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16 Modeling of Cellular Processes
Background
During the recent year, PSCI During the recent year, PSCI has intensified and expanded its efforts in computational
has intensified and expanded biology and medicine. Among other things, this includes extending contacts with
pharmaceutical companies, and collaboration with the recently established
its efforts in computational
bioinformatics center in Stockholm funded by SSF and with the SANS research
biology and medicine.
group at NADA. The latter has been doing research in computational neuroscience
and neurocomputing for more than ten years. Furthermore, a literature survey in
the field of modeling of intracellular biochemical networks and cell signaling has
been carried out [Kotaleski and Lansner, 1999]. This is a field that is starting to get
more attention since, for example, when the whole human genome has been
sequenced a lot of ”post-genomics” research will deal with the understanding of
networks, pathways, intracellular cascades, signal transduction, and metabolism as
well as the coupling to the genetic machinery. During the spring of1999, PSCI also
supported and participated in a bioinformatics conference (Bioinformatics*99). This
was the first Scandinavian bioinformatics conference. It took place in April in Lund
and 250 participants attended the conference. The aims of the conference were to
focus on technologies and methodologies used when extracting essential informa-
tion from biological data and to cover the different levels of detail of biological
data, from sequence data up to higher level physiological behavior. The sessions
included: comparative genomics, databases and new technologies, structure/function
prediction and finally modeling of cellular processes. This last session concerning
modeling of intracellular networks gave examples of how models will help when
trying to bridge the gap between the molecular level events and the cell (tissue)
behavior. This is also the goal of the current PSCI biocomputing project and is
further motivated below.
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prominent is bioinformatics and neuroinformatics/computational neuroscience.
There one finds many examples of large-scale computational models (e.g. of the
DNA or some part of the brain) that require the use of powerful parallel computers.
The traditional emphasis in bioinformatics has been on the molecular level aimed
at, for instance, activity predictions from biosequeces. Until quite recently the
structural complexity of the cell interior and the multitude of biomolecules and
their complex interactions has been much less studied. There is now, however, a
growing understanding that an insight into the intracellular biochemical networks
that determine cell function is necessary to enable full use of knowledge at the
molecular level and that specific research efforts are needed to build such insight.
New measuring techniques like DNA chips which allow for collection of massive
amounts of data on dynamic protein expression patterns emphasize the need for
such efforts. In order to complement rather than compete with existing bioinformatics
activities in Sweden the PSCI effort has focused on the computational modeling of
these cellular level processes and interactions.
Most data in the bioinformatics field represent ”static” information, for example
data concerning sequences and predicted function of certain genes (e.g. an enzyme
involved in the step A to B in a certain biochemical pathway) is in some sense non-
dynamical information. However, static data is not sufficient to capture and predict
the behavior and the processing in networks of biochemical pathways, since these
systems are composed of a large number of non-linearly interacting elements. A
well developed computational model can, for instance, be used to predict the outcome
of different alterations made to cells and therefore help in identifying intracellular
targets for drugs and cellular or genetic engineering. Another important role is to
bridge between the different levels of description of biological phenomena, from
receptor to physiological phenomena. However, a working computational model
requires a much more detailed description than a formulation of a theoretical or
heuristical model. The former needs quantitative data of each event involved or
mechanism that will influence the behavior of the model.
The temporal dynamics of the cell machinery spans several orders of magnitude.
For example, the actual regulations of the genes, i.e. processes that may require
some sort of protein synthesis, can occur over parts of hours to several years (life-
time), while a chemical reaction or a conformational change in a protein may only
take tens of ms up to minutes. These different systems are then interdependent and
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influence each other.
Fortunately, several Fortunately, several techniques are developing that can measure experimentally
techniques are developing that the dynamics of different biochemical pathways over several time scales [Koshland,
can measure experimentally 1998]. Such techniques include scanning confocal microscopes,
the dynamics of different electrophysiological recordings of the behavior of membrane channels, and fluores-
biochemical pathways and cent dyes that can visualize different reacting substrates. An important technique is
over several time scales to study the expression of genes over time and relate this to the particular situation
the cell is involved in, e.g. differentiation, starvation or division [DeRisi et al.,
1997]. This technique allows estimation of expression of several tens or hundreds
thousands of genes in parallel. In the near future gene expression profiles generated
by DNA chip technologies will be available.
To describe the dynamics of the cell, a type of quantitative models that are intuitively
easy and have been broadly used, are first order kinetic models describing a substrate
changing into a product [Kotaleski and Lansner, 1999] [Destexhe et al., 1994a].
Depending on the problem the model can be formulated using Markov type of
formalism or simplified to Michaelis-Menten equations. Such kinetic modeling
schemes can be used and interpreted for a variety of cellular processes, not only
including ”typical” enzymatic biochemical reaction steps, but also gating of
membrane ion channels, G protein and other complex cascades, regulation of ge-
nes, etc.
Note, however, that for some systems, understanding the cellular and molecular
mechanisms underlying different properties is not at all sufficient. This is especially
true for the nervous system, endocrine system and immune system.
One such process is diffusion For certain subcellular reactions other modes of description are appropriate. One
such process is diffusion of some molecules which often occur as a rate limiting
of some molecules which often
step at some point in a biochemical pathway. An important example is Ca2+ that
occur as a rate limiting step at
has an effect on many intracellular and intercellular processes. Consequently, models
some point in a biochemical may need to take the dynamics of Ca2+ into account. Other molecules that sometimes
pathway. need to be modeled are e.g. diffusible gases like NO/CO. See [Hellums et al.,
1996] for a review of the background and progress in placing the simulation of gas
transport processes on a more accurate quantitative basis.
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as concerning gene expression and biosequences. Given the complexity of the
intra-cellular processes, detailed mechanisms where the dynamics are also taken
into account can be understood only by computational modeling, using fairly realistic
molecular-level models, which integrate the network of relevant intracellular
reactions with cellular and organelle geometry, diffusion of second messengers,
distribution of elements of signaling pathways and also the factors involved in
gene regulation, the latter in general occurring over a slower time scale. Therefore Therefore computational
computational modeling is predicted to become a more important tool [Bray, 1997, modeling is predicted to become
Palsson, 1997] in the near future. Progression along these lines would have a strong a more important tool in the
impact on both the pharmaceutical and biomedically oriented industry as well as
near future.
for society as a whole.
The suggestion is that most of the resources are allocated to doctorands. A doctorand
project concerning modeling of stimulus-secretion coupling in insulin producing
cells has just started (see [Kotaleski and Lansner, 1999]). In this context it is also
very important to establish the necessary cooperation with experts at the Karolin-
ska Institute. Another related activity is to model conditioning of reflexes in the
cerebellum based on detailed intracellular mechanisms. This work is to be conducted
as postdoc work in cooperation with a research group in USA. Furthermore, it is
recommended that e.g. a biannual conference or workshop is organized. Here the
most obvious alternative would be to sponsor a cellular modeling session at the
Scandinavian Bioinformatics Conference every second year. Since the 1999
conference was already PSCI sponsored the next turn would be in 2001.
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