morphological form and morphogenesis, which are of salient importance for inves-
tigations on cancer, which after all is also a phenomenon of development at the tissue
level” [24].The present volume precisely focuses on methodological aspects of Systems Biology in
order to provide this new theoretical approach with a robust and tailored experimental
support.
As Editor, I have collected an eclectic assortment of articles. This is not a “one view fits
all” approach. It is rather one to “let a hundred flowers bloom,” specifically aimed to identify
key methodological issues that actually challenge the reliability of “true” Systems Biology
studies.
The present volume addresses many of these questions: First, by introducing a few key
conceptual hallmarks required for proper modeling. Indeed, the universe of potential
models for any complex system like the function of a cell has very large dimensions and, in
the absence of any theory of the system, there is no guide to constrain the choice of model.
The authors A. Paldi, M. Montevil, and M. Bertolaso extensively discuss the theoretical
principles on which the “architecture of the model is conceived. The conceptual framework
proposed is alleged to capture the insights made at different levels of cellular organization
and considered previously as contradictory. It also provides a formal strategy for further
experimental studies. This is a preliminary, fundamental task as “a typical research project in
biology usually follows a naive inductive logic and the role of the underlying theory is usually
underestimated. Concepts are usually taken for granted and rarely questioned directly. As a
consequence, biology has a tendency to see methodological or technical problems even
when the difficulty is conceptual” (A. Paldi). M. Bertolaso and E. Ratti aptly examine this
difficulty. Accordingly, “a relational ontology is a necessary tool to ground both the
conceptual and explanatory aspects of Systems Biology” (M. Bertolaso and E. Ratti). A
relational ontology emphasizes the fact that even if properties that seem to be “internal” are
actually relational. This is because a relational ontology assumes that the identity of the
objects depends strictly on the existence of the web of relations an object is embedded
within it. Therefore, “in order to understand what certain biological entities (e.g., genes,
proteins) do, we need to recreate the web of relations they are usually part of (M. Bertolaso
and E. Ratti)”.
Sonnenschein and Soto discussed the need of a theory of organisms on which a reliable
Systems Biology approach (both from the theoretical and the methodological point of view)
needs to be established. As far as “theory” is needed, basic premises on which any theoretical
attempt should be based are also required. The authors identified three of such very
fundamental principles: the default state of the cell, a principle of variation, and one of
organization. Accordingly, development as well as pathological developments (like cancer)
are argued to be explained as a relational problem whereby release of the constraints created
by cell interactions and the physical forces generated by cellular agency lead cells within a
tissue to regain their default state of proliferation with variation and motility.
M. Montevil outlines limits and possibility of (mathematical) modeling. Indeed, it is not
sufficient for a model to reproduce a process (in both its qualitative or quantitative aspects)
for this model to be correct. “The validation of a model is based on the validation of a
process and of the way this process takes place. As a result, it is necessary to explore the
predictions of the model to verify them experimentally” (M. Montevil). Second, modeling
usually entails only a specific, limited part of a complex behavior that—obviously—occurs in
a tissue and in an organism. Thereby, the biological “meaning” should be mandatorily
Preface vii