Mechanical regulation of cell states

• Sara Wickström (Max Planck Institute for Molecular Biomedicine)

Room: Seminar room - ground floor The structure of tissues is tightly linked to their function. During formation of functional organs, large-scale changes in tissue elongation, stretching, compression, folding/buckling, and budding impact the shape, position, packing, and contractility state of cells. Conversely, changes in single cell contractility, shape and position locally alter tissue organization and mechanics. Thus, forces function as important ques that are transmitted to the nucleus to coordinate gene expression programs to control cell states. On the other hand, excessive mechanical stresses have the potential to damage cells and tissues. In my presentation I will discuss our recent research on how cells use the nucleus and the nuclear envelope/chromatin interface to sense mechanical forces and how these mechanosignals are integrated with biochemical inputs to alter cell states and to generate and maintain tissue architecture.

Melody Swartz

• Melody Swartz (University of Chicago)

Room: Seminar room - ground floor

Genetic Instability – from matrix rigidity effects to physics of tumor elimination by eng’d macrophages

• Dennis Discher (University of Pennsylvania)

Room: Seminar room - ground floor Cancer always exhibits genetic changes, but solid tumors show more changes and greater variance than liquid cancers and soft tumors. To visualize chromosome loss at single cell resolution, a novel fluorescence ‘ChReporter’ method was developed and enables tracking of heritable losses in colonies. Systems studied thusfar range from in vivo tumors to spheroids in gels of controlled stiffness and single cell confinement. ChReporter loss following interphase nuclear rupture is compared to mitotic perturbations, particularly in strong confinement relevant to solid tissues and tumors. The mean and variance of changes conform to the seminal theory of Luria & Delbruck for genetic evolution. Chromosome number changes often associate with poor prognosis in solid tumor types, and for melanoma therapy with Tcell checkpoint blockade also fails. Using poorly immunogenic mouse melanoma, we pharmacologically induce chromosome losses & gains, and find it skews macrophages towards an anti-cancer phenotype. We measure the cohesiveness of the tumors, and upon macrophage addition, cooperativity of low entropy macrophage clusters is revealed in tumor elimination. Success benefits from disrupting the tumor’s Macrophage checkpoint and yields durable cures with anti-cancer antibodies.

The wisdom of the crowd: How bacterial collectives (re)shape themselves

• Sujit Datta (Princeton University)

Room: Seminar room - ground floor Bacteria are arguably the simplest form of life; and yet, as multi-cellular collectives, they perform complex functions critical to environment, food, health, and industry. What principles govern how complex behaviors emerge in bacterial collectives? And how can we harness them to control bacterial behavior? In this talk, I will describe my group's work addressing this question using tools from soft matter engineering, 3D imaging, and biophysical modeling. We have developed the ability to (i) directly visualize bacteria from the scale of a single cell to that of an entire multi-cellular collective, (ii) 3D-print precisely structured collectives, and (iii) model their large-scale motion and growth in complex environments. I will describe how, using this approach, we are developing new ways to predict and control how bacterial collectives — and potentially other forms of "active matter" — spread large distances, adapt shape to resist perturbations, and self-regulate growth to access more space by processing chemical information in their local environments.

Forces at play in receptor-mediated cell adhesion

• Elisabetta Ada Cavalcanti-Adam (University of Bayreuth)

Room: Seminar room - ground floor Over the past decades, advancements in the field of cell adhesion mechanobiology have revealed how cells interact with and respond to their physical environment. This talk will present our findings on the spatial and mechanical regulation of cell-matrix and cell-cell adhesion, and how these interactions affect cell behavior. The integration of multi-scale experimental approaches, ranging from the mechanical regulation of molecular adhesion to the influence of forces in the transition in multicellular systems, will be discussed.

A physics approach to understand aging

• Uri Alon (Weizmann Institute of Science)

Room: Seminar room - ground floor Aging shows nearly universal quantitative patterns. We explain them using a stochastic ODE for damage production and removal, deduced from experiments on damage dynamics in mice and in individual bacteria, the latter done by us. This simple model explains a wide range of phenomena in human aging and age-related diseases, as well as in model organisms. It pinpoints core molecular and cellular drivers of aging, and suggests interventions that, at least in mice, can compress the relative sickspan (fraction of lifespan that an individual is disabled).

Soft matter physics for the rheology of a cell

• David Weitz (Harvard University)

Room: Seminar room - ground floor The mechanical properties of a cell are determined primarily by an interpenetrating network of biopolymers.  This talk will revisit several features of the mechanical properties of a cell.  By using magnetic tweezers to pull a magnetic particle through the cytoplasm of a cell, we show that the particle exhibits unusual behavior:  Its velocity is independent of the force pulling the particle.  This velocity can be used as a probe of the mechanics within the cell and the contribution of the different filament networks.  We suggest that this behavior requires a different constitutive equation to describe the rheology of the cell.  We also reexamine the properties of vimentin intermediate filaments and suggest that their behavior is reminiscent of a self-assembled structure, a worm-like micelle, formed by surfactants.  This perspective accounts for many properties that are observed for vimentin intermediate filament networks.  Vimentin also forms phase-separated liquid droplets that are a precursor to formation of the filament network.  These properties demonstrate how soft-matter physics can be used to describe the mechanical properties of a cell.

How personalised is our immune repertoire?

• Aleksandra Walczak (Ecole Normale Supérieure)

Room: Seminar room - ground floor Immune repertoires provide a unique fingerprint reflecting the immune history of individuals, with potential applications in precision medicine. Can this information be used to identify a person uniquely?  If it really is a personalised medical record, can it inform us about the outcomes of a COVID-19 infection? I will show how statistical analysis of immune repertoires sequencing experiments can answer these questions.

Kandice Tanner

• Kandice Tanner (National Cancer Institute)

Room: Seminar room - ground floor

Emergent memory effects in cell polarity and migration

• Raphael Voituriez (Centre National de la Recherche Scientifique)

Room: Seminar room - ground floor Living cells actively migrate in their environment to perform key biological functions—from unicellular organisms looking for food to single cells such as fibroblasts, leukocytes or cancer cells that can shape, patrol or invade tissues. Cell migration results from complex intracellular processes that enable cell self-propulsion, and has been shown to also integrate various chemical or physical extracellular signals. While it is established that cells can modify their environment by depositing biochemical signals or mechanically remodelling the extracellular matrix, the impact of such self-induced environmental perturbations on cell trajectories at various scales remains broadly unexplored. I will discuss examples where such interactions with the environment can have deep consequences on the large scale cell dynamics, and show that they can effectively endow cells with a memory of their past trajectory.

Geometry-driven organisation in living matter

• Anna Erzberger (EMBL Heidelberg)

Room: Seminar room - ground floor The spontaneous generation of patterns and structures occurs in many living systems and is linked to biological form and function. Such processes often take place on domains which themselves evolve in time, and they can be guided by or coupled to geometrical features. The role of geometry in the self-organisation of functional structures however is not understood. I will present two biophysical examples that illustrate how geometry directs spatial organization across scales. I will discuss how boundary geometry controls a topological defect transition that guides lumen nucleation in embryonic development [1], and how shape can act as a form of memory in cell-cell signaling [2]. [1] Guruciaga et al. arXiv:2403.08710 (2024) [2] Dullweber et al. arXiv:2402.08664v2 (2024)

Lipid membranes and membrane proteins: an intimate relationship

• Patricia Bassereau (Institut Curie)

Room: Seminar room - ground floor Cell membranes, being highly deformable, undergo significant bending during processes like intracellular trafficking. This curvature relies on specific proteins, particularly those intrinsically curved or transmembrane proteins with a conical shape. Proteins diffuse within membranes, enabling redistribution based on changes in membrane shape. In vitro membrane systems with controlled curvature, coupled with theoretical models, help unravel the intricate interplay between membrane shape, protein distribution, lateral diffusion, and their impact on sorting, clustering, and protein activity.

Bottom-up mechanobiology: from cell sheets to organoids

• Xavier Trepat (Institute for Bioengineering of Catalonia (IBEC))

Room: Seminar room - ground floor Epithelial sheets form specialized 3D structures suited to their physiological roles, such as branched alveoli in the lungs, tubes in the kidney, and villi in the intestine. To generate and maintain these structures, epithelia must undergo complex 3D deformations across length and time scales. How epithelial shape arises from active stresses, viscoelasticity and luminal pressure remains poorly understood. I will present different approaches to study the mechanobiology of epithelial shape from the bottom up. I will discuss new technologies to design epithelia of arbitrary size and geometry and to subject them to controlled mechanical deformations in 3D. I will show that monolayers exhibit superelastic behavior when stretch is applied and that they readily buckle when compressed. We use this phenomenology and a 3D vertex model to rationally direct spontaneous pattern formation, and hence engineer tissue folding. I will also present our recent advances to understand the mechanobiology of intestinal organoids. We show that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. Finally, I will discuss how intestinal mechanobiology is derailed in patient-derived colorectal cancer organoids.

Super-resolution imaging of transcription in living cells

• Ibrahim Cisse (Max Planck Institute for Immunobiology and Epigenetics)

Room: Seminar room - ground floor We will discuss the latest efforts in our laboratory to develop highly sensitive methods of microscopy, to go directly inside living cells and uncover the behavior of single biomolecules as they effect their function in transcription. Transcription is the first step in gene expression regulation, during which genetic information on DNA is decoded into RNA transcripts. Methodologically, the so-called live cell single molecule and super-resolution techniques – that break the optical diffraction limit– are revealing with unprecedented spatial and temporal resolutions, novel emergent phenomena inside the living cells. We will discuss our recent discoveries on highly dynamic biomolecular clustering, and phase transitions in vivo. These discoveries are challenging the ‘textbook view’ on how our genome (DNA) is decoded in living cells.

Global coordination of protrusive forces in migrating immune cells

• Michael Sixt (Institute for Science and Technology Austria)

Room: Seminar room - ground floor When migrating through mesenchymal tissues with fibrillar architecture, leukocytes rarely digest or permanently remodel their environment. Instead, they probe their vicinity to sense and select the path of least resistance. To do so they use their frontward-positioned nucleus as a gauge to choose larger pores over smaller ones. We now show that in very dense tissues, where even the largest pores preclude free passage, cells push and laterally displace the surrounding matrix in order to transiently open a path for translocation of the cell body. To this end the cells revert from their usual amoeboid configuration, where the organelles like Golgi and Lysosomes are positioned behind the nucleus, to the mesenchymal configuration, where organelles are positioned towards the front. Associated with organelles we find a central actin pool that responds to mechanical compression and serves to laterally push into the surrounding matrix to transiently dilate a path. This central actin pool communicates with lamellipodial actin, which advances the cell body along the longitudinal axis, establishing a system that either creates space for passage or translocates forward. When we specifically delete the central actin pool, cells migrate faster in unrestricted environments because lamellipodial actin is enhanced. In complex 3D environments, locomotion is impaired because passage through constrictions depends on lateral pushing. Moreover, unleashed lamellipodial protrusion causes dissociation between leading edge and cell body, visible as actively detaching cell fragments that migrate away from the cell body.

Engineering synthetic cells with RNA origami

• Kerstin Göpfrich (Heidelberg University)

Room: Seminar room - ground floor Today’s living cells emerge from the complex interplay of thousands of molecular constituents. Our vision is to create a simpler model of a cell that consists of a lipid vesicle and operates based on our own custom-engineered molecular hardware made from highly functional and folded RNA realized using the co-transcriptional folding of RNA origami. Building on previous work with DNA nanotechnology, where we demonstrated DNA-based mimics of cytoskeletons, capable of cargo transport, force generation and signal transduction [1], we now demonstrated that similar functions can be genetically encoded with RNA origami and expressed inside of vesicles. We developed a high-throughput image-based screening technology based on photopolymerization, to select for highly functional variants of the initially rationally engineered synthetic cells. Ultimately, by coupling vesicle division [2] to their informational content and their function, we aim for a prototype of a synthetic cell capable of evolution. In the context of Physics and Medicine, I will highlight the relevance of both, DNA/RNA origami and image-based selection, for applications in organoid research [3] and immunology [4]. [1] Zhan, P., Jahnke, K., Liu, N., & Göpfrich, K. (2022). Functional DNA-based cytoskeletons for synthetic cells. Nature Chemistry, 14(8), 958-963. [2] Dreher, Y., Jahnke, K., Bobkova, E., Spatz, J. P., & Göpfrich, K. (2021). Division and regrowth of phase‐separated giant unilamellar vesicles. Angewandte Chemie International Edition, 60(19), 10661-10669. [3] Afting, C., Walther, T., Drozdowski, O.M., Schlagheck, C., Schwarz, U.S., Wittbrodt, J., & Göpfrich, K. DNA microbeads for spatio-temporally controlled morphogen release within organoids. Under review in Nature Nanotechnology. [4] Göpfrich, K., Platten, M., Frischknecht, F. & Fackler, F. Bottom-up synthetic immunology. Nature Nanotechnology, accepted.

Elias Barriga

• Elias Barriga (Technical University Dresden)

Room: Seminar room - ground floor

The material world of the human body: from molecule to tissue to disease

• Gijsje Koenderink (Technical University Delft)

Room: Seminar room - ground floor Our bodies are built up of cells and tissues with unique physical properties. Cells and tissues are living materials that combine high mechanical stability with active reshaping. This paradoxical mechanical behavior is governed by fibrous protein scaffolds known as the cytoskeleton and the extracellular matrix. Fibrous networks have many advantageous mechanical properties: fibers can form space-filling elastic networks at low volume fractions and they reversibly stress-stiffen, which provides protection from damage. However, it is still poorly understood how biopolymer networks can combine these features with the ability to dynamically adapt their structure and mechanics. I will summarize recent insights in the fundamental mechanisms from molecule-to-tissue obtained via quantitative measurements on cells and tissues and on simplified reconstituted model systems. In addition, I will discuss connections to applications in biomedicine, in particular for understanding the role of aberrant cell and tissue mechanics in cancer, fibrosis, and osteoarthritis.