Tasks Makyth Models: Machine Learning Assisted Surrogates for Tipping Points

We present a machine learning (ML)-assisted framework bridging manifold learning, neural networks, Gaussian processes, and Equation-Free multiscale modeling, for (a) detecting tipping points in the emergent behavior of complex systems, and (b) characterizing probabilities of rare events (here, catastrophic shifts) near them. Our illustrative example is an event-driven, stochastic agent-based model (ABM) describing the mimetic behavior of traders in a simple financial market. Given high-dimensional spatiotemporal data -- generated by the stochastic ABM -- we construct reduced-order models for the emergent dynamics at different scales: (a) mesoscopic Integro-Partial Differential Equations (IPDEs); and (b) mean-field-type Stochastic Differential Equations (SDEs) embedded in a low-dimensional latent space, targeted to the neighborhood of the tipping point. We contrast the uses of the different models and the effort involved in learning them.Comment: 29 pages, 8 figures, 6 table

Advances in colloidal manipulation and transport via hydrodynamic interactions

In this review article, we highlight many recent advances in the field of micromanipulation of colloidal particles using hydrodynamic interactions (HIs), namely solvent mediated long-range interactions. At the micrsocale, the hydrodynamic laws are time reversible and the flow becomes laminar, features that allow precise manipulation and control of colloidal matter. We focus on different strategies where externally operated microstructures generate local flow fields that induce the advection and motion of the surrounding components. In addition, we review cases where the induced flow gives rise to hydrodynamic bound states that may synchronize during the process, a phenomenon essential in different systems such as those that exhibit self-assembly and swarming

Molecular Modeling of Bacterial Nanomachineries

Proteins have the ability to assemble in multimeric states to perform their specific biological function. Unfortunately, characterizing experimentally these structures at atomistic resolution is usually difficult. For this reason, in silico methodologies aiming at predicting how multiple protein copies arrange to forma multimeric complex would be desirable. We present Parallel OptimizationWorkbench (POW), a swarm intelligence based optimization framework able to deal, in principle, with any optimization problem. We show that POW can be applied to biologically relevant problems such as prediction of protein assemblies and the parameterization of a Coarse-Grained force field for proteins. By combining POW optimizations, Molecular Dynamics simulations, Poisson-Boltzmann calculations and a variety of experiments, we subsequently study two bacterial nanomachieries: Aeromonas hydrophila's pore-forming toxin aerolysin, and Yersinia enterocolitica injectisome. These structures are challenging both for their size, and for the timescales involved in their functioning. Aerolysin is a pore-forming toxin secreted as an hydrophilic monomer. By means of large conformational changes, the protein heptamerizes on the target cell's surface, and finally inserts β-barrel into its lipid bilayer, causing cell death. The main hurdle in the study of this structure is the complexity of the mode of action, which spans timescales currently unreachable by classical molecular dynamics. We show that aerolysin C-terminal region has the dual role of preventing premature oligomerization and helping the folding of tertiary structure, qualifying therefore as an intramolecular chaperone. We study the transmembrane β-barrel properties and compare them with those of the homologous protein α-hemolysin. We show that aerolysin's barrel is more rigid than α-hemolysin's, and should be anion selective. We present models for aerolysin heptamer both in prepore and, for the first time, in membrane-inserted conformation. Our results are validated experimentally, and are consistent with known biochemical and structural data. The injectisome is an example of a type III secretion system. Its most striking feature is probably its size: hundreds of proteins assemble in a unique structure spanning the Gram-negative bacterial double membrane, and protruding outside the cell as a needle for tenth of nanometers. Obtaining an atomistic representation of this massive structure, and therefore some insights about its mode of action, is one of the greatest challenges. We show that the final length of injectisome's needle is determined by the secondary structure content of a ruler protein located inside its cavity during assembly. Using POW, we also produce the first model for Yersinia injectisome's basal body, highlighting the flexibility of this region in adapting between the inner and outer membranes. As a whole, this work demonstrates that a synergy of dry and wet experiments can provide precious insights into macromolecular structure and function

From single-cell migration to the emergence of collective motion using microstructured surfaces

Cell migration is a fundamental process that is essential for the development, maintenance, and functionality of multicellular organisms. A detailed understanding of the underlying mechanisms and phenomenological characteristics of cell migration is hence of central interest in life sciences. However, the bio-mechanical machinery propelling the cell is highly complex and its emergent migration patterns are difficult to grasp, even in the case of individually migrating cells. Additionally, at the scale of multi-cellular assemblies, interaction mechanisms that are not entirely understood result in long-ranged correlations and a rich set of collective phenomena in cell motion. A possible approach to break down this complexity is to restrict cell adhesion and migration to predefined areas by using micropatterning techniques. By choosing suitable pattern geometries, the degrees of freedom of the confined cells can be diminished so that specific features of cell migration can be addressed and studied selectively. Furthermore, micropatterning techniques allow to create large arrays of standardized microenvironments, thereby enabling the automated analysis of multiple experimental systems in parallel. In the course of this work, micropatterning techniques were developed and employed to systematically study single-cell migration and the emergence of collective motion in small cell assemblies. The developed micropatterning technique termed “microscale plasma-induced protein patterning” (µPIPP) is easy to implement and produces homogeneous protein patterns on various biocompatible substrates such as glass, tissue culture polystyrene, cyclic olefin copolymers, and parylene C. Moreover, the _PIPP protocol was extended to enable the formation of surface-bound protein gradients as well as of pattern designs featuring multiple proteins. Utilizing the controlled environment provided by micropatterning, we studied single-cell migration within arrays of ring-shaped microlanes. In contrast to conventional descriptions of cell migration, the resulting quasi-one-dimensional motion showed pronounced bimodality, exhibiting states of directionally persistent migration (“run states”) as well as states of localized erratic motion (“rest states”). Applying a change-point analysis based on cumulative sum statistics, the lifetimes of both states were identified to be exponentially distributed. The corresponding characteristic persistence times together with the cell velocity in the run state provided a set of parameters characterizing cell motion. By introducing cell-repellent barriers of different width into the setup, this parameter set was extended by quantifying the turning probability both in the presence and in the absence of chemical barriers. Similar to a migrational “fingerprint”, these five phenomenological measures were used to thoroughly quantify and compare the migration behavior of different cell types as well as the effect of different pharmaceutics. The corresponding results illustrate that micropattern-based assays in combination with detailed, multi-parameter assessment of cell motion have potential applications in cell biology as well as in sophisticated drug screening. In a second assay, the emergence of collective behavior in the motion of small cell assemblies was studied. As pattern geometry, we chose circles of different diameters, in which collective migration manifests in form of a coherent angular motion (CAMo) of the confined cells. Analyzing the dynamics in dependence on the number of cells, N, within a system, periods of CAMo as well as periods of disordered motion (DisMo) were identified. Both states showed exponential lifetime distributions. The persistence of CAMo was found to increase with N but exhibited a pronounced discontinuity between systems containing four and systems containing five cells. An assessment of the cell conformations within the patterns revealed that this discontinuity was accompanied by a geometric rearrangement of cells towards a configuration containing a central cell. Numerical simulations, which are based on the cellular Potts model and account for intracellular polarization as well as intercellular coupling via mechanotransduction, reproduced these features and hence confirmed our finding that the persistence of rotational states depends on the interplay of spatial arrangement and internal polarization of neighboring cells. The distinct migration states within confined environments hence provides significant insights into the local interaction rules guiding collective migration. Taken together, the results of this thesis shed new light on the process of cell migration and illustrate how the controlled and standardized microenvironments provided by micropatterning techniques can be used to systematically assess and examine cell migration on a quantitative basis. Furthermore, the introduced techniques and assays are a step towards establishing micropatterning as a standard tool for cell science.Zellmigration ist ein essenzieller Prozess in der Entwicklung und Erhaltung vielzelliger Organismen. Ein tiefgreifendes Verständnis der involvierten Mechanismen und phänomenologischen Charakteristika ist folglich von zentralem Interesse für die Zellforschung. Allerdings ist die involvierte Maschinerie komplex, was sich in Bewegungsmustern wiederspiegelt, die schon für vereinzelte Zellen schwer zu fassen sind. Zusätzlich führen auf der Skala größerer Zellansammlungen Interaktionsmechanismen, deren genaue Funktionsweise noch nicht geklärt ist, zu langreichweitigen Korrelationen und vielfältigen kollektiven Phänomenen in den Bewegungsmustern. Eine Möglichkeit diese Komplexität im Experiment herunterzubrechen bietet die räumliche Begrenzung der Migration durch Mikrostrukturierung. Durch die Wahl geeigneter Strukturgeometrien können auf diese Weise die Freiheitsgrade der Zellen so eingeschränkt werden, dass spezifische Merkmale der Zellmigration gezielt adressiert und untersucht werden können. Zusätzlich können mit geeigneten Techniken weite Oberflächenbereiche strukturiert werden, was die automatisierte und parallelisierte Auswertung großer Anzahlen standardisierter Einzelexperimente ermöglicht. Im Zuge dieser Arbeit wurden daher neue Verfahren zur Mikrostrukturierung entwickelt und verwendet, um Einzelzellmigration wie auch die Interaktion kleiner Zellgruppen systematisch zu untersuchen. Die hier entwickelte Mikrostrukturierungsmethode, genannt “microscale plasma-induced protein patterning” (µPIPP), ist einfach in der Anwendung und produziert homogene Proteinstrukturen auf verschiedenen biokompatiblen Oberflächen wie Glas, Zellkultur Polystyrol, Cyclo-Olefin-Copolymeren, und Parylen C. Darüber hinaus wurde das µPIPP-Protokoll erweitert, um die Generierung von oberflächengebundenen Proteingradienten sowie Strukturen bestehend aus mehreren Proteinkomponenten zu ermöglichen. Um das Migrationsverhalten von Einzelzellen zu untersuchen, wurden ringförmige Mikrostrukturen verwendet. Im Kontrast zu klassischen Beschreibungen der Zellmigration zeigte die quasi-eindimensionale Bewegung der Zellen in diesen Systemen ausgeprägte Bimodalität, alternierend zwischen Phasen persistenter Migration und Phasen der Zufallsbewegung. Durch Einführung eines Algorithmus’ zum Erfassen charakteristischer Änderungen im Migrationsverhalten wurden die typischen Lebensdauern beider Zustände bestimmt. Zusammen mit der Zellgeschwindigkeit im persistenten Zustand ergaben diese einen charakteristischen Parametersatz um das Bewegungsverhalten einer Zelle zu beschreiben. Durch das Einbinden einer zellabweisenden Barriere in das System wurde dieser noch um die Umkehrwahrscheinlichkeiten in Abwesenheit und Anwesenheit chemischer Grenzflächen erweitert. Zusammengenommen wurden diese fünf Parametern gleich einem Fingerabdruck des Migrationsverhaltens einer Zelle verwendet, um die Bewegungsmuster von Zelltypen verschiedener Invasivität und den Effekt verschiedener Pharmazeutika auf diese detailliert zu charakterisieren und zu quantifizieren. Die verwendete Untersuchungsmethode gibt somit ein umfassendes Bild des Migrationsverhaltens von Einzelzellen und hat zudem Potential im Hinblick auf die Entwicklung eines Standardverfahrens zur vergleichenden Analyse von Zellmotilität in Zellbiologie und Pharmakologie. In einer zweiten Versuchsanordnung wurde das Auftreten kollektiven Verhaltens in der Migration kleiner Zellgruppen untersucht. Hierfür wurden kreisförmige Mikrostrukturen von verschiedenem Durchmesser eingesetzt, in welchen kollektive Bewegung in der Form kohärenter Rotation aller Zellen innerhalb einer Kreisstruktur auftritt. Die Zellbewegung innerhalb der Systeme wurden in Abhängigkeit der enthaltenen Zellenanzahl untersucht, wobei immer sowohl Phasen kohärenter Rotation als auch Phasen ungeordneter Bewegung zu beobachten waren. Die Persistenz der Rotationszustände stieg dabei zwar generell mit steigender Zellenzahl an, dieser Trend wurde jedoch durch einen starken Abfall der Persistenz zwischen Systemen mit vier und Systemen mit fünf Zellen unterbrochen. Das Auslesen der relativen Zellpositionen innerhalb der Einzelsysteme zeigte, dass dieser Abfall mit einer Veränderung der Zellkonformation einherging. Numerische Simulationen basierend auf dem zellulären Potts- Modell, welche sowohl intrazelluläre Polarisation als auch interzelluläre Koppelung durch Mechanotransduktion berücksichtigen, reproduzierten diese Ergebnisse und lassen somit den Schluss zu, dass das Wechselspiel von relativer räumlicher Anordnung und der Ausrichtung der internen Polarisationsachsen benachbarter Zellen die Lebensdauer kollektiver Rotationszustande in der Zellmigration bestimmt. Die Untersuchung der verschiedenen Bewegungszustände innerhalb derMikrostrukturen gibt somit Einblick in die, der kollektiven Zellbewegung zugrundeliegenden, Interaktionsmuster. Zusammengefasst liefern die Ergebnisse dieser Arbeit somit tiefere Erkenntnis über den Prozess der Zellmigration und stellen einen weiteren Schritt dar, Mikrostrukturierung als Standardverfahren zur Analyse und Quantifizierung von Zellbewegung zu etablieren

Towards cellular hydrodynamics: collective migration in artificial microstructures

The collective migration of cells governs many biological processes, including embryonic development, wound healing and cancer progression. Observed phenomena are not simply the sum of the individual motion of many isolated cells, but rather emerge as a consequence of their interactions. The movements in epithelial cell sheets display rich phenomenology, such as the occurrence of vortices spanning several cell diameters and the transition from fluid-like behavior at low densities to glass-like behavior at high densities. In this thesis, collective invasion of epithelial cell sheets into microchannels was studied on a phenomenological level within the scope of theoretical approaches to active fluids. In a first project, the motion profile of a cell layer in straight channels was investigated using single cell tracking and particle image velocimetry (PIV) on timelapse microscopy data. A defined plug-flow like velocity profile was observed across the channels. The cell density profile is well-described by the Fisher-Kolmogorov reaction-diffusion equation, which includes active migration and the contribution of proliferation. This study revealed a change in the short scale noise behavior in the presence of this global invasion into a channel. For a closer look at the system’s proliferation component, the effect of an underlying global migration direction on the orientation of the cells’ division axes was examined. We found strong alignment of the axes’ orientation with the imposed movement direction. Specifically, the strongest correlations were observed between the orientation of the cells’ division axes and the local strain rate tensor’s main axis. This is in agreement with the notion that stresses in the migrating cell sheet orient the cell divisions. Expanding the assay of invasion into straight channels, we introduced a constriction, which the cell sheet needs to pass through in order to progress. A plateau of low velocities was observed in the region ahead of the constriction, which was attributed to an increase in local cell density accompanied by jamming. These results were compared to an active isotropic-nematic mixture model. The suitability of this model to describe this assay could be ruled out, however, as it showed qualitatively very different behavior than the experiments. Finally, the frequency of topological nearest-neighbor T1 transitions within a cell sheet was investigated in minimal model systems. In order to study the smallest possible fundamental unit for such transitions, groups of four cells were confined to cloverleaf patterns, which could be shown to inhibit the onset of collective rotation states. Results showed that T1 transitions occurred more frequently for groups of cells with a lower average length of the cell-cell junction that shrinks in the process of this transition. These results are consistent with the notion that the energy barrier which needs to be overcome by the cells in order to perform this transition, scales with the original length of the shrinking junction. Taken together, the results of this thesis contribute to a better understanding of the flow fields for collective cell migration processes in confined geometries. In addition to the insights the phenomenological observations in this work could provide directly, they will also continue to prove useful as a standard for validating detailed theoretical models

From single-cell migration to the emergence of collective motion using microstructured surfaces

Cell migration is a fundamental process that is essential for the development, maintenance, and functionality of multicellular organisms. A detailed understanding of the underlying mechanisms and phenomenological characteristics of cell migration is hence of central interest in life sciences. However, the bio-mechanical machinery propelling the cell is highly complex and its emergent migration patterns are difficult to grasp, even in the case of individually migrating cells. Additionally, at the scale of multi-cellular assemblies, interaction mechanisms that are not entirely understood result in long-ranged correlations and a rich set of collective phenomena in cell motion. A possible approach to break down this complexity is to restrict cell adhesion and migration to predefined areas by using micropatterning techniques. By choosing suitable pattern geometries, the degrees of freedom of the confined cells can be diminished so that specific features of cell migration can be addressed and studied selectively. Furthermore, micropatterning techniques allow to create large arrays of standardized microenvironments, thereby enabling the automated analysis of multiple experimental systems in parallel. In the course of this work, micropatterning techniques were developed and employed to systematically study single-cell migration and the emergence of collective motion in small cell assemblies. The developed micropatterning technique termed “microscale plasma-induced protein patterning” (µPIPP) is easy to implement and produces homogeneous protein patterns on various biocompatible substrates such as glass, tissue culture polystyrene, cyclic olefin copolymers, and parylene C. Moreover, the _PIPP protocol was extended to enable the formation of surface-bound protein gradients as well as of pattern designs featuring multiple proteins. Utilizing the controlled environment provided by micropatterning, we studied single-cell migration within arrays of ring-shaped microlanes. In contrast to conventional descriptions of cell migration, the resulting quasi-one-dimensional motion showed pronounced bimodality, exhibiting states of directionally persistent migration (“run states”) as well as states of localized erratic motion (“rest states”). Applying a change-point analysis based on cumulative sum statistics, the lifetimes of both states were identified to be exponentially distributed. The corresponding characteristic persistence times together with the cell velocity in the run state provided a set of parameters characterizing cell motion. By introducing cell-repellent barriers of different width into the setup, this parameter set was extended by quantifying the turning probability both in the presence and in the absence of chemical barriers. Similar to a migrational “fingerprint”, these five phenomenological measures were used to thoroughly quantify and compare the migration behavior of different cell types as well as the effect of different pharmaceutics. The corresponding results illustrate that micropattern-based assays in combination with detailed, multi-parameter assessment of cell motion have potential applications in cell biology as well as in sophisticated drug screening. In a second assay, the emergence of collective behavior in the motion of small cell assemblies was studied. As pattern geometry, we chose circles of different diameters, in which collective migration manifests in form of a coherent angular motion (CAMo) of the confined cells. Analyzing the dynamics in dependence on the number of cells, N, within a system, periods of CAMo as well as periods of disordered motion (DisMo) were identified. Both states showed exponential lifetime distributions. The persistence of CAMo was found to increase with N but exhibited a pronounced discontinuity between systems containing four and systems containing five cells. An assessment of the cell conformations within the patterns revealed that this discontinuity was accompanied by a geometric rearrangement of cells towards a configuration containing a central cell. Numerical simulations, which are based on the cellular Potts model and account for intracellular polarization as well as intercellular coupling via mechanotransduction, reproduced these features and hence confirmed our finding that the persistence of rotational states depends on the interplay of spatial arrangement and internal polarization of neighboring cells. The distinct migration states within confined environments hence provides significant insights into the local interaction rules guiding collective migration. Taken together, the results of this thesis shed new light on the process of cell migration and illustrate how the controlled and standardized microenvironments provided by micropatterning techniques can be used to systematically assess and examine cell migration on a quantitative basis. Furthermore, the introduced techniques and assays are a step towards establishing micropatterning as a standard tool for cell science.Zellmigration ist ein essenzieller Prozess in der Entwicklung und Erhaltung vielzelliger Organismen. Ein tiefgreifendes Verständnis der involvierten Mechanismen und phänomenologischen Charakteristika ist folglich von zentralem Interesse für die Zellforschung. Allerdings ist die involvierte Maschinerie komplex, was sich in Bewegungsmustern wiederspiegelt, die schon für vereinzelte Zellen schwer zu fassen sind. Zusätzlich führen auf der Skala größerer Zellansammlungen Interaktionsmechanismen, deren genaue Funktionsweise noch nicht geklärt ist, zu langreichweitigen Korrelationen und vielfältigen kollektiven Phänomenen in den Bewegungsmustern. Eine Möglichkeit diese Komplexität im Experiment herunterzubrechen bietet die räumliche Begrenzung der Migration durch Mikrostrukturierung. Durch die Wahl geeigneter Strukturgeometrien können auf diese Weise die Freiheitsgrade der Zellen so eingeschränkt werden, dass spezifische Merkmale der Zellmigration gezielt adressiert und untersucht werden können. Zusätzlich können mit geeigneten Techniken weite Oberflächenbereiche strukturiert werden, was die automatisierte und parallelisierte Auswertung großer Anzahlen standardisierter Einzelexperimente ermöglicht. Im Zuge dieser Arbeit wurden daher neue Verfahren zur Mikrostrukturierung entwickelt und verwendet, um Einzelzellmigration wie auch die Interaktion kleiner Zellgruppen systematisch zu untersuchen. Die hier entwickelte Mikrostrukturierungsmethode, genannt “microscale plasma-induced protein patterning” (µPIPP), ist einfach in der Anwendung und produziert homogene Proteinstrukturen auf verschiedenen biokompatiblen Oberflächen wie Glas, Zellkultur Polystyrol, Cyclo-Olefin-Copolymeren, und Parylen C. Darüber hinaus wurde das µPIPP-Protokoll erweitert, um die Generierung von oberflächengebundenen Proteingradienten sowie Strukturen bestehend aus mehreren Proteinkomponenten zu ermöglichen. Um das Migrationsverhalten von Einzelzellen zu untersuchen, wurden ringförmige Mikrostrukturen verwendet. Im Kontrast zu klassischen Beschreibungen der Zellmigration zeigte die quasi-eindimensionale Bewegung der Zellen in diesen Systemen ausgeprägte Bimodalität, alternierend zwischen Phasen persistenter Migration und Phasen der Zufallsbewegung. Durch Einführung eines Algorithmus’ zum Erfassen charakteristischer Änderungen im Migrationsverhalten wurden die typischen Lebensdauern beider Zustände bestimmt. Zusammen mit der Zellgeschwindigkeit im persistenten Zustand ergaben diese einen charakteristischen Parametersatz um das Bewegungsverhalten einer Zelle zu beschreiben. Durch das Einbinden einer zellabweisenden Barriere in das System wurde dieser noch um die Umkehrwahrscheinlichkeiten in Abwesenheit und Anwesenheit chemischer Grenzflächen erweitert. Zusammengenommen wurden diese fünf Parametern gleich einem Fingerabdruck des Migrationsverhaltens einer Zelle verwendet, um die Bewegungsmuster von Zelltypen verschiedener Invasivität und den Effekt verschiedener Pharmazeutika auf diese detailliert zu charakterisieren und zu quantifizieren. Die verwendete Untersuchungsmethode gibt somit ein umfassendes Bild des Migrationsverhaltens von Einzelzellen und hat zudem Potential im Hinblick auf die Entwicklung eines Standardverfahrens zur vergleichenden Analyse von Zellmotilität in Zellbiologie und Pharmakologie. In einer zweiten Versuchsanordnung wurde das Auftreten kollektiven Verhaltens in der Migration kleiner Zellgruppen untersucht. Hierfür wurden kreisförmige Mikrostrukturen von verschiedenem Durchmesser eingesetzt, in welchen kollektive Bewegung in der Form kohärenter Rotation aller Zellen innerhalb einer Kreisstruktur auftritt. Die Zellbewegung innerhalb der Systeme wurden in Abhängigkeit der enthaltenen Zellenanzahl untersucht, wobei immer sowohl Phasen kohärenter Rotation als auch Phasen ungeordneter Bewegung zu beobachten waren. Die Persistenz der Rotationszustände stieg dabei zwar generell mit steigender Zellenzahl an, dieser Trend wurde jedoch durch einen starken Abfall der Persistenz zwischen Systemen mit vier und Systemen mit fünf Zellen unterbrochen. Das Auslesen der relativen Zellpositionen innerhalb der Einzelsysteme zeigte, dass dieser Abfall mit einer Veränderung der Zellkonformation einherging. Numerische Simulationen basierend auf dem zellulären Potts- Modell, welche sowohl intrazelluläre Polarisation als auch interzelluläre Koppelung durch Mechanotransduktion berücksichtigen, reproduzierten diese Ergebnisse und lassen somit den Schluss zu, dass das Wechselspiel von relativer räumlicher Anordnung und der Ausrichtung der internen Polarisationsachsen benachbarter Zellen die Lebensdauer kollektiver Rotationszustande in der Zellmigration bestimmt. Die Untersuchung der verschiedenen Bewegungszustände innerhalb derMikrostrukturen gibt somit Einblick in die, der kollektiven Zellbewegung zugrundeliegenden, Interaktionsmuster. Zusammengefasst liefern die Ergebnisse dieser Arbeit somit tiefere Erkenntnis über den Prozess der Zellmigration und stellen einen weiteren Schritt dar, Mikrostrukturierung als Standardverfahren zur Analyse und Quantifizierung von Zellbewegung zu etablieren

Computational aspects of cellular intelligence and their role in artificial intelligence.

The work presented in this thesis is concerned with an exploration of the computational aspects of the primitive intelligence associated with single-celled organisms. The main aim is to explore this Cellular Intelligence and its role within Artificial Intelligence. The findings of an extensive literature search into the biological characteristics, properties and mechanisms associated with Cellular Intelligence, its underlying machinery - Cell Signalling Networks and the existing computational methods used to capture it are reported. The results of this search are then used to fashion the development of a versatile new connectionist representation, termed the Artificial Reaction Network (ARN). The ARN belongs to the branch of Artificial Life known as Artificial Chemistry and has properties in common with both Artificial Intelligence and Systems Biology techniques, including: Artificial Neural Networks, Artificial Biochemical Networks, Gene Regulatory Networks, Random Boolean Networks, Petri Nets, and S-Systems. The thesis outlines the following original work: The ARN is used to model the chemotaxis pathway of Escherichia coli and is shown to capture emergent characteristics associated with this organism and Cellular Intelligence more generally. The computational properties of the ARN and its applications in robotic control are explored by combining functional motifs found in biochemical network to create temporal changing waveforms which control the gaits of limbed robots. This system is then extended into a complete control system by combining pattern recognition with limb control in a single ARN. The results show that the ARN can offer increased flexibility over existing methods. Multiple distributed cell-like ARN based agents termed Cytobots are created. These are first used to simulate aggregating cells based on the slime mould Dictyostelium discoideum. The Cytobots are shown to capture emergent behaviour arising from multiple stigmergic interactions. Applications of Cytobots within swarm robotics are investigated by applying them to benchmark search problems and to the task of cleaning up a simulated oil spill. The results are compared to those of established optimization algorithms using similar cell inspired strategies, and to other robotic agent strategies. Consideration is given to the advantages and disadvantages of the technique and suggestions are made for future work in the area. The report concludes that the Artificial Reaction Network is a versatile and powerful technique which has application in both simulation of chemical systems, and in robotic control, where it can offer a higher degree of flexibility and computational efficiency than benchmark alternatives. Furthermore, it provides a tool which may possibly throw further light on the origins and limitations of the primitive intelligence associated with cells