By Jennifer Jenks and Nairi Strauch
From the tropical savannas of Sub-Saharan Africa to the islands of Southeast Asia, the dengue virus affects the lives of millions around the world. Transmitted primarily through the bites of pathogen-carrying mosquitoes Aedes aegypti and Aedes albopictus, dengue infection is a leading cause of morbidity and mortality in the tropics and subtropics. It poses a serious threat to nearly 2.5 billion people glob
ally – two-fifths of the world’s population 1. The World Health Organization estimates that as many as 100 million people are infected every year through transmission by mosquitoes 2. First documented only in the 1950s, the disease is now endemic in more than 100 countries and the number of cases is increasing as the disease spreads to new areas. Symptoms of the dengue include fever, headache, skin rashes, and muscle and joint pains. The disease can progress to life-threatening complications such as dengue hemorrhagic fever (DHF), where capillaries become excessiv
ely permeable and cause abdominal pain, hemorrhage, and potentially circulatory collapse. DHF affects mostly children, and without proper treatment, DHF fatality rates can exceed 20% 1.
There are currently no licensed vaccines to prevent infection with dengue virus, and other preventive measures, such as the treatment of water around homes and the use of insecticides and mosquito nets, have been mostly ineffective. However, in the last few decades, experts in microbiology and immunology have made innovative advances in preventing the spread of dengue leading to one of the most promising techniques today: genetic modification of Aedes mosquitoes.
One of the leaders in this research is Dr. Anthony James, distinguished Professor of Microbiology & Molecular Genetics at the University of California, Irvine’s School of Medicine. Currently, Dr. James and his team are exploring genetic manipulation in Aedes mosquitoes as a cost-effective preventative method for dengue. They are taking two primary approaches to reduce dengue carriers using genetic modification: population suppression and population replacement.
The population suppression strategy aims to reduce the source pool of dengue by limiting the mosquito population. One method used to achieve such reduction involves increasing the death rate of wild mosquitoes. In this approach, mosquitoes are genetically engineered in a lab to become lethal to their own kind. When released into the wild, these insects mate with the wild mosquitoes and kill them, decreasing the number of disease-carrying wild mosquitoes and therefore decreasing the chance of transmission. Another technique to reduce the number of disease carriers is to genetically modify male mosquitoes to be sterile, reducing the total number of fertilized mosquito eggs in the wild 3.
The primary advantage to the population suppression approach is its built-in safety mechanism. Because these mosquitoes do not produce offspring with the wild mosquitoes, there is no chance of introducing modified genes into wild mosquito populations. As Dr. James explains, “When people are anxious about genetic control, they understand that if you put something out there that isn’t designed to survive, then maybe that’s a good thing.” Additionally there is no evidence to suggest that removal of mosquitoes would have a significant impact on the ecosystem. In fact, the mosquito removal may be “an aspect of bio-remediation and bringing the local system back to what it was before.” Studies of these field suppression approaches have already been initiated in Malaysia and the Cayman Islands 4.
However, these self-limiting approaches are ultimately unsustainable. Because the lab mosquitoes only affect the immediate growth of the wild mosquito population, this method cannot account for the migration of carrier mosquitoes back into the area.
The more sustainable approach is population replacement, in which mosquitoes are engineered to be resistant to the dengue virus and then are introduced into a wild population. When the modified mosquitoes mate with the wild mosquitoes, the modified genes are passed onto future generations, eventually altering the genetic character of the population to make them dengue-resistant.
According to Dr. James, although these technologies are sustainable, they are “much more complicated in the sense that they leave a genetic residue out there in the population.” Introducing a modified variant of a naturally occurring species may have off-target effects, and the full impact cannot be entirely understood. Scientists are currently working to incorporate design features that increase efficacy and ensure safety. They are making a large effort to ensure that these genes have very limited or no potential for moving outside of the species for which they are targeted. Additional precautions aim to avoid increasing the mosquitoes’ ability to carry another target pathogen. Says Dr. James, “for example, if you put in something that knocks down the ability of the insect to support dengue viruses, do you have an impact on yellow fever?” Further research is also examining the impact on insecticide resistance. Labeling the mosquitoes with fluorescence may also make them readily distinguishable from the wild population 2.
Furthermore, the population replacement approach must work in a reasonable time frame. To have a relevant impact on the environment, the genes must spread rapidly through the population. “You don’t want to put a gene out there and have to wait ten thousand years,” explains Dr. James.
Perhaps the greatest challenge to this work is gaining social acceptance for the use of genetically modified insects. Because it is impossible to gain the individual consent of every member affected by this public health measure, social issues of consent and authorization become supremely significant. Says Dr. James, “the question is, how do we work toward developing world standards for community consent, community involvement, to circumstances, where it’s less clear how that would actually work?” Scientists will need to collaborate with public health leaders to educate them on the effects of this protective measure to ensure that these leaders can make an informed decision. Researchers will also need to work with the local communities in these developing countries with populations of low literacy, a project that is difficult but essential. Today, even in the scientific community, the future use of genetically modified mosquitoes is not entirely accepted. “We know there are a lot of people uncomfortable with what we’re doing,” explains James. “So my challenge is ‘All right, come up with something better!’”
Research to prevent transmission of dengue is ongoing, and there is much to be learned. The use of genetically modified mosquitoes to suppress the population of wild mosquitoes or modify their disease-carrying characteristics over time could prove to be a solution, and may improve the lives of millions. Dr. James notes, “Personal gratification comes from being able to use the things that I was trained in to offer something to humanity.” Efforts from researchers like Dr. James could be essential in reducing the morbidity and mortality caused by the most rapidly spreading mosquito-borne disease in the world.
References
1. Dengue and dengue haemorrhagic fever. World Health Organization. 2009. Available at: http://www.who.int/mediacentre/factsheets/fs117/en/index.html. Accessed April 28, 2011.
2. Dengue. Centers for Disease Control and Prevention. 2011. Available at: http://www.cdc.gov/Dengue/. Accessed April 28, 2011.
3. Mosquito wars. (2009). Bulletin of the World Health Organization [serial online]. 2011;87(3). Available at: http://www.who.int/bulletin/volumes/87/3/09-020309/en/. Accessed April 28, 2011.
4. Enserik M. GM mosquito release in Malaysia surprises opponents and scientists–again. ScienceInsider. 2011. Available at: http://news.sciencemag.org/scienceinsider/2011/01/gm-mosquito-release-in-malaysia.html?. Accessed April 28,2011.
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