This weekly seminar aims at gathering researcher form different thematics (physicists, biologists and chemists) and from different institutes in the center of Paris. The objective is to cover an interface between physics, chemistry and biology as broad as possible, with experimental, numerical and/or theoretical approaches. To describe life sciences all scales are needed, from single molecules, cell biology, organisms, population dynamics. That's why the range of our seminar is quite broad form embryonic development, genetic regulation, evolution, mechanics and cell migration, immunology, microbiology, synthetic biology, etc.
22 March 2019, 1pm - Remy Kusters (Institut Curie)
The coordinated flight of bird flocks is a striking example of collective behavior in biology. Using 3D positions and velocities of large natural flocks of starlings, I will show how to build an explicit mapping of flock behaviour onto statistical physics models of magnetism. Learning the parameters of these models allows us to infer the local rules of alignment, and to reveal that flocks are poised close to a critical point, where susceptibility to external perturbations is maximal. Extending the approach to alignment dynamics shows that flocks are in a state of local quasi-equilibrium.
Developing tissues have the capacity to cope with perturbations, including the modification of cell growth rate and the elimination of a large number of cells through wounding. This plasticity is well illustrated by cell competition, a process that drives the elimination of suboptimal cells (so called “losers”) by fitter cells (so called “winners”) through apoptosis without morphological defects. In the past years, the number of genetic and tissular contexts leading to cell competition has been constantly increasing. Yet, the mechanisms allowing recognition and elimination of suboptimal cells is still actively debated. I will present here our attempt to characterize quantitatively the process of cell competition which led to the characterization of two independent modes of elimination: first a contact dependent elimination which can be modulated by the shape of the interfaces between the two populations, secondly a compaction-driven competition where cell elimination is triggered by mechanical stress and differential sensitivity to compaction. I will then present recent results regarding the characterization of the pathway sensing cell compaction and triggering cell elimination in the Drosophila pupal notum (a single layer epithelium). Eventually I will present our ongoing characterization of the process of cell extrusion (the concerted removal of one cell from the epithelial layer) and its regulation by caspases.
In a similar way to bacteria that have to navigate in their environment, soaring birds try to minimize their effort by finding and exploiting ascending currents. However the environment is highly turbulent and unpredictable with thermals constantly forming, disintegrating and being transported within minutes timescales. How the birds navigate these environments remains unknown. It is a notoriously difficult/impossible task to assess what cues are used by the soaring birds and what strategies they developed to explore and exploit such turbulent environments. For this investigation, we chose to emulate how an agent could learn to see what strategies would emerge. I then set up an experimental reinforcement learning framework that I implemented in a two-meter wingspan glider. Here, the soaring agent measured its state (height and a set of cues), took actions (change the left/right direction it is heading to) and recorded what resulted from these actions given the previous state. After an initial learning period, the glider chose the actions according to their state that would maximize the gain in altitude. In short, the glider learned to soar through its past experience. The learned strategy was based on accurate estimates of local wind accelerations and roll-wise torque. In the field, the glider could typically gain hundreds of meters in height in a few minutes when facing environments with thermals. Our results not only highlight the vertical wind accelerations and roll-wise torques as effective mechanosensory cues for soaring birds but also provide navigational strategy that is directly applicable to the development of autonomous soaring vehicles to increase their time aloft with minimal energy cost.
Fertilization is one of the fundamental processes of living systems. Here I will address marine external fertilization and comment on recent work on mammals. I will show experiments that substantiate that sea urchin sperms exhibit chemotaxis as they swim towards the ovum. They are guided by flagellum internal [Ca2+] concentration fluctuations triggered by the binding of chemicals from the oocyte surroundings. Based on experiment, I present a family of logical regulatory networks for the [Ca2+] fluctuation signaling-pathway that reproduce previously observed electrophysiological behaviors and provide predictions, which have been confirmed with new experiments. These studies give insight on the operation of drugs that control sperm navigation. In this systems biology approach, global properties of the [Ca2+] discrete regulatory network dynamics such as: stability, redundancy, degeneracy, chaoticity and criticality can be determined. Our models operate near a critical dynamical regime, where robustness and evolvablity coexist. This regime is preserved under a class of strong perturbations. Based on global dynamics considerations, we have implemented a network node-reduction method. The coincidence of this reduced network with our bottom-up step-by-step, continuous differential equation modeling is reassuring. For the case of mammals our research has centered on the understanding of capacitation and acrosomal reaction. The first is a process by means of which roughly one third of the spermatozoa acquire the “capacity” to fertilize; the second enables the spermatozoa to penetrate the egg´s surrounding zona pellucida. Overall, our studies might contribute to fertility issues such as the development of male contraception treatments, which is an area of intense research.
The development of most metazoans can be divided in an early phase of embryogenesis and a subsequent phase of post-embryonic development. Developmental dynamics during the post-embryonic phase are generally much slower and often controlled by very different molecular mechanisms that, e.g., ensure tissue synchrony and integrate metabolic queues. However, obtaining long-term in-vivo quantitative imaging data post-embryonically with good statistical and cellular resolution has been highly challenging because animals must be allowed to grow, feed, and move in order to properly develop after embryogenesis. In this talk, I will discuss our recent progress in overcoming these challenges in the model organism C. elegans, using microfluidics technology. I will then outline two of our studies, in which quantitative in-vivo imaging data of post-embryonic development allows novel insights into mechanisms of cell-fate acquisition and the regulation of oscillatory gene expression in C. elegans.
Early embryogenesis of most metazoans is characterized by rapid and synchronous cleavage divisions. After fertilization, Drosophila embryos undergo 13 swift rounds of DNA replication and mitosis without cytokinesis, resulting in a multinucleated syncytium containing about 6,000 nuclei. The very first cycles involve substantial flows, both in the bulk and at the cortex of the syncytial embryo. Waves of activity of Cdk1, the main regulator of the cell cycle, are observed in late cycles. I shall discuss the corresponding experimental data and models that capture those dynamics.
Microtubules are dynamic polymers that are used for intracellular transport and chromosome segregation during cell division. Their unique property to grow and shrink at steady state conditions stems from the low energy of dimer interactions, which sets the growing polymer close to its disassembly conditions. Microtubules function in coordination with molecular motors, such as kinesins and dyneins, which use ATP hydrolysis to produce mechanical work and move on microtubules. This raises the possibility that the forces produced by walking motors can break dimer interactions and trigger microtubule disassembly. We tested this hypothesis by studying the interplay between non-stabilized microtubules and moving molecular motors in vitro. Our results show that the mechanical work of molecular motors is able to remove tubulin dimers from the lattice and rapidly destroys microtubules. This effect was not observed when free tubulin dimers were present in the assay. Using fluorescently labelled tubulin dimers we found that motor motion fosters the insertion of free tubulin dimers into the microtubule lattice. This self-repair mechanism allows microtubules to survive the damages induced by molecular motors as they move along their tracks. Thus, our study reveals the existence of a coupling between the motion of molecular motors and the renewal of microtubules lattice.
In order to guide spatial behaviour the brain has the complex task of keeping track of movement through space, which it accomplishes by integrating information about learned environmental features together with information about movements, both linear and angular. The system that performs this integration contains several canonical cell types including place cells, head direction cells and grid cells. How these neurons achieve this environment/movement integration in two-dimensional space is relatively well understood, but movement in more than two dimensions introduces additional problems such as non-commutativity and anholonomy. This talk will review these problems, and discuss emerging evidence that the brain deals with the resulting complexity by a process of dimension reduction - that is, by reducing the problem to the lowest number of dimensions that will suffice to solve a given task. Not only does this allow for efficient processing of three-dimensional space, it might even be possible, at least in humans, that the brain could learn to apprehend four-dimensional space in this way.
The nuclear pore complex is the unique gateway between the nucleus and the cytoplasm of the cells. It ensures both directional and selective transport of nucleic acids and proteins. Its detailed mechanism is still highly debated. We study its dynamic through two complementary approaches. In a bottom-up approach we use hydrophobic polymer grafted nanopores that mimic the crowding of the native pore. We show using a near field optics (ZMW, ) that we can measure the free energy of translocation and reproduce some of the selectivity and directionality features of the nuclear pore. In a top-down approach we extract nuclear membranes from Xenopus Laevis. Our results obtained using ZMW and optical super-resolution (dSTORM) indicates that the nuclear pore has a plastic architecture. Its large scale organization and its internal structure are strongly influenced by transporters molecular crowding, developmental stage and transcriptional activity .  Zero-mode waveguide detection of flow-driven DNA translocation through nanopores. Auger T, Mathé J, Viasnoff V, Charron G, Di Meglio JM, Auvray L, Montel F. Phys Rev Lett. 2014 Jul 11;113(2):028302.  Nuclear pore complex plasticity during developmental process as revealed by super-resolution microscopy. Sci Rep. 2017 Nov 7;7(1):14732. Sellés J, Penrad-Mobayed M, Guillaume C, Fuger A, Auvray L, Faklaris O, Montel F.
Embryo morphogenesis relies on highly coordinated movements of different tissues as well as cell differentiation and patterning. However, remarkably little is known about how tissues coordinate their movements to shape the embryo and whether and how dynamic changes in signalling and tissue rheology affect tissue morphogenesis. In zebrafish embryogenesis, coordinated tissue movements first become apparent during "doming," when the blastoderm begins to spread over the yolk sac, a process involving coordinated epithelial surface cell layer expansion and deep cell intercalations. In this talk, I will first present how using a combination of active-gel theory and experiments (performed by Dr. Hitoshi Morita, Yamanashi University, Japan) shows that active surface cell expansion represents the key process coordinating tissue movements during doming. I will then talk about the analysis of the intrinsic mechanical properties of the blastoderm at the onset of doming and how, by the aid of a simpler toy model and experiments (performed by Dr. Nicoletta Petridou, IST Austria), blastoderm movement relies on a rapid, pronounced and spatially patterned tissue fluidisation which is found to be linked to local activation of non-canonical Wnt signalling mediating cell cohesion.
Fitness landscapes have moved from theoretical constructions to observable data in last decades, while several experimental fitness landscapes were partially or completely resolved. We have developped few metrics to get a better sense on what are these highly dimensionnal objects. We are now trying to infer what class of models can generate the observed experimental fitness landscapes: clearly none of the ones that were proposed so far. We however found some clues on what to search and where to garden in these landscapes.
The overdamped Langevin equation describes the inertialess motion of a particle under deterministic drift and thermal noise. The deterministic drift is the result of the combined action of active forces and the diffusivity gradient (the “spurious” force). For biological applications, it is important to distinguish between the two components, because the former indicates specific interactions, while the latter is due to a heterogeneous environment, in which these interactions take place. The spurious force is always proportional to the diffusivity gradient, but the proportionality coefficient is only known for equilibrium systems. This leads to a range of possible spurious force values in out-of-equilibrium systems and leads to ambiguity in the interpretation of the observed drift. This ambiguity is known as the Itô-Stratonovich dilemma. In this work, we do not try to resolve the dilemma, but analyze the information that can be extracted about the active forces in an a priori unknown out-of-equilibrium system. To this end, we propose a Bayesian method that marginalizes over all possible values of the spurious force and allows robust identification of active forces in both equilibrium and out-of-equilibrium setups. Under certain assumptions, the main result can be obtained in a closed form. The method has a significantly decreased false positive rate of active force detection as compared to conventional approaches. We illustrate the practical value of the method by integrating it into the open-source software project TRamWAy and applying it to both numerical trajectories and experimental single-biomolecule tracks (HIV capsids assembly) recorded on the cell membrane.
Spatially growing populations are ubiquitous across scales, ranging from the human migration out of Africa to the spreading of diseases. In contrast to well-mixed populations where an individual’s chance to survival is only determined by its fitness, in spatially growing populations the physical location of an individual is determinant for its survival: the individuals at the edge of the expanding front benefit from having access to virgin territory and giving their offspring the same advantage. The emerging population dynamics results in an evolutionary dynamics dominated by noise, with extreme consequences such as the accumulation of deleterious mutations at the front of the population. To explore experimentally how spatial constraints affect evolutionary dynamics, we employ bacteriophage T7, an E. coli virus that allows to cover many generations in short periods of times while controlling the underlying resource constraints, i.e., the bacterial host. In an evolutionary experiment lasting only 7 days, we were able to evolve a T7 strain that more than doubled its spreading speed on a bacterial lawn compared to its ancestor. The results from the experiments pointed out specific properties that are under strong selection in viral expansions and uncovered new remarkable properties of phage spreading dynamics that we believe are shared across viruses and pathogens in general.
Understanding how groups of species diversified, and how species phenotypes evolved during evolutionary history, is key to our understanding patterns of biodiversity as we see them around us today. Phylogenetic comparative methods have been developed to study diversification and phenotypic evolution from present-day data. I will present recent developments that allow testing the effect of past environmental changes on rates of speciation, extinction and phenotypic evolution, as well as models that allow testing the role of species interactions -- such as competitive, mutualistic, and antagonistic interactions – on phenotypic evolution. Empirical applications of these new phylogenetic comparative methods to large empirical datasets demonstrate the pervasive effect of past environmental changes on evolutionary rates across diverse clades spanning micro and macroorganims. They also demonstrate a distinct effect of interspecific competition in traits involved in resource use versus social signaling. Past environmental changes and species interactions have been key in driving the heterogeneity of evolution rates repeatedly observed across the tree of life.
The migration of immune cells is guided by specific chemical signals, such as chemokine gradients. Their trajectories can also be diverted by physical cues and obstacles imposed by the cellular environment, such as topography, rigidity, adhesion, or hydraulic resistance. On the example of hydraulic resistance, it was shown that neutrophils preferentially follow paths of least resistance, a phenomenon referred to as barotaxis. We here combined quantitative imaging and physical modeling to show that barotaxis results from a force imbalance at the scale of the cell, which is amplified by the actomyosin intrinsic polarization capacity. Strikingly, we found that macropinocytosis specifically confers to immature dendritic cells a unique capacity to overcome this physical bias by facilitating external fluid transport across the cell, thereby enhancing their space exploration capacity and promoting their tissue-patrolling function both in silicoand in vivo. Conversely, mature dendritic cells, which down-regulate macropinocytosis, were found to be sensitive to hydraulic resistance. Theoretical modeling suggested that barotaxis, which helps them avoid dead-ends, might accelerate their migration to lymph nodes, where they initiate adaptive immune responses. We conclude that the physical properties of the microenvironment of moving cells can introduce biases in their migratory behaviors but that specific active mechanisms such as macropinocytosis have emerged to diminish the influence of these biases, allowing motile cells to reach their final destination and efficiently fulfill their functions.
My colleague Sunil Laxman has observed the spontaneous emergence of subpopulations of cells in different metabolic states in growing populations of budding yeast. I'll talk about two situations - one where the yeast is in a well-mixed chemostat, and the other where it grows on agar plates. The chemostat produces incredibly regular oscillations between quiescence and proliferation which can sustain for days. I'll spend most time in the talk discussing a simple mathematical model that we think captures many aspects of this oscillation. The model helped us deduce that the the key metabolites triggering the switch from quiescence to proliferation are probably Acetyl-CoA and NADPH. If there is time, I'll also discuss the results of experiments and modelling of the spatial colonies where cells in two different metabolic states self-organize into a complex intermingled spatial pattern, with one state dependent on the other for metabolic raw material.
Our understanding of bacterial cell size control is based mainly on stress-free growth conditions in the laboratory. In the real-world however, bacteria are routinely faced with stresses that produce long filamentous cell morphologies. E. coli is observed to filament in response to DNA damage, antibiotic treatment, host immune systems, temperature, starvation, and more; conditions which are relevant to clinical settings and food preservation. This shape plasticity is considered a survival strategy. Size control in this regime remains largely unexplored. Here we report that E. coli cells use a dynamic size ruler to determine division locations combined with an adder-like mechanism to trigger divisions. As filamentous cells increase in size due to growth, or decrease in size due to divisions, its multiple Fts division rings abruptly reorganize to remain one characteristic cell length away from the cell pole, and two such length units away from each other. These rules can be explained by spatio-temporal oscillations of Min proteins. Upon removal of filamentation stress, the cells undergo a sequence of division events, randomly at one of the possible division sites, on average after the time required to grow one characteristic cell size. These results indicate that E. coli cells continuously keep track of absolute length to control size, suggest a wider relevance for the adder principle beyond the control of normally sized cells, and provide a new perspective on the function of the Fts and Min systems.
Cells exhibit rich repertoire of dynamical behaviors, which depend on cell phenotype and microenvironment. Collective dynamics is not just a product of many individually moving units. Instead, cells coordinate their movements and move as collective entities. Various biological processes, including morphogenesis, cancer progression and tissue remodeling, largely depends on the coordinated behavior of cells. Using in vitro experiments, I will show that very different cell types, such as mesenchymal cells and epithelial cells, which look very unlike in their dynamics and morphology, actually move and self-organize according same physical principles. Nematodynamics - theory of active non-polar gels allows to formulate unified description of collective motion of cells, where different modes of motion determined by small set of parameters (activity, elastic constant, viscosity and friction). I will present examples of (1) spontaneous left-right symmetry breaking and emergence of collective shear flows of spindle-shaped cells when they confined in adhesive stripes; (2) chaotic vorticity in human bronchial epithelial cell monolayers; and (3) critical dimensions required for collective invasion of fibrosarcoma cells. I will discuss the mechanism behind these phenomena and their effect on cell organization and function.
Actin is a major component of biological cells and forms filaments that constantly polymerize and depolymerize. This activity is used by the cell to generate forces in order to crawl on a surface or to pinch part of its membrane during endocytosis. The cortex, a dense actin network, endows its viscoelastic properties to the cell and protects it from unwanted deformations. The in vitro reconstitution of dense actin networks on micron-size spheres was a seminal step to understand these processes. Here I will describe two experiments where we reconstituted actin networks around non-spherical micro-objects. In the first one, actin grows from the faces of magnetic cylinders arranged in a string. A load is applied by the attraction of neighboring cylinders to monitor the actin network’s growth under stress and measure its elasticity. We evidenced a peculiar non-linear elastic behavior of the network and a direct interaction between growth velocity and viscoelastic behavior. In the second experiment, we revisit the problem of the symmetry breaking occurring in an actin gel growing from a spherical object by growing the actin from star and diamond-shaped prisms. I will show unexpected results on where the fracture arises that downplay the role of mechanical stress in this phenomenon.
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