Fluid Physics of Life

Nonequilibrium statistical physics of dense active matter is a fascinating and rich playground in which a variety of emergent behaviour is observed. A natural consequence of the high density in the system will be that the active elements will strongly interact with each giving rise to enhancement and inhibition in their collective activity. This nonequilibrium interaction should ultimately give rise to a dynamic arrest at sufficiently high densities, which yields a diffusivity edge. This effect has so far been neglected in all contributions in the literature of dense active matter. In my talk, I will show how one can build on the recent surge in developing generalized thermodynamic descriptions for scalar active matter, and formulate a generic theoretical description for a large class of active matter systems, which can be described by a density field, and incorporated the notion of a diffusivity edge for the first time. This is a density threshold beyond which the effective (density-dependent) diffusivity of the system vanishes. The model can be solved exactly for the stationary-state behaviour of the system - which has been the subject of recent intense investigations - despite being highly singular. The exact solution shows a remarkable emergent feature in the system; a dynamical phase transition that is formally equivalent to Bose-Einstein condensation, despite the system being intrinsically classical. I have characterized the relevant generalized thermodynamic properties of the system, and demonstrated how signatures of such behaviour can be sought in experiments.

Fluid flows can induce long-ranged interactions and propagate information on large scales. Especially during the development of an organism, coordination on large scales is essential. What are the principal mechanisms of how fluid flows induce, transmit and respond to biological signals and thus control morphology? Fluid flows are particularly prominent during the growth and adaptation of transport networks. Here, the network-forming slime mold Physarum polycephalum emerged as a model system. Investigating the pivotal role of fluid flows in this live transport network we find that flows are patterned in a peristaltic wave across the network thereby optimizing transport. In fact, flows are hijacked by signals to propagate throughout the network. This simple mechanism is sufficient to explain surprisingly complex dynamics of the organism like scaling of peristaltic wave with network size and finding the shortest path through a maze.

von Willebrand factor (VWF) and blood platelets play a key role in blood clotting by forming VWF-platelet aggregates. Such aggregates form at high shear rates and dissolve reversibly at low shear rates, which leads to an interesting behaviour of these aggregates in microvessels. In blood flow, red blood cells (RBCs) migrate to the centre of a vessel and facilitate margination (or migration) of both VWF molecules and platelets toward vessel walls. In the near-wall region, where the shear rate is largest, VWF-aggregates start forming and grow. After reaching a certain size, such aggregates penetrate into the bulk flow populates by RBCs, where local shear rates are relatively small, and dissociate reversible to single components. Consequently, this process continues in the steps just described. Using mesoscale hydrodynamic simulations, we investigate the formation and dynamics of VWF-platelet aggregates in blood flow. We show that shear activation of VWF and the interactions between VWF and platelets are the main determinants of this process. Thus, a significant change in the VWF activation or VWF-platelet interactions may lead to no aggregate formation or to the formation of irreversible aggregates.

One approach to quantifying biological diversity consists of characterizing the statistical distribution of specific properties of a taxonomic group or habitat. Microorganisms living in fluid environments, and for whom motility is key, exploit propulsion resulting from a rich variety of shapes, forms, and swimming strategies. Here, we explore the variability of swimming speed for unicellular eukaryotes based on published data. The data naturally partitions into that from flagellates (with a small number of flagella) and from ciliates (with tens or more). Despite the morphological and size differences between these groups, each of the two probability distributions of swimming speed are accurately represented by log-normal distributions, with good agreement holding even to fourth moments. Scaling of the distributions by a characteristic speed for each data set leads to a collapse onto an apparently universal distribution. These results suggest a universal way for ecological niches to be populated by abundant microorganisms.

Active fluids, such as dense suspensions of bacteria or microtubules and molecular motors, display a fascinating range of dynamical states. Active stresses exerted by the individual agents, along with their hydrodynamic interactions, generically lead to the emergence of mesoscale vortex patterns reminiscent of two-dimensional turbulence. In this presentation, we discuss how ordered flows emerge in a minimal continuum model of active fluids. In particular, we focus on a novel type of turbulence-driven pattern formation: a self-organized active vortex crystal. Crucially, this state emerges from an extended disordered transient characterized by an upscale energy transfer. Exploring the transition from active turbulence to the vortex crystal state with a focus on the role of fluctuations and system size, we find surprising analogies to classical phase transitions. For example, we observe locally ordered crystal domains, which share similarities with magnetic domains in ferromagnetic materials, separated by turbulent boundaries. Our results therefore explore one route to self-organization in active fluids.

Tissue of neural stem (NS) cells has peculiar properties such as attraction of cell population toward +1/2 topological defect and repelling from -1/2 topological defect with enhancing bending deformation and without contact inhibition of locomotion. Nevertheless, it is not yet fully understood how the extensile character arises from the interaction of NS cells. In this talk, we will present results of experiment and analysis on the dynamics of NS cells in confined and unconfined geometries. The behavior of NS cells is compared with nematohydrodynamics of actively moving cells and dry active matter descriptions.

Motile cilia are membrane protrusions at the cellular surface that reach into the extracellular space. Cilia exert a stereotypic, oscillating motion to induce directional flow. In mammals, early developmental processes rely on flow generated by primary cilia in the node whereas multiciliated cells in the respiratory tract are known for their protective function by formation of a fluid compartment. In the mammalian brain, however, the regulation and function of multiciliated cells has long been misunderstood. The surface of the fluid-filled ventricular system is covered by billions of motile cilia that we show are individually regulated to form a complex pattern. We developed a sophisticated toolset to study ciliary motion, resulting flow and transport properties. This methodological toolset involves life-imaging techniques at spatio-temporal resolution combined with computational simulation of cilia-induced fluid mechanics. We found ciliary motion generates a complex network of flow channels and barriers and in this way partitions fluid. This network presents with the characteristics of a complex transport system that adjusts to physiological and environmental cues. Our findings suggest precise arrangement of ciliary motion parameters are important for balancing between local accumulation of substances, coherent transport and clearance. Application of our toolset to samples from patients and genetically modified mice reveals minor changes in ciliary motion can have far-reaching effects on fluid dynamics in the brain. Overall, our work establishes that cilia-driven logistics are geared to accommodate local requirements of diverse brain areas with implication for human disease.

The human brain accounts for just 2% of the body's mass but metabolizes 25% of its calories, producing significant metabolic waste. However, waste buildup links to neurodegenerative diseases like Alzheimer's and Parkinson's. The brain removes waste via the recently-discovered glymphatic system, a combination of spaces and channels through which cerebrospinal fluid flows to sweep away toxins like amyloid-beta. With an interdisciplinary group of neuroscientists and physical scientists, I study the fluid physics of the glymphatic system: Where does fluid flow, and how fast? What drives flow? Does flow shear cause waste accumulation? What characteristics of the system enable essential functions? How can we improve waste removal? Can we use glymphatic flow to deliver drugs? The team combines physics tools like particle tracking and newly-invented front tracking with biological tools like two-photon imaging through cranial windows in order to address these questions with in vivo flow measurements. I will talk about recent results showing that glymphatic flow proceeds along vessels with near-optimal shapes, pulses with the heart, is driven by artery walls, can be manipulated by changing the wall motion, and is the dominant source of swelling soon after ischemic stroke.

During embryonic development, the orientation of motile cilia is established in part through the action of hydrodynamic forces, but a direct test of this mechanism has remained outstanding. Using multiciliated cells on the larval skin of Xenopus Laevis, the role of fluid flow in development of cilia orientational polarity is investigated by a combination of live fluorescence imaging of basal structures, high-speed cilia imaging, microfluidics, and theory. First, a systematic description of the flow profile about a multiciliated cell in vivo is presented, revealing the underling mechanical forces at cell and tissue scales. Second, the live response of the system to hydrodynamic forces is tested by applying an exogenous flow. At the cell scales, basal bodies increase their alignment following cell shape changes and cytoskeleton remodelling. At the tissue scale, cell flows lead to an overall refinement of cilia orientational polarity in the direction of the exogenous flow. Overall, cilia orientational polarity appears to be mediated by a combination of local hydrodynamic forces applied to each cilium, and the stress building up at the larger tissue scales.

The production of blood platelets is a fascinating biophysical process: first, large stem cells residing in the bone marrow extend long cylindrical protrusions into neighboring blood vessels. Subsequently, these protrusions develop a regular pattern of bulges and eventually fragment into separate pieces which eventually convert into platelets. Interestingly, experiments have shown a drastic acceleration of this process as a function of blood flow. The biophysical mechanism behind platelet production and its connection to blood flow is at present not understood. Here we use Lattice-Boltzmann computer simulations and analytical theory to provide evidence that platelet production is determined – in essence – not by biochemistry but rather by a physical instability analogous to the well-known Rayleigh-Plateau (RP) instability of fluid jets. For our simulations, we have developed a novel method to simulate the dynamic deformation of active cell membranes surrounded by arbitrary external flows in full three dimensions [1]. Our simulations semi-quantitatively reproduce the main features observed in-vivo and in-vitro: external flow strongly accelerates break-up but, at the same time, hardly influences the break-up wave length and thus the size of the final platelets. [1] C. Bächer and S. Gekle. Computational Modeling of active deformable membranes embedded in 3D flows. arXiv:1903.08529 [physics.bio-ph] (2019)

Coordinated beating of motile cilia leads to a directional fluid flow, which is important for various biological processes from respiration to reproduction. In the nervous system, motile ciliary beating of ependymal cells allows the cerebrospinal fluid (CSF) to flow through the ventricular system. Such flow plays a central role in the nervous system as human patients or animal models with ciliary defects develop neurological features including hydrocephalus and spine curvature. Still, very little is known about how the nervous system generates and regulates specific flow patterns and how flow controls neural activity and animal behavior. Here, I will first describe the mechanisms used by motile cilia to generate specific flow pattern in the zebrafish olfactory epithelium and the function of the flow in olfactory processing. Later, I will discuss how motile cilia and other physiological factors act jointly to regulate cerebrospinal fluid flow dynamics in the brain ventricles. I will also describe the importance of ciliary beating during brain development using zebrafish as model system.

Throughout the last decades, genetic perturbations massively advanced our molecular understanding of biological processes. At the same time however, the spatio-temporal organization of cells and developing embryos is widely believed to also depend on physical transport processes such as diffusion or flows, which are hard to manipulate. Here we demonstrate focused-light induced cytoplasmic-streaming (FLUCS). FLUCS uses light controlled thermoviscous expansion phenomena to induce well-defined flows in single cells and developing embryos. These non-invasive flows are localized, directed, highly dynamical, probe-free, and non-invasive. By controlling flows inside the cytoplasm of one-cell C. elegans embryos, we directly demonstrate the causal role of flows for the establishment of the head-to-tail body axis (aka PAR-polarization). Moreover, we show how FLUCS perturbations are suitable for an active micro-rheology of the cytoplasm and even within cell nuclei. References: i) Mittasch et al, Nature Cell Biology 20 (2018) ii) Kreysing, Developmental Cell (in press)

Chromatin structure and dynamics control all aspects of DNA biology yet are poorly understood. In interphase, time between two cell divisions, chromatin fills the cell nucleus in its minimally condensed polymeric state. Chromatin serves as substrate to a number of biological processes, e.g. gene expression and DNA replication, which require it to become locally restructured. These are energy-consuming processes giving rise to non-equilibrium dynamics. Chromatin dynamics has been traditionally studied by imaging of fluorescently labeled nuclear proteins and single DNA-sites, thus focusing only on a small number of tracer particles. Recently, we developed an approach, displacement correlation spectroscopy (DCS) based on time-resolved image correlation analysis, to map chromatin dynamics simultaneously across the whole nucleus in cultured human cells [1]. DCS revealed that chromatin movement was coherent across large regions (4–5$\mu$m) for several seconds. Regions of coherent motion extended beyond the boundaries of single-chromosome territories, suggesting elastic coupling of motion over length scales much larger than those of genes [1]. These large-scale, coupled motions were ATP-dependent and unidirectional for several seconds. Following these observations, we developed a hydrodynamic theory [2] as well as a microscopic model [3] of active chromatin dynamics. In this work we investigate the chromatin interactions with the nuclear envelope and compare the surface dynamics of the chromatin globule with its bulk dynamics [4], which we also explore using naturally present cellular probes [5]. [1] Zidovska A, Weitz DA, Mitchison TJ, PNAS, 110 (39), 15555-15560, 2013 [2] Bruinsma R, Grosberg AY, Rabin Y, Zidovska A, Biophys. J., 106 (9), 1871-1881, 2014 [3] Saintillan D, Shelley MJ, Zidovska A, PNAS, 115 (45) 11442-11447, 2018 [4] Chu F, Haley SC, Zidovska A, PNAS, 114 (39), 10338-10343, 2017 [5] Caragine CM, Haley SC, Zidovska A, PRL, 121, 148101, 2018

The inside of a cell is an active place, with molecular machines busy positioning subcellular organelles, organizing themselves within membranes, and remodeling DNA in the nucleus. I'll survey how mathematical modeling and large-scale simulations has interacted fruitfully with experimental measurements and perturbations in studying these motor-driven processes. I will then focus on recent work exploring how motor activity and hydrodynamic interactions may underlie an apparently self-organizing dynamics of chromatin in the interphase nucleus.

We model the fluid dynamics of vesicle transport into dendritic spines, micron-sized structures located at the postsynapses of neurons. Dendritic spines are characterized by their thin necks and bulbous heads, and recent high-resolution 3D images show a fascinating variety of spine morphologies. Our model reduces the fluid dynamics of vesicle motion to two essential parameters representing the system geometry and elasticity and allows us to thoroughly explore phase space. Upon including competing molecular motor species that push and pull on vesicles, we observe multiple stable solutions reminiscent of the observed behavior. We discuss whether it would be feasible for neurons could exploit such a switch to control the strength of synapses.

Cilia and flagella produce rapid and regular bending waves responsible for the propulsion of organisms in fluids or for the promotion of fluid transport. It is known that the main contribution to their beating is due to motor proteins that drive sliding of the microtubule doublets. However, the fundamental mechanism of the motors-microtubule interaction is still a puzzle. Here we investigate their mechanical interaction and emergent behavior by analyzing minimal synthetic systems that we experimentally assemble by using microtubules and few molecular motors. We investigated two different set-up and we observe that the microtubules undergo persistent oscillations and cyclical association/dissociation interactions through rhythmic bending. By considering the shearing force produced by the motors when they move along the adjacent microtubule and the finite elasticity of the system, we describe this beating cycle in terms of the curvature and motors-microtubule binding force.

Motile cilia on ciliated epithelia in airways, brain and oviduct display coordinated beating in the form of metachronal waves, presumably due to mutual hydrodynamic coupling, which is important for efficient fluid transport. How the shape of the cilia beat determines the direction and wavelength of metachronal waves is not fully understood, nor is robustness with respect to noise in the presence of multiple synchronized states. We perform hydrodynamic simulations of cilia carpets, using experimental beat patterns, using a computationally efficient framework of Lagrangian Mechanics of Active Systems (LAMAS). Thereby, we determine all metastable synchronized states and their fundamental perturbation modes, which characterize the dispersion relation of metachronal waves.

Bacteria can engage a wide range of collective behaviors. One such behavior is the formation of multicellular communities termed biofilms, which is the most abundant for of life on earth. Such biofilms display strongly increased tolerance to antibiotics, and constitute the most abundant form of biomass on Earth. I will first present a new microscopy and imaging technique we recently developed to follow dynamical processes in biofilms at the single-cell level, and bacterial swarming at the single-cell level. Based on data from these new imaging techniques, bacterial genetics, and mathematical models, I will then demonstrate how two bacterial collective behaviors, swarming and biofilm formation, are unified by physical interactions, chemical signaling, and dynamical transitions.

Bacterial and other active suspensions can exhibit striking symmetry breaking phenomena, ranging from the spontaneous formation of vortex lattices to the emergence of large-scale unidirectional flows. Borrowing ideas from classical pattern formation theory, we will discuss generalized Navies-Stokes (GNS) equations as an analytically tractable minimal model of stress-driven active fluids. The GNS equations permit exact stress-free bulk solutions in planar and curved geometries, including Abrikosov-type lattices in 2D and Beltrami flows in 3D. A triad analysis shows that the combination of a generic linear instability and a standard advective nonlinearity can give rise to spontaneous chiral symmetry breaking that supports inverse energy transport in 3D.

The advent of self-propelled colloids that move absent external force brings important and as yet largely untapped degrees of freedom to interfacial engineering. Bacteria and reactive Janus beads are examples of structures that propel themselves and interact with fluid boundaries. Because of their directed motion, such active colloids accumulate near interfaces. There, they can become trapped and swim adjacent to interfaces via hydrodynamic interactions, or they can adsorb directly and swim in an adhered state with complex trajectories that differ from those in bulk in both form and spatio-temporal implications. We study individual swimmers on and near interfaces and their interactions. We seek to understand how an interface covered with active agents forms a two dimensional active sheet that interacts with the adjacent fluids.

Microorganismal motility is often characterised by complex responses to environmental physico-chemical stimuli. Although the biological basis of these responses is often not well understood, their exploitation already promises novel avenues to directly control the motion of living active matter at both the individual and collective level. Here we leverage the phototactic ability of the model microalga {\it Chlamydomonas reinhardtii} to precisely control the timing and position of localised cell photo-accumulation, leading to the controlled development of isolated bioconvective plumes. This novel form of photo-bio-convection allows a precise, fast and reconfigurable control of the spatio-temporal dynamics of the instability and the ensuing global recirculation, which can be activated and stopped in real time. A simple continuum model accounts for the phototactic response of the suspension and demonstrates how the spatio-temporal dynamics of the illumination field can be used as a simple external switch to produce efficient bio-mixing.

The vast majority of microorganisms are exposed to fluid flow, whether in natural environments, the human body, or artificial systems. However, despite the pervasive occurrence and implications of a fluid dynamic environment, its influence on the transport and attachment of bacteria to surfaces (1–3) remains poorly understood, especially in complex geometries that best describe real systems. We will show that fluid flow and surface geometry greatly influence transport and surface colonization by swimming microorganisms such as Pseudomonas aeruginosa and Escherichia coli (4). Using a combination of microfluidic experiments and numerical modelling, we will demonstrate that flow preferentially promotes bacterial attachment on specific regions of curved surfaces, i.e., on the leeward side of isolated cylindrical pillars and directly after the apexes of regular and randomly corrugated surfaces. Colonization is tightly linked to bacterial motility, which increases the attachment rates by two orders of magnitude compared to the case of non-motile bacteria or passive particles. Moreover, for relatively low flow rates (i.e., for fluid velocities not greater than 10 times the swimming speed of bacteria) a simple scaling law for the pillar capture efficiency is found, which means that the density of adhered bacteria is independent of the size of the pillar. In contrast, for high flow rates, the behaviour of motile bacteria is equivalent to that of passive particles, for which the attachment rate per unit surface decreases with increasing pillar dimensions. Taken together, these results underscore the importance of fluid flow in governing bacterial colonization and biofilm formation under common environmental conditions, with significant ecological, industrial, and clinical implications. 1. Rusconi, R., Guasto, J. S. & Stocker, R. Bacterial transport suppressed by fluid shear. Nat. Phys. 10, 2–7 (2014). 2. Peruzzo, P., Defina, A., Nepf, H. M. & Stocker, R. Capillary interception of floating particles by surface-piercing vegetation. Phys. Rev. Lett. 111, 164501 (2013). 3. Lecuyer, S. et al. Shear stress increases the residence time of adhesion of Pseudomonas aeruginosa. Biophys. J. 100, 341–350 (2011). 4. Secchi, E. et al., under revision in Nature Communications

Hierarchically patterned blood vessel networks are important for the proper distribution of fluids, nutrients and oxygen throughout the body. In order to provide efficient transport routes, blood vessels organize in hierarchical structures, resembling trees. I will discuss the role of blood flow in the establishment of vascular trees and how biophysical forces interact with gene expression networks during this process. I will further illustrate how mutations in components of the transforming growth factor beta pathway can lead to aberrantly patterned blood vessel networks, causing the human disease condition hereditary hemorrhagic telangiectasia.

One of the characteristic features of many marine dinoflagellates is their bioluminescence, which lights up night-time breaking waves or seawater sliced by a ship’s prow. While the internal biochemistry of light production by these microorganisms is now well-established, the manner by which external fluid shear triggers bioluminescence is still poorly understood. We report here [1] controlled measurements of the force and shear thresholds for flow-induced light production at the single-cell level, using high-speed imaging of micropipette-held cells of the marine dinoflagellate Pyrocistis lunula subjected to localized fluid flows. Combined with calculations of flow-induced surface tractions, these results help constrain theories of how cells sense shear. [1] Jalaal, Schramma, Raufaste, de Maleprade, Dode, and Goldstein, preprint (2019)

Growth and remodeling of the endothelial cells that surround blood vessels is known to be controlled by a fluid shear stress set point. If the shear stress exerted on the cells by the blood flowing through the vessel is smaller than the set point, then the vessel decreases in radius. If it is larger than the set point, then the vessel radius is directed to increase. But when a shear stress finding algorithm is applied mathematically to a network, then all loops are purged, and the networks produced look very unlike real microvascular networks. Accordingly it is generally assumed that some other mechanism beyond fluid stresses must act within the network to produce realistic flows. However, we will show that if the non-Newtonian nature of blood flow is considered, then shear stresses alone are capable of directing the network toward stable, realistic equilibria. In fact, shear stresses are remarkably adept at sculpting networks that uniformize flow in every vessel -- a property that our own data suggests may govern microvascular networks. Finally we show that a model based on shear stress set points produces results that accord quantitatively with the flows and vessel diameters of the real zebrafish trunk, including under genetic perturbations that change the number of red blood cells.

In plants, plasmodesmata (PD) are nanopores that serve as channels for molecular cell-to-cell transport. Precise control of PD permeability is essential to regulate phloem loading and unloading; moreover it is involved in growth, tissue patterning, and defense against pathogens. Callose deposition modulates PD transport but little is known of the rapid events that lead to PD closure in response to tissue damage or osmotic shock. We propose a new mechanism of PD closure as a result of mechanosensing. Pressure forces cause the cell wall, or the dumbbell-shaped ER-desmotubule-complex, to be displaced from the equilibrium position, thus closing the PD aperture. Cell wall elasticity and the filamentous protein tethers that link the plasma membrane (PM) to the ER complex play a key role in determining the selectivity of the PD pore. This model of PD control compares favorably with experimental data on the pressure-generated closure of PD.