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April 21, 2011

Scientific roadblock overcome in designing genetic controls against malaria-transmitting mosquitoes

In the future, global health experts may be able to cast a genetic net over mosquitoes to prevent them from spreading malaria to people.  A major step forward in genetic control of malaria-transmitting mosquitoes has been reported by scientists at Imperial College London and at the University of Washington in Seattle. The findings appear in the April 20 online edition of Nature. The results demonstrate a new mechanism by which genetic control measures could be implemented against mosquitoes that carry human malaria.

The lead author of the study is Dr. Nikolai Windbichler, of the Department of Life Sciences at Imperial College. Dr. Austin Burt from Imperial College and Dr. Andrea Crisanti from Imperial College and the University of Perugia, Italy were the senior authors. Scientists from the University of Washington who worked on the study are Summer B. Thyme, of the UW Department of Biochemistry and the Graduate Program in Biomolecular Structure and Design; Blake Hovde, of the UW Department of Genome Sciences Graduate Program; Dr. Hui Li of the UW Department of Pathology; Dr. Umut Ulge, of the UW Cell & Molecular Biology and Medical Scientist Training Programs; Dr. David Baker of the UW Department of Biochemistry; and Dr. Raymond J. Monnat, Jr., of the UW Departments of Pathology and Genome Sciences.

Previously, the authors of the Nature article had suggested that a class of simple ‘selfish genes could be called into service for this purpose.  Selfish genes are genetic elements that excel at promoting their own propagation from generation to generation. In this case, the scientists worked with homing endonuclease genes (HEGs). These genes, found in fungi and bacteria, are part of genetic elements that are efficiently transferred between organisms and within populations. The scientists found that they could create a synthetic genetic element consisting of a type of HEG called I-Scel and certain regulator regions from the mosquito genome to control expression. These two components constitute a gene-drive system that project scientists used to demonstrate efficient gene transfer in the germ line of mosquitoes. The mosquitoes used for these experiments were Anopheles gambiae, the species that transmits one of the most lethal forms of human malaria.

To test their idea, the scientists bred a population of laboratory mosquitoes that produced a green fluorescent protein.  These bugs glowed. The scientists then introduced into cages a few transgenic mosquitoes with a selfish gene-drive element. This element was designed to cut and inactive the fluorescent protein gene in mosquito sperm cells, then take its place on the chromosome. This process ensures that the selfish genetic element—not the green fluorescent protein gene—would be inherited and passed to subsequent generations. As predicted, with each generation the cages grew dimmer as fewer glowing mosquitoes were produced.

The results showed, the researchers noted, that a selfish genetic element in a few mosquitoes could transform a large population in a relatively short time. To build on this advance, the researchers hope to design a gene-drive system that targets and replaces on or more genes that are essential for malaria transmission. They currently have about a dozen genes in mind to test.

The scientists admit they still have a long way ahead to designing an effective genetic control of malaria-transmitting mosquitoes, but this latest advance has opened new inroads in the search for a reliable method.

The study was funded by a grant from the Foundation for the National Institutes of Health through the Vector-Based Control of Transmission: Discovery Research program of the Grand Challenges in Global Health initiative.