The article, led by Carsten Janke of Institut Curie and Université Paris-Saclay together with Anna Akhmanova of Utrecht University and an international consortium of sixteen colleagues from institutions spanning Europe and the United States, lays out a coordinated agenda for the microtubule field. Its authors span structural biology, biophysics, cell biology, neuroscience, parasitology and computational modelling, reflecting their central conviction that progress will come not from any single discipline but from a deliberate fusion of them. The paper is punctuated by the admission that some of the most basic questions remain unexplored, including how the properties and functions of microtubules are affected by the chemical marks known as tubulin post-translational modifications, by disease-related mutations in tubulin genes, or by variation in the microtubule lattice itself.

Microtubules are hollow tubes assembled from αβ-tubulin dimers that stack into protofilaments, typically thirteen of which align laterally to form the wall of the polymer. What makes these structures extraordinary is their behaviour: individual microtubules stochastically switch between phases of growth and rapid shrinkage, a phenomenon called dynamic instability, which was first described by Tim Mitchison and Marc Kirschner in 1984. A stabilizing cap of GTP-bound tubulin at the growing plus end controls this behaviour, and its loss triggers catastrophic depolymerization. Beyond pure polymerization, microtubules can self-repair by incorporating new tubulin along damaged stretches of lattice, a property revealed in studies showing that lattice defects actually induce self-renewal and protect the polymers from destruction by molecular motors. These discoveries have transformed the view of microtubules from static beams into dynamic, self-healing machines.

The Roadmap emphasizes that microtubule function is not determined by the polymer alone but by a dense layer of regulation encoded on the tubulin subunit itself. Enzymes of the tubulin tyrosine ligase-like family decorate the unstructured carboxy-terminal tails of tubulin with modifications such as tyrosination, detyrosination, acetylation, glutamylation and glycylation, creating what has become known as the tubulin code. Recent structural work has shown, for example, that enzymes involved in polyglutamylation recognize microtubules through a quadrivalent mechanism that links microtubule geometry to the generation of localized modification patterns, and that protofilament-specific nanopatterns of these marks tune the mechanics of beating cilia. The Roadmap argues that understanding how this chemical language is written, read and erased across cellular contexts is one of the field’s most pressing challenges, particularly because disruptions in the code are now firmly linked to neurodegeneration, ciliopathies and other disorders.

Nowhere is the clinical relevance more evident than in the nervous system. Neurons depend on microtubule tracks for the long-range transport of organelles, messenger RNAs and signalling endosomes along axons and dendrites, a process powered by kinesin and dynein motor proteins. Mutations in tubulin genes such as TUBA1A cause lissencephaly, a severe developmental brain malformation, by perturbing neuronal migration, and variants in a growing list of tubulin genes underlie a spectrum of neurodevelopmental disorders collectively known as tubulinopathies. Defective axonal transport is a shared hallmark of motor neuron diseases, and recent work has shown that excessive polyglutamylation of tubulin in the brain is sufficient to drive neurodegeneration by disrupting transport, while restoring the balance of these modifications can rescue affected neurons. The Roadmap positions a systems-level understanding of these processes as essential for translating molecular insight into therapies.

The heart and the immune system tell equally compelling stories. In beating cardiomyocytes, detyrosinated microtubules act as load-bearing elements that buckle under contraction and stiffen the cell, and suppressing this modification improves cardiac function in models of heart failure. In immune cells, microtubule networks orchestrate cell shape, migration and the directed release of lytic granules by natural killer cells, while platelets, whose tubulin repertoire is dominated by the β1-tubulin isotype, rely on precisely regulated microtubule assembly during their biogenesis; mutations in the TUBB1 gene cause congenital macrothrombocytopenia and thyroid dysgenesis. The Roadmap argues that these tissue-specific roles cannot be understood piecemeal and demand approaches that bridge the molecular properties of tubulin to the physiology of whole organs.

Technological innovation sits at the centre of the proposed strategy. Cryo-electron microscopy and cryo-electron tomography now reveal microtubules and their associated proteins at near-atomic and in situ resolution, while expansion microscopy and ultrastructure expansion microscopy allow researchers to visualize centrioles, cilia and mitotic spindles in whole cells and tissues with nanometre precision. In vitro reconstitution, a tradition stretching back to the pioneering work of Tim Mitchison and Marc Kirschner and continued in landmark experiments showing that purified microtubules and motors can self-organize into asters and vortices, remains indispensable for dissecting minimal systems. These experimental approaches are increasingly paired with computational and physical models that simulate spindle assembly, microtubule network organization and chromosome movement, and the Roadmap calls for tighter coupling between modelling and experiment, including the development of virtual cells powered by artificial intelligence.

Recombinant tubulin technology is highlighted as a particularly transformative advance. For decades, biochemists were limited to native tubulin purified from brain tissue, a mixture of isotypes and modifications that obscured cause and effect. The ability to produce functional human tubulin dimers in defined isotypes, with controlled post-translational modifications, has now enabled researchers to show directly that different isotypes confer distinct dynamic properties, that detyrosination tunes microtubule stability through selective recruitment of associated factors, and that systematic mutagenesis can map the functional landscape of disease-linked variants. Combined with deep mutational scanning and artificial-intelligence-driven phenotyping, the authors argue, these tools will allow the effects of every clinically observed tubulin mutation to be predicted and tested, a goal that seemed out of reach only a few years ago.

The Roadmap also looks beyond animal cells, drawing attention to the diversity of microtubule arrays across eukaryotes, from the cortical arrays that guide plant cell morphogenesis to the subpellicular arrays of trypanosomes and the specialized mitotic machinery of parasites. Comparative studies of parasites such as Plasmodium have revealed that adaptations in tubulin sequence generate distinct microtubule architectures, mechanics and drug susceptibilities, opening avenues for species-selective therapeutics. The authors contend that this evolutionary breadth is not a curiosity but a resource: organisms that build microtubules with unusual lattices, modifications or assembly mechanisms offer natural experiments that can illuminate principles hidden in familiar model systems.

Ultimately, the Roadmap is an invitation to think bigger. Its authors conclude that the microtubule cytoskeleton will continue to inspire scientists for decades precisely because so many fundamental questions remain open: how microtubule arrays are organized and diversified in different cell types, how the tubulin code is orchestrated across space and time, how mechanical forces reshape and stabilize microtubule lattices in living cells, and how all of this integrates into the physiology of tissues and organisms in health, ageing and disease. By bridging the atomic structure of the tubulin dimer with the behaviour of mitotic spindles, migrating neurons and beating hearts, the field aims to transform its fragmented molecular knowledge into a coherent systems-level picture, one that could reshape how disorders ranging from neurodegeneration and cancer to ciliopathies and heart failure are understood and treated.

The historical depth of the field is worth appreciating. Microtubules were first visualized in the late nineteenth and early twentieth centuries, but their protein building block was only identified in the late 1960s, when colchicine-binding assays led to the isolation of what was soon named tubulin, and amino-acid analysis of sperm flagella confirmed it as the universal subunit of the polymer. The discovery of dynamic instability two decades later established that these polymers are fundamentally nonequilibrium structures, a insight that continues to shape how spindle assembly and chromosome movement are understood today.

Equally important is the cast of regulatory proteins that act on microtubules. Microtubule-associated proteins such as tau can condense on the lattice in regulated phases, altering how motors and severing enzymes engage the polymer, while enzymes that cut microtubules generate new seeds and reshape networks. Proteins like doublecortin, which is mutated in human brain malformations, illustrate how even lattice geometry itself can be read selectively, recognizing only specific protofilament numbers. These layered interactions, spanning motors, maps, severing enzymes and modifying enzymes, form the mechanistic vocabulary that any systems-level account of the cytoskeleton will ultimately need to integrate.

Subject of Research: Systems-level integration of microtubule cytoskeleton structure, regulation and function in physiology and disease

Article Title: Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease

Article References: Janke, C., Akhmanova, A., Bartolini, F., Bodakuntla, S., Del Bene, F., Hamel, V., Mitchison, T. J., Müller-Reichert, T., Nédélec, F., Nogales, E., Pigino, G., Roll-Mecak, A., Schiavo, G., Surrey, T., & Lansky, Z. (2026). Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-026-01011-w

Image Credits: AI Generated

DOI: 10.1038/s41580-026-01011-w

Keywords: microtubules, tubulin code, post-translational modifications, dynamic instability, axonal transport, tubulinopathies, ciliopathies, neurodegeneration, mitotic spindle, cryo-electron tomography, in vitro reconstitution, systems biology

Despite decades of research into the composition and function of the spindle apparatus, how thousands of microtubules collectively organize, self-assemble, and coordinate their behaviors to execute chromosome segregation has remained an enduring scientific enigma. Recent advances leverage an interdisciplinary approach, invoking principles of physics and materials science, to shed light on this puzzle, treating the spindle as an active liquid crystal—a state of matter inhabited by elongated, dynamic units that generate forces from within rather than being passively oriented by external fields.

Liquid crystals are widely known in the context of display technologies, where electric fields align their elongated molecules to manipulate light. However, biological active liquid crystals are far more complex, consisting of molecular filaments like microtubules that consume energy to generate motion and exert forces. Applying this framework to the spindle allows researchers to conceptualize how microtubules spontaneously organize into functional patterns and exert collective mechanical forces critical for cell division. Until recently, this theoretical paradigm had not been rigorously validated against empirical data derived from human cells.

Researchers at the Simons Foundation’s Flatiron Institute, along with collaborators, have now bridged this gap by integrating high-resolution microscopy data from dividing human cells with sophisticated theoretical models. Their findings, published in the Proceedings of the National Academy of Sciences, provide compelling evidence that the spindle’s behavior largely conforms to the predictions of active liquid crystal theory. This breakthrough offers unprecedented insight into the physical principles that govern the spindle’s structure and dynamics, marking a significant advance in cell biology and biophysics.

By combining live-cell light microscopy, which captures spindle dynamics over time, with electron microscopy, which resolves individual microtubules in exquisite detail, the team constructed an integrative view of spindle organization at multiple scales. This hybrid approach allowed them to validate their models against real biological data, revealing that the spindle’s macro-scale morphology, microtubule orientation, and density varied in manners consistent with theoretical predictions. Such concordance underscores the power of cross-disciplinary methodologies in deciphering complex biological systems.

Intriguingly, the study uncovered limitations in the current active liquid crystal models when applied to a specific subpopulation of microtubules known as kinetochore microtubules. These specialized fibers, which physically connect to chromosomes, exhibited patterns and behaviors not fully accounted for by existing theories. This shortfall illuminates gaps in understanding how chromosome-spindle attachments are integrated into the overall spindle mechanics and suggests avenues for refined modeling that incorporate additional biological complexities.

Moreover, the research identified a fundamental spatial scale below which the liquid crystal model becomes less predictive. At dimensions smaller than approximately 300 nanometers, the number of microtubules diminishes and their interactions become less collective, transitioning to discrete filament dynamics that require alternative theoretical treatment. This finding delineates the scale-dependent nature of spindle organization and will guide future efforts in developing multi-scale computational models.

The implications of this work extend beyond basic scientific curiosity. Understanding the fundamental mechanics of spindle assembly and chromosome segregation has profound relevance to medicine, particularly in fertility treatments such as in vitro fertilization (IVF). Spindle malfunctions can compromise egg viability and embryo development, leading to infertility or developmental disorders such as Down syndrome. Quantitative biophysical assays grounded in these new insights could enable clinicians to assess spindle integrity in gametes and embryos, refining selection criteria and potentially improving IVF outcomes.

Cancer research stands to benefit substantially from these advancements as well. Because cancer cells proliferate uncontrollably, many chemotherapy regimens target the mitotic spindle to disrupt cell division preferentially in tumors. A richer mechanistic understanding of spindle assembly and dynamics can reveal vulnerabilities, inspire novel therapeutic targets, and mitigate side effects by enhancing drug specificity. Deciphering how spindles fail under pharmacological perturbation could revolutionize personalized cancer treatment strategies.

This research embodies the fruitful synergy between physics, mathematics, and biology, exemplifying how computational and experimental collaboration accelerates scientific discovery. The Flatiron Institute’s Center for Computational Biology (CCB) spearheads such integrative efforts through the CCBx initiative, fostering close partnerships between theoreticians and experimentalists. By iterating between model predictions and empirical observations, the team refined both experimental protocols and theoretical frameworks, demonstrating that such dialogue is indispensable for tackling complex life-science problems.

The study’s success was contingent on an array of complementary expertise, ranging from applied mathematics to advanced microscopy, highlighting the interdisciplinary nature of contemporary biological research. The authors emphasize that this reciprocal relationship between data acquisition and theoretical innovation is essential, as relying solely on pre-existing data would have precluded the generation of novel insights requiring fresh experiments.

Looking ahead, the investigators aim to unravel the unresolved physics of kinetochore microtubules and expand their predictive models to encompass heterogeneous microtubule populations within the spindle. Such efforts promise to forge a comprehensive physical theory of spindle mechanics that accounts for all components and scales, advancing precision in biological modeling.

The confluence of rigorous experimentation and mathematical modeling epitomized by this work opens exciting paths for understanding the fundamental physical principles underpinning living systems. As the study reveals, biological structures like the mitotic spindle are not merely biochemical assemblies but also sophisticated materials systems governed by physics. This recognition heralds a new era where quantitative biology, informed by principles of active matter physics, will unlock the secrets of life’s most intricate processes.

Subject of Research: Cells

Article Title: Human mitotic spindles as active liquid crystals: From collective behaviors to discrete filaments

News Publication Date: 9-Feb-2026

Web References:
https://www.pnas.org/doi/10.1073/pnas.2520490123

References:
Maddu S, Kelleher C, Basaran M, Needleman DJ, Müller-Reichert T, Shelley MJ. Human mitotic spindles as active liquid crystals: From collective behaviors to discrete filaments. Proc Natl Acad Sci U S A. 2026 Feb 9.

Image Credits: Credit: Reza Farhadifar/Flatiron Institute

Keywords:
Cell biology, Cell division, Materials science, Liquid crystals, Spindle apparatus