Bbs 061
Bbs 061
Bbs 061
1093/bib/bbs061
Advance Access published on 14 October 2012
Abstract
Mathematical and computational models are increasingly used to help interpret biomedical data produced by
high-throughput genomics and proteomics projects. The application of advanced computer models enabling the
Corresponding author. Santo Motta, Department of Mathematics and Computer Science, University of Catania, V.le A. Doria, 6,
95125 Catania, Italy. Tel.: þ39 095 7383073. Fax: þ39 095 330094. Email.: motta@dmi.unict.it
Santo Motta, Laurea in Physics (University of Catania,1970) and MSc in Applied Mathematics (University of London, Queen Mary
College, 1971). Associate professor of Mathematical Physics (Faculty of Pharmacy, Department of Mathematics and Computer Science,
University of Catania). His present scientific interests are BioMaths, BioComputing and BioInformatics.
Francesco Pappalardo is a researcher at the University of Catania. He was a visiting research scientist at the Dana-Farber Cancer
Institute in Boston and at the Molecular Immunogenetics Labs, IMGT in Montpellier. His major research area is computational
biology.
ß The Author 2012. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com
412 Motta and Pappalardo
terms of constitutive objects and the relationships This article is organized as follows: in the next two
among them, where the description itself is, in gen- sections (Models of Systems and The Modeling
eral, decodable or interpretable by humans. Process), we describe the types of models and the
Generally speaking, a system is an unknown ‘black modeling processes in scientific investigations in a
box’ (S) which, under a specific external stimulus general context; then in the next section (Models
(input E) produces a response (output R) [19]. in Biology: Scales and Complexity) we go more spe-
Using this general definition, one can identify three cific and talk about models in biology and medicine;
primary scientific uses of models [12]: (i) synthesis or few examples of models are briefly shown in the
knowledge discovery; to use the knowledge of section ‘Tools and Applications’; finally we draw
inputs E and outputs R to infer system characteris- our ‘Conclusions’ in the last section.
tics; (ii) analysis and prediction; to use the knowledge
of the parts and their stimuli (i.e. the inputs E) to
MODELS OF SYSTEMS
different interpretations of terms and concepts. If a different parts or compartments (i.e. organs) with
‘domain ontology’ is available, then the meaning of different functions. In this case, ‘Compartment
the variety of terms used should be linked to it. Once models’ are widely used and each compartment
the domain concepts have been modeled, the model may pick a different mathematical representation.
becomes a stable basis for subsequent development of Models can also represent physical variables in
applications in that specific domain. Furthermore, different ways. Besides, the model may or not con-
the concepts behind the conceptual model can be sider the evolution of the system with respect to time
mapped to physical design or implementation con- (dynamic versus static models). Time can be treated
structs using either manual or automated code gen- as continuous or discrete variable (time-continuous
eration approaches. versus time-discrete models). Likewise, spatial distri-
A conceptual model can be described using vari- bution of objects in each compartment may or
ous notations, such as Unified Modeling Language not be relevant (spatially-heterogeneous versus
(UML) [34, 9], Object Modeling Technique (OMT)
relations will be described in a diagram where the set loose relations in strict mathematical terms. Notice-
of objects are fully clarified and relations bounded. ably, model objectives play an important role
because, a detailed description of the biological
Mathematical formulation system may turn out to be useless if not required
This is usually the trickiest part of the modeling pro- by the model objectives.
cess, requiring the choice of a mathematical struc- Choosing a mathematical formulations is a map-
ture, which is appropriate for the model objectives ping of the model into the mathematical domain to
and is able to describe in quantitative form the obtain a formal model. A good formal model must
hypotheses. This step of the process requires a certain be a compromise between the competing properties
level of mathematical sophistication and, more im- of any model (Realism, Precision and Generality)
portantly, it requires to define vague concepts and and should take into account some specificity of
416 Motta and Pappalardo
the mathematical domain. Accordingly, we can need to be carefully chosen. Models of biological
identify the major properties of formal models as systems can involve scores of dynamic variables and
follows: ‘relevance’, capturing the essential properties thousands of parameters, especially when spatial pro-
of the phenomenon; ‘computability’, transfer model cesses are investigated. In this respect, checking the
hypothesis into a mathematical/computational infra- computer results to match available data is not a triv-
structure that can be solved to give the desired results ial exercise.
with the required precision; ‘understandability’,
offering a conceptual framework for thinking about
the scientific domain; ‘extendibility’, allowing the Parameter estimation and tuning
inclusion of additional real-world objects in the Once the model formulation has been translated on a
same mathematical scheme. Taking into account computer, a further step is necessary before a simu-
the biological complexity, a very detailed model of lation can be run. Complex models usually contain
many parameters whose numerical value must be
MODELS IN BIOLOGY: SCALES AND processes. Cellular scale is thus highly connected
COMPLEXITY with the sub-cellular scale but, modeling at this
As already pointed out, any natural phenomena can scale, one may forget the details of single cell
be observed at different scales thus, in describing the models and consider them as BBM. The areas of
phenomenon by conceptual and quantitative models mathematical methods and tools involved in this
one needs to choose to appropriate scale to describe description refer to statistical mechanics, cellular
the experimental data available. automata, lattice gas and other similar approaches.
However, in almost all complex natural phenom- The ‘macroscopic scale’ include tissues, organs
ena there are aspects that cannot be even observed at (i.e. a collection of tissues joined in structural unit
just one scale of description (either temporal or spa- to serve a common function), systems (i.e. a group of
tial). To study these specific facets of reality, multi- organs working together to perform a certain task)
scale models that represent objects and relationships and organism.
consider the age structure of the population and the not an easy task. Phenomena occurring at different
effects of environments. At variance for small size scales have usually different characteristic time scales
populations, like modeling the effect of a new vac- and models’ output should be properly fitted.
cine for a small trial, a sufficiently detailed description Interested readers are referred to another study [3]
of the organism and the effect of the vaccine on each in this issue.
organism should be required. A variety of different
techniques are available for these classes of models. In
the former case, one uses both, ordinary or stochastic TOOLS AND APPLICATIONS
differential equations to describe the populations Whether we investigate the growth and interactions
dynamics or agent-based models (simple agents of an entire population, the evolution of DNA
representing a single organism) to study the result- sequences, the inheritance of traits, the spread of dis-
ing complex phenomena. In the latter case, a ease or the immune system response to a pathogen,
single components or not activated OT1 T cells have and chemistry, i.e. genetics and biochemistry. Mole-
no success. The in silico experiments performed with cular biology provides the understanding of the
the presented computational model show very good interactions between the various systems of a cell,
agreement with their in vivo counterpart. As many including the interactions between the different
aspects of CD137 molecule biology are still not types of DNA, RNA and protein biosynthesis.
fully understood and the investigating of these as- Understanding how drugs and diseases are asso-
pects requires many difficult and expensive wet lab ciated in the molecular level, is of critical importance
experiments, the model is a good candidate for for better understanding of disease mechanisms and
becoming a predictive tool. treatments. Recently in a study [38], the authors
define a network-based gene closeness profile to
Circulatory system relate drug to disease and then develop a Bayesian
Circulatory system represents a biological system partition method to identify drug–gene–disease
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