Engineering networks

In the line of the modular paradigm of gene network organization a new field of research has emerged in the last five years under the name of "Synthetic Biology" aiming at constructing artificial regulatory modules in cells. Standard molecular biology cloning and recombinant DNA techniques are applied in order to incorporate in bacterial cells sets of exogenous interacting genes that form in vivo engineered genetic circuits with predefined functions.

Synthetic genetic circuits provide relatively well controlled test beds in which functions of design principles can be isolated and functions char acterized in detail. Several bacterial strains have been obtained that exhibit programmed behavior: oscillators,4'14'19 toggle switches,22 and auto-regulatory homeostatic systems.6 The implemented modules are not direct derivatives of natural circuits but were constructed with a theoretical model in mind to accomplish a given functionality and with biological insight in order to use components (inserted genes, plasmids) that try to avoid interference with the metabolism of the engineered cell. These explorations essentially confirmed the operating principles and theoretical approaches of isolated genetic regulators and opened the way to new biotechnologi-cal perspectives with the de novo creation of bio-engineered systems with sophisticated functionality. Libraries of synthetic modules are already being compiled to facilitate new constructions suitable to different conditions and environments.65 First steps towards implementation of cell-cell communication have also been achieved exploiting genes from natural quorum sensing, the ability of a microorganism to perceive and respond to microbial population.65'67

Considering the importance of cell synchronization, an exciting successive step would be to combine this cellular interaction with cell oscil-lations.41 The synthetic oscillator implemented by Elowitz -termed the "Repressilator"-14 showed individual cells to oscillate differently, exhibiting cell-cell variation in period length, as well as variations within single cells between successive periods. Garcia-Ojalvo et al.21 showed theoretically that coupling these oscillators with quorum sensing enables self-synchronization of the cells. Individual oscillation fluctuations would thus be reduced and the population would behave as a collective oscillator. Although different genetic circuit designs of communicating oscillating cells have been proposed,37'41 collective synchronization of engineered cells has to our knowledge not yet been obtained. However, a first step towards engineered spatio-temporal cell behaviors has been achieved recently in populations with two kinds of engineered cells5 that differentiate forming ring-like patterns.

Synthetic biology is a rapidly progressing field contributing in an innovative fashion to better understanding the natural regulatory processes and opening the way to futuristic biotechnological applications. As with prototyping and simulation in mechanical and electronics engineering, theoretical modeling and dynamical analysis are essential procedures in the development of programmed cells. This new field of biological/biotechnological research will include mathematical approaches in an unprecedented way in Life Science.

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