Photo by Clay Eals
Ulcers, stomach cancer and a type of lymphoma that affects the gastrointestinal tract are distinct diseases, but the same culprit is at the root of each ailment.
It's a spiral-shaped bacterium that makes its home in the lining of the stomach.
Helicobacter pylori caused a stir in the medical community in the early 1980s, when scientists identified it as the primary cause of stomach ulcers. The finding has had enormous consequences for medical care, shifting treatment from surgery and admonishments about stress-reduction to prescriptions for antibiotics.
More recently, the wily bug, whose mode of transmission is unknown, has been associated with two forms of gastrointestinal cancer: gastric adenocarcinoma and mucosa-associated lymphoid-tissue lymphoma.
Wide spectrum of diseases
How a single organism can cause such a wide spectrum of diseases - and in most people, cause no obvious illness at all - has scientists such as the Hutchinson Center's Dr. Nina Salama scratching their heads.
"H. pylori is a very common infection," she said. "About half the population worldwide is infected, although the incidence is higher in developing countries than in the United States. But about 90 percent don't present any clinical symptoms. And those with symptoms can suffer from a variety of disorders. I'm trying to understand how this happens from the bug's point of view."
Salama - who joined the Human Biology Division in September and who holds a secondary appointment in the Public Health Sciences Division - combs the bacterium's genome for clues to its diverse pathogenic abilities.
Combining this tactic with studies using mice as a model, she is well on her way to tackling the complex interaction between disease-causing microbes and the cells they infect, said Dr. Barbara Trask, division director.
"Nina's work on H. pylori is setting a new paradigm for bacterial pathogenesis," she said.
"What she's done is to assemble a powerful set of tools to understand the dynamics of the process."
The first of those tools is a DNA microarray, a so-called DNA chip that enables whole genomes to be rapidly scanned and compared for subtle differences. Salama developed such a chip as a postdoctoral fellow in Dr. Stanley Falkow'slaboratory at Stanford University.
DNA representing every gene known to be present in two previously sequenced H. pylori strains has been spotted onto the chip, allowing Salama to probe other clinical isolates of bacteria for their genetic composition.
"Because it is such a medically relevant organism, H. pylori was one of the first bacterial genomes to be completely sequenced," she said.
"The thinking among a number of scientists was that different diseases were caused by infection with genetically distinct organisms, so two different clinical isolates were sequenced, one from a patient with a duodenal ulcer and the other from a patient with gastritis. But initial comparison of the two sequences didn't reveal major genome-wide differences."
Distinct genetic diversity
Using microarray analysis, though, Salama and her colleagues at Stanford discovered distinct genetic diversity among 15 clinical isolates from infected individuals who experienced varied levels of disease severity.
"We wanted to see what genes were present in the different isolates," she said. "What we found was a fairly complex picture.
"There are 1,660 genes on the array, and 1,281 of those were common to all 15 strains we examined. About another 375 were variable among the isolates. This says to me that there's a core set of genes for basic metabolic activity that makes an organism H. pylori, but also that there are other genes that can come in or out that can impart capabilities related to pathogenicity."
Just what those variable genes do, and which are most critical for the bug's ability to establish infection, is the question Salama would most like to answer.
One method to do this is to introduce mutations in genes suspected to be important for pathogenicity and cultivate them in the laboratory alongside the cells that line the stomach.
She's also developed a mouse model system to learn how H. pylori attaches to cells and establishes a persistent infection inside the body.
H. pylori does not normally infect rodents. Its only natural hosts are humans and non-human primates. But scientists have identified one variant of H. pylori that does establish a chronic infection in mice.
"Infected mice don't show overt symptoms, but they do have inflammation that mimics parts of what we see in humans," Salama said. "We'll be able to use this system to identify strains of H. pylori that can't establish infection, and then, using the microarrays, figure out which genes are critical for the disease process. We'll also be able to ask questions about the role of the immune system in pathogenesis."
The organism's complex effects on human health make Salama's work a natural fit for collaborations with PHS epidemiologists.
"Part of my excitement for coming to the Hutch is to push this project further by looking at different patient populations and risk factors and correlating the disease outcomes with different genotypes," she said.
In addition, she is collaborating with Dr. Brian Reid, a PHS investigator and director of the Seattle Barrett's Esophagus Project, and Dr. David Kearney, a gastroenterologist at the Seattle Veterans Affairs Medical Center, to obtain biopsy samples from patients with H. pylori infections.
"The holy grail would be to take biopsies and analyze gene expression for that particular strain," she said. "That would help us understand which genes are critical for which type of infection."
The potential for impacting human health was what drew Salama to the study of H. pylori, a project that intrigued her while she completed graduate work at the University of California at Berkeley in the laboratory of Dr. Randy Schekman.
"I was studying secretion - how proteins are exported from the cell - in yeast," she said. "It was an excellent system for learning genetics and biochemistry because yeast is such a great model organism. But I was interested in working on a project that had a more direct connection to a medical issue."
Two- to four-fold increased risk
At the Hutch, she can focus on cancer, one of the more serious medical conditions associated with H. pylori. The bacterium was designated a carcinogen in 1994 for its ability to cause a two- to four-fold increased risk of gastrointestinal cancer.
Among her collaborations to explore H. pylori's role in cancer will be a project with Dr. Chris Kemp's laboratory to examine the disease process in strains of mice with increased susceptibility to tumor development.