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The Parasite and the Mosquito
Malaria's deadly partners are sequenced
By Kate Dalke

Featured Article.

Scientists have sequenced the genome of the most dangerous human malaria parasite Plasmodium falciparum and the genome of Anopheles gambiae, the mosquito that transports the deadly disease from person to person. Malaria kills more than two million people every year, most of them children in sub-Saharan Africa.

The Anophles gambiae mosquito is the primary malaria-causing vector in humans.

With the draft sequence of the human genome, researchers now have access to three key genomes in the life cycle of malaria: the parasite, the carrier and the host. Details about the biology of the disease have begun to emerge—along with new ideas about how to curb the spread of malaria with drugs, vaccines and insecticides.

The genomes, researchers say, will not bring relief to those suffering from malaria now, nor do they guarantee the development of better drugs. While the genomes open new avenues of research, more money for research and the delivery of drugs to the people who need them remains an urgent priority.

"This is just the beginning," says Malcolm Gardner, who led the sequencing of the parasite at The Institute for Genomic Research (TIGR) in Rockville, Maryland. "Despite decades of research, we don't know as much about the parasite as we once thought."

Resistance is one of the big obstacles to controlling malaria. In Africa, the parasite's resistance to the inexpensive and commonly used drug chloroquine is widespread. Meanwhile, the mosquito's resistance to DDT and other insecticides has grown, making some insecticide-coated nets useless.

Currently, no effective vaccines exist. The malaria parasite is a crafty pathogen; it can change proteins on the surfaces of its cells to evade detection by the human immune system. As soon as the immune system begins to recognize and attack the parasite, it switches its surface armor of proteins.

Plasmodium on the basal side of the mosquito midgut.

But there is hope that a vaccine could one day be developed. Children from endemic areas that survive beyond the age of three develop natural immune resistance to the disease. Thus, the body can be trained to recognize and fight malaria.

The P. falciparum genome may help identify potential proteins to target in a new vaccine. The scientists identified over 200 genes involved in immune evasion and plan to study the signals that allow P. falciparum to constantly present different combinations of proteins.

Over half of the parasite's genes code for proteins that have never been seen before. This may prove useful because these proteins are not found in humans and they may make good drug targets.

"If finding a malaria vaccine is like finding a needle in a haystack," says Neil Hall of The Wellcome Trust Sanger Institute in the U.K. and a member of the genome project, "then we just provided the haystack."

The parasite and mosquito genome projects had different origins and obstacles. The P. falciparum project began six years ago, at a time when money and technology for genomics were sparse and only three microbial genomes had been finished. The A. gambiae genome was sequenced in a matter of months and completed in about a year.

Due to the daunting size of the parasite genome—considered large at the time—chromosomes were sequenced one-by-one by researchers at Sanger, TIGR, and the Stanford Genome Technology Center in Palo Alto, California.

The international project involved over 150 researchers from these institutions, including the Naval Medical Research Center in Silver Spring, Maryland, and others. Over the last six years, the scientists released their data via the Web.

Assembling the parasite genome was hard work, because it consists almost entirely of two letters of the genetic code—As and Ts, and only a few Cs and Gs. "It's like trying to put together a jigsaw that's all one color," says Hall.

The mosquito, Anopheles gambiae, transmits the malaria-causing parasite, Plasmodium falciparum, to humans, where the parasite completes several stages of its life cycle.

The more recent Anopheles project benefited from new technology and methods of sequencing. The whole-shotgun sequencing was a public-private partnership, including researchers from the United States, Germany, Israel, Greece, Spain, and Italy. Sequencing of the 278 million base pairs was led by Celera Genomics in Rockville, Maryland.

For the project, the researchers collected DNA from hundreds of male and female mosquitoes that was combined to assemble the final genome sequence. The researchers found genes that may make mosquitoes resistant to insecticides and that give them an uncanny preference for human blood.

For instance, researchers identified a family of odor receptor genes found only in Anopheles that may influence how the mosquito picks its human blood meal. The receptors are expressed in the antennae during feeding. These 19 genes could be used to help design an insect repellant that would deter the mosquitoes from biting humans.

The scientists also discovered four genes involved in resistance to DDT that help the mosquito metabolize natural products rather than those found in insecticides.

"Historically, some of the greatest advances in malaria research have come from mosquito controls, rather than directly targeting the parasite," says Robert Holt of Celera Genomics, a member of the Anopheles sequencing project published in Science.

Efforts to block the parasite have been confounded because P. falciparum is hard to work with in the laboratory. Certain stages of its life cycle cannot be recreated in the lab, and the parasite does not grow inside non-human hosts.

As a way to study the disease in mice, scientists have used other malaria parasites. They have now also sequenced Plasmodium yoelii yoelii—one of four species of rodent malaria parasites.

Plasmodium yoelii yoelii was originally isolated from the African thicket rat 40 years ago and has since been adapted to grow in laboratory rats, mice and hamsters. Experimental procedures developed with P. y. yoelii have been used on the human malaria parasite.

"Yoelii is a good model system, but not an excellent model system for Plasmodium falciparum," says Jane Carlton of TIGR, who led the P. y. yoelii sequencing project.

Many of the host-evasion genes found in P. falciparum are not found in P. y. yoelii. The very genes that may be useful for developing a vaccine are not found in the rodent malaria parasite.

The shrinking range of malaria is depicted by overlaying WHO maps for malaria risk for the years 1946 ( pink), 1966 (red), and 1994 (brown).

Carlton is now leading a project to sequence another major human malaria parasite called Plasmodium vivax. This pathogen is less virulent, seldom fatal and the most frequent of all human malaria strains.

Plasmodium vivax will usher in yet another milestone in malaria research with access to three malaria parasite genomes: P. falciparum, P. y. yoelii, and P. vivax. Scientists hope to compare these three genomes to find molecular markers to study the spread of resistance and what makes one strain more virulent in its host than the others.

"Comparative malaria genomics has really taken off with these sequences, and it will only get better with the vivax genome coming quickly behind," Carlton says.

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Carlton, J.M. et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature 419, 512-519 (October 03, 2002).
Gardner, M.J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498-511 (October 03, 2002).
Holt, R.A. et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science 297, 129-149 (October 04, 2002).

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