Although gathering more parasite samples will likely turn up many more SNPs, this initial survey, like the recent HapMap project in humans, provides a starting point for a systematic effort to identify genes essential to malaria’s development and spread.
As Sabeti explains, SNPs passed together from one generation to the next are like signposts for genes and other functional segments of DNA that would otherwise lie buried among billions of nucleotides. Already the SNP map has spotlighted one DNA region associated with resistance to pyrimethamine and another involved in chloroquine resistance.
By looking for similarities and differences among the collected P. falciparum genomes, Sabeti says, “We can see what’s changed over time and what’s been conserved and is presumably essential to the parasite’s survival. We can also see what’s changing in response to the human immune system, which itself changes as it interacts with the parasite. That information might inform how we select drugs, or how we build vaccines.”
“We can make an educated guess about what a particular region of DNA does, then test our theory,” HSPH’s Sarah Volkman adds. “For instance, we might guess that the region represents a gene that helps transport a drug out of the parasite’s digestive vacuole, and then test that idea by artificially altering the parasite’s DNA in the lab, growing the parasite in culture, then adding in an antimalarial drug to see whether or not our change has made the parasite drug-resistant.” But rather than be guided by—and perhaps blinded by—assumptions, Volkman notes, the investigators will sort through the complete genomes of strains resistant to, say, chloroquine, in search of nucleotide segments unique to those strains.
Only a few malarial parasite genes have been identified so far. But the search should move quickly, Volkman says, given cutting-edge technologies like those developed at the Broad within the last two years.
A vaccine to prevent malaria is many researchers’ holy grail. But Wirth, who works at the forefront of this effort, says she and others are rethinking their approach in light of P. falciparum’s extraordinary genetic diversity.
Much of the variation affects proteins on the parasite’s surface, which changes constantly as it wrestles with its hosts’ immune cells. Given that an effective vaccine must lock horns with these proteins, a vaccine that works against one parasite strain might not work on another. Wirth now suspects that the best public health officials may be able to hope for is a vaccine akin to that for the flu virus, derived annually from a mix of a few predominating strains.
Meanwhile, the Boston-Senegal team’s genome mapping project marches on. Researchers have begun to analyze fresh samples from additional malaria-endemic regions, such as India, and to fine-tune their technology to permit analyses in the field. The more scientists know about P. falciparum, they say, the better the chances of subduing this formidable one-celled foe.
Karin Kiewra is the associate director of Development Communications at HSPH and editor of the Review.
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