Science by the beach

Malaria is still one of the most severe infectious diseases and
the underlying mechanisms are far from being understood. The lifecycle of the malaria parasite is complex and strongly shaped by the requirement to frequently switch between different physical environments.

We first discuss the case of sporozoites, which are the slender forms injected by female mosquitoes into the skin of the vertebrate hosts, and show that its motion patterns are strongly determined by right-handed chirality. We then discuss the blood stage, when the malaria parasite induces a system of adhesive knobs on the surface of infected red blood cells, in order to increase residency time in the vasculature and to avoid clearance by the spleen. In both cases, we combine theoretical models and experimental data to uncover the underlying mechanisms.

Mechanical forces play essential roles in development, most evidently as the drivers of morphogenesis, but also as long-range signals that can support self-organization. Drawing in particular on studies of avian embryogenesis, I will discuss different ways that mechanical self-organization can underlie development across scales, from the emergence of active tissue behaviours to the establishment of an entire body plan.

Aggregates of stem cells can break symmetry and self-organize the morphogenesis of embryo-like structures in vitro. How multicellular patterns emerge from signaling interactions between stem cells is not well understood. We investigate developmental self-organization by engineering stem cells with synthetic genetic circuits that can measure, record, and control morphogen signaling activity. We will describe how this approach can be used to investigate the origins of anterior-posterior patterning in the gastruloid model.

Chromatin, the physiological form of our genome, is composed of DNA and histone proteins. Post-translational modifications of these components, along with their regulatory factors, are essential for maintaining cellular integrity, tissue health, and the overall functioning of organisms. Large-scale sequencing efforts have revealed that alterations in chromatin and epigenetic regulators are commonly associated with human diseases, including developmental disorders and cancers. While significant attention has been directed toward understanding chromatin-modifying enzymes and their dysregulation in disease, less is known about the role of chromatin adaptor/scaffold proteins, which assemble these enzymatic complexes. Our research focuses on this underexplored area, particularly the catalytic-independent activities and scaffolding functions of chromatin-modifying enzymes. By leveraging our expertise in cancer biology and chromatin biochemistry, we investigate how chromatin adaptors decode chemical signals and regulate gene expression in both healthy and diseased states.  One such adaptor, TRIM28 (KAP-1), has been identified as a key regulator of heterochromatin formation and cellular differentiation. Our recent studies have uncovered TRIM28 as an essential epigenetic regulator in acute myeloid leukemia (AML). Inhibiting TRIM28, either biochemically or genetically, significantly reduces leukemia cell proliferation in vivo, accompanied by changes in gene expression, including the upregulation of neutrophil-associated transcriptional programs. These findings suggest that TRIM28 functions as a dual transcriptional regulator, modulating gene expression through its context-specific interactions with proteins and chromatin. The scaffolding function of TRIM28 underscores its potential as a novel therapeutic target in AML treatment, with further research poised to advance targeted leukemia therapies and broaden clinical intervention strategies.

Feedback regulation is one of the overarching principles of biology, acting across scales from molecules to ecosystems. Mechano-chemical feedbacks are at the center of attention of developmental biologists trying to understand the complex interplay between genome regulation and mechanical forces during morphogenesis. How such feedback is initiated remains an open question in many contexts. I will present two recent projects that aim to answer this question in evolution and in development, presenting evidence for the “mechanics first” hypothesis. The models we study are the flies and Hydra.

We investigate how molecular signals, cellular behaviours, and tissue-level changes integrate to generate distinct neuronal subtypes in a defined spatial pattern in the vertebrate neural tube. We focus on how the morphogen Sonic Hedgehog (Shh) coordinates gene regulatory networks to control cell fate decisions. By combining in vivo and in vitro experimental approaches with computational modelling and theoretical frameworks, we examine how dynamic processes – including tissue growth, cell arrangement, and temporal changes in signalling – contribute to the pattern, pace, precision, and proportions of the developing neural tube.

Organoid models are transforming the way we can study human reproduction by enabling modelling of complex tissues and processes that were once inaccessible. In this seminar, I will present how organoid systems derived from the endometrium and placenta provide new insights into the cyclical regeneration of the uterus, its preparation for pregnancy, and how it regulates the development of the placenta. Together, these models offer a unique window into women’s reproductive health across the lifespan.

A central question in biology is how genetic information is integrated across many length scales to shape and pattern cells, organs and organisms. Theoretical biophysics have proven instrumental in proposing minimal conceptual frameworks to understand the self-organizing potential of living matter, as well as to identify key predictions that can be verified experimentally. However, a key feature of multicellular development is not simply the emergence of increasing complex shapes and form, but the fact that this process is robust and reproducible. In this talk, I will present two recent works from our group on understanding how checkpoints for robustness can emerge from simple mechanical principles. Firstly, in the context of intestinal organoid morphogenesis, we show how mechano-sensitive feedbacks can give rise to mechanical bistability, rendering morphogenesis robust to subsequent mechanical perturbations once it’s completed. Secondly, in the context of early mammalian embryogenesis, we show how mechanical compaction can buffer developmental variability and allow embryos to converge towards robust shapes.

We have mapped the branching lineage decisions through which human pluripotent stem cells (hPSCs) differentiate into 25+ different cell-types. At each lineage decision, by activating signals that induce a desired cell-type while repressing signals that induce an alternative fate, we can coerce hPSCs to differentiate into a desired cell-type with high speed and efficiency. This seminar will feature recent vignettes of how we applied this strategy to tackle various developmental questions, including the
diversification of forebrain/midbrain vs. hindbrain neurons and the segregation of artery vs. vein cells from hPSCs.

The overall goal of the Huisken Lab is to systematically study developmental processes in living organisms using custom, non-invasive biomedical imaging techniques. Over the years, we have developed and perfected imaging tools that offer unique possibilities for analyzing vertebrate development. Our primary tool is advanced, customized light sheet microscopy (LSFM, SPIM), which is ideal for imaging biological samples across scales, from small, living organisms to large, fixed, and cleared tissues. Besides the low photo-toxicity and fast acquisition, LSFM offers the advantage of high scalability and customizability: the experimental setup can be optimized for the given sample, which is often crucial to a successful experiment. We have now developed a modular and portable light sheet microscope framework (Flamingo) to streamline this process. Several geometries for various samples have already been realized, and more are to come. The microscope is modular and portable, opening many new opportunities for collaborations, fieldwork in remote areas, teaching, training, and, generally, sharing with other scientists. Despite the instrument’s portability,

Engineering Turing patterns has been one of the most challenging problems in synthetic biology. The patterns have been unsuccessfully pursued by many because they have been notoriously hard to engineer. In the 70 years since the great mathematician Alan Turing first proposed his famous reaction-diffusion patterns, many biologists have tried to get a handle on how these repetitive self-organizing patterns might form from deceptively simple interaction networks. The main problem has been that the classical 2-component Turing circuits are not very robust: even tiny changes in the reaction parameters destroy the patterning. Natural systems, for example those involved in embryonic development (e.g. in bone, tooth and hair formation patterns), are thought to be bootstrapped and somehow stabilize the patterning with larger, more complex dynamical networks. However, how to accomplish this in artificial Turing patterns remained unknown. To solve this conundrum and be able to engineer artificial Turing patterns in a biological system, we identified a more robust 3-node circuit that can be computationally and rationally built with defined genetic components in E. coli. The circuit is a complex pattern generator, generating different kinds of reproducible spot and stripe patterns. Our system is highly tunable and, importantly, is accompanied by a computer model that has been fitted with real, experimentally measured parameters to predict Turing patterning behaviour. This is the first engineered synthetic Turing patterning gene circuit that makes regular repeat spatial patterns.

In the last decade, adult stem cell-derived organoids have become versatile tools in disease modelling and bioengineering. The possibilities to expand healthy human tissue of almost every organ and control its differentiation states makes these 3D tissue models a suitable platform for studies in diverse research areas. Among these are host-microbiome interactions, where numerous clinical associations await functional validation. Here, I highlight our recent advances in modelling cancer-microbiome interactions using organoids and organs-on-chips. I discuss approaches to expose human intestinal organoids to cancer-associated bacteria and the various read-outs which can provide mechanistic insights into their crosstalk. A particular focus is laid on genotoxic bacteria that can induce mutations in cancer genomes and on intracellular bacteria and their roles in colorectal cancer disease progression and metastasis.

Nicolas Rivron has promoted the self-organization of stem cells into models of mouse and human blastocysts, named blastoids. Blastoids are morphologically and transcriptionally similar to the blastocyst and contain analogs of all three cell types that would eventually develop into the complete organism (embryonic and extraembryonic). Using this approach, he is investigating the genome evolution underlying species-specific aspects of blastocyst development and implantation, with the long-term goal of understanding the evolutionary basis of suboptimal human pregnancy (50% of fertilized eggs never develop). This knowledge could help solve the global health problems of family planning and developmental origin of health and disease.

Vivian Li lab studies signalling regulation of intestinal stem cell and cancer. Their recent findings have redefined the transcriptional regulation of intestinal stem cell fate decision. The Li lab has also pioneered the use of organoids for organ reconstruction and disease modelling. They have recently developed intestinal tissue engineering strategies to reconstruct patient-specific functional and transplantable jejunal grafts using patient-derived organoids, offering treatment hopes to intestinal failure patients.

The shaping of epithelial tissues into functional organs often depends on dynamic changes of mechanical tension at the apicala nd basal side of cells. While at the apical side, tension is known to be regulated by the apical actomyosin meshwork, basal tension regulation remains elusive due to the presence of a basal sheet of specialized extracellular matrix, the basement membrane. I am presenting a study in which we used atomic force microscopy to provide direct measurements of mechanical tension in the basal surface of the wing disc epithelium of the fruit fly Drosophila. We find that there is a homeostatic elastic stretch of the solid-like basement membrane in the epithelium that generates a major contribution to basal tension.

I will discuss how reaction-diffusion (RD) unreasonably recapitulates the diversity of skin patterns observed in real animals, how cell biology validates RD as an effective description of skin colour patterning, how hysteresis and manifold shape can have large impacts on RD patterns, how dimensionality reduction can generate high-ordering of Turing patterns, how Cellular-Automaton dynamics emerge from non-trivial interactions between RD and Geometry, how RD predicts a diversity of scale-by-scale patterns in lizards, and how unreasonably robust phenomenological RD models are.

Cancer initiation results from a complex interaction between genetic mutations and environmental insults that reprogram cell identity and tissue state. These changes are highly reminiscent of wound healing processes yet, paradoxically, contribute to cancer development and metastatic progression. I will present our work combining profiling methods and functional genomics tools to dissect how physiological cell and tissue plasticity is co-opted during tumor development. We uncover aberrant chromatin states induced by the cooperative effects of tissue damage and oncogenic KRAS that distinguish neoplastic from regenerative processes and prime discrete epithelial cell populations for neoplastic transformation.

My lab focuses on the study of cancer from a genomics perspective. We have contributed in the identification of cancer genes and driver mutations across cancer types, in the interpretation of tumor genomes for precision cancer medicine, in the discovery of the variation of mutation rate along the genome, in the identification of mutational signatures of cancer treatment and in the identification of genes involved in clonal hematopoiesis.

Flow networks are essential for both living organisms and engineered systems. Very often they are successfully modeled as networks of linear resistors, however, in the animal and plant circulatory system the resistance of each element can be highly nonlinear, and even present negative differential resistance. Inspired by these systems, we have proposed a mathematical model for nonlinear flow networks. We will describe its complex phenomenology and show how we are building such systems in the lab, where we exploit fluid-structure interactions to build tunable valves that can be arranged to create nonlinear flow networks. Finally, we will discuss preliminary experimental results of a network that behaves as a fluidic memristor.

The correct communication between neurons is crucial for development and survival of the organism. Defects in neurotransmission lead to neurological disorders or misinterpretion of perceived threats. To overcome defects in cellular communication, we developed a synthetic, photon-based signaling system that enables the transmission of information from one neuron to another, a feature inherent to synaptic communication.

All animals go through morphogenesis during their embryonic development, but the evolutionary origin of this process is mysterious. Recently, insights have come from the study of the closest living relatives of animals: the choanoflagellates. Choanos are aquatic
microeukaryotes that can alternate between being unicellular and developing into facultative multicellular colonies, and thus represent a possible proxy to very early steps in the evolution of animal embryonic development. I will discuss recent insights from our lab and others in the control of cellular and multicellular shape and movement in choanos, and what they might teach us about our own evolutionary history.

Microfluidic devices have opened the door to a new era of time-lapse microscopy, where the processing of the high number of images and their analysis will become crucial. We will show the potential strength of a new paradigm arising in the integration of microfluidic devices (i.e., organ on chip), time-lapse
microscopy analysis, and machine learning approaches with some application examples.

Oocytes are born within syncytial structures where interconnected germ cells exchange cytoplasm with each-other — only a few grow and others shrink
away. Using quantitative analysis and concepts of mechanics and hydraulics, I will discuss what physical mechanisms underlie this crucial decision making of
growth-shrinkage and hence life-death in germ cell fate. I will end with a general outlook of the mechanics of syncytial organs and the emerging field of tissue hydraulics.

The Bartfeld lab is interested in the molecular basis of epithelial diseases, especially host cell responses to infections of the gastrointestinal tract. While asking basic mechanistic questions in infection, innate immune signaling and cancer biology, the group always strives to develop and improve in vitro models. The group almost exclusively works with adult stem cell-derived organoids as model for human physiology and pathology.

Relative to conventional two-dimensional (2-D) culture, three-dimensional (3-D) suspension culture of epithelial cells more closely mimics the in vivo cell microenvironment regarding cell architecture, cell to matrix interaction, and osmosis exchange. By applying mechanical cell culture switching from a 2D culture context to a 3D culture environment, we demonstrate that skin keratinocytes can be phenotypically reprogrammed to spatiotemporally pattern wound healing ex vivo.

Francis Corson, Laboratoire de Physique de l’École Normale Supérieure

Harry McNamara, Yale University

Yadira Soto-Feliciano, Massachusetts Institute of Technology

Pavel Tomancak, Max Planck Institute of Molecular Cell Biology and Genetics

James Briscoe, The Francis Crick Institute

Margherita Turco, Friedrich Miescher Institute

Jens Puschhof, German Cancer Research Center

Mark Isalan, Imperial College of London

Jan Huisken, University of Göttingen

Kyle Loh, Stanford University

Edouard Hannezo, Institute of Science and Technology of Austria

Trudy Oliver, Duke University

Arnau Sebé-Pedrós, Centre de Regulació Genòmica, Barcelona

Michael Krieg, The Institute of Photonic Sciences, Castelldefels

Miguel Ruiz García, Universidad Carlos III de Madrid

Núria Lopez-Bigas, Institut de Recerca Biomèdica de Barcelona

Direna Alonso-Curbelo, Institut de Recerca Biomèdica de Barcelona

Michel C Milinkovitch, University of Geneva & Swiss Institute of Bioinformatics

Elisabeth Fischer-Friedrich, Technische Universität of Dresden

Vivian Li, The Francis Crick Institute

Nicolas Rivron, Institute of Molecular Biotechnology of Austria

Elias Barriga, Technische Universität Dresden

Yvon Woappi, Columbia University in the City of New York

Sina Bartfeld, Technische Universität Berlin

Arghyadip Mukherjee, École Normale Supérieure, Paris

Eugenio Martinelli, University of Rome Tor Vergata

Elena Martinez, Institute for Bioengineering of Catalonia

Stephan Grill, Max Plank Institute

Thibaut Brunet, Institute Pasteur

Juan Garaycoechea, Hubrecht Institute

Olivier Pourquie, Hardvard University

Bertrand Benazeraf, Centre de biologie du développement, Toulouse