Biomedical Engineering Reference
In-Depth Information
of commitment to cell death (apoptosis), etc. (30). During proliferation, cells are
in a biochemical state in which they can replicate DNA and divide to increase
tissue cell mass. During differentiation, cells undergo a phenotypic change from
an immature precursor cell to a distinct cell type, such as a red blood cell, liver
cell or nerve cell, that carries out tissue-specific tasks. In apoptosis, cells re-
spond to particular signals by switching on a suicide program and undergo cell
death. Each cell fate is characterized by a distinct profile of activation of the
30,000 or so genes in the human genome.
Cell fates are stable, typically mutually exclusive cellular states (27,30,67).
The conditional selection of these cell fates within the population of cells in a
tissue gives rise to the next level of emergence: the tissue and organs that consist
of distinct spatial patterns of cells that exhibit different fates, including various
specialized cell types. The tissue is a cellular society that requires social behav-
ior of its members in order to maintain its global structural and functional stabil-
ity. Thus, the balance between division, differentiation, and death of individual
cells needs to be tightly regulated within different tissue microenvironments so
that the whole tissue optimally responds to all environmental signals.
Cell fate switching is governed by a molecular network of genes, proteins,
and other cellular components that give rise to the emergent property we recog-
nize as cell fate. For simplicity, let us here focus on the gene regulatory network,
and ask the more general question: How can the mutual regulation of ~30,000
genes in the genome give rise to stable, mutually exclusive cellular states (fates),
each characterized by a distinct gene activation profile? For example, why does
a differentiated liver cell not drift away to become a nerve cell if the difference
is just in the pattern of gene activation? As described above, another important
property for development is that cells unite stability (maintenance of identity in
response to perturbations) with flexibility (ability to change identity in response
to critical stimuli); in fact, it is this property that allows development to take
place in the first place. This and other qualities are fundamental, emergent prop-
erties that, as we will see, arise as a consequence of how information is proc-
essed by the underlying gene regulatory network and the architecture of that
network.
4.2.2. Network Dynamics Leads to Stable States: Attractors in Gene
Regulatory Networks
Let us examine how gene regulatory interactions can collectively give rise
to a global network behavior that satisfies the requirements for development of a
specialized cell phenotype, and eventually, a whole living organism. Without
distinct regulatory interactions between the genes, any combination of gene ac-
tivities across the genome would be possible. This would result in an unstruc-
tured continuum of gene activation profiles, but no directed developmental
