A woman stops Haque to discuss her daughter, one of 235 children he is monitoring to learn about amebiasis, a parasitic disease that each year causes about 50 million illnesses and up to 100,000 deaths worldwide. Haque is an HHMI international research scholar who heads the parasitology lab at the Center for Health and Population Research in Dhaka, Bangladesh's capital city.
Haque and the anxious mother review the familiar questions. Does the child have diarrhea? For how long? Is there blood in her stool? Haque's colleague, Lutfar Rahman, who accompanies him on these weekly tours and lives in a house around the corner, arranges for the girl to receive free treatment.
Hasna. Sultana. Amir. Rafique. Kalim. They are the children of Mirpur, one of many such neighborhoods in Dhaka, and they get amebiasis at an alarming rate. In some children, infection from the parasite Entamoeba histolytica does not necessarily lead to illness, and when illness does occur, it tends to be less acute than other diarrheal diseases such as cholera and rotavirus. In children and adults of poor families who are already malnourished, however, the bug can sap strength and cause liver abscesses.
Haque has been studying the children of Mirpur for several years and recently published what a reviewer for The Journal of Infectious Diseases called "critical insights" into why some become infected more than others. Combining epidemiology with molecular biology, Haque showed that children with antibodies to E. histolytica in the mucous lining of their digestive tracts were less likely to become re-infected (see figure at right). Their immunity was only partial and short-lived, but the fact that it existed and was mediated by antibodies in the gutrather than in the bloodstreamcaught the attention of amebiasis researchers and others interested in the underlying science of how deadly parasites infect the children of the developing world.
"Until recently, scientists were using traditional techniques like microscopy to study parasitic diseases," says David Sack, a Johns Hopkins University researcher who directs the Dhaka center. "Now, with new molecular tools, we're in a position to make real progress. It's essential that we not limit these tools to places like Hopkins, Harvard and Stanford, where you don't get the reality check of patients coming through the door with these diseases every day."
Haque gets his daily reality check as he walks up to his office. Beside the stairs are rows of beds from the Center's hospital, still known locally as "the cholera hospital." The beds have mattresses with holes in their centers for patients too weak to rise during bouts of diarrhea.
The children's wards are the most crowded, filled with mothers who dab at their children's bottoms with pieces of saris and feed them water mixed with sugar and salts. Last year, the Bill & Melinda Gates Foundation presented its first $1 million global health award to the Center for its role in developing oral rehydration therapy, which has saved countless lives in Bangladesh and elsewhere.
Upstairs, in Haque's laboratory, a poster displays "eggs and larvae found in faeces." A tray holds test tubes with saliva samples from the children, which Haque's team will test for antibodies. Inside a drawer are the latest stool samples, to be tested with an assay that Haque helped develop to distinguish between E. histolytica and E. dispar, a nonpathogenic infection that looks identical under the microscope. About two decades ago, the discovery that there are genetically distinct varieties of the parasite cast doubt on the validity of much of the previous research on amebiasis.
Haque's laboratory has curiosities such as a huge jar filled with 2,269 Ascaris lumbricoides worms gathered from 114 people, but it lacks expensive equipment such as the fluorescence-activated device he'd like that would speed the sorting of different cell types from samples. Still, Haque has been able to probe how T cells, B cells and other players in the immune system respond when parasites invade.
"Recently, I've been focusing on the cellular immune response, which involves the T cells," he explains. "We're hoping to begin some new kinds of genetic analysis, since there has to be a reason why some children get infected more easily than others, and why only a few get sick while most are asymptomatic. Their genes may play a role."
Haque's collaborator, William Petri, Jr., of the University of Virginia, has identified and characterized the part of the parasite that latches onto human cells, and demonstrated that the attachment sets off intracellular signals that cause the cells to commit suicide. Working in vastly different settings, the two men have become close friends, communicating daily by e-mail and meeting at each other's laboratories, although Haque jokes that he still cannot persuade Petri to eat spicy Bengali cuisine.
"Sometimes when you have a collaboration, you give more than you get," Petri says. "It's been just the opposite for me. This is definitely not a program that's intellectually driven from the United States." Petri notes that it was Haque who suggested they check the children for antibodies in their digestive tracts as well as their blood. "It didn't occur to me to test for an immune response in the stool," Petri recalls, "but Rashidul was familiar with the cholera literature and thought we should do it."
Both men say their goal is to develop a vaccine for amebiasis, which afflicts people throughout the world. "Understanding the natural history and immune response to amebiasis is essential," says Petri, who has begun talking with companies about such an effort. Vaccine developers may well seek to mimic the immune response that Haque and the others discovered in the gut, but they'll need to boost this protection and make it last longerand provide it cheaply to children in places like Mirpur.
Walking through the slum during his weekly visit, Haque reflects on the special problems he faces carrying out biomedical research, which he began pursuing as a doctoral student in Bulgaria. During this two-hour visit to Mirpur, the power has gone out three times, the water stopped and a political demonstration blocked the roads. Haque is also concerned about the delivery of supplies from abroad and about his three-year-old daughter, who just got diarrhea after eating at a fast-food shop.
Still, he remains focusedand remarkably optimistic. "There are very few of us working on amebiasis around the world," he says. "It doesn't get as much attention as a lot of diseases that affect fewer people, but with all of these new tools, we really are making progress."
Petri concurs, emphasizing that high-tech research into everything from the molecular structure of the antigen to the genetic variations among both people and parasites must be accompanied by studies in places like Mirpur. "If you're doing laboratory research, you need to see if your ideas will work in the real world," he says. "I couldn't possibly do the kind of study that Rashidul is doing, even if I was there every day. His team knows the people and can relate to them. They provide them with free medical care. If it weren't for them, we'd have no idea whether the research we're doing here in the States makes sense."
Photo: Fakrul Alam
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Reprinted from the HHMI Bulletin,
December 2001, pages 22-25.
©2001 Howard Hughes Medical Institute