Advanced Review Noise in biological circuits Michael L. Simpson, 1,2∗ Chris D. Cox, 2 Michael S. Allen, 3 James M. McCollum, 4 Roy D. Dar, 2 David K. Karig 1 and John F. Cooke 2 Noise biology focuses on the sources, processing, and biological consequences of the inherent stochastic ﬂuctuations in molecular transitions or interactions that control cellular behavior. These ﬂuctuations are especially pronounced in small systems where the magnitudes of the ﬂuctuations approach or exceed the mean value of the molecular population. Noise biology is an essential component of nanomedicine where the communication of information is across a boundary that separates small synthetic and biological systems that are bound by their size to reside in environments of large ﬂuctuations. Here we review the fundamentals of the computational, analytical, and experimental approaches to noise biology. We review results that show that the competition between the beneﬁts of low noise and those of low population has resulted in the evolution of genetic system architectures that produce an uneven distribution of stochasticity across the molecular components of cells and, in some cases, use noise to drive biological function. We review the exact and approximate approaches to gene circuit noise analysis and simulation, and review many of the key experimental results obtained using ﬂow cytometry and time-lapse ﬂuorescent microscopy. In addition, we consider the probative value of noise with a discussion of using measured noise properties to elucidate the structure and function of the underlying gene circuit. We conclude with a discussion of the frontiers of and signiﬁcant future challenges for noise biology.  2009 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol 2009 1 214–225 T he emerging ﬁeld of noise biology focuses on the sources, processing, and biological consequences of the inherent stochastic ﬂuctuations in the popula- tions, concentrations, positions, or states of molecules that control cellular behavior. Such ﬂuctuations are found in all systems where discrete events occur at random times (i.e., essentially all physical systems), but are especially pronounced in small systems where the magnitudes of the ﬂuctuations approach or exceed the mean values of the state variables (e.g., regulatory molecule population). Consequently, noise biology is an essential component of nanomedicine. For exam- ple, besides noise in the delivery of nanoparticles to cells, engineered nanoparticles operate on the same ∗ Correspondence to: Michael L. Simpson, Oak Ridge National Laboratory, Oak Ridge, TN, USA. E-mail: SimpsonML1@ornl.gov 1 Oak Ridge National Laboratory, Oak Ridge, TN, USA. 2 University of Tennessee, Knoxville, TN, USA. 3 University of North Texas, Denton, TX, USA. 4 Virginia Commonwealth University, Richmond, VA 23284. DOI: 10.1002/wnan.022 scale as cellular machinery and must interface to the noisy processes of the cell. One could argue that noise biology has a long history. In 1940, Max Delbruck recognized that ﬂuctuations in small populations of enzyme molecules could have profound impacts on cell physiology, 1 and later proposed that ﬂuctuations of this type could explain the variation in the number of viruses produced upon lyses of infected bacteria. 2 However, noise biology as a distinct ﬁeld has emerged over the last decade in the broader context of computational, physical science, and engineering approaches to biology that have also spawned bioinformatics, systems biology, and synthetic biology. In these approaches, biology, perhaps in a very fundamental sense, is thought to be an informational science 3 in which biochemical processes are conceptualized as circuits and networks. This conceptualization places the focus ﬁrmly on the transport and processing of information within these systems, and begs the question of how such seemingly robust function emerges from information that resides within the inherent noise of low molecular populations. 214  2009 John Wiley & Sons, Inc. Volume 1, March/April 2009