Team:William and Mary/Proof Of Concept

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Proof of Concept

The overarching goal of our project, TheraPUFA, was to (1) design a broad spectrum “smart” probiotic, and (2) test the feasibility of our probiotic using extensive mathematical modeling. We chose the latter approach for “Proof of Concept” not only because we did not have access to the wetlab during this iGEM season, but also, because the type of mathematical modeling that we employed provided an excellent means of assessing feasibility and improving upon design.

We determined that our initial design and model using parameters from the literature was not feasible, however using more biologically relevant parameters for mucociliary clearance made our model feasible. The results of our mathematical models emphasized the effect of mucociliary clearance, probiotic dosage, frequency of probiotic replenishment, and PUFA production rate on the effectiveness of our probiotic. We varied these parameters and seven others to determine the optimal functioning of TheraPUFA, and quantify the improvement necessary to achieve this optimal state. For example, our mathematical models demonstrated the need to greatly extend the retention time of the probiotic within the nasal cavity, despite mucociliary clearance. The need to extend retention time led us to research mucoadhesive poloxamer gels, as suggested by Dr. Shikani. Without this technology, the probiotic would be swept away too quickly to produce a significant effect. Similarly, our model provided the optimal frequency of probiotic replenishment within the nasal cavity, which was greater than those suggested by medical doctors we interviewed. When replenished at insufficient frequencies, the model predicted little to no effect on viral titer. These results led us to research alternative proposed implementation strategies with respect to dosage. Finally, the model’s results implied that we would need to increase PUFA production rate to achieve significant reduction of viral titer. In light of these results, we researched means to optimize PUFA production, such as by knockout of the FadE gene such that heterologous PUFA synthases no longer compete significantly with endogenous fatty acid synthases for starting substrates. With the needed modifications highlighted by the profound mathematical model and the suggestions from Integrated Human Practices, we determined that our design was indeed feasible - but would require further testing and development. These steps are described in detail on our implementation page.

For more detailed information regarding our model and design, please visit our model and design pages.