Constraints Shape Cell Function and Morphology by Canalizing the Developmental Path along the Waddington's Landscape

Abstract

Studies performed in absence of gravitational constraint show that a living system is unable to choose between two different phenotypes, thus leading cells to segregate into different, alternative stable states. This finding demonstrates that the genotype does not determine by itself the phenotype but requires additional, physical constraints to finalize cell differentiation. Constraints belong to two classes: holonomic (independent of the system's dynamical states, as being established by the space‐time geometry of the field) and non‐holonomic (modified during those biological processes to which they contribute in shaping). This latter kind of “constraints”, in which dynamics works on the constraint to recreate them, have emerged as critical determinants of self‐organizing systems, by manifesting a “closure of constraints.” Overall, the constraints act by harnessing the “randomness” represented by the simultaneous presence of equiprobable events restraining the system within one attractor. These results cast doubt on the mainstream scientific concept and call for a better understanding of causation in cell biology.

Paradoxical Behavior of Oncogenes Undermines the Somatic Mutation Theory

“…Such a statement implies that the reductionist-based framework, which has shaped the theoretical background of molecular biology [127], is inadequate for grasping the complexity embedded in the carcinogenic process. In fact, emergent phenomena concerning morphogenetic and neoplastic processes involve a plethora of interactions among different entrenched levels, in which the lower levels (molecules, cells) are strongly influenced by higher level organization constraints [18,128].…”

Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains

“…A high cell variability, presence of “rebellious cells,” and involvement of the paracrine feedback mechanisms in the differentiation time course (up to 7 days) were also described in similar models ( 67 , 68 ). Such unstable transitory states are sensitive to external stimuli and cells are searching for a compromise between instructive and permissive paths ( 69 ). The second transition in our model involves transcription upregulation of the pericentric lncRNA and the second peak of the early gene stress response.…”

Phylostratic Shift of Whole-Genome Duplications in Normal Mammalian Tissues towards Unicellularity Is Driven by Developmental Bivalent Genes and Reveals a Link to Cancer

“…The prevalence of ancient unicellular state of cancer cells with respect to normal tissue corresponds to a partial "going back" to the more ancient unicellular pattern preceding the rise of multicellularity. This implies we do not expect that cancer cells become 'identical to unicellular organism' but that lose some phenotypic characters essential for the existence of an organized tissue like contact inhibition, the crucial role played by shape changes in cancer development is consistent with this view [42,43].…”