Computer-aided design of biological circuits using TinkerCell

Abstract

Synthetic biology is an engineering discipline that builds on modeling practices from systems biology and wet-lab techniques from genetic engineering. As synthetic biology advances, efficient procedures will be developed that will allow a synthetic biologist to design, analyze, and build biological networks. In this idealized pipeline, computer-aided design (CAD) is a necessary component. The role of a CAD application would be to allow efficient transition from a general design to a final product. TinkerCell is a design tool for serving this purpose in synthetic biology. In TinkerCell, users build biological networks using biological parts and modules. The network can be analyzed using one of several functions provided by TinkerCell or custom programs from third-party sources. Since best practices for modeling and constructing synthetic biology networks have not yet been established, TinkerCell is designed as a flexible and extensible application that can adjust itself to changes in the field.

Keywords: CAD; computational; design; modeling; simulation; software; standards; synthetic biology; systems biology.

Figure 1

A screenshot of TinkerCell, showing a simple model of lactose import. The bacterial cell in the model contains a plasmid with a promoter, RBS and a coding region. The protein produced from the coding region is the membrane protein that is responsible for importing lactose, which in turn inhibits the transcription factor, LacI. LacI negatively regulates the promoter on the plasmid.

Figure 2

TinkerCell uses a catalog of biological components for constructing models. Each component in the catalog belongs to an ontology, which is transparent to the user. Models that are built using components in the catalog will contain the mathematical descriptions as well as the biological descriptions.

Figure 3

The model summary window is an interface that allows the user to view and edit any of the parameters in the model. The window shows the parameters according to the component that they belong with, e.g., a promoter's strength parameter.

Figure 4

This figure shows the control coefficients of different fluxes in an incoherent feed-forward network on the steady state value of the second protein (p2 in the Figure). The control coefficients are computed using PySCeS. The output from PySCeS is displayed visually: the reaction arcs are colored green for positive control coefficients and red for negative and the line widths are also adjusted according to the control coefficients. This example illustrates how Python scripts in TinkerCell can produce visual outputs.

Figure 5

TinkerCell integrates third-party functions written in Python and C with its user interface. Python programs and C programs are loaded from designated folders and made available as buttons in TinkerCell, as shown in this figure. In future, TinkerCell will also support programs written in other languages such as Ruby, R and Perl.

Figure 6

TinkerCell is extensible at different layers. The bottom-most layer is a Core library that provides all the basic drawing functions. The C⁺⁺ extensions form a second-layer. These extensions provide the modeling framework and various use interface features. A C programmer interface is built on the C⁺⁺ extensions and the Core library, providing over two hundred functions that can be used to add new C extensions. Each C function is extended to higher level languages such as Python, allowing Python extensions. The right-hand side of the figure lists some example features that are provided by each layer.

Figure 7

This figure shows three modules connected to form a larger circuit. The internal details of each module are hidden from view to provide the user with a concise view diagram, which can often provide a clearer conceptual understanding of the circuit. The internal details of each module still can be viewed and changed in a separate window, as shown at the right-hand side of the figure. One of the future plans of TinkerCell is to allow users to upload and download modules from a central repository. When that feature is complete, this interface can be used to construct circuits using other researchers' modules.

Figure 8

Integrating the Synthetic Biology Open Language semantic standards with TinkerCell will allow users to design circuits in TinkerCell and query local and remote databases for biological parts that are suitable for the design. The user would only interact via TinkerCell; standard exchange formats will make the database queries transparent to the user. The different components required to complete this process are under development at present.

Figure 9

Some of the tools in TinkerCell, such as sliders, allows users to interactively study the effects of parameters on the dynamic behavior of a circuit. Such interactive features can be useful as educational tools. The figure shows a genetic network that behaves like an OR gate. The sliders can be used to show how the different parameters affect the threshold, steepness and height of the curve.