Morphogenesis: Geometry and Physics

Just over a century ago, the biologist, mathematician and philologist D’Arcy Thompson wrote “On growth and form”. The book – a literary masterpiece – is a visionary synthesis of the geometric biology of form. It also served as a call for mathematical and physical approaches to understanding the evolution and development of shape. In the century since its publication, we have seen a revolution in biology following the discovery of the genetic code, which has uncovered the molecular and cellular basis for life, combined with the ability to probe the chemical, structural, and dynamical nature of molecules, cells, tissues and organs across scales. In parallel, we have seen a blossoming of our understanding of spatiotemporal patterning in physical systems, and a gradual unveiling of the complexity of physical form. So, how far are we from realizing the century-old vision that “Cell and tissue, shell and bone, leaf and flower, are so many portions of matter, and it is in obedience to the laws of physics that their particles have been moved, moulded and conformed” ?

To address this requires an appreciation of the enormous ‘morphospace’ in terms of the potential shapes and sizes that living forms take, using the language of mathematics. In parallel, we need to consider the biological processes that determine form in mathematical terms is based on understanding how instabilities and patterns in physical systems might be harnessed by evolution.

In Fall 2018, CMSA will focus on a program that aims at recent mathematical advances in describing shape using geometry and statistics in a biological context, while also considering a range of physical theories that can predict biological shape at scales ranging from macromolecular assemblies to whole organ systems.
The first workshop will focus on the interface between Morphometrics and Mathematics, while the second will focus on the interface between Morphogenesis and Physics.The workshop is organized by L. Mahadevan (Harvard), O. Pourquie (Harvard), A. Srivastava (Florida).

As part of the program on Mathematical Biology a workshop on Morphogenesis: Geometry and Physics will take place on December 3-5, 2018.  The workshop will be held in room G10 of the CMSA, located at 20 Garden Street, Cambridge, MA.

For a list of lodging options convenient to the Center, please visit our recommended lodgings page.


Please Register Here

PDF of the Schedule



Monday, December 3

Time Speaker Title/Abstract
8:30 – 9:00am Breakfast
9:00 – 9:15am Welcome and Introduction
9:15 – 10:00am Elliot Meyerowitz Title: Mechanical Feedbacks in Plant Morphogenesis

Abstract: We study how the stem cells of the Arabidopsis thaliana shoot apical meristem form developmental patterns such as patterns of cell division, cell expansion, gene expression and floral primordium appearance. Our research and that of others shows that a major component of pattern formation in the meristem results from mechanical interactions between cells, and within the tissue as a whole.

I will discuss two different modes of mechanical interaction. The first is cytoskeletal. The pattern of mechanical stresses in the meristem epidermis results from the shape of the meristem and the balance of turgor pressure and cell wall properties in the tissue. This stress pattern controls the microtubule cytoskeleton such that cortical microtubules align parallel to the maximal tensional stress direction when stress is anisotropic. Alignment of microtubules leads to subsequent alignment of cellulose in the cell wall, causing cells to expand anisotropically, leading to new stress patterns. Overall this mechanism allows cells to know the shape of the tissue in which they reside, and then to change that shape by changing their patterns of expansion and division – thus providing a feedback between morphogenesis and cellular behavior.

The second mechanical signal results from local cell expansion, which changes patterns of stress in the shared walls between cells expanding at different rates, due to their possession of different concentrations of the plant hormone auxin. This local stress causes asymmetric localization of an auxin transporter, which in turn changes the flow of auxin in the epidermis, therefore changing the stress pattern. The feedbacks in involved in this mechanism control phyllotactic pattern, and new floral primordia and induced by high concentrations of auxin at sites in the meristem.

Recent work points toward potential mechanisms for both mechanical feedbacks, and also demonstrates additional mechanical responses of meristem cells.

10:00 – 10:45pm Raymond Keller Title: The Shape of Things to Come: Geometry and Timing of Cell Intercalation in Shaping the Body Plan of Xenopus. Ray Keller, University of Virginia, Charlottesville
Abstract: Low angle epi-illumination and epi-fluorescent time-lapse, live imaging of explants revealed a cell behavior called “mediolateral intercalation behavior” (MIB) in the axial and paraxial mesoderm of the Xenopus (frog) gastrula. MIB consists of polarization of cell protrusive activity parallel to the presumptive mediolateral axis of the tissue, traction on adjacent cells, subsequent mediolaterally-oriented cell elongation, and finally, mediolaterally oriented intercalation of the cells between one another as they undergo myosin-dependent contraction, which results in a narrower, longer tissue (CE-Convergent Extension). Time-lapse imaging revealed that MIB is expressed progressively, beginning at the presumptive anterior(A) and spreading progressively toward the posterior (P) and, at all A-P levels, originating laterally (next to the vegetal endoderm) and progressing medially toward the midline. There, the two arrays of MIB-expressing cells from each side meet to form a continuous hoop-like array of intercalating cells, anchored at their origin at the endoderm and arcing across the dorsal marginal zone (DMZ). The array shortens by MIB at and after the point of involution, and it generates myosin-dependent forces of 4 μN or more. This geometry and progressive expression of MIB is essential for blastopore closure and elongation of the body axis by CE. Progressively later inhibition of Nodal receptors from the mid-blastula stage into gastrulation results in progressively more posterior truncations of the body axis. MIB-mediated CE is preceded by a previously uncharacterized force-generating convergence mechanism, Convergent Thickening (CT), which acts in the pre-involution region. The cells expressing CT transition into expressing CE at the blastopore lip. CT appears to be driven, in part, by changes in cell affinity and tissue surface tension. CT and CE are mechanically integrated, act together as pre- and post-involution convergence force generating mechanisms in Xenopus and likely occur in varying degrees throughout the amphibians, depending on variations in egg architecture. The morphogenesis driving gastrulation and shaping the body plan is context-dependent, relies on the geometry and timing of expression of force generating cell behaviors, and their mechanical integration. Supported by grants from the NSF, NIH, and the Alumni Council Thomas Jefferson Professorship.
10:45 – 11:00am Coffee Break
11:00 – 11:45am Olivier Pourquié Title: Mechanics of avian embryo elongation
11:45 – 12:30pm Sebastian Streichan Title: Tissue flow genetics: mapping the forces that shape complex organs

Abstract: Developmental biology established principles of how the body plan is laid out, morphogens setup axes, and gene expression patterns determine cell fates – yet how the form of organs emerges from coordinated action of multiple domains of distinct cell types remains elusive. We combine in toto live imaging and automated data analysis with physical modeling to investigate the link between kinetics of global tissue transformations and patterns of force generation during Drosophila gastrulation. We find our visco-elastic model driven by stress proportional to the spatial distribution and anisotropy of two quantitatively measured myosin pools achieves a 90% accurate description of the measured tissue flow – using only 3 parameters. Our analysis shows (i) forces driving the flow arise from non-uniformity of stress, thus spatial myosin modulation is critical for dynamics. Long-range modulation of the anisotropic part along the Dorso-Ventral (DV) axis suggests a novel role for the DV patterning system in convergent extension. (ii) The relation between flow and myosin forcing is non-local, and a transition towards areal incompressibility during germband extension further enhances non-locality. (iii) Mutant analysis indicates mechanical feedback on myosin recruitment relating it to the local strain rate. We conclude that understanding morphogenetic flows requires a fundamentally global perspective.

12:30 – 2:00pm Lunch
2:00 – 2:45pm Yohanns Bellaiche Title: Mitosis and epithelial morphogenesis

Abstract: Questions related to embryo shape or morphogenesis have haunted developmental biologists for decades. Recent advances in imaging, cell biology, signal transduction and biophysics have framed the study of tissue morphogenesis in terms of collective cell dynamics and the interplay between biochemical and mechanical processes. Recent findings have confirmed that proliferative epithelial tissues reshape via morphogenetic processes such as cell shape change and cell rearrangements. Yet cell division remodels adherent junctions and modulates both tissue mechanics and tissue dynamics. Therefore its role and interplay with the other morphogenetic processes need to be understood to decipher the mechanisms of tissue morphogenesis. During my talk I will describe some of our latest works on the interplay between morphogenetic force and cell division in epithelial tissue.

2:45 – 3:30pm Cristina Marchetti Title: Collective cell migration and patterning in epithelial tissue

Abstract: The mechanical properties of dense tissues control many biological processes, from wound healing to embryonic development to cancer progression. In this talk I will describe recent theoretical work that combines established developmental models with active matter physics to show that confluent tissues exhibit a jamming-unjamming transition tuned by cell shape and cell motility. The coordination of cell migration through mechanical feedback modifies this transition, providing a mechanism for the formation of collective migratory patterns where large groups of cells organize in coherent structures. We find that direct alignment of cell motility promotes solidification in dense tissue, while preferential cell migration towards regions of lower shear stiffness yields a flocking fluid state where cells move in packs. This work aims at quantifying the relation between properties at the single cell scale, such as cell shape and polarized cell motility, and mechanics on the tissue scale. It provides insights on the role of mechanical mechanisms, complementary to well explored biochemical ones, for regulating rheology, collective migration and cell patterning in dense tissue.

3:30 – 4:00pm Coffee Break
4:00 – 4:45pm Ian Jermyn Title: The elastic metric for surfaces and its use

Abstract: Shape analysis requires methods for measuring distances between shapes, to define summary statistics, for example, or Gaussian-like distributions. One way to construct such distances is to specify a Riemannian metric on an appropriate space of maps, and then define shape distance as geodesic distance in a quotient space. For shapes in two dimensions, the ‘elastic metric’ combines tractability with intuitive appeal, with special cases that dramatically simplify computations while still producing state of the art results. For shapes in three dimensions, the situation is less clear. It is unknown whether the full elastic metric admits simplifying representations, and while a reduced version of the metric does, the resulting transform is difficult to invert, and its usefulness has therefore been questionable. In this talk, I will motivate the elastic metric for shapes in three dimensions, elucidate its interesting structure and its relation to the two-dimensional case, and describe what is known about the representation used to construct it. I will then focus on the reduced metric. This admits a representation that greatly simplifies computations, but which is probably not invertible. I will describe recent work that constructs an approximate right inverse for this representation, and show how, despite the theoretical uncertainty, this leads in practice to excellent results in shape analysis problems. This is joint work with Anuj Srivastava, Sebastian Kurtek, Hamid Laga, and Qian Xie.
5:00 – 6:00pm Reception

Tuesday, December 4

Time Speaker Title/Abstract
8:30 – 9:00am Breakfast
9:00 – 9:45am Arkhat Abzhanov Title: Use it or lose it: mechanisms of integration of cranial skeleton and musculature from plasticity to genetic assimilation.

Abstract: Integration of musculature and skeleton is one of the key functional interactions in the developing embryonic and juvenile animals.  The complex interplay of both genetics and plasticity is required for a successful integration and the nature of this interaction also changes during evolutionary time. In some species the muscle-bone interaction, for example between cranial muscles and jaw bones, is largely plastic and environmentally regulated while in others it is highly deterministic and driven primarily by genetics. Our research explores specific examples of bone-musculature integration found in nature and looks to find the exact mechanisms by which these are established, regulated and altered in both ontogeny and phylogeny.
9:45 – 10:30am Cheng Ming Chuong Title: How do feather arrays form? Coupling biochemical signaling and biophysical force to realize geometric arrangement

Abstract: Feathers arrayed in dorsal chicken skin represent a population of feather primordia spread on a 2D body surface, arranged in a regular pattern, oriented in the same direction, and are interconnected by a muscle network. Here we will highlight two of these morphogenetic stages, each with distinct combinations of biochemical signals and biophysical forces. 1) Feather bud orientation. We observe exposure to electric current pulses alters orientations of a feather bud population, collectively. Transcriptome profiling and functional assays implicate contributions of Ca2+ channels and gap junctions. 4D imaging shows random calcium oscillations in feather mesenchymal cells are coordinated by epithelial SHH dependent modulation of gap junction networks to become synchronous, leading to directed cell movement. Thus, we uncovered a novel mechanism coupling bioelectric and biochemical signaling to achieve coordinate collected cell movement within a single feather bud and among a population of buds. 2) Assembly of a feather muscle network. Here we show the self-assembly of feather muscle networks arise through the implementation of a few simple rules. Muscle fibers emit from each feather primordia centrifugally in every direction, but only those muscle fibers connecting two neighboring follicles are eventually stabilized. After connections between nearest neighboring feathers, the network can be reconfigured, adapting to perturbed bud arrangements and changing mechanical force cues. Thus, we identify the self-assembly of an adaptive biological network that integrates numerous elements into one functional unit and maintains a balance between efficiency, robustness, and flexibility.

10:30 – 11:00am Coffee Break
11:00 – 11:45am Zev Gartner Title: Building tissues to understand how tissues build themselves

Abstract: The capacity of cells to self-organize into tissues is critical to their normal developmental and their ability to self-repair. Thus, a better understanding of how tissues self-organize will improve our ability to synthesize tissues and organs in the lab, and suggest new strategies to slow the breakdown of tissue structure that contributes to the initiation and progression of disease. We are working to understand the mechanisms used by cells to self-organize robustly into specific tissue structures, and how these program are susceptible to the perturbations that underlie diseases such as breast cancer.

11:45 – 12:30pm Lisa Manning Title: What do guitar strings and balloons have in common with biological tissues?

Abstract: Both guitar strings and balloons are floppy unless rigidified by geometrically induced self-stresses. Similar kinds of rigidity transitions have recently been described in biopolymer networks and cellular biological tissues, and recent work suggests that these rigidity transitions are utilized to regulate and drive morphogenesis. Here, we propose a general, geometric approach to quantitatively describe such transitions. Based on a minimal length function, which scales linearly with intrinsic fluctuations in the system and quadratically with shear strain, we make concrete predictions about the elastic response of these materials, which we verify numerically and which are consistent with previous experiments.  Our approach may provide a gateway towards connecting macroscopic rheological properties of acellular and cellular biological tissues to their microscopic structure, and thereby to cell-level signaling processes in morphogenesis.
12:30 – 2:00pm Lunch
2:00 – 2:45pm Leonardo Morsut Title: Programming self-organization of multicellular structures with synthetic cell-cell signaling coupled to morphogenetic effectors

Abstract: During embryonic development, complex multicellular tissues form based on genetically encoded algorithms that specify how cells will behave both individually and collectively. We develop synthetic biology tools and approaches to implement in cells such self-organization programs and understand their overall logic.
Extensive studies of natural developmental programs have implicated many genes that control cell-cell signaling and cell morphology. Despite their molecular diversity, a common theme in these developmental systems is the use of cell-cell signaling interactions to conditionally induce morphological responses. Thus, we explored whether simple synthetic circuits in which morphological changes are driven by cell-cell signaling interactions could suffice to generate self-organizing multicellular structures. As a modular platform for engineering new, orthogonal cell-cell signaling networks, we focused on using the synthetic notch receptor system, which allows a cell to detect molecular signals from its neighbors and, in response, to induce user-specified transcriptional programs. As morphological effectors, we focused on changes in cell-adhesion in fibroblasts, by changing expression of cadherin molecules. Despite their simplicity, these programs can drive the spontaneous generation of multicellular structures in 3D with key hallmarks of natural developmental systems: they can self-organize into multilayer structures, form through sequential steps, display divergence of genotypically identical cells into distinct cell types, break symmetry, and they can regenerate upon injury. Through computational modeling, we show how these trajectories allow the multicellular system a more exhaustive exploration of the space of forms (morphospace), when compared to systems with signaling only, or with sorting only. These results provide insights into the evolution of multicellularity and demonstrate the potential to engineer customized self-organizing tissues or materials.

2:45 – 3:30pm Dagmar Iber
3:30 – 4:00pm Coffee Break
4:00 – 4:45pm Ben Simons Title: A unifying theory of branching morphogenesis
Abstract: Branching morphogenesis has been a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how the macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Here we show that, in the mouse mammary gland, kidney and pancreas, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on large-scale organ reconstructions, genetic lineage tracing and proliferation kinetics, we show that morphogenesis follows from the collective proliferative activity of sublineage-restricted equipotent self-renewing progenitors localized at ductal tips that drive a process of ductal elongation and stochastic tip bifurcation. By correlating ductal termination with proximity to maturing ducts, this dynamics results in the specification of a complex network of defined density and statistical organization. These results show that branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a strikingly simple, but generic, set of local rules, without recourse to a rigid and deterministic sequence of genetically programmed events.

Wednesday, December 5

Time Speaker Title/Abstract
8:30 – 9:00am Breakfast
9:00 – 9:45am Aryeh Warmflash Title: Studying self-organized pattern formation with human embryonic stem cells

Abstract: During embryonic development, an entire organism is generated from a single cell. Genetics and biochemistry have identified developmental signaling pathways, however, how embryonic patterns emerge in space and time remains more obscure. I will discuss our work engineering systems in which developmental patterns are generated in vitro starting from human embryonic stem cells and using these systems to understand the mechanisms underlying mammalian pattern formation. This work demonstrates than combining quantitative analysis and stem cell culture is a promising approach for addressing fundamental questions in developmental biology and has important implications for using stem cells for tissue engineering.

9:45 – 10:30am Thomas Gregor Title: Optimal decoding of cellular identities

Abstract: In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. Using the gap gene network in the early fly embryo as an example, we use such a framework to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds. Precise cellular identities are thus available at the earliest stages of development, contrasting the prevailing view of positional information being slowly refined across successive layers of the patterning network. Our results suggest that developmental enhancers closely approximate a mathematically optimal decoding strategy.
10:30 – 11:00am Coffee Break
11:00 – 11:45am Eric Siggia Title: Exploring embryonic patterning with colonies of human embryonic stem cells.

Abstract: Embryology at the beginning of the 21st century finds itself in a situation similar to neurobiology; the behavior of the component pieces is understood in some detail, but how they self-assemble to become life is still very hazy. There are 100’s of molecules that enable cell communication and genetics defines their function by classifying aberrant embryos at a suitable intermediate stage of development, which is difficult for mammals and impossible for humans. Embryonic stem cells can be expanded indefinitely and in the context of the embryo give rise to all cells in the body. The colloquium will describe synthetic systems that coax these stem cells to recapitulate aspects of gastrulation, which is the process by which the embryo transforms from a sphere to a cylinder, builds its anterior-posterior and dorsal-ventral axes, and segregates cells into ectoderm (skin and neurons), mesoderm (muscle bones and blood), and endoderm (gut lungs pancreas etc) lineages.

11:45 – 12:30pm Allon Klein Title: Ordering events during fate balance in tissue homeostasis

Abstract: Maintenance of adult tissues depends on sustained activity of resident stem cell populations, which must precisely balance cell division and loss. To enforce this balance, cells must be able to sense and respond to fluctuations in local cell density — a coarse-grained quantity that demands cells average in both space and time. In epithelial tissues, it is not even clear what is the time scale and length scale of density response, let alone the molecular mechanism that underpin such responses. I will discuss observations on length/timescales of response from live imaging tissues with different geometries the stratified epidermis of living mice (Mesa*/Kawaguchi*/Cockburn* et al., Cell Stem Cell 2018); monolayers of MDCK cells cultured to homeostatic confluence; and intestinal crypt stem cells cultured into 3D “organoids”. In the adult mouse epidermis, we show that stochastic exit from the stem cell compartment drives extremely localized cell deformation followed by cell cycle entry, with no inverse feedback between cell division to differentiation. This pattern is not universal to the other examples considered. I will highlight observations from live imaging that we do not yet fully understand.

12:30 – 1:15pm Sean Megason Title: Mechanisms for robust patterning in zebrafish

Abstract: We are interested in understanding the mechanisms that generate precise spatial organization in developmental systems despite numerous sources of variation in their underlying parts using a combination of imaging, modeling, and perturbation in zebrafish. Our results have revealed a variety of molecular as well as physical mechanisms for robustness. Looking at patterning of the neural tube by the morphogen Sonic hedgehog, we have found significant noise both in its expression and in the response of target cells. This noise can be corrected by sorting of specified cells into precise domains using an adhesion code of different cadherins and protocadherins. Also in the neural tube, we have found that differentiation rate is under negative feedback control

1:15 – 2:30pm Lunch


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