• 5/17/2005
  • New York, NY
  • Nicholas Bakalar
  • New York Times (www.nytimes.com)

Infectious disease used to be a simple matter: this germ causes that illness. Doctors just had to find the germ, kill it, and cure the disease.

But the old rules no longer apply.

A report issued last month by the American Academy of Microbiology paints a much more complex picture of infectious disease. Germs, scientists are learning, are probably the cause of many illnesses that were never thought to be infectious, and determining exactly how a germ contributes to disease is no longer simple.

The old rules date to 1883, when the German bacteriologist Robert Koch laid down three laws – now called Koch’s postulates – that infectious disease specialists have used ever since to determine whether an organism causes a disease: The suspected germ must be consistently associated with the disease; it must be isolated from the sick person and cultured in the laboratory; and experimental inoculation with the organism must cause the symptoms of the disease to appear.

In 1905, a fourth rule was added: The organism must be isolated again from the experimental infection.

Using Koch’s postulates as a starting point, scientists figured out the cause, prevention and treatment for one infectious disease after another. In the mid-20th century, some experts began to believe that infectious disease might be permanently conquered. But microbes have been found to metamorphose into new and more destructive forms, to jump from animals to humans, to hide where they are hard to find and to resist the most powerful antibiotics available.

Moreover, said Dr. Ronald Luftig, an author of the academy’s report and a professor of microbiology at the Louisiana State University Health Science Center, “There have been a lot of chronic human illnesses thought to be genetic or environmental, but when you look at them in more detail, it turns out there’s involvement of bacteria, groups of bacteria or viruses.”

Microbes use a variety of mechanisms to attack cells and create havoc. Human papillomavirus, for example, inserts its nucleic acid into host cells, integrating into the cell’s genes and altering the normal process of cell division to cause the uncontrolled growth of cervical cancer.

Hepatitis B invades the liver, provoking an immune response that stimulates the scarring, cirrhosis and fibrosis that can lead to liver failure. At the same time, it causes genetic mutations that promote tumor growth and deadly liver cancer. Crohn’s disease, a chronic inflammation of the intestines, may result from the presence of an infectious organism combined with a person’s genetic susceptibility.

By suppressing the immune system, inhibiting cell division and directly affecting the function of cells, germs demonstrate an astounding subtlety and resourcefulness in creating biological chaos.

And it gets worse. Some microbes can contribute to more than one disease. The papillomavirus, for example, can lead not only to cervical cancer, but also to cancer of the penis and anus, venereal warts, common warts and cancers of the head and neck. Epstein-Barr virus, the cause of infectious mononucleosis, is almost as versatile, associated with Burkitt’s lymphoma in Africa and with throat cancer and Hodgkin’s disease, among other cancers.

Helicobacter pylori, found in the mid-1980’s to be a cause of peptic ulcer disease, was later implicated as a contributor to gastric lymphoma as well.

Even saying that a microbe “causes” a cancerous lesion is problematic. Dr. David S. Pisetsky, a professor of medicine at Duke University Medical Center, points out that most infections do not lead to cancer, and he hesitates to alarm patients by overstating the connection.

“These viruses are associated with cancer, but causality is complicated,” he said. “In many instances, the viral infection is part of a chain of causality, and not the sole factor.”

The important questions to ask, Dr. Pisetsky adds, are “What’s the risk, and how can I reduce the risk?”

“If you have a virus associated with neck and head cancer,” he said, “that’s one more reason to quit smoking.” In the case of a virus known to lead to cervical cancer, he went on, increased vigilance is in order, with Pap smears and regular examinations.

All of this, combined with the fact that many germs (especially viruses) are impossible to culture in a laboratory, make it all the harder to find the microbe that causes the illness.

Often, the first step is a simple observation of patients by clinicians, really little more than a hunch: a doctor notices a chronic illness that always seems to be associated with something that looks infectious.

This is exactly what happened when Dr. N. M. Gregg, an Australian ophthalmologist, discovered congenital rubella syndrome. He made the connection between the cataracts he was seeing in children and their mothers’ German measles during pregnancy.

Sometimes epidemiological patterns offer the initial hint, as was the case with Kaposi’s sarcoma, once a rare lesion caused by a type of herpes virus that began to occur frequently in gay men whose immune systems were compromised.

Once the association is made, the search for the organism can begin. The gut is inhabited by hundreds of species of microbes, and the guilty party may be hiding among them. Germs can lurk in the nervous system, like the varicella virus that causes chickenpox and then lies in wait to cause herpes zoster, or shingles, decades later. And some germs can cause infection in one place in the body, and a disease in an entirely different place. Even the most sensitive molecular techniques are sometimes not good enough to find the guilty microbe.

There are almost certainly still unknown microbes creating chronic illness. “One of the suspects in multiple sclerosis is Epstein-Barr virus,” Dr. Luftig said. “The DNA of the virus integrates into your cells; it’s there permanently. Is it a cause? Maybe.”

Dr. Luftig suggests several other diseases that may have microbial triggers. “There’s an enterovirus that’s involved in destroying pancreatic islet cells,” he said. “Maybe diabetes is caused by an immune reaction to infection. Intrauterine exposure to infection may play a role in schizophrenia.”

No one yet knows for sure. But researchers – doctors, microbiologists, epidemiologists, geneticists – have their suspicions, and are searching carefully.

“We’re not saying that everything is due to microbes,” Dr. Luftig said. “But the more investigative tools we develop and the more we have interacting groups of researchers with varying specialties, the more we can start to pick out potential agents that were never before suspected.”