Genome of a giant problem: MBL unravels Giardia lamblia

WOODS HOLE - Researchers at the Marine Biological Laboratory have sequenced the genome of Giardia lamblia, a parasite that causes more than 20,000 intestinal infections in Americans every year. The successful project, which reveals the entire lineup of genes in the parasite, offers hope for improved drug treatments of the infection. It might also lead to vaccines to protect against the ailment.

Symptoms of giardiasis, the infection caused by the parasite, can include abdominal discomfort, flatulence and diarrhea. "About half the cases show no symptoms, but if you have symptoms, you know something is wrong with you," says Mitchell Sogin, director of MBL's Josephine Bay Paul Center in Comparative Molecular Biology and Evolution, who led the project.

"If it is not treated, typically symptoms will last for weeks or months before abating," adds team member Rodney Adam of the University of Arizona College of Medicine. "When people have this persistent giardiasis, they will have malabsorption of nutrients from the intestine, so they will lose weight and be malnourished."

Giardiasis usually results from poor sanitation. Children exposed to diaper-changing are vulnerable to it. So are campers, hikers and swimmers who drink contaminated water in the great outdoors. That source accounts for the condition's nicknames of "beaver fever" and "backpacker's disease."

The ailment also can affect individuals unaware of any exposure. During a three-month period starting in November 1985, more than 700 cases were reported in the Western Massachusetts city of Pittsfield. Public health officials found that an auxiliary reservoir contained the parasites. More recently, researchers blamed a children's wading pool at a local country club for starting an outbreak of giardiasis near Boston in June 2003. Person-to-person contact caused the outbreak to persist until December of that year.

The most common treatment involves doses of a drug called metronidazole, or Flagyl, for five to 10 days. This eradicates the disease in more than 85 percent of cases. It can, however, cause side effects such as nausea. The U.S. Food and Drug Administration has not approved it for use against giardiasis. The only FDA-approved treatment is furazolidine, known commercially as Furoxone, administered for seven to 10 days or as a single dose.

Neither approach is entirely satisfactory. "A number of people get chronic giardiasis, which is difficult to eliminate," says Hilary Morrison, an associate research scientist at MBL who worked on the sequencing project. "So there is interest in new treatments."

Sogin and his team had more than treatments in mind when they proposed sequencing the Giardia genome. Giardia seemed to represent a very early type of eukaryote. These are organisms whose cells have well-defined nuclei. The group includes fungi, plants and people, but not bacteria and algae. "We wanted to explore whether there was evolutionary significance to Giardia," Sogin explains. "We also saw it as an unusual source of disease."

The project started in 1998. It suffered a

hiccup in late 2003, when the available technology proved inadequate. But advances in sequencing methods enabled the researchers to complete the task. They reported in the journal Science that the project provided some unexpected results.

"The first surprise was that the genome was so well behaved," Morrison recalls, meaning that the genome didn't contain any surprises, such as groupings of genes that the research team hadn't expected. "It couldn't have been more wonderful."

The research also showed that the parasite has its own strategy for evading the immune response of humans exposed to it. Its genes are scattered throughout the genome rather than existing in clusters like other parasites' genes. That enables Giardia to dodge the immune response by moving around proteins on its surfaces.

That finding points the way to potential new treatments for giardiasis.

"The genome sequence will greatly improve our understanding of the biochemistry and metabolism of the parasite," Adam explains. "We can then examine ways in which it is different from humans. That, in turn, will allow development of drugs that will inhibit Giardia but not human metabolism, and kill the parasite. The genome project will also help us better understand how the organism resists the immune response of the human who is infected, and may help in designing useful vaccines."

To develop drugs that can combat Giardia, researchers start by identifying targets on the genome. These are regions vulnerable to chemical attack intended to kill or cripple the parasite without harming the human patient who carries the disease. Morrison has identified about 100 such "druggable" targets.

The next step will be to characterize them chemically and biologically and determine what specific drug formulations might damage them.