Application to synthetic biology of CAD methods

Synthetic biology is an emerging science whose objective is to create new biological functions, still nonexistent in nature, from the knowledge of living things acquired over the last century. Until recently, artificial synthetic biological systems were of reasonable complexity. This is no longer the case today, which has led to the development of much computer-aided design software. One of the ways allowing the rapid and efficient development of this software is the adaptation of tools already existing in different fields of engineering, and in particular microelectronics.

Biological systems

Beyond the similarities that we can find in design approaches, electronics and biology also come close in the way of describing systems. At a high level of abstraction, a biological system can be represented as a network of interactions where the production, or not, of each chemical molecule can be controlled by the presence, or absence, of other molecules. The system described is a genetic regulation network (or RGN for gene regulatory network), a two-state memory which corresponds to one of the first artificial biological circuits produced in 2000 by Gardner. The operation of the system can be summarized by the following logical propositions:

- GFP (green fluorescent protein) is only synthesized if the P1 promoter is active.

- The transcription factor R2 is only synthesized if the promoter P1 is active.

- The transcription factor R1 is only synthesized if the promoter P2 is active.

- The P1 promoter is active if the transcription factor (repressor) R1 is absent or if it is present but itself inhibited by I1.

- The P2 promoter is active if the transcription factor (repressor) R2 is absent or if it is present but itself inhibited by I2.

CAD software for systems biology and synthetic biology

The needs of computer-aided design (CAD) tools for synthetic biology were expressed very early in the genesis of this new science. Since the middle of the last decade, many CAD tools for systems biology and for synthetic biology have emerged. We can classify them into three main categories, tools used to describe biological systems, simulation tools, and tools to assist in the design or its automation.

First of all, it is important to be able to describe a biological system in a unique way, usable by software and understandable by a user. In recent years, the system biology markup language (SBML) has established itself as a standard. SBML is, in fact, used today by more than 200 tools and, first of all, those which are used for the graphic description of biological systems. Virtual Cell is an example. This software platform makes it possible to draw complex biological networks by defining sections, chemical species interacting in these compartments, and the equations of the speed of the reactions involved, then to generate an SBML file that corresponds to this graph. SBML is also a language used as a domain sharing standard for many databases such as BioModel, which groups mathematical models of biological interest.

With regard to CAD for synthetic biology, several tools have also been developed. GenoCAD is one of the pioneers. It offers a graphical interface allowing the design of protein expression vectors and artificial gene networks. Internally, it is based on a formal language allowing easily describing and manipulating genetic circuits. In GenoCAD, the user manipulates known parts take out from a library and assembles them manually until the desired result is obtained. The automation step should predict the assembly to be performed directly from the function that one wants to achieve. This step can be carried out using certain software, for example, BioJADE , but more often than not, it confines itself to the high-level (i.e., Boolean) description of the systems.

Among the most complete and successful CAD software, we can also mention TASBE (tool chain to accelerate synthetic biology engineering project) which is a software suite composed of a language used to describe a high-level biological function (Proto). This a tool to transform this description in a gene regulatory network abstract ( BioCompiler ). This tool is used for positioning on this genetic network shares (Matchmaker), and an assembly tool making it possible to directly give the DNA sequence to be synthesized corresponding to this genetic regulation network. The Cello software suite is an equivalent of TASBE. It also makes it possible to synthesize genetic regulatory networks (GRN) from a Boolean description through different stages, some sharing the same tools as TASBE.

Discussion and conclusion

The global design approach of synthetic biology, as well as the specific works described in this review shows the advantage of transferring certain tools and certain CAD methodologies from microelectronics. However, CAD is not the only key to success. What has enabled the development of microelectronics, from the early 1970s to the present day, is a subtle combination of three main ingredients: high-performance CAD tools, circuit development, and circuit manufacturing processes integrated standard, reliable and low cost, and a strong economic model constantly pushing the limits of performance. Today, despite the incredible advances in biotechnology in recent years,

If the potential for applications of synthetic biology is strong, in particular in fields with great economic power (therapeutics, environment, etc.), the transfer of technologies from university circles to industry is still rare and difficult. Jay Keasling's research work on artemisinin, whose patent has been used by Sanofi since 2013, is an exception. The main obstacle to this transfer is the cost and unreliability of the manufacturing processes. This is the main weakness in which synthetic biology will have to progress in the years to come. The absence of standard methods for manufacturing biological circuits is also an obstacle to the democratization of these technologies. Today, to develop new systems in synthetic biology, it is necessary to have heavy material resources and a team mastering all aspects, from their in silico design to their realization in vivoby integrating all the test phases. Electronics have succeeded, through a number of standards, in separating these trades, and, today, a team of engineers can design an integrated circuit using CAD tools without having any idea. The way in which it will be carried out thereafter: the practical realization of the circuit will be entrusted to a subcontractor who will work from data files provided by the CAD software.

Author: Vicki Lezama