by Iciar Iturmendi-Sabater

Graphic design by Andrew Janeczek

Don Quixote¹ was published in 1615, 44 years after Miguel de Cervantes lost all sensitivity in his left hand in the largest naval battle of Western history. Had the Ottoman beat the Spanish Empire in the Battle of Lepanto, the foundations of Europe could have been rooted in Islam rather than Christianism. Perhaps less thought of is what would have happened if Cervantes’ left hand had not been hurt. Or if he had lost his right hand instead. Would Cervantes never have had the time to write what is now considered the first modern novel of time? Would Don Quixote ever have fought windmills confusing them for giants? What if there had been a remedy for Cervantes’ lesion?

Current neuroscience is exploring if nerve regeneration is possible. Nerves consist of bundles of axonal fibres which transmit electrochemical signals from neuron to neuron, connecting the central nervous system (CNS)—the brain and the spinal cord—with the rest of the body, allowing for the control of movement and sensibility. Prior to learning that electrochemical signalling allows communication between neurons, the first surgical treatments for nerve damage were performed as early as the 1820’s. Had Cervantes been born 200 years later, his left-hand median nerve could have been invasively substituted with another, not so important nerve. Give it another 50 years and physicians may have considered ‘decompression’ to treat Cervantes, whereby external pressure could have been released from his left median nerve to recover its function.²

These surgical approaches may have helped Cervantes because axonal and neural regeneration generally (i.e., neurogenesis) is possible in the peripheral nervous system (PNS). The PNS, to which the hand median nerve and other axonal bundles connecting the CNS to the rest of the body belong to, provides an ideal environment for regeneration.³ Yet had Cervantes’ lesion taken place in the CNS, regeneration would have been unlikely even today. In 1913, Santiago Ramón y Cajal, father of modern neuroscience and a Spanish compatriot of Cervantes’, already believed that neurogenesis in the CNS was impossible.⁴ Still, whether nerve regeneration can be achieved in the CNS remains a controversial research topic today. 

A recent Nature publication by Grégorie Courtine’s team in Lausanne reported that a patient with damage in his cervical spinal cord, which caused total paralysis of his four limbs and torso (i.e., tetraplegia), recovered his ability to walk through a digital interface that transmitted brain signals from his brain to his spine.⁵ Those who don’t believe axonal regeneration in the CNS is possible may be supportive of approaches whereby functionality is recovered through external aids, such as brain-computer digital interfaces or exoskeletons. These however may better serve those more psychologically resilient and in better health, who are more likely to stick to demanding training programs—the participant in Courtine’s study had endured three years of neurorehabilitation. Still, external aids are far from facilitating natural gait and body movements, as one can tell watching Courtine’s patient walk against a dreamy Swiss lake background.⁶ 

Accomplishing better intervention outcomes for patients with tetraplegia also lies in the hands of neuroscientists who defy the evidence that a neural master plan prenatally dictates and determines all postnatal neurodevelopment, making human neurogenesis in the CNS impossible after birth.⁷ Neurogenesis has been allegedly found in the primate neocortex,⁸ which carries out high level cognitive processes, and in the human hippocampi,⁹ two seahorse-shaped brain nuclei involved in long-term memory formation and spatial navigation. However, these findings have been readily criticized since they could be attributed to statistical false positive errors. An influential critical review on this topic alluded to this in its title: “everything that glitters isn’t gold”.¹⁰

Fighting against statistical power limitations and what embryological development dictates, biomaterial and tissue engineers still hope that nanomaterials such as graphene, a honeycomb-like spongy bi-dimensional material made of hexagonal carbon atoms whose first developers were awarded the 2010 Physics Nobel Prize, can provide an optimal environment to promote neurogenesis in vitro. Graphene sponges have been then transplanted into mice and rats’ spinal cords, achieving partial regeneration in the CNS in vivo.¹¹ Still, there is a long way to go until scientists can conclude if graphene facilitates long-term neurogenesis and if animal models are optimal models for predicting transplantation success in humans.

Whether neural regeneration is possible in the CNS seems now more of an open-ended question than it was to Ramón y Cajal. Believing in this possibility may provide comfort to patients with tetraplegia and neurodegenerative diseases like dementia. But there may also be a reason why our CNS insists on preserving its structure immutable. In a hypothetical reality where Cervantes’ brain, instead of his hand, had been injured and then regeneration been achieved… I doubt if Cervantes’ sense of self and personality had been well preserved to still imagine Don Quixote’s adventures in the fields of “somewhere in La Mancha, in a place whose name I never care to remember…”

References

1. De Cervantes M. Don Quixote. Lulu. com; 2016. 
2. Krishnan KG, Worsch M, Boroumand M, Uhl E. Retractor endoscopic techniques in the treatment of entrapment peripheral neuropathies. Neurology, Psychiatry and Brain Research. 2018 Jun 1;28:19–23. 
3. Huebner EA, Strittmatter SM. Axon Regeneration in the Peripheral and Central Nervous Systems. Results Probl Cell Differ. 2009;48:339–51. 
4. Ramón y Cajal S. Estudios sobre la degeneración y regeneración del sistema nervioso. Madrid: Imprenta de Hijos de Nicolás Moya. 1913; 
5. Lorach H, Galvez A, Spagnolo V, Martel F, Karakas S, Intering N, et al. Walking naturally after spinal cord injury using a brain–spine interface. Nature. 2023 Jun;618(7963):126–33. 
6. Paralyzed man walks again with brain-spine device [Internet]. 2023. Available from: https://www.youtube.com/watch?v=lwt3nEoAAtQ
7. Rubenstein JLR, Martinez S, Shimamura K, Puelles L. The Embryonic Vertebrate Forebrain: the Prosomeric Model. Science. 1994 Oct 28;266(5185):578–80. 
8. Gould E, Reeves AJ, Graziano MSA, Gross CG. Neurogenesis in the Neocortex of Adult Primates. Science. 1999 Oct 15;286(5439):548–52. 
9. Moreno-Jiménez EP, Terreros-Roncal J, Flor-García M, Rábano A, Llorens-Martín M. Evidences for Adult Hippocampal Neurogenesis in Humans. J Neurosci. 2021 Mar 24;41(12):2541–53. 
10. Breunig JJ, Arellano JI, Macklis JD, Rakic P. Everything that Glitters Isn’t Gold: A Critical Review of Postnatal Neural Precursor Analyses. Cell Stem Cell. 2007 Dec;1(6):612–27.
11. Domínguez-Bajo A, González-Mayorga A, López-Dolado E, Serrano MC. Graphene-Derived Materials Interfacing the Spinal Cord: Outstanding in Vitro and in Vivo Findings. Frontiers in Systems Neuroscience [Internet]. 2017 [cited 2023 Jul 25];11. Available from: https://www.frontiersin.org/articles/10.3389/fnsys.2017.00071