Team:ETH Zurich/Modeling/Lactate Module

"What I cannot create I do not understand."
- Richard Feynmann

Lactate Module

Introduction

The initial idea was to implement a fold change sensor in order to measure the lactate production rate. We assumed that on our timeframe, the lactate production might not reach steady state. That is why our sensor has the topology of a fold change sensor. However due to the topology of the natural detection system in E coli. Our system does not behave as a fold change sensor but rather amplifies the difference between the production of cancer and normal cells.

Chemical species

Name Description
Lacout Lactate produced by mammalian cells
Lacin Lactate inside E. coli cells
L2 Lldr, regulatory protein of lld operon, acts as a repressor
DLL Dimer formed between Lactate and LLdr dimer
LacI Lac repressor, DNA-binding protein, acts as a protein
IPTG Isopropyl β-D-1-thiogalactopyranoside, prevents LacI from repressing the gene of interest
IL Dimer formed between LacI and IPTG
LldP Lactate permease, active transporter

Reactions

\begin{align*} \text{Lac}_{\text{out}}&\mathop{\xrightarrow{\hspace{4em}}}^{K_{\mathrm{m,p}},v_\mathrm{max,p}} \text{Lac}_{\text{in}}\\ 2 \cdot \text{Lac}_{\text{in}} + \text{L}_{2} &\mathop{\mathop{\xrightarrow{\hspace{4em}}}^{\xleftarrow{\hspace{4em}}}}_{k_{\mathrm{DLL}}}^{k_{\mathrm{-DLL}}} \text{DLL}\\ &\mathop{\xrightarrow{\hspace{4em}}}^{\displaystyle\mathop{\bot}^{\text{L}_2}} \text{LacI}\\ &\mathop{\xrightarrow{\hspace{4em}}}^{\displaystyle\mathop{\bot}^{\text{L}_2}} \text{GFP}\\ &\mathop{\xrightarrow{\hspace{4em}}}^{\displaystyle\mathop{\bot}^{\text{LacI}}} \text{GFP}\\ \text{IPTG} + \text{LacI} &\mathop{\mathop{\xrightarrow{\hspace{4em}}}^{\xleftarrow{\hspace{4em}}}}_{k_{\mathrm{IL}}}^{k_{\mathrm{-IL}}} \text{IL}\\ \end{align*}

Initial model and predictive modeling

Assumptions

  1. We used the quasi steady state approximation to model the fast dimerization of Lactate to L2 and of IPTG to LacI

Equations

For the initial model, we chose to model the input of lactate as a step input. \begin{align*} [L_2] &=\frac{L_\mathrm{2tot}}{\frac{[Lac_\mathrm{in}]^2}{K_\mathrm{DLL}}+1}\\ \frac{d[LacI]}{dt}&=\frac{a_{\mathrm{LacI}}}{1+(\frac{[L_2]}{K_{\mathrm{RL}}})^2}-d_{\mathrm{LacI}}[LacI]\\ \frac{d[GFP]}{dt}&=\frac{a_\mathrm{GFP}}{1+(\frac{[L_2]}{K_{\mathrm{RL}}})^2}*\frac{1}{1+(\frac{[LacI]}{K_{\mathrm{RLacI}}})^2}-d_{\mathrm{GFP}}[GFP]\\ \end{align*}

Characteristics of the model