Harvard Public Health Review Winter 2007
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The Wily Malaria Parasite

Sarah Volkman, Dyann Wirth, Pardis Sabeti

MAP MASTERS At the Broad Institute of Harvard and MIT, these scientists are mapping the evolution of malaria parasite strains around the world (left to right): Sarah Volkman, senior research scientist in the Department of Immunology and Infectious Diseases at HSPH; Dyann Wirth, the department’s chair, the Richard Pearson Strong Professor of Infectious Diseases, and co-director of the Broad’s Infectious Disease Initiative; and Broad post-doctoral fellow Pardis Sabeti.

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.

Harvard + MIT =
The Broad Institute

Explorations of genomes — human, microbial, and otherwise — happen at the intersection of basic science and advanced technology. The Broad Institute, a joint venture of MIT and Harvard University, was built at that crossroads. It is home to one of the most advanced genome-sequencing laboratories in the world.
“Genomic tools have largely been applied to first-world diseases up to now,” says Eric Lander, the Broad’s director, a driving force behind the Human Genome Project, and an author of the
Nature Genetics P. falciparum genome-mapping study led by HSPH’s Dyann Wirth. The study “underscores the power and importance of applying these tools to the devastating diseases of the developing world,” he says.

“Knowing the enemy will be a crucial step in fighting it.”
Created in 2004 and named for founding philanthropists Eli and Edythe Broad (pronounced “Broad” as in “genetic code”), the Broad Institute grew out of longstanding collaborations among geneticists, physicians, and molecular, chemical, and computational biologists. Member institutions include MIT’s Whitehead Institute for Biomedical Research; the Harvard School of Public Health; Harvard University’s Faculty of Arts and Sciences; the Institute of Chemistry and Cell Biology at Harvard Medical School; and five Harvard-affiliated institutes and teaching hospitals.

The Broad’s eight major research programs include the Infectious Disease Initiative, co-led by Wirth, which encompasses malaria, tuberculosis, HIV, and other communicable diseases. One of two U.S. centers funded by the National Institutes of Allergy and Infectious Disease, the Broad is a national hub for sequencing and analyzing more than 100 bacterial, fungal, and parasite genomes. Data from its Microbial Sequencing Center are available without charge to scientists worldwide who are studying drug resistance, disease transmission and pathogenicity, and vaccine development.

For more information, visit the Broad Institute’s website at http://www.broad.mit.edu.

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.

For more information
The P. falciparum genome mapping project was made possible by several philanthropic organizations, most notably the Bill & Melinda Gates Foundation, the Burroughs-Wellcome Fund, and the Exxon Mobil Foundation. Data are available at no cost from the public database Plasmo DB (www.plasmodb.org); the Broad Institute’s website, at http://www.broad.mit.edu/seq/msc/; and the National Center for Biotechnology Information, http://www.ncbi.nlm.nih.gov/.

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