Abstract
Systemic approaches have gained a prominent role in cancer research, enhancing the possibility of dealing with complex molecular networks and even expanding the focus of research to higher levels of organization above the cell. In this chapter I review some major examples: network models of the cell, with their landscapes of functional states and switch-like transitions, applied to gene expression and cell processes (particularly worthwhile is Laforge et al.’s Autostabilization-Selection Model); dynamic models of the regulatory interactions between cells and the Extra-Cellular Matrix; large scale descriptions of genomic heterogeneity. In systems theory, the whole is more than the sum of its parts, in so far as it has properties that are not encountered in the parts themselves. Also, the parts are transformed once the whole has been integrated. In the end, I will argue, that a Systemic Approach is interested not only in accounting relationally for how systems work, but in how their organization comes about, opening to deeper epistemological, theoretical and experimental challenges.
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Notes
- 1.
- 2.
However, a systemic thought is much more antique in science. In chemistry and thermodynamics such notion of system was already clear and commonly assumed in scientific practice since the end of the nineteenth century. The same can be said about electromagnetic field and electric circuits. In 1952, Tellegen proved a theorem that states the dependence of systems’ behaviours on two independent components: constitutive laws of elements and emergent laws from their relational structure (Tellegen 1952; Penfield et al. 1970). Tellegen’s theorem – and other similar discoveries – have important practical consequences, which are related to the relevance of the relational structure that is irrespective of the single elements that compose the system. I have to thank Alessandro Giuliani for clarifying this and other points, eventually related to what I have called “non-trivial determinism” in the volume (see Chap. 6).
- 3.
Various authors have confronted this subject since the early decades of the twentieth century. Amongst them, we can mention Goldstein, Jonas, Bergson, Simondon, Ruyer, Haldane, Whitehead. Some philosophers, such as Quine or Duhem, developed extreme conclusions in the philosophical sphere. Some form of extreme anti-reductionism is presented as ‘vitalism’. ‘Holistic’ positions can be found in contemporary biology too. Radical view points have been expressed, for example, by biologist Hans Driesch. In general, the systemic perspectives that we consider here are those inspired by the works of L. von Bertalanffy (von Bertalanffy 1968) or other authors like C.H. Waddington and J. Needham or P. Weiss. We will see how a systemic approach can be compatible with reductionist accounts.
- 4.
However, mechanistic accounts are, sometimes, implicitly assumed. The concept of functional state, for example, is implicitly assumed in the definition of some explanatory frameworks (like the concept of stem cell, see Sect. 2.7) but not without epistemological implications, as we will see more specifically in Chap. 7.
- 5.
The model incorporates experimental data from gene expression studies, more specifically about the modulation of the concentration of transcriptional regulators in the cell in relation to differentiation. The model incorporates stochastic gene expression with computer simulation models. It also takes into account similarities with models pertaining to the theories of morphogenesis (cf. with Sect. 1.2.1). One important difference is that in the Autostabilization-Selection Model the molecules only act as stabilizers of a prior state reached stochastically, not as promoters of a change in cellular state, as in morphogenesis. Embryogenesis is the evolution of the first cell, the zygote, as it moves towards the balance mentioned here; instead, cancer is the destruction of the same balance.
- 6.
Mesenchyme is a type of tissue composed of loose cells embedded in the extracellular matrix (a mesh of proteins and fluid) which allows mesenchymal cells to migrate easily and play a crucial role in the origin and development of morphological structures during early development (especially those concerning connective tissues, from bones and cartilage to the lymphatic and circulatory systems). The interactions between mesenchyme and another tissue component, epithelium, help to form nearly every organ in the body.
- 7.
Some discussions pointed out how classical physical science attempts to reduce noise by simply increasing the sample size. However, in complex biological systems this does not solve the issue of heterogeneity, because variability is not simply a “noise” tied to a specific experimental approach (see also Heng et al. 2008).
- 8.
Taking inspiration from evolutionary theory (Serrelli and Gontier 2015), this literature employs the terms “macroevolution” and “microevolution” for demarcating genetic mutations from genomic alterations, punctual events from dynamic processes. In this sense, a macro-evolutionary change would be an overall change of the organizational dynamics, which might give way to cancer (cfr. Heng et al. 2009).
- 9.
A philosophical frame for this problem is proposed in Sect. 6.4, with the idea that “stability wins over specificity” in biological entities. That is, relational stability of a system is the viability condition for causal specificity of specific events (e.g., genetic mutation) within it.
- 10.
For a philosophical discussion of this dimension of causality see Sect. 5.2.
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- 12.
References
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular biology of the cell. New York: Garland Science.
Ao, P. (2007). Orders of magnitude change in phenotype rate caused by mutation. Cell Oncology, 29, 67–69; author reply on Cell Oncol, 29(1), 71–72 Comment on: Duesberg, P., Li, R., Fabarius, A., & Hehlmann, R. (2005). The chromosomal basis of cancer. Cell Oncology, 27, 293–318.
Ao, P., Galas, D., Hood, L., & Zhu, X. (2008). Cancer as robust intrinsic state of endogenous molecular-cellular network shaped by evolution. Medical Hypotheses, 70, 678–684. Epub 2007 Sep 4.
Aranda-Anzaldo, A. (2002). Understanding cancer as a formless phenomenon. Medical Hypotheses, 59, 68–75.
Bechtel, W., & Richardson, C. (2010). Discovering complexity. Decomposition and localization as strategies in scientific research. Cambridge, MA/London: MIT Press.
Berrier, A. L., & Yamada, K. M. (2007). Cell-matrix adhesion. Journal of Cellular Physiology, 213(3), 565–573.
Biskind, M. S., & Biskind, G. S. (1944). Development of tumors in the rat ovary after transplantation in the spleen. Proceedings of the Society for Experimental Biology and Medicine, 55, 176–181.
Bissell, M. J., Hall, H. G., & Parry, G. (1982). How does the extracellular matrix direct gene expression? Journal of Theoretical Biology, 99(1), 31–68.
Bissell, M. J., Kenny, P. A., & Radisky, D. C. (2005). Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: The role of extracellular matrix and its degrading enzymes. Cold Spring Harbor Symposia on Quantitative Biology, 70, 343–356.
Bizzarri, M., & Cucina, A. (2007). Reversibilità ed irreversibilità della trasformazione neoplastica: ipotesi per un nuovo paradigma. In Cancro, complessità e derive psicoanalitiche. A cura di Franchi, F. Milano: Franco Angeli Editore.
Boogerd, F. C., Bruggeman, F. J., Hofmeyr, J. H. S., & Westerhoff, H. V. (Eds.). (2007). Systems biology. Philosophical foundations. Amsterdam: Elsevier.
Bruggeman, F. J., Westerhoff, H. V., & Boogerd, F. C. (2002). BioComplexity: A pluralist research strategy is necessary for a mechanistic explanation of the ‘live’ state. Philosophical Pshycology, 15, 411–440.
Collins, F. S., & Barker, A. D. (2007). Mapping the cancer genome. Pinpointing the genes involved in cancer will help chart a new course across the complex landscape of human malignancies. Scientific American, 296, 50–57.
Editorial, N. (2006). All systems go! in system biology: A user’s guide. Nature Review. Molecular Cell Biology, 1179.
Felli, N., et al. (2010). Hematopoietic differentiation: A coordinated dynamical process towards attractor stable states. BMC Systems Biology, 4, 85.
Fogarty, M. P., Kessler, J. D., & Wechsler-Reya, R. J. (2005). Morphing into cancer: The role of developmental signalling pathways in brain tumor formation. Journal of Neurobiology, 64, 458–475.
Fusco, G., Carrer, R., & Serrelli, E. (2014). The landscape metaphor in development. In A. Minelli & T. Pradeu (Eds.), Towards a theory of development (pp. 114–128). Oxford: Oxford University Press. doi:10.1093/acprof:oso/9780199671427.003.0007.
Greaves, M. (2001). Cancer: The evolutionary legacy. Oxford: Oxford University Press.
Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G., Davies, H., Teague, J., Butler, A., Stevens, C., Edkins, S., O’Meara, S., Vastrik, I., Schmidt, E. E., Avis, T., Barthorpe, S., Bhamra, G., Buck, G., Choudhury, B., Clements, J., Cole, J., Dicks, E., Forbes, S., Gray, K., Halliday, K., Harrison, R., Hills, K., Hinton, J., Jenkinson, A., Jones, D., Menzies, A., Mironenko, T., Perry, J., Raine, K., Richardson, D., Shepherd, R., Small, A., Tofts, C., Varian, J., Webb, T., West, S., Widaa, S., Yates, A., Cahill, D. P., Louis, D. N., Goldstraw, P., Nicholson, A. G., Brasseur, F., Looijenga, L., Weber, B. L., Chiew, Y. E., De Fazio, A., Greaves, M. F., Green, A. R., Campbell, P., Birney, E., Easton, D. F., Chenevix- Trench, G., Tan, M. H., Khoo, S. K., Teh, B. T., Yuen, S. T., Leung, S. Y., Wooster, R., Futreal, P. A., & Stratton, M. R. (2007). Patterns of somatic mutation in human cancer genome. Nature, 446, 153–158.
Hagios, C., Lochter, A., & Bissell, M. J. (1998). Tissue architecture: The ultimate regulator of epithelial function? Philosophical transactions of the Royal Society of London Series B, Biological sciences, 353, 857–870.
Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.
Heng, H. H., Bremer, S. W., Stevens, J., Ye, K. J., Miller, F., Liu, G., & Ye, C. J. (2006a). Cancer progression by non-clonal chromosome aberrations. Journal of Cellular Biochemistry, 98, 1424–1435.
Heng, H. H., Liu, G., Bremer, S., Ye, K. J., Stevens, J., & Ye, C. J. (2006b). Clonal and non-clonal chromosome aberrations and genome variation and aberration. Genome, 49, 195–204.
Heng, H. H., Stevens, J. B., Liu, G., Bremer, S. W., Ye, K. J., Reddy, P. V., Wu, G. S., Wang, Y. A., Tainsky, M. A., & Ye, C. J. (2006c). Stochastic cancer progression driven by non-clonal chromosome aberrations. Journal of Cellular Physiology, 208, 461–472.
Heng, H. H., Stevens, J. B., Lawrenson, L., Liu, G., Ye, K. J., Bremer, S. W., & Ye, C. J. (2008). Patterns of genome dynamics and cancer evolution. Cellular Oncology, 30, 513–514.
Heng, H. H., Bremer, S. W., Stevens, J. B., Ye, K. J., Liu, G., & Ye, C. J. (2009). Genetic and epigenetic heterogeneity in cancer: A genome-centric perspective. Journal of Cellular Physiology, 220, 538–547.
Hetzer, M. W., Walther, T. C., & Mattaj, I. W. (2005). Pushing the envelope: Structure, function, and dynamics of the nuclear periphery. Annual Review of Cell and Developmental Biology, 21, 347–380.
Hillenmeyer, M. E., Fung, E., Wildenhain, J., Pierce, S. E., Hoon, S., Lee, W., Proctor, M., St Onge, R. P., Tyers, M., Koller, D., Altman, R. B., Davis, R. W., Nislow, C., & Giaever, G. (2008). The chemical genomic portrait of yeast: Uncovering a phenotype for all genes. Science, 320, 362–365.
Huang, S., & Ingber, D. E. (2000). Shape-dependent control of cell growth, differentiation, and apoptosis: Switching between attractors in cell regulatory networks. Experimental Cell Research, 261, 91–103.
Huang, S., & Ingber, D. E. (2006–2007). A non-genetic basis for cancer progression and metastasis: Self-organizing attractors in cell regulatory networks. Breast Disease, 26, 27–54.
Huang, S., & Wikswo, J. (2006). Dimensions of systems biology. Reviews of Physiology, Biochemistry and Pharmacology, 157, 81–104.
Hull, D. L. (1981). Philosophy and biology. In G. Eløistad (Ed.) Contemporary philosophy: A new survey (Vol. 2, pp. 281–316). The Hague: Martinus Nijhoff.
Ingber, D. E. (2000). The origin of cellular life. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 22(12), 1160–1170.
Ingber, D. E. (2008). Can cancer be reversed by engineering the tumor microenvironment? Seminars in Cancer Biology, 18, 356–364.
Kalluri, R. (2003). Basement membranes: Structure, assembly and role in tumour angiogenesis. Nature Reviews Cancer, 3, 422–433.
Kahn, C. R., et al. (1978). Direct demonstration that receptor crosslinking or aggregation is important in insulin action. Proceedings of the National Academy of Sciences of the United States of America, 75(9), 4209–4213.
Klein, G. (2002). Perspectives in studies of human tumor viruses. Frontiers in Bioscience, 7, d268–d274.
Krohs, U., & Callebaut, W. (2007). In F. C. Boogerd, F. J. Bruggeman, J. H. S. Hofmeyer, & H. V. Westerhoff (Eds.), Systems biology. Philosophical foundations (pp. 181–214). Elsevier. op. cit.
Laforge, B., Guez, D., Martinez, M., & Kupiec, J. J. (2005). Modeling embryogenesis and cancer: An approach based on an equilibrium between the autostabilization of stochastic gene expression and the interdependence of cells for proliferation. Progress in Biophysics and Molecular biology, 89(1), 93–120.
Lewontin, R., & Levins, R. (2007). Biology under the influence (p. 105). New York: Monthly Review Press.
Liu, H., Radisky, D. C., Wang, F., & Bissell, M. J. (2004). Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells. Journal of Cell Biology, 164, 603–612.
McCawley, L. J., Wright, J., LaFleur, B. J., Crawford, H. C., & Matrisian, L. M. (2008). Keratinocyte expression of MMP3 enhances differentiation and prevents tumor establishment. American Journal of Pathology, 173(5), 1528–1539.
Meadows, D. H., Meadows, D. L., & Randers, J. (1992). Beyond the limits. In R. Lewontin, & R. Levins (Eds.). (2007). Biology under the influence (p. 105). New York: Monthly Review Press.
Murillo, J. I. (2010). El tiempo y los métodos de la biologia. StudiaPoliana, 12, 55–68.
Nelson, C. M., & Bissell, M. J. (2006). Of extracellular matrix, scaffolds, and signaling: Tissue architecture regulates development, homeostasis, and cancer. Annual Review of Cell and Developmental Biology, 22, 287–309.
Nicholson, D. J. (2010). Biological atomism and cell theory. Studies in History and Philosophy of Biological and Biomedical Sciences, 41, 202–211.
O’Malley, M. A., & Dupré, J. (2005). Fundamental issues in systems biology. Bioessays, 27, 1270–1276.
Penfield, P., Spence, R., & Duinker, S. (1970, August). Generalized form of Tellegen’s theorem. IEEE Transactions on Circuit Theory CT, 17(3), 302–305.
Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., Fata, J. E., Leake, D., Godden, E. L., Albertson, D. G., Nieto, M. A., Werb, Z., & Bissell, M. J. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436, 123–127.
Schlessinger, J. (1980). The mechanism and role of hormone-induced clustering of membrane receptors. Trends in Biochemical Sciences, 5(8), 210–214.
Serrelli, E. (2015). Visualizing macroevolution: From adaptive landscapes to compositions of multiple spaces. In E. Serrelli & N. Gontier (Eds.), Macroevolution: Explanation, interpretation and evidence (Interdisciplinary evolution research series, pp. 113–162). Cham: Springer. doi:10.1007/978-3-319-15045-1_4.
Serrelli, E., & Gontier, N. (Eds.). (2015). Macroevolution: Explanation, interpretation and evidence. Springer. doi:10.1007/978-3-319-15045-1.
Spencer, V. A., Xu, R., & Bissell, M. J. (2007). Extracellular matrix, nuclear and chromatin structure, and gene expression in normal tissues and malignant tumors: A work in progress. Advances in Cancer Research, 97, 275–294.
Sternlicht, M. D., Lochter, A., Sympson, C. J., Huey, B., Rougier, J. P., Gray, J. W., Pinkel, D., Bissell, M. J., & Werb, Z. (1999). The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell, 98, 137–146.
Strange, K. (2005). The end of “naïve reductionism”: Rise of systems biology or renaissance of physiology? American Journal of Physiology—Cell Physiology, 288(5), C968–C974.
Tellegen, B. D. H. (1952, August). A general network theorem, with applications. Philips Research Reports, 7, 259–269.
Urbani Ulivi, L. (Ed.). (2011a). Strutture di mondo. Il pensiero sistemico come specchio di una realtá complessa. Bologna: Il Mulino.
Urbani Ulivi, L. (2011b). La struttura dell’umano. Linee di un’antropologia sistemica in Strutture di mondo. Il pensiero sistemico come specchio di una realtà complessa. Bologna: Il Mulino.
Von Bertalanffy, L. (1968). General system theory. New York: Braziller.
Waddington, C. H. (1935). Cancer and the theory of organizers. Nature, 135, 606–608.
Westerhoff, H. V., & Kell, D. B. (2007). The methodologies of systems biology. In F. C. Boogerd, F. J. Bruggeman, J. H. S. Hofmeyr, & H. V. Westerhoff (Eds.), Systems biology: Philosophical foundations. Amsterdam: Elsevier.
Xu, R., Boudreau, A., & Bissell, M. J. (2009a). Tissue architecture and function: Dynamic reciprocity via extra- and intra-cellular matrices. Cancer and Metastasis Reviews, 28, 167–176.
Xu, R., Nelson, C. M., Muschler, J. L., Veiseh, M., Vonderhaar, B. K., & Bissell, M. J. (2009b). Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary specific function. Journal of Cell Biology, 184, 57–66.
Ye, C. J., Liu, G., Bremer, S. W., & Heng, H. H. (2007). The dynamics of cancer chromosomes and genomes. Cytogenetic and Genome Research, 118, 237–246.
Zhang, Q., et al. (2001). Nesprins: A novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. Journal of Cell Science, 114(Pt 24), 4485–4498.
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Bertolaso, M. (2016). The Systemic Approach to Cancer: Models and Epistemology. In: Philosophy of Cancer. History, Philosophy and Theory of the Life Sciences, vol 18. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-0865-2_3
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