Over the last 20 years, research on a tiny, S-shaped stomach bacterium has overturned doctors' notions about the origins and history of diseases from ulcers to cancer of the stomach.
Now, some scientists who study the bacterium, Helicobacter pylori, say the tiny bug may help trace the migration of human populations across the globe.
Next week, enthusiasts from around the globe will gather in Australia to celebrate the discovery of H. pylori. While the discovery of a stomach bacterium may seem an odd thing to celebrate, this one did something big.
Two Australian scientists discovered H. pylori. Pathologist Robin Warren had noticed tiny bacteria in stomach ulcer specimens and his group managed to grow them where others had failed, in part because the members left the cultures incubating for an extra long time during their Easter vacation.
When it later proved impossible to infect animals with the microbes, colleague Barry Marshall swallowed some of the bacteria to find out if they really induced stomach inflammation.
A biopsy from his stomach showed they did.
"In retrospect, it was a little bit risky," recalls Marshall, now a scientist at the University of Western Australia's department of microbiology. "But at the time it was the only way I could see to advance knowledge of the new bug."
In the years that followed, doctors tossed out theories about stress and salty food as the primary causes of ulcers. (At one time, even "obsessional and dominant" mothers were blamed for the ulcers of their children.)
In came a new model of infectious disease--and new therapeutic approaches with antibiotics to treat ulcers and prevent stomach cancer, the world's second-leading cancer killer.
Researchers now know far more about the bacterium. They know that once inside the stomach, the bacterium uses a set of whip-like tails--called flagella--to swim briskly toward the layer of mucus that protects the lining of the stomach.
Inside the mucus, H. pylori sticks to the cells lining the stomach and uses an enzyme to neutralize the stomach's fierce acidity. While there, the microbe produces proteins that cause changes in stomach cells. Those changes, in turn, lead to inflammations that over time can produce ulcers or cancer.
Researchers also have determined the precise structure of the microbe's genome several times over. They're beginning to understand how its genes function to help it survive in the stomach and trigger disease.
They've discovered that roughly half of all human beings are infected with H. pylori--but that rates of infection vary enormously from place to place. In countries and communities with impure water, poor sanitation and crowding, infection rates are high--and higher, too, are incidences of stomach cancer and ulcers.
Microbe's DNA Varies Greatly
Scientists also have snaked tubes into stomachs all over the world to study H. pylori more closely--and, by doing so, have found great genetic variability in the microbe's DNA. Even individual stomachs can contain dozens of genetically distinct bacteria, as if H. pylori is constantly reshaping its genome.
But there are clear, more global patterns also. Strains sampled from Asian stomachs, European stomachs and African stomachs differ distinctly--and the differences persist in the stomachs of offspring, even when they're now living in other parts of the world.
"Give me a bacterium and I can tell you generally where a person's ancestors came from," says Dr. David Graham, chief of gastroenterology at the Veterans Affairs Medical Center in Houston, one of the scientists who has made a study of this florid variability.
These global genetic signatures offer much more than the chance to perform a neat party trick: by comparing strains, scientists hope to track where and when H. pylori first took up residence in humans, and how it traveled to stomachs across the globe.
Though the details of H. pylori infection are unclear, it is believed to occur via the mouth, possibly via water, during the early years of life. And it clearly involves close community contact: in a study recently reported at a conference at UCLA, Himalayan Buddhists and Muslims who have lived in the same area for several hundred years retained genetically distinguishable populations of the microbe. But where did H. pylori come from? Is it a new or ancient resident in the human body?
Some researchers argue that H. pylori got into human stomachs hundreds of thousands, even millions of years ago. Others believe that the bug took up residence far more recently--perhaps caught from close contact with animals after the advent of agriculture, says Douglas Berg, professor of microbiology and genetics at Washington University School of Medicine in St. Louis.
Berg believes that H. pylori wasn't yet in people when they found their way across the land bridge that crossed what is now the Bering Strait separating Asia from Alaska. Human residents of North America had no H. pylori in their stomachs until the advent of the Spanish conquistadors in the 16th century, says Berg, who bases his belief on studies of the stomachs of Peruvians. The H. pylori he found in Peruvian stomachs looks Spanish, Berg says.
Others disagree. Graham and Dr. Martin Blaser, chairman and professor of the department of medicine at New York University, have studied H. pylori taken from remote tribes in the Amazon basin. They've compared these bugs with bacteria taken from Latin Americans who have mixed European, African and Indian heritage.
Those with mixed ancestry, Graham and Blaser say, have H. pylori genetic patterns that look European. Those from the remote parts of the Amazon, however, have patterns more closely related to Asian H. pylori--as would be expected if the bacteria originated in people who crossed the Bering Strait from Siberia thousands of years ago.
However far back in human history H. pylori goes, the coexistence is today drawing to an end. Scientists and companies are researching vaccines and drugs that could eliminate H. pylori, potentially wiping out most ulcers and stomach cancers.
Not everyone thinks that is a good idea.
Blaser, for example, believes that the bacterium has been with us for a long time--and that it may be part of the normal flora of the human body: "If it's been present in humans for thousands or millions of years and now it's gone, what's going to take its place?" he asks.
What's more, argues Blaser, while the bug is strongly linked to ulcers and stomach cancer, it appears to offer protection against diseases of the esophagus, such as gastroesophageal reflux disease (in which the stomach's acidic contents flow back into the esophagus) that can cause esophageal cancer.
Scientists Disagree on Bug's Usefulness
Other experts take strong issue with Blaser. Stomach cancers, they say, are far more common than esophageal cancers, which also can easily be prevented.
"I know Martin very well, and I really do not agree," says Dr. George Sachs, professor of medicine and physiology at UCLA's school of medicine. "I can treat esophageal reflux disease--and provided I prevent the acid reflux there won't be consequent esophageal cancer. On the other hand, it's very hard to treat gastric cancer."
To some extent, however, the issue of whether to eradicate the bug is moot, says Dr. Julie Parsonnet, associate professor of medicine in the division of infectious disease at Stanford University. H. pylori infections still cause large problems in certain countries and ethnic groups, but wherever sanitation, socioeconomic conditions and crowding improve, rates of H. pylori infection--and stomach cancers and ulcers--are dropping, she says.
"We are doing it already," she says, "whether we're meant to be doing it or not."