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F E B R U A R Y 1 9 9 9
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
by Judith Hooper
ALATE-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-brickbuildings 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 thatcauses cholera were growing nearby, in the Life Sciences Building. If they had known, they wouldprobably not have grasped the implications. But these particular strains of cholera make Paul Ewaldsmile; they are strong evidence that he is on the right track. Knowing the rules of evolutionarybiology, 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 thehome of Amherst's biology department, where Paul Ewald is a professor. He is also the author ofthe 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-fiveyears. Conspicuously outdoorsy for an academic, he would not seem out of place in an L. L. Beancatalogue, with a golden retriever by his side. Ewald rides his bike to the campus every day indecent weather -- and in weather one might not consider decent -- from the nearby hill village ofShutesbury, 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, fromprotozoa to Presidents, and yet its essence is simple and transparent. "Darwin only had a couple ofbasic tenets," Ewald observed recently in his office. "You have heritable variation, and you've gotdifferences 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 fundamentalorganizing 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 amoment 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 aspecies called Harris's sparrow in Kansas that a bad case of diarrhea laid himup for a few days and changed the course of his career. The more hemeditated on how Darwinian principles might apply to the organismsresponsible for his distress -- asking himself, for instance, what impacttreating the diarrhea would have on the vast populations of bacteria evolvingwithin his intestine -- the more obsessed he became. Was his diarrhea astrategy used by the pathogen to spread itself, he wondered, or was it adefense 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 theJournal 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 causedisease. The time scale is so much shorter and the selective pressures so much more intense. You canget evolutionary change in disease organisms in months or weeks. In something like zebras you'dhave 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 pathogenitself toward mildness, because it is in the germ's interest to keep its host alive. This soundsplausible, but it happens to be wrong. The Darwinian struggle of people and germs is notnecessarily so benign. Evolutionary change in germs can go either way, as parasitologists andpopulation geneticists have realized -- toward mildness or toward virulence. It was Ewald's insightto 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 ofthe common cold; or the mycobacterium that causes tuberculosis; or perhaps the pathogen thatimmobilized 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 yourhost before you can spread. If you're the average airborne respiratory virus, it's best if your host iswell 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
Paul Ewald
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 fortransmission: it is generally waterborne, traveling easily by way of fecal matter shed into the watersupply. 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 industrialrefrigerators after their arrival from hospitals in Peru, Chile, and Guatemala. "We always weargloves." A medical-school-bound senior from the Boston suburbs, Saunders is one of Ewald's honorstudents. As she guided me around, pointing out centrifuges, -80 degree freezers, and doors withBIOHAZARD warnings, we passed a closet-sized room as hot and steamy as the tropical zoneswhere hemorrhagic fevers thrive. She said, "This is the incubation room, where we grow thecholera." 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 hadpresented to the assembled biology department her honors project, "Geographical Variations in theVirulence 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 toyour advantage. Saunders used a standard assay, called ELISA, to measure the amount of toxinproduced 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 -- whatpercentage of the population had potable water, for example -- and looked for correlations. Ifvirulent strains correlated with a contaminated water supply, and if, conversely, mild strains tookover 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 throughfecal matter in the water system, its transmission depends on infected people moving into contactwith healthy ones. In this scenario the less-toxic variants would prevail, because these strains do notincapacitate or kill the host before they can be spread to others. If this turned out to be true, itwould 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 howquickly 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 wecan also change the organism itself. If you can make an organism very mild, it works like a naturalvaccine against the virulent strains. That's the most preventive of preventive medicine: when youcan change the organism so it doesn't make you sick." Strains of the cholera agent isolated fromTexas and Louisiana produce such small amounts of toxin that almost no one who is infected withthem will come down with cholera. 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 ofan evolutionary theory to public health could save millions of lives. It's astunning idea. If we're able to manipulate the evolutionary trajectory of ourfriends -- domestic animals and crops -- why not do the same with ourenemies, with cholera, malaria, and HIV? As Thomas Huxley said when heread Darwin, "How stupid of me not to have thought of that before." Ithought when I heard Paul's idea, "Gee, why didn't Ithink 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 inDarwinian medicine or its equivalent. "I regard him as a major figure in thefield," says Robert Trivers, a prominent evolutionary biologist who holdsprofessorships in anthropology and biology at Rutgers University. "It is ashame his work isn't better known to the public-health and medical
establishments, who are willfully ignorant of evolutionary logic throughout their training." Whilepraising Ewald's boldness and originality, some of his peers caution that his data need to beindependently corroborated, and others object that his hypotheses are too crude to capture theteeming complexity of microbial evolution. "Evolutionary biologists have had very poor success inexplaining how an organism evolves in response to its environment," says James Bull, anevolutionary geneticist at the University of Texas. "Trying to understand a two-species interactionshould 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 ofhumanity's chronic and most baffling illnesses. Ewald's view, to put it simply, is that the culpritswill 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 RobertKoch, took medicine out of the Dark Ages. It wasn't "bad air" or "bad blood" that causeddiseases 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 alsorevolutionized medical epidemiology by laying out his famous four postulates, which have set thestandard 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) injectedinto a healthy experimental animal, producing the disease in question; and then (d) recovered fromthe 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, andTB, were understood to be caused by pathogens. Vaccines were devised against some, and by the1950s antibiotics could easily cure many others. Smallpox was actually wiped off the face of theearth (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 infectiousdisease is that it will be very dull." At least in the developed world, infectious diseases no longerseemed very threatening. Far scarier were the diseases that the medical world said were notinfectious: heart disease, cancer, diabetes, and so on. No one foresaw the devastation of AIDS, or theserial 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,"Byguiding 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 chanceof fulfilling the postulates." That is, just because we couldn't readily discover their cause, we ratherarbitrarily decided that the so-called chronic diseases of the late twentieth century must behereditary or environmental or "multifactorial." And, Ewald contends, we have frequently beenwrong. 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 organismand its environment, the term has come to mean the evolutionary success of an organism relative tocompeting organisms. Genetic traits that may be unfavorable to an organism's survival orreproduction 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 impacton fitness must fade over time, because the genes that spell out that disease or trait will be passedon to fewer and fewer individuals in future generations. Therefore, in considering common illnesseswith severe fitness costs, we may presume that they are unlikely to have a genetic cause. If wecannot track them to some hostile environmental element (including lifestyle), Ewald argues, thenwe must look elsewhere for the explanation. "When diseases have been present in humanpopulations 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 almosteveryone -- 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 agray field of small print punctuated by subheads in boldface. Under "Etiology" we scanned severalpages: 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. Thebacteria were assumed to be irrelevant to ulcer pathology, but Marshall and J. R. Warren, ahistopathologist who had previously observed the bacteria, reviewed the records of patients whosestomachs were infected with large numbers of these bacteria. They noticed that when one patientwas treated with tetracycline for unrelated reasons, his pain vanished, and an endoscopy revealedthat 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 worldulcer patients continued to dine on bland food, swear off stress, and swill Pepto-Bismol. FinallyMarshall 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 90percent 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 patientsseeking medical attention for ulcer symptoms are never tested for H. pylori by their physicians.) Antibiotics Against Heart Disease? EWALD closed the medical textbook on his knee. "This was
published twenty years ago," he said. "If we looked up'atherosclerosis' in a textbook from ten years ago, we'd
find the same kind of things -- stress, lifestyle, lots about diet,nothing about infection." Heart disease is now being linked to Chlamydia pneumoniae, a
newly discovered bacterium that causes pneumonia andbronchitis. The germ is a relative of Chlamydia trachomatis, which
causes trachoma, a leading cause of blindness in parts of theThird World. C. trachomatis is perhaps more familiar to us as a
sexually transmitted disease that, left untreated in women, canlead to scarring of the fallopian tubes, pelvic inflammatorydisease, ectopic pregnancy, and tubal infertility. Pekka Saikku and Maija Leinonen, a Finnish husband-and-wife
team who have evoked comparisons to the Curies, discovered the new type of chlamydial infectionin 1985, though its existence was not officially recognized until 1989. Saikku and Leinonen foundthat 68 percent of Finnish patients who had suffered heart attacks had high levels of antibodies to C.
pneumoniae, as did 50 percent of patients with coronary heart disease, in contrast to 17 percent of the
healthy controls. "We were mostly ignored or laughed at," Saikku recalls. While examining coronary-artery tissues at autopsy in 1991, Allan Shor, a pathologist in
Johannesburg, saw "pear-shaped bodies" that looked like nothing he'd ever seen before. Hementioned his observations to a microbiologist colleague, who had read about a new species ofchlamydia with a peculiar pear shape. The colleague referred Shor to an expert on the subject, Cho-Chou Kuo, of the University of Washington School of Public Health, in Seattle. After Shor shippedKuo the curious coronary tissue, Kuo found that the clogged coronary arteries were full of C.
pneumoniae. Before long, others were reporting the presence of live C. pneumoniae in arterial plaque
fresh from operating tables. Everywhere the bacterium lodges, it appears to precipitate the samegrim sequence of events: a chronic inflammation, followed by a buildup of plaque that occludes theopening of the artery (or, in the case of venereal chlamydia, a buildup of scar tissue in the fallopiantube). Recently a team of pathologists at MCP-Hahnemann School of Medicine, in Philadelphia,found the same bacterium in the diseased sections of the autopsied brains of patients who had hadlate-onset Alzheimer's disease: it was present in seventeen of nineteen Alzheimer's patients and inonly one of nineteen controls. By the mid-1990s a radical new view was emerging of atherosclerosis as a chronic, lifelong arterial
infection. "I am confident that this will reach the level of certainty of ulcer and H. pylori, " says
Saikku, who estimates that at least 80 percent of all coronary heart disease is caused by thebacterium. Big questions remain, of course. Studies show that about 50 percent of U.S. adults carryantibodies to C. pneumoniae -- but how many will develop heart disease? Even if heart patients can
be shown to have antibodies to C. pneumoniae, and even if colonies of the bacteria are found living
and breeding in diseased coronary arteries, is it certain that the germ caused the damage? Perhaps
it's an innocent bystander, as some critics have proposed; or a secondary, opportunistic infection. But suppose that a Chlamydia pneumoniae infection during childhood can initiate a silent, chronic
infection of the coronary arteries, resulting in a "cardiovascular event" fifty years later. Couldantibiotics help to address the problem? A few early studies suggest they might. Researchers in Salt Lake City infected white rabbits with C.
pneumoniae, fed them a modestly cholesterol-enhanced diet, killed them, and found thickening of the
thoracic aortas, in contrast to the condition of uninfected controls fed the same diet. Additionally,treatment of infected rabbits with antibiotics in the weeks following infection prevented thethickening. Saikku and colleagues reported a similar finding, also in rabbits. Coronary patients inEurope who were treated with azithromycin not only showed a decline in antibodies and othermarkers of infection but in some studies had fewer subsequent cardiovascular events than patientswho were given placebos. (These findings are preliminary; in a few years we may know more. Thefirst major clinical trial is under way in the United States, sponsored by the National Institutes ofHealth and the Pfizer Corporation: 4,000 heart patients at twenty-seven clinical centers will be giveneither the antibiotic azithromycin or a placebo and followed for four years to gauge whether theantibiotic affects the incidence of further coronary events.) Smoking, stress, cholesterol, and heredity all play a role in heart disease. But imagine if our No. 1
killer -- with its vast culture of stress-reduction theories, low-fat diets, high-fiber cereals, cholesterol-lowering drugs, and high-tech bypass surgery -- could in many instances be vanquished with anantibiotic. Numerous precedents exist for long-smoldering bacterial infections with consequencesthat appear months or years later. Lyme disease, leprosy, tuberculosis, and ulcers have a similarcourse. Ewald is confident that the association of C. pneumoniae and heart disease is real. He doesn't
believe that the germ is an innocent bystander. "It reminds you a lot of gonorrhea in the 1890s," hesays. "When they saw the organism there, people said, 'Well, we don't know if it's really causing thedisease, or is just living there.' Every month the data are getting stronger. This is a smoking gun, justlike Helicobacter. " Evolutionary Byways
IHAVE a motto," Gregory Cochran told me recently. "'Big old diseases are
infectious.' If it's common, higher than one in a thousand, I get suspicious.And if it's old, if it has been around for a while, I get suspicious." The fact that Ewald has dared to conceive of a big theory for the medical
sciences owes much to Cochran's contributions. A forty-five-year-old Ph.D.physicist who lives in Albuquerque with his wife and three small children,Cochran makes a living doing contract work on advanced optical systems forweaponry and other devices. Whereas Ewald is an academic insider, withdepartment meetings to attend and honors theses to monitor, Cochran is asolo player, with an encyclopedic mind (he is a former College Bowl
contestant) and a manner that verges on edginess. These days he spends a lot
of time at his computer, as rapt as a conspiracy theorist, cruising Medline for new data on infectiousdiseases and, one imagines, almost cackling to himself when he finds something really good.Cochran's background in a field dominated by grand theories and universal laws may serve as avaluable counterpoint to the empirical and theory-hostile universe of the health sciences. Ewald and Cochran encountered each other serendipitously, after Cochran decided to pursue a
certain line of thinking about a very sensitive subject. "I was reading an article in Scientific American
in 1992 about pathogens manipulating a host to get what they want," Cochran recalls. "It described aflowering plant infected by a fungus, and the fungus hijacks the plant's reproductive machinery so
Gregory Cochran
that instead of pollen it produces fungal spores. I thought, Could it be? " Cochran strayed from his
field to try his hand at writing an article on biology -- elaborating an audacious theory that humanhomosexuality might result from a "manipulation" of a host by a germ with its own agenda. He senthis draft to a prestigious biology journal, which sent it out to three scientists for peer review. Twowere unconvinced, even appalled; the third was Paul Ewald, who thought the article was flawedbut who was nonetheless impressed by the logic of the idea. The article was rejected, but Ewald andCochran began their association. To illustrate his thinking about infectiousness and disease, Cochran not long ago gave me a tour of
his conceptual bins, into which he sorts afflictions according to their fitness impact. Remember thatfitness can be defined as the evolutionary success of one organism relative to competing organisms.Only one thing counts: getting one's genes into the future. Any disease that kills host organismsbefore they can reproduce reduces fitness to zero. Obviously, fitness takes a major hit whenever thereproductive system itself is involved, as in the case of venereal chlamydia. Consider a disease with a fitness cost of one percent -- that is, a disease that takes a toll on survival
or reproduction such that people who have it end up with one percent fewer offspring, on average,than the general population. That small amount adds up. If you have an inherited disease with aone percent fitness cost, in the next generation there will be 99 percent of the original number in thegene pool. Eventually the number of people with the disease will dwindle to close to zero -- or,more precisely, to the rate produced by random genetic mutations: about one in 50,000 to one in100,000. We were considering the bin containing diseases that are profoundly antagonistic to fitness, with a
fitness cost of somewhere between one and 10 percent by Cochran's calculations. My eye took in acatalogue of human ills -- some familiar, some exotic, some historically fearsome but close to extinct,some lethal in the tropics but of little concern to inhabitants of the temperate zones. This list alsoshowed prevailing medical opinion about cause. Each name of a disease was trailed by a lower-caseletter: i(for infectious), g(genetic), g+(genetic defense against an infectious disease), e(caused by an
environmental agent), or u(unknown). I read, "Atherosclerosis ( u), ... chlamydia (venereal) ( i),
cholera ( i), diphtheria ( i), endometriosis ( u), filariasis ( i), G6PD deficiency ( g+), ... hemoglobin E
disease ( g+), hepatitis B ( i), hepatitis C ( i), hookworm disease ( i), kuru ( i), ... malaria (vivax) ( i), ...
pertussis ( i), pneumococcal pneumonia ( i), polycystic ovary disease ( u), scarlet fever ( i), ...
tuberculosis ( i), typhoid ( i), yellow fever ( i)." Of the top forty fitness-antagonistic diseases on the list, thirty-three are known to be directly
infectious and three are indirectly caused by infection; Cochran believes that the others will turn outto be infectious too. The most fitness-antagonistic diseases must be infectious, not genetic, Ewaldand Cochran reason, because otherwise their frequency would have sunk to the level of randommutations. The exceptions would be either diseases that could be the effect of some newenvironmental factor (radiation or smoking, for example), or genetic diseases that balance theirfitness cost with a benefit. Sickle-cell anemia is one example of the latter. Though sickle-cell anemia is strictly heritable according to Mendelian laws, it is widely believed to
have persisted in the population in response to infectious selective pressures. It heads the list ofgenetic diseases that Ewald dubs "self-destructive defenses," in which a disease fatal in itshomozygous form (two copies of the gene) carries an evolutionary advantage to heterozygouscarriers (with one copy), protecting against a terrible infection: in this case falciparum malaria,common in Africa. Similarly, cystic fibrosis, some argue, evolved in northern Europe as a defenseagainst Salmonella typhi, the cause of typhoid fever. Infection thus explains why these deadly genetic
diseases have remained in the human gene pool when they should have died out. But what about something like atherosclerosis? I asked. Leaving aside the evidence concerning C.
pneumoniae, it is not apparent why a genetic cause for atherosclerosis should be dismissed out of
hand on evolutionary grounds. If it hits people in midlife or later, after they have launched theirgenes, how could it possibly affect fitness? Cochran's response illustrates some of the intricacies of evolutionary thinking. "Well, obviously, it's
not as bad as a disease that kills you before puberty, but I think it does have a fitness cost. First ofall, it's really common. Second, people think that all you have to do to pass your genes along is have
children, but that's not true. You still need to raise the offspring to adulthood. In a hunter-gathereror subsistence-farming culture, the fitness impact of dying in midlife might be considerable,especially during bad times, like famines. You've got to feed your family. Also, cardiovasculardisease is a leading cause of impotence, and any disease that makes males impotent at age forty-fivehas got to affect reproduction somewhat." But fifty-year-olds? Sixty-year-olds? Grandmothers do a large proportion of the food-gathering in some tribal cultures, according to
recent anthropological reports. "They aren't hampered by babies anymore, and they don't have to goaround chucking spears like the men," says George C. Williams, a professor emeritus of ecology andevolution at the State University of New York at Stonybrook, and one of the pillars of modernevolutionary biology. "They contribute substantially to the family diet." If long-lived eldershistorically have made a difference by fostering the survival of their descendants, and thereforetheir genes, Cochran figures, then a disease that kills sixty-year-olds could have a fitness impact ofaround one percent. The Cause-and-Effect Conundrum
KNOW what that is?" Ewald asked. We were standing in the main corridor of the Life SciencesBuilding, gazing up at a decorative metalwork frieze that runs along the walls just abovedoor height. A pair of hummingbirds chase each other in a circle. A human eye and an
octopus eye face off. A human hand is juxtaposed with a chimpanzee hand. Ewald pointed tosomething that looked like a daddy longlegs with a video camera for a head. "Some kind of insect? "I ventured. "It's a virus," he said. "See, it's like a spaceship. That" -- he pointed at the head -- "is itsDNA. It injects it inside the cell." There is something unsettling and fascinating about a virus, an organism that is neither strictly alive
nor strictly inanimate, and that replicates by sneaking inside a host cell and commandeering itsmachinery. "Viruses are essentially bits of nucleic acid -- either DNA or RNA -- wrapped in a proteincapsule," Ewald explained. "A retrovirus, like HIV , is an RNA virus with a protein called reversetranscriptase built into it, and once it gets into a cell, it uses the reverse transcriptase to make a DNAcopy of its RNA. This viral DNA copy can insert itself into our DNA, where it can be read by ourprotein-making machinery the same way our own instructions are read." The modus operandi of the world's most feared virus, HIV , is clever, killing its hosts very, very
slowly. A sexually transmitted pathogen, without the luxury of being spread through sneezes orcoughs, must await its few opportunities patiently; if those infected have no symptoms and don'tknow they are sick, so much the better. A mild, chronic form of AIDS had in all likelihood beenaround for centuries in Africa, according to Ewald. Suddenly in the 1970s -- owing to changingpatterns of sexual activity and to population movements -- deadly strains spread in the populationof Central and East Africa. HIV has an extremely high mutation rate, which means that it is continually evolving, even within a
single patient, producing competing strains that fight for survival against the weapons produced bythe immune system. If selective pressures -- in this case a high potential sexual transmission -- have
forced the virus to evolve toward virulence, the opposite selective pressures could do the reverse. Conceivably, we could "tame" HIV , encouraging it to evolve toward comparative harmlessness. Itwas already known that preventive measures such as safe sex, fewer partners, clean needles, and soforth could curb the spread of the disease. But Ewald pointed out early on that social modificationwas a far more potent weapon than anyone realized. Once HIV was cut off from easy access to newhosts, milder strains would flourish -- ones that the host could tolerate for longer and longerperiods. Indeed, Ewald argues, given limited public-health budgets, it might make sense to putmore money into transmission-prevention programs and less into the search for vaccines. (He alsohas strong opinions about how drugs should be used to treat AIDS. He asserts that every time weuse an antiviral drug like AZT, we produce an array of AZT-resistant HIVs in the population; if viralevolution is taken into account, antiviral drugs can be used more judiciously.) Ewald's theories tilt him decidedly toward the optimistic camp. Even in the absence of a vaccine the
AIDS epidemic will not inevitably worsen; it can be curbed without reducing transmission to zero.A natural experiment now occurring in Japan, he says, could be a test case for his theories. In theearly 1990s highly virulent strains of HIV from Thailand took root in Japan, but Ewald predicts thatlow rates of sexual transmission in that country -- due to widespread condom use and other factors-- will act as a selective pressure on these strains so that they evolve toward mildness. If this is true,the trend should become evident over the next ten years. Like HIV , many other viruses have an indolent course, with a long latency between infection and
the development of symptoms. Herpes zoster, the agent of chicken pox, lingers in the body forever,capable of erupting as painful shingles decades later. There are also so-called hit-and-run infections,in which a pathogen or its products disrupt the body's immunological surveillance system; once themicrobes are gone (or when they are present in such low frequency as to be undetectable), theimmune response stays stuck in the "on" mode, causing a lingering inflammation. By the timesymptoms occur, the microorganism itself has disappeared, and its genome will not be detectable inany tissue. "The health sciences are still grappling with the masking effects of long delays between the onset of
infection and the onset of disease," Ewald says. "Any time you have hit-and-run infections, slowviruses, lingering or relapsing infections, or a time lag between infection and symptoms, the causeand effect is going to be very cryptic. You won't find these newly recognized infections by themethods we used to find old infectious diseases. We have to be ready to think of all sorts of new,clever ways to identify pathogens. We will have to abandon Koch's postulates in some cases." 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 whichthe 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 underparticular scrutiny because his hypothesis arrives detached from a vast corpus of laboratory data. Itis helpful to think of Ewald as continuing the tradition of the great scientific synthesizers. Darwinhimself 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 beenmentioned. 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 beendiscovered in animals. And yet until 1979, despite broad hints from the animal world, not a singlehuman cancer was generally accepted as infectious. Rous had been lucky: his chickens became sickonly two weeks after infection. Human cancers follow a more languorous course, which means thatby the time symptoms show up, any infectious causation may well be buried under a lifetime ofirrelevant 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 cancerappeared decades after infection. The Epstein-Barr virus (the agent that causes mononucleosis) hasnow been associated with some B-cell lymphomas, with a nasopharyngeal cancer common in southChina, and with Burkitt's lymphoma, a deadly childhood cancer of Africa. Some 82 percent of allcases 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-gradegastric lymphoma under the influence of this bacterium. Early reports indicate that the lymphoma iscured 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. "Thereis no reason to believe that this flurry of discovery has now completed the list of infectious agents ofcancer," 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 istransmitted from mother to offspring through mother's milk, lying latent in the daughter'smammary tissue until activated by hormones during her own lactation. Could such a virus be afactor in human breast cancer? In the mid-1980s researchers announced that they had found inmalignant human breast tumors a DNA sequence resembling MMTV , but the excitement wanedwhen the same sequence was found in normal breast tissue as well. Interest has been revived by theresearch of Beatriz G-T. Pogo, a professor in the departments of medicine and microbiology atMount 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 otherhuman cancers. She remains guarded about the implications. Can You "Catch" Schizophrenia? MICROBES obviously can cause mental disorders -- as syphilitic dementia, to name but oneexample, makes brutally clear. But most post-Freudian discussions of psychiatricdysfunction have tended not to invoke infection. Recently, however, some cases of
childhood obsessive compulsive disorder (OCD) have hinted at a new set of possibilities. Childrenwho 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 strongresemblances between OCD and a disease called Sydenham's chorea, formerly known as SaintVitus's dance, which, like rheumatic heart disease, is a rare complication of an untreatedstreptococcal infection. Streptococcal antibodies find their way into the brain and attack a regioncalled the basal ganglia, causing characteristic clumsiness and arm-flapping movements along withobsessions, 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 asPANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus), wasrecognized. 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 whetheradult-onset OCD -- whose most famous avatar was the germ-phobic Howard Hughes -- also resultsfrom some sort of infection. But it is certainly provocative that a mental disorder can result from alingering 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 ifschizophrenia might result from a flu infection. Later researchers pointed to data that showedseasonal and geographic patterns in the births of schizophrenics, suggestive of infection -- though itmust be said that the viral theorists were largely regarded as inhabiting the fringe. Genetic theoriesgrabbed center stage, and by the 1990s most researchers were pinning their hopes on the geneticmarkers 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 tobe true," Cochran said one day when I mentioned genetic markers. "I think they found and unfoundthe 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 isendorsing 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 foundhave been for rarediseases. 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 backgroundmutation rate -- the ratate which a gene spontaneously mutates -- is typically about one in 50,000 toone 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 fewcases, however, the gene involved may be especially error-prone, resulting in a higher frequency ofmishaps. One of the most common genetic diseases, Duchenne's muscular dystrophy, afflicts boys ata 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 haveroughly 75 percent as many. Schizophrenia should therefore approach the level of a randommutation after many generations. (To explain this away, some genetic theorists have proposed thatin 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 stackof 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 animalsinfected 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 learningdisorders, 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 associatingBorna virus with schizophrenia, Waltrip believes that "there is something there, though I don't knowif it's a perinatal infection or an adult infection or what." When he started looking for antibodies toBorna in mental patients, he found that 14 percent of the schizophrenic patients had antibodies totwo or three Borna proteins, whereas none of the healthy controls did. Waltrip speculates that Bornavirus is not thecause 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. Thereare probably different routes to schizophrenia, and there is probably more than one infectiouspathway." 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 wassupposed 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 onceagain how widespread schizophrenia is. "At this frequency -- one percent of the population -- we'dexpect 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 andreproduction. The relentless engine of natural selection should have eliminated any genes thatinfringed on them. So why are these fitness-antagonistic traits still around? 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 recentyears, by prominent researchers, for some sort of genetic component to homosexuality. The questionarises as to whether natural selection would sustain a homosexual trait in the gene pool for anylength of time. The best estimates of the fitness cost of homosexuality hover around 80 percent: inother words, gay men (in modern times, at least) have only 20 percent as many offspring asheterosexuals have. Simple math shows how quickly an evolutionarily disadvantageous trait likethis should dwindle, if it is a simple genetic phenomenon. The researchers Richard Pillard, at theBoston University School of Medicine, and Dean Hamer, at the National Cancer Institute, are notpersuaded that natural selection would necessarily have eliminated a homosexual trait, and offeringenious counterarguments. (And they note that historically the fitness cost may not have beenvery 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 morethan that. But Ewald and Cochran contend that the severe "fitness hit" of homosexuality is a red flagthat should not be ignored, and that an infectious process should at least be explored. "It's a verysensitive subject,"Ewald admits, "and I don't want to be accused of gay-bashing. But I think the ideais viable. What scientists are supposed to do is evaluate an idea on the soundness of the logic andthe 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 journalEmerging 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 lupuserythematosus, Wegener's granulomatosis, diabetes mellitus, primary biliary cirrhosis, tropicalsprue, and Kawasaki disease." Ewald and Cochran's list of likely suspects would include all of theabove plus many forms of heart disease, arteriosclerosis, Alzheimer's disease, many if not mostforms of cancer, multiple sclerosis, most major psychiatric diseases, Hashimoto's thyroiditis, cerebralpalsy, polycystic ovary disease, and perhaps obesity and certain eating disorders. From anevolutionary perspective, Cochran says, anorexia is strikingly inimical to the survival principle. "Imean, 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? Multiplesclerosis seems pretty clearly infectious, because you have these island populations where there wasno MS and then you see it spread like a wave through the population. And you have this latitudinalgradient ... "
"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 upin Mississippi. Some people have tried to say that's because Canadians are genetically different fromAmericans." 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 sitesdevoted to MS. Like other autoimmune diseases, MS looks suspiciously infectious for a number ofreasons: epidemiological evidence of childhood exposure to disease agents, geographic clusters,abnormal immune responses to a variety of viruses, resemblances to animal models and humandiseases with a relapsing-remitting course. And, in fact, a virus has been nominated: the humanherpes 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 ColumbiaUniversity 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 isstill as mysterious as an alien planet. "It has been estimated that only 0.4 percent of all extantbacterial species have been identified," David Relman has written. "Does this remarkable lack ofknowledge pertain to the subset of microorganisms both capable of and accomplished in causinghuman 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 -- arelargely unknown, he points out. Most of them are presumably benign, up to a point. There aredisquieting suggestions in the literature of a link between bacteria in dental plaque and coronarydisease. "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 aboutit. The textbooks say, In 1900 most people died of infectious diseases, and today most people don'tdie 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 mostpeople have died of infectious disease, and most people continue to die of infectious disease."
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F E B R U A R Y 1 9 9 9
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
by Judith Hooper
ALATE-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-brickbuildings 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 thatcauses cholera were growing nearby, in the Life Sciences Building. If they had known, they wouldprobably not have grasped the implications. But these particular strains of cholera make Paul Ewaldsmile; they are strong evidence that he is on the right track. Knowing the rules of evolutionarybiology, 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 thehome of Amherst's biology department, where Paul Ewald is a professor. He is also the author ofthe 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-fiveyears. Conspicuously outdoorsy for an academic, he would not seem out of place in an L. L. Beancatalogue, with a golden retriever by his side. Ewald rides his bike to the campus every day indecent weather -- and in weather one might not consider decent -- from the nearby hill village ofShutesbury, 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, fromprotozoa to Presidents, and yet its essence is simple and transparent. "Darwin only had a couple ofbasic tenets," Ewald observed recently in his office. "You have heritable variation, and you've gotdifferences 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 fundamentalorganizing 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 amoment 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 aspecies called Harris's sparrow in Kansas that a bad case of diarrhea laid himup for a few days and changed the course of his career. The more hemeditated on how Darwinian principles might apply to the organismsresponsible for his distress -- asking himself, for instance, what impacttreating the diarrhea would have on the vast populations of bacteria evolvingwithin his intestine -- the more obsessed he became. Was his diarrhea astrategy used by the pathogen to spread itself, he wondered, or was it adefense 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 theJournal 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 causedisease. The time scale is so much shorter and the selective pressures so much more intense. You canget evolutionary change in disease organisms in months or weeks. In something like zebras you'dhave 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 pathogenitself toward mildness, because it is in the germ's interest to keep its host alive. This soundsplausible, but it happens to be wrong. The Darwinian struggle of people and germs is notnecessarily so benign. Evolutionary change in germs can go either way, as parasitologists andpopulation geneticists have realized -- toward mildness or toward virulence. It was Ewald's insightto 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 ofthe common cold; or the mycobacterium that causes tuberculosis; or perhaps the pathogen thatimmobilized 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 yourhost before you can spread. If you're the average airborne respiratory virus, it's best if your host iswell 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
Paul Ewald
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 fortransmission: it is generally waterborne, traveling easily by way of fecal matter shed into the watersupply. 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 industrialrefrigerators after their arrival from hospitals in Peru, Chile, and Guatemala. "We always weargloves. " A medical-school-bound senior from the Boston suburbs, Saunders is one of Ewald's honorstudents. As she guided me around, pointing out centrifuges, -80 degree freezers, and doors withBIOHAZARD warnings, we passed a closet-sized room as hot and steamy as the tropical zoneswhere hemorrhagic fevers thrive. She said, "This is the incubation room, where we grow thecholera. " 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 hadpresented to the assembled biology department her honors project, "Geographical Variations in theVirulence 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 toyour advantage. Saunders used a standard assay, called ELISA, to measure the amount of toxinproduced 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 -- whatpercentage of the population had potable water, for example -- and looked for correlations. Ifvirulent strains correlated with a contaminated water supply, and if, conversely, mild strains tookover 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 throughfecal matter in the water system, its transmission depends on infected people moving into contactwith healthy ones. In this scenario the less-toxic variants would prevail, because these strains do notincapacitate or kill the host before they can be spread to others. If this turned out to be true, itwould 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 howquickly 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 wecan also change the organism itself. If you can make an organism very mild, it works like a naturalvaccine against the virulent strains. That's the most preventive of preventive medicine: when youcan change the organism so it doesn't make you sick. " Strains of the cholera agent isolated fromTexas and Louisiana produce such small amounts of toxin that almost no one who is infected withthem will come down with cholera. 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 ofan evolutionary theory to public health could save millions of lives. It's astunning idea. If we're able to manipulate the evolutionary trajectory of ourfriends -- domestic animals and crops -- why not do the same with ourenemies, with cholera, malaria, and HIV. As Thomas Huxley said when heread Darwin, "How stupid of me not to have thought of that before. " Ithought when I heard Paul's idea, "Gee, why didn't Ithink 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 inDarwinian medicine or its equivalent. "I regard him as a major figure in thefield," says Robert Trivers, a prominent evolutionary biologist who holdsprofessorships in anthropology and biology at Rutgers University. "It is ashame his work isn't better known to the public-health and medical
establishments, who are willfully ignorant of evolutionary logic throughout their training. " Whilepraising Ewald's boldness and originality, some of his peers caution that his data need to beindependently corroborated, and others object that his hypotheses are too crude to capture theteeming complexity of microbial evolution. "Evolutionary biologists have had very poor success inexplaining how an organism evolves in response to its environment," says James Bull, anevolutionary geneticist at the University of Texas. "Trying to understand a two-species interactionshould 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 ofhumanity's chronic and most baffling illnesses. Ewald's view, to put it simply, is that the culpritswill 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 RobertKoch, took medicine out of the Dark Ages. It wasn't "bad air" or "bad blood" that causeddiseases 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 alsorevolutionized medical epidemiology by laying out his famous four postulates, which have set thestandard 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) injectedinto a healthy experimental animal, producing the disease in question; and then (d) recovered fromthe 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, andTB, were understood to be caused by pathogens. Vaccines were devised against some, and by the1950s antibiotics could easily cure many others. Smallpox was actually wiped off the face of theearth (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 infectiousdisease is that it will be very dull. " At least in the developed world, infectious diseases no longerseemed very threatening. Far scarier were the diseases that the medical world said were notinfectious: heart disease, cancer, diabetes, and so on. No one foresaw the devastation of AIDS, or theserial 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,"Byguiding 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 chanceof fulfilling the postulates. " That is, just because we couldn't readily discover their cause, we ratherarbitrarily decided that the so-called chronic diseases of the late twentieth century must behereditary or environmental or "multifactorial. " And, Ewald contends, we have frequently beenwrong. 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 organismand its environment, the term has come to mean the evolutionary success of an organism relative tocompeting organisms. Genetic traits that may be unfavorable to an organism's survival orreproduction 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 impacton fitness must fade over time, because the genes that spell out that disease or trait will be passedon to fewer and fewer individuals in future generations. Therefore, in considering common illnesseswith severe fitness costs, we may presume that they are unlikely to have a genetic cause. If wecannot track them to some hostile environmental element (including lifestyle), Ewald argues, thenwe must look elsewhere for the explanation. "When diseases have been present in humanpopulations 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 almosteveryone -- 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 agray field of small print punctuated by subheads in boldface. Under "Etiology" we scanned severalpages: 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. Thebacteria were assumed to be irrelevant to ulcer pathology, but Marshall and J. R. Warren, ahistopathologist who had previously observed the bacteria, reviewed the records of patients whosestomachs were infected with large numbers of these bacteria. They noticed that when one patientwas treated with tetracycline for unrelated reasons, his pain vanished, and an endoscopy revealedthat 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 worldulcer patients continued to dine on bland food, swear off stress, and swill Pepto-Bismol. FinallyMarshall 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 90percent 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 patientsseeking medical attention for ulcer symptoms are never tested for H. pylori by their physicians. ) Antibiotics Against Heart Disease. EWALD closed the medical textbook on his knee. "This was
published twenty years ago," he said. "If we looked up'atherosclerosis' in a textbook from ten years ago, we'd
find the same kind of things -- stress, lifestyle, lots about diet,nothing about infection. " Heart disease is now being linked to Chlamydia pneumoniae, a
newly discovered bacterium that causes pneumonia andbronchitis. The germ is a relative of Chlamydia trachomatis, which
causes trachoma, a leading cause of blindness in parts of theThird World. C. trachomatis is perhaps more familiar to us as a
sexually transmitted disease that, left untreated in women, canlead to scarring of the fallopian tubes, pelvic inflammatorydisease, ectopic pregnancy, and tubal infertility. Pekka Saikku and Maija Leinonen, a Finnish husband-and-wife
team who have evoked comparisons to the Curies, discovered the new type of chlamydial infectionin 1985, though its existence was not officially recognized until 1989. Saikku and Leinonen foundthat 68 percent of Finnish patients who had suffered heart attacks had high levels of antibodies to C. pneumoniae, as did 50 percent of patients with coronary heart disease, in contrast to 17 percent of the
healthy controls. "We were mostly ignored or laughed at," Saikku recalls. While examining coronary-artery tissues at autopsy in 1991, Allan Shor, a pathologist in
Johannesburg, saw "pear-shaped bodies" that looked like nothing he'd ever seen before. Hementioned his observations to a microbiologist colleague, who had read about a new species ofchlamydia with a peculiar pear shape. The colleague referred Shor to an expert on the subject, Cho-Chou Kuo, of the University of Washington School of Public Health, in Seattle. After Shor shippedKuo the curious coronary tissue, Kuo found that the clogged coronary arteries were full of C. pneumoniae. Before long, others were reporting the presence of live C. pneumoniae in arterial plaque
fresh from operating tables. Everywhere the bacterium lodges, it appears to precipitate the samegrim sequence of events: a chronic inflammation, followed by a buildup of plaque that occludes theopening of the artery (or, in the case of venereal chlamydia, a buildup of scar tissue in the fallopiantube). Recently a team of pathologists at MCP-Hahnemann School of Medicine, in Philadelphia,found the same bacterium in the diseased sections of the autopsied brains of patients who had hadlate-onset Alzheimer's disease: it was present in seventeen of nineteen Alzheimer's patients and inonly one of nineteen controls. By the mid-1990s a radical new view was emerging of atherosclerosis as a chronic, lifelong arterial
infection. "I am confident that this will reach the level of certainty of ulcer and H. pylori, " says
Saikku, who estimates that at least 80 percent of all coronary heart disease is caused by thebacterium. Big questions remain, of course. Studies show that about 50 percent of U. S. adults carryantibodies to C. pneumoniae -- but how many will develop heart disease. Even if heart patients can
be shown to have antibodies to C. pneumoniae, and even if colonies of the bacteria are found living
and breeding in diseased coronary arteries, is it certain that the germ caused the damage. Perhaps
it's an innocent bystander, as some critics have proposed; or a secondary, opportunistic infection. But suppose that a Chlamydia pneumoniae infection during childhood can initiate a silent, chronic
infection of the coronary arteries, resulting in a "cardiovascular event" fifty years later. Couldantibiotics help to address the problem. A few early studies suggest they might. Researchers in Salt Lake City infected white rabbits with C. pneumoniae, fed them a modestly cholesterol-enhanced diet, killed them, and found thickening of the
thoracic aortas, in contrast to the condition of uninfected controls fed the same diet. Additionally,treatment of infected rabbits with antibiotics in the weeks following infection prevented thethickening. Saikku and colleagues reported a similar finding, also in rabbits. Coronary patients inEurope who were treated with azithromycin not only showed a decline in antibodies and othermarkers of infection but in some studies had fewer subsequent cardiovascular events than patientswho were given placebos. (These findings are preliminary; in a few years we may know more. Thefirst major clinical trial is under way in the United States, sponsored by the National Institutes ofHealth and the Pfizer Corporation: 4,000 heart patients at twenty-seven clinical centers will be giveneither the antibiotic azithromycin or a placebo and followed for four years to gauge whether theantibiotic affects the incidence of further coronary events. ) Smoking, stress, cholesterol, and heredity all play a role in heart disease. But imagine if our No. 1
killer -- with its vast culture of stress-reduction theories, low-fat diets, high-fiber cereals, cholesterol-lowering drugs, and high-tech bypass surgery -- could in many instances be vanquished with anantibiotic. Numerous precedents exist for long-smoldering bacterial infections with consequencesthat appear months or years later. Lyme disease, leprosy, tuberculosis, and ulcers have a similarcourse. Ewald is confident that the association of C. pneumoniae and heart disease is real. He doesn't
believe that the germ is an innocent bystander. "It reminds you a lot of gonorrhea in the 1890s," hesays. "When they saw the organism there, people said, 'Well, we don't know if it's really causing thedisease, or is just living there. ' Every month the data are getting stronger. This is a smoking gun, justlike Helicobacter. " Evolutionary Byways
IHAVE a motto," Gregory Cochran told me recently. "'Big old diseases are
infectious. ' If it's common, higher than one in a thousand, I get suspicious. And if it's old, if it has been around for a while, I get suspicious. " The fact that Ewald has dared to conceive of a big theory for the medical
sciences owes much to Cochran's contributions. A forty-five-year-old Ph. D. physicist who lives in Albuquerque with his wife and three small children,Cochran makes a living doing contract work on advanced optical systems forweaponry and other devices. Whereas Ewald is an academic insider, withdepartment meetings to attend and honors theses to monitor, Cochran is asolo player, with an encyclopedic mind (he is a former College Bowl
contestant) and a manner that verges on edginess. These days he spends a lot
of time at his computer, as rapt as a conspiracy theorist, cruising Medline for new data on infectiousdiseases and, one imagines, almost cackling to himself when he finds something really good. Cochran's background in a field dominated by grand theories and universal laws may serve as avaluable counterpoint to the empirical and theory-hostile universe of the health sciences. Ewald and Cochran encountered each other serendipitously, after Cochran decided to pursue a
certain line of thinking about a very sensitive subject. "I was reading an article in Scientific American
in 1992 about pathogens manipulating a host to get what they want," Cochran recalls. "It described aflowering plant infected by a fungus, and the fungus hijacks the plant's reproductive machinery so
Gregory Cochran
that instead of pollen it produces fungal spores. I thought, Could it be. " Cochran strayed from his
field to try his hand at writing an article on biology -- elaborating an audacious theory that humanhomosexuality might result from a "manipulation" of a host by a germ with its own agenda. He senthis draft to a prestigious biology journal, which sent it out to three scientists for peer review. Twowere unconvinced, even appalled; the third was Paul Ewald, who thought the article was flawedbut who was nonetheless impressed by the logic of the idea. The article was rejected, but Ewald andCochran began their association. To illustrate his thinking about infectiousness and disease, Cochran not long ago gave me a tour of
his conceptual bins, into which he sorts afflictions according to their fitness impact. Remember thatfitness can be defined as the evolutionary success of one organism relative to competing organisms. Only one thing counts: getting one's genes into the future. Any disease that kills host organismsbefore they can reproduce reduces fitness to zero. Obviously, fitness takes a major hit whenever thereproductive system itself is involved, as in the case of venereal chlamydia. Consider a disease with a fitness cost of one percent -- that is, a disease that takes a toll on survival
or reproduction such that people who have it end up with one percent fewer offspring, on average,than the general population. That small amount adds up. If you have an inherited disease with aone percent fitness cost, in the next generation there will be 99 percent of the original number in thegene pool. Eventually the number of people with the disease will dwindle to close to zero -- or,more precisely, to the rate produced by random genetic mutations: about one in 50,000 to one in100,000. We were considering the bin containing diseases that are profoundly antagonistic to fitness, with a
fitness cost of somewhere between one and 10 percent by Cochran's calculations. My eye took in acatalogue of human ills -- some familiar, some exotic, some historically fearsome but close to extinct,some lethal in the tropics but of little concern to inhabitants of the temperate zones. This list alsoshowed prevailing medical opinion about cause. Each name of a disease was trailed by a lower-caseletter: i(for infectious), g(genetic), g+(genetic defense against an infectious disease), e(caused by an
environmental agent), or u(unknown). I read, "Atherosclerosis ( u),. chlamydia (venereal) ( i),
cholera ( i), diphtheria ( i), endometriosis ( u), filariasis ( i), G6PD deficiency ( g+),. hemoglobin E
disease ( g+), hepatitis B ( i), hepatitis C ( i), hookworm disease ( i), kuru ( i),. malaria (vivax) ( i),. pertussis ( i), pneumococcal pneumonia ( i), polycystic ovary disease ( u), scarlet fever ( i),. tuberculosis ( i), typhoid ( i), yellow fever ( i). " Of the top forty fitness-antagonistic diseases on the list, thirty-three are known to be directly
infectious and three are indirectly caused by infection; Cochran believes that the others will turn outto be infectious too. The most fitness-antagonistic diseases must be infectious, not genetic, Ewaldand Cochran reason, because otherwise their frequency would have sunk to the level of randommutations. The exceptions would be either diseases that could be the effect of some newenvironmental factor (radiation or smoking, for example), or genetic diseases that balance theirfitness cost with a benefit. Sickle-cell anemia is one example of the latter. Though sickle-cell anemia is strictly heritable according to Mendelian laws, it is widely believed to
have persisted in the population in response to infectious selective pressures. It heads the list ofgenetic diseases that Ewald dubs "self-destructive defenses," in which a disease fatal in itshomozygous form (two copies of the gene) carries an evolutionary advantage to heterozygouscarriers (with one copy), protecting against a terrible infection: in this case falciparum malaria,common in Africa. Similarly, cystic fibrosis, some argue, evolved in northern Europe as a defenseagainst Salmonella typhi, the cause of typhoid fever. Infection thus explains why these deadly genetic
diseases have remained in the human gene pool when they should have died out. But what about something like atherosclerosis. I asked. Leaving aside the evidence concerning C. pneumoniae, it is not apparent why a genetic cause for atherosclerosis should be dismissed out of
hand on evolutionary grounds. If it hits people in midlife or later, after they have launched theirgenes, how could it possibly affect fitness. Cochran's response illustrates some of the intricacies of evolutionary thinking. "Well, obviously, it's
not as bad as a disease that kills you before puberty, but I think it does have a fitness cost. First ofall, it's really common. Second, people think that all you have to do to pass your genes along is have
children, but that's not true. You still need to raise the offspring to adulthood. In a hunter-gathereror subsistence-farming culture, the fitness impact of dying in midlife might be considerable,especially during bad times, like famines. You've got to feed your family. Also, cardiovasculardisease is a leading cause of impotence, and any disease that makes males impotent at age forty-fivehas got to affect reproduction somewhat. " But fifty-year-olds. Sixty-year-olds. Grandmothers do a large proportion of the food-gathering in some tribal cultures, according to
recent anthropological reports. "They aren't hampered by babies anymore, and they don't have to goaround chucking spears like the men," says George C. Williams, a professor emeritus of ecology andevolution at the State University of New York at Stonybrook, and one of the pillars of modernevolutionary biology. "They contribute substantially to the family diet. " If long-lived eldershistorically have made a difference by fostering the survival of their descendants, and thereforetheir genes, Cochran figures, then a disease that kills sixty-year-olds could have a fitness impact ofaround one percent. The Cause-and-Effect Conundrum
KNOW what that is. " Ewald asked. We were standing in the main corridor of the Life SciencesBuilding, gazing up at a decorative metalwork frieze that runs along the walls just abovedoor height. A pair of hummingbirds chase each other in a circle. A human eye and an
octopus eye face off. A human hand is juxtaposed with a chimpanzee hand. Ewald pointed tosomething that looked like a daddy longlegs with a video camera for a head. "Some kind of insect. "I ventured. "It's a virus," he said. "See, it's like a spaceship. That" -- he pointed at the head -- "is itsDNA. It injects it inside the cell. " There is something unsettling and fascinating about a virus, an organism that is neither strictly alive
nor strictly inanimate, and that replicates by sneaking inside a host cell and commandeering itsmachinery. "Viruses are essentially bits of nucleic acid -- either DNA or RNA -- wrapped in a proteincapsule," Ewald explained. "A retrovirus, like HIV, is an RNA virus with a protein called reversetranscriptase built into it, and once it gets into a cell, it uses the reverse transcriptase to make a DNAcopy of its RNA. This viral DNA copy can insert itself into our DNA, where it can be read by ourprotein-making machinery the same way our own instructions are read. " The modus operandi of the world's most feared virus, HIV, is clever, killing its hosts very, very
slowly. A sexually transmitted pathogen, without the luxury of being spread through sneezes orcoughs, must await its few opportunities patiently; if those infected have no symptoms and don'tknow they are sick, so much the better. A mild, chronic form of AIDS had in all likelihood beenaround for centuries in Africa, according to Ewald. Suddenly in the 1970s -- owing to changingpatterns of sexual activity and to population movements -- deadly strains spread in the populationof Central and East Africa. HIV has an extremely high mutation rate, which means that it is continually evolving, even within a
single patient, producing competing strains that fight for survival against the weapons produced bythe immune system. If selective pressures -- in this case a high potential sexual transmission -- have
forced the virus to evolve toward virulence, the opposite selective pressures could do the reverse. Conceivably, we could "tame" HIV, encouraging it to evolve toward comparative harmlessness. Itwas already known that preventive measures such as safe sex, fewer partners, clean needles, and soforth could curb the spread of the disease. But Ewald pointed out early on that social modificationwas a far more potent weapon than anyone realized. Once HIV was cut off from easy access to newhosts, milder strains would flourish -- ones that the host could tolerate for longer and longerperiods. Indeed, Ewald argues, given limited public-health budgets, it might make sense to putmore money into transmission-prevention programs and less into the search for vaccines. (He alsohas strong opinions about how drugs should be used to treat AIDS. He asserts that every time weuse an antiviral drug like AZT, we produce an array of AZT-resistant HIVs in the population; if viralevolution is taken into account, antiviral drugs can be used more judiciously. ) Ewald's theories tilt him decidedly toward the optimistic camp. Even in the absence of a vaccine the
AIDS epidemic will not inevitably worsen; it can be curbed without reducing transmission to zero. A natural experiment now occurring in Japan, he says, could be a test case for his theories. In theearly 1990s highly virulent strains of HIV from Thailand took root in Japan, but Ewald predicts thatlow rates of sexual transmission in that country -- due to widespread condom use and other factors-- will act as a selective pressure on these strains so that they evolve toward mildness. If this is true,the trend should become evident over the next ten years. Like HIV, many other viruses have an indolent course, with a long latency between infection and
the development of symptoms. Herpes zoster, the agent of chicken pox, lingers in the body forever,capable of erupting as painful shingles decades later. There are also so-called hit-and-run infections,in which a pathogen or its products disrupt the body's immunological surveillance system; once themicrobes are gone (or when they are present in such low frequency as to be undetectable), theimmune response stays stuck in the "on" mode, causing a lingering inflammation. By the timesymptoms occur, the microorganism itself has disappeared, and its genome will not be detectable inany tissue. "The health sciences are still grappling with the masking effects of long delays between the onset of
infection and the onset of disease," Ewald says. "Any time you have hit-and-run infections, slowviruses, lingering or relapsing infections, or a time lag between infection and symptoms, the causeand effect is going to be very cryptic. You won't find these newly recognized infections by themethods we used to find old infectious diseases. We have to be ready to think of all sorts of new,clever ways to identify pathogens. We will have to abandon Koch's postulates in some cases. " 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 whichthe 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 underparticular scrutiny because his hypothesis arrives detached from a vast corpus of laboratory data. Itis helpful to think of Ewald as continuing the tradition of the great scientific synthesizers. Darwinhimself 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 beenmentioned. 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 beendiscovered in animals. And yet until 1979, despite broad hints from the animal world, not a singlehuman cancer was generally accepted as infectious. Rous had been lucky: his chickens became sickonly two weeks after infection. Human cancers follow a more languorous course, which means thatby the time symptoms show up, any infectious causation may well be buried under a lifetime ofirrelevant 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 cancerappeared decades after infection. The Epstein-Barr virus (the agent that causes mononucleosis) hasnow been associated with some B-cell lymphomas, with a nasopharyngeal cancer common in southChina, and with Burkitt's lymphoma, a deadly childhood cancer of Africa. Some 82 percent of allcases of cervical cancer have been associated with the sexually transmitted human papilloma virus,a once relatively innocent-seeming pathogen responsible for genital warts.
Paul Ewald
Who is the author of the book "Evolution of Infectious Disease"?
Not mentioned in the passage
What is the name of the disease that was recently linked to Alzheimer's disease?
Trachoma
What is the name of the disease that is responsible for a leading cause of blindness in parts of the world?
Not mentioned in the passage
What is the name of the virus that is believed to be responsible for a form of childhood obsessive-compulsive disorder?
Barry J. Marshall
Who is the scientist who discovered the link between H. pylori and stomach cancer?
Not mentioned in the passage
What is the name of the disease that is mentioned as being potentially curable with antibiotics?