COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 141
An example of a cellular simulation environment is E-CELL, an open-source system for modeling
biochemical and genetic processes. Organizationally, E-CELL is an international research project aimed
at developing theoretical and functioning technologies to allow precise “whole cell” simulation; it is
supported by the New Energy and Industrial Technology Development Organization (NEDO) of Japan.
E-CELL simulations allow a user to model hypothetical virtual cells by defining functions of pro-
teins, protein-protein interactions, protein-DNA interactions, regulation of gene expression, and other
features of cellular metabolism.^47 Based on reaction rules that are known through experiment and
assumed concentrations of various molecules in various locations, E-CELL numerically integrates dif-
ferential equations implicitly described in these reaction rules, resulting in changes over time in the
concentrations of proteins, protein complexes, and other chemical compounds in the cell.
Developers hope E-CELL will ultimately allow investigators a cheap, fast way to screen drug
candidates, study the effects of mutations or toxins, or simply probe the networks that govern cell
behavior. One application of E-CELL has been to construct a model of a hypothetical cell capable of
Box 5.5
BioSPICEBioSPICE, the Biological Simulation Program for Intra-Cellular Evaluation, is in essence a modeling framework
that provides users with model components, tools, databases, and infrastructure to develop predictive dynam-
ical models of cellular function. BioSPICE seeks to promote a synergy between experiment and model, in
which model predictions drive experiment and experimental results identify areas in which a given model
needs to be improved, and the intent is that researchers go from data to models to analysis and hypothesis
generation, iteratively refining their understanding of the biological processes.An important component of BioSPICE is a library of experimentally validated (and hence trusted) model
components that can be used as starting points in larger-scale simulations, as elements from this library are
composed in new ways or adapted to investigate other biological systems. Many biological parts and process-
es are represented as components, including phosphorylization events, chemotaxis, and conserved elements
of various pathways. Also, because BioSPICE is designed as an open-source environment, it is hoped that the
user community itself will make available a repertoire of model components that span a wide range of spatial,
temporal, and functional scales, including those that simulate a single chemical reaction with high fidelity,
those that simulate entire pathways, and those that simulate more abstract higher-order motifs.BioSPICE tools are intended to enable researchers to use public databases and local resources to formulate a
qualitative description of the cellular process of interest (e.g., models of networks or pathways), to annotate
the links between entities with biochemical interactions, and finally to convert this annotated qualitative
description to a set of equations that can be analyzed and simulated. In addition, BioSPICE provides a number
of simulation engines with the capability to simulate ordinary, stochastic, and partial differential equations
and other tools that support stability and bifurcation analysis and qualitative reasoning that combines proba-
bilistic and temporal logic.SOURCE: Sri Kumar, Defense Advanced Research Projects Agency, June 30, 2003.(^47) See http://www.e-cell.org/project/. For a view of the computer science challenges, see also K. Takahashi, K. Yugi, K.
Hashimoto, Y. Yamada, C.J.F. Pickett, and M. Tomita, “Computational Challenges in Cell Simulation: A Software Engineering
Approach,” IEEE Intelligent Systems 17(5):64-71, 2002.