Yves Gendrault

Synthetic biology methodology and model refinement based on microelectronic modeling tools and languages.

In microelectronics, the design of new systems is based on a proven time-tested design flow. The goal of this paper is to determine to what extend this design flow can be adapted to biosystem design. The presented methodology is based on a top-down approach and consists of starting with a behavioral description of the system to progressively refine it to its final low-level system representation, composed of DNA parts. To preserve accuracy and simplicity, the design flow relies on refined models of biological mechanisms, which can be expressed by the hardware description languages and simulation tools traditionally used in microelectronics. A case study, the complete modeling of a priority encoder, is presented to demonstrate the effectiveness of the method.

Modeling Biology With HDL Languages: A First Step Toward a Genetic Design Automation Tool Inspired From Microelectronics

Nowadays, synthetic biology is a hot research topic. Each day, progresses are made to improve the complexity of artificial biological functions in order to tend to complex biodevices and biosystems. Up to now, these systems are handmade by bioengineers, which require strong technical skills and leads to nonreusable development. Besides, scientific fields that share the same design approach, such as microelectronics, have already overcome several issues and designers succeed in building extremely complex systems with many evolved functions. On the other hand, in systems engineering and more specifically in microelectronics, the development of the domain has been promoted by both the improvement of technological processes and electronic design automation tools. The work presented in this paper paves the way for the adaptation of microelectronics design tools to synthetic biology. Considering the similarities and differences between the synthetic biology and microelectronics, the milestones of this adaptation are described. The first one concerns the modeling of biological mechanisms. To do so, a new formalism is proposed, based on an extension of the generalized Kirchhoff laws to biology. This way, a description of all biological mechanisms can be made with languages widely used in microelectronics. Our approach is therefore successfully validated on specific examples drawn from the literature.

Using digital electronic design flow to create a Genetic Design Automation tool

Synthetic bio-systems become increasingly more complex and their development is lengthy and expensive. In the same way, in microelectronics, the design process of very complex circuits has benefited from many years of experience. It is now partly automated through Electronic Design Automation tools. Both areas present analogies that can be used to create a Genetic Design Automation tool inspired from EDA tools used in digital electronics. This tool would allow moving away from a totally manual design of bio-systems to assisted conception. This ambitious project is presented in this paper, with a deep focus on the tool that automatically generates models of bio-systems directly usable in electronic simulators.

A game-of-life like simulator for design-oriented modeling of BioBricks in synthetic biology

This paper deals with the development of a new simulator that will be very helpful to establish new accurate and predictive design-oriented models for the BioBricks used in synthetic biology. The simulator uses the principle of the game-of-life: molecules can move on a grid and, at every iteration, binding and dissociation rules are applied when two molecules are on same node. The principle is elementary but it can highlight interesting biological phenomenon. Those can be modeled by mathematical equations to achieve design-oriented models. In this case, the simulator also helps to make to link between mathematical parameters and the microscopic parameters. A first version of the software has been implemented in MATLAB. It permits to retrieve very interesting results, such as the Hills equation and the properties of Hills coefficient.

Multi-abstraction modeling in synthetic biology

Synthetic biology is a science resulting from the connection between biotechnology and engineering sciences. It aims to design and build new biological systems and functions. The ability to design a new biological function according to given specifications includes many steps. One of the big issues is to formalize a design methodolgy and to develop adapted tools. One way to explore is to adapt the design flow used in digital microelectronics to synthetic biology. The paper focuses on a key point of the design flow, which is the development of a multi-abstraction model library for BioBricks, which is the basis of a design kit, provided to biodesigners, for simulation purposes. For each abstraction level, we present the way the model is built. The pertinence of each model is presented as well.

A general framework improving teaching ligand binding to a macromolecule.

The interaction of a ligand with a macromolecule has been modeled following different theories. The tenants of the induced fit model consider that upon ligand binding, the protein-ligand complex undergoes a conformational change. In contrast, the allosteric model assumes that only one among different coexisting conformers of a given protein is suitable to bind the ligand optimally. In the present paper, we propose a general framework to model the binding of ligands to a macromolecule. Such framework built on the binding polynomial allows opening new ways to teach in a unified manner ligand binding, enzymology and receptor binding in pharmacology. Moreover, we have developed simple software that allows building the binding polynomial from the schematic description of the biological system under study. Taking calmodulin as a canonical example, we show here that the proposed tool allows the easy retrieval of previously experimental and computational reports. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

Fuzzy logic, an intermediate description level for design and simulation in synthetic biology

Synthetic biology, or biological engineering, is a new science which may take advantage of the know-how of engineering science in order to build new in-vivo biological functions. The complete design process implies lots of modeling and simulation tasks. The design flow for this technology uses “digital” models at high level of abstraction as well as “analogue” ones at low level. Nevertheless, contrary to electronics, high-level digital descriptions are far away from low-level ones. In this paper, an intermediate modeling level using the principle of fuzzy logic is proposed to fill the gap between high and low abstraction level. The main advantage of this approach is to obtain quantitative simulation results while keeping a behavioral description of mechanisms. This is pointed out through two examples. The first one, encountered in literature, tends to prove that this modeling level is sufficient to obtain reliable results in comparison with the experimental ones. The second one, which is more theoretical, demonstrates the interest of fuzzy logic from a designing point of view.

EDA inspired open-source framework for synthetic biology

The topic of this paper is to develop an open-source framework to help bio-engineers through the different stages of a top-down design process for new artificial biosystems (synthetic biology). The presented tools address the upstream stages of the design, starting from a high-level behavioral description of the targeted biological function and ending with a working assembly of abstract BioBricks performing that very function. For that purpose, EDA (Electronic Design Automation) tools are indeed adapted to synthetic biology. The framework involves three main steps: the interpretation of the high-level description into a netlist of logical functions, the optimization of the netlist with respect to BioBricks capabilities and the automated generation of a SystemC-AMS abstracted simulatable netlist that can be used for further analysis (low-level simulation, optimization ...). Throughout the paper, each stage of the framework is detailed and illustrated with a simple (from a logical point of view) but complex (from the biological viewpoint) example: an in-vivo chemical species regulation system.

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.

Computer-aided design in synthetic biology: a system designer approach

The development of computer-aided design tools for synthetic biology is currently a hot research topic. However the field is not mature enough to provide a generic, adaptable and reliable tool for potential applications. The purpose of this paper is to present a system designers approach. We highlight, through the work carried out by our team in recent years, the potential, but also the difficulties, of structuring an assisted design flow for synthetic biology. For this task, our idea is to build the design flow for synthetic biology on the foundations of the Electronic Design Automation tools that have proven their efficiency during the past 30 years. Although the overall approach of the microelectronics can be adapted to synthetic biology, some specific steps have to be created from scratch.