J. Math. Biol.

(2009) 58:1–5
DOI 10.1007/s00285-008-0207-x Mathematical Biology
INTRODUCTION

Computational Cell Biology:

Second Theme Issue on “Computational Biology”

Wolfgang Alt · Andreas Deutsch · Luigi Preziosi

Published online: 27 August 2008

© Springer-Verlag 2008

0 Introduction

Biological cells, the elementary units of life, are in the focus of modern biosciences
and thus, also of theoretical and mathematical biology. One reason is the fact that quan-
titative modelling and simulation of the processes that determine cellular processes
(as in genetics, metabolism, signalling, motility or tissue formation) are of central
importance for the investigation of general biological phenomena and applications in
the rapidly growing areas of biomedicine and biotechnology.
For instance, the behaviour of simple cellular organisms as bacteria, amoebae, or
yeast has always attracted theoreticians, and more and more sophisticated mathe-
matical models have been developed in the recent past that take into account newly
detected effects on the molecular or micromechanical level. The mechanisms learned
by studying such “simple” organisms allow to take up the challenge of modelling and
simulating, thus better understanding the more complex behaviour of eukaryotic and,
particularly, of human cells.
Therefore, we gladly took the offered opportunity to conceive a special JMB
theme issue on the computational and modelling aspects related to the biology of

W. Alt (B)
Theoretical Biology, University of Bonn, Bonn, Germany
e-mail: wolf.alt@uni-bonn.de

A. Deutsch
Centre for Information Services and High Performance Computing (ZIH),
Technical University Dresden, Dresden, Germany
e-mail: andreas.deutsch@tu-dresden.de

L. Preziosi
Department of Mathematics, Politecnico di Torino, Torino, Italy
e-mail: preziosi@calvino.polito.it

123
2 W. Alt et al.

cells. Most of the collected contributions reflect invited talks presented within an
embedded meeting at the International Conference on Industrial and Applied Math-
ematics (ICIAM’07) in Zurich. The meeting was organized by the European Society
of Mathematical and Theoretical Biology (ESMTB).
This resulting theme issue on “Computational Cell Biology” attempts to present an
overview of some of the important mathematical modelling concepts and simulation
methods that have recently been developed to describe cellular processes at different
spatio-temporal scales, ranging from molecular kinetics over cell mechanics up to
problems of cellular tissue architecture or cell-related diseases. According to this
wide spectrum of cell biological topics, the contributions are ordered in three parts as
specified below.
The most frequently used modelling framework tries to explore suitable combi-
nations of parameter functions for (ordinary or partial) differential/integral equations
and/or stochastic processes, which adequately describe the specific cell biological
phenomena. Furthermore, in some of the contributions, suitable algorithms and tech-
niques for numerical simulation or statistical analysis are presented and applied.
Four of the articles offer electronic supplementary material (esm) containing down-
loadable movies that show different types of cellular motion and/or corresponding
simulations.

1 Intracellular processes and systems biology

Systems biology is the science that aims to understand how biological function, absent
from macromolecules in isolation, arises when they become components of an inter-
acting system. The first article by H.V .W esterhoff et al. on “Systems biology
towards life in silico: mathematics of the control of living cells” is dedicated to the
memory of the late Reinhart Heinrich, a pioneer of systems biology. The article dis-
cusses the origin and evolution of the new part of systems biology that relates to
metabolic and signal transduction pathways and describes how to extend mathemati-
cal biology so as to address postgenomic experimental reality. Various approaches to
modeling the dynamics generated by metabolic and signal-transduction pathways are
compared.
More recently, the importance of space in intracellular networks has been recog-
nized. The article by J.Stelling & B.N.Kholodenko discusses “Signaling cas-
cades as cellular devices for spatial computations”. Signaling networks usually include
protein modification cycles. Cascades of such cycles are the backbones of multiple
signaling pathways. Protein gradients emerge from the spatial separation of opposing
enzymes, such as kinases and phosphatases, or guanine nucleotide exchange factors
(GEFs) and GTPase activating proteins (GAPs) for GTPase cycles. The authors show
that different diffusivities of active and inactive protein forms may lead to spatial gra-
dients of protein abundance in the cytoplasm. Furthermore, it is demonstrated how
different cascade designs filter and process the input information to generate pre-
cise, complex spatial guidance for multiple GTPase effector processes. Thus, protein-
modification cascades may serve as devices to compute complex spatial distributions
of target proteins within intracellular space.

123
Computational Cell Biology: Second Theme Issue on “Computational Biology” 3

An essential ingredient for efficient research in systems biology is image analysis

of spatially resolved molecular systems. In the contribution “Multiple objects tracking
in fluorescence microscopy” by Y.Kalaidzidis the focus is on the movement of
compact entities—intracellular vesicles and even single molecules. The tracking of
individual objects is important for the understanding of cellular dynamics. In the
article, tracking algorithms which have been developed in nonbiological fields are
successfully applied to object detection and tracking in biological applications. In
addition, the characteristic features of the different algorithms are compared.

2 Molecular cell mechanics and single cell motility

Due to the rapid development of ever more precise microscopic techniques and image
processing tools in the last decades, we are now equipped with detailed data on protein
allocation during the processes of cell deformation, adhesion and migration at high
spatio-temporal resolution. Correspondingly, more specific hypotheses about possible
molecular mechanisms have been formulated and tested under various experimental
conditions. However, successful data evaluation and interpretation requires the for-
mulation and analysis of quantitative models that consider the essential biochemical
ingredients and biophysical relations in order to reproduce the observed intracellular
movement, cell shape deformation or cell motility characteristics.
The first article by R.B.Dickinson on “Models for actin polymerization motors”
studies the dynamics of cell membrane protrusion induced by polymerizing actin fil-
aments. Frequently used “fluctuating polymer ratchet” models are confronted with
alternative models, in which certain end-tracking motor proteins actively elongate
actin filaments, while staying anchored in the plasma membrane. Stringent biophys-
ical reasoning in relation to several experimental situations and careful estimation of
parameters in different mathematical model equations lead to relevant conclusions
about the postulated mechanisms. Further modelling and simulation would be help-
ful to clarify more details, with the eventual outcome that cells probably use several
alternative mechanisms in a cooperative manner.
During the last two decades the challenging task of understanding and simulating
autonomous cell locomotion has evoked an “unusually high modelling activity” and
a “pioneering vision of the area’s leaders”, as formulated by A.Mogilner in his
comprehensive review article “Mathematics of cell motility: have we got its number?”
By careful presentation of various modelling approaches for the different “modu-
lar” characteristics of cell motility (protrusion, contraction, adhesion, polarization)
he elucidates not only all the so far achieved theoretical proposals and computational
results on cytoskeletal kinetics, dynamics and nematics but, for each sub-problem, also
open questions and mathematical work yet to be done. One particular approach is the
description of cytoplasm as an anisotropic, contractile and viscous fluid, dynamically
interacting with adhesion proteins represented by a reaction-diffusion-transport sys-
tem in the plasma membrane. For such a two-dimensional “Continuum model of cell
adhesion and migration”, E.Kuusela & W.Alt offer a detailed biophysical deriva-
tion and an efficient numerical analysis, including appropriate balance conditions and
discretized algorithms at the moving lamella tip of migrating cells or cell fragments.

123
4 W. Alt et al.

Whereas the so far presented mathematical methods concentrate on model

simulations of actin filaments and their mechanically computed forces onto mem-
branes or adhesive substrates, the article by D.Ambrosi et al. on “Traction patterns
in tumor cells” is devoted to the classical inverse problem: Given the deformation
pattern that a migrating cell leaves on a two-dimensional elastic substratum, the corre-
sponding traction forces applied underneath the cell are to be calculated under suitable
regularity constraints. The chosen algorithm uses a simple energy penalization, so that
the unique solution of the adjoint elasticity equations for the substrate yields reason-
able force field patterns of e.g. tumor cells migrating on polyacrylamid substrates of
different stiffness.
A population of migrating cells, within a tissue in vivo or on a substratum in vitro, can
interact by mechanical forces either onto the extracellular medium or onto contacting
neighbours directly—this is the main topic of the final part 3 below—or by mutual
response to emitted diffusible chemicals. The resulting continuum models providing
the well-known nonlinear parabolic Keller–Segel systems are critically reviewed by
T .H illen & K.J.P ainter as “A user’s guide to PDE models for chemotaxis”. The
authors discuss global existence, stability and numerical simulation of solutions for
a complete table of hitherto studied model variants including signal- and density-
dependent sensitivity, nonlocal sampling and nonlinear gradient response related to
different mechanisms of chemoreception.

3 Cell interactions and multi-cellular systems

A natural development stemming from the study of the sub-cellular mechanisms and
of the behaviour of single cells consists in the application of what has been learned at
the cellular level to the understanding of the interactions of cells with other structures
of the body and, in particular, with other cells of the same or of different type. In
this respect, the contribution by V .Capasso & D.Morale deals with “Stochastic
modelling of tumor-induced angiogenesis”. Both, vasculogenesis and angiogenesis
are two important processes occurring during embryogenesis and other physiological
and pathological conditions, such as tumor growth. By these processes single cells
proliferate and organise to form vascular networks. In other words, the behaviour of a
single cell is influenced by the chemical cues produced by the others, so that they all
co-operate to build a functional structure.
The article “Modeling cell interaction under flow” by C.V erdier et al. focuses
on cells flowing inside capillaries, studying the behaviour of a single cell and, more
importantly, the interaction of the cell with the endothelial lining covering the inside
of blood vessels. This problem is particularly important as it can help understanding
the mechanisms of inflammation and of evasion of tumor cells to form metastases.
In describing the behaviour of cell populations one of the currently most popular
methods is represented by the so-called individual cell-based models. These methods
allow not only to describe inter-cellular mechanisms, such as cell-cell interaction,
cell-matrix adhesion, or contact inhibition of growth, but also to insert in a natural
way intra-cellular mechanisms. In this respect, once the computational drawbacks are
overcome, they constitute a powerful method to link the models at the cellular scale

123
Computational Cell Biology: Second Theme Issue on “Computational Biology” 5

to the sub-cellular ones. The contribution by J.Galle et al. “From single cells to
tissue architecture” presents a review of some application of this method to the growth
and homeostasis of multi-cellular systems. There is a final contribution also dealing
with homeostatic problems, now within the blood system: C.F oley & M.C.Mackey,
“Dynamic hematological disease: a review”. The authors use a different modelling
approach, namely systems of ordinary population equations containing physiologi-
cally consistent time delays for the various interactions on the organic level.

In order to make the contributions understandable by the majority of readers, the

authors were requested to present the cell biological problem, explain the relevant
modeling and simulation approach(es) and provide insight into conditions and values
of the obtained computational results. For this reason the special issue is addressed
both to members of the “hard sciences” (physics, mathematics, chemistry) as well as
of the biological and biomedical communities.

123