Written by Sang K. (KIS'19)
━━ April 6, 2018 ━━
Introduction
In the current society with surging populations and increasing densities, our vulnerability to such infectious diseases has increased as well. Recently, diseases such as the H7N9 virus, Ebola, and Zika virus have shaken the international community and have urged nations to focus on advancements that could eradicate these viruses. In 2007, the Zika virus had its first major outbreak in the island of Yap. According to the World Health Organization round, 73% of the residents in Yap were infected with the Zika. By 2015, cases of Zika had been detected in regions of South America: Mexico, Paraguay, Guatemala, El Salvador, Brazil, and Bolivia. Towards 2016 and 2017, Zika had reached the borders of North America as well as parts of Asia and Europe. The Zika virus is transmitted mostly through a mosquito bite from the Aedes species. The virus shows active involvement in the reproductive organs and is classified as a sexually transmitted disease (STD). Zika can also be transmitted from a pregnant mother to its child, which can cause defects in the fetus. The virus shows similar symptoms as malaria or dengue as individuals exhibit general muscle pain, rashes, fevers, and headaches. However, the Zika virus can be especially fatal for the fetus of pregnant individuals. According to the Centers for Disease Control, Zika can be transmitted from the mother to her fetus and can cause brain defects in the baby. The most common brain defect exhibited by babies with Zika virus is microcephaly, a condition where a person’s head is abnormally smaller compared to a normal-sized head. When a pregnant mother is infected with the Zika virus, through vertical transmission, the virus may infect the placental trophoblasts and Hofbauer cells (placental macrophages) that cross the placenta and then enter the baby. Microcephaly causes poor brain development as well as impairment in social and basic functions. With complex infections such as Zika occurring, it has become extremely difficult to develop vaccines and medications for such diseases. However, recently, medicine has taken a turn. Instead of attempting to directly suppress the physiological symptoms of Zika, scientists have looked for methods to alter the source of the disease: the Aedes mosquitos.
With genetic engineering on the rise, it is only a matter of time until genetics crossover medicine. Recently, scientists have been altering the genes of animals and creating these genetically modified organisms that may be used for the purpose of medicine. However genetically modifying organisms is not a new concept as scientists have been modifying vegetables, crops, and food for decades. These genetically modified organisms (GMO) have benefited humans through the expression of favorable phenotypes. But now, our genetically engineering abilities have extended and is currently being used as a method to eradicate the Zika virus. Genetic engineers and scientists are specifically targeting the Aedes species, a carrier of the Zika virus, and modifying those organisms in order to prevent those mosquitos from being able to transmit the Zika virus to humans.
Genetically Modified Mosquitoes
Oxitec, a bioengineering company, has taken the first steps in creating a genetic cure for the Zika virus. As only female mosquitoes actually bite and feed off human blood, Oxitec targeted using male mosquitoes so that the mosquitoes they create and release don’t bite and further infect the population. Because the females are the only mosquitoes that actually bite humans, it means that female mosquitoes are the ones transmitting the Zika virus. In order to prevent this, Oxitec genetically modified non-biting male mosquitoes to mate with the females and regulate the insect population. The genetically modified males will have contained a gene that causes self-destruction. The hope is that when these modified males mate with infectious females, these deadly genes are passed onto their offsprings that may have the Zika virus, and ultimately killing the offspring before they can further infect humans. These genetically modified Aedes aegypti mosquitoes are called OX513A and they carry a potential to eradicate the Zika virus.
The Process of Creation
Scientists first synthesized or used segments of genes in order to produce their desired genes: the fluorescent indicator and lethality (self-destructing) gene. The lethality gene or tTAV gene is synthesized so that it only operates within insects. The tTAV creates a nontoxic protein which suppresses gene expression of the mosquitoes, therefore killing the mosquito before reaching adulthood. However, Oxitec has taken security measures to make sure the proteins produced by the tTAV gene are not toxic and do not disturb the food chain that depends on the mosquito population. So organisms that eat the mosquitos with these destructive proteins and genes will not be affected. The fluorescent marker is also needed in order to properly indicate that the mosquito that they are engineering contains and expresses the desired genes so that they don’t just release an army of mosquitoes that don’t carry any of the tTAV genes.
After creating the desired genes, these genes are inserted into the genome of a (male) mosquito egg. In genetic engineering, there are many methods to input this new gene into the organisms: retrovirus gene transfer, embryonic stem cell gene transplant, and sperm-mediated gene implant. However, for mosquitos, a method called micro-injection is used where the desired gene is directly inserted into the embryo (fertilized ovum) or, in this case, mosquito egg. You might ask: if these males have the destructive gene, then why aren’t they dying themselves? Good question. In the lab, these modified mosquitoes are fed an antidote called tetracycline which allows the modified mosquitoes to survive even with the lethality gene. Tetracycline specifically doesn’t allow the tTAV protein to bind to the tet0 operator, a site within the DNA sequence of a mosquito that promotes further tTAV release, therefore tTAV is produced anymore. This is done so that only the lab mosquitoes have the ability to survive the lethality gene and the wild mosquitoes, such as the offsprings they create with infectious mosquitoes, will die off. With the modified mosquitoes created and surviving, they breed more modified mosquitoes in the lab to create more mosquitoes with the desired genes. The scientists constantly use the fluorescent markers to see if the mosquito contains the tTAV gene. They do this by shining a certain wavelength of light at the larvae, and if the larvae glow or fluoresce it means that the organism is exhibiting the tTAV gene since both fluorescent and tTAV genes were inserted together in the same genome and are being expressed together.
Once these modified mosquitoes are checked they are released in small amounts. These male GMOs mate with the female mosquitoes carrying the Zika virus. Once they mate and the females lay eggs, their offspring will have the Zika virus, as the female mosquito passes the virus to its offspring, and it will also have the tTAV gene. Once the offsprings hatch, the lethality gene start working as it transcribes and translates to produce tTAV proteins. These tTAV proteins work in positive feedback, as the tTAV protein binds to the tet0 operator site and induces more tTAV proteins to be synthesized. A large amount of tTAV proteins will start binding to the transcriptional proteins such as RNA polymerase. These transcribing proteins are essential in gene expression and protein synthesis, and once they are suppressed by tTAV they can no longer transcribe the essential and important genes. Once these imperative genes are stopped
from transcription, they are no longer expressed and the necessary proteins and molecules the mosquito requires in order to function and survive starts to diminish, eventually leading to the mosquito offsprings death before adulthood. These mosquitoes die early on so that they do not further transmit Zika to their offsprings. In reality, these self-limiting (lethality) genes have been successful as small populations of these GMOs have been released in the Cayman Islands, Brazil, and Panama. Within these releases, the general Aedes population decreased by 90% and further research is still being done for their potential applications for other similar diseases.
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Conclusion
Although the case for OX513A has been extremely successful, it does not make genetic engineering and its applications reasonable for use whenever and for whatever reason. There are many ethical conflicts that lie behind genetic engineering as well as many security issues. The OX513A had gone through hundreds of trials and tests before being conducted in real environmental use. Such security measures must be taken before introducing products to our very own environment. Calculations and experiments must constantly be done in order to make sure that the things we add to our living world aren’t the things that take away our world. Even seeing the success of our ability to manipulate genes, there is a border between necessities and destruction. Knowledge is a key component in society, but how we use that knowledge is a different story. By genetically modifying everything around us and creating all organisms according to our standards of “perfection”, we may create issues with nature as well as diversity. These innovations and advancements must be looked at different perspectives and requires skepticism no matter how successful or how appealing the previous creations were.
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Bibliography:
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Pictures:
- All images with in the article drawn by Sang Kim
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