Program

Programming Languages for Molecular and Genetic Devices

Computational nucleic acid devices show great potential for enabling a broad range of biotechnology applications, including smart probes for molecular biology research, in vitro assembly of complex compounds, high-precision in vitro disease diagnosis and, ultimately, computational theranostics inside living cells. This diversity of applications is supported by a range of implementation strategies, including nucleic acid strand displacement, localisation to substrates, and the use of enzymes with polymerase, nickase and exonuclease functionality. However, existing computational design tools are unable to account for these different strategies in a unified manner. This talk presents a programming language that allows a broad range of computational nucleic acid systems to be designed and analysed. We also demonstrate how similar approaches can be incorporated into a programming language for designing genetic devices that are inserted into cells to reprogram their behaviour. The language is used to characterise the genetic components for programming populations of cells that communicate and self-organise into spatial patterns. More generally, we anticipate that languages and software for programming molecular and genetic devices will accelerate the development of future biotechnology applications.

What time is it?

Even without looking at a watch, we have an inner feeling for time. How do we measure time? Our body, in particular each of our cells has an inner clock enabling all our rhythmic biological activities like sleeping. Astonishingly, prokaryotic cyanobacteria, which can divide faster than ones a day, also use an inner timing system to foresee the accompanying daily changes of light and temperature and regulate their physiology and behavior in 24-hour cycles. Their underlying biochemical oscillator fulfills all criteria of a true circadian clock though it is made of solely three proteins. It ticks with a robust 24-hour period even under fluctuating or continuous conditions. Nevertheless, it can be entrained by light, temperature or nutrients. Reconstituted from the purified protein components, KaiC, KaiB, and KaiA, the cyanobacterial protein clock can tick autonomously in a test tube for weeks. This apparent simplicity has proven to be an ideal system for answering questions about information transfer and robustness of circadian clocks.

Computational modeling identified various aspects of this interesting system like nested feedback loops, period robustness against noise and seemingly conflicting synchronisation with the environment.

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Biomolecular Control Systems

Humans have been influencing the DNA of plants and animals for thousands of years through selective breeding. Yet it is only over the last three decades or so that we have gained the ability to manipulate the DNA itself and directly alter its sequences through the modern tools of genetic engineering. This has revolutionized biotechnology and ushered in the era of synthetic biology. It has also made it conceivable for the first time to engineer into living cells genetic feedback control systems that automatically monitor and steer the cell’s dynamic behavior. To realize the huge promise of such systems, new theory and methodologies are needed for designing controllers that function in the special and challenging environment of the cell. We refer to the resulting technology as Cybergenetics—a modern realization of Norbert Wiener’s Cybernetics vision.
Here I will present our theoretical framework for the design and synthesis of cybergenetic systems and discuss the main challenges in their implementation. I will then introduce the first designer gene network that attains integral feedback in a living cell and will demonstrate its tunability and disturbance rejection properties. A growth control application shows the inherent capacity of this genetic control system to deliver robustness and highlights its potential use as a universal controller for regulation of biological variables in arbitrary networks. I will end by exploring the potential impact of Cybergenetics in industrial biotechnology and medical therapy.

Modelling Biomimetic Structures and Machinery Using DNA

Nucleic acids, archetypal biomolecules, can be used to model and study natural biomolecular assembly processes and the operation of molecular machinery. The programmability of DNA and RNA base pairing has enabled the creation of a very wide range of synthetic nanostructures through control of the interactions between molecular components. More sophisticated design techniques allow control of the kinetics as well as the thermodynamics of these interactions, creating the potential to study and control assembly pathways and allowing the construction of both dynamic systems that process information and of biomimetic molecular machinery. Techniques of simulation and verification are important in understanding and designing these increasingly complex systems. I shall present a broad review of the rapidly developing research field of dynamic DNA nanotechnology, with particular emphasis on our use of a combination of experimental synthesis and computation to study DNA origami assembly pathways, kinetic control of strand displacement reactions, synthetic molecular motors, and molecular machinery for the creation of sequence-controlled polymers.

A Standard-Enabled Workflow for Synthetic Biology

A synthetic biology workflow is composed of data repositories that provide information about genetic parts, sequence-level design tools to compose these parts into circuits, visualization tools to depict these designs, genetic design tools to select parts to create systems, and modeling and simulation tools to evaluate alternative design choices. Data standards enable the ready exchange of information within such a workflow, allowing repositories and tools to be connected from a diversity of sources. This talk describes one such workflow that utilizes the growing ecosystem of software tools that support the Synthetic Biology Open Language (SBOL) to describe genetic designs, and the mature ecosystem of tools that support the Systems Biology Markup Language (SBML) to model these designs. In particular, this presentation will demonstrate a workflow using tools including SynBioHub, SBOLDesigner, and iBioSim. SynBioHub (http://synbiohub.org) is a database designed for storing synthetic biology designs captured using the SBOL data model, and it provides both a RESTful API for computational access and a user-friendly Web-based frontend. SBOLDesigner is a sequence editor that allows the designer to fetch parts from a SynBioHub repository and compose them to construct larger designs. Finally, iBioSim is genetic modeling, analysis, and design tool that provides a means to construct SBML models for these designs that can be simulated and analyzed using a variety of techniques. Both SBOLDesigner and iBioSim also support uploading these larger system designs back to the SynBioHub repository. Finally, this talk will demonstrate how this workflow can be utilized to produce a complete record of a genetic design facilitating reproducibility and reuse.

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