20.109(F13): Mod 2 Day 1 System Design

Introduction

Today we will begin our journey through Systems Biology and the careful consideration of experimental and computational design that is required for large-scale biological engineering studies. At the end of lab today, you will choose two chemical inhibitors that target the Epidermal Growth Factor Receptor (EGFR) signaling network with the goal of overcoming a growing common problem in the treatment of disease -- drug resistance.

Part 1: Simulation of the EGFR network

The first mathematical model published in the journal Cell described the binding of EGF to EGFR. That paper ushered in an era of multidisciplinary research which brought together scientists and engineers to build mathematical models used to interrogate intracellular signaling pathways. In fact, the field of Systems Biology, often defined as the use of computational models to study multiple signaling pathways across variable time and length scales, grew directly from these first collaborations.

There are many approaches to computational modeling each aiming to understand how information travels through a signaling network to ultimately produces a cell phenotype. In this module you will design an experiment that alters cell proliferation, a cell phenotype that is often dysregulated in cancer. There are several distinct signaling pathways downstream of EGFR activation that influence cell proliferation and viability. The best understood pathways are the MEK/Erk pathway, PI3K/Akt pathway, and the STAT transcriptional regulation pathway. One important tool that we can take advantage of as biological engineers is the wealth of mathematical models describing the dynamics of these pathways upon EGF stimulation. It is good practice to gather as much data as possible before designing an experiment -- therefore, we will use computational simulation to better understand how to best inhibit the MEK/Erk, PI3K/Akt, or STAT pathways.

In 2012, Bidkhori et al. employed an ordinary differential equation (ODE)-based mathematical model to study the effect of mutant EGFR proteins on the pathways that control cell proliferation/viability. Today we will utilize a web-based program, CellDesigner, that facilitates building and visualizing cell signaling models. In fact, the computational study of cell signaling has become such an useful tool that a standardized programing language [

1. Open CellDesigner
2. Under Database choose "Import model from BioModels.net..."
   • A large list of models opens in a subwindow.
   • Scroll all the way down to the bottom and choose BIOMD0000000452 Bidkhori2012 - normal EGFR signaling
     • Note: only models that have been curated (or validated) by an SBML expert are shown in the list
   • Click Description to go to the BioModels database and read the abstract that describes the model.
   • Click Reference to see the official paper reference -- notice how computational modeling of biological systems is happening all around the world!
   • Finally, click Import to load the model into CellDesigner. (You may ignore the two errors at this point.)
3. Next, clean up the CellDesigner workspace a bit to make things easier to view:
   1. Maximize the CellDesigner window.
   2. Under View:
      • unselect Show Reaction Id
      • under Change Toolbar Visible, select Hide all
4. Click the Proteins near the bottom of the window. How many proteins and protein-complexes are described by this model?
5. Click Reactions. How many different ODEs are used the describe this biochemical system?
6. Now, minimize the bottom panel using the small, gray arrows in the upper left hand corner.
7. The components of the EGFR network and their complexed states (for example EGF + EGFR --> EGF-EGFR) are illustrated in the large window in the middle of the screen. The number of model components makes it very difficult to view the structure of the model. To see a quick view of the system, under View choose Zoom Fit.
8. The 'hairball' view of the model includes arrows (edges) and boxes (nodes) that represent the different biochemical reactions of the system. To better organize the model for ease of visualizing the information flow, go to Layout and choose Hierarchic Layout.