Zebrafish photoreceptor cells stimulated with blue light show correct electrical activity. The picture was taken using the microscope that was custom-built for this study.
Readers may remember my recent post about how researchers have discovered that zebra fish can heal a transected spinal cord, and why creationists need to explain why their putative omnibenevolent designer apparently chose not to give this ability to all vertebrates, including its supposedly favourite special vertebrate, humans
.
Was it because it prefers to watch paraplegics suffer or because it forgot how to?
Well, now we have more evidence, if you accept the childish creationist 'intelligent [sic] design, nonsense, of how the same fish, have apparently been given another ability that would have hugely benefitted humans and other animals - they can repair damage to their visual receptors in their eyes, in other words, they can heal blindness.
A believer in intelligent [sic] design, must accept that, since their designer god apparently knew how to give this ability to zebra fish, it knew how to give it to all vertebrates and made the conscious decision not to.
Why is regenerating the photoreceptors in the eye impossible for humans and other vertebrates? Regenerating photoreceptors in the eye is considered impossible for humans and other vertebrates due to several biological and evolutionary factors:In humans this is something normally only managed by Christian evangelists in fundamentalist churches in front of a captive audience of troobuleevahs, the same skills apparently not being transferable to a hospital setting or during clinical trials.
Conclusion
- Limited Regenerative Capacity of the Retina
- The human retina, especially the photoreceptors (rods and cones), has a very limited ability to regenerate. Unlike some species (like fish or amphibians), humans and other vertebrates lack the cellular mechanisms to replace damaged or lost photoreceptor cells.
- In most vertebrates, once photoreceptor cells are damaged or die (due to injury, disease, or aging), they are not replaced. This is because the adult mammalian retina does not contain a significant population of progenitor or stem cells that can differentiate into new photoreceptors.
- Lack of Müller Glia Activation in Mammals
- In some lower vertebrates (like zebrafish), Müller glia cells in the retina can be reprogrammed to act like stem cells and regenerate retinal neurons, including photoreceptors.
- In mammals, Müller glia do not naturally have this ability to the same extent. While they can undergo limited reactivation under certain conditions, they do not efficiently divide or differentiate into new photoreceptors. This limited regenerative response in mammals may be due to evolutionary changes that have reduced the plasticity of these cells.
- Evolutionary Adaptations and Trade-offs
- The retina's limited regenerative capacity in humans and other vertebrates might be a trade-off for other complex visual functions. The human retina has evolved to support high-acuity vision (like that needed for reading and recognizing faces), which requires a precise and highly organized structure.
- In order to maintain the delicate architecture necessary for such high-resolution vision, the retina may have sacrificed some of its ability to regenerate and reorganize after damage.
- Scar Formation and Inhibitory Environment
- After injury to the retina in mammals, there is often scar formation, which creates a physical barrier and an environment that inhibits the regeneration of photoreceptors.
- The extracellular matrix components in the scar tissue, along with certain cellular signaling pathways, actively suppress cell proliferation and the regeneration of damaged neurons, including photoreceptors.
- Lack of Intrinsic Regenerative Signals
- The molecular signals necessary for photoreceptor regeneration, like certain growth factors and cytokines, are either not present or not active enough in the mammalian retina. These signals are crucial in species that can regenerate their photoreceptors, as they promote cell proliferation, differentiation, and tissue remodeling.
- Aging and Accumulation of Damage
- Over time, damage accumulates in the retina due to light exposure, metabolic stress, and environmental factors. As humans and other vertebrates age, the regenerative capacity of cells generally diminishes. The inability to regenerate photoreceptors is exacerbated by the aging process, which involves the decline in cell function and a reduced capacity for cellular repair and replacement.
These factors together contribute to the inability of humans and other vertebrates to regenerate photoreceptors in the eye. The combination of evolutionary adaptations, a lack of regenerative signaling and capacity, inhibitory environments, and aging-related decline make the regeneration of photoreceptors highly challenging for vertebrates. However, ongoing research in stem cell therapy and gene therapy is exploring ways to overcome some of these limitations, with the hope of eventually enabling some degree of photoreceptor regeneration in humans.
But zebra fish manage it without a travelling show, a hysterical audience and a team of actors and stage-set designers.
How they do so is the subject of a recent paper by a team of researchers led by Prof. Michael Brand at the Center for Regenerative Therapies Dresden (CRTD) of Dresden University of Technology, in the Cell Press journal Development Cell and a news release from the Technische Universität Dresden.
Of course, it has its explanation in evolutionary biology - the overarching theory of biology without which nothing in biology makes any sense.
The Technische Universität Dresden news release explains it:
Seeing the Future: Zebrafish Regenerates Fully Functional Photoreceptor Cells and Restores Its Vision
Blinding diseases lead to permanent vision loss by damaging photoreceptor cells, which humans cannot naturally regenerate. While researchers are working on new methods to replace or regenerate these cells, the crucial question is whether these regenerated photoreceptors can fully restore vision. Now, a team of researchers led by Prof. Michael Brand at the Center for Regenerative Therapies Dresden (CRTD) of Dresden University of Technology has made an important step forward. By studying zebrafish, an animal naturally capable of photoreceptor regeneration, the team showed that regenerated photoreceptors are as good as original ones and regain their normal function, allowing the fish to recover complete vision. Their results, published in the journal “Developmental Cell”, offer promising insights for the future of photoreceptor replacement therapies.
Vision is a complex sense that depends on the retina. This complex neural tissue in the back of our eyes is actually an external piece of the brain. It is where photoreceptor cells capture light and convert it into electrical signals. For humans, these photoreceptors are not replaced after damage. Once lost, they do not regenerate, leading to irreversible vision loss.
Therapies that are currently under development, including at the CRTD in Dresden, aim to replace damaged human photoreceptors and restore vision, either by stimulating stem cells within the retina to develop into new photoreceptors or by transplanting photoreceptors grown outside of the body.
Unlike humans, zebrafish have a remarkable ability to regenerate parts of their nervous system even after severe damage. Zebrafish can regrow photoreceptors from special stem cells located in the retina, known as Müller glia. This unique ability makes zebrafish an ideal model for studying the potential to restore vision through photoreceptor regeneration.
Mammalian retina, including human retina, has very similar Müller glia cells. However, our cells have lost the ability to regenerate during evolution. Since these cells are so very similar, however, it may be possible to rekindle this regeneration potential for therapeutic applications in the future. However, it is crucial to determine if such new photoreceptor cells can function as effectively as the originals.
Professor Michael Brand, senior author
CRTD - Center for Regenerative Therapies TU Dresden,
CMCB Technische Universität Dresden, Dresden, Germany
Making the Impossible Measurements
Researchers have long known that zebrafish can regenerate damaged retinas, with new photoreceptors appearing identical to the originals. Various groups, including the group of Prof. Brand, developed behavioral tests that confirmed that fish regained vision after regeneration. But these tests could not directly assess the extent to which the photoreceptor function was restored.
The only comprehensive test to see if the vision is fully restored is to directly measure the electrophysiological activity of the retinal cells. Are photoreceptors correctly stimulated by the various colors of light? Are they electrically active to the same extent? Are they connected to the neighboring cells? Are they passing the signal to them? Are all the typical circuits engaged?
Professor Michael Brand.
To answer these questions, the Brand team used a genetically modified zebrafish that let them use high-end microscopy to track the activity of photoreceptors at the photoreceptor synapse, i.e., directly where the photoreceptors connect to other nerve cells and pass the electric signal forward.
However, testing the function of regenerated photoreceptors proved to be a significant technical challenge. Photoreceptors convert light into electrical signals. But using light to observe cells under the microscope simultaneously stimulates them. This technical difficulty seemed almost impossible to overcome. However, with input from Prof. Tom Baden from the University of Sussex in Brighton, U.K., and Dr. Hella Hartmann, leader of the Light Microscopy Facility at the Center for Molecular and Cellular Bioengineering at TUD, it was possible to build a custom microscope that allowed the team to uncouple the stimulation from observation and measurement for different light colors, and to overcome this technical hurdle.
Using this advanced custom setup, the Brand team could show that the regenerated photoreceptors indeed regain their normal physiological function. They respond to light at different wavelengths, transmit the electric signal to neighboring cells, and do so with the same sensitivity, quality, and speed as original photoreceptors in an intact retina.
Hope for the Future
Restoring all of these aspects of photoreceptor function, together with our previous work on restoring vision-controlled behavior, confirmed on a molecular level that the fish can fully ‘see’ again.
Humans and fish have a common evolutionary ancestry and share most of the genes and types of cells. Therefore, we hope that humans can learn this ‘regeneration trick’ from the zebrafish. It is important to note that, at this stage, our work is classical basic research. It is still a long way until it can be applied in the clinic. However, being able to eventually achieve such functional regeneration from stem cells already located in the human retina could potentially revolutionize the treatment of currently untreatable diseases like retinitis pigmentosa or macular degeneration. This study brings us one step closer to that dream.
> Michael Brand.
Original PublicationEvelyn Abraham, Hella Hartmann, Takeshi Yoshimatsu, Tom Baden, Michael Brand
Restoration of cone-circuit functionality in the regenerating adult zebrafish retina. Developmental Cell (August 2024)
Highlights
- UV cones in the adult zebrafish retina are color opponent.
- Regenerating UV cones progressively recover to normal physiological light responses.
- Regenerating UV cones recover color-opponent responses.
- Endogenously regenerating neurons can achieve physiological circuit functionality.
Summary
Unlike humans, teleosts like zebrafish exhibit robust retinal regeneration after injury from endogenous stem cells. However, it is unclear if regenerating cone photoreceptors regain physiological function and integrate correctly into post-synaptic circuits. We used two-photon calcium imaging of living adult retina to examine photoreceptor responses before and after light-induced lesions. To assess functional recovery of cones and downstream outer retinal circuits, we exploited color opponency; UV cones exhibit intrinsic Off-response to blue light, but On-response to green light, which depends on feedback signals from outer retinal circuits. Accordingly, we assessed the presence and quality of Off- vs. On-responses and found that regenerated UV cones regain both Off-responses to short-wavelength and On-responses to long-wavelength light within 3 months after lesion. Therefore, physiological circuit functionality is restored in regenerated cone photoreceptors, suggesting that inducing endogenous regeneration is a promising strategy for human retinal repair.
IntroductionGraphical abstract
Visual impairment or blindness due to neuronal degeneration is a severe problem affecting humans.1 In contrast to mammals, zebrafish (Danio rerio) harbor a robust intrinsic capacity to regenerate photoreceptors and other retinal neurons shortly after injury and serve as an excellent model with potential translational impact.2,3 Upon retinal damage, the radial glia in the adult zebrafish retina, Müller glia (MGs) cells, re-enter the cell cycle and function as the primary stem cell source.4 De-differentiated MG produce multipotent neuronal progenitors, which subsequently proliferate and differentiate to regenerate lost retinal cells, leading to a remarkable restoration of the retina’s cellular and synaptic layers.5,6 Although the regeneration of retinal morphology is evident through histological observations, achieving functional recovery remains a critical challenge, especially for newborn retinal neurons and the central nervous system.7
Therefore, we asked two fundamental questions:To this end, we developed a neural activity readout from cone photoreceptor terminals that enables us to study light-evoked activity as well as synaptic feedback from post-synaptic circuits in the adult zebrafish retina and combined it with a reliable and non-invasive cell ablation paradigm to induce retinal regeneration. Intense light lesion is a sterile and effective photoreceptor-specific ablation method that allows to study newly regenerating photoreceptors.8 Intense light lesion with diffuse UV light has been characterized with respect to photoreceptor subtype specificity, cell death, retinal topography, histology, and optical coherence tomography in normally pigmented adult zebrafish.9 Shortly after lesion, UV cones are maximally ablated, followed by blue, green, and red cones in a wavelength-dependent manner across the retinal surface, with the central retina entirely ablated of all photoreceptors. Histological recovery of photoreceptor regeneration is complete within 28 days post-lesion (dpl).9 Hence, diffuse UV light lesion is an effective method for examining the loss of photoreceptor function and its recovery. We thus sought to understand whether UV cones and the surrounding non-UV (blue, green, and red) cones regenerate normal physiology and light responses.
- Do regenerated neurons themselves recover normal light-evoked physiology?
- Can regenerated neurons integrate functionally into post-synaptic circuits?
Here, we established a customized two-photon (2P) setup for adult zebrafish retinal explants and combined it with calcium imaging of cone photoreceptors and light stimulation. We found that the chromatic responses of regenerating UV cones showed robust functional recovery with overall response quality, kinetics, and functional connectivity comparable with the unlesioned retina, gradually over 3 months post-lesion (mpl). Importantly, both before ablation and after regeneration, cones exhibited light-evoked Off- and On-signals. Since cones are intrinsically Off-cells, the presence of On-signals reflects feedback from the horizontal cell (HC) outer retinal network, substantiated through pharmacological validation. This suggests that functional recovery not only occurs in cones themselves but also reflects their circuit integration into the outer retinal network. Our findings show that physiological function is restored in cone photoreceptors regenerating from endogenous MG stem cells and indicate that cone-HC circuits are restored, culminating in functional regeneration of adult retina.
Abraham, Evelyn; Hartmann, Hella; Yoshimatsu, Takeshi; Baden, Tom; Brand, Michael (2024)
Restoration of cone-circuit functionality in the regenerating adult zebrafish retina Developmental Cell 59(16) 2158-2170.e6 DOI: 10.1016/j.devcel.2024.07.005.
Copyright: © 2024 The authors.
Published by Elsevier. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
Some simple questions for creationists:
- Was this ability intelligently designed and if so, why did the same designer, allegedly, choose not to give the same ability to other vertebrates?
- Why should this apparent negligence or deliberate omission be regarded as an act of an omnibenevolent creator god, who could, if it so chose, give all of us the ability to heal blindness the way we can heal other minor injuries?
- Or is this better regarded as the product of an evolutionary process in which this ability was traded for something else, such as higher visual acuity, early in the evolutionary history of the vertebrates?
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.
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
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