Engineering scalable biological systems

Abstract

Synthetic biology is focused on engineering biological organisms to study natural systems and to provide new solutions for pressing medical, industrial and environmental problems. At the core of engineered organisms are synthetic biological circuits that execute the tasks of sensing inputs, processing logic and performing output functions. In the last decade, significant progress has been made in developing basic designs for a wide range of biological circuits in bacteria, yeast and mammalian systems. However, significant challenges in the construction, probing, modulation and debugging of synthetic biological systems must be addressed in order to achieve scalable higher-complexity biological circuits. Furthermore, concomitant efforts to evaluate the safety and biocontainment of engineered organisms and address public and regulatory concerns will be necessary to ensure that technological advances are translated into real-world solutions.

Keywords: biological circuits; biological modulators; biological probes; engineered organisms; high-throughput design; modelling; regulatory issues; synthetic biology.

Figure 1

A basic design cycle for synthetic biology includes creating well-characterized parts (e.g., regulatory elements, genes, proteins, RNAs), constructing synthetic devices and modules and designing and assembling higher-order networks. All steps of this cycle are aided by modelling, probes and modulators to analyze circuit performance. Debugging is an iterative process based on parts optimization, fine-tuning regulatory components, modelling and changing circuit architecture.

Figure 2

DNA sequencing and synthesis technologies are advancing at exponential rates, outpacing the ability of synthetic biologists to construct useful and scalable biological circuits. These trends are similar to Moore's law for integrated circuits and suggest that there is substantial room for growth in the field of synthetic circuits.

Figure 3

Combinatorial high-throughput methods will be useful in the assembly of well-characterized libraries of synthetic parts and devices. For example, transcriptional regulators and their cognate inducers can be analyzed for (A) single-component performance, (B) interactions between multiple components and (C) inducer crosstalk (e.g., cross-activation and/or cross-inhibition).

Figure 4

Control theory techniques for modelling synthetic biological circuits. (A) Small-signal linearization of biological components in different regions of operation enables the development of linear models. (B) Linearization can enable frequency-domain analysis, systems modelling using block diagrams and deeper insights into system dynamics. For example, transcription and translation can be understood as low-pass filters and block diagrams can be drawn for simple negative-feedback loops to yield understanding into system interconnections and responses to different input types., In the block diagram shown, s refers to jω where j is √−1 and ω is angular frequency.