Malaria's genetic secrets revealed

By LIDIA WASOWICZ, UPI Senior Science Writer  |  Oct. 2, 2002 at 2:42 PM
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Taking aim to strike out a disease that infects some 500 million humans and kills nearly 3 million a year, international teams of geneticists announced Wednesday they have completed a landmark triple play against malaria.

In simultaneous reports, deemed significant enough to warrant special sections in two prestigious scientific periodicals -- the American journal Science and the British journal Nature -- and news conferences on two continents, investigators said they have deciphered the complex genetic code of a parasite that causes the scourge and an insect that spreads it. They have, in scientific parlance, sequenced the genomes of Plasmodium falciparum -- the most lethal malaria parasite -- and its transport vehicle, the mosquito Anopheles gambiae.

With the human hereditary roadmap already in hand, the added genetic blueprints present scientists with unprecedented opportunities to finally rein in the world's deadliest tropical disease. Most prevalent among African preschoolers, the infection kills one child every 20 to 30 seconds.

"The sequencing of both P. falciparum and its insect vector heralds a new era in the fight against malaria," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "When joined with information we have about the human genome, a much fuller understanding of this disease and its transmission is now possible ... This extraordinary scientific achievement ... will speed efforts to investigate and develop control strategies for this devastating disease," Fauci said.

No one expects an overnight cure. However, few seem to question the importance of the work, by nearly 300 scientists at two dozen institutes around the globe.

"The published sequence must be regarded as a milestone that will be a major asset to biomedical researchers," said Russell Doolittle of the Center for Molecular Genetics at the University of California at San Diego, who analyzed the findings.

"This detailed map of the parasite's 5,300 genes and their predicted functions is a milestone in malaria research," agreed Michael Gottlieb, chief of NIAID's parasitology and international programs branch. "The information it provides will enable investigators to design antimalarial drugs targeted precisely to areas of genetic vulnerability,"

The findings, described at news conferences in both Washington and London, will be published in the Oct. 3 issue of Nature and on Oct. 4 in Science, the journal of the American Academy for the Advancement of Science. Nature carries the parasite results, Science includes the mosquito research.

"Alleviating the (large, and growing) burden of malaria (500 million cases of illness and 2 to 3 million deaths each year) will depend on both public health measures and scientific advances," said David Roos, Merriam Professor of Biology, director of the Genomics Institute and Burroughs Wellcome Scholar in Molecular Parasitology at the University of Pennsylvania in Philadelphia, who wrote a commentary on the findings.

"In the latter category, we need better strategies for malaria vaccine development, and new targets for chemotherapeutic drugs," he told United Press International.

Already, two new vaccine candidates, developed in England, are headed for a trial run in Gambia, a malaria hotspot on the North Atlantic shores of west Africa. Both are based on data the researchers had posted on the Internet overnight to give other scientists instant access as the project progressed.

"We've given people a head start," said Richard Hyman, research associate at the Stanford Genome Technology Center in Palo Alto, Calif., and lead author of one of seven Nature papers on the parasite sequencing.

Due to the unusual nature of falciparum's genetic structure, the painstaking work was divvied up among investigators at Stanford, the Wellcome Trust Sanger Institute in Cambridge, England, and The Institute for Genomic Research in Rockville, Md.

"It took six years of extremely hard work to decipher and analyze the malaria parasite's genetic code," said Claire Fraser, president and director of TIGR.

Perhaps because of its unusual composition, Plasmodium's genetic material cannot be broken up into strips of varying lengths, only into very short segments. This makes handling it as difficult as trying to repair a vase shattered into hundreds of smashed shards, a task far more demanding than fixing a vessel broken into a few large pieces, scientists explained.

The technique devised to tackle the problem will come in handy in future research on tricky genomes: As soon as work was underway, the investigators began sharing their raw data -- four years before publication.

"Sequencing will not relieve the suffering of people with malaria, and drugs and vaccines take a long time to develop and test," said Neil Hall, project manager at the Sanger Institute who helped construct the genetic map of the single-cell organism. "But because we have released our data freely to the scientific community throughout the project, this should bring new discoveries forward," he told UPI.

More than 200 scientific articles on malaria that relied in part on the preliminary data already have been published, including reports of newly discovered parasite molecules that could be targeted by anti-malarial drugs.

One group began a "proteomic" analysis of the parasite two and a half years ago, an action they normally could not take until after publication of the genome sequence. Proteomics specialists link proteins to disease by noting their altered production levels in normal and abnormal states.

"This is the first time a large-scale proteomic study is being published at the same time as a genome paper," said cell biologist Laurence Florens of The Scripps Research Institute in La Jolla, Calif., co-author of the Nature paper taking a proteomic view of the malaria parasite.

"In general, large-scale gene and protein expression studies depend on finished genome sequences and hence lag one step behind genome completions," he told UPI. "Because (of the early malaria data release), we were able to get a head start on the proteomic project."

Proteins have a hand in such everyday, life-sustaining processes as bringing sugar molecules into the body's cells, he noted. A snapshot of these processes could give clues to the most effective modes of attack.

"The impact of these findings is already being felt," Roos told UPI. "As a result (of their early release), numerous potential drug and vaccine targets are already being studied."

Some of the 60 percent of the newly identified genes with unknown functions may hold the key to the parasite's survival -- and destruction, said Dyann Wirth of the Department of Immunology and Infectious Disease at the Harvard School of Public Health in Boston, who analyzed the findings.

"The complete genome ... provides a complete catalog of all enzymes and structural proteins in the cell, which can be assembled to produce an essentially complete metabolic pathway map for the parasite," Roos told UPI.

"Mapping these pathways, and comparing them with their human counterparts (because a drug that killed both parasite and patient would not be very useful), serves to highlight promising targets for drug design."

Other groups used the information to start comparing the genetic makeup of P. falciparum to that of the rodent malaria parasite, P. yoelii yoelii, which is used as a model to study the human form of the disease.

"(The finding) has opened up the field of comparative malaria genomics, which is a step towards the goal of designing better antimalarial drugs and constructing an effective malaria vaccine," first study author Jane Carlton, TIGR associate investigator, told UPI.

The research -- reported and reviewed in 37 articles -- represents a technical tour de force, with manifold implications for basic research and medicine, researchers said.

"This is the first time that we know all the 'secrets' of malaria's 'private life' and understand the full extent of its armory at its disposal to cause havoc within the human population, particularly among young children in sub-Saharan Africa," said study co-author Arnab Pain, senior computer biologist at the Sanger Institute.

"The comprehensive atlas of the genome of the malaria parasites serves as the foundation for all future studies in search for new/novel drugs and/or vaccines to fight malaria," he told UPI.

United Nations Secretary General Kofi Annan said in a statement the deciphering of the malaria parasite and mosquito genomes "constitute a potential major breakthrough for the development of novel strategies in combating malaria."

The achievements mark an important advance against the stubborn scourge that holds much of the developing world in a deadly grip, scientists said.

Seemingly impervious to international efforts to defuse it, the malaria epidemic runs rampant in sub-Saharan Africa and other sub-tropical and tropical countries, decimating populations of preschoolers, resisting drug treatments and posing a quandary for those who would vaccinate it out of existence.

The most immediate applications of the new findings might include gauging the extent of the parasite's drug resistance, Wirth told UPI.

"It will now be possible to examine parasites where resistance has appeared but not yet spread," she said in a telephone interview. "This could serve as an early warning system that the effectiveness of a particular drug is being compromised and that it's time to switch to another therapy."

In the Science reports, which culminate three years of research by 123 investigators, scientists describe the ordering of 14,000 genes in the A. gambiae mosquito, without which the malaria parasite could do no harm.

The feat could lead to the development of new mosquito repellants, insecticides and mosquito vaccines, said lead author Robert Holt of Celera Genomics, Inc. of Rockville.

The completion of the genetic map points to a new approach to the study of mosquitoes, including how to reduce the spread of malaria by the Anopheles mosquito, and of diseases such as West Nile, encephalitis, dengue and yellow fever by other mosquitoes, scientists said.

The failure to eradicate malaria bespeaks the complexity of the disease.

Of the handful of mosquito species that carry the microscopic malaria parasite, only the genus anopheles transmits the disease characterized by fever, chills, headache and sweating and, in the most severe cases, organ failure, coma and death. Of the four species of malaria parasite, falciparum presents the deadliest threat. Once infected through a mosquito, the patient faces a lifelong threat of recurrence, even after successful drug treatment.

Subduing the malaria menace has become an increasing challenge with the emergence of drug-resistant parasite strains and insecticide-tolerant mosquitoes. No vaccine is available, and the best protection is avoidance of mosquitoes, the obligatory hosts for malaria because the parasite cannot be passed from human to human.

"The completion of the malaria parasite genome and the results of large-scale gene and protein expression studies are not the end of the road," Florens told UPI. "Malariologists have now a better map to explore new avenues to potentially defeat the disease."

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