One way to stop malaria is to make the mosquitoes that carry the disease themselves resistant to the pathogen. Getting disease-fighting genes into the mosquito population can be tricky, however, because bugs carrying disease-resistance genes are likely to be less reproductively fit than their wild counterparts, and thus less likely to spread their genes naturally.
Associate Professor of Biology Bruce Hay of the California Institute of Technology, postdoctoral fellow Chun-Hong Chen, and their colleagues at Caltech and the University of California, Los Angeles, have come up with a novel method for introducing such genes into insect populations. The work, published recently in the journal Science, involves the creation of a selfish genetic element that is uniquely adapted to spread itself quickly throughout the population.
"This spread is essential," says Hay, "because people who live in areas affected by malaria and other mosquito-borne diseases are bitten often, so there will be little benefit unless most of the mosquito population is disease resistant."
"What we need," says Chen, the first author of the study, "is some way of forcing, or helping, these disease-resistance genes to spread rapidly throughout the wild population."
The technique Chen, Hay, and their colleagues have come up with uses a maternal-effect dominant embryonic arrest--or Medea--genetic element, a particularly spiteful selfish genetic element.
"Selfish genetic elements (single genes or clusters of genes) are basically units of genetic information that 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 the entity in populations of the common flour beetle Tribolium castaneum.
Beeman and his colleagues do not yet know the molecular nature of Tribolium Medea, but their work suggests that Medea consists of two linked genes. One gene, whose expression is activated in the mother, encodes a toxin that is deposited into all oocytes, or eggs. Embryos that do not inherit a Medea element die because of the toxin. Embryos that inherit Medea from either their mother's or their father's genome, however, will survive because they produce an antidote that neutralizes the toxin. As a result, chromosomes that carry Medea end up in offspring more often than those that do not, and Medea can spread rapidly through a population.
"We spent several years trying to create a selfish genetic element based on these principles," says Chen, "but it was difficult to get the insects to produce just the right amount of toxin; enough to kill the embryo, but not so much that the toxin couldn't be inhibited by the antidote." The researchers eventually switched to a system in which the toxin caused the loss of an essential function, and the antidote restored that function. "We generated flies in which maternal expression of small noncoding RNAs, known as microRNAs, were used to silence a gene known as myd88, which is crucial for embryonic development. Embryos from mothers expressing these microRNAs all died, unless they also expressed a microRNA-insensitive version of the myd88 gene: the antidote," said Chen.
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. It provides a simple proof-of-principle experiment demonstrating that, at least in a highly controlled laboratory environment, in a model organism, we can change the genetic makeup of a population," says Hay.
The team now plans to use the technique to transmit a real payload--a disease-resistance gene--into the mosquito.
Says Hay: "Mosquitoes with a decreased capacity to transmit malaria and other mosquito-borne diseases have already been identified in the wild and created in the laboratory by other researchers. These observations tell us that we can manipulate the mosquito immune system and thereby, at least in principal, stop this and other mosquito-borne diseases at their source in the mosquito. When combined with a mechanism such as Medea that helps to spread these resistance genes through the wild population, there is a real possibility that disease transmission can be suppressed in an environmentally friendly way that does not involve the wholesale use of insecticides or modification of the environment; the mosquitoes will still be there but with one or two tiny genetic changes that make them unable to transmit these dreadful diseases."
"This work is a prime example of how fundamental research can lead to breakthroughs that have huge implications for bettering human health," says Marion Zatz, chief of the Developmental and Cellular Processes Branch at the National Institute of General Medical Sciences, which partially supported the research. "Dr. Hay's work on how microRNAs regulate cell death in the innocuous fruit fly has 'borne fruit' in potential applications for limiting the spread of malaria."
This work was supported by National Institutes of Health grants GM057422 and GM70956 to Bruce Hay, and NS042580 and NS048396 to Ming Guo, assistant professor in the departments of neurology and pharmacology at UCLA's Brain Research Institute, David Geffen School of Medicine.
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