Interdisciplinary approaches to dynamics in biology

Gene expression can be surprisingly dynamic and heterogeneous. This variability in gene expression, even in a clonal population of cells grown under the same condition, has been observed in diverse organisms, from mammalian stem cells to bacteria. It remains unclear how this variability is generated and what function it can serve. By using a combination of single cell time-lapse microscopy, mathematical modelling and synthetic biology techniques, the Locke group are attempting to understand how gene circuits generate dynamic gene expression, and how this dynamic information is transferred to downstream processes and other pathways. They work on simpler model systems such as cyanobacteria and B. subtilis, where it is possible to have precise single cell control of gene regulation, but have also extended this approach to the model plant Arabidopsis. In Arabidopsis, they are building on their work on simpler systems to examine the functional role of dynamic, and even stochastic, gene regulation in development.

Dr James Locke, Sainsbury Laboratory, University of Cambridge, UK

Dr James Locke, Sainsbury Laboratory, University of Cambridge, UK

James Locke is the Associate Director of the Sainsbury Laboratory, University of Cambridge. James graduated from the University of Warwick (2000) in Physics, before completing Maths Part III at Cambridge (2001). James then studied for a PhD at the University of Warwick (2006). He used an iterative process of experiment and theory to propose a new feedback loop in the plant circadian (24-hour) clock. He then conducted his postdoctoral work in the lab of Professor Michael Elowitz at the California Institute of Technology. He applied single cell time-lapse microscopy, modelling, and synthetic biology techniques to understand how cells amplify small molecule differences (noise) into alternative transcriptional states. Since 2012 he has been a group leader at the Sainsbury laboratory investigating gene expression dynamics in microbial and plant systems. He was awarded the Merrimack-CSB2 Prize in Systems Biology in 2013 and a Royal Society University Fellowship in 2015.

During early development, extrinsic triggers prompt a collection of pluripotent cells in the blastocyst to begin the dramatic and long process of differentiation that gives rise to the tissues of the three germ layers (endoderm, mesoderm and ectoderm). Precise temporal control during these early fate-choices is paramount and impacts on the success of differentiation. Changes in morphology, gene expression signatures and epigenetic patterns and cell division cycles are believed to mark the point of no-return in fate choices. However, when and how cells irreversibly commit to differentiation is a fundamental, yet unanswered question. Poised to differentiate, embryonic stem (ES) cells are an invaluable model to address this question. Given appropriate differentiation cues, ES cells can recapitulate in vitro all the hallmark events that occur during differentiation and are our system of choice to understand fate decisions at the single cell level. During Silvia’s talk she will share two stories that illustrate how Silvia’s lab combines single cell imaging, genomic approaches and mathematical modeling to study how cells encode fate choices during early development.

Dr Silvia Santos, The Francis Crick Institute, UK

Dr Silvia Santos, The Francis Crick Institute, UK

Originally Portuguese, Silvia Santos left sunny Portugal to study Molecular and Cell Biology in the UK. Silvia did her PhD at the EMBL in Heidelberg where she worked as a Marie Curie E-Star fellow. She moved to Stanford University for her post-doctoral training with Jim Ferrell and Tobias Meyer where she worked initially as an EMBO fellow, and, later as HFSP fellow. Silvia started her independent research at the MRC-LMS in Imperial College London in 2014 as an MRC career development awardee (MRC-CDA). She is joining the Francis Crick Institute in December 2017 as a group leader to establish the Quantitative Cell Biology lab.

Since her PhD Silvia combines experimental and theoretical approaches to understand decision-making during transitions. In this context, her lab studies cell division and cellular differentiation in early development, using human embryonic stem (hES) cells as a model system.

 

 

A major question in developmental biology is how cell fate decisions are coordinated precisely in space and time to generate emergent patterns of gene expression. The timing of cell transitions is regulated at multiple length scales in a highly integrated manner. Within individual cells, gene regulatory networks (GRNs) drive cell state transitions with an inherent timing. These are in turn patterned across cell populations by extracellular signals that diffuse or are transported between cells. This talk focuses on the multi-tissue level and considers how multicellular ensembles shift relative to each other to influence the timing at which competent cells receive signals. Such ‘tissue tectonics’ provide a causal relationship between processes at higher levels of biological organization (ie the relative positioning of signalling and responding tissues) to the control of processes at lower levels (ie cell biology and the activity of GRNs). As such, it is an example of downward causation and provides a multi-scale feedback mechanism to enable the self-organisation of developmental processes. The vertebrate tailbud offers a unique system to explore the relationship between multi-tissue morphogenesis and cell fate coordination in vivo. This will be discussed together with recent work showing how the inhibition of convergence and extension within multi-cellular aggregates of embryonic cells disrupt the shaping of BMP and Wnt/beta-catenin signalling gradients. This leads to alterations in the anterior-posterior patterning of neural marker expression, demonstrating a role for tissue tectonics in pattern formation.

Dr Ben Steventon, University of Cambridge, UK

Dr Ben Steventon, University of Cambridge, UK

Ben began his studies in Developmental Biology as a PhD student with Roberto Mayor at UCL in 2004. After graduating in 2008, he moved to KCL to work with Andrea Streit. Subsequently he moved to the lab of Jean-Francois Nicolas and  Estelle Hirsinger at the Institut Pasteur, Paris. There, he began to work with zebrafish embryos to further the understanding of the tissue deformations that lead to the elongation of the embryonic body axis. To develop imaging and analytical techniques to study this process at the cellular and molecular levels, he was awarded a Marie-Curie fellowship to work with Scott Fraser (University of California, USA) and Alfonso Martinez-Arias (University of Cambridge). With his Sir Henry Dale fellowship, he is now applying these techniques to investigate how cell fate decisions are orchestrated in space and time during axis patterning in zebrafish embryos.

Some biological oscillators function throughout the life of an organism, for example the circadian clock, whereas others have a more restricted duration, particularly in embryogenesis. The “segmentation clock” is a multi-cellular patterning system of genetic oscillators thought to control the rhythmic and sequential formation of the vertebrate embryo's body segments. Individual oscillating cells are synchronized with their neighbours, forming a coherent wave pattern of gene expression. How these wave patterns arise and how they are regulated during embryogenesis is not clear. Dr Oates will describe recent progress in understanding the behaviour of individual cells from the zebrafish as they slow their oscillations and differentiate during segmentation, and discuss how this gives rise to the tissue-level wave patterns. Central to this understanding is the concept of a timer that regulates the duration of a clock. This perspective reveals what part of the oscillatory cycle is changing as the cells slow and stop.

Dr Andy Oates, Swiss Federal Institute of Technology Lausanne, Switzerland

Dr Andy Oates, Swiss Federal Institute of Technology Lausanne, Switzerland

Andrew Oates received his PhD at the Ludwig Institute for Cancer Research and the University of Melbourne. His postdoctoral time was at Princeton University and the University of Chicago in the lab of Robert Ho, where his studies on the segmentation clock in zebrafish began in 1998. In 2003 he moved to Germany and started his group at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden. In 2012 he accepted a position at University College London as Professor of vertebrate developmental genetics and moved his group to the MRC-National Institute for Medical Research at Mill Hill in London. From April 2015, he became a member of the Francis Crick Institute in London. In September 2016, he joined École Polytechnique Fédéral de Lausanne (EPFL) in Switzerland as a Professor, where he is the head of the Timing, Oscillation, Patterns Laboratory and the Director of the Institute of Bioengineering. The Oates group is composed of biologists, engineers, and physicists using molecular genetics, quantitative imaging, and theoretical analysis to study a population of coupled genetic oscillators in the vertebrate embryo termed the segmentation clock. This system drives the rhythmic, sequential, and precise formation of embryonic body segments, exhibiting rich spatial and temporal phenomena spanning from molecular to tissue scales. 

Different species have different tempos of embryonic development: larger animals tend to grow more slowly than smaller animals. Dr Ebisuya's group has been trying to understand the molecular basis of interspecies differences in developmental time by using in vitro segmentation clock as a model system. The segmentation clock is the oscillatory gene expressions that regulate the timing of body segment formation from presomitic mesoderm (PSM) during embryogenesis. The group has recently succeeded in inducing PSM from both human iPS cells and mouse ES cells, recapitulating the oscillation and travelling wave of segmentation clock in vitro. Interestingly, the oscillation period of human segmentation clock was 5-6 hours while that of mouse was 2-3 hours. Taking advantage of our in vitro system, the group measured several biochemical reaction parameters of the core gene of the oscillation mechanism, Hes7, finding out that the degradation and production processes of Hes7 are 2-3 times slower in human PSM cells compared to mouse cells. The mathematical model quantitatively explained how the slower biochemical reactions in human cells give rise to the longer oscillation period in the human segmentation clock.

Dr Miki Ebisuya, EMBL Barcelona, Spain

Dr Miki Ebisuya, EMBL Barcelona, Spain

Miki Ebisuya did her undergraduate and PhD research at Kyoto University, Japan. After getting her PhD in 2008, she became a group leader at Kyoto University in 2009. Her lab moved to RIKEN in 2013, and then moved again to EMBL Barcelona, Spain, in 2018. The research interest of her group is reconstituting developmental mechanisms in cell culture. 

Segmentation in arthropods is established during development, often concurrently with posterior elongation. Much about this patterning process is still poorly characterised, but recent years have seen considerable progress towards grasping its basic regulatory structure and logic. Many of the genes that affect segmentation appear to be linked into small networks that form dynamical components such as timers, oscillators, and switches. Additional cross-regulation between these components creates a dynamical interplay that is fundamental to producing the segmental pattern. Several of these dynamical components appear to be strikingly similar to ones involved in patterning the nervous system, suggesting perhaps that they evolved within a more ancient developmental context and were only later recruited to a role in body segmentation. Alternatively, body segmentation might have originated from an ancestral neuromuscular patterning process which involved these components from the start. Simple models that capture the essential dynamical properties of the segmentation network show how linking developmental processes that create traveling waves (velocities) with others that measure time is sufficient to generate segmental patterns, even in the absence of instructive initial conditions. In addition, through adjusting the relative timescales of these components, a given system can produce a range of different output patterns, demonstrating how different body forms might easily evolve. On the other hand, the example of Drosophila shows that instructive positional gradients can also be incorporated into such a system, replacing a robust but relatively slow self-organising capacity with finely-tuned top-down control. Even in this extreme case, however, it is clear that dynamical processes still form a fundamental, ancestral, core.

Dr Erik Clark, Harvard Medical School, USA

Dr Erik Clark, Harvard Medical School, USA

Erik Clark is a developmental systems biologist interested in patterning, gene regulation, and evolution. He is currently working in the DePace lab in the Department of Systems Biology at Harvard Medical School, on an EMBO postdoctoral fellowship. He is also a Junior Research Fellow at Trinity College, Cambridge. He did his PhD with Michael Akam at the University of Cambridge, graduating in 2017. He also has a BA in Biological Sciences from the University of Oxford and an MSc in Bioinformatics and Theoretical Systems Biology from Imperial College London. He studies anterior-posterior patterning processes in arthropod embryos, focusing in particular on the regulation and function of the “pair-rule” genes in the fruit fly Drosophila melanogaster.

Embryonic development and tissue regeneration both require a high degree of spatiotemporal coordination. Dr Di Talia will describe my lab efforts to understand the synchronization of the cell cycle in early Drosophila embryos and the coordination of tissue growth in zebrafish bone regeneration. Dr Di Talia will show how synchronization of the cell cycle in Drosophila embryo is linked to precise nuclear positioning, which is in turn driven by cytoplasmic flows generated by actomyosin cortical contractions. Cortical contractions are regulated by oscillations in the activity of mitotic phosphatase PP1, thus forming a self-organized mechanism through which nuclei drive their positioning and synchronization. Dr Di Talia will also show how the cell cycle oscillator is interfaced with zygotic histone biogenesis by mediating the formation of the histone locus body by phase separation. Finally, Dr Di Talia will show that excitable waves of growth factor signalling drive cell and tissue growth in the osteoblast population controlling zebrafish scale regeneration, thus highlighting a novel principle of large-scale coordination for regeneration of large adult structures. 

Dr Stefano Di Talia, Duke University Medical Center, USA

Dr Stefano Di Talia, Duke University Medical Center, USA

Stefano received his PhD from The Rockefeller University where he worked on the mechanisms of cell size control in budding yeast. As a postdoc in Princeton University, he initiated a new research line on the mechanisms of cell cycle regulation during Drosophila embryonic development. He established his lab in the Department of Cell Biology at Duke University, where he works on physical principles of spatiotemporal organisation in early Drosophila embryos. Recently, the lab has also initiated a new research direction to understand how tissue growth is controlled during zebrafish regeneration. 

During development, sequential cell fate decisions generate diversity by carefully orchestrating their organisation across space and time. Often the dynamics of cell fate decisions directly relate to spatial location, such as in the case of somitogenesis where decisions are organised along the embryonic anterior-posterior axis. Advances in single-cell transcriptomics have enabled the characterisation of numerous cell states to be identified with high-resolution, yet these methods typically require cellular dissociation which disrupts such spatial information. In silico techniques, such as pseudotime approaches, often aim to ‘reintroduce’ dynamics by using information inherent in the data but make several assumptions. Instead, the group sought to identify spatial information inherent in such single-cell datasets using a parallel spatially-defined bulk RNA-sequencing and complementary single-cell data. The group developed a pipeline to recover spatial information at single-cell resolution, which allows them to reconstruct cellular arrangements that closely reflect the original organisation of source tissues. This method has potential implications for transcriptomic assays, where preserving spatial information in high-resolution data could allow the identification of novel spatial and dynamic trends along embryonic axes.  

Dr Naomi Moris, University of Cambridge, UK

Dr Naomi Moris, University of Cambridge, UK

Naomi Moris is a Junior Research Fellow in the Department of Genetics at the University of Cambridge. She is particularly interested in understanding how cell fate decisions are coordinated during development. To explore this question, she makes use of three-dimensional in vitro model systems, such as ‘gastruloids’, to explore self-organisation principles using embryonic stem cells. In particular, she is interested in understanding how developmental programmes are organised in both space and time, to generate coordinated patterns as a result of underlying gene regulatory networks.

Embryonic development is a process of orchestrated progressive steps, which lead to the generation of patterned structures. While the sequence of developmental events is highly conserved, the speed at which they occur or “tempo” (“embryonic tempo” as a term was defined by Ebisuya and Briscoe, 2018) is a unique feature of a species and is highly variable within chordata and even between closely related species. Embryonic tempo is a mostly unexplored field presenting an opportunity to investigate and develop a fundamental area of biology with far reaching implications for many fields, including stem cell research, developmental biology, life-long health, ecology and food production. Variability in tempo, suggests that changes can be effected through few pleiotropic changes and there is evidence that the control of tempo is genetic. Dr Davey will describe the preliminary steps we are taking to define embryonic tempo and understand the genetic control of tempo using commercial duck species and chicken breeds and other avian species which demonstrate highly regulated embryonic tempo.

Dr Megan Davey, University of Edinburgh, UK

Dr Megan Davey, University of Edinburgh, UK

Megan Davey undertook her BSc Hons in Anatomy and Developmental Biology at UCL 1994 – 1997 and her PhD at The University of Dundee 2000 – 2003, specialising in understanding the development and patterning of the limb, using chicken developmental mutants. Starting as a postdoc at The Roslin Institute in 2004 and becoming a BBSRC Fellow there in 2007, Megan has continued to explore the function of causative mutations which lead to variations in phenotype using comparative anatomy, genomics and embryonic manipulation of avian species, including chickens, quails, ducks and emus. As well as practical applications for human developmental differences, Megan’s group are interested in understanding how differences in developmental tempo are controlled genetically and how these contribute to pattern formation in the embryo. Megan is also Academic Lead for Public Engagement at the Roslin Institute and Secretary of the British Society for Developmental Biology.