Elucidating the genotype-phenotype map by automatic enumeration and analysis of the phenotypic repertoire.

BackgroundThe gap between genotype and phenotype is filled by complex biochemical systems most of which are poorly understood. Because these systems are complex, it is widely appreciated that quantitative understanding can only be achieved with the aid of mathematical models. However, formulating models and measuring or estimating their numerous rate constants and binding constants is daunting. Here we present a strategy for automating difficult aspects of the process.MethodsThe strategy, based on a system design space methodology, is applied to a class of 16 designs for a synthetic gene oscillator that includes seven designs previously formulated on the basis of experimentally measured and estimated parameters.ResultsOur strategy provides four important innovations by automating: (1) enumeration of the repertoire of qualitatively distinct phenotypes for a system; (2) generation of parameter values for any particular phenotype; (3) simultaneous realization of parameter values for several phenotypes to aid visualization of transitions from one phenotype to another, in critical cases from functional to dysfunctional; and (4) identification of ensembles of phenotypes whose expression can be phased to achieve a specific sequence of functions for rationally engineering synthetic constructs. Our strategy, applied to the 16 designs, reproduced previous results and identified two additional designs capable of sustained oscillations that were previously missed.ConclusionsStarting with a system's relatively fixed aspects, its architectural features, our method enables automated analysis of nonlinear biochemical systems from a global perspective, without first specifying parameter values. The examples presented demonstrate the efficiency and power of this automated strategy

Synthetic biology and microdevices : a powerful combination

Recent developments demonstrate that the combination of microbiology with micro-and nanoelectronics is a successful approach to develop new miniaturized sensing devices and other technologies. In the last decade, there has been a shift from the optimization of the abiotic components, for example, the chip, to the improvement of the processing capabilities of cells through genetic engineering. The synthetic biology approach will not only give rise to systems with new functionalities, but will also improve the robustness and speed of their response towards applied signals. To this end, the development of new genetic circuits has to be guided by computational design methods that enable to tune and optimize the circuit response. As the successful design of genetic circuits is highly dependent on the quality and reliability of its composing elements, intense characterization of standard biological parts will be crucial for an efficient rational design process in the development of new genetic circuits. Microengineered devices can thereby offer a new analytical approach for the study of complex biological parts and systems. By summarizing the recent techniques in creating new synthetic circuits and in integrating biology with microdevices, this review aims at emphasizing the power of combining synthetic biology with microfluidics and microelectronics

Optimising Simulation Data Structures for the Xeon Phi

In this paper, we propose a lock-free architecture to accelerate logic gate circuit simulation using SIMD multi-core machines. We evaluate its performance on different test circuits simulated on the Intel Xeon Phi and 2 other machines. Comparisons are presented of this software/hardware combination with reported performances of GPU and other multi-core simulation platforms. Comparisons are also given between the lock free architecture and a leading commercial simulator running on the same Intel hardware

A temporal logic approach to modular design of synthetic biological circuits

We present a new approach for the design of a synthetic biological circuit whose behaviour is specified in terms of signal temporal logic (STL) formulae. We first show how to characterise with STL formulae the input/output behaviour of biological modules miming the classical logical gates (AND, NOT, OR). Hence, we provide the regions of the parameter space for which these specifications are satisfied. Given a STL specification of the target circuit to be designed and the networks of its constituent components, we propose a methodology to constrain the behaviour of each module, then identifying the subset of the parameter space in which those constraints are satisfied, providing also a measure of the robustness for the target circuit design. This approach, which leverages recent results on the quantitative semantics of Signal Temporal Logic, is illustrated by synthesising a biological implementation of an half-adder

A Binaural Neuromorphic Auditory Sensor for FPGA: A Spike Signal Processing Approach

This paper presents a new architecture, design flow, and field-programmable gate array (FPGA) implementation analysis of a neuromorphic binaural auditory sensor, designed completely in the spike domain. Unlike digital cochleae that decompose audio signals using classical digital signal processing techniques, the model presented in this paper processes information directly encoded as spikes using pulse frequency modulation and provides a set of frequency-decomposed audio information using an address-event representation interface. In this case, a systematic approach to design led to a generic process for building, tuning, and implementing audio frequency decomposers with different features, facilitating synthesis with custom features. This allows researchers to implement their own parameterized neuromorphic auditory systems in a low-cost FPGA in order to study the audio processing and learning activity that takes place in the brain. In this paper, we present a 64-channel binaural neuromorphic auditory system implemented in a Virtex-5 FPGA using a commercial development board. The system was excited with a diverse set of audio signals in order to analyze its response and characterize its features. The neuromorphic auditory system response times and frequencies are reported. The experimental results of the proposed system implementation with 64-channel stereo are: a frequency range between 9.6 Hz and 14.6 kHz (adjustable), a maximum output event rate of 2.19 Mevents/s, a power consumption of 29.7 mW, the slices requirements of 11 141, and a system clock frequency of 27 MHz.Ministerio de Economía y Competitividad TEC2012-37868-C04-02Junta de Andalucía P12-TIC-130

Delay-Based Controller Design for Continuous-Time and Hybrid Applications

Motivated by the availability of different types of delays in embedded systems and biological circuits, the objective of this work is to study the benefits that delay can provide in simplifying the implementation of controllers for continuous-time systems. Given a continuous-time linear time-invariant (LTI) controller, we propose three methods to approximate this controller arbitrarily precisely by a simple controller composed of delay blocks, a few integrators and possibly a unity feedback. Different problems associated with the approximation procedures, such as finding the optimal number of delay blocks or studying the robustness of the designed controller with respect to delay values, are then investigated. We also study the design of an LTI continuous-time controller satisfying given control objectives whose delay-based implementation needs the least number of delay blocks. A direct application of this work is in the sampled-data control of a real-time embedded system, where the sampling frequency is relatively high and/or the output of the system is sampled irregularly. Based on our results on delay-based controller design, we propose a digital-control scheme that can implement every continuous-time stabilizing (LTI) controller. Unlike a typical sampled-data controller, the hybrid controller introduced here -— consisting of an ideal sampler, a digital controller, a number of modified second-order holds and possibly a unity feedback -— is robust to sampling jitter and can operate at arbitrarily high sampling frequencies without requiring expensive, high-precision computation

Automatic Design of Synthetic Gene Circuits through Mixed Integer Non-linear Programming

Automatic design of synthetic gene circuits poses a significant challenge to synthetic biology, primarily due to the complexity of biological systems, and the lack of rigorous optimization methods that can cope with the combinatorial explosion as the number of biological parts increases. Current optimization methods for synthetic gene design rely on heuristic algorithms that are usually not deterministic, deliver sub-optimal solutions, and provide no guaranties on convergence or error bounds. Here, we introduce an optimization framework for the problem of part selection in synthetic gene circuits that is based on mixed integer non-linear programming (MINLP), which is a deterministic method that finds the globally optimal solution and guarantees convergence in finite time. Given a synthetic gene circuit, a library of characterized parts, and user-defined constraints, our method can find the optimal selection of parts that satisfy the constraints and best approximates the objective function given by the user. We evaluated the proposed method in the design of three synthetic circuits (a toggle switch, a transcriptional cascade, and a band detector), with both experimentally constructed and synthetic promoter libraries. Scalability and robustness analysis shows that the proposed framework scales well with the library size and the solution space. The work described here is a step towards a unifying, realistic framework for the automated design of biological circuits

On delayed genetic regulatory networks with polytopic uncertainties: Robust stability analysis

Copyright [2008] IEEE. This material is posted here with permission of the IEEE. Such permission of the IEEE does not in any way imply IEEE endorsement of any of Brunel University's products or services. Internal or personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution must be obtained from the IEEE by writing to [email protected]. By choosing to view this document, you agree to all provisions of the copyright laws protecting it.In this paper, we investigate the robust asymptotic stability problem of genetic regulatory networks with time-varying delays and polytopic parameter uncertainties. Both cases of differentiable and nondifferentiable time-delays are considered, and the convex polytopic description is utilized to characterize the genetic network model uncertainties. By using a Lyapunov functional approach and linear matrix inequality (LMI) techniques, the stability criteria for the uncertain delayed genetic networks are established in the form of LMIs, which can be readily verified by using standard numerical software. An important feature of the results reported here is that all the stability conditions are dependent on the upper and lower bounds of the delays, which is made possible by using up-to-date techniques for achieving delay dependence. Another feature of the results lies in that a novel Lyapunov functional dependent on the uncertain parameters is utilized, which renders the results to be potentially less conservative than those obtained via a fixed Lyapunov functional for the entire uncertainty domain. A genetic network example is employed to illustrate the applicability and usefulness of the developed theoretical results

Automatic Compilation from High-Level Biologically-Oriented Programming Language to Genetic Regulatory Networks

Background The field of synthetic biology promises to revolutionize our ability to engineer biological systems, providing important benefits for a variety of applications. Recent advances in DNA synthesis and automated DNA assembly technologies suggest that it is now possible to construct synthetic systems of significant complexity. However, while a variety of novel genetic devices and small engineered gene networks have been successfully demonstrated, the regulatory complexity of synthetic systems that have been reported recently has somewhat plateaued due to a variety of factors, including the complexity of biology itself and the lag in our ability to design and optimize sophisticated biological circuitry. Methodology/Principal Findings To address the gap between DNA synthesis and circuit design capabilities, we present a platform that enables synthetic biologists to express desired behavior using a convenient high-level biologically-oriented programming language, Proto. The high level specification is compiled, using a regulatory motif based mechanism, to a gene network, optimized, and then converted to a computational simulation for numerical verification. Through several example programs we illustrate the automated process of biological system design with our platform, and show that our compiler optimizations can yield significant reductions in the number of genes () and latency of the optimized engineered gene networks. Conclusions/Significance Our platform provides a convenient and accessible tool for the automated design of sophisticated synthetic biological systems, bridging an important gap between DNA synthesis and circuit design capabilities. Our platform is user-friendly and features biologically relevant compiler optimizations, providing an important foundation for the development of sophisticated biological systems.National Institutes of Health (U.S.) (Grant # 7R01GM74712-5)United States. Defense Advanced Research Projects Agency (contract HR0011-10-C-0168)National Science Foundation (U.S.) (NSF CAREER award 0968682)BBN Technologie