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
Simple Eradication
These strategies are designed to spread an anti-parasite gene that would interrupt disease transmission but leave the mosquito population otherwise intact. Although entomologists view this approach as the best, most efficient means of genetic control, the earliest implementation is at least 10 years away. An alternative strategy is to use existing genetic tools to temporarily eradicate local mosquito populations. The U.S. Department of Agriculture had a similar objective in 1958 when it began eradicating the wound-infesting screwworm fly in Florida by releasing millions of radiation-sterilized adult males. The project achieved ratios of up to 100:1 sterile to normal males, so most native females mated with irradiated males to produce embryos that quickly died. Unlike the tactics above, the sterile males never passed any genes into the natural population, so factories had to produce more males for irradiation in each generation. Although it was labor-intensive, the strategy worked: Over the past 40 years, entomologists have pushed the flies to extinction from the United States to the Panama Canal.
One of the problems with sterilization is that radiation often weakens the flies to the point that they are not very competent mating partners. Furthermore, the strategy is typically only practical with pest species that allow entomologists to separate easily males from females.
Molecular geneticists have overcome these obstacles by engineering an insect that lived and mated normally, but produced progeny that could only survive on a special laboratory diet that contained the antibiotic tetracycline. The investigators use the tetracycline not to help the insect fend off bacteria, but to control the on/off switch on a lethal transgene carried by the insect.
In 1998, Walter J. Gehring and colleagues at the Universität Basel in Switzerland created the first Drosophila strains whose progeny survived only if their mothers were fed on a diet containing tetracycline. In 2005, a research team at the University of Oxford led by Luke S. Alphey reported on the first success in applying the so-called Tet-Off technique to a pest species, the Mediterranean fruit fly. If entomologists could rear such a transgenic pest strain in factories on a tetracycline-laced diet, they could release the mutants to mate with native pests and produce young that would not live without the drug. This strategy, in which both the males and females die when deprived of tetracycline, has the potential to be much more efficient than the old irradiation method.
A twist on this offspring-killing strategy was introduced in 2000 in a pair of papers from two independent laboratories, one headed by Alphey and the other by Maxwell J. Scott at Massey University in New Zealand. Both teams developed transgenic Drosophila in which only the female was dependent on tetracycline—a feature that would allow scientists to rear high numbers in a factory and then remove tetracycline from the diet in the last generation, leaving only adult males ready for release. A further advantage to this approach is that all female offspring of these males would die in the field, but the male offspring would survive and transmit the female-killing genes to some of their offspring, which would repeat the pattern.
Paul Schliekelman, a former graduate student in our laboratory who is now at the University of Georgia, developed models to examine how specific strains of mosquitoes with female killing genes are likely to affect the native populations. His work showed that a strain containing multiple copies could be 10 to 100 times more efficient at reducing the native population than a strain that killed males and females. As with the other genetic control methods discussed here, minimizing the impact of the inserted constructs on mosquito fitness is critical to success. When there are no fitness costs, more insertions result in higher efficiency because more progeny will carry at least one female-killing gene. However, as the fitness cost increases, the optimal number of insertions goes down. One nonintuitive prediction from modeling fitness costs was that the first transgenic strains released should have few copies of the engineered construct, but strains with more constructs should be released as the population declines. A Gates-funded research team led by Anthony A. James at the University of California, Irvine, is examining the possibility of using the female-killing approach for control of Aedes aegypti, the mosquito vector of dengue. But James and other investigators realize that in addition to solving the challenging technical problems involved in developing these and other types of engineered mosquitoes, they must address a host of social and ethical concerns about release of such transgenic organisms.
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