Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 443

hypothesis-driven linear science. The emergence of a need for this systems-
level appreciation of biological processes, for example, b -arrestin signaling
profiles, was created by the technological advances made in mass data col-
lection and analytical approaches we have discussed previously. As systems-
level approaches generate far larger datasets than reductionist linear science,
the data-dominance of individual genes/proteins has been superseded by the
prominence of coherent groups and networks of genes/proteins. Within
systems-level scale datasets, there are still computational hierarchies of rele-
vant genes/proteins in these systems, but the singular reliance on cause-
and-effect monolithic linear signaling paradigms within the actual network
has hopefully been relegated to historical science.
Our emerging appreciation of the coherent connectivity between mul-
tiple physiological systems has generated the need to empirically develop the
systems biology “higher-order” level of understanding of the integration of
these systems. This concept of network or “systems” biology implies that
biological functions are mediated by strongly or weakly connected groups
of genes/proteins rather than simple linear signaling pathways. Resistance
to such concepts is related to the opinion that network-based analyses are
too diffuse and non-specific to yield actionable data for biomedical or phar-
maceutical science. Advances in the mathematical modeling of “small-
world” networks have demonstrated that, in most cases, complex network
systems are not connected in an equitable and homogenous manner but
rather typically consist of at least two levels of connectivity. Therefore, net-
works may contain small, tightly connected, “subnetworks” which are then
collected together into larger constellations of groups of multiple subnet-
works. 156 Within a biological framework, it is simple to analogize the
“subnetworks” to biological programs such as kinase signaling cascades
(e.g., mitogen-activated protein kinase cascades) or receptor signaling sys-
tems (e.g., b -arrestin-mediated GPCR signaling) in different tissues, while
endocrine or neuronal axes could represent the constellations of these groups
of smaller subnetworks. While the functional output of any given gene/pro-
tein network may be an eventual function of the activity of all of the con-
stituent components, the relative contribution (to the eventual functional
output) of each gene/protein in this network is highly unlikely to be per-
fectly equal. 157,158 Therefore, within networks of functionally related
genes/proteins, there are likely to exist specific nodes that consist of
genes/proteins that form the most important bridges, or “ loose connections, ”
between the smaller functional programs (subnetworks) contained within
the global system. Such genes/proteins within a functional network are