In a landmark contribution to the age-old battle against malaria, a consortium of scientists including The Institute for Genomic Research (TIGR) announced today that they have deciphered the complex genetic code of the parasite that causes the deadliest form of the disease. Malaria is one of the world's most devastating infectious diseases, killing more than a million people a year in developing nations.

The scientific paper analyzing the genome of that parasite, Plasmodium falciparum, is being published this week in the journal Nature along with a comparison of the genome to the genetic sequence of a rodent malaria parasite, P. yoelii yoelii, which is used as a model to study the human form of the disease.

Claire M. Fraser, Ph.D., president and director of TIGR, said the institute's six years of research to help sequence the two malarial genomes represented only the first steps in its ambitious parasite genomics program. TIGR researchers are now tackling the genomes of the second major human malaria parasite, P. vivax, as well as deciphering the genetic codes of other pathogens that sicken or kill millions of people – including parasites that cause African sleeping sickness, Chagas disease, schistosomiasis, amoebic dysentery, lymphatic filariasis, and opportunistic infections in HIV/AIDS patients.

"It took six years of extremely hard work to decipher and analyze the malaria parasite's genetic code," said Fraser. "This achievement has built a solid foundation for a new generation of research to find more effective drugs and vaccines to treat this devastating disease." She added: "The lessons we learned from the work on the malaria parasite's genetic code are now helping TIGR and others to investigate a host of other parasites."

The P. falciparum genome project involved a total of about 150 researchers at TIGR and the Naval Medical Research Center in Silver Spring, MD; the Wellcome Trust Sanger Institute in Hinxton, U.K, and at the Stanford Genome Technology Center in Palo Alto, CA. Sanger sequenced nine of the parasite's chromosomes; TIGR sequenced four and Stanford completed one chromosome. In addition to its sequencing work, TIGR played an organizational role in coordinating the analysis of the genome and serving as the central repository for the data from the three sequencing centers.

"It's one of the most difficult genome projects we have ever tackled," said Malcolm J. Gardner, the TIGR Associate Investigator who is the first author of the main P. falciparum genome paper and has been working on the project since it started in 1996. The genome was so tough to decode because about 80% of its sequence consists of only two of the four DNA chemical building blocks. "That makes the parasite's DNA very difficult to isolate and to sequence," Gardner said. "We persevered because we knew that this project would lay the groundwork for future research that will help combat malaria."

Lessons From the Genetic Code

The malaria parasite's success as a pathogen depends partly on its ability to evade elimination by the human immune system. Gardner said the genome analysis identified about 200 parasite genes that produce proteins involved in that elaborate evasion.

Previous research had shown that, during the stage of its life cycle when it develops inside red blood cells, the parasite produces at least two types of proteins that are exposed on the surface of the infected blood cells. In a sort of complex disguise, the parasite evades the host's immune response by expressing different versions of the proteins on the blood cell's surface – thus confounding the immune responses that aim to destroy the infected cells.

The genes for most of those evasive proteins are found near the ends of chromosomes. That location makes it easier for the parasite – during the reproductive stage when it is carried by a mosquito – to alter the structure of these proteins through changes in the genes that encode them. Gardner said the genome sequence now defines, for the first time, a complete set of those evasive proteins from a single parasite. Further genome studies of other P. falciparum parasites isolated from malaria patients will identify other variants and provide insights into the pathogen's immune evasion process.

Overall, researchers said, the P. falciparum genome consists of about 24 million DNA base pairs that are distributed among 14 chromosomes and encode nearly 5,300 genes. The genome analysis revealed many of the parasite's metabolic pathways – the processes by which the parasite produces the energy and components it needs to survive. The malaria parasite has much lower metabolic capability than other free-living microbes such as yeast, and relies on the host to provide many of the nutrients required for its growth. However, some of the enzymes identified in Plasmodium have no counterparts in the human host and may make good targets for chemotherapy, Gardner said. Many of those enzymes appear to be located within a specialized structure called the apicoplast, which is found only in the malaria parasite and a few similar organisms.

Impact On Malaria Research

Much of the P. falciparum sequencing data has been made available to other scientists via the Internet during the six-year project. More than 200 scientific articles on malaria already have been published which relied in part on the preliminary genomic data released by the consortium, including reports of newly-discovered parasite enzymes that could be targeted by anti-malarial drugs.

In the United States, the major funders of the P. falciparum research were the National Institute for Allergy and Infectious Diseases (NIAID), The Burroughs Wellcome Fund, the Naval Medical Research Center, and the U.S. Army Medical Research and Materiel Command. In the United Kingdom, the major funding agency was the Wellcome Trust.

Also this week, the journal Science is publishing the genome of the mosquito Anopheles gambiae – the insect "vector" that carries the deadly form of human malaria. TIGR researchers contributed to that sequencing effort – which was led by Rockville-based Celera Genomics Corp.-- by producing about 40,000 BAC end sequences (large fragments of DNA), which were essential to the assembly of the Anopheles genome sequence.

J. Craig Venter, Ph.D., the founder and current Board chairman of TIGR, led Celera's sequencing of the human genome and was one of the originators of both the mosquito and malaria genome projects. He said that deciphering the genetic code of all three organisms involved in the disease -- the parasite, the vector and human host -- represents "a major development in the fight against malaria and a victory for genomics as a crucial tool that promises to help biomedical researchers fight an array of diseases." Venter is president of The Center for the Advancement of Genomics (TCAG) and the Institute for Biological Energy Alternatives (IBEA) in Rockville, MD.

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

Dr. Mike Dexter, director of the Wellcome Trust, said: "Some scientists believed it would never be possible to finish this program because of the technical difficulties. But a high-caliber international collaboration has shown that sometimes you can achieve what other people claim would be impossible."

Comparative Genomics

An accompanying TIGR paper in Nature compares the genome sequence of the human malaria to that of the rodent malaria P. y. yoelii. This represents the first time that scientists have compared the entire genetic code of a "model" parasite – one used to represent the human parasite in laboratory experiments with mice or rats -- with the genome of the human parasite.

TIGR Associate Investigator Jane M. Carlton, the first author of that paper who led the team that sequenced the P. y. yoelii genome, said a detailed analysis indicated that the rodent malaria is a useful model for certain – but not all -- aspects of the human parasite. The analysis found that 60% of the genes identified in P. falciparum were also in the rodent malaria parasite's genome, but that there were not counterparts for many of the antigen genes that might be useful for the development of a vaccine.

In contrast, a large family of variant antigen genes in the rodent malaria were identified which are very similar to a family of genes involved in evading the host's immune system in P. vivax, the most widespread (but rarely fatal) human malaria. "This means that the rodent parasite may be a better model for studying how the P. vivax malaria parasite evades the immune system than how the deadlier P. falciparum parasite does so," Carlton said.

"Identifying common genes between the two species provides an extremely useful resource for malaria researchers who focus on one or a handful of particular genes in seeking to develop better drug targets or intervention strategies to treat malaria," she added.

The P. y. yoelii genome project was supported by the U.S. Department of Defense (DOD). Carlton's team is now nearing completion of the P. vivax genome, in a TIGR project funded by DOD and NIAID.

TIGR researchers, along with scientific collaborators at Sanger and elsewhere, are also now sequencing the genomes of several other parasites, including:

• Trypanosoma brucei, which causes African sleeping sickness
• Trypanosoma cruzi, which causes Chagas' disease, mainly in the Americas
• Schistosoma mansoni, a parasitic worm that causes schistosomiasis
• Toxoplasma gondii, which causes opportunistic infections in HIV/AIDS patients
• Entamoeba histolytica, an enteric parasite that causes amoebic dysentery
• Brugia malayi, a parasitic nematode that causes lymphatic filariasis
• Trichomonas vaginalis, a protozoan parasite which causes vaginitis
• Theileria parva, a malaria-like parasite that causes East Coast fever in African cattle.

The Institute for Genomic Research (TIGR) is a not-for-profit research institute based in Rockville, Maryland. TIGR, which sequenced the first complete genome of a free-living organism in 1995, has been at the forefront of genomic research since it was founded by J. Craig Venter in 1992. TIGR conducts research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes--higher animals and plants.

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Additional Media Contacts:

Malcolm J. Gardner, TIGR Associate Investigator
Tel. 301-838-3519
E-mail: gardner@tigr.org

Jane M. Carlton, TIGR Associate Investigator
Tel. 301-838-5855
E-mail: carlton@tigr.org

Contact: Robert Koenig, rkoenig@tigr.org, 301-838-5880, The Institute for Genomic Research

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