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See Inside December 2010

Pinning Down a Deadly Shape-Shifter: Progress against the Malaria Parasite

A parasite's genome is yielding clues to how malaria kills



Cecil H. Fox Photo Researchers, Inc.

More people have died from malaria than from any other disease in history. If we look at the African parasite that causes its most severe form, it is obvious why the pathogen is so deadly. Plasmodium falciparum has a multistage life cycle and highly mutable genes. It’s already widely resistant to one of the most common medications used to treat it, chloroquine, and it is starting to evolve around a newer drug, artemisinin. Falciparum is also a shape shifter, presenting different proteins on its surface as it develops in the body and remaining one step ahead of the immune system.

All this complexity is bad news for victims. But, in a sense, it may be good news for scientists, who sequenced the organism’s genome in 2002 and are starting to figure out what malaria’s intricate biology says about its natural history. Until recently, for instance, researchers thought falciparum had jumped into humans from chimps. But in September a team from Alabama—known for its work on the origin of HIV—showed that all falciparum parasites are descended from a single lineage that jumped from gorillas millions of years ago. Since then, the parasite has been furiously evolving. Drug resistance is part of that. But a much more important factor, according to researchers at the Broad Institute of M.I.T. and Harvard, is the human body itself. The malarial genes under the most intense selection pressure—those with the most variation, generated over a millennium-long cat-and-mouse game with the immune system’s antibody response—are the ones that encode the identifying proteins on the surface of the parasite. Scientists have struggled to explain why some people get very sick from falciparum, whereas others suffer only mild symptoms; early work suggests that some of these “var” genes are behind serious cases in children.

One of the crucial next steps in understanding malaria’s genome will be assessing how it differs from parasite to parasite and region to region. “Knowing the amount of variation within an individual is crucial,” says Dominic Kwiatkowski, who leads malaria genomics research at the Wellcome Trust Sanger Institute near Cambridge, England. “Fortunately, we can quantify that with extraordinary precision.” Kwiatkowski’s group and others recently built MapSeq, an interactive database of genotyped samples from several hundred patients around the world. Researchers can use it to look for mutations unique to their areas—and to tailor their control strategies around them.

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