Paris Biological Physics Community Day 2016

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★ Silvia Santos - Imperial College, London, UK
   "Positive feedback keeps duration of mitosis temporally insulated from upstream cell cycle events"Abstract »

The cell cycle is characterized by a sequence of events by which a cell gives rise to two daughter cells. Quantitative measurements of cell cycle dynamics in single cells showed that despite variability in G1, S and G2-phases, duration of mitosis is kept short and remarkably constant. Surprisingly, there is no correlation between cell cycle length and mitotic duration, suggesting that mitosis is temporally insulated from variability in earlier cell cycle phases. By combining live cell imaging and computational modeling we showed that positive feedback is the molecular mechanism underlying the temporal insulation of mitosis. Perturbing positive feedback gave rise to a sluggish, more variable entry and progression through mitosis and uncoupled duration of mitosis from variability in cell cycle length. We show that positive feedback is important to keep mitosis short, constant and temporally insulated and anticipate it might be a commonly used regulatory strategy to create modularity in other biological systems.

★ Fred Wolf - University Goettingen, Germany
   "Understanding evolutionary convergence of visual cortical networks"Abstract »

TBA

★ Andrea Weisse - University of Edinburgh, UK
   "Mechanisms and trade-offs of cellular growth"Abstract »

Intracellular processes rarely work in isolation but continually interact with the rest of the cell. In microbes, for example, we now know that gene expression across the whole genome typically changes with growth rate. The mechanisms driving such global regulation, however, are not well understood. Here we consider a mechanistic model of growing cells that accounts for trade-offs, which because of limitations in levels of cellular energy, free ribosomes and proteins are faced by all living cells. The model couples gene expression with growth rate and growth rate with a growing population of cells. It recovers typical growth behaviour of microbes such as Monod's law and empirical relationships connecting growth rate to the ribosomal cell content. Further, we can explain global regulatory effects, predict host-circuit interactions in synthetic biology and investigate evolutionary trade-offs that shape the cellular behaviour we observe.

★ Greg Stephens - AMOLF, Amsterdam, Netherlands
   "Towards a biophysics of organisms: Capturing the continuous complexity of natural behavior in the movement of C. elegans"Abstract »

We all instinctively recognize behavior: it’s what organisms do, from single cells searching for nutrients to the stunning aerial displays of bird flocks. If we want to understand behavior, however, we have to be able to characterize such actions as precisely and completely as their underlying molecular and cellular mechanisms. Here we leverage a low-dimensional but complete encoding of worm postures to quantitatively characterize the 2D movement behavior of the nematode C. elegans. While behavior is often described as transitions among discrete categories, even simple classes such as forward crawling can display substantial variability and we reconstruct a continuous phase space to understand these motions. The invariant dimension of the reconstructed phase space reveals a scale-dependent attracting manifold reflecting short-scale variability and large-scale stereotypy. Furthermore we find an exponential divergence of nearby-trajectories and a full Lyapunov spectrum with an approximate Hamiltonian subspace containing two chaotic dimensions. We suggest that a simple model of coupled, chaotic oscillators may underlie the motor control of C. elegans.

★ Sophie Marbach - LPS, École Normale Supérieure, Paris
   "Principles of a biomimetic kidney-on-a-chip for advanced nanofiltration"Abstract »

The clear need in fresh water is one of the main challenges now faced by humanity. While water desalination and water recycling involve costly separation processes in terms of energy, the domain has been boosted over the last decades by the progresses made in membrane technology for water purification, such as reverse osmosis or nanofiltration [1], and more recently by the possibilities offered by nanoscale materials [2,3]. In this paper we investigate the physical mechanisms underlying one of the most efficient filtration devices: the kidney. Building on a minimal model of the Henle Loop - the central part of the kidney filtration -, we investigate theoretically the detailed out-of-equilibrium fluxes in this separation process in order to obtain theoretical bounds for its efficiency in terms of separation ability and energy consumption. A key discovery is that this separation device operates at a remarkably small energy cost as compared to traditional sieving processes, while working at much smaller pressures This unique energetic efficiency originates in the serpentine geometry of the nephron, which operates as an active osmotic exchanger. The principles for such a "kidney on a chip" could be readily mimicked based on existing technologies to build compact and low-energy artificial dialytic devices. They also point to new avenues for advanced water recycling, in particular during sea-water pretreatment for decontamination and hardness reduction.

References:
[1] Elimelech M. and Phillip W.A., Science. 333, 712 (2011).
[2] Humplik T. et al., Nanotechnology. 22, 292001 (2011).
[3] Holt K. et al., Science 312, 1034 (2006).

★ Mélanie Tobin - Institut Curie, Paris
   "Gradients in the mechanical properties of auditory hair cells"Abstract »

Our ability to communicate and appreciate music relies on acute frequency discrimination over a broad range of sound frequencies. This property results from the operation of mechanosensory “hair” cells, which are each tuned to respond maximally to a characteristic frequency that varies monotically along the axis of the auditory organ, the cochlea. The cellular and molecular mechanisms that set the characteristic frequency of a hair cell and regulate its value among different cells to cover the auditory range have remained elusive.
Our working hypothesis is that tuning results in part from passive and active mechanical properties of the “hair” bundle, the mechanosensory antenna of the hair cell. Using an excised preparation from the rat cochlea, we combined iontophoresis of a calcium chelator (BAPTA or EDTA) to break the tip links that interconnect neighboring stereocilia of the hair-cell bundle, fluid-jet stimulation to estimate hair-bundle stiffness and patch-clamp recordings of transduction currents to count the number of intact transduction channels contributing to the response. From the movements evoked by tip-link breakage and our stiffness measurements, we were able to estimate tension in the whole hair bundle as well as, knowing the number of tip links contributing to this tension, in a single tip link. In outer hair cells, which are involved in sound amplification but do not send neural information to the brain, we observed a gradient of tension and stiffness from the low-frequency to the high-frequency end of the cochlea, suggesting that these physical parameters may help tune the hair cell to its characteristic frequency. Interestingly, with inner hair cells ‒the true sensors of the cochlea, our observations do not show any significant gradient. Furthermore, we observed calcium-evoked hair-bundle movements corresponding to an increased tension in the tip links at decreased concentrations of calcium. These movements were similar to those evoked in other classes of vertebrates, such as the frog or the turtle. Together, our results reconcile experiments performed in lower vertebrates with those performed in mammals and show the implication of hair-bundle mechanical gradients in the sharp frequency tuning of the cochlea.

★ Jérémie Mathurin - Université Paris-Sud Orsay
   "IR Nano-spectro-imaging: Characterization of polymeric nanoparticles and in vitro study of their interaction with cells."Abstract »

Recently near-field techniques play a fundamental role in Nanoscience microscopy. Two different ways exist to make infrared studies with near-field techniques: optical techniques measuring the transmitted signal coming from the nano-object or photothermal approaches using thermometer to link temperature to absorption measurements. Considering the limitations of the optical techniques, we have developed in our team an innovative photothermal technique called AFM-IR [1]. The AFM-IR technique is a user-friendly benchtop technique that enables infrared spectroscopy with a spatial resolution well below conventional optical diffraction limits. It acquires IR absorption imaging spectrally resolved with lateral resolution of tens of nanometer [2]. First we will present the experimental set-up and some of the critical technical sides and then illustrate technological advances. Then we will show the result obtained on biodegradable polymeric nanoparticles where the AFM-IR is used as a new label free technique to localize inside fixed macrophages at the subcellular scale. This work has been done in collaboration with the Institute of molecular science (ISMO).

[1] A.Dazzi, R.Prazeres, F.Glotin, J.M.Ortega, Opt. Lett., Vol. 30, Issue 18, 2388-2390 (2005).
[2] F. Lu, M. Jin, M.A. Belkin, Nat. Photon. 8, 307–312 (2014).

★ Ido Lavi - University Pierre and Marie CURIE, Paris
   "Deterministic patterns in cell motility"Abstract »

Cell migration paths are generally described as random walks, associated with both intrinsic and extrinsic noise. However, complex cell locomotion is not merely related to such fluctuations, but is often determined by the underlying machinery. Cell motility is driven mechanically by actin and myosin, two molecular components that generate contractile forces. Other cell functions make use of the same components and therefore will compete with the migratory apparatus. l will present our physical model of such a competitive system, namely dendritic cells whose antigen capture function and migratory ability are coupled by Myosin-II. The model predicts that this coupling gives rise to a dynamic instability whereby cells switch from persistent migration to unidirectional self-oscillation through a Hopf bifurcation. Cells can then switch to periodic polarity reversals through a homoclinic bifurcation. These predicted behaviors are characterized by robust deterministic features that we identify through in-vitro trajectories of dendritic cells over long timescales and distances.

For more context, please refer to: "Cell biophysics: How to eat on the go" by Herbert Levine http://www.nature.com/nphys/journal/vaop/ncurrent/full/nphys3866.html

★ Mathieu Rivière - Université Paris Diderot
   "Growth and motions of a compound leaf"Abstract »

Plant growth, the irreversible volume increase of a cell or an organ, remains an exciting biological puzzle. Growth is essential for shape regulation of the developing organ. It is also the key for every plant, developing or mature, to adapt to its environment.
The cellular mechanisms of plant growth rely on a competition between the inner pressure of the cell and the elastic properties of the cell-wall. Heterogeneities of these mechanical properties across the tissue result in differential growth and eventually lead to growth motions at higher scales. These macroscopic motions can thus be read as an outward signal of the cellular mechanisms underlying shape regulation and growth itself. Here, we propose to take benefit from the intimate link between growth and its related motions to gain a new insight on growth through a multiscale approach, from the organ to the cell-wall level.
Averrhoa carambola's compound leaves display two marked motions, unfurling and nutation, that are widespread among developing leaves. Our approach consists in assuming that different phases of the motion correspond to different growth status within the plant's tissues. First, we characterize motions and growth kinematics using several imaging techniques. Second, we probe the mechanical properties of the cell-wall thanks to Atomic Force Microscopy. It is at last possible to compare the biochemical changes and heterogeneities in the cell-wall thanks to immunohistochemistry. We hope that, altogether, our approach will confirm recent findings in the plant model Arabidopsis thaliana.

★ Daria Bonazzi - Institut Pasteur, Paris
   "Type-IV pili mediated intermittent forces generate viscous liquid aggregates of N. meningitidis"Abstract »

Neisseria meningitidis is a pathogenic bacterium responsible for septicemia and meningitis in humans. Once in the blood stream, circulating bacteria initiate infection by binding to the vessel walls, proliferating and forming tight aggregates. The ability of these bacteria to interact with both the endothelium (adhesion) and between bacteria (auto-aggregation) rely on type-IV pili (T4P), several microns-long fibers which extrude out of the bacterial body and can retract thus exerting forces in the pico-Newton range. We first show that bacteria unable to auto-aggregate show reduced efficiency in the process of vascular colonization in vivo, leading to decreased vascular damage. Bacteria in liquid suspension spontaneously form auto-aggregates, which are spherical, dynamic and can rapidly fuse together, showing a peculiar liquid-like behavior. Using micropipette aspiration, we found that these aggregates are highly viscous (9 Pa*s, close to honey viscosity) but possess a low surface tension (0.1 mN/m). A detailed analysis of bacterial motility within the aggregate revealed T4P-dependent active diffusion which decreases as a function of the distance from the aggregate center. Time lapse microscopy of isolated bacteria pairs in micro-fabricated chambers show alternating phases of fast mutual approaching, coordinated movement and release. With this approach, we could determine some of the fundamental parameters of bacteria-bacteria interaction, such as optimal interaction distance, probability of interaction and disconnection. Based on these experimental measurements, we built up a stochastic model of this telegraphic process which recapitulates the liquid-like behavior of bacterial aggregates and predicts a phase diagram of aggregation phenotypes based on T4P dynamics. Altogether, these results highlight the impact of microscopic properties of active, interacting bacterial cells on the overall mechanics and dynamics of multicellular assemblies that trigger tissue destruction during infection.

★ Quentin Marcou - Laboratoire de Physique Théorique, École normale supérieure, Paris
   "Statistical inference of B-cell repertoire formation and evolution processes"Abstract »

An individual’s adaptive immune system needs to face repeated challenges of a constantly evolving environment with a virtually infinite number of threats. To achieve this task, the adaptive immune system relies on large diversity of B-cells, each carrying a unique receptor specific to a small number of pathogens. These receptors are initially randomly built through the process of V(D)J recombination. Upon recognition of a pathogen the B cell will divide and its offsprings will undergo several rounds of successive somatic hypermutations and selection in an evolutionary process called affinity maturation. I will present a principled probabilistic procedure to infer the probability distribution underlying the recombination process and characterize the somatic hypermutation process.

★  Édouard Hannezo - University of Cambridge, UK
   "Quantitative models of branching morphogenesis"Abstract »

At birth, the mouse mammary gland consists of a rudimentary tree that, by ductal elongation and terminal end-bud (TEB) bifurcation, develops during puberty into a highly branched epithelial network. Here, we developed a multidisciplinary approach based on whole gland reconstruction, unbiased genetic lineage tracing and quantitative mathematical modelling to define the identity and fate of stem cells during mammary epithelial morphogenesis. At the organ scale, morphogenesis happens in a time-invariant manner driven by TEB termination and bifurcation, occurring stochastically with near equal probability, leading to a heterogeneous network topology. We show that the bulk of TEBs consist of a population of highly proliferative, heterogeneous stem cells. Yet, through high effective diffusivity, each stem cell is able to actively contribute to the growth of the epithelial network. Together, our findings point to a simple multi-scale design principle for the morphogenesis of complex branched ductal tissues.