone -- turns out to be responsible.

    When I visited him one afternoon, Ewald pulled off his shelves a standard medical textbook from the 1970s and opened the heavy volume to the entry on peptic ulcers. We squinted together at a gray field of small print punctuated by subheads in boldface. Under "Etiology" we scanned several pages: environmental factors ... smoking ... diet ... ulcers caused by drugs ... aspirin ... psychonomic factors ... lesions caused by stress. In the omniscient tone of medical texts, the authors concluded, "It is plausible to hypothesize a wealth of these factors.... " There was no mention of infection at all.

    In 1981 Barry J. Marshall was training in internal medicine at the Royal Perth Hospital, in Western Australia, when he became interested in incidences of spiral bacteria in the stomach lining. The bacteria were assumed to be irrelevant to ulcer pathology, but Marshall and J. R. Warren, a histopathologist who had previously observed the bacteria, reviewed the records of patients whose stomachs were infected with large numbers of these bacteria. They noticed that when one patient was treated with tetracycline for unrelated reasons, his pain vanished, and an endoscopy revealed that his ulcer was gone.

    An article by Marshall and Warren on their culturing of "unidentified curved bacilli" appeared in the British medical journal The Lancet in 1984, and was followed by other suggestive studies. For years, however, the medical establishment remained deaf to their findings, and around the world ulcer patients continued to dine on bland food, swear off stress, and swill Pepto-Bismol. Finally Marshall personally ingested a batch of the spiral bacteria and came down with painful gastritis, thereby fulfilling all of Koch's postulates.

    There is now little doubt that Helicobacter pylori, found in the stomachs of a third of adults in the United States, causes inflammation of the stomach lining. In 20 percent of infected people it produces an ulcer. Nearly everyone with a duodenal ulcer is infected. H. pylori infections can be readily diagnosed with endoscopic biopsy tests, a blood test for antibodies, or a breath test. In 90 percent of cases the infections can be cured in less than a month with antibiotics. (Unfortunately, many doctors still haven't gotten the news. A Colorado survey found that 46 percent of patients seeking medical attention for ulcer symptoms are never tested for H. pylori by their physicians.)


    The online version of this article appears in three parts. Click here to go to part two. Click here to go to part three.

    Judith Hooper, a former newspaper reporter and magazine editor, is the author of Would the Buddha Wear a Walkman? (1989) and The 3-Pound Universe (1986).

    Illustrations by Dave Jonason

    Copyright © 1999 by The Atlantic Monthly Company. All rights reserved.
    The Atlantic Monthly; February 1999; A New Germ Theory; 283, No. 2; pages 41 - 53.

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