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F E B R U A R Y  1 9 9 9

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

The Great Synthesizer

AS of this writing, the ideas at the core of Germ Theory, Part II, have been presented by Ewald mostly in the form of lectures, and in communications with colleagues. The papers in which the ideas will be formally articulated are in preparation. Given Ewald's prominence, the ideas are bound to cause a stir. They will also draw criticism. In the medical sciences, where "theory" is a bad word and "Stick to the data" is the reigning motto, Ewald will come under particular scrutiny because his hypothesis arrives detached from a vast corpus of laboratory data. It is helpful to think of Ewald as continuing the tradition of the great scientific synthesizers. Darwin himself was a synthesizer extraordinaire, who composed the thesis of The Origin of Species largely out of hundreds of odds and ends contributed by others, from pigeon breeders to naturalists. "Professor So-and-so has observed ... " is a recurring motif in Darwin's book.

Ewald's theory about evolution and infectiousness provides a framework that potentially unites diverse research on the front lines of various afflictions. Ulcers and heart disease have already been mentioned. Here are two more: cancer and mental illness.

In 1910 a man named Peyton Rous discovered the eponymous Rous sarcoma virus, demonstrating that chickens infected with it developed cancer. Over the years many other cancer viruses have been discovered in animals. And yet until 1979, despite broad hints from the animal world, not a single human cancer was generally accepted as infectious. Rous had been lucky: his chickens became sick only two weeks after infection. Human cancers follow a more languorous course, which means that by the time symptoms show up, any infectious causation may well be buried under a lifetime of irrelevant risk factors.

In 1979 HTLV-1, a retrovirus endemic in parts of Asia, Africa, and the Caribbean, and transmitted either sexually or from mother to child, was linked to certain leukemias and lymphomas; the cancer appeared decades after infection. The Epstein-Barr virus (the agent that causes mononucleosis) has now been associated with some B-cell lymphomas, with a nasopharyngeal cancer common in south China, and with Burkitt's lymphoma, a deadly childhood cancer of Africa. Some 82 percent of all cases of cervical cancer have been associated with the sexually transmitted human papilloma virus, a once relatively innocent-seeming pathogen responsible for genital warts.

H. pylori, the ulcer pathogen, confers a sixfold greater risk of stomach cancer, and accounts for at least half of all stomach cancers. Also, the lymphoid tissue of the stomach can produce a low-grade gastric lymphoma under the influence of this bacterium. Early reports indicate that the lymphoma is cured in 50 percent of cases by resolving the H. pylori infection -- which may mark the first time in medical history that cancer has been cured with an antibiotic.

Hepatitis B and C, two of the ever-growing alphabet soup of hepatic diseases, have been linked to liver cancer. Herpes virus 8 has recently been discovered to be the cause of Kaposi's sarcoma. "There is no reason to believe that this flurry of discovery has now completed the list of infectious agents of cancer," Ewald says.

Among the many known animal cancer viruses is a closely studied retrovirus known as mouse mammary tumor virus (MMTV), which causes mammary-gland cancer in mice. This virus is transmitted from mother to offspring through mother's milk, lying latent in the daughter's mammary tissue until activated by hormones during her own lactation. Could such a virus be a factor in human breast cancer? In the mid-1980s researchers announced that they had found in malignant human breast tumors a DNA sequence resembling MMTV, but the excitement waned when the same sequence was found in normal breast tissue as well. Interest has been revived by the research of Beatriz G-T. Pogo, a professor in the departments of medicine and microbiology at Mount Sinai School of Medicine, in New York. Examining some 400 to 500 breast-cancer samples, she has found DNA sequences resembling MMTV that are not present in normal tissue or in other human cancers. She remains guarded about the implications.

Can You "Catch" Schizophrenia?

MICROBES obviously can cause mental disorders -- as syphilitic dementia, to name but one example, makes brutally clear. But most post-Freudian discussions of psychiatric dysfunction have tended not to invoke infection. Recently, however, some cases of childhood obsessive compulsive disorder (OCD) have hinted at a new set of possibilities. Children who have this disease may compulsively count the crayons in their book bags over and over again, or meticulously avoid each crack in the pavement, in order to ward off some imagined evil. Susan E. Swedo, of the National Institute of Mental Health, in Bethesda, Maryland, noticed strong resemblances between OCD and a disease called Sydenham's chorea, formerly known as Saint Vitus's dance, which, like rheumatic heart disease, is a rare complication of an untreated streptococcal infection. Streptococcal antibodies find their way into the brain and attack a region called the basal ganglia, causing characteristic clumsiness and arm-flapping movements along with obsessions, compulsions, senseless rituals, and idées fixes. Could some cases of childhood OCD be a milder version of this illness? The hunch paid off. In the early 1990s a new syndrome, known as PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), was recognized.

Some children with OCD get better when they are given intravenous immunoglobulin or undergo therapeutic plasma exchange to remove the antibodies from their blood. It is not known whether adult-onset OCD -- whose most famous avatar was the germ-phobic Howard Hughes -- also results from some sort of infection. But it is certainly provocative that a mental disorder can result from a lingering immune response. The phenomenon makes some people wonder about schizophrenia.

For years, amid the smorgasbord of theories about the etiology of schizophrenia, there has been recurring speculation about a schizophrenia virus. Karl Menninger wondered in the 1920s if schizophrenia might result from a flu infection. Later researchers pointed to data that showed seasonal and geographic patterns in the births of schizophrenics, suggestive of infection -- though it must be said that the viral theorists were largely regarded as inhabiting the fringe. Genetic theories grabbed center stage, and by the 1990s most researchers were pinning their hopes on the genetic markers being identified in the Human Genome Project.

In Ewald and Cochran's view, evolutionary laws dictate that infection must be a factor in schizophrenia. "They announced they had the gene for schizophrenia, and then it turned out not to be true," Cochran said one day when I mentioned genetic markers. "I think they found and unfound the gene for depression about six times. Nobody's found a gene yet for any common mental illness. Maybe instead of the Human Genome Project we should have the Human Germ Project." Cochran is endorsing a suggestion made by several scientists in a recent issue of Nature. "I don't mean to say that the Human Genome Project isn't worthwhile for many reasons, but all the genes we've found have been for rare diseases. I don't think the common diseases are going to turn out that way."

Schizophrenia affects about one percent of the population, and thus in Ewald and Cochran's scheme is too common for a genetic disease that profoundly impairs fitness. As noted, the background mutation rate -- the ratate which a gene spontaneously mutates -- is typically about one in 50,000 to one in 100,000. Not surprisingly, genetic diseases that are severely fitness-impairing (for example, achondroplastic dwarfism) tend to have roughly the same odds, depending on the gene. (In a few cases, however, the gene involved may be especially error-prone, resulting in a higher frequency of mishaps. One of the most common genetic diseases, Duchenne's muscular dystrophy, afflicts boys at a rate of one in 7,000, reflecting the fragility of an uncommonly long gene.)

From the fitness perspective, schizophrenia is a catastrophe. It is estimated that male schizophrenics have roughly half as many offspring as the general population has. Female schizophrenics have roughly 75 percent as many. Schizophrenia should therefore approach the level of a random mutation after many generations. (To explain this away, some genetic theorists have proposed that in hunter-gatherer cultures schizophrenics were the tribal shamans -- desirable as sexual partners -- and thus did not incur a reproductive disadvantage.)

No one has found a schizophrenia virus yet, but some think they may be close. Following a tip from Ewald and Cochran, I typed "Borna virus" into my online search engine and ended up with a stack of scientific papers. Borna virus was first recognized as the cause of a neurologic disease in horses, and can infect nearly all warm-blooded animals, from birds to primates. Horses and other animals infected with Borna virus may exhibit depressed or apathetic behavior, weakness of the legs, abnormal body postures, or a staggering gait. Borna-infected laboratory rats exhibit learning disorders, exaggerated startle responses, and hyperactivity, among other things.

Royce Waltrip, an associate professor of psychiatry at the University of Mississippi with an expertise in virology, studies Borna virus. Despite being leery of a rash of inconsistent studies associating Borna virus with schizophrenia, Waltrip believes that "there is something there, though I don't know if it's a perinatal infection or an adult infection or what." When he started looking for antibodies to Borna in mental patients, he found that 14 percent of the schizophrenic patients had antibodies to two or three Borna proteins, whereas none of the healthy controls did. Waltrip speculates that Borna virus is not the cause of schizophrenia. "I think that schizophrenia is an etiologically heterogeneous disease," he said. "I think there are a finite number of ways the brain can respond to injury. There are probably different routes to schizophrenia, and there is probably more than one infectious pathway." One route, he hypothesizes, is Borna virus.

Ewald and Cochran do not doubt that multiple pathogens or multiple factors may be implicated in some broad disease syndromes, among them schizophrenia. But they worry, in general, that the "multifactorial"argument has become too facile a response. "That's what they always say when they don't know the cause of a disease," Cochran said on the phone. "They say it's multifactorial. Ulcers and heart disease were supposed to be multifactorial. But they're infections! Tuberculosis was supposed to be multifactorial. It's an infection!"

I happened to be visiting Ewald in his office when Cochran called, so we were having a three-way conversation, with Cochran's voice echoing over the static on a speaker phone. Outside the window the scene was shifting subtly into mid-autumn. Patches of orange and rust speckled the blue-green flanks of the Holyoke hills, and the students on the playing fields were wearing sweatpants.

But what about random accidents in utero as a cause of schizophrenia? I asked. Some kind of damage to the wiring?

"You'd have to say what caused the damage," Ewald responded, pointing out that the word "random" is often used to refer to something we haven't been able to understand. He noted once again how widespread schizophrenia is. "At this frequency -- one percent of the population -- we'd expect that natural selection would have led to protective mechanisms."

The same holds true for severe depression, Ewald believes. A tendency toward suicide doesn't make evolutionary sense in a world of organisms driven by the twin urgencies of survival and reproduction. The relentless engine of natural selection should have eliminated any genes that infringed on them. So why are these fitness-antagonistic traits still around?
From the archives:

  • "Homosexuality and Biology," by Chandler Burr (March, 1993)
    An introduction to a muddled and sometimes contentious world of scientific research -- one whose findings, now as tentative as they are suggestive, may someday shed light on the sexual orientation of everyone.

  • This leads to a subject that Ewald is not shy about bringing up in discussions with colleagues and in professional lectures: homosexuality. Various pieces of evidence have been adduced in recent years, by prominent researchers, for some sort of genetic component to homosexuality. The question arises as to whether natural selection would sustain a homosexual trait in the gene pool for any length of time. The best estimates of the fitness cost of homosexuality hover around 80 percent: in other words, gay men (in modern times, at least) have only 20 percent as many offspring as heterosexuals have. Simple math shows how quickly an evolutionarily disadvantageous trait like this should dwindle, if it is a simple genetic phenomenon. The researchers Richard Pillard, at the Boston University School of Medicine, and Dean Hamer, at the National Cancer Institute, are not persuaded that natural selection would necessarily have eliminated a homosexual trait, and offer ingenious counterarguments. (And they note that historically the fitness cost may not have been very high, when gay men stayed in the closet, married, and had children.)

    No one, of course, has ever isolated a bacterium or a virus responsible for sexual orientation, and speculations about the manner in which such an agent would be transmitted can be nothing more than that. But Ewald and Cochran contend that the severe "fitness hit" of homosexuality is a red flag that should not be ignored, and that an infectious process should at least be explored. "It's a very sensitive subject,"Ewald admits, "and I don't want to be accused of gay-bashing. But I think the idea is viable. What scientists are supposed to do is evaluate an idea on the soundness of the logic and the testing of the predictions it can generate."

    The Search for Telltale Signs

    AFTER I had spent time talking to Ewald and Cochran and reading back issues of the journal Emerging Infectious Diseases, everything began to look infectious to me. The catalogue of suspected chronic diseases caused by infection, according to David A. Relman, an assistant professor of medicine, microbiology, and immunology at Stanford University, now includes "sarcoidosis, various forms of inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, Wegener's granulomatosis, diabetes mellitus, primary biliary cirrhosis, tropical sprue, and Kawasaki disease." Ewald and Cochran's list of likely suspects would include all of the above plus many forms of heart disease, arteriosclerosis, Alzheimer's disease, many if not most forms of cancer, multiple sclerosis, most major psychiatric diseases, Hashimoto's thyroiditis, cerebral palsy, polycystic ovary disease, and perhaps obesity and certain eating disorders. From an evolutionary perspective, Cochran says, anorexia is strikingly inimical to the survival principle. "I mean, not to eat -- what would cause that?"

    "In all these situations you look for little signs of infectious spread," Ewald said in his office. "Is there geographic variation? Temporal variation? Does it go up or down across decades? Multiple sclerosis seems pretty clearly infectious, because you have these island populations where there was no MS and then you see it spread like a wave through the population. And you have this latitudinal gradient ... "

    "Yes!" Cochran burst from the speaker phone. "The farther you get from the Equator, the more common it is. It's three to four times more common if you grow up in Ontario than if you grow up in Mississippi. Some people have tried to say that's because Canadians are genetically different from Americans."

    I downloaded a paper about extremely high rates of multiple sclerosis in the Shetland and Orkney Islands and other regions of Scotland, and I made a mental note of the many Canadian Web sites devoted to MS. Like other autoimmune diseases, MS looks suspiciously infectious for a number of reasons: epidemiological evidence of childhood exposure to disease agents, geographic clusters, abnormal immune responses to a variety of viruses, resemblances to animal models and human diseases with a relapsing-remitting course. And, in fact, a virus has been nominated: the human herpes virus 6, the agent of roseola infantum, a very mild disease of childhood. The connection, however, is by no means proved.

    "No doubt everywhere people look there will be more and more examples of chronic diseases with infectious etiology," says Stephen S. Morse, an expert in infectious diseases at the Columbia University School of Public Health. "Helicobacter is probably the tip of the iceberg." Although we have wielded the tools of microbial cultivation for a hundred years, much of the microbial world is still as mysterious as an alien planet. "It has been estimated that only 0.4 percent of all extant bacterial species have been identified," David Relman has written. "Does this remarkable lack of knowledge pertain to the subset of microorganisms both capable of and accomplished in causing human disease?" Even the germs that inhabit our bodies -- the so-called "human commensal flora," such as the swarming populations of organisms that live in the spaces between our teeth -- are largely unknown, he points out. Most of them are presumably benign, up to a point. There are disquieting suggestions in the literature of a link between bacteria in dental plaque and coronary disease.

    "Some people think it's scary to have these time bombs in our bodies," Ewald says, "but it's also encouraging -- because if it's a disease organism, then there's probably something we can do about it. The textbooks say, In 1900 most people died of infectious diseases, and today most people don't die of infectious disease; they die of cancer and heart disease and Alzheimer's and all these things. Well, in ten years I think the textbooks will have to be rewritten to say, "Throughout history most people have died of infectious disease, and most people continue to die of infectious disease."

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

    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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