Systems Biology (Methods in Molecular Biology)

(Tina Sui) #1
within endogenous network theory. This and other recent devel-
opments strongly suggest that we need to look for new directions,
to diversify our resource away from mutation theory.

3.5 Major Possible
Caveats
in Endogenous
Molecular-Cellular
Network Approach


Ten years ago there were two real and major problems standing on
the way to the development of research program on endogenous
network approach to cancer genesis and progression: first, whether
or not the endogenous network would really exist; and second,
whether or not there would be a functional landscape
corresponding to the nonlinear stochastic dynamics of the network.
After more than 10 years’ effort, the second problem has been
essentially solved: The corresponding functional landscape does
exist, at least in the mathematical and/or theoretical sense. This
second problem has now been replaced by a more practical and
potentially important question: For a given endogenous network,
how can we know for sure that all the major stable functional states
(and all major transition states) would have been found? If not,
some critical information on biology might have been missed. This
will be a challenging problem on the computational side for years
to come.
The first problem has not been solved very satisfactorily. We still
do not know the endogenous network for a given biological system
for sure. This will be a major effort for both experimental (cancer)
biologists and computational modelers now and in the future.
Nevertheless, it is clear that there does appear to have a common
core network for all cancers. This finding forms a workable base for
the further development. Based on the current evident, it is unlikely
that the hypothesized endogenous network would not eventually
be discovered. It may turn out even simpler than we would have
imagined: In biology we have witnessed such solutions several
times. One of the most famous is the discovery of double helix
for heredity processes: Much simpler than biologists would have
been anticipated.

4 Conclusion


Using HCC as an example we have realized the recently proposed
cancer endogenous molecular-cellular network hypothesis. The
working network of the liver was quantified by a set of nonlinear
differentiation equations. We have then demonstrated that the
working network reproduces the main features of the normal liver
and HCC at both the modular and molecular levels, as a first set of
evidence of the validity of the hypothesis. We explicitly obtain two
additional testable predications for the further validation. Specifi-
cally, (1) the potential strategies to cure or relieve HCC may be
inhibiting proliferation and inflammation, and simultaneously
inducing liver differentiation; (2) the genesis and regression of

240 Gaowei Wang et al.

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