Team:Tec-Monterrey/Model

MATHEMATICAL MODEL

Transcriptional Amplifiers for Drug Discovery

Designing synthetic biological circuits using genetic elements has become a research field for developing novel biochemical sensors. Specifically Bacterial cell based biosensors have been studied for the environmental monitoring, clinical diagnostics and drug discovery. One of the main challenges for this biosensors to meet real-life applications is the low sensibility and deficient detection limits.

The rise of multiple antibotic resistant bacteria and the evident crisis in drug discovery has become one of the main challenges in human history. Traditional screening not only takes longer times,from years to decades, but often fails to discover novel biomolecules. Bacterial biosensors have provided a novel benchmark for the screening of secondary metabolites producers, boosting the discovery of antibiotics and broadening the spectrum of the latter. One of main aspects that should be considered for the development of novel antibiotic biosensors is the sensibility, since they can only work properly below the minimum inhibitory concentration.

Our project consists of a series of engineered multi-layered transcriptional amplifiers that sequentially increases the output expression level of a GFP reporter protein by the presence of an antibiotic belonging to a specific mechanism of action (MOA) in order to enhanced the process of drug discovery and bacterial screening.

Modelling Biological systems has become an area of interest for multidisciplinary areas of science, medicine and engineering. Mathematical models allow to understand and predict the behavior of complex systems using simple concepts.

Bacterial bio-sensors can be divided into three modules, the first comprising a sensing module that recognizes the external signal and transduces into a transcriptional output, the computing module that modulates the transduced sensor signal and the output module which executes the physiological output response. In this project, we develop mathematical models for the engineered multi-layered transcriptional amplifiers which acts as a computing module using both exact deterministic differential equations and stochastic simulations to provide a proof of concept for the amplification signal of the antibiotic biosensor.

The structure of the following sections goes as follows: First we derive the mathematical equations for an already characterized heavy metal biosensor consisting of a constitutive promoter expressing a repressor protein inhibiting the later expression of a reporter gene. Then we will consider the effect of adding a mono-layer orthogonal transcriptional amplifier to the signal amplification. After that we will extrapolate this same models to our antibiotic biosensor.

Microfluidics Model

Compared to single phase flows, microfluidic two-phase flows relies on several physical phenomena that need to be controlled for the droplets to fully form. The flow properties in microchannels rely on three parameters: the channel geometry, the properties of both fluids, and the flow conditions. These factors can be described by some important dimensionless parameters.