Malaria fighters got ill tidings this week. A new analysis reveals that the microorganisms causing the disease have much greater genetic variability than previously realized, which means they could have more tricks than researchers thought for evading drugs and vaccines.
Plasmodium falciparum, the single-celled parasite that causes the most deadly of four different types of malaria, has been giving researchers trouble since the 1970s, when it developed resistance to the "wonder drug" chloroquine. Ten years ago, scientists found that large populations of the parasite died off between 3000 and 5000 years ago, creating a "bottleneck" that reduced the species's genetic variability. This spurred hopes that effective new drugs could be easily developed--and objections from some malaria researchers who thought the pathogen was more complex. To cut through the controversy, parasitologist Xin-zhuan Su of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, took another look at the bug's genes.
Su and his colleagues sequenced 204 genes in each of five Plasmodium isolates from around the globe--the most extensive survey yet. In the 18 July issue of Nature, they report that 118 of the genes showed at least one difference when isolates were compared. Using these genetic differences to reconstruct the Plasmodium family tree, the team estimates that the isolates branched off from each other between 100,000 and 180,000 years ago. Su points out that this more accurate value for Plasmodium's age corresponds to the first human population explosion, when the dramatically rising number of hosts allowed the parasite to diversify its genome.
In another study in the same issue, Su and his team compared hotspots of genetic variability on all 14 of Plasmodium's chromosomes in 87 different isolates, some of them chloroquine-sensitive and others chloroquine-resistant. They found that mutations occurred most often in the gene that allows Plasmodium to pump chloroquine out of itself. The remaining mutations could be grouped into four related batches, suggesting that Plasmodium gained chloroquine resistance four times, once in each genetically distinct set.
The results are "bad news," says population geneticist Andrew Clark of Cornell University in Ithaca, New York. The extent of genetic variability and Plasmodium's track record "makes you think, 'Whoa--these guys will be able to adapt pretty quickly to new drugs,'" Clark says. These results confirm that vaccines will need to target several aspects of parasite infection at the same time, adds parasitologist Thomas Richie of the Naval Medical Research Center in Silver Spring, Maryland.