Team:UCL/Safety

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UCL iGEM 2016 | BioSynthAge



SAFETY CONSIDERATIONS

An integral part of Biosynthage






OVERVIEW

As our therapies will be integrating into the human body, safety forms a major part of our project. Not only do we want to prove that our devices work, but we also want to create therapies that can be safe to be used on humans. Therefore we have greatly incorporated the safety of our gene therapy into our design of the biobricks. As well as this, there is huge concerns over using synthetic biology as a method of bio-control. Hence, why we also have discussed how we can incorporate safety into the design of our vitellogenin device.



Superoxide Dismutase: Gene therapy


Security


The use of viral vectors has been controversial since the inception of gene therapy. However, numerous advances have increased the security of this transfer method. The selection of lentiviral vector as a gene therapy vehicle has three different security measures. The first is the segregation of the viral genome into multiple viral plasmids, reducing the possibility of the vector to produce a replication-competent retrovirus (RCV). The next measure is the use of a chimeric LTR to reduce dependence on the structural gene tat. Finally, the deletion of large portions of the U3 regions leads to production of self-inactivating lentiviral vectors.


Integrating human practices


William Bains described, it is possible to incorporate an additional security measure to our gene therapy. This safety lock would be based on the use of a drug capable as positive feedback. This effect could be achieved by the interaction of the drug with a regulatory element of the genetic circuit; if the drug is present, the expression of SOD is activated and vice versa. The proposed mechanism would allow controlling the gene therapy in case of undesired effects.


As explained on our human practices, we also integrated the idea of adding an nfkb promotor which would be engineered to have more binding sites. This would mean that the final SOD3 device will only respond to high levels of oxidative stress. This would make our system safer as increasing evidence suggests that our bodies require small amounts of oxidative stress for certain processes, as free radicals also act as signalling molecules. We believe that this approach would be a significant improvement as we can control the release of our SOD3 enzyme only to be released when needed.



Vitellogenin


UCL Biosynthage Vitellogenin project has two aspects: the application of RNAi in pest control and anti-anging in human.


Pest control:


As stated in the vitellogenin proposal, pest control can be achieved via feeding the silverleaf whitefly B.tabaci using the species-specific RNAi-mixed food. It is expansive if applied widely and may provide food resources to other species of pests. Once B.tabaci has taken up the RNAi-mixed food, its vitellogenin level will be lowered and oxidative stress will increase, which becomes more susceptible to death. At this moment we do not know if this will induce any other potential mutation that makes the pest selectively more competitive. As the pest is involved in virus transmission, does the change in vitellogenin gene alter the virus? When the parasitic wasps E.formosa lay eggs in the larvae of B. tabaci, what effects can the lowered Vitellogenin level exert on the development of E.formosa that lives on the host? These questions need to be answered in the future research to be conducted.


Anti-aging in human:


Due to the time limit and the amount of grant sponsored, we have not been able to conduct this part of research. According to the proposal, we plan to test whether vitellogenin can reduce oxidative stress in human cells using the recombinant yeast cells P.pastoris. If it works then potential gene therapy can be conducted to transfer the recombinant cell into human. However, there has not been any research published explaining the side effect of the up-regulation of vitellogenin in human. The recombinant P.pastoris cells have been studied previously, does P. pastoris vitellogenin behave in the same way as human cell?

The next step of research is to increase the expression of vitellogenin human cells to test the level of oxidative stress.


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