# Presentation: 417812

## Analysis and engineering of cellular circuitry

- Courtesy of IBM

- From: Wasserman Lab, Loyola

- _Asynchronous Digital Telephone Switching Circuit_
- Full knowledge of parts list
- Full knowledge of  “device physics”
- Full knowledge of  interactions
**No one fully understands how this circuit works!!**
- Its just too complicated.
- Designed and prototyped on a computer (SPICE analysis)
- Experimental implementation fault tested on computer

- _Asynchronous Analog Biological Switching Circuit_
- Partial knowledge of parts list
- Partial knowledge of  “device physics”
- Partial knowledge of  interactions
**No one fully understands how this circuit works!!**
- Its just too complicated.
- We ***need*** a SPICE-like analysis for biological systems

## A foundation for cell network analysis

- Compile a list of parts that
-  make up your system.

- Group subsets of parts based
- on function, physics and
- interactions

- Determine “device physics”
- for the parts and their
- interactions.

- Create databases of the
- above and the “circuits”
- that are to be considered
- for analysis

- Create quantitative
- simulations and analyses of
- the dynamics of
- complex networks.

## SPICE: Simulation Program for Integrated Circuit Evaluation

- Parts
- database

- From
- subcircuit
- database

- Integrated
- circuit
- database

- Automated
- fault
- diagnosis

## BIO/SPICE: Databasing, simulation and analysis

***Bio/Spice: ***A Web-Servable, Biologist-Friendly,  database, analysis and simulation interface was developed into a true beta product.
- Interfaces to ReactDB, MechDB, and ParamDB.
- With Kernel, performs basic:
- flux-balance analysis,
- stochastic and deterministic kinetics,
- Scientific Visualization of results.
- Notebook/Kernel design optimized for distributed computing.

## Components of Bio/Spice

- Local Kernel

- Local Data

- ReactDB

- MechDB

- Center Data

- Remote Kernel

- Remote Kernel

- Remote Kernel

- Center
- Tool
- Repository

- ParamDB

- BIO/SPICE

- Internet

- Internet

- Local

## Kernel overview

**Update Object Parameters**
**Operator combinatorial logic**
**Statistical and thermodynamic parameters**
**Instantaneous enzyme kinetics**

**Mesoscopic Regime**
**Stochastic object update procedures**
**Cumulate discrete reaction events to project signal levels**

**Macroscopic Regime**
**Deterministic object update procedures**
**Classical integration routines to project signal levels**

**Master Simulation Controller**
**Dynamically selects object level update procedures**
**Schedules object updates**
**Maintains global parameter and state variable database**
**Manages parameter and data I/O**

**Modeling procedure dynamically selected by master controller based on current  concentrations and other model parameters**

**Model Object-Level Chemistry**
**Model events internal to each object independently**
**Report changes in object’s output signal levels**

**Inputs**
**Network definition**
**User-defined new objects**
**Kinetic parameters**

## Bio/Spice data structure overview

- World

- Compartment

- Pathway

- Reactions

- Species

- Mechanisms

## Bio/Spice Simulation Objects

- Bio-Object1

- Bio-Object2

- Bio-Objects accept inputs in two stages:
- 	1) resolution
- 	2) parameterization.

- Resolution determines if the output from Bio-Object 1 is of a valid type.
- If it is, and there are more than one input of that type, then the user is prompted for which input they mean.
- Parameterization determines how the equations of **both** Bio-Object1 and Bio-Object2 are affected.
- The user is prompted to enter the physical data (e.g., kinetic constants) for the interaction or to look them up in a database

## Example of linking

- User is modeling a competitive inhibition reaction. Thus, the user creates a ***Reaction*** Bio-Object, and
- four ***Species*** Bio-Objects:

- E	ES	E+P
- EI

- S

- I

- v= kcat Etot KI[S]/(KSKI+KS[I]+KI[S])

- Linking of S to NCI-1 results in a prompt for whether or not the species
- object named “M1” plays the role of the internal variable, E, S, I or P.
- If user chooses ‘S’, then the program prompts for KS.
- If user chooses ‘E’ then the object prompts to user to enter or select all objects in
- the model that have an ‘M1’ molecule or complex within them.
- Currently, complex equilibria are resolved using mass action kinetics.

## Using Bio/Spice to analyze phage : Starting your notebook

- Using Bio/Spice to analyze phage : Starting your notebook

## Using Bio/Spice to analyze phage : Adding infrastructure 

## Using Bio/Spice to analyze phage : Adding the parts 

## Using Bio/Spice to analyze phage : Linking parts together

## Using Bio/Spice to analyze phage : Entering data