Medea’s Antimalarial Mosquitoes

Malaria infects more than half a billion people every year, and kills more than one million, mostly children. Despite decades of effort, no effective vaccine exists for the disease, caused by single-celled Plasmodium parasites. The parasites are transmitted to humans via the bite of infected mosquitoes. One way to stop malaria is to make the mosquitoes themselves fight the disease. This can be tricky, however, because bugs carrying the disease-resistance genes are likely to be less reproductively fit than their wild counterparts, and thus less able to spread their genes. But now Caltech Associate Professor of Biology Bruce Hay, postdoc Chun-Hong Chen, and colleagues have developed a way to make such genes spread themselves quickly throughout an insect population.

“People who live in areas affected by malaria and other mosquito-borne diseases are bitten often,” says Hay, “so there will be little benefit unless most of the local mosquito population is disease resistant.”

The technique exploits a maternal-effect dominant embryonic arrest—or Medea—genetic element, a particularly spiteful selfish genetic element. (In Greek mythology, Medea killed her own children to revenge herself upon her unfaithful husband.) “Selfish genetic elements, single genes or clusters of genes, are more successful than your average gene at passing themselves from generation to generation,” says Chen, even if their presence makes an organism less fit. “Our idea was to create a selfish genetic element that could be linked with a specific cargo, the disease-resistance gene, as a way of rapidly carrying this gene through the population.”

Medea elements were first described in 1992 by Richard Beeman and colleagues at Kansas State University, who found one in the common flour beetle Tribolium castaneum. The version developed in this project uses two linked genes. One gene, the “poison,” is turned on in the mother and produces a piece of small noncoding RNA, or microRNA, that prevents a protein known as myd88, which is crucial for embryonic development, from being made. The second gene, the “antidote,” codes for a microRNA-insensitive version of the gene that produces myd88. Since all of the mother’s egg cells will contain the poison microRNA, only the fertilized eggs that get the antidote from either parent will survive.

Fruit flies carrying this synthetic Medea element spread quickly throughout a laboratory population of wild-type flies. After just a few generations, all of the flies in the population carried at least one copy of Medea. “To our knowledge, this work represents the first de novo synthesis of a selfish genetic element able to drive itself into a population,” says Hay. “It provides proof of principle that, at least in a highly controlled laboratory experiment, we can change the genetic makeup of a population.” The team now plans to use the technique to transmit a real payload—a disease-resistance gene—into the mosquito. “There is a real possibility that disease transmission can be suppressed in an environmentally friendly way,” Hay continues. “The mosquitoes will still be there, but with one or two tiny genetic changes that make them unable to transmit these dreadful diseases.”

Even mosquitoes can only breed so fast, and in order for this approach to work, about 10 percent of the local population needs to contain the Medea element. “So it has to be introduced into the population reasonably frequently, which is very doable,” says Hay. “In the ’70s when people were doing biological mosquito control, they would breed mosquitoes in factories, and they would sort out the males and sterilize them with radiation. They were releasing millions of sterile mosquitoes every day. You really didn’t want to be trapped in that factory overnight.”

A paper describing the work appeared in the April 27 issue of Science, with Chen as the lead author. The other authors include Caltech postdoc Haixia Huang; grad student Catherine Ward; incoming freshman Jessica Su; biology staff member Lorian Schaeffer; Ming Guo, assistant professor in the departments of neurology and pharmacology at UCLA’s Brain Research Institute, David Geffen School of Medicine; and Hay. —KS