A New Germ Theory

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
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(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.
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.

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.

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