During development, initially equivalent cells acquire different identities, in a determined spatial order. Although much is known about the mechanisms through which fates are specified, the dynamics by which spatial patterns arise, and the underlying logic, often remain elusive. Drawing on several concrete examples, I will present a geometric approach to cell fate specification - in the spirit of Waddington's epigenetic landscape - and discuss its implications for how we can approach the collective dynamics of self-organized patterning.

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It has been argued that the historical nature of evolution makes it a highly path-dependent process. Under this view, the outcome of evolutionary dynamics could result in organisms with different forms and functions. At the same time, there is ample evidence that convergence and constraints strongly limit the domain of the potential design principles that evolution can achieve. Are these limitations relevant in shaping the fabric of the possible? Here, we argue that fundamental constraints are associated with the logic of living matter. We illustrate this idea by considering the thermodynamic properties of living systems, the linear nature of molecular information, the cellular nature of the building blocks of life, the limits to multicellular complexity, the threshold nature of computations in cognitive systems, and the discrete nature of the architecture of ecosystems. In all these examples, we present available evidence and suggest potential avenues towards a well-defined theoretical formulation. One implication of this proposal is that life elsewhere should share profound commonalities with the life we know from our biosphere, and potential synthetic living designs might also be deeply constrained by the same universal principles.

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Epithelial sealing is a fundamental process occurring during animal development and tissue repair. During this process, mechanical forces are coordinated in order to rearrange biological tissues and ensure a perfect sealing of the epithelium. The mechanisms at the origin of the generation and regulation of these forces during development and wound healing to ensure correct cell positioning and tissue shaping remain elusive. Using Drosophila as a model system, my group is interested in understanding the principles underlying the control of epithelial sealing during embryogenesis and during tissue repair. Here, I will start by presenting how tissue respond to mechanical stretch during tissue sealing in embryonic development. I will highlight the similarities between processes of tissue sealing in development and wound healing. I will then show new results on how the mechanics of sealing is impacted by the size of the gap and present a quantitative model of epithelial mechanics and sealing during wound healing. Finally, I will show how cells can sense mechanical changes occurring during wound generation and how they actively respond to these dramatic tensional changes. I will particularly focus on how wound generation affect chromatin and nuclear architecture and, as a consequence, how changes in chromatin architecture can impact cellular mechanics. 

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The cell cycle is a tightly regulated process that ensures accurate genetic replication and transmission of cellular states across generations. Pluripotent stem cells (PSCs) exhibit a unique balance of robust self-renewal and responsiveness to differentiation cues, resulting in a rapid cell cycle and a heterogeneous, asynchronous differentiation process in vitro. Evidence suggests that the activation of cell-type-specific genes is confined to the G1 phase, which lengthens during differentiation, hinting at a critical link between cell-cycle regulation, pluripotency, and differentiation. However, the regulators and epigenetic mechanisms governing this relationship remain unclear. To address this question, we have developed a novel approach to study gene expression and chromatin accessibility dynamics during the cell cycle. We combined high-depth single-cell multiome sequencing, biophysical modeling, and advanced deep learning techniques. We first used a novel deep learning tool to assign cell cycle phases to individual cells based on spliced and unspliced mRNA levels. Then, we developed a biophysical model that describes mRNA metabolism, including synthesis, splicing, nuclear export, and degradation. Our approach allowed us to unveil temporal waves of transcriptional and post-transcriptional regulation, controlling mRNA synthesis, degradation, and nuclear export during the cell cycle. Additionally, we quantified chromatin accessibility dynamics and identified transcription factor activities at high temporal resolution, uncovering key TFs that coordinate cell-cycle regulation, including known pluripotency factors. Finally, we applied our approach to spatial transcriptomics to study the spatial organization of the cell cycle in tissues and tumors. Overall, we believe that our novel approach will open the possibility to shed new light on the interplay between cell cycle regulation and cell plasticity in health and disease.

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Propagating, storing and processing information is key to take smart decisions – for organisms as well as for autonomous devices. In search for the minimal units that allow for complex behaviour, the slime mould Physarum polycephalum stands out by solving complex optimization problems despite its simple make-up. Physarum’s body is an interlaced network of fluid-filled tubes lacking any nervous system, in fact being a single gigantic cell. Yet, Physarum finds the shortest path through a maze. We unravel that Physarum’s complex behaviour emerges from the physics of active flows shuffling through its tubular networks. Flows transport information, information that is stored in the architecture of the network. Thus, tubular adaptation drives processing of information into complex behaviour. Taking inspiration from the mechanisms in Physarum we outline how to embed complex behaviour in active microfluidic devices and how to program human vasculature.

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Mutations in tumours can serve as markers that allow tracking of past evolution from current samples but also provide insights into future dynamics. In this talk, I present two limiting cases: The first case is a collaboration with the Weghorn lab where we explore the spatio-temporal dynamics of early tumours. We leverage published data from resected hepatocellular carcinomas, each with several hundred samples taken in two and three dimensions. Using spatial metrics of evolution, we find that tumour cells grew predominantly uniformly within the tumour volume rather than at its boundary. We examine how mutations and cells are dispersed throughout the tumour and how cell death contributes to the overall tumour growth. The second case focuses on late tumour evolution under molecularly targeted therapy. In practice, targeted therapy is severely limited by the expansion of therapy-resistant mutants which typically preexist at the start of treatment. How many distinct resistance mechanisms can be found in a realistically-sized population of tumour cells? And can all of them be treated upfront by a suitable combination therapy? An answer is provided for a cell-line model of non-small cell lung cancer.

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My talk will touch on two rather distinct research topics in my lab. First, I will discuss how the adaption of complex traits depends on genetic background. Then we will switch to embryogenesis of C. elegans. How can we optimally leverage the information contained in confocal microscopy imaging of a developing animal system? We use spherical harmonics to systematically describe cell shapes and a biophysical simulation environment to infer the forces in a cellular system.

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DNA methylation changes have emerged as powerful biomarkers of biological aging, yet the underlying mechanisms driving these epigenetic alterations remain incompletely understood. In this talk I will review the rise of epigenetic clocks as biomarkers of biological age and motivate the need for a mathematical description of methylation changes to accurately translate insights from epigenetic clocks into a biological framework. I will show how a parsimonious Markovian model of methylation dynamics successfully leverages age-related methylation changes to uncover mechanisms of longevity across mammalian species and within human populations, suggesting stem cell dynamics as a fundamental driver of aging.

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Active matter systems are intrinsically out of equilibrium in the absence of any external driving. Their collective behavior emerges from a balance between direct interactions and indirect couplings through the medium they move in, and a self-consistent dynamical approach is required to analyze their evolution. The mechanical balance that determines their collective behavior makes these systems very versatile. An understanding on the basic principles underlying the emergence and self-assembly on active systems poses fundamental challenges. I will consider simple models to address the fundamental properties of active systems, which require a consistent dynamic treatment, and will discuss the generic implications that self-propulsion has in the emergence of structures in suspensions of model self-propelled particles. I will discuss the interactions between passive inclusions in an active suspension, where passive particles couple to the active suspension and quickly react to the active particles’ rearrangements. Hence, their relative dynamics plays an important role in the features that characterize the emergent interactions among the inclusions. Moreover, for systems where active particles develop long range polar order, the presence of passive obstacles triggers spontaneous macroscopic structures that give rise to non-reciprocal interactions. I will also discuss the susceptibility of polar active systems to small inclusions and the implications this has on the nature of their ordered phases.

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We suggest a rule-based approach to modeling the development of organs and body plans of animals. We subdivide the problem into gene-regulated cell differentiation, cell-cell signaling, and the physical dynamics of interacting cells that shape organs and bodies. In this talk I will focus on the latter, starting with the overall phenomenology of our bodies as a collection of sheets that forms hollow spheres, tubes and branching tubes. The physics of these two symmetry-breaking events is governed by two types of cell-cell interactions: the Apical-Basal polarity (AB) that directs sheet formation, and the Planar Cell Polarity (PCP) that direct tube formation.  I describe a working dynamical model that deals with these two polarities. The model is applied to the biological process of gastrulation, of neural tube formation, and to mimic the dynamics of branching tubes seen in the growth of lungs or kidneys.

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