List on ORCID, Europe PubMed, NCBI PubMed, dblp or Google Scholar.
PhD thesis
 | Walter de Back Multicellular Systems Biology of Development PhD Thesis Technische Universität Dresden, 2015. @phdthesis{deBack2015, title = {Multicellular Systems Biology of Development}, author = {Walter de Back}, url = {http://walter.deback.net/wp-content/uploads/2015/11/Thesis_WdB.pdf}, year = {2015}, date = {2015-11-03}, school = {Technische Universität Dresden}, abstract = {Embryonic development depends on the precise coordination of cell fate specification, patterning and morphogenesis. Although great strides have been made in the molecular understanding of each of these processes, how their interplay governs the formation of complex tissues remains poorly understood. New techniques for experimental manipulation and image quantification enable the study of development in unprecedented detail, resulting in new hypotheses on the interactions between known components. By expressing these hypotheses in terms of rules and equations, computational modeling and simulation allows one to test their consistency against experimental data. However, new computational methods are required to represent and integrate the network of interactions between gene regulation, signaling and biomechanics that extend over the molecular, cellular and tissue scales. In this thesis, I present a framework that facilitates computational modeling of multi-scale multicellular systems and apply it to investigate pancreatic development and the formation of vascular networks. This framework is based on the integration of discrete cell-based models with continuous models for intracellular regulation and intercellular signaling. Specifically, gene regulatory networks are represented by differential equations to analyze cell fate regulation; interactions and distributions of signaling molecules are modeled by reaction-diffusion systems to study pattern formation; and cell-cell interactions are represented in cell-based models to investigate morphogenetic processes. A cell-centered approach is adopted that facilitates the integration of processes across the scales and simultaneously constrains model complexity. The computational methods that are required for this modeling framework have been implemented in the software platform Morpheus. This modeling and simulation environment enables the development, execution and analysis of multi-scale models of multicellular systems. These models are represented in a new domain-specific markup language that separates the biological model from the computational methods and facilitates model storage and exchange. Together with a user-friendly graphical interface, Morpheus enables computational modeling of complex developmental processes without programming and thereby widens its accessibility for biologists. To demonstrate the applicability of the framework to problems in developmental biology, two case studies are presented that address different aspects of the interplay between cell fate specification, patterning and morphogenesis. In the first, I focus on the interplay between cell fate stability and intercellular signaling. Specifically, two studies are presented that investigate how mechanisms of cell-cell communication affect cell fate regulation and spatial patterning in the pancreatic epithelium. Using bifurcation analysis and simulations of spatially coupled differential equations, it is shown that intercellular communication results in a multistability of gene expression states that can explain the scattered spatial distribution and low cell type ratio of nascent islet cells. Moreover, model analysis shows that disruption of intercellular communication induces a transition between gene expression states that can explain observations of in vitro transdifferentiation from adult acinar cells into new islet cells. These results emphasize the role of the multicellular context in cell fate regulation during development and may be used to optimize protocols for cellular reprogramming. The second case study focuses on the feedback between patterning and morphogenesis in the context of the formation of vascular networks. Integrating a cell-based model of endothelial chemotaxis with a reaction-diffusion model representing signaling molecules and extracellular matrix, it is shown that vascular network patterns with realistic morphometry can arise when signaling factors are retained by cell-modified matrix molecules. Through the validation of this model using in vitro assays, quantitative estimates are obtained for kinetic parameters that, when used in quantitative model simulations, confirm the formation of vascular networks under measured biophysical conditions. These results demonstrate the key role of the extracellular matrix in providing spatial guidance cues, a fact that may be exploited to enhance vascularization of engineered tissues. Together, the modeling framework, software platform and case studies presented in this thesis demonstrate how cell-centered computational modeling of multi-scale and multicellular systems provide powerful tools to help disentangle the complex interplay between cell fate specification, patterning and morphogenesis during embryonic development.}, keywords = {}, pubstate = {published}, tppubtype = {phdthesis} } Embryonic development depends on the precise coordination of cell fate specification, patterning and morphogenesis. Although great strides have been made in the molecular understanding of each of these processes, how their interplay governs the formation of complex tissues remains poorly understood. New techniques for experimental manipulation and image quantification enable the study of development in unprecedented detail, resulting in new hypotheses on the interactions between known components. By expressing these hypotheses in terms of rules and equations, computational modeling and simulation allows one to test their consistency against experimental data. However, new computational methods are required to represent and integrate the network of interactions between gene regulation, signaling and biomechanics that extend over the molecular, cellular and tissue scales. In this thesis, I present a framework that facilitates computational modeling of multi-scale multicellular systems and apply it to investigate pancreatic development and the formation of vascular networks. This framework is based on the integration of discrete cell-based models with continuous models for intracellular regulation and intercellular signaling. Specifically, gene regulatory networks are represented by differential equations to analyze cell fate regulation; interactions and distributions of signaling molecules are modeled by reaction-diffusion systems to study pattern formation; and cell-cell interactions are represented in cell-based models to investigate morphogenetic processes. A cell-centered approach is adopted that facilitates the integration of processes across the scales and simultaneously constrains model complexity. The computational methods that are required for this modeling framework have been implemented in the software platform Morpheus. This modeling and simulation environment enables the development, execution and analysis of multi-scale models of multicellular systems. These models are represented in a new domain-specific markup language that separates the biological model from the computational methods and facilitates model storage and exchange. Together with a user-friendly graphical interface, Morpheus enables computational modeling of complex developmental processes without programming and thereby widens its accessibility for biologists. To demonstrate the applicability of the framework to problems in developmental biology, two case studies are presented that address different aspects of the interplay between cell fate specification, patterning and morphogenesis. In the first, I focus on the interplay between cell fate stability and intercellular signaling. Specifically, two studies are presented that investigate how mechanisms of cell-cell communication affect cell fate regulation and spatial patterning in the pancreatic epithelium. Using bifurcation analysis and simulations of spatially coupled differential equations, it is shown that intercellular communication results in a multistability of gene expression states that can explain the scattered spatial distribution and low cell type ratio of nascent islet cells. Moreover, model analysis shows that disruption of intercellular communication induces a transition between gene expression states that can explain observations of in vitro transdifferentiation from adult acinar cells into new islet cells. These results emphasize the role of the multicellular context in cell fate regulation during development and may be used to optimize protocols for cellular reprogramming. The second case study focuses on the feedback between patterning and morphogenesis in the context of the formation of vascular networks. Integrating a cell-based model of endothelial chemotaxis with a reaction-diffusion model representing signaling molecules and extracellular matrix, it is shown that vascular network patterns with realistic morphometry can arise when signaling factors are retained by cell-modified matrix molecules. Through the validation of this model using in vitro assays, quantitative estimates are obtained for kinetic parameters that, when used in quantitative model simulations, confirm the formation of vascular networks under measured biophysical conditions. These results demonstrate the key role of the extracellular matrix in providing spatial guidance cues, a fact that may be exploited to enhance vascularization of engineered tissues. Together, the modeling framework, software platform and case studies presented in this thesis demonstrate how cell-centered computational modeling of multi-scale and multicellular systems provide powerful tools to help disentangle the complex interplay between cell fate specification, patterning and morphogenesis during embryonic development. |
Journal Articles |
|
 | Maria Herberg, Thomas Zerjatke, Walter de Back, Ingmar Glauche, Ingo Roeder Image-based quantification and mathematical modeling of spatial heterogeneity in ESC colonies Journal Article Cytometry: Part A, 2015, ISSN: 1552-4930. @article{Herberg2015, title = {Image-based quantification and mathematical modeling of spatial heterogeneity in ESC colonies}, author = {Maria Herberg and Thomas Zerjatke and Walter de Back and Ingmar Glauche and Ingo Roeder}, url = {http://dx.doi.org/10.1002/cyto.a.22598 http://walter.deback.net/wp-content/uploads/2015/01/CytoA_Herberg2015.pdf}, issn = {1552-4930}, year = {2015}, date = {2015-01-01}, journal = {Cytometry: Part A}, abstract = {Pluripotent embryonic stem cells (ESCs) have the potential to differentiate into cells of all three germ layers. This unique property has been extensively studied on the intracellular, transcriptional level. However, cultured ESCs form clusters of distinct size and shape, and establish spatial structures that are essential for the maintenance of pluripotency. Even though it is recognized that the cellsʼ arrangement and local interactions play a role in fate decision processes, the relations between transcriptional and spatial patterns have not yet been studied. We present a systems biology approach which combines live-cell imaging, quantitative image analysis, and multi-scale, mathematical modeling of ESC growth. In particular, we develop quantitative measures on the morphology and on the spatial clustering of ESCs with different expression levels and apply them to images of both in vitro and in silico cultures. Using the same measures, we are able to compare model scenarios with different assumptions on cell-cell adhesions and intercellular feedback mechanisms directly with experimental data. Applying our methodology to microscopy images of cultured ESCs, we demonstrate that the emerging colonies are highly variable regarding both morphological and spatial fluorescence patterns. Moreover, we can show that clusters of ESCs with a high self-renewing capacity are preferentially located in the interior of a colony structure. The integrated approach combining image analysis with mathematical modeling allows us to infer transcription factor related cellular and intercellular mechanisms behind the emergence of observed patterns that cannot be derived from images directly. }, keywords = {}, pubstate = {published}, tppubtype = {article} } Pluripotent embryonic stem cells (ESCs) have the potential to differentiate into cells of all three germ layers. This unique property has been extensively studied on the intracellular, transcriptional level. However, cultured ESCs form clusters of distinct size and shape, and establish spatial structures that are essential for the maintenance of pluripotency. Even though it is recognized that the cellsʼ arrangement and local interactions play a role in fate decision processes, the relations between transcriptional and spatial patterns have not yet been studied. We present a systems biology approach which combines live-cell imaging, quantitative image analysis, and multi-scale, mathematical modeling of ESC growth. In particular, we develop quantitative measures on the morphology and on the spatial clustering of ESCs with different expression levels and apply them to images of both in vitro and in silico cultures. Using the same measures, we are able to compare model scenarios with different assumptions on cell-cell adhesions and intercellular feedback mechanisms directly with experimental data. Applying our methodology to microscopy images of cultured ESCs, we demonstrate that the emerging colonies are highly variable regarding both morphological and spatial fluorescence patterns. Moreover, we can show that clusters of ESCs with a high self-renewing capacity are preferentially located in the interior of a colony structure. The integrated approach combining image analysis with mathematical modeling allows us to infer transcription factor related cellular and intercellular mechanisms behind the emergence of observed patterns that cannot be derived from images directly. |
 | Jörn Starruß, Walter de Back, Lutz Brusch, Andreas Deutsch Morpheus: a user-friendly modeling environment for multiscale and multicellular systems biology Journal Article Bioinformatics, 30 (9), pp. 1331–1332, 2014. @article{Starrus2014b, title = {Morpheus: a user-friendly modeling environment for multiscale and multicellular systems biology}, author = {Jörn Starruß and Walter de Back and Lutz Brusch and Andreas Deutsch}, url = {http://dx.doi.org/10.1093/bioinformatics/btt772}, year = {2014}, date = {2014-01-01}, journal = {Bioinformatics}, volume = {30}, number = {9}, pages = {1331--1332}, institution = {Center for Information Services and High Performance Computing, Technische Universität Dresden, 01062 Dresden, Germany.}, abstract = {Morpheus is a modeling environment for the simulation and integration of cell-based models with ordinary differential equations and reaction-diffusion systems. It allows rapid development of multiscale models in biological terms and mathematical expressions rather than programming code. Its graphical user interface supports the entire workflow from model construction and simulation to visualization, archiving and batch processing.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Morpheus is a modeling environment for the simulation and integration of cell-based models with ordinary differential equations and reaction-diffusion systems. It allows rapid development of multiscale models in biological terms and mathematical expressions rather than programming code. Its graphical user interface supports the entire workflow from model construction and simulation to visualization, archiving and batch processing. |
 | Alvaro Köhn-Luque, Walter de Back, Yoshimi Yamaguchi, Kenji Yoshimura, Miguel Angel Herrero, Takashi Miura Dynamics of VEGF matrix-retention in vascular network patterning Journal Article Phys Biol, 10 (6), pp. 066007, 2013. @article{Koehn-Luque2013b, title = {Dynamics of VEGF matrix-retention in vascular network patterning}, author = {Alvaro Köhn-Luque and Walter de Back and Yoshimi Yamaguchi and Kenji Yoshimura and Miguel Angel Herrero and Takashi Miura}, url = {http://dx.doi.org/10.1088/1478-3975/10/6/066007 http://walter.deback.net/old/media/KohnLuque_etal_PhysBiol_2013.pdf}, year = {2013}, date = {2013-11-05}, journal = {Phys Biol}, volume = {10}, number = {6}, pages = {066007}, institution = {Faculty of Mathematics, Department of Applied Mathematics, Universidad Complutense de Madrid, E-28040 Madrid, Spain. Department for Innovative Methods of Computing, Center for Information Services and}, abstract = {Vascular endothelial growth factor (VEGF) is a central regulator of blood vessel morphogenesis, although its role in patterning of endothelial cells into vascular networks is not fully understood. It has been suggested that binding of soluble VEGF to extracellular matrix components causes spatially restricted cues that guide endothelial cells into network patterns. Yet, current evidence for such a mechanism remains indirect. In this study, we quantitatively analyse the dynamics of VEGF retention in a controlled in vitro situation of human umbilical vascular endothelial cells (HUVECs) in Matrigel. We show that fluorescent VEGF accumulates in pericellular areas and colocalizes with VEGF binding molecules. Analysis of fluorescence recovery after photobleaching reveals that binding/unbinding to matrix molecules dominates VEGF dynamics in the pericellular region. Computational simulations using our experimental measurements of kinetic parameters show that matrix retention of chemotactic signals can lead to the formation of reticular cellular networks on a realistic timescale. Taken together, these results show that VEGF binds to matrix molecules in proximity of HUVECs in Matrigel, and suggest that bound VEGF drives vascular network patterning.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Vascular endothelial growth factor (VEGF) is a central regulator of blood vessel morphogenesis, although its role in patterning of endothelial cells into vascular networks is not fully understood. It has been suggested that binding of soluble VEGF to extracellular matrix components causes spatially restricted cues that guide endothelial cells into network patterns. Yet, current evidence for such a mechanism remains indirect. In this study, we quantitatively analyse the dynamics of VEGF retention in a controlled in vitro situation of human umbilical vascular endothelial cells (HUVECs) in Matrigel. We show that fluorescent VEGF accumulates in pericellular areas and colocalizes with VEGF binding molecules. Analysis of fluorescence recovery after photobleaching reveals that binding/unbinding to matrix molecules dominates VEGF dynamics in the pericellular region. Computational simulations using our experimental measurements of kinetic parameters show that matrix retention of chemotactic signals can lead to the formation of reticular cellular networks on a realistic timescale. Taken together, these results show that VEGF binds to matrix molecules in proximity of HUVECs in Matrigel, and suggest that bound VEGF drives vascular network patterning. |
 | Walter de Back, Roland Zimm, Lutz Brusch Transdifferentiation of pancreatic cells by loss of contact-mediated signaling Journal Article BMC Syst Biol, 7 , pp. 77, 2013. @article{deBack2013b, title = {Transdifferentiation of pancreatic cells by loss of contact-mediated signaling}, author = {Walter de Back and Roland Zimm and Lutz Brusch}, url = {http://dx.doi.org/10.1186/1752-0509-7-77}, year = {2013}, date = {2013-01-01}, journal = {BMC Syst Biol}, volume = {7}, pages = {77}, institution = {Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, 01062, Germany.}, abstract = {Replacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into β-cells. Despite accumulating evidence that contact-mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood.In this study, we propose that the crosstalk between two contact-mediated signaling mechanisms, lateral inhibition and lateral stabilization, controls cell fate stability and transdifferentiation of pancreatic cells. Analysis of a mathematical model combining gene regulation with contact-mediated signaling reveals the multistability of acinar and islet cell fates. Inhibition of one or both modes of signaling results in transdifferentiation from the acinar to the islet cell fate, either by dedifferentiation to a multipotent state or by direct lineage switching.This study provides a theoretical framework to understand the role of contact-mediated signaling in pancreatic cell fate control that may help to improve acinar-to-islet cell transdifferentiation strategies for β-cell neogenesis.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Replacement of dysfunctional β-cells in the islets of Langerhans by transdifferentiation of pancreatic acinar cells has been proposed as a regenerative therapy for diabetes. Adult acinar cells spontaneously revert to a multipotent state upon tissue dissociation in vitro and can be stimulated to redifferentiate into β-cells. Despite accumulating evidence that contact-mediated signals are involved, the mechanisms regulating acinar-to-islet cell transdifferentiation remain poorly understood.In this study, we propose that the crosstalk between two contact-mediated signaling mechanisms, lateral inhibition and lateral stabilization, controls cell fate stability and transdifferentiation of pancreatic cells. Analysis of a mathematical model combining gene regulation with contact-mediated signaling reveals the multistability of acinar and islet cell fates. Inhibition of one or both modes of signaling results in transdifferentiation from the acinar to the islet cell fate, either by dedifferentiation to a multipotent state or by direct lineage switching.This study provides a theoretical framework to understand the role of contact-mediated signaling in pancreatic cell fate control that may help to improve acinar-to-islet cell transdifferentiation strategies for β-cell neogenesis. |
 | Walter de Back, Joseph Xu Zhou, Lutz Brusch On the role of lateral stabilization during early patterning in the pancreas Journal Article J R Soc Interface, 10 (79), pp. 20120766, 2012. @article{deBack2012, title = {On the role of lateral stabilization during early patterning in the pancreas}, author = {Walter de Back and Joseph Xu Zhou and Lutz Brusch}, url = {http://dx.doi.org/10.1098/rsif.2012.0766 http://walter.deback.net/old/media/deback_etal_Interface_2012.pdf}, year = {2012}, date = {2012-01-01}, journal = {J R Soc Interface}, volume = {10}, number = {79}, pages = {20120766}, institution = {Center for Information Services and High Performance Computing, Technische Universität Dresden, Dresden, Germany.}, abstract = {The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell-cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell-cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell-cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell-cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development. |
 | Alvaro Köhn-Luque, Walter de Back, Jörn Starruss, Andrea Mattiotti, Andreas Deutsch, José María Pérez-Pomares, Miguel A. Herrero Early embryonic vascular patterning by matrix-mediated paracrine signalling: a mathematical model study Journal Article PLoS One, 6 (9), pp. e24175, 2011. @article{Koehn-Luque2011b, title = {Early embryonic vascular patterning by matrix-mediated paracrine signalling: a mathematical model study}, author = {Alvaro Köhn-Luque and Walter de Back and Jörn Starruss and Andrea Mattiotti and Andreas Deutsch and José María Pérez-Pomares and Miguel A. Herrero}, url = {http://dx.doi.org/10.1371/journal.pone.0024175}, year = {2011}, date = {2011-01-01}, journal = {PLoS One}, volume = {6}, number = {9}, pages = {e24175}, institution = {Department of Applied Mathematics and Institute for Interdisciplinary Mathematics, Faculty of Mathematics, Universidad Complutense de Madrid, Madrid, Spain.}, abstract = {During embryonic vasculogenesis, endothelial precursor cells of mesodermal origin known as angioblasts assemble into a characteristic network pattern. Although a considerable amount of markers and signals involved in this process have been identified, the mechanisms underlying the coalescence of angioblasts into this reticular pattern remain unclear. Various recent studies hypothesize that autocrine regulation of the chemoattractant vascular endothelial growth factor (VEGF) is responsible for the formation of vascular networks in vitro. However, the autocrine regulation hypothesis does not fit well with reported data on in vivo early vascular development. In this study, we propose a mathematical model based on the alternative assumption that endodermal VEGF signalling activity, having a paracrine effect on adjacent angioblasts, is mediated by its binding to the extracellular matrix (ECM). Detailed morphometric analysis of simulated networks and images obtained from in vivo quail embryos reveals the model mimics the vascular patterns with high accuracy. These results show that paracrine signalling can result in the formation of fine-grained cellular networks when mediated by angioblast-produced ECM. This lends additional support to the theory that patterning during early vascular development in the vertebrate embryo is regulated by paracrine signalling.}, keywords = {}, pubstate = {published}, tppubtype = {article} } During embryonic vasculogenesis, endothelial precursor cells of mesodermal origin known as angioblasts assemble into a characteristic network pattern. Although a considerable amount of markers and signals involved in this process have been identified, the mechanisms underlying the coalescence of angioblasts into this reticular pattern remain unclear. Various recent studies hypothesize that autocrine regulation of the chemoattractant vascular endothelial growth factor (VEGF) is responsible for the formation of vascular networks in vitro. However, the autocrine regulation hypothesis does not fit well with reported data on in vivo early vascular development. In this study, we propose a mathematical model based on the alternative assumption that endodermal VEGF signalling activity, having a paracrine effect on adjacent angioblasts, is mediated by its binding to the extracellular matrix (ECM). Detailed morphometric analysis of simulated networks and images obtained from in vivo quail embryos reveals the model mimics the vascular patterns with high accuracy. These results show that paracrine signalling can result in the formation of fine-grained cellular networks when mediated by angioblast-produced ECM. This lends additional support to the theory that patterning during early vascular development in the vertebrate embryo is regulated by paracrine signalling. |
Marco Wiering, Stefan Leijnen, Koster Andrew, Walter de Back Institute Presentation: Autonomous Intelligent Robots at Utrecht University Journal Article International Journal of Advanced Robotics Systems, 1 (2), 2004. @article{Wiering2004b, title = {Institute Presentation: Autonomous Intelligent Robots at Utrecht University}, author = {Marco Wiering and Stefan Leijnen and Koster Andrew and Walter de Back}, url = {http://walter.deback.net/wp-content/uploads/2014/09/wiering_04_autonomous21.pdf}, year = {2004}, date = {2004-01-01}, booktitle = {International Journal of Advanced Robotics Systems}, journal = {International Journal of Advanced Robotics Systems}, volume = {1}, number = {2}, abstract = {The Autonomous Intelligent Robot (AIR) Laboratory consists of researchers and students aiming to develop goal-directed, adaptive, and autonomous behaviors in a wide variety of robots. Since the foundation of the Lab in 1997, we have done a number of different projects including (1) Developing self-localisation algorithms and behaviors for the Pioneer-2 robot participating in the mid-sized RoboCup league, (2) Research on evolutionary robotics using spiking neural networks, (3) Education projects using Lego Mindstorm robot competitions, and (4) Developing behaviors and team strategies for our Aibo robots participating in the four-legged RoboCup competition. In the future we want to study higher-order cognition and emotions in robots, the use of reinforcement learning for learning behaviors and team strategies, and machine learning algorithms for robot-vision and sensor-data fusion.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Autonomous Intelligent Robot (AIR) Laboratory consists of researchers and students aiming to develop goal-directed, adaptive, and autonomous behaviors in a wide variety of robots. Since the foundation of the Lab in 1997, we have done a number of different projects including (1) Developing self-localisation algorithms and behaviors for the Pioneer-2 robot participating in the mid-sized RoboCup league, (2) Research on evolutionary robotics using spiking neural networks, (3) Education projects using Lego Mindstorm robot competitions, and (4) Developing behaviors and team strategies for our Aibo robots participating in the four-legged RoboCup competition. In the future we want to study higher-order cognition and emotions in robots, the use of reinforcement learning for learning behaviors and team strategies, and machine learning algorithms for robot-vision and sensor-data fusion. | |
Books |
|
Walter de Back, Tijn van der Zant, Lars Zwanepol Robo Sapiens: Proceedings of the First Dutch Symposium on Embodied Intelligence Book Utrecht University, 2001, ISBN: 9789039327302. @book{de2001robob, title = {Robo Sapiens: Proceedings of the First Dutch Symposium on Embodied Intelligence}, author = {Walter de Back and Tijn van der Zant and Lars Zwanepol}, url = {http://dspace.library.uu.nl/bitstream/handle/1874/27687/preprint24.pdf}, isbn = {9789039327302}, year = {2001}, date = {2001-01-01}, publisher = {Utrecht University}, series = {Artificial intelligence}, keywords = {}, pubstate = {published}, tppubtype = {book} } | |
Book Chapters |
|
Dylan Evans, Walter de Back Evolutionary Robotics Book Chapter Roberts, Craig S (Ed.): Applied Evolutionary Psychology, Chapter Evolutionary Robotics, pp. 414–424, Oxford University Press, 2011, ISBN: 978-0-19-958607-3. @inbook{Evans2011, title = {Evolutionary Robotics}, author = {Dylan Evans and Walter de Back}, editor = {S. Craig Roberts}, url = {http://walter.deback.net/media/Evans_deBack_EvoPsy_2012.pdf http://ukcatalogue.oup.com/product/9780199586073.do}, isbn = {978-0-19-958607-3}, year = {2011}, date = {2011-01-01}, booktitle = {Applied Evolutionary Psychology}, pages = {414--424}, publisher = {Oxford University Press}, chapter = {Evolutionary Robotics}, abstract = {Robotics has been influences by cognitive psychology and evolutionary biology, but the child prodigy of these two disciplines, evolutionary psychology, has not yet had such a large impact on the field. Here we describe how evolutionary psychology may come to have a greater impact on robotics in the near future. First, however, we will briefly outline the role that the two parent disciplines of evolutionary psychology have played in the development of robotics, and describe a few lessons that have been drawn so far by roboticists from evolutionary psychology itself.}, keywords = {}, pubstate = {published}, tppubtype = {inbook} } Robotics has been influences by cognitive psychology and evolutionary biology, but the child prodigy of these two disciplines, evolutionary psychology, has not yet had such a large impact on the field. Here we describe how evolutionary psychology may come to have a greater impact on robotics in the near future. First, however, we will briefly outline the role that the two parent disciplines of evolutionary psychology have played in the development of robotics, and describe a few lessons that have been drawn so far by roboticists from evolutionary psychology itself. | |
Incollections |
|
Walter de Back, Andreas Deutsch, Dirk Drasdo, Akira Funahashi, Adelinde M. Uhrmacher Towards a standard exchange format for spatial, multilevel multicellular models Incollection Gilbert, David; Heiner, Monika; Takahashi, Koichi; Uhrmacher, Adelinde M (Ed.): Multiscale Spatial Computational Systems Biology, Dagstuhl Reports, 2015, ISSN: 2192-5283. @incollection{deBack2015a, title = {Towards a standard exchange format for spatial, multilevel multicellular models}, author = {Walter de Back and Andreas Deutsch and Dirk Drasdo and Akira Funahashi and Adelinde M. Uhrmacher}, editor = {David Gilbert and Monika Heiner and Koichi Takahashi and Adelinde M. Uhrmacher}, url = {http://dx.doi.org/10.4230/DagRep.4.11.138}, doi = {10.4230/DagRep.4.11.138}, issn = {2192-5283}, year = {2015}, date = {2015-03-20}, booktitle = {Multiscale Spatial Computational Systems Biology}, publisher = {Dagstuhl Reports}, abstract = {Standardization of model descriptions has boosted the field of systems biology over the last decade. Standard formats such as SBML and CellML have allowed the exchange of models of biochemical reaction networks between users and simulation software, enhanced reproducibility of models and enables the creation of public model repositories. However, the recent shift in systems biology towards spatial multilevel models requires new modeling formalisms and simulation software for which existing exchange formats are not suitable. Here, we discuss the major challenges in defining a standard exchange format for computational models of multilevel and multicellular systems and formulate some suggestions for the establishment of a standard exchange format for such simulation models.}, type = {Dagstuhl Seminar Report}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } Standardization of model descriptions has boosted the field of systems biology over the last decade. Standard formats such as SBML and CellML have allowed the exchange of models of biochemical reaction networks between users and simulation software, enhanced reproducibility of models and enables the creation of public model repositories. However, the recent shift in systems biology towards spatial multilevel models requires new modeling formalisms and simulation software for which existing exchange formats are not suitable. Here, we discuss the major challenges in defining a standard exchange format for computational models of multilevel and multicellular systems and formulate some suggestions for the establishment of a standard exchange format for such simulation models. | |
Anja Voß-Böhme, Walter de Back, Jörn Starruß Cellular Potts Model Incollection Dubitzky, Werner; Wolkenhauer, Olaf; Cho, Kwang-Hyun; Yokota, Hiroki (Ed.): Encyclopedia of Systems Biology, Springer, 2012, ISBN: 978-1-441-99862-0. @incollection{Voss-Boehme2012, title = {Cellular Potts Model}, author = {Anja Voß-Böhme and Walter de Back and Jörn Starruß}, editor = {Werner Dubitzky and Olaf Wolkenhauer and Kwang-Hyun Cho and Hiroki Yokota}, url = {http://walter.deback.net/media/Voss_etal_Encyclo_SysBio_2012_proof.pdf}, isbn = {978-1-441-99862-0}, year = {2012}, date = {2012-01-01}, booktitle = {Encyclopedia of Systems Biology}, publisher = {Springer}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } | |
Krzystof Kurowski, Walter de Back, Werner Dubitzky, Laszlo Gulyas, George Kampis, Mariusz Mamonski, Gabor Szemes, Martin Swain Complex System Simulations with QosCosGrid Incollection Computational Science – ICCS 2009, pp. 387–396, Springer Science + Business Media, 2009. @incollection{Kurowski2009b, title = {Complex System Simulations with QosCosGrid}, author = {Krzystof Kurowski and Walter de Back and Werner Dubitzky and Laszlo Gulyas and George Kampis and Mariusz Mamonski and Gabor Szemes and Martin Swain}, url = {http://dx.doi.org/10.1007/978-3-642-01970-8_38}, year = {2009}, date = {2009-01-01}, booktitle = {Computational Science – ICCS 2009}, pages = {387--396}, publisher = {Springer Science + Business Media}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } | |
Walter de Back, László Gulyás, George Kampis Niche Differentiation and Coexistence in a Multi-resource Ecosystem with Competition Incollection Advances in Artificial Life, pp. 143–152, Springer Science + Business Media, 2007. @incollection{deBack2007b, title = {Niche Differentiation and Coexistence in a Multi-resource Ecosystem with Competition}, author = {Walter de Back and László Gulyás and George Kampis}, url = {http://walter.deback.net/wp-content/uploads/2015/03/niche-diff-final.pdf http://dx.doi.org/10.1007/978-3-540-74913-4_15}, year = {2007}, date = {2007-01-01}, booktitle = {Advances in Artificial Life}, pages = {143--152}, publisher = {Springer Science + Business Media}, abstract = {As a step towards modeling the evolution of food webs from an individual-based perspective, here we study the evolutionary dynamics of a simple multi-resource ecosystem model at the basal level of a food web. We combine two trade-off mechanisms in resource utilization (consumption abilities) and stoichiometric constraints (consumption needs) into a minimal model, and study the evolution of niche differentiation and coexistence through the interaction. Under a broad range of circumstances the model shows the emergence of specialization. By introducing stoichiometric constraints various evolutionary trajectories become possible but in this simple model we found no evidence for the coexistence of specialists and generalists.}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } As a step towards modeling the evolution of food webs from an individual-based perspective, here we study the evolutionary dynamics of a simple multi-resource ecosystem model at the basal level of a food web. We combine two trade-off mechanisms in resource utilization (consumption abilities) and stoichiometric constraints (consumption needs) into a minimal model, and study the evolution of niche differentiation and coexistence through the interaction. Under a broad range of circumstances the model shows the emergence of specialization. By introducing stoichiometric constraints various evolutionary trajectories become possible but in this simple model we found no evidence for the coexistence of specialists and generalists. | |
Inproceedings |
|
Walter de Back, George Kampis Emergence and analysis of complex food webs in an individual-based artificial ecology Inproceedings 2009 IEEE Symposium on Artificial Life, IEEE, 2009. @inproceedings{deBack2009, title = {Emergence and analysis of complex food webs in an individual-based artificial ecology}, author = {Walter de Back and George Kampis}, url = {http://dx.doi.org/10.1109/ALIFE.2009.4937704 http://walter.deback.net/old/media/deBackIEEE09_web.pdf}, year = {2009}, date = {2009-01-01}, booktitle = {2009 IEEE Symposium on Artificial Life}, publisher = {IEEE}, abstract = {Food webs are complex networks of trophic interactions in ecological communities that are crucial in creating and maintaining biodiversity, and are prominent examples of biological complexity. In this paper, we present an individual-based model of an artificial ecology demonstrating the emergence of complex food webs through the evolution of rich phenotypes. Individuals are simple structures that map several traits in a nonlinear fashion. Interaction and evolution of these structures leads to the self-assembly of food webs in complex ecological communities. Ecological and network analysis of the evolved artificial ecologies shows remarkable similarities in various patterns known from natural ecological communities.}, keywords = {}, pubstate = {published}, tppubtype = {inproceedings} } Food webs are complex networks of trophic interactions in ecological communities that are crucial in creating and maintaining biodiversity, and are prominent examples of biological complexity. In this paper, we present an individual-based model of an artificial ecology demonstrating the emergence of complex food webs through the evolution of rich phenotypes. Individuals are simple structures that map several traits in a nonlinear fashion. Interaction and evolution of these structures leads to the self-assembly of food webs in complex ecological communities. Ecological and network analysis of the evolved artificial ecologies shows remarkable similarities in various patterns known from natural ecological communities. | |
Laszlo Gulyas, Walter de Back, Gabor Szemes, George Kampis Templates for Distributed Agent-Based Simulations Inproceedings 5th International Conference on e-Social Science, 2009. @inproceedings{Gulyas2009ab, title = {Templates for Distributed Agent-Based Simulations}, author = {Laszlo Gulyas and Walter de Back and Gabor Szemes and George Kampis}, year = {2009}, date = {2009-01-01}, booktitle = {5th International Conference on e-Social Science}, abstract = {gent-based modeling is a new branch of computer simulation, especially suited for the modeling of complex social systems. Its main tenet is to model the individual, together with its imperfections (e.g., limited cognitive and computational abilities), its idiosyncrasies, and unique interactions. Thus, the approach builds the model from \'the bottom-up\', focusing mostly on micro rules and seeking the understanding of the emergence of macro behavior. According to Epstein and Axtell, in these artificial societies, social structure and group behavior emerges from the interaction of individuals, under rules that place only bounded demands on each agent\'s information and computational capacity. One caveat of the approach, however, that in total, it creates high computational demands for any realistic population size. To match these, one needs to capitalize on the recent advances of ICT technology: network, grid and cloud computing, multi-core systems and graphical processing units, etc. However, the real benefit of these new solutions can only be exploited if the computational program of the artificial society is implemented in a distributed fashion. Unfortunately, most of today\'s modelers are not skilled in creating distributed versions of their simulations, and the common agent-based modeling platforms (like NetLogo, Repast, MASON, etc.) offer little to help this process. Moreover, distributed operation complicates the model development significantly, especially, in cases of experimental, incremental model development, where the model structure may change dramatically during the process. To face these issues, we are developing an integration between the agent simulation toolkit Repast (North et al, 2006) and ProActive (Baude et al, 2006), a middleware for multi-threading, parallel and distributed computing. This combination facilitates the design and deployment of distributed agent-based simulations over multiple computational nodes on multi-core machines, local clusters, and grid environments. Naturally, the distribution and parallelization of computer programs, and thus simulations, cannot be fully automatized. Parallelization is a multi-dimensional optimization problem. Two of the major dimensions are the minimalization of communication between nodes, and the balancing of the processing load among the }, keywords = {}, pubstate = {published}, tppubtype = {inproceedings} } gent-based modeling is a new branch of computer simulation, especially suited for the modeling of complex social systems. Its main tenet is to model the individual, together with its imperfections (e.g., limited cognitive and computational abilities), its idiosyncrasies, and unique interactions. Thus, the approach builds the model from 'the bottom-up', focusing mostly on micro rules and seeking the understanding of the emergence of macro behavior. According to Epstein and Axtell, in these artificial societies, social structure and group behavior emerges from the interaction of individuals, under rules that place only bounded demands on each agent's information and computational capacity. One caveat of the approach, however, that in total, it creates high computational demands for any realistic population size. To match these, one needs to capitalize on the recent advances of ICT technology: network, grid and cloud computing, multi-core systems and graphical processing units, etc. However, the real benefit of these new solutions can only be exploited if the computational program of the artificial society is implemented in a distributed fashion. Unfortunately, most of today's modelers are not skilled in creating distributed versions of their simulations, and the common agent-based modeling platforms (like NetLogo, Repast, MASON, etc.) offer little to help this process. Moreover, distributed operation complicates the model development significantly, especially, in cases of experimental, incremental model development, where the model structure may change dramatically during the process. To face these issues, we are developing an integration between the agent simulation toolkit Repast (North et al, 2006) and ProActive (Baude et al, 2006), a middleware for multi-threading, parallel and distributed computing. This combination facilitates the design and deployment of distributed agent-based simulations over multiple computational nodes on multi-core machines, local clusters, and grid environments. Naturally, the distribution and parallelization of computer programs, and thus simulations, cannot be fully automatized. Parallelization is a multi-dimensional optimization problem. Two of the major dimensions are the minimalization of communication between nodes, and the balancing of the processing load among the | |
Laszlo Gulyas, Gabor Szemes, George Kampis, Walter de Back A Modeler-Friendly API for ABM Partitioning Inproceedings Volume 2: 29th Computers and Information in Engineering Conference, Parts A and B, ASME, 2009. @inproceedings{Gulyas2009b, title = {A Modeler-Friendly API for ABM Partitioning}, author = {Laszlo Gulyas and Gabor Szemes and George Kampis and Walter de Back}, url = {http://dx.doi.org/10.1115/DETC2009-86650}, year = {2009}, date = {2009-01-01}, booktitle = {Volume 2: 29th Computers and Information in Engineering Conference, Parts A and B}, publisher = {ASME}, keywords = {}, pubstate = {published}, tppubtype = {inproceedings} } | |
Walter de Back, Marco Wiering, Edwin de Jong Red Queen dynamics in a predator-prey ecosystem Inproceedings Proceedings of the 8th annual conference on Genetic and evolutionary computation - GECCO'06, ACM Press, 2006. @inproceedings{deBack2006b, title = {Red Queen dynamics in a predator-prey ecosystem}, author = {Walter de Back and Marco Wiering and Edwin de Jong}, url = {http://dx.doi.org/10.1145/1143997.1144066}, year = {2006}, date = {2006-01-01}, booktitle = {Proceedings of the 8th annual conference on Genetic and evolutionary computation - GECCO'06}, publisher = {ACM Press}, keywords = {}, pubstate = {published}, tppubtype = {inproceedings} } | |
PhD Theses |
|
| Walter de Back Multicellular Systems Biology of Development PhD Thesis Technische Universität Dresden, 2015. @phdthesis{deBack2015, title = {Multicellular Systems Biology of Development}, author = {Walter de Back}, url = {http://walter.deback.net/wp-content/uploads/2015/11/Thesis_WdB.pdf}, year = {2015}, date = {2015-11-03}, school = {Technische Universität Dresden}, abstract = {Embryonic development depends on the precise coordination of cell fate specification, patterning and morphogenesis. Although great strides have been made in the molecular understanding of each of these processes, how their interplay governs the formation of complex tissues remains poorly understood. New techniques for experimental manipulation and image quantification enable the study of development in unprecedented detail, resulting in new hypotheses on the interactions between known components. By expressing these hypotheses in terms of rules and equations, computational modeling and simulation allows one to test their consistency against experimental data. However, new computational methods are required to represent and integrate the network of interactions between gene regulation, signaling and biomechanics that extend over the molecular, cellular and tissue scales. In this thesis, I present a framework that facilitates computational modeling of multi-scale multicellular systems and apply it to investigate pancreatic development and the formation of vascular networks. This framework is based on the integration of discrete cell-based models with continuous models for intracellular regulation and intercellular signaling. Specifically, gene regulatory networks are represented by differential equations to analyze cell fate regulation; interactions and distributions of signaling molecules are modeled by reaction-diffusion systems to study pattern formation; and cell-cell interactions are represented in cell-based models to investigate morphogenetic processes. A cell-centered approach is adopted that facilitates the integration of processes across the scales and simultaneously constrains model complexity. The computational methods that are required for this modeling framework have been implemented in the software platform Morpheus. This modeling and simulation environment enables the development, execution and analysis of multi-scale models of multicellular systems. These models are represented in a new domain-specific markup language that separates the biological model from the computational methods and facilitates model storage and exchange. Together with a user-friendly graphical interface, Morpheus enables computational modeling of complex developmental processes without programming and thereby widens its accessibility for biologists. To demonstrate the applicability of the framework to problems in developmental biology, two case studies are presented that address different aspects of the interplay between cell fate specification, patterning and morphogenesis. In the first, I focus on the interplay between cell fate stability and intercellular signaling. Specifically, two studies are presented that investigate how mechanisms of cell-cell communication affect cell fate regulation and spatial patterning in the pancreatic epithelium. Using bifurcation analysis and simulations of spatially coupled differential equations, it is shown that intercellular communication results in a multistability of gene expression states that can explain the scattered spatial distribution and low cell type ratio of nascent islet cells. Moreover, model analysis shows that disruption of intercellular communication induces a transition between gene expression states that can explain observations of in vitro transdifferentiation from adult acinar cells into new islet cells. These results emphasize the role of the multicellular context in cell fate regulation during development and may be used to optimize protocols for cellular reprogramming. The second case study focuses on the feedback between patterning and morphogenesis in the context of the formation of vascular networks. Integrating a cell-based model of endothelial chemotaxis with a reaction-diffusion model representing signaling molecules and extracellular matrix, it is shown that vascular network patterns with realistic morphometry can arise when signaling factors are retained by cell-modified matrix molecules. Through the validation of this model using in vitro assays, quantitative estimates are obtained for kinetic parameters that, when used in quantitative model simulations, confirm the formation of vascular networks under measured biophysical conditions. These results demonstrate the key role of the extracellular matrix in providing spatial guidance cues, a fact that may be exploited to enhance vascularization of engineered tissues. Together, the modeling framework, software platform and case studies presented in this thesis demonstrate how cell-centered computational modeling of multi-scale and multicellular systems provide powerful tools to help disentangle the complex interplay between cell fate specification, patterning and morphogenesis during embryonic development.}, keywords = {}, pubstate = {published}, tppubtype = {phdthesis} } Embryonic development depends on the precise coordination of cell fate specification, patterning and morphogenesis. Although great strides have been made in the molecular understanding of each of these processes, how their interplay governs the formation of complex tissues remains poorly understood. New techniques for experimental manipulation and image quantification enable the study of development in unprecedented detail, resulting in new hypotheses on the interactions between known components. By expressing these hypotheses in terms of rules and equations, computational modeling and simulation allows one to test their consistency against experimental data. However, new computational methods are required to represent and integrate the network of interactions between gene regulation, signaling and biomechanics that extend over the molecular, cellular and tissue scales. In this thesis, I present a framework that facilitates computational modeling of multi-scale multicellular systems and apply it to investigate pancreatic development and the formation of vascular networks. This framework is based on the integration of discrete cell-based models with continuous models for intracellular regulation and intercellular signaling. Specifically, gene regulatory networks are represented by differential equations to analyze cell fate regulation; interactions and distributions of signaling molecules are modeled by reaction-diffusion systems to study pattern formation; and cell-cell interactions are represented in cell-based models to investigate morphogenetic processes. A cell-centered approach is adopted that facilitates the integration of processes across the scales and simultaneously constrains model complexity. The computational methods that are required for this modeling framework have been implemented in the software platform Morpheus. This modeling and simulation environment enables the development, execution and analysis of multi-scale models of multicellular systems. These models are represented in a new domain-specific markup language that separates the biological model from the computational methods and facilitates model storage and exchange. Together with a user-friendly graphical interface, Morpheus enables computational modeling of complex developmental processes without programming and thereby widens its accessibility for biologists. To demonstrate the applicability of the framework to problems in developmental biology, two case studies are presented that address different aspects of the interplay between cell fate specification, patterning and morphogenesis. In the first, I focus on the interplay between cell fate stability and intercellular signaling. Specifically, two studies are presented that investigate how mechanisms of cell-cell communication affect cell fate regulation and spatial patterning in the pancreatic epithelium. Using bifurcation analysis and simulations of spatially coupled differential equations, it is shown that intercellular communication results in a multistability of gene expression states that can explain the scattered spatial distribution and low cell type ratio of nascent islet cells. Moreover, model analysis shows that disruption of intercellular communication induces a transition between gene expression states that can explain observations of in vitro transdifferentiation from adult acinar cells into new islet cells. These results emphasize the role of the multicellular context in cell fate regulation during development and may be used to optimize protocols for cellular reprogramming. The second case study focuses on the feedback between patterning and morphogenesis in the context of the formation of vascular networks. Integrating a cell-based model of endothelial chemotaxis with a reaction-diffusion model representing signaling molecules and extracellular matrix, it is shown that vascular network patterns with realistic morphometry can arise when signaling factors are retained by cell-modified matrix molecules. Through the validation of this model using in vitro assays, quantitative estimates are obtained for kinetic parameters that, when used in quantitative model simulations, confirm the formation of vascular networks under measured biophysical conditions. These results demonstrate the key role of the extracellular matrix in providing spatial guidance cues, a fact that may be exploited to enhance vascularization of engineered tissues. Together, the modeling framework, software platform and case studies presented in this thesis demonstrate how cell-centered computational modeling of multi-scale and multicellular systems provide powerful tools to help disentangle the complex interplay between cell fate specification, patterning and morphogenesis during embryonic development. |