Science Editor

Three key co-conspirators, implicated in the war against malaria, gathered Wednesday morning at auditoriums in London and Washington. The triad represented, first, a pathogenic parasite called Plasmodium falciparum, which wreaks the deadly infection in human victims. The second, an insect, Anopheles gambiae, flies the P. falciparum to its grim rendezvous. The third, Homo sapiens, is the target of the other two perpetrators. Humans supply those two with their daily lifeblood.

The simultaneous trans-Atlantic press conference was co-sponsored by two weekly journals, the American Science and the British Nature. Science's cover story, dated Oct. 4, 2002, is titled: "The genome sequence of the malaria mosquito Anopheles gambiae."

The paper's 124 listed co-authors are researchers at 20 international sequencing centers - nine American, three British, two French, and one each in Israel, Spain, Germany, Russia, Greece and Italy.

Nature's cover story - which depicts the microorganism emerging from its human red blood cell - carried the title: "Genome sequence of the human malaria parasite Plasmodium falciparum." Its 26 co-authors are at seven American, five British and one Australian centers. In a show of unwonted collegiality, both consortia listed Claire Fraser at the Institute for Genomic Research and her husband, J. Craig Venter, at the Center for the Advancement of Genomics, both in Rockville, Md.

Half a dozen supplementary papers in Nature, and 24 numbered back-up articles in Science flesh out the genomic and proteomic analysis of the insect and the pathogen.

"The parasite Plasmodium falciparum," Nature's lead paper began, "is responsible for hundreds of millions of cases of malaria, and kills more than 1 million African children annually. Its 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,268 genes, and is the most (A+T)-rich genome sequenced to date. A large proportion of its genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in P. falciparum's fatty-acid metabolism. It's a relict plastid, homologous to the chloroplasts of plants and algae. The apicoplast is essential for parasite survival, but its exact role is unclear," Greenwood observed. "It does seem like an attractive target for antimalarial drugs."

"The P. falciparum, Anopheles gambiae and Homo sapiens genome sequences have been completed in the past two years," the Nature paper concluded, "and represent new starting points in the centuries-long search for solutions to the malaria problem. For the first time, a wealth of information is available for all three organisms that comprise the life cycle of the malaria parasite, providing abundant opportunities for the study of each species and their complex interactions that result in disease.

"The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria."

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There are an estimated 300 million to 500 million cases and up to 2.7 million deaths from malaria each year. The mortality levels are greatest in sub-Saharan Africa, where children under 5 years of age account for 90 percent of all deaths due to malaria. Approximately 40 percent of the world's population lives in malarial areas.

P. falciparum's genomic size totals 22.8 million base pairs, nearly twice the 12.5 million bp of Saccharomyces cerevisiae, baker's yeast. Its 5,628 gene count is slightly under the yeast's 5,770. Its percent of coding genes is estimated at 52.6 percent, compared to the yeast's 70.5 percent.

"From a public health perspective," commented one of Science's 124 co-authors, "Anopheles gambiae is the most important insect in the world. Its genome will help scientists design better methods to control this insect vector, accelerating the design of new insecticides and repellants, and possibly leading to the development of genetically modified mosquitoes. The insect's sequenced genome totals 278 million base pairs, an inferred 444,963 SNPs (single-nucleotide polymorphisms) and 15,189 Anopheles gene predictions. Those numbers compare with fruit fly Drosophila melanogaster's 122 million base pairs. Their gene populations differ by less than 20 percent."

Analysis of the human protein set revealed 1,077 duplicated blocks containing 10,310 gene pairs, including some blocks harboring fewer than 200 genes. Thus, the human analysis revealed more than 10 times the number of potential segmental duplication blocks found in the mosquito, despite a proteome that is only twice as large.

A. gambiae is both an elegant, exquisitely adapted organism - and a scourge of humanity. It's the major vector of P. falciparum in Africa, and is one of the most efficient malaria vectors in the world. Its blood meals come almost exclusively from humans, its larvae develop in temporary bodies of water produced by human activities, such as agricultural irrigation or flooded human or domestic animal footprints. The adult insects rest primarily in human dwellings, where the living is easy.

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After metamorphosis into an adult mosquito, female anophelines take sugar meals to maintain basal metabolism and to energize flight. Flying is needed for mating and finding a host that will provide a protein-rich blood meal source. The Anopheles genome should spur genomic studies of other species of mosquitoes that carry diseases, such as West Nile virus.

Entomologist Thomas Scott at the University of California at Davis, commented: "The optimism that mosquito-borne diseases can be effectively controlled, or even eradicated, with inexpensive drugs, vaccines or insecticides has been sorely tested. The impact of drugs is debatable, vaccine development is slow, and mosquitoes are becoming resistant to insecticides, including those used to impregnate bed netting. Such shortfalls have been used to justify research on mosquito population replacement - that is, the release into natural mosquito populations of genetically modified mosquitoes rendered refractory to pathogenic infection - to reduce or eliminate malaria's transmission to humans."

Editor's note: The A. gambiae sequence data are all available in publicly accessible online databases at the European Bioinformatics Institute (www.ebi.ac.uk), the National Center for Biotechnology Information (www.nebi.nlm.nih.gov), and elsewhere.