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Simbiology-based Model

2022 WHU-China

Simbiology-based Model

Introduction

Aiming to achieve periodic drug delivery for depressed patients, we tend to construct a kind of engineered bacterium with Bifidobacterium longum as the chassis. To enable the strain to periodically produce drug proteins, we designed an oscillator module and a production module. We also added a transporter module to enable the target protein to be excreted outside the bacteria. In addition, since the engineered bacteria have unpredictable effects and impacts on the external ecology, we designed a biosafety module to kill the engineered bacteria if necessary.
To verify the feasibility of this whole system, it is unrealistic to wait until the engineered bacteria are constructed due to the long periodicity of biological experiments. Therefore, we decided to verify the feasibility of the system by first simulating the whole system with a mathematical model, which can avoid unnecessary biological experiments.
We used MATLAB’s add-on application, SimBiology. SimBiology is a tool designed for systems biology. It allows for the creation and simulation of a series of biological processes: translation, transcription, gene regulation, species degradation, etc.

System and Reactions

Our designed system is shown in Figure 1. In our modelled genetic system, three kinds of DNA element, t e t R tetR , λ c l λcl , l a c I lacI , are transcribed into corresponding mRNAs in ossilator module. Then in production module, mRNAs are translated into three kinds of protein, TetR, λcl, LacI. Importantly, the three proteins cyclically repress the translation of the corresponding one protein, making three protine increase one after another. In other words, oscillation appeares. Notably, our drug protein SAMe synthetase opSam2 is co-expressed with one of the three proteins, say TetR. So the SAMe concentration upregulated by opSam2 will change with the same periodic oscillations as TetR.
Figure 1: Genetic system modelled with MatLab SimBiology
In the transporter module, the engineered bacteria produce the corresponding transporter protein to transport SAMe outside the bacteria. In the biosafety module, toxin protein is expressed under certain conditions and kill the bacteria to minimize the impact of the engineered bacteria on the external ecology.

Assumptions

In order to simplify the model and to highlight the main features of the whole design, the following assumptions are made:
  • The influence of other engineered bacteria in the surrounding area is not considered;
  • The regulatory proteins and other molecules produced by this circuit only affect this genetic circuit;
  • The volume of immobilized cells stays constant, therefore dilution is insignificant in the measuring time-frame.

Model Result and Analysis

The model is initialized based on the data in the previous section, while we trigger the release of the toxin protein at time t = 100 t = 100 to simulate the real situation. Result are shown in Figure 2.
Figure 2: Result on SimBiology
We can see that, the oscillator is working properly and the drug is periodically discharged into the digestive organ, and given t > 100 t > 100 , the toxin protein is released and the oscillation stops, which is in line with our expected results.

Conclusion

From the results, we can figure out that the mathematical feasibility of our designed engineered bacteria make sense, and we can next proceed with our biological design and biofunctional validation with more confidence.
However, due to the finite nature of the mathematical model, we have to admit that our model has several limitations below:
  • The effect of the system can only be simulated within a single cell and cannot take into account the interactions between cells during the growth of the colony;
  • Due to the strong coupling of the overall design, the insight of the oscillator are imperceptible to us.