Zebra fish in the lab of Robin Tanguay at Oregan Stae University.
Photo: Lynn Ketchum
Just as amputees can't regrow a lost limb, so spine-injured patients can't repair a damaged spine, and yet, several species of amphibian can grow new limbs and Zebra fish can grow a new spinal cord.
Which leaves intelligent [sic] design creationists to explain why, if their putative designer can give some species the ability to regrow a lost limb or repair a transected spinal cord, he chose not to give that ability to his supposedly favourite, 'special' creation, humans.
But of course, those are not the only abilities and systems that could have been better in humans if the same designer designed other animals with superior abilities and systems:
Birds of prey have a vastly superior visual acuity to humans; birds in general have a much more efficient respiratory system which enables then to fly at heights at which we would be unconscious for lack of oxygen. Many animals have a vastly superior sense of hearing to what we have, and bats have a better immune system. Elephants and sharks both rarely get cancer, and so the list goes on.
Why is it impossible to repair and heal a transected spinal cord? Repairing and healing a transected (completely severed) spinal cord is extremely challenging, and currently impossible, due to several biological and physiological factors:The inescapable conclusion, if you believe in creationism's omnipotent, omniscient creator is that, since it knew how to give zebra fish this ability it could have given that ability to other vertebrates, including humans but made a conscious choice not to. The alternative is to hold two diametrically opposite views simultaneously: that this intelligent designer if omnipotent and, MO, USA, omniscience but lacked the ability to give to other vertebrates what it gave to zebra fish or didn't realise they would benefit from the ability.
- Complex Structure of the Spinal Cord
The spinal cord is composed of a complex network of neurons (nerve cells), glial cells, and axons (nerve fibers) that transmit signals between the brain and the rest of the body. When the spinal cord is transected, these structures are not only physically separated but also severely damaged, disrupting both the motor and sensory pathways.
- Lack of Regenerative Ability in the Central Nervous System (CNS)
Unlike the peripheral nervous system (PNS), where axons can regenerate to some extent, the central nervous system (which includes the brain and spinal cord) has very limited regenerative capacity. Several factors contribute to this:
- Inhibitory Environment: The CNS environment is rich in molecules that inhibit axon growth. Myelin-associated inhibitors, such as Nogo, MAG, and OMgp, are proteins found in the myelin sheath that actively prevent axon regeneration.
- Formation of Glial Scar: After injury, astrocytes (a type of glial cell) proliferate and form a glial scar at the injury site. This scar physically blocks axon regeneration and also produces molecules that inhibit regrowth.
- Neuronal Cell Death
A spinal cord injury often leads to the death of neurons at the site of injury and even in areas remote from the injury. Once these neurons die, they cannot be replaced, and their connections are permanently lost.
- Disruption of Synaptic Connections
The spinal cord contains intricate networks of synapses (connections between neurons). When the spinal cord is transected, these connections are severed, and re-establishing them in the correct pattern is incredibly complex, even if axons could regrow.
- Inflammation and Immune Response
A spinal cord injury triggers a robust inflammatory response, which can exacerbate tissue damage. The immune cells involved in this response release substances that further damage neurons and axons, making recovery even more difficult.
- Loss of Support Cells
Oligodendrocytes, the cells that produce the myelin sheath around CNS axons, are often damaged or destroyed during spinal cord injuries. Without these cells, even if some axonal regrowth occurred, it would likely be insufficient to restore function because the axons would lack the necessary myelination for proper signal transmission.
- Complexity of Functional Recovery
Even if the spinal cord were somehow physically repaired, the functional recovery would require the precise reconnection of thousands of axons with their original targets. This reconnection would need to happen with perfect accuracy to restore normal motor and sensory functions, which is currently beyond the capability of medical science.
- Current Therapeutic Limitations
While there is ongoing research into potential therapies such as stem cells, gene therapy, and biomaterials to bridge the gap, none have yet proven effective in humans for complete spinal cord transections. The primary challenges remain the issues mentioned above—especially creating a permissive environment for regrowth and precisely guiding the regeneration.
Conclusion
Due to the combination of inhibitory factors in the CNS, the formation of glial scars, the lack of regenerative capacity, and the complexity of restoring precise synaptic connections, it is currently impossible to repair and heal a transected spinal cord. Research is ongoing, and there is hope that future advancements may one day address these challenges.
So, how does a zebra fish manage to do what any paraplegic would probably give their right arm for - the ability to repair a transected spinal cord? It seems the key is in the ability of injury-survivor neurons to transform themselves into iNeurons and reactivate genes involved in embryonic development. In effect, iNeurons overcome the specialisation imposed by the epigenetic settings, reverting them back to a less specialised form.
This is the subject of a research paper by three researchers from Washington University School of Medicine in St. Louis, MO, USA, just published, open access, in Nature Communications and explained in a Washington University press release:
Zebrafish use surprising strategy to regrow spinal cord
Detailed blueprint of nerve cells’ dramatic changes could help identify ways to heal spinal cord damage
Zebrafish are members of a rarefied group of vertebrates capable of fully healing a severed spinal cord. A clear understanding of how this regeneration takes place could provide clues toward strategies for healing spinal cord injuries in people. Such injuries can be devastating, causing permanent loss of sensation and movement.
A new study from Washington University School of Medicine in St. Louis maps out a detailed atlas of all the cells involved — and how they work together — in regenerating the zebrafish spinal cord. In an unexpected finding, the researchers showed that survival and adaptability of the severed neurons themselves is required for full spinal cord regeneration. Surprisingly, the study showed that stem cells capable of forming new neurons — and typically thought of as central to regeneration — play a complementary role but don’t lead the process.
The study is published Thursday, Aug. 15, in the journal Nature Communications.
Unlike humans’ and other mammals’ spinal cord injuries, in which damaged neurons always die, the damaged neurons of zebrafish dramatically alter their cellular functions in response to injury, first to survive and then to take on new and central roles in orchestrating the precise events that govern healing, the researchers found. Scientists knew that zebrafish neurons survive spinal cord injury, and this new study reveals how they do it.
We found that most, if not all, aspects of neural repair that we’re trying to achieve in people occur naturally in zebrafish. The surprising observation we made is that there are strong neuronal protection and repair mechanisms happening right after injury. We think these protective mechanisms allow neurons to survive the injury and then adopt a kind of spontaneous plasticity — or flexibility in their functions — that gives the fish time to regenerate new neurons to achieve full recovery. Our study has identified genetic targets that will help us promote this type of plasticity in the cells of people and other mammals.
Associate Professor Mayssa K. Mokalled, PhD, senior author
Department of Developmental Biology
Washington University School of Medicine, St. Louis, MO, USA.
By mapping out the evolving roles of various cell types involved in regeneration, Mokalled and her colleagues found that the flexibility of the surviving injured neurons and their capacity to immediately reprogram after injury lead the chain of events that are required for spinal cord regeneration. If these injury-surviving neurons are disabled, zebrafish do not regain their normal swim capacity, even though regenerative stem cells remain present.
When the long wiring of the spinal cord is crushed or severed in people and other mammals, it sets off a chain of toxicity events that kills the neurons and makes the spinal cord environment hostile against repair mechanisms. This neuronal toxicity could provide some explanation for the failure of attempts to harness stem cells to treat spinal cord injuries in people. Rather than focus on regeneration with stem cells, the new study suggests that any successful method to heal spinal cord injuries in people must start with saving the injured neurons from death.
There is some evidence that this capacity is present but dormant in mammalian neurons, so this may be a route to new therapies, according to the researchers. While this study is focused on neurons, Mokalled said spinal cord regeneration is extremely complex, and future work for her team will delve into a new cell atlas to understand the contributions of other cell types to spinal cord regeneration, including non-neuronal cells, called glia, in the central nervous system as well as cells of the immune system and vasculature. They also have ongoing studies comparing the findings in zebrafish to what is happening in mammalian cells, including mouse and human nerve tissue.Neurons by themselves, without connections to other cells, do not survive. In zebrafish, we think severed neurons can overcome the stress of injury because their flexibility helps them establish new local connections immediately after injury. Our research suggests this is a temporary mechanism that buys time, protecting neurons from death and allowing the system to preserve neuronal circuitry while building and regenerating the main spinal cord.
We are hopeful that identifying the genes that orchestrate this protective process in zebrafish — versions of which also are present in the human genome — will help us find ways to protect neurons in people from the waves of cell death that we see following spinal cord injuries.
Associate Professor Mayssa K. Mokalled, PhD.
Learn about the zebrafish facility at WashU Medicine that enabled this study.
AbstractOn the face of it, there appears to be no reason why an omnipotent, intelligent designer couldn't give other vertebrates this ability to repair a transected spinal cord to full functionality since the same difficulties apply to all vertebrates as to zebra fish in that the neurons are highly specialised cells with epigenetic settings that restrict their function to that of transmitters of electrical messages along an axon and across synaptic junctions.
Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair. Neurogenesis of glutamatergic and GABAergic neurons restores the excitatory/inhibitory balance after injury. In addition, a transient population of injury-responsive neurons (iNeurons) show elevated plasticity 1 week post-injury. We found iNeurons are injury-surviving neurons that acquire a neuroblast-like gene expression signature after injury. CRISPR/Cas9 mutagenesis showed iNeurons are required for functional recovery and employ vesicular trafficking as an essential mechanism that underlies neuronal plasticity. This study provides a comprehensive resource of the cells and mechanisms that direct spinal cord regeneration and establishes zebrafish as a model of plasticity-driven neural repair.
Introduction
Mammalian spinal cord injuries (SCI) elicit complex multi-cellular responses that impede regeneration and cause permanent functional deficits in mammals1,2,3,4,5,6. Anti-regenerative neuron-extrinsic factors comprise chronic inflammation, fibrotic scarring, demyelination and the acquisition of a regeneration restricting extracellular milieu. These injury complications exacerbate the inherently limited ability of the mammalian spinal cord (SC) to replenish lost neurons via adult neurogenesis or to regrow lesioned axon tracts. Consequently, even the most groundbreaking regenerative therapies targeting select cell types or individual molecules have only yielded modest improvement in cellular and functional outcomes6,7. SCI studies have since pursued combinatorial strategies as a more promising therapeutic avenue8,9,10,11. We propose that comprehensive and simultaneous examination of neuronal and non-neuronal cells after SCI is fundamental to understanding and manipulating the multi-cellular complexities of neural injuries.
Unlike mammals, adult zebrafish have an innate ability to spontaneously recover from severe SCI. Following complete transection of SC tissues, zebrafish reverse paralysis and regain swim function within 6 to 8 weeks of injury12,13,14. Pro-regenerative injury responses involving immune and progenitor cells, neurons and glia, cooperate to achieve spontaneous and efficient repair in zebrafish15,16,17,18,19,20,21. Early after SCI, potent populations of progenitor cells, including central canal-surrounding ependymo-radial glial cells (ERGs), are activated to replenish lost neurons and glia16,18,20,21,22. Newly differentiated motor neurons and interneurons populate the regenerate tissue, as pre-existing neurons regrow axons across lesioned tissues19,20,21. Though less studied, glial cells are thought to enact instrumental pro-regenerative responses throughout the course of regeneration14,18,22,23. However, a holistic understanding of the cellular interactions that coordinate the pro-regenerative responses to direct SC regeneration in zebrafish is to be acquired.
The advent of single-cell transcriptomics provided the tools to achieve a refined understanding of molecular SCI responses across species and cell types. Multiple single-cell RNA sequencing (scRNA-seq) atlases have been generated for mouse SCI, rat SCI or human SC tissues24,25,26,27,28. Single-cell studies from mice revealed new insights into macroglial cell-cell interactions, revealed a rare population of lumbar spinocerebellar neurons that elicit a regeneration signature, or characterized astrocyte responses after injury26,27,28,29. However, single-cell studies from zebrafish SC tissues have been limited to isolated immune or progenitor motor neuron cells and to larval stages17,30. Thus, a complete resource of the regenerative cells and mechanisms from adult zebrafish is required to develop a molecular understanding of the cell identities that enable or limit spontaneous plasticity and regeneration.
The fundamental principles that determine or limit regenerative capacity across species have eluded scientists for ages. While pro-regenerative injury responses are overwhelmed by anti-regenerative complications in mammals, zebrafish cells exhibit increased potency and exclusively pro-regenerative signatures after SCI. Molecular and cellular studies of select cell types or regenerative pathways revealed key insights into the cellular contributions and molecular signatures associated with elevated regenerative capacity. Specifically, while ependymal cells elicit limited stem cell potential in adult mice31,32, zebrafish ERGs retain radial glial features and contribute to neurogenesis and gliogenesis after SCI16,18,20,21,22. The disparities in neuron progenitor capacities between zebrafish and mammals yielded an assumption that neurogenesis-based neural repair is unachievable in mammals and directed the community’s efforts toward plasticity-based neural repair strategies. However, while zebrafish have been an established model of neuron regeneration, it remains unclear whether zebrafish could contribute insights and applications into plasticity-driven repair mechanisms. Thus, how and why neuronal injury responses differ between zebrafish and mammals require comprehensive molecular investigation and cross-species comparisons.
This study presents an atlas of the dynamic responses across major spinal cell types during early, intermediate and late stages of regeneration in adult zebrafish. Single nuclear RNA sequencing (snRNA-seq) was performed at 0, 1, 3 and 6 weeks post-injury. Neurons elicit elevated signaling activity relative to the dozens of cell types that respond to injury. While SCI disrupts the excitatory/inhibitory (E/I) neuron balance, sequential neurogenesis of excitatory and inhibitory neurons restores the homeostatic neuronal landscape at late stages of regeneration. In addition to regenerating new neurons, a transient regenerative signature emerges in a population of injury-responsive neurons (iNeurons) at 1 week post-injury. EdU labeling showed iNeurons are injury surviving neurons that acquire a neuroblast-like transcriptional signature after SCI. iNeuron markers genes are required for functional SC repair, and dynamic vesicular trafficking is a central mechanism that promotes spontaneous neuronal plasticity. This study identifies multi-layered modes of regenerative neurogenesis and neuronal plasticity during innate SC regeneration, and establishes zebrafish as a platform to identify and manipulate regeneration- and plasticity-based modes of neural repair.
Saraswathy, V.M., Zhou, L. & Mokalled, M.H.
Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair. Nat Commun 15, 6808 (2024). https://doi.org/10.1038/s41467-024-50628-y
Copyright: © 2024 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
So, if you believe, as creationists are obliged to, that all organisms, including human and non-human vertebrates were designed by just such a designer, there appears to be no escape from the conclusion that paraplegics never recover because their intelligent [sic] designer intended them not to and chose not to give them the same ability if gave to zebra fish - which is a strange choice for an omnibenevolent god.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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