We present a topology grounded, multiscale simulation platform for morphogenesis and biological active matter. Morphogenesis and biological active matter represent keystone problems in biology with additional, far-reaching implications across the biomedical sciences. Addressing these problems will require flexible, cross-scale models of tissue shape, development, and dysfunction that can be tuned to understand, model, and predict relevant individual cases. Current approaches to simulating anatomical or cellular subsystems tend to rely on static, assumed shapes. Meanwhile, the potential for topology to provide natural dimensionality reduction and organization of shape and dynamical outcomes is not fully exploited. TopoSPAM combines ease of use with powerful simulation algorithms and methodological advances, including active nematic gels, topological-defect-driven shape dynamics, and an active 3D vertex model of tissues. It is capable of determining emergent flows and shapes across scales.

Mechanical forces are crucial for driving and shaping tissue morphogenesis during embryonic development1-3. However, their relevance for the evolution of development remains poorly understood4. Here we show that an evolutionary novelty of fly embryos-the patterned embryonic invagination known as the cephalic furrow5-7-has a mechanical role during Drosophila gastrulation. By integrating in vivo experiments and in silico simulations, we demonstrate that the head-trunk boundary of the embryo is under increased compressive stress due to the concurrent formation of mitotic domains and germ band extension and that the cephalic furrow counteracts these stresses, preventing mechanical instabilities during gastrulation. Then, by comparing the genetic patterning of species with and without the cephalic furrow, we find evidence that changes in the expression of the transcription factor buttonhead are associated with the evolution of the cephalic furrow. These results suggest that the cephalic furrow may have evolved through the genetic stabilization of morphogenesis in response to the mechanical challenges of dipteran gastrulation. Together, our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.

How complex 3D tissue shape emerges during animal development remains an important open question in biology and biophysics. Here, we discover a mechanism for 3D epithelial shape change based on active, in-plane cellular events that is analogous to inanimate “shape programmable” materials, which undergo blueprinted 3D shape transformations from in-plane gradients of spontaneous strains. We study eversion of the Drosophila wing disc pouch, when the epithelium transforms from a dome into a curved fold, quantifying 3D tissue shape changes and mapping spatial patterns of cellular behaviors on the evolving geometry using cellular topology. Using a physical model inspired by shape programming, we find that active cell rearrangements are the major contributor to pouch eversion and validate this conclusion using a knockdown of MyoVI, which reduces rearrangements and disrupts morphogenesis. This work shows that shape programming is a mechanism for animal tissue morphogenesis and suggests that patterns in nature could present design strategies for shape-programmable materials.

How morphogenetic movements are robustly coordinated in space and time is a fundamental open question in biology. We study this question using the wing of Drosophila melanogaster, an epithelial tissue that undergoes large-scale tissue flows during pupal stages. Previously, we showed that pupal wing morphogenesis involves both cellular behaviors that allow relaxation of mechanical tissue stress, as well as cellular behaviors that appear to be actively patterned (Etournay et al., 2015). Here, we show that these active cellular behaviors are not guided by the core planar cell polarity (PCP) pathway, a conserved signaling system that guides tissue development in many other contexts. We find no significant phenotype on the cellular dynamics underlying pupal morphogenesis in mutants of core PCP. Furthermore, using laser ablation experiments, coupled with a rheological model to describe the dynamics of the response to laser ablation, we conclude that while core PCP mutations affect the fast timescale response to laser ablation they do not significantly affect overall tissue mechanics. In conclusion, our work shows that cellular dynamics and tissue shape changes during Drosophila pupal wing morphogenesis do not require core PCP as an orientational guiding cue.

Mechanical forces are crucial for driving and shaping the morphogenesis of tissues and organs during embryonic development. However, their relevance for the evolution of morphogenetic processes remains poorly understood. Here we show that a morphogenetic innovation present in fly embryos—a deep epithelial fold known as the cephalic furrow—plays a mechanical role during Drosophila gastrulation. By integrating in vivo experiments and in silico simulations, we find that the formation of the cephalic furrow effectively prevents mechanical instabilities at the head–trunk epithelium by absorbing the compressive stresses generated by concurrent morphogenetic movements. Furthermore, by comparing the expression of known and novel genes involved in cephalic furrow formation between fly species, we find that the presence of the cephalic furrow is linked to the appearance of a novel buttonhead expression domain at the head–trunk boundary. These data suggest that the genetic control of cephalic furrow formation was established through the integration of a new player into the ancestral head–trunk patterning system, and that mechanical instability may have been the selective pressure associated with the evolution of the cephalic furrow. Our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.

Cell migration is crucial for organismal development and shapes organisms in health and disease. Although a lot of research has revealed the role of intracellular components and extracellular signaling in driving single and collective cell migration, the influence of physical properties of the tissue and the environment on migration phenomena in vivo remains less explored. In particular, the role of the extracellular matrix (ECM), which many cells move upon, is currently unclear. To overcome this gap, we use zebrafish optic cup formation, and by combining novel transgenic lines and image analysis pipelines, we study how ECM properties influence cell migration in vivo. We show that collectively migrating rim cells actively move over an immobile extracellular matrix. These cell movements require cryptic lamellipodia that are extended in the direction of migration. Quantitative analysis of matrix properties revealed that the topology of the matrix changes along the migration path. These changes in matrix topologies are accompanied by changes in the dynamics of cell-matrix interactions. Experiments and theoretical modeling suggest that matrix porosity could be linked to efficient migration. Indeed, interfering with matrix topology by increasing its porosity results in a loss of cryptic lamellipodia, less-directed cell-matrix interactions, and overall inefficient migration. Thus, matrix topology is linked to the dynamics of cell-matrix interactions and the efficiency of directed collective rim cell migration during vertebrate optic cup morphogenesis.

Diverse modes of cell migration shape organisms in health and disease and much research has focused on the role of intracellular and extracellular components in different cell migration phenomena. What is less explored, however, is how the arrangement of the underlying extracellular matrix that many cells move upon in vivo influences migration. Combining novel transgenic lines and image analysis pipelines, reveals that during zebrafish optic cup formation cells use cryptopodia-like protrusions to migrate collectively and actively over a topologically changing matrix. These changing topologies correspond to different cell-matrix interactions. Interference with matrix topology results in loss of cryptopodia and inefficient migration. Thus, matrix topology influences the efficiency of directed collective cell migration during eye morphogenesis, a concept likely conserved in other developmental and disease contexts. One-Sentence Summary Dynamic cell-matrix interactions, crucial for successful collective rim cell migration, rely on extracellular matrix topologies during optic cup development in vivo .

Liquid crystal elastomers (LCEs) can undergo large reversible contractions along their nematic director upon heating or illumination. A spatially patterned director within a flat LCE sheet thus encodes a pattern of contraction on heating, which can morph the sheet into a curved shell, akin to how a pattern of growth sculpts a developing organism. Here we consider, theoretically, numerically and experimentally, patterns constructed from regions of radial and circular director, which, in isolation, would form cones and anticones. The resultant surfaces contain curved ridges with sharp V-shaped cross-sections, associated with the boundaries between regions in the patterns. Such ridges may be created in positively and negatively curved variants and, since they bear Gauss curvature (quantified here via the Gauss-Bonnet theorem), they cannot be flattened without energetically prohibitive stretch. Our experiments and numerics highlight that, although such ridges cannot be flattened isometrically, they can deform isometrically by trading the (singular) curvature of the V angle against the (finite) curvature of the ridge line. Furthermore, in finite thickness sheets, the sharp ridges are inevitably non-isometrically blunted to relieve bend, resulting in a modest smearing out of the encoded singular Gauss curvature. We close by discussing the use of such features as actuating linear features, such as probes, tongues and limbs, and highlighting the similarities between these patterns of shape change and those found during the morphogenesis of several biological systems.

As a lab, we fondly remember the last session of a recent lab retreat in a remote and peaceful venue in Poland that Suzanne loved very much, which was reserved for discussing the lab’s vision. Dressed in a bright orange dress, she vividly talked about how temperature changes can affect both the physical properties of materials and the regulation of cellular metabolism. The way she presented unapparent connections to us, while wildly gesticulating, inspired everyone to look beyond our own project focus. With Suzanne’s death, the world has lost not only a remarkably passionate scientist but also a wonderful woman and a kind human being, one who has given so much and had so much more to give. We have lost the ground from under our feet, the joy of having her melodic voice guiding us through our everyday work, and the endless supply of positivity and excitement for science. Beyond her passion and enthusiasm, it was her broad curiosity and brilliant capacity to take in and synthesize information from multiple areas that made her exceptional. Those of us who have stayed longer in Suzanne’s lab were lucky enough to witness the changes and growth that her thoughts and interests underwent. Suzanne said once that our research directions should evolve, not because all questions are answered but because new ideas and enthusiasm emerge from discovering a different field. As she herself expressed in her 2013 interview with The Journal of Cell Biology, “. . . what a powerful thing it is to take two supposedly separate fields—cell biology and developmental biology—and wear both hats at the same time” (Sedwick, J Cell Biol. 202, 184–185). While Suzanne’s experimental approaches and interests were dynamic and ever-evolving, a common thread through her career was the question of how tissue growth and pattern are regulated during development. She aimed to address this question from multiple angles and ultimately unify our collective understanding of how cell-cell signaling, physical forces, and metabolic reactions are intricately intertwined. These interests stemmed from her diverse training in genetics, cell biology, and development. She began her career earning a PhD focused on the regulation of transcription before moving on to her first postdoc position with Tom Kornberg, with the goal of understanding how spatial patterns of transcription emerge in developing tissues. Then, rather than stay in the realm of transcription, Suzanne chose to delve into the field of cell biology, joining Kai Simons at the EMBL for a second postdoc. There, she investigated the mechanisms underlying the emergence of tissue polarity and membrane organization. As an independent group leader, she established and maintained two primary research directions for her lab, stemming from her experiences in both postdoc positions: how lipids influence signaling pathways and what mechanisms generate tissue-scale polarity and morphology. While either of these topics could have been the subject of a lab on its own, it was her juxtaposition of these topics and her commitment to cross-disciplinary research that not only made her lab such an excellent training environment for us as young scientists but also advanced the field of developmental biology as a whole in exciting ways. As Suzanne was beginning her independent research, a major question in the field of development concerned the mechanism by which certain important signaling molecules, specifically Hedgehog (Hh) and Wingless (Wg), could have long-range effects on tissue patterning. What was puzzling was the fact that these proteins, now recognized as morphogens, are covalently modified by lipid moieties and thus are strongly associated with cell membranes. How then are they secreted and how do they travel to influence the spatial pattern of gene expression at the tissue scale? Suzanne’s lab investigated this question using the Drosophila wing imaginal disc, a system with powerful tools for investigating spatial patterning. During her time at EMBL she showed that Drosophila membranes contain sterol-rich microdomains where GPI- and sterol-linked proteins are targeted. Interestingly, she demonstrated that such proteins can be released and travel through the tissue to be received several cells away from the source. Upon further investigation, she made the discovery that lipid-linked Hh and Wg associate with lipoprotein particles—lipid-protein assemblies that are the major vehicles for systemic lipid transport. This landmark result opened up new avenues by which morphogen signaling pathways could be regulated in complex ways. Anything affecting the uptake and travel of lipoproteins, such as heparan-sulfate proteoglycans, could thereby also affect tissue patterning. Furthermore, anything associated with those particles could potentially affect the signaling of these morphogens in the receiving tissues. Indeed, she showed that endocannabinoids packaged in lipoproteins could inhibit the Hh pathway. This regulation by inhibitory lipids involves a synergy between two distinct forms of secreted Hh: the lipoprotein-associated, long-range acting form and the non-sterol-modified, short-range acting form. In later years, she confirmed that many of these fundamental insights into Hh signaling are conserved through mammals. In this direction, she plunged into exploring the clinical aspects of the Hh signaling pathway in mammalian tissue culture and mouse disease models. Because lipoproteins are systemically circulating, Suzanne also became increasingly interested in the connection between the signaling occurring within any given tissue and the inter-organ communication underlying systemic-level coordination of growth and nutrition. Along this line, she made the surprising discovery that Hh could not only affect tissue patterning but also serves as a circulating endocrine factor helping to globally coordinate nutrient availability, resource utilization during starvation, and the growth and developmental progression of the whole organism. Another interesting discovery, achieved in close collaboration with mass spectrometry experts in Dresden, was that the entire lipid and sterol composition of the fly could be altered by changing its food source. This result demonstrated the unique power of using Drosophila to address how lipids influence developmental signaling on many levels. For example, she found that lipids coming from the yeast that the flies were eating could cross the blood-brain barrier and signal to insulin-producing neurons to accelerate larval development. In addition, she found that the plant-derived lipids are the feeding choice of flies at lower temperatures, because the dietary plant lipids maintain membrane fluidity, thus representing an adaptive behavioral response that increases survival in cold environments. Together, her research along this direction demonstrates Suzanne’s success in connecting multiple scales of biological organization: molecule, cell, tissue, and organism. Another major focus of Suzanne’s research involved the coupling between the tissue-patterning systems discussed above to the mechanical forces that are involved during morphogenesis, the dynamic series of events that shape a tissue into its final form. During her second postdoc with Kai Simons, she investigated the molecular players that regulate the actin cytoskeleton to establish and maintain the polarity of cells—along both apical/basal and planar axes—in the Drosophila wing epithelium. She studied the role of two small GTPases, Cdc42 and Rac1, in organizing the apical and basal pools of actin and the importance of this organization for cell and tissue morphology during the larval stages of wing development. Additionally, she found that these GTPases are required during pupal stages for accurate positioning and growth of the hairs that eventually emerge from each cell of the wing and cover its entire surface. The orientation of these hairs is globally coordinated so that each hair points in the same direction, along the proximal-distal axis of the wing. Suzanne undoubtably recognized this system again as a powerful model for addressing multi-scale coordination, from the molecular players regulating actin polymerization, to the definition of polarity in individual cells, to the tissue-scale alignment of these axes among its thousands of component cells. Suzanne’s independent work in this direction began by studying the emergence of this characteristic hair pattern and its relationship to the packing of the cells within the epithelium. A complex of interacting proteins termed the “planar cell polarity (PCP)” system had been identified as being essential for the global alignment of wing hairs. However, Suzanne also observed that the cell shape patterns are perturbed in PCP mutants. In wild type, by the end of wing development, the tightly packed cells of the epithelium are globally organized into an almost crystalline, hexagonal array. How then does the PCP system affect the geometry of cell packing? Her curiosity in this question, coupled with her characteristic penchant for seeking out new perspectives, triggered a long-lasting collaboration with the theoretical physicist, Frank Jülicher, at the Max Planck Institute for the Physics of Complex Systems, a neighboring institution to her then-newly established Max Planck Institute for Cell Biology and Molecular Genetics in Dresden. Together, they developed a model, inspired by the physics underlying the packing and behavior of inanimate soap bubbles, to explain how the physical forces acting on epithelial cell boundaries influence the way that cells pack within a tissue. Their model includes three parameters that describe the mechanics involved, which they then experimentally estimated using the wing tissue. The so-called vertex model was published in a landmark paper at the dawn of the recent resurgence of interest in the physical basis of morphogenesis, and since then, the vertex model has been re-used and expanded upon in many other systems. Suzanne continued investigating how tissue-scale patterns of PCP emerge and reorient during growth and morphogenesis. To answer the original question of how PCP mutants end up with strange packing patterns, she sought to investigate the dynamics of pupal wing morphogenesis, developing live imaging methods to follow exactly what the tissue and its component cells were doing. What Suzanne and Frank found was that the tissue was extremely dynamic at this stage, with one part of the tissue contracting and seemingly pulling on the rest of the epithelium, causing cells to stretch and rearrange. Interestingly, these large-scale tissue flows correlated with a global realignment of the PCP pattern, from an almost radial pattern oriented toward the margin to a pattern aligned along the proximal-distal axis of the wing. This result was a fundamentally important example that physical forces, not just signaling by molecules such as Hh and Wg, could be important for global, tissue-scale pattern formation. Suzanne also investigated the question of how these PCP patterns first emerge by probing at earlier stages of wing development. Together with Frank, she identified when these patterns begin to emerge and demonstrated that they are oriented by the signaling systems that pattern the tissue, including her favorites, Hh and Wg. They observed that disturbing the activity in these pathways did not prevent the emergence of the pattern, only its global orientation. They proposed that the global alignment of PCP patterns is coordinated at both earlier and later stages by the dynamics and mechanics of growth and morphogenesis. Recently, she again began exploring this idea by first pushing forward the technical advancements necessary to probe cellular behaviors using live imaging of wing disc explants. This work illustrates Suzanne’s vision of a holistic understanding of tissue development that encompasses both morphogen signaling and physical forces. Suzanne seemed undaunted by the complexity involved in the development of tissue form and pattern, which involves the coordinate behaviors of thousands of cells over long stretches of time. Her efforts to understand this problem in its entirety, and her commitment to incorporating physical modeling in her work, led to the development of two new tools for systematically quantifying cellular activity and patterns of polarity during tissue morphogenesis: Tissue Analyzer and Tissue Miner. These tools fully quantify tissue behavior from the additive contributions of different types of cellular behaviors, which is critical for bridging the scales between cellular activity and tissue morphology. Having developed these novel tools, Suzanne was recently excited to explore how molecular perturbations affect these large-scale behaviors. Her last paper describes how altering the endocytic trafficking of E-cadherin, an important molecular requirement for cell adhesion and tissue cohesion, affects the viscoelasticity of the entire tissue and speed by which the tissues respond to the mechanical forces generated during tissue flows. This piece of work again demonstrates that Suzanne was already succeeding in her long-term goal of understanding the complexity of tissue development from the molecular to tissue scales. Suzanne’s intricate understanding of the multi-scale regulation of tissue development was unique. Her research contributed greatly to our knowledge of the cellular machinery involved in morphogen spread and the spatial patterning of gene expression during development. Furthermore, her vision was to connect these spatial patterns in gene expression and signaling to the physical forces underlying dynamic morphogenetic events. We believe that her research vision and style will continue to inspire the broader community for generations to come. Suzanne was considered an outstanding and influential scientist across multiple fields by many of her colleagues. In the words of one of her collaborators, Prof. Stefan Bornstein, Suzanne “had not only built a successful career for herself but was also instrumental in making Dresden one of the leading research centers in Germany and beyond.” Striving to enhance the interdisciplinary scientific environment in Dresden, she was a leading force behind the establishment of the new cluster of excellence, “Physics of Life.” Having lost our mentor and role model, we can only hope we inherited some of her vision and passion for science and life. She taught us to stay excited about new results but be critical in their interpretation, to stand by our hypothesis but be open to modifying it in the face of new findings. We admired her diverse interests and the way she made fitting them all in a 24 h day seem possible and even effortless. We especially loved her everlasting positivity, compassion, passion for her work, and thoughtfulness. Thank you, Suzanne, for showing us what a successful scientist, woman, and person looks like, in its most basic and pure form. Your spirit will live with us forever.

This year's Lasker-Bloomberg Public Service Award goes to GAVI, the Vaccine Alliance, for providing sustained access to childhood vaccines around the globe, saving millions of lives, and highlighting the power of immunization to prevent disease.