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Systems Biology: A Brief Overview: S B: T G, L, B
Systems Biology: A Brief Overview: S B: T G, L, B
REVIEW
To understand biology at the system level, we must examine the structure periments to identify specific interactions and
and dynamics of cellular and organismal function, rather than the char- conducting extensive literature surveys. Several
acteristics of isolated parts of a cell or organism. Properties of systems, attempts are under way to create a large-scale,
such as robustness, emerge as central issues, and understanding these comprehensive database on gene-regulatory
properties may have an impact on the future of medicine. However, many and biochemical networks (4). Although such
breakthroughs in experimental devices, advanced software, and analytical databases are useful sources of knowledge,
methods are required before the achievements of systems biology can live many network structures remain to be identi-
up to their much-touted potential. fied. Substantial research has been done on
expression profiling, in which clustering analy-
Since the days of Norbert Weiner, system-level must first examine how the individual com- sis is used to identify genes that are coexpressed
understanding has been a recurrent theme in ponents dynamically interact during opera- with genes of known function (5, 6). Although
biological science (1). The major reason it is tion. We must seek answers to questions such clustering analysis provides insight into the
gaining renewed interest today is that progress as: What is the voltage on each signal line? “correlation” among genes and biological phe-
REVIEW
Advanced technologies and biology have extremely different physical ty in components or the environment (14).
implementations, but they are far more alike in systems-level organization Biologists and biophysicists new to study-
than is widely appreciated. Convergent evolution in both domains pro- ing complex networks often express surprise at
duces modular architectures that are composed of elaborate hierarchies of a biological network’s apparent robustness
protocols and layers of feedback regulation, are driven by demand for (15). They find that “perfect adaptation” and
robustness to uncertain environments, and use often imprecise compo- homeostatic regulation are robust properties of
nents. This complexity may be largely hidden in idealized laboratory networks (16, 17), despite “exploratory mech-
settings and in normal operation, becoming conspicuous only when con- anisms” that can seem gratuitously uncertain
tributing to rare cascading failures. These puzzling and paradoxical fea- (18 –20). Some even conclude that these mech-
tures are neither accidental nor artificial, but derive from a deep and anisms and their resulting features seem absent
necessary interplay between complexity and robustness, modularity, feed- in engineering (20, 21). However, ironically, it
back, and fragility. This review describes insights from engineering theory is in the nature of their robustness and complex-
and practice that can shed some light on biological complexity. ity that biology and advanced engineering are
most alike (22). Good design in both cases (e.g.,
The theory and practice of complex engineer- approaches in biology have a long history (1, 2) cells and bodies, cars and airplanes) means that
ing systems have progressed so radically that but are just now receiving renewed mainstream users are largely unaware of hidden complexi-
they often embody Arthur C. Clarke’s dictum, attention (3–13), whereas systems-level design ties, except through system failures. Further-
“Any sufficiently advanced technology is in- has consistently been at the core of modern more, the robustness and fragility features of
distinguishable from magic.” Systems-level engineering, motivating its most sophisticat- complex systems are both shared and neces-
ed theories in controls, information, and com- sary. Although the need for universal principles
1
Departments of Anesthesiology and Cell and Devel- putation. The hidden nature of complexity of complexity and corresponding mathematical
opmental Biology, University of Michigan Medical (“magic”) and discipline fragmentation with- tools is widely recognized (23), sharp differenc-
School, Ann Arbor, MI 48109, USA. 2Control and in engineering have been barriers to a dialog
Dynamical Systems, Electrical Engineering, and Bio-
es arise as to what is fundamental about com-
engineering, California Institute of Technology, Pasa- with biology. A key starting point in devel- plexity and what mathematics is needed (24).
dena, CA 91125, USA. oping a conceptual and theoretical bridge to This article sketches one possible view, using
*To whom correspondence should be addressed. E- biology is robustness, the preservation of experience and theoretical insights from engi-
mail: doyle@cds.caltech.edu particular characteristics despite uncertain- neering complexity that are relevant to biology.
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