Almost 100 years after Santiago Ramón y Cajal founded the field of modern neuroscience, many of the key issues he identified for research still remain open today. Among these is the question of why the adult CNS has only a very limited capacity for regeneration after injury or disease.

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The Cajal's Challenge is an initiative of the Maimon Laboratory to study the challenge of adult CNS regeneration that has been left by Santiago Ramón y Cajal, the founder of modern neuroscience. The Laboratory is using the tools of molecular and cell biology to investigate ways in which dormant neural stem cells can be re-activated and re-directed to replace lost neurons in adults. The ultimate aim of the work is to develop regenerative therapies for a variety of debilitating neurodegenerative diseases and injuries of the brain.

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The research of the Maimon Laboratory to address the Cajal's Challenge focuses on the mechanisms that control the identity and activation of neural stem cells in the adult brain, using cutting-edge technologies including single cell sequencing, CRISPR gene editing, and antisense oligonucleotides. The aim of this research is to uncover the limitations and possibilities of the brain’s endogenous regenerative capacity.

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The effort reflects the remarkable continuity of scientific inquiry. At the turn of the twentieth century, Cajal demonstrated that successful regeneration in the peripheral nervous system depended upon active growth from surviving neurons and the supportive environment provided by Schwann cells. He further recognized that regeneration within the central nervous system was profoundly limited, concluding that the adult brain and spinal cord lacked the conditions necessary for effective repair. These observations helped establish one of neuroscience's fundamental challenges—a challenge that continues to motivate investigators today.

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With support from the Cajal Club, two Cajal's Challenge Awards were presented to recognize exceptional contributions to regenerative neuroscience presented during the workshop.

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Dr. Marie d'Orange (Christoph Heinrich Laboratory) was recognized for her research investigating the direct reprogramming of reactive glial cells into functional inhibitory neurons in the adult mouse hippocampus. Using single-cell transcriptomic analyses, her work identifies the molecular pathways that govern successful glia-to-neuron conversion and demonstrates how newly generated neurons can integrate into neural circuits and reduce seizure activity in models of drug-resistant epilepsy.

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Dr. Marina Pavlou (Tom Reh Laboratory) was recognized for her research demonstrating that adult Müller glia in the mammalian retina, including non-human primates, can be reprogrammed into functional neurons through vector-mediated expression of the transcription factor Ascl1. Her work advances the possibility of endogenous cell replacement therapies aimed at restoring vision following retinal degeneration.

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Although the tools of today’s researchers are vastly different from those of Cajal’s era, the fundamental objective of the current work remains grounded in the observations of the Nobel laureate. Specifically, the long-sought goal of Cajal’s Challenge is to explore ways in which the nervous system can repair itself.

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The Cajal Club is pleased to highlight the Cajal's Challenge as an example of how Santiago Ramón y Cajal's scientific legacy continues to influence contemporary neuroscience, inspiring new generations of researchers working toward therapies that may one day transform the treatment of neurological disease.

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Cajal's Challenge was made possible through the leadership of workshop co-organizers Daniel Tornero and Sergio Gascón, and the generous support of the University of Barcelona.

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More information on this project can be found on the Cajal Challenge page of the Maimon Laboratory website.

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