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Researchers genetically alter mosquitoes to impair malaria transmission
George Stamatis, 216-368-3635 or

Malaria kills about 2 million people annually, mostly African children under the age of 5. While conventional approaches to controlling the disease have been ineffective, Case Western Reserve University (CWRU) School of Medicine researchers are developing a genetically altered mosquito that one day could be added to the arsenal in the war against the disease.

The May 23 issue of the journal Nature features a paper by a team of CWRU Department of Genetics scientists, led by Professor of Genetics Marcelo Jacobs-Lorena, Ph.D., that discusses research into transgenic—or genetically altered —mosquitoes that prevent the passage of malaria from one individual to the next. The paper is titled "Transgenic Anopheline Mosquitoes Impaired in Transmission of a Malaria Parasite."

There are thousands of types of mosquitoes, but very few carry the malaria parasite, and only the genus, anopheles, transmits malaria. Mosquitoes are the obligatory host for malaria since the parasite cannot be passed from human to human. When a mosquito ingests blood from an infected host, the parasite Plasmodium enters the mosquito's body and goes through several transformations before taking a form that the mosquito can pass on by biting another person.

Jacobs-Lorena explained that when a mosquito feeds on an infected individual, the parasite reproduces in the mosquito's midgut and takes the form of an ookinete. The ookinetes then move through the epithelial layer of the midgut into the body cavity of the mosquito and mature into oocysts. After a period of 10 to 15 days, the cysts burst and thousands of sporozoites are released and invade the salivary glands, where they stay until a mosquito bites the next person.

CWRU researchers created a gene—SM1—in the laboratory that encodes a protein that interferes with the development of the parasite in the mosquito. Scientists injected this gene into the embryos of Anopheles stephensi mosquitoes, which incorporated itself into the genome of the mosquitoes, becoming part of the mosquito's DNA. The protein encoded by the SM1 gene binds to the epithelial surface of the mosquito's midgut, competing with the parasite and inhibiting its development by about 80 percent. The parasites that fail to cross the midgut die.

Another avenue researchers are pursuing is inhibition of parasite invasion of the mosquito's salivary glands. Jacobs-Lorena said it is important to find ways to block the parasite at various points of its development because no method is 100 percent effective.

"I think the value of this research is that it will provide an extra weapon," Jacobs-Lorena said. "Drugs and insecticides exist and help, but they are not very effective because of resistance. Vaccines are very hard to develop.What we need is a multipronged approach. The more weapons we have, the more effective it will be in our fight against malaria."

The Anopheles stephensi mosquitoes have been found to transmit the malaria parasite on the Indian continent, but not in Africa. Jacobs-Lorena said technology to introduce genes into the mosquitoes that spread malaria through Africa has only recently been achieved, while the technique for introducing genes into Anopheles stephensi was created about two years ago. Future research endeavors will test the SM1 gene on the African mosquitoes as well.

This is the first time researchers have reported blocking malaria parasite transmission by a transgenic approach. Another researcher previously used a modified virus to infect a mosquito and stop the spread of the parasite. But that method had several drawbacks, including the fact that the virus also could infect people and the virus could not be transmitted from one mosquito generation to the next. Once the mosquito died, so ended the virus' capabilities in fighting malaria.

Genetically altering mosquitoes with SM1 does not affect the fitness of a mosquito, including longevity or egg production. This is important because one of the challenges to using insecticides is that once spraying stops, a biological niche remains. If there was a large population of mosquitoes in an area to begin with, that means conditions are appropriate to sustain a large population of mosquitoes. If genetically modified mosquitoes were released into an area where the local population has been destroyed, they would occupy that niche. Jacobs-Lorena said this type of population replacement could be tested in the future.

Another challenge researchers face is the development of resistant parasites. That, said Jacobs-Lorena, is why transforming mosquitoes with multiple genes, each inhibiting parasite development in a different way, is a more effective approach.

"It's the same kind of problem when you treat bacterial infections with antibiotics; insects become resistant to insecticides," Jacobs-Lorena said. "No approach is 100 percent effective 100 percent of the time. The more varied tools we have, the better it is."

This research was supported by grants from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, and from the National Institutes of Health.



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