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The War on Malaria

Virginia Tech scientists combine entomology, chemistry, genetics, and computer science to fight a deadly disease

by Michael Sutphin

A mosquito bite disturbed a Tanzanian child’s sleep. The mosquito, a female of the genus Anopheles, discovered a way through the net over the girl’s bed and infected her with a mobile, single-celled parasite known as Plasmodium falciparum. After finding its way to her liver, the parasite multiplied and escaped into the bloodstream to devour her red blood cells. Unless properly diagnosed and treated in the weeks that follow, she may develop a life threatening fever and become part of one of the largest public health crises in Sub-Saharan Africa.

According to figures available from the World Health Organization, malaria will infect more than 10 million individuals in Tanzania alone and claim more than 14,000 lives in the East African country—a fraction of the devastation the continent suffers each year.

“As many as 2.5 million people are estimated to die each year from malaria, most of them under the age of five,” says Sally Paulson, an associate professor of entomology. Although this figure fluctuates each year, the World Malaria Report marked the death toll as high as 3 million in 2005.

Virginia Tech scientists such as Paulson are on the front lines of the most recent battle against malaria.

Jeffrey Bloomquist, a professor of toxicology and pharmacology in the Department of Entomology, hopes a $2.7 million grant will allow his research team to develop an improved insecticide for mosquito nets. These nets, such as the one in the anecdote with the Tanzanian girl, are draped over beds at night, the feeding time for Anopheles mosquitoes. Although proven effective, only one in 20 Africans uses a mosquito net at night according to one study.

The insecticide sprayed on these nets, however, raises a number of concerns. “Our primary issue is making sure it is safe,” Bloomquist says.

Insecticides used for this purpose must be nontoxic to humans and safe for the untrained individuals who apply them to the mosquito nets. Although newer, long-lasting nets exist, the most commonly used nets must be re-impregnated with insecticide every six months. But Bloomquist says Anopheles mosquitoes have evolved a genetic resistance to certain popular insecticides. This means researchers must hurry before the epidemic worsens.

Bloomquist’s project, “Molecular Design of Selective Anticholinesterases for Mosquito Control,” aims to develop an insecticide that targets a specific mosquito species, Anopheles gambiae, the most dangerous mosquito vector for malaria in Africa. Despite its particular focus, this research has tremendous potential for other applications.

“What we are doing can be applicable to other parts of the world, other types of mosquitoes that transmit malaria, and other types of pests that spread diseases,” Bloomquist says.

The researchers are using the biological target—in this case, the enzyme acetylcholinesterase—as a scaffold upon which to assemble its own chemical inhibitor. To build this scaffold, investigators are using “in situ click chemistry.” This approach to drug and insecticide design combines two small inactive molecules into one that disables the function of the protein target. Bloomquist says this is a novel, safe way to create a potent insecticide with species selectivity.

Some progress has already been made in this research. “We have so far identified a number of chemistries that show promise,” Bloomquist says.

This research borrows from a broad range of disciplines. While Bloomquist designs the enzyme assays and optimizes them for mosquito toxicity, Paulson, his colleague in the College of Agriculture and Life Sciences, oversees mosquito rearing and whole-insect bioassays. Deborah Carlier, another colleague in the college, serves as project manager and liaison with research collaborators.

Paul Carlier, an associate professor of chemistry in the College of Science, designs and synthesizes the inhibitors, and Eric Wong, a professor of animal and poultry sciences in the College of Agriculture and Life Sciences, uses his genetics expertise to clone the acetylcholinesterase genes and create enzyme expression systems for bioassays. John Githure, head of the Human Health Division for the International Centre for Insect Physiology and Ecology, brings an international component to the research by supervising field trials with candidate insecticides in Kenya.

The project even requires a computer scientist. Max Totrov, of Molesoft, guides the insecticide design by using computational determination of the Anopheles gambiae acetylcholinesterase enzyme and how it interacts with inhibitors at the atomic level.

The group has completed the first year of a three-year project supported by a $2.7 million grant from the Foundation for the National Institutes of Health (FNIH). Congress established the FNIH to support the National Institutes of Health’s mission to improve health through scientific discovery. The project is one of 44 projects in the Grand Challenges in Global Health initiative. Financed in part by the Bill and Melinda Gates Foundation, the $436 million initiative funds researchers around the world who hope to make scientific breakthroughs against diseases that kill millions in poor, underdeveloped countries each year.

Most Americans, who by comparison live in one of the world’s wealthiest countries, do not live in fear of malaria, but this has not always been the case.

“As short a time ago as the 1940s, malaria was still endemic in the United States,” Paulson says.

Health officials sprayed pesticides, introduced screened windows and air conditioning, and drained breeding sites to thwart the illness. By 1951, they declared the country malaria-free.

Bloomquist and Paulson agree that scientists cannot curb Africa’s malaria infection rate without a plan resembling what happened in the United States a half century ago. Pest control, drug treatment, political and economic development, improved living conditions, and access to health care will all be needed. A multifaceted approach might be the only way to combat such a complex and widespread disease, they say.

For more information about this research project, visit the Malaria Project Webpage.