Gene Maps of Malaria Mosquito, Parasite Achieved

WASHINGTON, DC, October 3, 2002 (ENS) - Genome sequences of the most lethal malaria parasite, and of a mosquito that transmits the parasite to humans, are now complete, two international research teams announced Wednesday. Scientists believe they can use this information to design new insecticides, new repellants, and new drugs.

The simultaneous publication in the journal "Science" of the genome of the mosquito Anopheles gambiae and in the journal "Nature" of the genome of the parasite Plasmodium falciparum was marked by press conferences held in Washington, DC, and London.

"We are hopeful that this wealth of information will translate into new drugs, vaccines, and insecticides that will more effectively control malaria and, ultimately, lift a burden of suffering from millions," says Michael Gottlieb, Ph.D., chief of parasitology and international programs branch of the National Institute of Allergy and Infectious Diseases (NIAID) which partly funded the research.

Anopheles gambiae: adult female bloodfeeding on human skin (Photo by Sinclair Stammers courtesy World Health Organization Special Programme for Research and Training in Tropical Diseases (TDR))

"The new genes we have found are the first ones that make the Anopheles mosquito highly resistant to real, natural populations of the most deadly of the human malaria parasites, as opposed to laboratory parasite strains, and there are several ways that this basic research finding could help prevent malaria transmission," says Kenneth Vernick, Ph.D., associate professor in the NYU Department of Medical and Molecular Parasitology, who led the research.

Malaria is transmitted from person to person through the bite of female mosquitoes in the genus Anopheles, which carry malaria parasites. In order to sustain itself, the parasite must undergo a part of its lifecycle inside of the mosquito.

Announcement of the decoding of the genomes of the most dangerous malaria parasite, Plasmodium falciparum, and of the most important mosquito which transmits it, Anopheles gambiae, signals a turning point for global public health, said Carlos Morel, director of the World Health Organization's Tropical Disease Research program.

"This is an extraordinary moment in the history of science," said Morel. "At last, the enormous power of modern technology is penetrating the mysteries of an ancient disease, a disease which continues to kill millions."

Some 40 percent of the world's population lives in areas where malaria is transmitted.

Malaria, the most important parasitic disease in the world, is thought to be responsible for 300 million cases of illness and up to a million deaths annually, more than 90 percent of which occur in sub-Saharan Africa.

Public health campaigns against malaria have been stymied over the last decade as both the mosquito and the parasite have evolved mechanisms to escape the limited, affordable technologies available in the developing world.

Dr. Peter Atkinson, associate professor of entomology at the University of California, Riverside, and a co-author of the paper mosquito genome paper, said, "The economic cost to affected nations is immense. No vaccine has been developed for malaria and, due to a number of factors, the incidence of the disease is on the rise. Understanding the genetic makeup of the mosquito that transmits malaria will help with the design of new strategies to fight this disease."

"There is a high frequency of resistance genes in mosquitoes in nature, indicating that the parasite and the mosquito are in an intense evolutionary battle," says Dr. Vernick. "The vector is trying to escape the parasite by developing a myriad of resistance mechanisms. The parasite, of course, doesn't want to go extinct, so it is permanently compelled to develop counter measures to these mechanisms."

The NYU study took place in the West African country of Mali. Dr. Vernick and NYU colleagues Oumou Niaré and Frederick Odoul collected some 5,000 mosquitoes that had bitten people infected with malaria, and counted the number of oocysts, one of the life stages of the malaria parasite, in the guts of the insects.

Water storage pots which Anopheles gambiae and other mosquitos can use as breeding sites. (Photo courtesy Liverpool School of Tropical Medicine)

Because female mosquitoes mate only once, the offspring analyzed in the study came from a single pair mating that occurred in nature. This approach insured that the results gave an accurate picture of the real mosquito genes that block the actual parasites currently infecting people in the endemic area.

Scientists from the University of Mali School of Medicine in Bamako and from the European Molecular Biology Laboratories in Heidelberg, Germany collaborated with Dr. Vernick.

The genome of the parasite P. falciparum was sequenced as the result of a six year $17.9 million effort involving 185 researchers from the United Kingdom, the United States, and Australia.

The lead investigator, Malcolm Gardner, Ph.D., of The Institute for Genomic Research, co-authored the "Nature" paper on the parasite with 44 researchers working in sites in the United States, the United Kingdom and Australia.

The genome of the parasite P. falciparum was sequenced as the result of a six year $17.9 million effort involving 185 researchers from the United Kingdom, the United States, and Australia.

"It's one of the most difficult genome projects we have ever tackled," said Gardner, who has been working on the P. falciparum project since it started in 1996.

The genome was difficult ot decode because about 80 percent 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."

Drugs targeting the parasite are losing their effectiveness. Today, resistance to choloroquine, the cheapest and most widely used antimalarial drug, is common throughout Africa. The next most effective but more expensive drug, sulfadoxine-pyrimethamine, is being resisted in highly endemic areas of eastern and southern Africa.

In a related development, two scientists at The Scripps Research Institute led a collaborative effort involving 18 researchers at half a dozen laboratories in the United States and Great Britain to determine the "proteome" of the most deadly form of the malaria pathogen Plasmodium falciparum. The study identified more than 2,400 proteins that cause malaria in the single celled Plasmodium falciparum.

This study, in the current issue of the journal "Nature," accompanies the article detailing the completion of the parasite genome sequencing.

"This is the first instance that I know of where these proteomics studies have gone along side-by-side with the genome sequencing project," says lead scientist Scripps Research Institute cell biology professor John Yates, Ph.D.

The newly identified proteins may lead to the development of new malaria vaccines.

Besides NIAID, funding for the mosquito gene sequencing research came from the Wellcome Trust, the Burroughs Wellcome Fund and the U.S. Department of Defense. Sequencers worked at The Institute for Genomic Research (TIGR) in Rockville, Maryland, the Stanford Genome Center in Palo Alto, California, and the Wellcome Trust Sanger Institute in the United Kingdom.

In 1999, NIAID joined the Anopheles Gambiae Genome Consortium to accelerate sequencing of Anopheles' 14,000 genes.

Most open drains are too polluted to be used as breeding sites by most malaria vectors, although Anopheles gambiae have adapted to this habitat in several places, such as here in Accra, Ghana. (Photo by Dr. Steven Lindsay courtesy WHO TDR)

In August 2001, NIAID expanded its support for Anopheles genome sequencing with a $9 million award to Celera Genomics Group of Rockville, Maryland. Celera's Dr. Robert Holt, heads a list of 123 authors on the "Science paper," submitted on behalf of the Anopheles Gambiae Genome Consortium.

The software used for the genetic analysis was designed by Kyriacos Markianos and Leonid Kruglyak from the Fred Hutchinson Cancer Research Center in Seattle, who are co-authors on the study.

Claire Fraser, Ph.D., president and director of The Institute for Genomic Research, 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."

In April 2001, a database allowing genomic analysis of Plasmodium falciparum was published on the Internet, facilitating research for teams all over the world. Developed as a collaboration between two research groups at the University of Pennsylvania, the Plasmodium genome database broke new ground in bioinformatics by permitting detailed analysis of a genome even before its sequencing is complete. It is online at: http://PlasmoDB.org.

"Like the sequencing of the human genome, that of Plasmodium falciparum has generated huge amounts of data," said David Roos, director of Penn's Genome Institute, who has spearheaded the Plasmodium database project. "While it may take years before all the i's are dotted and t's are crossed, it is important to provide researchers with access to the raw data as soon as possible and to equip them with tools to transform this data into a useful form."

For more information on NIAID's malaria research and research support, visit http://www.niaid.nih.gov/dmid/malaria

The Institute for Genomic Research is online at: http://www.tigr.org/