I am an experienced postdoctoral research scholar in the Allen Discovery Center at Tufts University and Tufts University Center for Regenerative and Developmental Biology. My passion is for understanding regenerative processes as well as teaching and mentoring undergraduate students. Following my PhD studies at the European Molecular Biology Laboratory studying the biomechanics of cell division processes, I joined the Levin Lab to investigate the control of pattern formation in regenerative processes in the planarian flatworm. Find out more at johannabischof.com Address: Cambridge, Massachusetts, USA
Control of axial polarity during regeneration is a crucial open question. We developed a quantita... more Control of axial polarity during regeneration is a crucial open question. We developed a quantitative model of regenerating planaria, which elucidates self-assembly mechanisms of morphogen gradients required for robust body-plan control. The computational model has been developed to predict the fraction of heteromorphoses expected in a population of regenerating planaria fragments subjected to different treatments, and for fragments originating from different regions along the anterior-posterior and medio-lateral axis. This allows for a direct comparison between computational and experimental regeneration outcomes. Vector transport of morphogens was identified as a fundamental requirement to account for virtually scale-free self-assembly of the morphogen gradients observed in planarian homeo-stasis and regeneration. The model correctly describes altered body-plans following many known experimental manipulations, and accurately predicts outcomes of novel cutting scenarios , which we tested. We show that the vector transport field coincides with the alignment of nerve axons distributed throughout the planarian tissue, and demonstrate that the head-tail axis is controlled by the net polarity of neurons in a regenerating fragment. This model provides a comprehensive framework for mechanistically understanding fundamental aspects of body-plan regulation, and sheds new light on the role of the nervous system in directing growth and form. Author summary Understanding how large-scale anatomy emerges from the activity of cellular pathways is a key goal of evolutionary developmental biology. Elucidating the rules of body-wide mor-phogenesis is especially essential for transitioning molecular signaling data at the cellular level into advances in regenerative biomedicine. We constructed and analyzed a comprehensive , multiscale computational model to explain the determination of axial polarity during planarian regeneration. Uniquely, our model explains the various head-tail pat-terning outcomes of a wide range of molecular and physiological manipulations. Testing the novel predictions of this model revealed the nervous system as an instructive regulator of axial patterning. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.
Axial patterning during planarian regeneration relies on a transcriptional circuit that confers d... more Axial patterning during planarian regeneration relies on a transcriptional circuit that confers distinct positional in-formation on the two ends of an amputated fragment. The earliest known elements of this system begin demarcating differencesbetween anterior and posterior wounds by 6 h post amputation. However, it is still unknown what upstream events break the axial symmetry, allowing a mutual repressor system to establish invariant, distinct biochemical states at the anterior and posterior ends. Here, we show that bioelectric signaling at 3 h is crucial for the formation of proper anterior-posterior polarity in planaria.Briefly manipulating the endogenous bioelectric state by depolarizing the injured tissue during the first 3 h of regeneration alters gene expression by 6 h post amputation and leads to a double-headed phenotype upon regeneration despite confirmed washout of ionophores from tissue. These data reveal a primary functional role for resting membrane potential taking place within the first3 h after injury and kick-starting the downstream pattern of events that elaborate anatomy over the following 10 days. We pro-pose a simple model of molecular-genetic mechanisms to explain how physiological events taking place immediately after injury regulate the spatial distribution of downstream gene expression and anatomy of regenerating planaria
Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medic... more Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medicine, evolutionary biology, morphogenetic engineering, robotics, and unconventional computation. Despite recent advances in the molecular genetics of stem cell differentiation, this model organism's remarkable anatomical homeostasis provokes us with truly fundamental puzzles about the origin of large-scale shape and its relationship to the genome. In this review article, we first highlight several deep mysteries about planarian regeneration in the context of the current paradigm in this field. We then review recent progress in understanding of the physiological control of an endogenous, bioelectric pattern memory that guides regeneration, and how modulating this memory can permanently alter the flatworm's target morphology. Finally, we focus on computational approaches that complement reductive pathway analysis with synthetic, systems-level understanding of morphological decision-making. We analyze existing models of planarian pattern control and highlight recent successes and remaining knowledge gaps in this interdisciplinary frontier field.
Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, ... more Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, such as oocytes and eggs in early animal development. Here we show that cytoplasmic flows in starfish oocytes, which can be imaged well with transmission light microscopy, are fully determined by the cortical dynamics during surface contraction waves. We first show that the dynamics of the oocyte surface is highly symmetric around the animal-vegetal axis. We then mathematically solve the Stokes equation for flows inside a deforming sphere using the measured surface displacements as boundary conditions. Our theoretical predictions agree very well with the intracellular flows quantified by particle image velocimetry, proving that during this stage the starfish cytoplasm behaves as a simple Newtonian fluid on the micrometer scale. We calculate the pressure field inside the oocyte and find that its gradient is too small as to explain polar body extrusion, in contrast to earlier suggestions. Myo-sin II inhibition by blebbistatin confirms this conclusion, because it diminishes cell shape changes and hydrodynamic flow, but does not abolish polar body formation. Author summary As already noted by Aristotle, life is motion. On the molecular scale, thermal motion leads to diffusive transport. On cellular scales, however, diffusion starts to become inefficient, due to the general property of random walks that their spatial excursions grow less than linear with time. Therefore more directed transport processes are needed on cellular scales, including transport by molecular motors or by hydrodynamic flows. This is especially true for oocytes and eggs in early animal development, which often have to be large in order to store sufficient amounts of nutrients. Here we use starfish oocytes as a convenient model system to investigate the nature and function of cytoplasmic flows in early development. These cells are very large and optically transparent, and therefore ideal for live cell imaging that here we combine with image processing and mathematical PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.
Surface contraction waves (SCWs) in oocytes and embryos lead to large-scale shape changes coupled... more Surface contraction waves (SCWs) in oocytes and embryos lead to large-scale shape changes coupled to cell cycle transitions and are spatially coordinated with the cell axis. Here, we show that SCWs in the starfish oocyte are generated by a traveling band of myosin II-driven cortical contractility. At the front of the band, contractility is activated by removal of cdk1 inhibition of the RhoA/RhoA kinase/myosin II signaling module, while at the rear, contractility is switched off by negative feedback originating downstream of RhoA kinase. The SCW's directionality and speed are controlled by a spatiotemporal gradient of cdk1-cyclinB. This gradient is formed by the release of cdk1-cyclinB from the asymmetrically located nucleus, and progressive degradation of cyclinB. By combining quantitative imaging, biochemical and mechanical perturbations with mathematical modeling, we demonstrate that the SCWs result from the spatiotemporal integration of two conserved regulatory modules, cdk1-cyclinB for cell cycle regulation and RhoA/Rok/NMYII for actomyosin contractility.
Control of axial polarity during regeneration is a crucial open question. We developed a quantita... more Control of axial polarity during regeneration is a crucial open question. We developed a quantitative model of regenerating planaria, which elucidates self-assembly mechanisms of morphogen gradients required for robust body-plan control. The computational model has been developed to predict the fraction of heteromorphoses expected in a population of regenerating planaria fragments subjected to different treatments, and for fragments originating from different regions along the anterior-posterior and medio-lateral axis. This allows for a direct comparison between computational and experimental regeneration outcomes. Vector transport of morphogens was identified as a fundamental requirement to account for virtually scale-free self-assembly of the morphogen gradients observed in planarian homeo-stasis and regeneration. The model correctly describes altered body-plans following many known experimental manipulations, and accurately predicts outcomes of novel cutting scenarios , which we tested. We show that the vector transport field coincides with the alignment of nerve axons distributed throughout the planarian tissue, and demonstrate that the head-tail axis is controlled by the net polarity of neurons in a regenerating fragment. This model provides a comprehensive framework for mechanistically understanding fundamental aspects of body-plan regulation, and sheds new light on the role of the nervous system in directing growth and form. Author summary Understanding how large-scale anatomy emerges from the activity of cellular pathways is a key goal of evolutionary developmental biology. Elucidating the rules of body-wide mor-phogenesis is especially essential for transitioning molecular signaling data at the cellular level into advances in regenerative biomedicine. We constructed and analyzed a comprehensive , multiscale computational model to explain the determination of axial polarity during planarian regeneration. Uniquely, our model explains the various head-tail pat-terning outcomes of a wide range of molecular and physiological manipulations. Testing the novel predictions of this model revealed the nervous system as an instructive regulator of axial patterning. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.
Axial patterning during planarian regeneration relies on a transcriptional circuit that confers d... more Axial patterning during planarian regeneration relies on a transcriptional circuit that confers distinct positional in-formation on the two ends of an amputated fragment. The earliest known elements of this system begin demarcating differencesbetween anterior and posterior wounds by 6 h post amputation. However, it is still unknown what upstream events break the axial symmetry, allowing a mutual repressor system to establish invariant, distinct biochemical states at the anterior and posterior ends. Here, we show that bioelectric signaling at 3 h is crucial for the formation of proper anterior-posterior polarity in planaria.Briefly manipulating the endogenous bioelectric state by depolarizing the injured tissue during the first 3 h of regeneration alters gene expression by 6 h post amputation and leads to a double-headed phenotype upon regeneration despite confirmed washout of ionophores from tissue. These data reveal a primary functional role for resting membrane potential taking place within the first3 h after injury and kick-starting the downstream pattern of events that elaborate anatomy over the following 10 days. We pro-pose a simple model of molecular-genetic mechanisms to explain how physiological events taking place immediately after injury regulate the spatial distribution of downstream gene expression and anatomy of regenerating planaria
Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medic... more Planarian behavior, physiology, and pattern control offer profound lessons for regenerative medicine, evolutionary biology, morphogenetic engineering, robotics, and unconventional computation. Despite recent advances in the molecular genetics of stem cell differentiation, this model organism's remarkable anatomical homeostasis provokes us with truly fundamental puzzles about the origin of large-scale shape and its relationship to the genome. In this review article, we first highlight several deep mysteries about planarian regeneration in the context of the current paradigm in this field. We then review recent progress in understanding of the physiological control of an endogenous, bioelectric pattern memory that guides regeneration, and how modulating this memory can permanently alter the flatworm's target morphology. Finally, we focus on computational approaches that complement reductive pathway analysis with synthetic, systems-level understanding of morphological decision-making. We analyze existing models of planarian pattern control and highlight recent successes and remaining knowledge gaps in this interdisciplinary frontier field.
Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, ... more Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, such as oocytes and eggs in early animal development. Here we show that cytoplasmic flows in starfish oocytes, which can be imaged well with transmission light microscopy, are fully determined by the cortical dynamics during surface contraction waves. We first show that the dynamics of the oocyte surface is highly symmetric around the animal-vegetal axis. We then mathematically solve the Stokes equation for flows inside a deforming sphere using the measured surface displacements as boundary conditions. Our theoretical predictions agree very well with the intracellular flows quantified by particle image velocimetry, proving that during this stage the starfish cytoplasm behaves as a simple Newtonian fluid on the micrometer scale. We calculate the pressure field inside the oocyte and find that its gradient is too small as to explain polar body extrusion, in contrast to earlier suggestions. Myo-sin II inhibition by blebbistatin confirms this conclusion, because it diminishes cell shape changes and hydrodynamic flow, but does not abolish polar body formation. Author summary As already noted by Aristotle, life is motion. On the molecular scale, thermal motion leads to diffusive transport. On cellular scales, however, diffusion starts to become inefficient, due to the general property of random walks that their spatial excursions grow less than linear with time. Therefore more directed transport processes are needed on cellular scales, including transport by molecular motors or by hydrodynamic flows. This is especially true for oocytes and eggs in early animal development, which often have to be large in order to store sufficient amounts of nutrients. Here we use starfish oocytes as a convenient model system to investigate the nature and function of cytoplasmic flows in early development. These cells are very large and optically transparent, and therefore ideal for live cell imaging that here we combine with image processing and mathematical PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.
Surface contraction waves (SCWs) in oocytes and embryos lead to large-scale shape changes coupled... more Surface contraction waves (SCWs) in oocytes and embryos lead to large-scale shape changes coupled to cell cycle transitions and are spatially coordinated with the cell axis. Here, we show that SCWs in the starfish oocyte are generated by a traveling band of myosin II-driven cortical contractility. At the front of the band, contractility is activated by removal of cdk1 inhibition of the RhoA/RhoA kinase/myosin II signaling module, while at the rear, contractility is switched off by negative feedback originating downstream of RhoA kinase. The SCW's directionality and speed are controlled by a spatiotemporal gradient of cdk1-cyclinB. This gradient is formed by the release of cdk1-cyclinB from the asymmetrically located nucleus, and progressive degradation of cyclinB. By combining quantitative imaging, biochemical and mechanical perturbations with mathematical modeling, we demonstrate that the SCWs result from the spatiotemporal integration of two conserved regulatory modules, cdk1-cyclinB for cell cycle regulation and RhoA/Rok/NMYII for actomyosin contractility.
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Papers by Johanna Bischof