Biology Reference
In-Depth Information
Petri net with extension (HFPNe) [10,12], which is optimized to be suitable for biopathway modeling
and simulation. HFPNe was introduced to handle any type of objects to match with the original Petri
net concept. In HFPNe, the new elements generic entity and process are introduced to handle these
objects (Fig. 1). Additionally, by using discrete and continuous entities and processes, HFPNe can
handle the discrete and continuous events at once and any kind of functions can be assigned to the delay,
weight and speed parameters of these elements. ODE can be easily modelled using the subset of HFPNe
elements,
i.e.
, continuous entity, continuous process, and setting all input connector weight parameters
to be “nocheck”. For detailed formal definition and properties of HFPNe, readers are referred to [12,13].
With Cell Illustrator, we can model and simulate any biological objects in biopathways, not only
biochemical reactions, molecular density, and 3D localization information, but also sequence-level
information (Fig. 2),
e.g.
, translated product with frame-shift and translation with codon table.
Some modeling applications, including E-CELL [14], Gepasi [15] and BioSPICE [16], require some
skills in mathematics and programming. The concept of Cell Illustrator, in contrast, does not require any
prior knowledge in differential equations and programming. To achieve this, we developed biologically
sophisticated GUIs and related tools described in the following sections. Prerequisites of Cell Illustrator
are advertised as “interest in biology, ability to operate a cell phone, and the mathematical ability of
standard middle school student or better.” Since 1999, new versions of Cell Illustrator have been released
almost every two years. Although there is a policy to distribute software applications as open source
in the community, Cell Illustrator is distributed as commercial software in order to afford the ability
to attend to every user's need and make continuous improvements quickly. Cell Illustrator Player (CI
Player), a full viewer of Cell Illustrator models without the simulation engine, is freely distributed. Thus,
users can share and view complete models similarly to what Adobe Reader does for PDF documents.
The text book [13] and [17] present use of Cell Illustrator and its applications in detail.
With Cell Illustrator, a considerable number of users have been conducting biopathway modeling
and simulation for their interested networks and have proven its practicality in their research. For
example, Troncale
et al.
[18] modeled the regulation of hematopoiesis and investigated the role of
interleukin-6 in human early hematopoiesis by simulations with an HFPNe model constructed with Cell
Illustrator. Koh
et al.
[19] conducted parameter estimation by applying an evolutionary technique to
their HFPNe model of Akt and MAPK signaling pathways and investigated their working hypothesis
on crosstalk interaction. Hardy and Robillard [20] simulated the Ca
2+
/calmodulin-dependent protein
kinase II (CaMKII) regulation network with Cell Illustrator, and then analyzed the dynamics of signal
propagation in the CaMKII regulation pathway. Sato
et al.
[21] modeled the olfactory transduction
pathway and implied that increased PDE1C dosage extends the longevity of the depolarization signals
of the olfactory receptor neuron. Wu and Voit [22] demonstrated how the canonical GMA and S-system
models in BST can be directly implemented in HFPNe framework using Cell Illustrator. In addition,
they described on Cell Illustrator how to account for different types of time delays as well as for discrete,
stochastic, and switching effects [23].
The above mentioned researches have shown that pathway modeling based on the Petri net concept is
practically accepted by biological scientists. We believe that Cell Illustrator will enhance more biological
research using biopathway modeling and simulation. In the Methods section, we address new functions
of Cell Illustrator 4.0 for graph layout, exchange of formats from/to CSML, CSO with visualized icons,
and SaaS (Software as a Service) technology and modules. Finally, we discuss limitations of Cell
Illustrator 4.0 and further functionalities that should be built up for large scale Systems Biology.
