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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-
in molecular biology, particularly in genome How are the signals encoded? How can we nomena, it does not reveal the “causality” of
sequencing and high-throughput measure- stabilize the voltage against noise and exter- regulatory relationships. Several methods have
ments, enables us to collect comprehensive data nal fluctuations? And how do the circuits been proposed to automatically discover regu-
sets on system performance and gain informa- react when a malfunction occurs in the sys- latory relationships solely on the basis of mi-
tion on the underlying molecules. This was not tem? What are the design principles and pos- croarray data (7–9). At present, such methods
possible in the days of Weiner, when molecular sible circuit patterns, and how can we modify use information derived from mRNA abun-
biology was still an emerging discipline. There them to improve system performance? dance, so there is limited scope to infer causal-
is now a golden opportunity for system-level A system-level understanding of a biolog- ity based on transcriptional regulation. Posttran-
analysis to be grounded in molecular-level un- ical system can be derived from insight into scriptional and posttranslational mechanisms of
derstanding, resulting in a continuous spectrum four key properties: regulation must be incorporated as large-scale
of knowledge. 1) System structures. These include the net- data become available, but many properties
System-level understanding, the approach work of gene interactions and biochemical have yet to be measured with sufficient accura-
advocated in systems biology (2), requires a pathways, as well as the mechanisms by which cy or in high throughput. Although it is not
shift in our notion of “what to look for” in such interactions modulate the physical proper- possible to incorporate all the desired data into
biology. While an understanding of genes and ties of intracellular and multicellular structures. the automated discovery system, analysis of
proteins continues to be important, the focus is 2) System dynamics. How a system be- transcriptional regulation may provide very
on understanding a system’s structure and dy- haves over time under various conditions can useful information because of the possible hy-
namics. Because a system is not just an assem- be understood through metabolic analysis, potheses it generates to allow us to infer the
bly of genes and proteins, its properties cannot sensitivity analysis, dynamic analysis meth- network structure. In general, when multiple
be fully understood merely by drawing dia- ods such as phase portrait and bifurcation hypotheses are generated by automated discov-
grams of their interconnections. Although such analysis, and by identifying essential mecha- ery analysis, it reflects a lack of information.
a diagram represents an important first step, it is nisms underlying specific behaviors. Bifurca- This type of analysis can be combined with
analogous to a static roadmap, whereas what we tion analysis traces time-varying change(s) in entropy-based decision-making algorithms to
really seek to know are the traffic patterns, why the state of the system in a multidimensional theoretically suggest an experiment that most
such traffic patterns emerge, and how we can space where each dimension represents a par- reduces the number of ambiguous network hy-
control them. ticular concentration of the biochemical fac- potheses. Although such algorithms have yet to
Identifying all the genes and proteins in an tor involved. reach a level of practical application, they may
organism is like listing all the parts of an 3) The control method. Mechanisms that prove useful for determining the optimal order
airplane. While such a list provides a catalog systematically control the state of the cell can of experiments needed to resolve ambiguous
of the individual components, by itself it is be modulated to minimize malfunctions and hypotheses (10). Progress in this area would
not sufficient to understand the complexity provide potential therapeutic targets for treat- lead to an increased emphasis on hypothesis-
underlying the engineered object. We need to ment of disease. driven research in biology (Fig. 1).
know how these parts are assembled to form 4) The design method. Strategies to mod- Once we have attained an understanding of
the structure of the airplane. This is analo- ify and construct biological systems having network structure, we will be able to investigate
gous to drawing an exhaustive diagram of desired properties can be devised based on network dynamics. In reality, analysis of dy-
gene-regulatory networks and their biochem- definite design principles and simulations, namics and structure on the basis of network
ical interactions. Such diagrams provide lim- instead of blind trial-and-error. dynamics are overlapping processes, because
ited knowledge of how changes to one part of Progress in any of the above areas re- dynamic analysis may yield useful predictions
a system may affect other parts, but to under- quires breakthroughs in our understanding of of unknown interactions. For dynamic analysis
stand how a particular system functions, we computational sciences, genomics, and mea- of a cellular system, we need to create a model.
surement technologies, and integration of But first it is important to carefully consider the
Sony Computer Science Laboratories, Inc., 3-14-13 such discoveries with existing knowledge. purpose of model building: Whether it is to
Higashi-Gotanda, Shinagawa, Tokyo 141-0022, Japan, Identification of gene-regulatory logic (3) obtain an in-depth understanding of system be-
and Kitano Symbiotic Systems Project, ERATO, JST,
and the Systems Biology Institute, Suite 6A, M31,
and biochemical networks is a major challenge. havior or to predict complex behaviors in re-
6-31-15 Jingumae, Shibuya, Tokyo 150-0001, Japan. The conventional methods for creating a net- sponse to complex stimuli, we must first define
E-mail: kitano@csl.sony.co.jp work model include performing a series of ex- the scope and abstraction level of the model.
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.