Jorge Cortés
Professor
Cymer Corporation Endowed Chair
Systems approaches and algorithms for discovery of combinatorial therapeutics
J. Feala, J. Cortés, P. Duxbury, C. Piermarocchi, A. McCulloch, G. Paternostro
Wiley Interdisciplinary Reviews: Systems Biology 2 (2) (2010), 181-193
Abstract
Effective therapy of complex diseases requires control
of highly non-linear complex networks that remain
incompletely characterized. In particular, drug
intervention can be seen as control of signaling in
cellular networks. Identification of control parameters
presents an extreme challenge due to the combinatorial
explosion of control possibilities in combination
therapy and to the incomplete knowledge of the systems
biology of cells. In this review paper we describe the
main current and proposed approaches to the design of
combinatorial therapies, including the empirical methods
used now by clinicians and alternative approaches
suggested recently by several authors. New approaches
for designing combinations arising from systems biology
are described. We discuss in special detail the design
of algorithms that identify optimal control parameters
in cellular networks based on a quantitative
characterization of control landscapes, maximizing
utilization of incomplete knowledge of the state and
structure of intracellular networks. The use of new
technology for high-throughput measurements is key to
these new approaches to combination therapy and
essential for the characterization of control landscapes
and implementation of the algorithms. Combinatorial
optimization in medical therapy is also compared with
the combinatorial optimization of engineering and
materials science and similarities and differences are
delineated. Combinatorial Biological Control is a
growing field that is benefiting from advances in
systems biology, targeted therapeutics, and
high-throughput biological measurement technologies as
well as from new and established approaches from
mathematics, physics and engineering. The study of
Combinatorial Therapies is the fastest expanding
sub-discipline within this field, though therapeutic
applications are not the only uses of the new principles
and methods that are being discovered. Combinatorial
approaches can also be used to optimize the survival and
differentiation of cells in vitro, in synthetic
genomics, to delay aging, and to improve physiological
performance. Additionally, work in this field can help
elucidate the strategies nature uses for combinatorial
control and optimization at different scales, from
evolution to organismal function. While until recently
combinatorial therapies were based on largely empirical
methods, new insights are arising from systems biology
and from the integration of several biological and non-
biological disciplines and are providing the prospect of
more rational approaches to the therapy of complex
diseases. In this review, we describe the state of the
art of combinatorial optimization of medical therapy,
starting with relevant contributions from systems
biology. We then compare it with more established
techniques of systematic optimization in engineering and
material sciences.
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Mechanical and Aerospace Engineering,
University of California, San Diego
9500 Gilman Dr,
La Jolla, California, 92093-0411
Ph: 1-858-822-7930
Fax: 1-858-822-3107
cortes at ucsd.edu
Skype id:
jorgilliyo