Biology Reference
In-Depth Information
with a variety of abnormalities in chromosomes, which
coexist even in a solid cancer. Therefore, even if a part of
a tumor cluster is eliminated by an anticancer drug, subsets
of tumor cells with genetic properties tolerant to anticancer
drugs will survive and continue to proliferate. This strategy
is made possible by the instability of chromosomes.
Modularity
Modularity provides isolation of a perturbation from the
rest of the system. The cell is the most significant example.
More subtle examples are modules of biochemical and
gene regulatory networks. Modules that buffer perturba-
tions also play an important role during developmental
processes, so that proper pattern formation can be accom-
plished
[12
MECHANISMS FOR ROBUSTNESS
Here we investigate basic mechanisms for making systems
robust. There are at least four basic mechanisms: systems
control, fault tolerance, modularity, and decoupling.
14]
. The definition of modules and the
methods for their detection are still controversial, but the
general consensus is that modules do exist and that they
play an important role
[15]
.
e
Systems Control
Extensive systems control is used in biological systems.
Negative feedback, positive feedback, and feedforward are
used to make a system dynamically stable around the
specific state of the system, or to form bistable and multi-
stable switches that drive transition of the state into
different attractors. Bacteria chemotaxis is an example of
how negative feedback enables robust, but fragile control
against a wide range of fluctuations in chemical concen-
tration
[4,7,8]
. Owing to integral feedback, bacteria can
sense changes in chemoattractant and chemorepellant
environments, independent of absolute concentration, so
that proper chemotaxis behaviour is maintained over a wide
range of ligand concentrations. In addition, the same
mechanism makes it insensitive to changes in rate constants
involved in the circuit. This is an example of how systems
control is used to maintain a system's state within an
attractor so that proper function can be maintained.
Positive feedbacks are often used to create bistability in
signal transduction and the cell cycle, so that the system is
tolerant against minor perturbations from stimuli. Details
are available elsewhere
[9
e
11]
.
Decoupling
Decoupling isolates low-level noise and fluctuations from
functional-level structures and dynamics. One example is
genetic buffering by Hsp90, in which misfolding of
proteins due to environmental stresses is repaired. Thus the
effects of such perturbations are isolated from the functions
of circuits. This mechanism also applies to genetic varia-
tions, where genetic changes in coding regions that may
affect protein structures are masked because protein folding
is fixed by Hsp90, unless such masking is removed by
extreme stress
[16
18]
. Emergent behaviour of complex
networks also exhibits such buffering properties
[19]
.
These effects may constitute canalization, as proposed by
Waddington
[20]
.
The airplane as an example of a sophisticated engi-
neering system clearly illustrates how these mechanisms
work as a whole system (
Figure 24.2
). An airplane is
supposed to maintain the pilot's desired flight path against
atmospheric perturbations and various internal perturba-
tions, including changes in the center of gravity due to fuel
consumption and movement of passengers, as well as
mechanical inaccuracies. This function is carried out by an
automatic flight control system (AFCS) using movable
flight control surfaces (rudder, flaps, elevators, etc.) and
a propulsion system (engines). Extensive negative feedback
control is used to correct deviations from the desired flight
path. The reliability of the AFCS is critical for stable flight.
To increase reliability, the AFCS is composed of three
independently implemented modules (a triple redundancy
system) that all meet the same functional specifications.
Most parts of the AFCS are digitized, so that low-level
noise from voltage fluctuations are effectively decoupled
from digital signals that define the function of the system.
Because of these mechanisms, modern airplanes are highly
robust against various perturbations.
e
Fault Tolerance
Fault-tolerant mechanisms increase tolerance against
component failure and environmental changes by providing
alternative components or methods to ultimately maintain
a function of the system. Sometimes there are multiple
components that are similar to each other and are redun-
dant. In other cases, multiple components or circuits with
overlapping functions may exist to compensate for any
component insufficiency. This is called diversity. The
difference between redundancy and diversity is clear. For
example, multiple phone lines are 'redundant', but alter-
native access to internet, phone, fax, and other means of
communication is 'diversity'. Redundancy and diversity
are often considered as opposites, but it is more consistent
to view them as different ways of providing alternative fail-
tolerant mechanisms.
MECHANISMS FOR CANCER ROBUSTNESS
Cancer is robust against various therapeutic interventions.
There are three groups of mechanisms that make cancer
