AMHERST, MASS.—Newton had a falling apple. Darwin mused on finches. Paul W. Ewald's inspiration was diarrhea. "I wish I had something more romantic," says the Amherst College evolutionary biologist. It gets uglier: Ewald, then a graduate student studying bird behavior, was camped near a Kansas garbage dump. As he waged a three-day battle against his sea of troubles, he contemplated the interactions between a host—himself, in this case—and a pathogen. "There's some organism in there," Ewald remembers thinking during that 1977 experience, "and this diarrhea might be my way of getting rid of the organism—or it might be the organism's way of manipulating my body" to maximize its chances of passage to the next victim by, for example, contaminating the water supply. "If it's a manipulation and you treat it, you're avoiding damage," he notes. "But if it's a defense and you treat it, you sabotage the host."

 

PAUL W. EWALD: EVOLUTION OF A HOST

Born in Wilmette, Ill., to physicist father, Arno, and psychologist mother, Sara; wife, Christine Bayer, two children Pursued sociobiology but has concentrated on evolutionary medicine; Ph.D. in zoology from University of Washington, 1980 Publishes with freelance physicist Gregory M. Cochran—source of idea about infectious causation of chronic illness Hobby and primary mode of 10-mile commute: bicycling

Host-pathogen relationships have dominated Ewald's thoughts ever since, leading to numerous articles, two books and, depending on whom you talk to, the respect or scorn of scientists and physicians. The admiration comes from those who think he was on to something really big in his earlier publications, which he summed up in his 1994 book Evolution of Infectious Disease. "I think that Paul Ewald has been a pioneer in using evolutionary theory to attack hard questions in pathogenesis," comments Stephen Morse, a virologist and epidemiologist at Columbia University. "His work has, for the first time, shown a way to generate testable hypotheses to study such questions as the evolution of virulence—once thought intractable—and infectious causes of chronic diseases." Indeed, the Atlantic Monthly referred to Ewald as "the Darwin of the microworld" (to which Ewald responds, "No, Darwin is Darwin of the microworld, too").

Any antipathy is the result of his latest research, outlined in last year's Plague Time. The 47-year-old Ewald argued in the book that infection may play a role in cancer, atherosclerosis, Alzheimer's and other chronic conditions ordinarily thought of as inevitable consequences of genetics, lifestyle or aging. "Some of his recent work is controversial," Morse states. "I'd personally prefer to reserve judgment for now on those questions, at least until more data are in." Others are less gracious. One prominent atherosclerosis researcher politely panned Ewald in public but privately referred to his ideas using an eight-letter word, the first half of which is "bull."

In an April 1993 Scientific American article, Ewald smashed the old, and unfortunately still widely accepted, notion that parasites and their hosts inevitably evolve toward a benign coexistence. The tendency toward benignity is reserved for conditions passed directly from person to person. Someone too sick to mingle with others would indeed be a dead end for the most dangerous infections, but Ewald showed that infectious agents that use intermediate vectors for transmission, such as malaria's mosquitoes and cholera's contaminated water, are free to evolve toward greater destructive power. After all, a mosquito is free to feed on the sickest malaria victims and thus pass on the worst pathogens. Even more provocative was Ewald's exegesis on our potential to drive the evolution of pathogens through judicious public health measures. "The evolutionary hypothesis says that if you can make it so that sick people cannot pass on infections and that only healthy people can, you should favor the evolution of more benign strains," he explains.

 

EWALD ponders the evolutionary interplay between microbes and large organisms such as ourselves.

Ewald suggests an experiment that could never be ethically done: "Select two countries, one with bad water and one with clean water, and introduce cholera into both." Theory holds that water in which microbes can thrive serves as a vector that lets dangerous virulence continue or worsen. On the other hand, treated water would kill cholera strains relying on diarrhea for transport; only mild strains would survive because their hosts would be healthy enough to transmit the pathogen directly to other people. "Essentially, that's what happened in 1991," Ewald says, referring to a cholera outbreak in Peru that spread through Latin America. He and his students analyzed cholera from Peru and Guatemala, which has unsafe water, and from Chile, whose water is trustworthy. They found that over the 1990s Chile's cholera did indeed become less virulent, whereas highly toxic strains persisted in the other countries. This concept should motivate public health officials to do things they should already be doing anyway, such as providing safe water and mosquito-proof housing. Although these ideas have yet to permeate medical school curricula fully, they seem beyond reproach theoretically. When Ewald wanders into the fields of chronic disease, however, he steps into some eight-letter castigation. Given evolutionary principles and the available evidence, he argues in Plague Time, infectious agents should be considered as at least part of the etiology of apparently noninfectious conditions. Of course, the connection between Helicobactor pylori and peptic ulcers is now taken for granted, although medical texts of 20 years ago were mute on the subject. Associations between infections and some cancers—hepatitis virus with liver cancer, papillomavirus with cervical cancer—have become accepted in only the past few decades. Ewald thinks that more cancers, perhaps the majority, as well as numerous other common, widespread and ancient chronic diseases, will eventually become linked with various infections: for atherosclerosis and Alzheimer's disease, he points to studies showing associations with Chlamydia pneumoniae. He even holds that schizophrenia may be related to infection with the protozoan Toxoplasma gondii.

"People have put much more emphasis on genetic causation and noninfectious environmental causation," Ewald says. "And when they find evidence that those kinds of causation are occurring, then they make this fundamental error in science: throwing out a hypothesis [infection] just because you have evidence that other hypotheses are probably at least partly right." Disease instead may result from a subtle interplay between a gene's product and an infectious agent.

Arguably, natural selection should have gotten rid of most of the solely genetic diseases long ago. (Genetic conditions such as sickle-cell disease get an evolutionary pass, however: one copy of the gene protects against disease—malaria, in the case of sickle cell—so the potentially destructive gene will survive in a population.) The standard argument is that genes that cause illness after the prime reproductive years don't get selected against. Ewald counters by arguing that the elderly—and he believes that there were always people who would be considered old by today's standards, even at times when life was supposed to be "nasty, brutish and short"—were important sources of information and caregiving, and evolution does indeed try to keep them around.

To find possible infectious relationships to seemingly noninfectious diseases, Ewald suggests the creation of a program akin to that used to monitor adverse reactions to vaccines: what he calls the Effects of Antimicrobials Reporting System, or EARS. Physicians worldwide may be sitting on a gold mine of data, in the form of anecdotes about remissions that accompany antibiotic treatment for a concurrent condition. "If you accumulate the shared experiences, real cause and effect should pop out," he says. "Then we'd know if this was something we should do a controlled study on."

Ewald believes that the associations between chronic diseases and infections will be slowly accepted, perhaps in a few decades. Should his viewpoint prevail some distant day, he may repeat the words his physicist father once spoke. The elder Ewald, recovering from a heart attack when Paul's 1993 article appeared in this, his favorite publication, said, "Well, this was worth living for."

PHOTOGRAPHS by Kathleen Dooher; skeleton located at Pratt Museum of Natural History, Amherst College

--By Steve Mirsky