Biology subjects

Friedrich, B. M.

Publications and source records attributed to Friedrich, B. M..

13 recordsLinked to original sources

bioRxiv2026

Developmental growth rates adapt to enable self-correction of organ morphology after injury.

Proportional organ growth requires tissue-level control of cell behavior. Yet the cues that adapt growth rates, especially after organ injury, remain unclear. Here, we uncover that developing organs are robust to extensive damage, triggering injury-specific mechanisms sufficient to override genetically-encoded size defects. Using precision microsurgery in developing zebrafish pectoral fins, we find that injury drives growth asynchronously across tissues and fin axes, by increasing proliferation and extracellular spacing. Growth compensation scales with the amount of tissue lost, restoring size and structure without compromising developmental timing. A feedback-control model captures these dynamics, suggesting that growth rates are regulated toward an organ-specific target area. At the molecular scale, injury signals bypass developmentally-regulated BMP gradient scaling. Injury instead activates de novo BMP signaling, which supports growth adaptation and rescues wildtype fin size in developmentally small mutants. Our findings identify an injury-dependent compensatory growth mechanism that resets developmental organ size, ensuring functional organ recovery.

developmental biology↗

bioRxiv2026

Programmable microactuators phase-lock cilia to local oscillatory flow

Hydrodynamic synchronization of motile cilia is essential for biological functions such as fluid transport, locomotion, and developmental patterning. It comprises the generation and the response to local flows in complex geometries. Besides their central role in physiology, direct experimental tests of ciliary responses to local flows at cellular length and time scales have remained elusive, largely due to the absence of tools capable of applying controlled, and localized flow stimuli. Here, we introduce programmable, nanometer-thin Ti/Pt microactuators that generate well-defined hydrodynamic forcing at biologically relevant frequencies while operating at biocompatible sub-Volt voltages. This platform is pioneering a controlled local hydrodynamic stimulation of individual motile cilia. We quantify the flow fields and forces produced by single microactuators using particle image velocimetry. Applying local oscillatory flows close to motile cilia of the green alga Chlamydomonas reinhardtii, we probe their dynamic response by quantifying phase-locking between cilia and microactuators. This quantification is aided by combining machine-learning-based image segmentation, oscillator phase reconstruction, and circular statistics. During actuation, we observe signatures of phase-locking: those include a reversible modulation of the fluctuations in phase-difference between cilium and actuator and a systematic shift in ciliary beating frequency. Beyond providing a bio-compatible and precise platform for local hydrodynamic stimulation, our approach establishes an experimental framework for directly testing theories of hydrodynamic synchronization and load adaptation in systems of motile cilia.

biophysics↗

bioRxiv2025

Static morphogen scaling enables proportional growth in tissue growth model inspired by axolotl limb regeneration

Axolotls can regenerate lost limbs throughout life, while they continue to grow. This poses the question of how the size and pattern of a regenerating limb is matched to a widely varying animal size. Two interacting signaling molecules, SHH and FGF8, are produced at opposite sides of the regenerating limb and sustain tissue growth through a pair of oppositely-oriented signaling gradients. As the size of the regrowing tissue can vary more than three-fold depending on the size of the animal, it is unclear how the activities of these mutually dependent morphogens are maintained and subsequently terminated to determine appropriate growth. Scaling of limb regeneration suggests a size-dependent adaptation of morphogen gradient parameters. Inspired by this biological example, we theoretically investigate general mechanisms of morphogen-controlled growth arrest and proportional growth. In the proposed mechanism, tissue growth increases the spatial distance between the two morphogen gradients, which eventually arrests morphogen activity and growth. We put forward two distinct scaling scenarios of morphogen gradients: either dynamic scaling with blastema size, where morphogen gradient parameters change dynamically with the growing tissue, or static scaling with animal size, where morphogen gradient parameters stay constant during blastema growth and only depend on animal size. We show that static scaling ensures proportional growth, but dynamic scaling does not. We compare theory predictions to experimental quantification of SHH and FGF8 morphogen gradient parameters at different time-points of regeneration in different-sized animals, indicating static scaling for some morphogen parameters, which is sufficient to ensure proportional growth in our model.

biophysics↗

bioRxiv2024

Muscle growth by sarcomere divisions

The sarcomere is the elementary contractile unit of muscles. Adult muscle cells chain thousands of sarcomeres into long periodic myofibrils that attach to the skeleton. How new sarcomeres are added during muscle growth is unknown. By live imaging and high-throughput image analysis, we have now tracked sarcomeric components during Drosophila muscle development and discovered that individual sarcomeres divide along the myofibril tension axis into daughter sarcomeres. This way, new sarcomeres can be inserted into contractile and mechanically intact myofibrils. We propose that sarcomere division is triggered by tension and local sarcomere damage originating from skeletal growth and muscle contractions. Sarcomere divisions repair damaged sarcomeres, ensure their mechanical integrity and synchronise sarcomere addition with skeletal growth during animal development.

developmental biology↗

bioRxiv2024

Active fluctuations of axoneme oscillations scale with number of dynein motors

Fluxes of energy generate active forces in living matter, yet also active fluctuations. As canonical example, collections of molecular motors exhibit spontaneous oscillations with frequency jitter caused by non-equilibrium phase fluctuations. We investigate phase fluctuations in reactivated Chlamydomonas axonemes, which are accessible to direct manipulation. We quantify the precision of axonemal oscillations after controlled chemical removal of dynein motors, providing an experimental test for the theory prediction that the quality factor of motor oscillations should increase with motor number. Our quantification reveals specialized roles of inner and outer arm dynein motors. This supports a model in which inner dyneins serve as master pace-makers, to which outer arm dyneins become entrained, consistent with recent insight provided by structural biology.

biophysics↗

bioRxiv2024

Twist - torsion coupling in beating axonemes

Motile cilia and flagella are ubiquitous cell appendages whose regular bending waves pump fluids across tissue surfaces and enable single-cell navigation. Key to these functions are their non-planar waveforms with characteristic torsion. It is not known how torsion, a purely geometric property of the shape, is related to mechanical deformations of the axoneme, the conserved cytoskeletal core of cilia and flagella. Here, we assess torsion and twist in reactivated axonemes isolated from the green alga Chlamydomonas reinhardtii. Using defocused darkfield microscopy and beat-cycle averaging, we resolve the 3D shapes of the axonemal waveform with nanometer precision at millisecond timescales. Our measurements reveal regular hetero-chiral torsion waves propagating base to tip with a peak-to-peak amplitude of 22 {o}/{micro}m. To investigate if the observed torsion results from axonemal twist, we attach gold nanoparticles to axonemes to measure its cross-section rotation during beating. We find that locally, the axonemal cross-section co-rotates with the bending plane. This co-rotation presents the first experimental evidence for twist-torsion coupling and indicates that twist waves propagate along the axoneme during beating. Our work thus links shape to mechanical deformation of beating axonemes, informing models of motor regulation that shape the beat of motile cilia.

biophysics↗

bioRxiv2024

Deciphering rapid cell signaling and control of cell motility by reverse opto-chemical engineering

Cells transform complex environmental stimuli into physiological responses. For time-varying stimuli or motile cells, the perception of the environment depends on the temporal stimulus pattern and cell motion, respectively. Here we report a concept, "reverse optochemical engineering" (ROCE), that uses temporal light patterns and photo-triggers to expose cells to virtual sensory landscapes while recording in real time their physiological responses and motor behavior. We studied cyclic-nucleotide signaling in cell lines, sperm, olfactory neurons, and cardiomyocytes. The technique can be employed for remote control of motility by light. We reprogrammed sperm from a chemotactic to a phototactic cell that is attracted towards light. The method provides new opportunities to decipher the mechanisms and signaling molecules underlying rapid cellular computations, and thus reveal the wire diagram of cellular networks.

biophysics↗

bioRxiv2023

Chemotactic agents combining spatial and temporal gradient-sensing boost spatial comparison if they are large, slow, and less persistent

Biological cells and small organisms navigate in concentration fields of signaling molecules using two fundamental gradient-sensing strategies: spatial comparison of concentrations measured at different positions on their surface, or temporal comparison of concentrations measured at different locations visited along their motion path. It is believed that size and speed dictate which gradient-sensing strategy cells choose, yet this has never been formally proven. Using information theory, we investigate the optimal gradient-sensing mechanism for an ideal chemotactic agent that combines spatial and temporal comparison. We account for physical limits of chemo-sensation: molecule counting noise at physiological concentrations, and motility noise inevitable at the micro-scale. Our simulation data collapses onto an empirical power-law that predicts an optimal weighting of information as function of motility and sensing noise, demonstrating how spatial comparison becomes more beneficial for agents that are large, slow and less persistent. This refines and quantifies the previous heuristic notion. Our idealized model assuming unlimited information processing capabilities serves as a benchmark for the chemotaxis of biological cells.

biophysics↗

bioRxiv2023

Theory of sarcomere assembly inferred from sequential ordering of myofibril components

Myofibrils in striated muscle cells are chains of regular cytoskeletal units termed sarcomeres, whose contractions drive voluntary movements of animals. Despite the well characterized order of the sarcomere components in mature sarcomeres, which explains the sarcomere contraction mechanism, the mechanism of molecular ordering during sarcomere assembly remains debated. Here, we put forward a theoretical framework for the self-assembly of sarcomeres. This theory is based on measurements of the sequential ordering of sarcomere components in developing Drosophila flight muscles, identified by applying a novel tracking-free algorithm: myosin, -actinin and the titin homologue Sallimus form periodic patterns before actin. Based on these results, we propose that myosin, Sallimus, and sarcomere Z-disc proteins including -actinin dynamically bind and unbind to an unordered bundle of actin filaments to establish an initial periodic pattern. As a consequence, periodicity of actin filaments is only established later. Our model proposes that non-local interactions between spatially extended myosin and titin/Sallimus containing complexes, and possibly tension-dependent feedback mediated by an -actinin catch-bond, drive this ordering process. We probe this hypothesis using mathematical models and derive predictive conditions for sarcomere pattern formation, guiding future experimental analysis.

biophysics↗

bioRxiv2023

Mechanism of branching morphogenesis inspired by diatom silica formation

The silica-based cell walls of diatoms are prime examples of genetically controlled, species-specific mineral architectures. The physical principles underlying morphogenesis of their hierarchically structured silica patterns are not understood, yet such insight could indicate novel routes towards synthesizing functional inorganic materials. Recent advances in imaging nascent diatom silica allow rationalizing possible mechanisms of their pattern formation. Here, we combine theory and experiments on the model diatom Thalassiosira pseudonana to put forward a minimal model of branched rib patterns - a fundamental feature of the silica cell wall. We quantitatively recapitulate the time-course of rib pattern morphogenesis by accounting for silica biochemistry with autocatalytic formation of diffusible silica precursors followed by conversion into solid silica. We propose that silica deposition releases an inhibitor that slows down up-stream precursor conversion, thereby implementing a self-replicating reaction-diffusion system featuring a non-classical Turing mechanism. The proposed mechanism highlights the role of geometrical cues for guided self-organization, rationalizing the instructive role for the single initial pattern seed known as primary silicification site. The mechanism of branching morphogenesis that we characterize here is possibly generic and may apply also in other biological systems. Significance statementThe formation of minerals by living organisms is a widespread biological phenomenon occurring throughout the evolutionary tree-of-life. The silica-based cell walls of diatom microalgae are impressive examples featuring intricate architectures and outstanding materials properties that still defy their reconstitution in vitro. Here, we developed a minimal mathematical model that explains the formation of branched patterns of silica ribs, providing unprecedented understanding of basic physico-chemical processes capable of guiding silica morphogenesis in diatoms. The generic mechanism of branching morphogenesis identified here could provide recipes for bottom-up synthesis of mineral-nanowire networks for technological applications. Moreover, similar mechanisms may apply in the biological morphogenesis of other branched structures, like corals, bacterial colonies, tracheal networks, fungal plexuses, or the vascular system.

biophysics↗

bioRxiv2021

Locally synchronized ciliary domains and tissue-scale cilia alignment underlie global metachronal wave patterns

Motile cilia are hair-like cell extensions present in multiple organs of the body. How cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine here experiments, novel analysis tools, and theory to address this knowledge gap. We investigate collective dynamics of cilia in the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Despite the fact that synchronization is local only, we observed global patterns of traveling metachronal waves across the multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right nose, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment are sufficient to generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.

biophysics↗

bioRxiv2018

Liquid-crystal organization of liver tissue

Functional tissue architecture originates by self-assembly of distinct cell types, following tissue-specific rules of cell-cell interactions. In the liver, a structural model of the lobule was pioneered by Elias in 1949. This model, however, is in contrast with the apparent random 3D arrangement of hepatocytes. Since then, no significant progress has been made to derive the organizing principles of liver tissue. To solve this outstanding problem, we computationally reconstructed 3D tissue geometry from microscopy images and analyzed it applying soft-condensed-matter-physics concepts. Surprisingly, analysis of the spatial organization of cell polarity revealed that hepatocytes are not randomly oriented but follow a long-range liquid-crystal order. This does not depend exclusively on hepatocytes receiving instructive signals by endothelial cells as generally assumed, since silencing Integrin-{beta}1 disrupted both liquid-crystal order and organization of the sinusoidal network. Our results suggest that bi-directional communication between hepatocytes and sinusoids underlies the self-organization of liver tissue.

biophysics↗

bioRxiv2018

Body size-dependent energy storage causes Kleibers law scaling of the metabolic rate in planarians

Kleibers law, or the [3/4]-power law scaling of the metabolic rate with body mass, is considered one of the few quantitative laws in biology, yet its physiological basis remains unknown. Here, we report Kleibers law scaling in the planarian Schmidtea mediterranea. Its reversible and life history-independent changes in adult body size over 2 orders of magnitude reveal that Kleibers law does not emerge from the size-dependent decrease in cellular metabolic rate, but from a size-dependent increase in mass per cell. Through a combination of experiment and theoretical analysis of the organismal energy balance, we further show that the mass allometry is caused by body size dependent energy storage. Our results reveal the physiological origins of Kleibers law in planarians and thus have general implications for understanding a fundamental scaling law in biology.

biophysics↗