Generative biology: new approaches to study developmental design principles

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 sense mechanical forces and how these mechanosignals are integrated with biochemical inputs to alter cell states in health and disease.

Dr Sara Wickström

Max Planck Institute for Molecular Biomedicine, Germany

Dr Sara Wickström

Max Planck Institute for Molecular Biomedicine, Germany

Sara Wickström received her MD in 2001 and PhD in 2004 from the University of Helsinki, Finland. After postdoctoral training at the Max Planck Institute (MPI) for Biochemistry she became Group Leader at the MPI for Biology of Ageing in 2010. In 2018 her laboratory moved to the University of Helsinki where she was professor of Cell and Developmental Biology. In 2022 Wickström was appointed as Director of the MPI for Molecular Biomedicine in Münster.

Research in the Wickström lab aims to understand how mammalian epithelial tissues are generated and maintained. We particularly focus on how mechanical forces and cellular interactions integrate single cell behaviours to pattern these structurally extremely robust yet dynamic tissues.

Cell-cell interactions profoundly influence cellular decision-making during development, in homeostasis, and during the onset and progression of disease. However, identifying these interactions and decoding their downstream effects remains technically challenging due to a shortage of relevant analytical approaches.

We have developed a series of engineering biology tools that make it possible to fluorescently label cells that neighbour any cell of interest. This allows us, for example, to fluorescently label healthy cells interacting with mutant cells, or pluripotent cells interacting with differentiated cells. Live labelled neighbours and unlabelled non-neighbours can be isolated by flow cytometry for further downstream analysis; this includes both ‘omics studies and functional assays on these live interacting cells.

The establishment of this type of technology relies on finely tuned genetic circuits, and requires iterative comparison of different transgenic structures through a series of design-build-test-learn cycles. Historically, these cycles have been complicated by “apples to pears” comparisons of different transgenes delivered episomally or randomly integrated in various genomic regions, which confound results due to variable delivery efficiencies, differing levels of transgene expression, and transgene silencing. To overcome this hurdle, we generated clonal “master” cell lines harbouring two insulated modular genomic landing pads integrated in safe harbour sites. These lines allow for rapid and convenient transgene integration in the same genomic loci, removing all variability caused by episomal delivery or random integration, and allowing for true "apples to apples" comparisons.

Dr Matthias Malaguti

University of Edinburgh, UK

Dr Matthias Malaguti

University of Edinburgh, UK

Mattias Malaguti has spent his entire career at the University of Edinburgh. From undergraduate research in Tom Burdon’s lab (Roslin Institute) through PhD and postdoctoral studies in Sally Lowell’s lab (Institute for Stem Cell Research), he has consistently focused on developing and adapting novel technologies for use in developmental biology models, aiming to address previously intractable biological questions.

Driven by an interest in how neighbouring cells influence each other's decisions, and frustrated by quantitative imaging limitations in growing embryos, Mattias recently developed engineering biology tools to identify and isolate live interacting cells.

He now leads his own group at the Centre for Engineering Biology, where he leverages these innovative tools to investigate how healthy cells sense and respond to mutant neighbours in models of development and disease.

Tissues are not random assemblies of cells; instead, they are highly organized structures in which cells of distinct types are spatially patterned to create tissue form and function. This organization is governed by precise, dynamic patterns of signalling activity that unfold across space and time. For simplicity, I refer to these coordinated signalling activities as a tissue’s signalling landscape. These landscapes shape how cells acquire their identities, interact with one another, and ultimately give rise to tissue architecture and function. While the core genetic components of key developmental signalling pathways are well studied, it remains unclear how they act together to establish the signalling landscapes. For example, how are such landscapes created with spatial precision and adapted for diverse tissue contexts? To address these questions, my lab uses synthetic reconstitution approaches to build signalling landscapes from the ground up in genetically minimal, “blank-slate” cells. By reconstructing modules, such as morphogen gradients and planar cell polarity systems, we aim to identify the minimal set of components required for the formation of signalling landscapes and uncover the general principles that govern their dynamics and evolution. In this talk, I will present our recent findings and the broader implications for understanding tissue patterning.

Dr Pulin Li

Whitehead Institute, MIT, US

Dr Pulin Li

Whitehead Institute, MIT, US

Pulin Li is the Eugene Bell Career Development Professor of Tissue Engineering at MIT and a member of the Whitehead Institute. She completed a PhD in Chemical Biology from Harvard University and did her postdoctoral work at Caltech. Her lab studies how cell-cell communication spatially organizes cells into patterns and shapes, by reconstituting such phenomena from the bottom up. Using quantitative imaging, synthetic engineering, and mathematical modelling, her lab asks two major questions: (1) How to build signalling pathways with self-organizing capabilities using molecular parts? (2) How to build structures of defined shapes and functions by putting different types of cells together, such as the branched structure of the lung? Her research program aims to provide fundamental insights into the principles of embryo development, and the tools necessary for engineering more sophisticated self-organization of organ models in a dish.

Changes in reproductive strategy are common across the evolution of vertebrate development. How this impacts the morphogenetic processes of gastrulation in manner that enables the emergence of a common body plan are not well understood. Gastruloids reduce the morphological complexity of pre-gastrulation embryos, can be compared across species and allow for a systematic exploration of the impact of changes in tissue geometry, ECM and mechanical environment. This enables us to determine the degree to which tissue-level flows associated with gastrulation are robust to the experimental disruption of these boundary conditions, and those that emerge through the interactions of cells with the acellular niche. To extract information about tissue-level flows, we have developed tools to conduct three-dimensional particle velocimetry analysis and applied them to zebrafish blastoderm explants (pescoids). We observed polonaise-like symmetric flows that become interrupted at the onset of elongation. Computational modelling indicates that converging and internalising flows are active forces that synergise to break these symmetric flows and sustain elongation. Consistently, we observe cell movements associated with both convergence and internalisation during explant elongation. I will also present work in mouse gastruloids that explores the role of substrate stiffness and ECM composition on the self-organisation of collective cell migration. We isolate conditions that enable the self-generation of multiple protrusions, that each self-organise a tailbud-like morphology with associated morphogen gradient systems. Together, our work determines examples of both robust genetically encoded morphogenesis, and the self-organisation of well conserved patterning mechanisms from altered starting conditions.

Dr Ben Steventon

University of Cambridge, UK

Dr Ben Steventon

University of Cambridge, UK

Ben Steventon trained in the labs of Roberto Mayor (as PhD 2004-2008, UCL, UK), Andrea Streit (as PostDoc 2008-2012, KCL, UK), Jean-Francois Nicolas and Estelle Hirsinger (as PostDoc 2011-2013, Institute Pasteur, France), Scott Fraser (as Marie-Curie Outgoing Fellow 2013-2014, USC, USA) and Alfonso Martinez Arias (as Marie-Curie Incoming Fellow 2014-2015, Cambridge). He started his research group in 2016 supported by a Wellcome Trust/Royal Society Sir Henry Dale fellowship. In November 2021 he transitioned to an Assistant Professor in the Department of Genetics (University of Cambridge).

Wnt proteins are essential regulators of organ development, homeostasis, and repair. They feature a unique post-translational lipid modification (palmitoleoylation), essential for engaging their signaling receptor Frizzled and consequently downstream signal transduction. Despite the inherent hydrophobicity caused by this lipid moiety, Wnts can spread in the extracellular space and act over many cell diameters in different tissue contexts. Work from our lab has shown that the glypican Dlp harbours a hydrophobic tunnel that stabilizes Wingless (Wg), the main Drosophila Wnt protein, at the cell surface and thus contributes to signalling activity. We found that glycosaminoglycans (GAG) chains can ‘solubilise’ Wingless independently of the lipid-binding tunnel of Dlp and that, in gain-of-function experiments, glypicans GAGs promote the spreads of Wingless along the surface of Drosophila wing imaginal discs and drive extracellular gradient formation. We are interested in uncovering the molecular mechanism that enable GAGs alone to promote Wg transport. Biophysical analysis of the GAG-Wg interaction suggests that GAGs induce the formation of multimeric Wg complexes, a conformation that may allow reciprocal lipid-shielding by Wg molecules. Our ultimate goal is to combine genetic engineering approaches, mathematical modelling, and in vitro reconstitution assays to reach a mechanistic understanding of how lipid- and GAG-dependent interactions cooperate to enable the extracellular transport of Wingless, and other Wnts.

Dr Jean-Paul Vincent FMedSci FRS

The Francis Crick Institute, UK

Dr Jean-Paul Vincent FMedSci FRS

The Francis Crick Institute, UK

After completing an M.Eng. in applied physics at the University of Louvain (Belgium), Jean-Paul obtained a Fulbright fellowship for postgraduate studies in Biophysics at U.C. Berkeley where he characterized the symmetry-breaking events that initiate frog development. As a post-doctoral Damon Runyon fellow with Patrick O’Farrell at UC San Francisco, he devised a caged dye approach to label single cells and study cell fate specification. Since moving to the UK as a group leader, first at MRC-LMB, then at MRC-NIMR, and currently at the Francis Crick Institute, Jean-Paul has been studying how cells signal to each other to ensure correct patterning and growth during development. He is interested in the biophysics of morphogen gradient formation, with a particular on a class of signaling proteins called Wnts. He also studies how signals involved in normal development mediate the response to tissue stress. Jean-Paul is a fellow of the Royal Society and the Academy of Medical Sciences. He co-founded Summit Therapeutics in 2001.

Patterns are ubiquitous in biology ranging from gene expression during development to the organization of microbial communities. While the molecular mechanisms underlying pattern formation are complex, they are believed to follow general principles. In my group we use a bottom-up synthetic biology approach to construct in bacteria synthetic gene regulatory networks capable of generating spatiotemporal patterns. We have for example worked on stripe-forming incoherent feed-forward loops, on bistable switches and on oscillators. This strategy not only enables precise control over pattern formation but also provides insights into the fundamental principles that govern these biological processes. In my talk, I will give an overview of some of our recent work on pattern formation.

Professor Yolanda Schaerli

University of Lausanne, Switzerland

Professor Yolanda Schaerli

University of Lausanne, Switzerland

Professor Yolanda Schaerli is Associate Professor at the University of Lausanne, Switzerland in the Department of Fundamental Microbiology, where she heads a research group in bacterial synthetic biology.

Professor Schaerli studied at the ETH Zurich, Switzerland and at Imperial College, London, UK before she carried out a PhD at the University of Cambridge, UK. She then joined the Centre for Genomic Regulation (CRG), Barcelona, Spain, to do a postdoc. In 2014 she returned to her home country as junior group leader at the University of Zurich. In 2017 she started as Tenure-Track Assistant Professor at the University of Lausanne and was promoted to Associate Professor in 2023.

Research in her laboratory uses synthetic biology to engineer synthetic circuits in bacteria, with a focus on gene regulatory networks involved in spatiotemporal pattern formation. The group also develops novel tools and approaches for synthetic biology.

Embryonic development is a spectacular display of self-organisation of multi-cellular systems, combining transformations of tissue mechanics and patterns of gene expression. These processes are driven by the ability of cells to communicate through mechanical and chemical signalling, allowing coordination of both collective movement and patterning of cellular states. To ensure proper biological function, such patterns must be established reproducibly, by controlling and even harnessing intrinsic and extrinsic fluctuations. While the relevant molecular processes are increasingly well understood, we lack principled frameworks to understand how tissues obtain information to generate reproducible patterns. I will discuss how combining dynamical systems models with information theory provides a mathematical language to analyse biological self-organization across diverse systems. Our approach can be used to define and measure the information content of observed patterns, to functionally assess the importance of various patterning mechanisms, and to predict optimal operating regimes of self-organizing systems. I will demonstrate how our framework reveals mechanisms of self-organization of in vitro stem cell systems in direct connection to experimental data, including intestinal organoids and gastruloids. This framework provides an avenue towards unifying the zoo of chemical and mechanical signalling processes that orchestrate embryonic development.

Professor David Brückner

Biozentrum, University of Basel, Switzerland

Professor David Brückner

Biozentrum, University of Basel, Switzerland

David Brückner is an Assistant Professor of Theoretical Biophysics at the Biozentrum and Department of Physics of the University of Basel, Switzerland. Previously, he was an EMBO and NOMIS Foundation Postdoctoral Fellow at the Institute of Science and Technology Austria. He performed his doctoral studies at the Ludwig Maximilian University in Munich. He has been awarded with the Gustav-Hertz-Prize of the German Physical Society.

Our research at Imperial College is focused on the engineering of bacteria, mammalian and synthetic cells to advance the applications of synthetic biology. Resource competition between host cells and genetic constructs is one of our main research themes, for its impact on our ability to reliably engineer cellular hosts. In order to tackle resource competition and the cellular burden derived from it, we are currently developing new tools to address measure and characterise competition in engineered cells, but also exploring the design of novel gene expression control platforms for low-footprint genetic engineering.

Dr Francesca Ceroni

Imperial College London, UK

Dr Francesca Ceroni

Imperial College London, UK

Francesca graduated in Pharmaceutical Biotechnology and received a PhD in Bioengineering from the University of Bologna before moving to Imperial College London for her PDRA. She is currently a Senior Lecturer in the Department of Chemical Engineering at Imperial College London. She has track record in host-aware gene construct design for synthetic biology. Her group currently focuses on developing novel strategies for improved gene expression control in bacteria and mammalian.