The TOTO Project: Towards a Theory of Tissue Organisation

The TOTO Project: Towards a Theory of Tissue Organisation

 ~ In biology, the exception is the rule. ~

 ~ With our work, we are not really interested in the unique, but in what is general in the unique.~

With this project, we want to address a biological and a methodological challenge. First, we wish to clarify how the functioning of cells, and the functioning of a tissue relate to each other. Do cells exercise a degree of autonomy, or is their behavior completely determined by the functioning of the tissue? Such questions are important in understanding the emergence and progression of diseases. For example, it remains unclear whether the causative origin of colon cancer is a cell, or a consequence of tissue organization.


We are using mathematical general systems theory to generalize state space representation from conventional general systems theory. The latter are frequently used to represent intracellular mechanisms. Through a generic, yet adequate level of abstraction, we arrive at a more general representation of a tissue. A first result from this work is that we found evidence for the autonomy of cells within a tissue (Figure below; open to enlarge). There is reciprocal determination between the stem cells in the intestinal niche and the tissue as a whole. This allows us to distinguish emergence (progressive determination) of the tissue and coordination of cellular function (regressive determination) within a single formal framework.


Cell-Tissue interaction summary


While mathematical modelling is well established in supporting research into cellular mechanism, there does not exist a formal framework to support the formulation of hypotheses about principles of tissue organization. Akin to rate equations supporting the formulation of hypotheses about cellular mechanisms, we are developing a conceptual framework to identify principles of tissue organization. Our project contributes to a better understanding of whole-part relationships in the context of disease focused research of tissue organisation.



Related publications

Whither Systems Medicine?

Apweiler R, Beissbarth T, Berthold MR, ... , Theis FJ, Vera J, Wolkenhauer O

Experimental & Molecular Medicine

Enabling multiscale modeling in systems medicine

Wolkenhauer O, Auffray C, Brass O, Clairambault J, Deutsch A, Drasdo D, Gervasio F, Preziosi L, et al.

Genome Medicine 2014, 6:21

Tracing organizing principles: Learning from the history of systems biology

Green S, Wolkenhauer O

History and Philosophy of the Life Sciences, 35 (4), 553 - 576

The Role of theory and Modelling in Medical Research

Wolkenhauer, O.

Front. Pysiol. 4:377.

The search for organizing principles as a cure against reductionism in systems medicine

Wolkenhauer O, Green S (2013)

FEBS Journal, 280 (23): 5938-48.

The role of theorem proving in systems biology

Wolkenhauer O, Shibata D, Mesarovic MD (2012)

Journal of Theoretical Biology 300: 57-61

A stem cell niche dominance theorem

Wolkenhauer O, Shibata D, Mesarovic MD (2011)

BMC Syst. Biol. 5: 4

An Abstract Cell Model that describes the Self-Organization of Cell Function in Living Systems

Wolkenhauer O, Hofmeyr J H (2007)

Journal of Theoretical Biology 246: 461-476