Mosquitoes genetically engineered for malaria resistance can outcompete their wild counterparts--at least in the lab, according to researchers at Johns Hopkins University. While previous studies have described the creation of malaria-resistant mosquitoes, this is the first time that researchers have shown a reproductive advantage for the genetically engineered organisms, which is an important requirement if such mosquitoes are to be used as a practical malaria-control strategy.

Malaria kills more than a million people worldwide each year, most of them children in sub-Saharan Africa, according to the World Health Organization. The disease is caused by Plasmodium parasites, protozoa that are transmitted from person to person by female Anopheles mosquitoes. Researchers have proposed a method of controlling the spread of malaria by introducing into the wild mosquitoes that can't transmit the parasite, but computer models suggest that malaria-resistant mosquitoes must almost completely replace the native population in order to stop the cycle of transmission.

In the current study, Marcelo Jacobs-Lorena and his colleagues at the Johns Hopkins School of Public Health, in Baltimore, put equal numbers of malaria-resistant mosquitoes and ordinary mosquitoes in a cage and allowed them to feed on mice infected with the malaria-causing parasite. The researchers then collected the eggs laid by the insects, reared them into adulthood, and allowed the new generation of mosquitoes to feed on infected mice.

After nine generations, 70 percent of the mosquitoes were malaria resistant, meaning that the genetically engineered insects had largely outcompeted their nonresistant counterparts. In contrast, mosquitoes that fed on uninfected mice did not show any fitness differences. The researchers published their findings in the early online edition of the Proceedings of the National Academy of Sciences.

Earlier work by Hillary Hurd, a parasitologist at Keele University, in the United Kingdom, showed that infection with Plasmodium affects mosquitoes' fertility. "There's a fitness cost to being infected," Hurd says, so mosquitoes that are protected from infection should have an advantage over those that aren't protected. The results of the Johns Hopkins study support that conclusion, she says.

Researchers have created different types of malaria-resistant mosquitoes by interfering with the Plasmodium parasite's complex developmental cycle. After a mosquito ingests the parasite from infected blood, the parasite invades the mosquito's gut and forms a cyst. That cyst eventually ruptures and releases spores into the mosquito's body, which migrate to the salivary glands. Then, when the mosquito bites another person, it transmits the parasite.

Jacobs-Lorena and his colleagues engineered mosquitoes to produce a peptide called SM1 that blocks Plasmodium from invading the mosquito's gut, thus interrupting the parasite's development. Since it is not a naturally occurring peptide, SM1 doesn't activate the mosquito's immune system, according to Hurd. "This is a very different strategy than what other groups are working on," she says. "If you induce an immune response ... there is a fitness cost too."

Unlike other groups that conducted experiments, the researchers bred the genetically engineered mosquitoes with ordinary ones, so the insects in their study had just one copy of the SM1 gene instead of two. "Our hypothesis is that there are many genes throughout the genome that confer fitness disadvantage, but they're recessive," says Jacobs-Lorena. So in mosquitoes engineered to have two copies of SM1, the traits coded by those recessive genes express themselves and reduce the fitness of the mosquitoes. Having just one copy of SM1 doesn't seem to reduce the insects' resistance to the malaria parasite, he adds.

Hurd cautions that the malaria-causing parasites used by the Johns Hopkins team infect mice, not humans. "Anyone taking this strategy needs to be certain that the molecule stops transmission of the human parasite," she says. "Many of them don't."

More work needs to be done before transgenic mosquitoes can be used in the field as a malaria-control method. "Transgenic mosquitoes by themselves will never be able to solve the problem," Jacobs-Lorena says. "The only way is to use a combination of approaches: a coordinated attack using drugs, insecticides, transgenic mosquitoes, and perhaps vaccines. Then we have a chance to make a significant change in the transmission of the disease. No one should think of this as a silver bullet."