Breakthroughs Put the Bite on Malaria. (Innovations)(Cover Story)
Tenenbaum, David J., Environmental Health Perspectives
Half a century ago, a potent combination of antibiotics, vaccines, and public health measures seemed poised to win the ancient war against infectious disease. Even malaria appeared to be succumbing to a mix of insecticides, larvicides (used to kill the mosquito vector), and drugs (used to kill the malaria-causing Plasmodium parasite in the human bloodstream). But while smallpox and polio were conquered, malaria was not; mosquito evolution and concerns about health effects from insecticides blunted mosquito eradication campaigns, and Plasmodium developed resistance to many drugs. Today, malaria is resurgent in many tropical regions, especially Africa. According to the World Health Organization, each year it infects more than 300 million people and kills at least 1 million, mostly children.
In the last year, however, major progress has been reported in basic research on malaria. One research group has reported a genetic manipulation that impairs the mosquito's ability to transmit the malaria parasite. Another has reported progress toward a vaccine that targets a newly discovered toxin made by Plasmodium. And this October, preliminary genomes were reported for the major malaria parasite, P. falciparum, and the major vector, the Anopheles gambiae mosquito.
An Antimalarial Mosquito
Human malaria is caused by four members of the genus Plasmodium, which goes through a complex life cycle. After a person is bitten by an infected mosquito, the parasite multiplies for a few days in the liver, and then is distributed through the blood. When other mosquitoes take a "blood meal" from an infected person, the parasite sexually reproduces in the mosquito's gut. The parasite leaves the gut and reaches the salivary glands, at which point the mosquito is poised to infect another person.
The first symptoms of malaria start when Plasmodium enters the blood, when the characteristic "paroxysms"--cycles of fevers and chills--begin. Malaria may also cause renal or pulmonary failure; cerebral malaria, which usually afflicts children and pregnant women, can cause coma, generalized convulsions, and death.
Whereas malaria fighters have historically attacked the parasite or the vector, other targets are emerging from the study of the complicated interaction of parasite, vector, host, and environment. Many mosquito species, for example, are resistant to infection with Plasmodium. Could that resistance be transferred to those that do transmit malaria? In the 23 May 2002 issue of Nature, Marcelo Jacobs-Lorena, a professor of genetics at Case Western Reserve University, and colleagues reported on a major advance toward answering that question--they genetically engineered a strain of mosquito with an impaired ability to spread a rodent malaria parasite.
The researchers focused on receptor molecules on the epithelium of the mosquito gut. During the ookinete life stage, the parasite links to these receptors as it migrates to the salivary glands. The researchers made about 1 billion artificial peptides and found one that bonded to the gut's lining, blocking receptors there. Because the blood meal is the point at which the mosquito becomes infected with Plasmodium, any gene activated when the blood is digested could possibly also be pressed into service as a malaria fighter. So the team inserted a gene for this peptide into the mosquito genome, and instructed the genome to activate the gene after the mosquito took a blood meal.
Only two of the three groups of modified mosquitoes actually failed to transmit malaria, says Jacobs-Lorena. He adds that the peptide is not 100% effective; there are always escapees. "That's one of many reasons why this is just a first step in the right direction," he says. Still, the experiments reported in Nature were proof in principle that it's possible to block the spread of malaria, he says.
Many questions about this application of transgenic technology remain to be answered. …