FEATURE ARTICLE
Genetic Strategies for Controlling Mosquito-Borne Diseases
Engineered genes that block the transmission of malaria and dengue can hitch a ride on selfish DNA and spread into wild populations
Fred Gould, Krisztian Magori, Yunxin Huang
Transgenes and Fitness
Setting aside concerns over the release of genetically modified mosquitoes (more on that later), there is reason to be optimistic that this strategy might work. Thanks to the tools of molecular biology, geneticists can make very specific changes in mosquito genomes. In 2002, a team led by Marcelo Jacobs-Lorena, then at Case Western Reserve University, modified Anopheles stephensi mosquitoes with genes that blocked the development of Plasmodium berghei, a relative of the malaria parasites that infect human beings. In March 2006, a team led by Ken E. Olson at Colorado State University showed that inserting a specific transgene—a piece of foreign, engineered DNA—into the genome of Aedes aegypti mosquitoes could substantially deactivate the dengue virus within hours of the female's blood meal from an infected person. Other scientists have developed genetic strategies that simply kill the mosquitoes that carry a specific engineered gene.
But having mosquitoes that don't transmit pathogens in the laboratory doesn't help people in the wider world. Even if scientists bred and released thousands of these transgenic mosquitoes, they wouldn't have much effect on public health unless the genetically altered insects competed with (and eventually replaced) the local strains.
If mosquitoes that carried anti-parasite genes were more evolutionarily fit (that is, if they left more offspring) than mosquitoes without these genes, then more and more of the wild mosquito population would become inhospitable to parasites with each generation. For example, if parasite-infected mosquitoes had shorter lives or fewer progeny, then a parasite-killing transgene might make its bearer more fit. Unfortunately, that isn't what happens: Mosquitoes susceptible to the dengue virus or Plasmodium are almost always just as fit as those without the susceptibility.
Not only do anti-parasite transgenes fail to improve fitness, they often reduce it. This penalty exists because the transgenes in many genetically modified organisms are just inserted randomly into the genome, where they often disrupt normal genes at the insertion site. And the transgene itself encodes RNA or protein that can change cell function, thereby decreasing the insect's fitness. Transgenic strains that bore these fitness costs would go extinct if released into the wild.
Despite the challenges, the process of engineering a disease-fighting, transgenic mosquito is not merely an academic exercise. The Bill and Melinda Gates Foundation recently contributed more than $35 million to the Foundation for the National Institutes of Health for the purpose of developing transgenic mosquitoes as a weapon against insect-borne diseases, and governmental agencies and other philanthropies in the United States and abroad have also funded this research.
Regardless of what the anti-pathogen transgene turns out to be—an antiviral or antiprotist gene, a lethal gene, or something else not yet developed—the project will succeed or fail based on the ability to drive that transgene into the wild population—even if it makes its bearers less fit. A practical system to meet this need is still far away, but it is possible. Using the rules of population genetics, a number of research groups are harnessing so-called selfish DNA, which spreads without regard to the overall fitness of its host, giving the illusion of turning natural selection on its head.
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