Ratiometric control for differentiation of cell populations endowed with synthetic toggle switches

We consider the problem of regulating by means of external control inputs the ratio of two cell populations. Specifically, we assume that these two cellular populations are composed of cells belonging to the same strain which embeds some bistable memory mechanism, e.g. a genetic toggle switch, allowing them to switch role from one population to another in response to some inputs. We present three control strategies to regulate the populations' ratio to arbitrary desired values which take also into account realistic physical and technological constraints occurring in experimental microfluidic platforms. The designed controllers are then validated in-silico using stochastic agent-based simulations.Comment: Accepted to CDC'201

Analysis and Control of Bacterial Populations in Synthetic Biology

Synthetic Biology is a new field of research that aims at engineering new functionalities in living beings. Analogously to electronic circuits, more advanced functionalities can be realised by putting together smaller functional modules that perform elementary tasks; however, the interaction of these basic pieces is somewhat complex and fragile. Therefore, to increase the robustness and reliability of the whole system, typical tools from Control Theory, such as feedback loops, can be employed. In the first part of this thesis we propose feedback control strategies to balance the gene expression of a bistable genetic circuit, known as genetic toggle switch, in an unstable region far away from its stable equilibria - a problem analogous to the stabilization of the inverted pendulum in mechanics. The effectiveness of the proposed control strategies is validated via realistic agent-based simulations of a bacterial population endowed with the genetic toggle switch. Later in the thesis we move towards the growth control of bacterial cells in bioreactors, introducing a novel open-source and versatile design of a turbidostat to host in vivo control experiments. In the last part, we want to control bioreactors to guarantee the coexistence of multiple species in the same environment. We analyse the dynamics of a simple one-chamber bioreactor, proposing control strategies to achieve the control goal. However, simple bioreactors have several drawback when the concentrations of multiple species are regulated at the same time; for these reason, we propose a novel layout for a bioreactor, with two growth chambers and a mixing one, to be used in multicellular in vivo control experiments

Design and analysis of genetic feedback architectures for synthetic biology

Synthetic Biology seeks to design and assemble novel biological systems with favourable properties. It allows us to comprehend and modify the fundamental mechanisms of life and holds significant promise in revolutionizing current technologies ranging from medicine and biomanufacturing to energy and environmental protection. Biological processes constitute remarkably complex dynamical systems operating impeccably well in messy and constantly changing environments. Their ability to do so is rooted in sophisticated molecular control architectures crafted by natural evolutionary innovation over billions of years. Such control architectures, often blended with human-engineering approaches, are the key to realizing efficient and reliable synthetic biological systems. Aiming to accelerate the development of the latter, the present thesis addresses some fundamental challenges in biomolecular systems and control design. We begin by elucidating biological mechanisms of temporal gradient computation, enabling cells to adjust their behaviour in response to anticipated environmental changes. Specifically, we introduce biomolecular motifs capable of functioning as highly tunable and accurate signal differentiators to input molecular signals around their nominal operation. We investigate strategies to deal with high-frequency input signal components which can be detrimental to the performance of most differentiators. We ascertain the occurrence of such motifs in natural regulatory networks and demonstrate the potential of synthetic experimental realizations. Our motifs can serve as reliable speed biosensors and can form the basis for derivative feedback control. Motivated by the pervasiveness of Proportional-Integral-Derivative (PID) controllers in modern technological applications, we present the realization of a PID controller via biomolecular reactions employing, among others, our differentiator motifs. This biomolecular architecture represents a PID control law with set point weighting and filtered derivative action, offering robust regulation of a single-output biological process with enhanced dynamic performance and low levels of stochastic noise. It is characterized by significant ease of tuning and can be of particular experimental interest in molecular programming applications. Finally, we investigate efficient regulation strategies for multi-output biological processes with internal coupling interactions, expanding previously established single-output control approaches. More specifically, we propose control schemes allowing for robust manipulation of the outputs in various ways, namely manipulation of their product/ratio, linear combinations of them as well as manipulation of each of the outputs independently. Our analysis is centered around two-output biological processes, yet the scalability of the proposed regulation strategies to processes with a higher number of outputs is highlighted. In parallel, their experimental implementability is explored in both in vivo and in vitro settings

Advances in Grid Computing

This book approaches the grid computing with a perspective on the latest achievements in the field, providing an insight into the current research trends and advances, and presenting a large range of innovative research papers. The topics covered in this book include resource and data management, grid architectures and development, and grid-enabled applications. New ideas employing heuristic methods from swarm intelligence or genetic algorithm and quantum encryption are considered in order to explain two main aspects of grid computing: resource management and data management. The book addresses also some aspects of grid computing that regard architecture and development, and includes a diverse range of applications for grid computing, including possible human grid computing system, simulation of the fusion reaction, ubiquitous healthcare service provisioning and complex water systems

Using MapReduce Streaming for Distributed Life Simulation on the Cloud

Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp