Do Chronic Diseases Have an Infectious Root?

To test his idea, Marshall swallowed a broth full of H. pylori, and sure enough, he soon developed gastritis, the prelude to ulcers. Marshall cured himself with antibiotics, and subsequently, he and his co-workers successfully treated a number of people suffering from ulcers, clearly pinning the bacterium as the culprit. Other researchers have since shown that H. pylori infects perhaps one-third of all people, causing not only ulcers but gastric cancers as well.

“All of us have been humbled by the Helicobacter story,” says Subramaniam Sriram of Vanderbilt University in Nashville, Tennessee. “It’s made us look at infectious agents once again.” Robert Yolken of John Hopkins University agrees: “The Helicobacter model is the big success story.” But it was not the only one. At about the same time that Marshall was swigging H. pylori, other researchers were finding some of the first compelling evidence that cancers could also be triggered by viruses. Hepatitis B was associated with liver cancer, for example, while human papillomaviruses were linked to cervical cancer.

For other chronic diseases, however, the evidence is little more than circumstantial. Multiple sclerosis, for example, sometimes strikes its victims more like an epidemic than a genetic disorder, as it did in the Faeroes. Similarly, schizophrenia has signs of being triggered by infections during pregnancy. It is more likely to strike people born in cities than on farms and to strike people born in winter (when the flu and other diseases are common) than other times of the year.

Even without decisive evidence, some biologists argue that pathogens must cause most common chronic diseases. Foremost among these advocates is Paul Ewald, an evolutionary biologist at Amherst College in Massachusetts. Ewald suggests that people with chronic diseases ought to leave fewer children and grandchildren behind to propagate their genes than do healthy individuals. And so genetic disorders should gradually reduce themselves to minuscule levels. (The only exceptions would be disorders that are balanced by some benefit provided by the same genes, as in the case of sickle cell anemia, which is linked to protection from malaria.)

Purely genetic disorders, Ewald contends, can’t cause more than about 1 death in 10,000. “That’s the point at which you’d be able to barely maintain a genetic disease,” he says. “When you get above that, you know that something must be maintaining it.”

To Ewald, that something is most likely a pathogen, because it can cause a chronic disease without paying this evolutionary penalty. As long as the pathogen can escape to new hosts before its own dies, it can continue to create sickness. Humans may evolve better defenses against a parasite, but the parasite can respond in kind, evolving new tricks for getting around them.

Ewald has captured public attention, with features on his work appearing in magazines like Newsweek and Atlantic Monthly. But he has had a mixed reception among specialists in chronic diseases. “Infection may be important at a broad level, but so is starvation,” says Paul Ridker of Brigham and Women’s Hospital in Boston. Although he finds the theory intellectually stimulating, Ridker argues that it is no substitute for detailed research. Perhaps not surprisingly, scientists who are investigating possible infectious causes tend to be positive. “Generally, I think Ewald’s right,” says Alan Hudson of Wayne State University in Detroit, Michigan. But even champions of pathogens like Barry Marshall, now at the University of Western Australia in Crawley, concede that “so far nothing looks as good as H. pylori—and most of the leads have been rather weak.”

Mysterious MS

Take MS, a disease in which immune system cells attack the insulating sheath of myelin that surrounds neurons in the brain and spine. As the disease progresses, its victims typically lose their muscle coordination, speech control, and eyesight. More than 300,000 people in the United States alone suffer from the disease—many more than evolutionary theory would predict if it were strictly a genetic disorder. Epidemiological studies also hint at a pathogen. People who migrate before age 15 from MS hot spots (such as Australia and Ukraine) to places with low rates are less likely to contract the disease than are those who stay behind. That decline is consistent with a scenario in which MS is caused by an infection that strikes in adolescence.

Experimental studies likewise hint that a pathogen could cause MS if its own proteins resembled myelin. Once the immune system became primed to attack the invader, it might inadvertently ravage the myelin as well. Indeed, in the July 2001 issue of the Journal of Clinical Investigation, a team of immunologists at Northwestern University Medical School in Chicago described creating symptoms resembling MS in a mouse by using an infectious agent. They injected the mouse with a normally harmless virus—but to which they had added a gene from a bacterium, Haemophilus influenzae, that makes a myelinlike protein. The mouse’s immune system quickly became primed to attack the engineered virus; within 2 weeks its myelin was under assault as well.

But this sort of research enables scientists to create animal models of MS—not to identify the actual culprit in humans. Over the years, scientists have prowled for pathogens that could cause this sort of mimicry in association with MS, and they’ve found no shortage of candidates, 17 microorganisms in all. But today researchers are focusing the hunt for an MS agent on two ubiquitous pathogens: a virus and a bacterium that were both discovered just 15 years ago.

Human herpesvirus 6 (HHV-6) usually infects people when they are just a few months old, causing a sizable fraction of the fevers experienced by babies. After causing a brief illness in its host, the virus goes into hiding and may lie dormant for the rest of the host’s life. But researchers have found that it sometimes becomes active again. Patients who receive bone marrow or organ transplants are often plagued by reactivated HHV-6, possibly because their immune systems are compromised.

Researchers studied this connection in 1995 at the Pathogenesis Corp. in Seattle, Washington (now part of Chiron), finding evidence of HHV-6 in the brains of several dozen people with MS. In these patients, the viruses were producing proteins, and they lurked close to the myelin of their hosts. In people who did not suffer from MS, the virus was there, but researchers found little evidence that it was active.

Since then, several groups have pursued this lead with distinctly mixed results. Donald Carrigan and Konstance Knox of the Institute for Viral Pathogenesis in Milwaukee, Wisconsin, published results last year showing that 56% of patients with MS had active HHV-6 in their brains, whereas healthy subjects had none. But several other teams have failed to find the virus in people with MS, while a paper this January in the Journal of Medical Virology found HHV-6 in one-third of healthy people’s brains.

Carrigan and Knox dispute those negative findings, arguing that other researchers did not check carefully enough to see whether the virus was active or dormant in the brains. That hasn’t been enough to sway many herpes experts, however. “I am frankly rather skeptical about the possible link between HHV-6 and MS,” says Steven Dewhurst of the University of Rochester in New York. Just this May, he had more reason for doubt: At the annual meeting of the American Academy of Neurology, a Swedish team reported treating people with MS with valacyclovir, an antiviral medication. It produced no change in the symptoms.

Another suspect in MS is the bacterial scourge Chlamydia pneumoniae(see table). Its cousin, C. trachomatis, is notorious as a sexually transmitted disease and this year was implicated in cervical cancer. C. pneumoniae invades the lungs, where it sometimes causes respiratory diseases. It can then settle into a host’s body for decades, living quietly in white blood cells. Like HHV-6, C. pneumoniae is practically universal. Just about everyone becomes its victim at some point.

C. pneumoniae was first suspected to play a role in heart disease. Shortly after its discovery in 1986, researchers encountered it lurking in the coronary blood vessels. Several teams also found that people with heart disease were more likely to have antibodies to C. pneumoniae than were healthy individuals. Later research has shown that the bacteria actually live in the lesions associated with atherosclerosis. In 1999, scientists reported that a protein made by C. pneumoniae closely resembles one found in heart muscle. As it tries to attack the bacteria, the immune system may attack the heart as well, creating the inflammation that may cause atherosclerosis (Science, 26 February 1999, p. 1335). Two clinical trials are now under way to see whether antibiotics can lessen further damage in people with heart disease. But many researchers still doubt that the connection is real. “The data are actually weaker than people think,” says Ridker.

In 1998, Vanderbilt’s Sriram reported that he had found C. pneumoniae in yet another part of the body: in the cerebrospinal fluid of a man with MS. Sriram subsequently looked at other people with MS and reported that genetic profiling revealed that 97% of them had the DNA of C. pneumoniae in the fluid, while only 18% of the controls did.

Sriram’s results raised the possibility that C. pneumoniae could trick the immune system into attacking myelin just as it attacked heart tissue, or at least make a bad situation worse by aggravating the inflammation. Animal experiments suggest there might be something to this idea. In the August 2001 Journal of Immunology, Hudson of Wayne State and his colleagues reported that when they injected a protein from C. pneumoniae into the brains of rats, it produced remarkably MS-like symptoms. “His is a very seminal paper,” says Sriram.