Feasibility and reliability of sequential logic with gene regulatory networks.

Gene regulatory networks exhibiting Boolean behaviour, e.g. AND, OR or XOR, have been routinely designed for years. However, achieving more sophisticated functions, such as control or computation, usually requires sequential circuits or so-called state machines. For such a circuit, outputs depend both on inputs and the current state of the system. Although it is still possible to design such circuits by analogy with digital electronics, some particularities of biology make the task trickier. The impact of two of them, namely the stochasticity of biological processes and the inhomogeneity in the response of regulation mechanisms, are assessed in this paper. Numerical simulations performed in two use cases point out high risks of malfunctions even for designed GRNs functional from a theoretical point of view. Several solutions to improve reliability of such systems are also discussed.

Efficient Modeling and Simulation of Space-Dependent Biological Systems.

We recently demonstrated the possibility to model and to simulate biological functions using hardware description languages (HDLs) and associated simulators traditionally used for microelectronics. Nevertheless, those languages are not suitable to model and simulate space-dependent systems described by partial differential equations. However, in more and more applications space- and time-dependent models are unavoidable. For this purpose, we investigated a new modeling approach to simulate molecular diffusion on a mesoscopic scale still based on HDL. Our work relies on previous investigations on an electrothermal simulation tool for integrated circuits, and analogies that can be drawn between electronics, thermodynamics, and biology. The tool is composed of four main parts: a simple but efficient mesher that divides space into parallelepipeds (or rectangles in 2D) of adaptable size, a set of interconnected biological models, a SPICE simulator that handles the model and Python scripts that interface the different tools. Simulation results obtained with our tool have been validated on simple cases for which an analytical solution exists and compared with experimental data gathered from literature. Compared with existing approaches, our simulator has three main advantages: a very simple algorithm providing a direct interface between the diffusion model and biological model of each cell, the use of a powerful and widely proven simulation core (SPICE) and the ability to interface biological models with other domains of physics, enabling the study of transdisciplinary systems.

[Application of microelectronics CAD tools to synthetic biology]. / Application à la biologie synthétique des méthodes et outils de CAO de la microélectronique.

Synthetic biology is an emerging science that aims to create new biological functions that do not exist in nature, based on the knowledge acquired in life science over the last century. Since the beginning of this century, several projects in synthetic biology have emerged. The complexity of the developed artificial bio-functions is relatively low so that empirical design methods could be used for the design process. Nevertheless, with the increasing complexity of biological circuits, this is no longer the case and a large number of computer aided design softwares have been developed in the past few years. These tools include languages for the behavioral description and the mathematical modelling of biological systems, simulators at different levels of abstraction, libraries of biological devices and circuit design automation algorithms. All of these tools already exist in other fields of engineering sciences, particularly in microelectronics. This is the approach that is put forward in this paper.

GeNeDA: An Open-Source Workflow for Design Automation of Gene Regulatory Networks Inspired from Microelectronics.

The topic of this article is the development of an open-source automated design framework for synthetic biology, specifically for the design of artificial gene regulatory networks based on a digital approach. In opposition to other tools, GeNeDA is an open-source online software based on existing tools used in microelectronics that have proven their efficiency over the last 30 years. The complete framework is composed of a computation core directly adapted from an Electronic Design Automation tool, input and output interfaces, a library of elementary parts that can be achieved with gene regulatory networks, and an interface with an electrical circuit simulator. Each of these modules is an extension of microelectronics tools and concepts: ODIN II, ABC, the Verilog language, SPICE simulator, and SystemC-AMS. GeNeDA is first validated on a benchmark of several combinatorial circuits. The results highlight the importance of the part library. Then, this framework is used for the design of a sequential circuit including a biological state machine.