The dengue virus causes more human mortality than any other vector-borne viral disease . The virus is a large-scale challenge facing our societies on a global scale; in fact, it is the second most widespread mosquito-borne disease in relation to malaria . At the moment, there is no vaccination for this virus. We do, however, know that it is spread primarily by a species of mosquito called Aedes aegypti. The logical solution to reduce the spread of the dengue virus is to remove the vectors, or virus-carrying mosquitoes. Up until currently, countries have resorted to methods such as insecticide beds and chemical spraying to kill Aedes aegypti with small rates of success.
In 2010, Oxford scientists with a company called Oxitec genetically engineered OX513A, a sterile male Aedes aegypti mosquito with a gene that causes its larvae to die. If this mosquito mates with enough females, who can only mate once, the population of the Aedes aegypti will decline. According to Michael Specter, a writer for The New Yorker, most biologists say that the potential benefits to this breakthrough far outweigh the risks . While he is not a primary source, he interviewed the people in charge of the project, who likely fed him this generalization.
As an engineer interested in genetics, and as a humanitarian, I wish to reduce the spread of the dengue virus that catastrophically affects the human population. As a broader scientific community, it is necessary to further develop the genetically engineered Aedes aegypti mosquito so that it mates more successfully with female vectors. Additionally, we need to work with people in the affected regions to secure approval for the implementation of this technology.
In this paper, I intend to discuss the use of the RIDL (or Release of Insects carrying a Dominant Lethal genetic system) method and the OX513A mosquito to prevent the spread of the dengue virus.
Each year, there are between 50 and 100 million new infections of the dengue virus, leading to around 25 thousand deaths . The virus is spread by female Aedes aegypti, who have adapted to breed in tropical and subtropical urban environments . When the female mosquito bites a human with dengue, it becomes infected with the virus. While the virus does not harm the mosquito, and while the mosquito remains infected for life, the virus can be spread to other humans through a single mosquito bite, as seen in Figure 1 .
FIGURE 1 
How the Dengue Virus is Spread
The female Aedes aegypti is infected with the virus by biting a human with the virus. One infected female mosquito can infect many people.
Aedes aegypti is an invasive species unintentionally spread around the world by human travel . With current globalization trends, this is not surprising. The mosquitoes rest indoors near our homes, and they are active at dusk and dawn . The females lay their eggs in small containers and refuse . They will lay their eggs almost anywhere moist. They do not fly far or live long; most travel a few hundred yards and survive an average of ten days . At first glance, they behave like everyday mosquitoes, but they also tend to carry the dengue virus.
The dengue virus consists of four serotypes, or variations, of the genus Flavivirus . When the human body is infected with the virus, it forms antibodies against the specific serotype . The infected human experiences symptoms ranging from flu-like symptoms to
high fever, rash, severe headache, pain behind the eyes, and muscle and joint pain . If a human is bitten again with a different serotype, they experience a more severe infection because the body is not immune to that serotype. After the second infection, the hosts experience dengue hemorrhagic fever (DHF), also known as breakbone fever, which is characterized by high fever, circulatory failure, and pain compared to the breaking of one's bones . According to Pankaj Garg in the Indian Journal of Dermatology, after the third infection, the human experiences dengue shock syndrome (DSS), which has mortality rates of 9.3% to 47% due to multiorgan dysfunction .
The dengue virus multiplied as Aedes aegypti, shown in Figure 2, has spread around the world. According to Pankaj Gard in the Indian Journal of Dermatology, in 2010, the dengue virus was an endemic in 112 countries, with significant outbreaks in five of six World Health Organization regions, putting 40% of the world's population at risk . According to a recent Natural Defense Resource Council report, 28 US states are risk of infection .
FIGURE 2 
Female Aedes aegypti mosquito
The female Aedes aegypti mosquito is known to carry the dengue virus.
Current interventions to reduce the Aedes aegypti population include spraying chemicals and larvicidal insecticides. Spraying chemicals into the air to kill adult mosquitoes is more widely used than larvicidal insecticides because insecticides are more expensive . Nonetheless, spraying chemicals near our homes, where the mosquitoes breed, is harmful to human health. The insecticides are put in breeding areas to kill mosquito larvae before they mature into adults. However, an increase in insecticide-resistant mosquitoes, environmental concerns, and the difficulty of distributing insecticide bed nets in urban areas make these current interventions less effective . If the mosquitoes are resistant to the insecticides, they will not die. Urban environments are difficult to enlace with insecticides because of the numerous breeding places that these mosquitoes access.
We need to reduce the spread of the dengue virus through Aedes aegypti because many people are dying. According to Hsi-Kai Wang of the Institute of Nanoengineering and Microsystems at National Tsing Hua University in Taiwan,
the emergence and spread of dengue from Asia to the Americas, Africa, and the Eastern Mediterranean regions represent a global pandemic threat . While the virus is not as widespread in the United States as it is in Southeast Asia, it is still an issue of consideration. According to Oxitec, the company that produced OX513A, dengue is the fastest-growing mosquito-borne disease . The key is to not let it become a larger issue; it still has the potential to be controlled. Fatality rates for DHF are around 5%, 90% of which are children under 15 .
From a humanitarian standpoint, the National Society of Professional Engineers' code of ethics requires that engineers
serve the public interest . It is in the public's interest to reduce the spread of the dengue virus. Therefore, we, as an engineering community, must reduce the population of the Aedes aegypti mosquito.
RIDL is essentially the genetic engineering of sterile insects . Through this process, two genes are inserted into male mosquito eggs. One gene produces a protein called tTA. tTA produces more of itself and, in turn, stops the cell from turning on other genes needed for survival . This tTA-producing gene is switched off by placing an antibiotic called tetracycline in the insects' food . When the eggs are released, the tetracycline is removed, and the lethal gene is turned on. The other gene inserted is a florescent marker used to distinguish modified mosquito larvae from normal ones. When these eggs are released, the males impregnate the females with the dominant lethal gene, and her eggs die before they become adults.
This engineered technology has broader potential. If a relatively simple process such as RIDL can be used successfully to combat dengue, it can be applied to other disease-spreading vectors as well. This aligns with the fields of biosystems engineering and ecological engineering, each of which focuses on creating a safe living environment for us to live in.
Before this technology was available, scientists used the Sterile Insect Technique (SIT) to create sterile male mosquitoes. However, since this method involved radiation treatment of small insects, the adult mosquitoes were damaged in the process, and they could not compete successfully for females . While SIT is affective against some insect pests, the mosquitoes do not stand up to the technique.
The RIDL process is valuable because it is successful. Oxitec, the company that created OX513A, quoted a
96% suppression of the dengue mosquito in Brazilian trials, and further stated that the
approach is sustainable over time . In other words, in isolated areas of Aedes aegypti concentration, OX513A works effectively in reducing the population of potential dengue-virus-carrying mosquitoes.
In a different study, Oxitec researchers on the Cayman Islands studied the success of the genetically engineered male mosquitoes as compared with normal males. They found that the OX513A mosquito is
imperfect in mating competitiveness relative to wild males, but the data still suggest that OX513A males can
compete well for mates in the field . This is one of the faults of OX513A; with further study and field trials, hopefully OX513A will improve its competitiveness.
From a more economic standpoint, OX513A is easy to produce. Andrew McKemey, Oxitec's chief field officer, says,
these mosquitoes are relatively easy to breed and cost almost nothing to transport . Then again, this source is biased because McKemey works for Oxitec, and he does not transparently mention the cost of production. The fertilized eggs themselves can be stored in a diapause, or a period of suspended development, state for many months . This simplifies the transportation of the eggs from the lab to the field where they are introduced into dengue areas. Plus, this approach involves longer-lasting effects than ineffective chemical spraying.
There is controversy in introducing OX513A into dengue fever areas. People are hesitant to release man-made mosquitoes into the environment, since this species of mosquito is known to carry dengue. People want evidence that the mosquitoes work . There has not been ample study as to the absolute effectiveness of the genetically modified mosquito in reducing the Aedes aegypti population.
Along the same line, Helen Wallace, the executive director of the British organization GeneWatch, called OX513A
Dr. Frankenstein’s monster, plain and simple . People are afraid of this man-made mosquito, since there is uncertainty as to its effects on the environment and on humans.
Politically and bureaucratically, many loopholes exist to jump through before open release of the genetically modified organisms. For example, in Malaysia, it took over three years to secure approval for a limited release and capture field experiment of OX513A . However, John Marshall, of the Department of Infectious Disease Epidemiology at the Imperial College in London, says,
[OX513A’s] biosafety implications are relatively manageable because [altered genes] are only expected to persist in the wild for a few generations after release . Since a generation lasts a little over a week, a
few generations is around 20 days. If the biosafety implications are irrelevant, the approval process should, theoretically, speed up.
From an environmental point of view, the wide extermination of mosquitoes could have serious ecosystem effects . For example, if other species depend on Aedes aegypti to survive, the reduced number of mosquitoes could affect the lives of other organisms. However, according to the correspondence of Michael Specter of The New Yorker, no species depend solely on Aedes aegypti for their survival, so this objection is trivial . Since the limitations of further study exclude environmental impact, bureaucratic structures and public hesitance primarily limit the success of these mosquito trials.
From a genetic engineering standpoint, I find this topic compelling. When dealing firsthand with mosquitoes, who would have ever thought the agitating insects could be modified to reduce the spread of a deadly virus? Furthermore, I find the connections between micro- and macro biology to be fascinating. As a future bioengineer, the study of genetics has great importance to my field of study.
As a member of Engineers Without Borders, I also play a role in helping developing communities abroad. Many of the areas that we, as an organization, strive to assist are also areas where the dengue virus is present. The primary countries where dengue is present are developing countries in Southeast Asia and Latin America. While we assist these regions with more general issues like a clean water supply and infrastructure, the inhabitants are experiencing the dengue virus in person. It would be ignorant of me, as a human being and as a member of Engineers Without Borders, to ignore this factor. Furthermore, through this organization, I am aware of the limitations of policy approval by governance structures.
In addition to being a humanitarian, I am also a Unitarian Universalist. One of our religious principles is the belief in the inherent worth and dignity of every person. Even though the dengue virus is not an overarching issue where I live, there are millions of people being infected annually. As a member of the world community, I feel obligated to help out.
As an engineer, I am bound by the engineering code of ethics. In the preamble of this document, it states that,
Engineering has a direct and vital impact on the quality of life for all people . Therefore, all services provided by engineers must be dedicated to the protection of public health. If the quality of life of people in Southeast Asia or South America suffers because of the dengue virus, then engineers have the obligation to impact their quality of life in a positive way.
From a biosystems engineering and ecological engineering perspective, the treatment and prevention of widespread diseases is of utter importance. If we can integrate human society successfully with the natural environment, both the human species and our environment will benefit.
As a society, we cannot ignore the reality that the dengue virus affects between 50 and 100 million people every year . That means that 1 in 70 people is affected every year. If that ratio were distributed evenly around our world, we would all know someone affected by the dengue virus. We have an obligation as a society to help those affected by dengue.
For people in areas affected by dengue, the release of genetically engineered mosquitoes is a frightening concept. However, the majority of people in these areas, such as Mali, are pragmatic towards the release of the genetically modified mosquitoes . Our scientific community must respect their needs and follow suit with the further development of OX513A and RIDL.
From a technology point of view, the RIDL method is a stepping stone for future large-scale genetically engineered solutions. If we continue to further develop the genetically modified Aedes aegypti mosquito, we can prevent the spread of the dengue virus. If we can alter mosquito genes to prevent the spread of a virus, then we can limit the spread of other viruses, such as West Nile.
I am hopeful for the OX513A research. I can only see positives along its path to further study. However, researchers must be able to overcome human resistance to the study of genetically engineered organisms in order for OX513A to be widely successful.
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I want to thank my roommate Victor for putting up with my late-night research and for reminding me to keep laughing. I want to thank Julianne McAdoo and Angela Farkas from the University of Pittsburgh Writing Center for helping me get started in outlining my paper and in revising it. In addition, I would like to thank Anne Schwan and Judy Brink from the Bevier Engineering Library for their support in the early and late stages of my research. I would also like to thank Rowan Walker for editing my paper.