SEVENTEENTH-CENTURY PERUVIANS looked to quinine, derived from the bark of the South American cinchona tree, as both prophylactic and cure for mosquito-borne malaria. In 1947, a synthetic version of quinine, chloroquine, became a powerful weapon against the disease. But by the mid-1960s, drug-resistant malaria strains were cropping up around the globe—and have since outfoxed a host of drugs, from sulfadoxine-pyrimethamine and mefloquine to atovaquone.
What accounts for the one-celled malarial parasite’s success in dodging these pharmaceutical bullets? A new study in Nature Genetics led by Harvard School of Public Health scientist Dyann Wirth points to the microbe’s remarkable facility at altering its genetic makeup. Whenever chance mutations in its DNA convey a survival advantage, the parasite will replicate unless drug regimens are strictly followed. In the developing world, where treatments are all too often inappropriate or incomplete, mutant parasites can proliferate—giving rise to drug-resistant strains. Over time, the parasite has rendered a succession of drugs virtually useless. Combinations that feature the ancient Chinese herbal derivative called artemisinin, currently hailed as the next miracle cure, could meet the same fate, experts say, given their increasingly widespread use.
In December, Wirth and her colleagues from the Broad Institute of MIT and Harvard University, and Cheikh Anta Diop University, in Senegal, unveiled a detailed map of the evolving genome that should help researchers track the global spread of virulent, drug-resistant strains, diagnose and treat malaria more effectively, revise their vaccine-making strategies, and guide the creation of better drugs. Already the new tool has helped identify two regions of the genome that may harbor genes underlying drug resistance.
“This study gives us one of the world’s first looks at genetic variation across the entire malaria parasite genome,” says Wirth, a world recognized authority on communicable tropical diseases who chairs HSPH’s Department of Immunology and Infectious Diseases, directs the Harvard Malaria Initiative, and co-directs Harvard’s Global Infectious Diseases Program as well as the Broad Institute’s Infectious Disease Initiative. So diverse are the strains, Wirth says, that a one-size-fits-all preventive vaccine may be unrealistic.
By building upon this genome map, “we should be able to develop a tool to detect the emergence of drug resistance in populations and track its spread,” Wirth says. Detecting drug resistance early is critical, both for choosing the optimal drug regimen for a patient and for interrupting disease transmission. If doctors can determine quickly that a patient is infected with a strain resistant to a particular therapy, she says, they can choose other medications and “get ahead of the curve, instead of waiting for clinical failure.”
According to the study’s co-first authors, HSPH Senior Research Scientist Sarah Volkman and Broad Institute postdoctoral fellow Pardis Sabeti, researchers compared 54
P. falciparum DNA samples to one another and to a benchmark strain, 3D7, which had previously been sequenced in a landmark paper published in 2002. They found extensive differences, including more than 47,000 single-nucleotide changes, known as single-nucleotide polymorphisms, or SNPs (“snips”).
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