Germs Rule the World

The new germ theory: Infections play a role in many, many diseases—in ways we're just beginning to understand.

A Tuberculosis vaccine at the Institute Pasteur in Paris, France in 1931. (Alfred Eisenstaedt/AP)

In 1882, Robert Koch discovered that a bacterium was behind the world's leading cause of death: tuberculosis (TB). This brilliant combination of investigative logic and savvy microscopy refuted the conventional wisdom that TB was an inherited disease, or some form of cancer. Rather, TB was caused by a particularly wily and insatiable germ. This finding didn’t just accurately identify the agent behind the world’s leading cause of death. It also established an essential new paradigm for medicine.

There are those diseases that are caused by bacteria (and later, viruses), such as tuberculosis, typhoid and typhus fevers, and diphtheria; and those diseases caused by the body’s own failures, such as heart disease and cancer. For more than a century, this distinction has served as a sharp and clear line in our understanding of disease. But it is a distinction that may be on the verge of being itself replaced. Germs, it seems, may be at the root of more disease than we have given them credit for.

In the last decade, several diseases understood as strictly noninfectious have, in fact, been found to have significant infectious components. Several forms of cancer, gastrointenstinal diseases, autoimmune illnesses including diabetes, and even some categories of heart disease are all being reconsidered in light of new research. Together, this research amounts to nothing less than a new germ theory, one that could once again alter contemporary definitions of medicine.

Heart disease, of course, has long been considered an ailment of exclusively human causes, rising in the developed world as traditional infectious disease has waned. Heart disease kills more people than any other condition worldwide, including 47 percent of Americans and Europeans and 30 percent of all global deaths. Scientific consensus points to some combination of behavioral and environmental links (smoking, diet, exercise, stress, and so on down the list), along with various genetic components. Except in rare cases of acute infections, such as infectious endocarditis, microbes have been considered irrelevant.

But in 2013, an infectious component revealed itself, in the form of trimethylamine-N-oxide, or TMAO. TMAO isn’t a bacterium itself; rather it’s created when bacteria digest carnitine, a compound found in meat, and lecithin, a fatty substance common in certain foods such as eggs, milk, and some nuts. In research published in Nature Medicine and The New England Journal of Medicine, a team led by Cleveland Clinic’s Stanley Hazen found that human subjects with the highest levels of TMAO in their blood had about twice the risk of having a heart attack, stroke, or death compared to those who had the lowest TMAO levels.

The chain of causation here requires a few clever links. First, the hypothesis goes, the human eats a diet high in meat or lecithin. The gut bacteria feed on carnitin and lectithin and release a substance that in the human liver is turned into TMAO. This excess  TMAO allows cholesterol to get into artery walls and also prevents the body from shedding extra cholesterol. Once there, the cholesterol accumulates on the blood vessels, causing atherosclerosis. Hazen’s research is only suggestive; it needs further replication in more human studies. But it suggests a profound departure from our conventional understanding of heart disease, and what role bacteria may play.

Other areas of noninfectious disease have also turned out to have infectious aspects in recent years. The best known example is that of cervical cancer, which was first associated with the human papillomavirus, or HPV, in the 1970s. A vaccine against the virus was developed in 2006, and is now frequently administered to young women before they become sexually active. These and other preventive efforts have helped reduce the rate of cervical cancer by more than 70 percent since the 1970s. But it turns out that HPV might be a more active virus than we have accounted for: It is likely also associated with rising rates of throat cancer, anal cancer, penile cancer, and other cancers. Though HPV is associated with women, a surprising 12,000 men each year develop an HPV-associated cancer, according to the CDC.

A similar blurring of the lines has happened in research into gastrointestinal and autoimmune diseases, driven by the growing awareness of a microbiome—those one trillion bacteria that live in our guts and on our skins, a trillion organisms that unwittingly affect the larger organism that is the human body. A study released last November suggested a strong connection between a bacteria named Prevotella copri and rheumatoid arthritis. Not only did researchers establish a significantly higher rate of the bacteria in humans with the disease, but when they administered doses of P. copri to mice the animals developed increased inflammation.

The first hint that these microbes might play a role occurred in 1982, when Australian scientists Barry Marshall and Robin Warren discovered helicobacter, a microbe that was persistently present in patients with chronic gastritis and gastric ulcers. At first, the notion that bacteria had anything to do with gastrointestinal ulcers seemed absurd; ulcers were well associated with stress and human biology.

Frustrated with the naysayers, Marshall decided to prove his point. In a classic demonstration of self-experimentation, Marshall swallowed a vial of helicobacter bacteria, and promptly developed a horrible ulcer. A subsequent round of antibiotics cleared the condition. Still, it would be a decade before other scientists had replicated their findings and changed the consensus opinion. In 2005, Marshall and Warren would be recognized with the Nobel Prize.

Alzheimer's disease, dementia, and even obesity may have a significant connection to infection. A December 2012 study found that Enterobacter, a kind of bacteria that produce endotoxins, were significantly elevated in morbidly obese volunteers. When samples of this gut bacteria were transferred to mice, the animals both gained weight and became insulin resistant—an early sign of diabetes. And this isn’t to mention the “hygiene hypothesis,” which suggests that the absence of germs in our systems may be linked to increasing rates of asthma, colitis, Crohn’s disease, and other inflammatory diseases.

Taken together, these insights argue for a new germ theory, one that would up-end our prejudices as profoundly as Robert Koch’s discovery did in 1882. This new germ theory would hold that the body is not a sterile instrument; that the interplay between our organism and those trillions of mircrobes is profoundly more complicated than it has seemed. It would allow that germs are not always, in fact, germs—that they can benefit us as well as harm us, and that knowing the difference is an essential challenge of 21st century medicine. Ultimately, the new germ theory would leave the door open to the fact that our convictions today might be proven wrong tomorrow.