The crux of this innovation lies in fabricating a model that not only replicates the physical architecture of axons but also their mechanical properties, a factor previously overlooked in drug screening. Axons, ensheathed by the protective myelin produced by oligodendrocytes, are essential conduits for electrical signals in the nervous system. In MS and related neurodegenerative diseases, myelin degradation disrupts neural communication, causing debilitating symptoms. The UCL team’s model, described in a recent paper published in Nature Methods, employs hydrogel-based micropillars that closely match the softness and structural characteristics of real axons—a stark contrast to the rigid plastic models traditionally used.

This hydrogel fabrication marks a profound technical achievement. Unlike plastic, which is orders of magnitude stiffer than biological tissue, hydrogel boasts a high water content and porosity, closely resembling living cells’ extracellular environment. Utilizing photolithography, the researchers crafted micro-scale molds to shape water-filled hydrogel into pillars tens of times thinner than a human hair. These micropillars emulate the delicate mechanical milieu wherein oligodendrocytes operate, allowing for more physiologically relevant interactions between the cells and their substrate.

Once these axon mimics were established, the research team cultured oligodendrocytes derived from both human and rodent sources around the micropillars to induce myelin formation. Crucially, this represents the first successful laboratory cultivation of myelin from human cells within a controlled, biomimetic system. The team then introduced various candidate drugs designed to stimulate myelin repair or regeneration, assessing their effectiveness in promoting myelin layering on the flexible hydrogel pillars.

The findings were illuminating and somewhat cautionary. Drugs that previously showed promise in conventional rigid models demonstrated diminished efficacy against the more life-like softer axons. This suggests that the rigidity of oversimplified models may have contributed to the proliferation of false-positive drug candidates, which ultimately failed when tested in human trials. The UCL model’s closer approximation to human tissue mechanics reveals the nuances that were missed and underscores the necessity of such sophisticated systems for early-stage drug validation.

Professor Emad Moeendarbary, senior author and expert in cellular mechanics, emphasized the significance of this work, stating that the replication of the brain’s physical microenvironment is crucial for reliable drug discovery in MS. He highlighted that conventional models’ stiffness—hundreds of times greater than actual axons—likely generates misleading results, potentially misguiding research investment and delaying clinical progress. The new model paves the way for more robust preclinical testing, reducing costly failures downstream.

Beyond MS, this approach has broader implications for understanding and treating other neurodegenerative disorders characterized by myelin damage, including Alzheimer’s, Parkinson’s, and motor neurone diseases. Myelin repair mechanisms invariably falter as these conditions progress, exacerbating neural dysfunction and cell death. By enabling detailed examination of myelinogenesis in a controlled yet realistic setting, this model offers a powerful platform for probing disease mechanisms and therapeutic responses.

One of the challenges surmounted by the researchers was engineering hydrogels fine enough to mimic axonal diameter while maintaining mechanical softness. Hydrogels must balance porosity with structural integrity—a demanding feat at microscale dimensions. The iterative optimization, led by PhD candidate Soufian Lasli and Dr. Claire Vinel, spanned five years of meticulous fabrication, biological validation, and refinement, culminating in a system that offers unprecedented fidelity to native nerve fiber properties.

This model’s adoption could revolutionize early drug screening pipelines by integrating both chemical and physical parameters impacting oligodendrocyte behavior. Researchers can now systematically vary stiffness and analyze how biophysical cues interface with biochemical signals—a multi-dimensional approach previously inaccessible. This capacity to deconstruct complex interactions holds promise for identifying novel molecular targets and compounds that genuinely enhance remyelination.

Moreover, the interdisciplinary nature of this study, combining mechanical engineering, molecular cell biology, neuroscience, and pharmacology, exemplifies the collaborative ethos needed to tackle complex biomedical problems. Contributions hail from multiple UCL faculties and partner institutions such as Universidad de Malaga and the University of Nottingham, illustrating the global impetus behind improving neurological therapeutics.

In summary, this new hydrogel-based axon model represents a paradigm shift in neurodegenerative disease research. It provides an essential tool for bridging the gap between in vitro experimentation and clinical efficacy, thereby accelerating the pathway to effective treatments for MS and other devastating brain disorders. By faithfully mirroring the brain’s microenvironment, the model holds promise not only for drug discovery but also for fundamental insights into the biology of myelin and nerve fiber regeneration.

Subject of Research: Development of a life-like hydrogel-based model of axons for enhanced drug discovery in neurodegenerative diseases

Article Title: Life-like Hydrogel Axon Model Unveils New Paradigms in Multiple Sclerosis Drug Discovery

News Publication Date: 2024

Web References: http://dx.doi.org/10.1038/s41592-026-03048-3

References: Soufian Lasli et al / Nature Methods

Image Credits: Soufian Lasli et al / Nature Methods

Keywords: Neurodegenerative diseases, Multiple sclerosis, Axon regeneration, Regeneration, Engineering, Drug discovery, Drug development, Myelin repair, Hydrogel, Cellular mechanics

Intrinsically disordered proteins evade conventional drug design strategies because they do not adopt a permanent three-dimensional conformation. Instead, they exist as dynamic ensembles of flexible structures, rendering traditional lock-and-key binding models ineffective. The research, led by Dr. Xavier Salvatella, overturns this dogma by demonstrating that during transient oligomerization—when multiple protein copies cluster—they momentarily assume semi-organized states that can be selectively recognized and modulated by small molecules.

The study, published in Science Advances, provides a detailed biophysical characterization of these fleeting conformations. Using sophisticated analytical tools, including nuclear magnetic resonance (NMR) spectroscopy and cellular assays, the team shows that a specific small molecule can intercalate into these temporarily rigidified condensates formed by IDP oligomers. This interaction induces an increase in the material rigidity of the condensates, effectively impeding the dysfunctional activity normally propagated by the protein assemblies.

Dr. Salvatella elucidates that the dynamic nature of IDPs should no longer be viewed as an insurmountable barrier. Instead, their propensity to form transiently ordered oligomeric states opens previously unrecognized therapeutic windows. These “moments of vulnerability” arise during protein assembly, creating binding pockets that a drug can exploit, thereby enabling targeted molecular intervention where none existed before.

The complexity of IDPs lies in their plasticity; their structure fluctuates rapidly, complicating the identification of stable druggable sites. However, this research reveals that as individual IDP molecules congregate, collective interactions stabilize certain structural motifs. Such transient, intermediate oligomeric states manifest emergent properties distinct from their monomeric counterparts, including novel binding surfaces critical for therapeutic targeting.

A pivotal advancement made by Dr. Stasė Bielskutė-García and colleagues involves elucidating the molecular mechanism underpinning this modulation. Their findings suggest that by increasing the condensates’ rigidity, the small molecule effectively ‘locks’ IDPs into non-functional states, halting pathological pathways dependent on their dynamic assembly. This mechanistic insight not only clarifies why this compound functions as it does but also informs the rational design of future drugs tailored to bind transient states in intrinsically disordered regions.

Scarce therapeutic options currently exist for diseases heavily driven by disordered proteins, notably aggressive cancers such as small-cell lung cancer and gastrointestinal malignancies. This innovative strategy ushers in a new dimension in drug discovery—one that capitalizes on the dynamic biophysical landscape of IDPs rather than being hindered by it. The ability to pharmacologically manipulate such proteins addresses a critical unmet medical need.

Capitalizing on these insights, IRB Barcelona has spun off Nuage Therapeutics, a pioneering biotechnology company dedicated to developing therapeutics that exploit the transient structural windows of IDPs. Nuage Therapeutics applies a highly specialized drug discovery platform designed to identify and optimize molecular candidates capable of selectively binding these fleeting conformations, setting the stage for breakthrough therapies across oncology and beyond.

Looking forward, Nuage Therapeutics envisions broadening its therapeutic portfolio by deploying this paradigm to diverse diseases characterized by protein disorder. By expanding the toolbox for targeting protein disorder, the company aims to become a leader in this novel field, potentially revolutionizing treatment strategies where conventional approaches have failed.

The study is a testament to the power of fundamental scientific research to catalyze transformative medical innovations. The collaboration between IRB Barcelona, the Max Planck Institute for Molecular Genetics, and the University of Florence underscores the interdisciplinary efforts required to decode the complex behavior of IDPs and harness them for therapeutic gains.

This work was supported by an array of prestigious funding bodies, including the Spanish Ministry of Science, Innovation and Universities, the Agency for Management of University and Research Grants (AGAUR), “la Caixa” Foundation, the Spanish Association Against Cancer (AECC), the Mark Foundation for Cancer Research, and the European Research Council (ERC). Their support affirms the critical importance of investing in cutting-edge basic research with the potential for high-impact clinical translation.

By unlocking the ability to drug intrinsically disordered proteins through their oligomerization-dependent transient states, this study not only pioneers a new frontier in molecular pharmacology but also offers hope for patients with conditions that have challenged traditional drug discovery efforts. The findings herald a new era in which the once “undruggable” may become druggable, fundamentally transforming biomedical science and therapeutic options.

Subject of Research: Intrinsically Disordered Proteins and Their Targeting by Small Molecule Drugs
Article Title: The key to attacking “undruggable” proteins: IRB Barcelona reveals a breakthrough drug mechanism
News Publication Date: March 3, 2026
Web References: https://dx.doi.org/10.1126/sciadv.adz74
References: Science Advances, DOI 10.1126/sciadv.adz74
Image Credits: IRB Barcelona
Keywords: Cancer, Cancer treatments, Proteins, Disordered regions, Target proteins, Intrinsically Disordered Proteins, Oligomerization, Drug discovery, Molecular pharmacology, Small-cell lung cancer, Gastrointestinal cancers