Rosa Rubicondior: Malevolent Designer - Does The Designer Favour Zebrafish Or Just Hate Humans?

Two zebrafish genes hold the key to regenerating inner ear cells, offering hope for future human therapies.

Stowers Institute for Medical Research

Regrowing hearing cells: New… | Stowers Institute for Medical Research

It's more bad news for Intelligent Design (ID) creationists who believe their putative designer is the anthropophilic, omnibenevolent God of the Bible. Hot on the heels of the discovery that some lemurs do not suffer from the age-related degenerative conditions that cause such misery for humans, comes the news that zebrafish can regenerate lost hair cells—cells that, in humans, enable hearing but cannot be replaced once lost.

These hair cells, located in the human inner ear, detect vibrations and are crucial for hearing. They can be destroyed through prolonged exposure to loud noise, resulting in permanent deafness. However, zebrafish possess homologous cells in their lateral lines—structures that allow them to detect vibrations in water, effectively functioning as a form of hearing. Remarkably, these cells can regenerate under the control of two specific genes.

It doesn't take a genius to realise that, if we accept the intelligent design argument that a divine designer deliberately created these genes, then the same designer could have endowed its supposed special creation—humans—with this regenerative ability too. Within the ID framework, the only possible conclusion is that the designer god chose *not* to give humans this ability, and instead preferred us to go deaf.

The problem for creationists deepens when one considers that these genes exemplify what William A. Dembski of the Discovery Institute cites as evidence of intelligent design: they are complex and specified, containing the genetic information to produce a defined result. Dembski insists that such "complex specified information" can only originate from an intelligent designer.

Creationists, of course, are compelled to reject the notion that these differences are simply the result of evolutionary processes. But if they also refuse to accept that this zebrafish trait—clearly underpinned by "complex specified genetic information"—constitutes evidence of intelligent design (and therefore points to a deliberate *absence* in humans), they are also undermining Dembski's single defining argument for intelligent design.

This striking discovery was made by researchers at the Stowers Institute for Medical Research and has just been published open access in Nature Communications.

The Role of Hair Cells in Hearing.
Hair cells are specialised sensory cells located within the cochlea of the inner ear. They are named for the tiny, hair-like projections (stereocilia) on their surface.

When sound waves enter the ear, they cause vibrations in the eardrum and the small bones of the middle ear (ossicles), which in turn set up fluid waves in the cochlea. These waves deflect the stereocilia on the hair cells, triggering electrical signals that are sent to the brain via the auditory nerve.

There are two main types of hair cells:

Inner hair cells, which convert mechanical vibrations into nerve impulses;
Outer hair cells, which amplify sound vibrations and improve frequency resolution.

In humans and other mammals, once these hair cells are damaged—whether by ageing, loud noise, or infection—they do not regenerate, leading to permanent hearing loss.

The Stowers Institute also explains the findings in a news release on their website.

Regrowing hearing cells: New gene functions discovered in zebrafish offer clues for future hearing loss treatments
Stowers scientists identify specific genes involved in zebrafish sensory hair cell regrowth, providing new insights that could inform future research into hearing loss treatments
While humans can regularly replace certain cells, like those in our blood and gut, we cannot naturally regrow most other parts of the body. For example, when the tiny sensory hair cells in our inner ears are damaged, the result is often permanent hearing loss, deafness, or balance problems. In contrast, animals like fish, frogs, and chicks regenerate sensory hair cells effortlessly.

Now, scientists at the Stowers Institute for Medical Research have identified how two distinct genes guide the regeneration of sensory cells in zebrafish. The discovery improves our understanding of how regeneration works in zebrafish and may guide future studies on hearing loss and regenerative medicine in mammals, including humans.

Mammals such as ourselves cannot regenerate hair cells in the inner ear. As we age or are subjected to prolonged noise exposure, we lose our hearing and balance.

Dr. Tatjana Piotrowski, Ph.D., corresponding author.
Stowers Institute for Medical Research
Kansas City, MO, USA.
New research from the Piotrowski Lab, published in Nature Communications on July 14, 2025, seeks to understand how cell division is regulated to both promote regeneration of hair cells and to also maintain a steady supply of stem cells. Led by former Stowers Researcher Mark Lush, Ph.D., the team discovered that two different genes regulating cell division each control the growth of two key types of sensory support cells in zebrafish. The finding may help scientists study whether similar processes could be triggered in human cells in the future.

During normal tissue maintenance and regeneration, cells need to proliferate to replace the cells that are dying or being shed — however, this only works if there are existing cells that can divide to replace them. To understand how proliferation is regulated, we need to understand how stem cells and their offspring know when to divide and at what point to differentiate.

Dr. Tatjana Piotrowski, Ph.D.

Zebrafish are an excellent system for studying regeneration. Dotted in a straight line from their head to tailfin are sensory organs called neuromasts. Each neuromast resembles a garlic bulb with “hair cells” sprouting from its top. A variety of supporting cells encompass the neuromast to give rise to new hair cells. These sensory cells, which help zebrafish detect water motion, closely resemble those in the human inner ear.

Graphic illustration of zebrafish neuromast showing where the progenitor and stem cells reside.
Because zebrafish are transparent during development and have accessible sensory organ systems, scientists can visualize, as well as genetically sequence and modify, each neuromast cell. This allows them to investigate the mechanisms of stem cell renewal, the proliferation of progenitor cells — direct precursors to hair cells — and hair cell regeneration.

We can manipulate genes and test which ones are important for regeneration. By understanding how these cells regenerate in zebrafish, we hope to identify why similar regeneration does not occur in mammals and whether it might be possible to encourage this process in the future.

Dr. Tatjana Piotrowski, Ph.D.

Two key populations of support cells contribute to regeneration within neuromasts: active stem cells at the neuromast’s edge and progenitor cells near the center. These cells divide symmetrically, which allows the neuromast to continuously make new hair cells while not depleting its stem cells. The team used a sequencing technique to determine which genes were active in each type and found two distinct cyclinD genes present in only one or the other population.

The researchers then genetically altered each gene in the stem and progenitor populations. They discovered that the different cyclinD genes were independently regulating cell division of the two types of cells.

When the proliferation gene responsible for progenitor populations is disrupted (right), progenitors regenerate hair cells through direct differentiation in the absence of proliferation. Wild type neuromast is on the left.

When we rendered one of these genes non-functional, only one population stopped dividing. This finding shows that different groups of cells within an organ can be controlled separately, which may help scientists understand cell growth in other tissues, such as the intestine or blood.

Dr. Tatjana Piotrowski, Ph.D.

Progenitor cells lacking their cell type-specific cyclinD gene did not proliferate; however, they did form a hair cell, uncoupling cell division with differentiation. Notably, when the stem cell-specific cyclinD gene was engineered to work in progenitor cells, progenitor cell division was restored.

This work illuminates an elegant mechanism for maintaining neuromast stem cells while promoting hair cell regeneration. It may help us investigate whether similar processes exist or could be activated in mammals.

Professor David Raible, Ph.D., (not involved in the study)
University of Washington.
Because cyclinD genes also regulate proliferation in many human cells, like those in the gut and blood, the team’s findings may have implications beyond hair cell regeneration.

Insights from zebrafish hair cell regeneration could eventually inform research on other organs and tissues, both those that naturally regenerate and those that do not.

Dr. Tatjana Piotrowski, Ph.D.

Additional authors include Ya-Yin Tsai, Shiyuan Chen, Daniela Münch, Julia Peloggia, Ph.D., and Jeremy Sandler, Ph.D.

Publication:
Lush, M.E., Tsai, YY., Chen, S. et al.
Stem and progenitor cell proliferation are independently regulated by cell type-specific cyclinD genes. Nat Commun 16, 5913 (2025). https://doi.org/10.1038/s41467-025-60251-0

Abstract
Regeneration and homeostatic turnover of solid tissues depend on the proliferation of symmetrically dividing adult stem cells, which either remain stem cells or differentiate based on their niche position. Here we demonstrate that in zebrafish lateral line sensory organs, stem and progenitor cell proliferation are independently regulated by two cyclinD genes. Loss of ccnd2a impairs stem cell proliferation during development, while loss of ccndx disrupts hair cell progenitor proliferation but allows normal differentiation. Notably, ccnd2a can functionally replace ccndx, indicating that the respective effects of these Cyclins on proliferation are due to cell type-specific expression. However, even though hair cell progenitors differentiate normally in ccndx mutants, they are mispolarized due to hes2 and Emx2 downregulation. Thus, regulated proliferation ensures that equal numbers of hair cells are polarized in opposite directions. Our study reveals cell type-specific roles for cyclinD genes in regulating the different populations of symmetrically dividing cells governing organ development and regeneration, with implications for regenerative medicine and disease.

Introduction
Tissue turnover and regeneration are essential for organismal function and survival and require the proliferation of stem cells. In most solid tissues, this process relies on symmetrically dividing adult stem cells¹. For instance, in the epithelia of the intestine, stomach, esophagus and the skin, stem cells divide symmetrically and—depending on their location in the stem cell niche—the daughter cells either maintain their stem cell characteristics, or if displaced from the niche proceed to ^{2,3,4,5,6,7,8,9}. Stem and progenitor cell proliferation need to be tightly controlled, as misregulation of niche signals or uncontrolled proliferation of stem and daughter cells can lead to serious diseases such as cancer. Despite the importance of symmetrically dividing stem cells and their progeny for tissue maintenance, regeneration and disease, whether their proliferation is differentially regulated has not been explored.

The zebrafish sensory lateral line is an excellent model to study the regulation of sensory organ homeostasis and regeneration at the cellular and molecular level within single cells^10,11,12. It consists of clusters of 50–80 cells, called neuromasts that are arranged in lines on the head and along the trunk of the fish (Fig. 1A–C). These neuromasts are deposited during embryonic development by migrating primordia¹³. Each neuromast contains mechanosensory hair cells surrounded by support cells and peripheral mantle cells (Fig. 1C, D). Hair cells possess a long, microtubule based kinocilium and shorter actin rich stereocilia that are sensitive to water motion (Fig. 1B¹⁴).

Fig. 1: ccndx and ccnd2a are dynamically expressed in different proliferating cells in the regenerating zebrafish lateral line.

A Representative image of a 5 dpf DAPI-stained zebrafish larva, posterior lateral line neuromast in boxed region. Scale bar = 200 µm. B Scanning electron micrograph of a 5 dpf zebrafish neuromast (dorsal view) with short stereocilia and long kinocilia in purple (adapted from Lush, M.E. and Piotrowski, T. (2014), Sensory hair cell regeneration in the zebrafish lateral line. Dev. Dyn., 243: 1187-1202. https://doi.org/10.1002/dvdy.24167”¹⁰). C Transmission electron micrograph of a transverse section of a 5 dpf neuromast with hair cells in purple and mantle cells in blue. Additional support cells are unlabeled (adapted from Lush, M.E. and Piotrowski, T. (2014), Sensory hair cell regeneration in the zebrafish lateral line. Dev. Dyn., 243: 1187-1202. https://doi.org/10.1002/dvdy.24167”¹⁰). Diagram of a neuromast showing a transverse section (D) and a dorsal view (E). Progenitor cells and hair cells are in purple, amplifying stem cells in the dorsal-ventral poles in pink and mantle cells in blue. F Integrated scRNA-seq UMAP plot of a neuromast regeneration time course (homeostasis, 0 min, 30 min, 1 h, 3 h, 5 h and 10 h after hair cell death; Baek et al., 202212). G–J scRNA-seq Feature Plots (Baek et al., 2022¹², https://piotrowskilab.shinyapps.io/neuromast_regeneration_scRNAseq_pub_2021/) illustrating gene-specific expression patterns. G pcna labels dividing, differentiating hair cell progenitors (purple arrow) and amplifying stem cells (pink arrow). H atoh1a is expressed in some central cells and marks the lineage from hair cell progenitors to hair cells (purple arrow). I ccndx is expressed in some central cells and along the hair cell lineage and is highest in progenitor cells undergoing differentiating divisions (purple arrow). J ccnd2a is more broadly expressed but is highest in the amplifying cell population (pink arrow) and absent from the hair cell lineage. K Heatmap of scaled gene expression across lateral line cell types during the averaged regeneration time course (Baek et al., 202212). L Heatmap of scaled gene expression during the regeneration time course. All genes are briefly upregulated at 0–30 min but show the largest activation between 3 − 10 h. atoh1a and ccndx show similar expression dynamics, whereas ccnd2a expression peaks slightly later. M Representative images of HCR in situ hybridization of ccndx (yellow) and ccnd2a (magenta) during the regeneration time course. Scale bar = 10 µm. Representative images of HCR in situ hybridization of ccndx (yellow) and atoh1a (magenta) during homeostasis (N) and 5 h after hair cell death (O). Scale bar = 10 µm.

Homeostasis and regeneration of neuromast cells are maintained by two populations of proliferating cells: amplifying support cells and differentiating hair cell progenitors (Fig. 1E, [15]). In the dorsal-ventral (D-V) poles, support cells (Fig. 1E, pink cells) divide and their daughter cells can adopt different fates: remain undifferentiated while in contact with mantle cells, the hypothetical niche, or, be displaced away from the niche and become a hair cell progenitor^15,16. Because amplifying cells self-renew and give rise to hair cells, we call them amplifying stem cells. Their degree of plasticity or potency to generate other neuromast cell types remains to be tested. Hair cell progenitors in the center of the organ will in turn divide again and give rise to two hair cells (Fig. 1E, purple cells^10,15,17,18,). After hair cell loss progenitors also arise from non-D-V pole support cells, demonstrating plasticity, similar to other epithelial cell lineages^19,20.

As in other mechanosensory organs in various species, zebrafish hair cell differentiation in neuromasts is negatively regulated via Notch-dependent lateral inhibition, and loss of Notch signaling causes the development of more hair cells at the expense of support cells^{15,17,18,21,22}. In addition to its function in progenitor fate specification, Notch signaling also inhibits proliferation of differentiating progenitor cells during regeneration^15,17. Therefore, during regeneration and immediately after hair cell death, Notch signaling is downregulated, leading to differentiation of progenitor cells, their proliferation and further differentiation into hair cells. The current belief is that cell proliferation is essential for neuromast hair cell regeneration, as cell cycle inhibition with pharmacological inhibitors leads to a failure in regeneration^18,23.

Progenitor cell division produces a pair of hair cells with opposing polarity, ensuring the equal generation of hair cells that are sensitive to either rostrad or caudad water flow²⁴. The transcription factor Emx2 determines hair cell polarity in both the lateral line and ear^{25,26,27,28,29,30}. In neuromasts, it is expressed in only one of the two sibling hair cells, where it reverses the cell’s default anterior polarity. Notch-mediated lateral inhibition between the two initially equal progenitors inhibits the expression of Emx2 in one progenitor, and loss of Notch signaling causes both hair cells in the pair to acquire the same polarity^25,28,30.

As proliferation is not only essential for life-long regeneration but also for correct hair cell polarity it is essential to elucidate how it is controlled. We previously characterized gene expression dynamics during regeneration in all neuromast cell types using single cell RNA-seq (scRNA-seq)^11,12. Here we show that the proliferating amplifying stem cell and progenitor cell populations of the zebrafish lateral line express different cyclinD genes, which are G1-regulators that bind and activate cyclin-dependent kinases (CDK4/6) to initiate the cell cycle^31,32. Amplifying cells express ccnd2a and dividing, differentiating progenitor cells express ccndx. Loss of ccndx causes lack of differentiating progenitor divisions while leaving amplifying divisions unaffected. Hair cells still regenerate in lower numbers, demonstrating that progenitor cell proliferation is not required for differentiation and regeneration of hair cells. In contrast, loss of ccnd2a only affects amplifying cell divisions, at least during development. ccnd2a driven by the ccndx promoter rescues progenitor proliferation in ccndx mutants, demonstrating that the effects of these two D-type cyclins are caused by their cell type-specific expression, not because they interact with different targets. Thus, proliferation in amplifying cells and differentiating progenitor cells is mechanistically uncoupled. We also show that Notch signaling inhibits ccndx during homeostasis and that the increase in hair cell progenitor proliferation after Notch downregulation during hair cell regeneration requires ccndx. Lastly, we demonstrate using scRNA-seq and functional analyses that loss of ccndx and progenitor proliferation lead to hair cell polarity defects due to hes2 downregulation and ectopic Emx2 expression. Our findings have important implications for the understanding of how proliferation of symmetrically dividing stem and progenitor cells is controlled during homeostasis and disease.

Lush, M.E., Tsai, YY., Chen, S. et al.
Stem and progenitor cell proliferation are independently regulated by cell type-specific cyclinD genes. Nat Commun 16, 5913 (2025). https://doi.org/10.1038/s41467-025-60251-0

Copyright: © 2025 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

The discovery that zebrafish can regenerate the sensory hair cells essential for detecting vibrations—cells homologous to those responsible for hearing in humans—poses a serious challenge to the claims of Intelligent Design creationists. According to ID theory, such complex biological systems can only arise through the purposeful actions of an intelligent agent, since they allegedly exhibit “irreducible complexity” or “complex specified information” that cannot be explained by natural processes like evolution.

Yet if we accept that the genes enabling zebrafish to regenerate hair cells were intentionally designed, it begs the obvious question: why would the same designer withhold this vital repair mechanism from humans, especially if humans are considered the designer's "special creation"? Hearing loss is a widespread and often debilitating condition that significantly reduces quality of life. The absence of a regenerative mechanism in humans, despite its presence in a relatively simple fish, appears arbitrary at best—and malevolent at worst—if attributed to a conscious design decision.

This contradiction undermines one of the core assumptions of ID: that nature reflects not just intelligent, but beneficent design. If the ability to regenerate hair cells is the result of divine foresight in zebrafish, then its absence in humans must also be seen as a deliberate omission. Such an interpretation challenges the idea of an all-loving designer and is difficult to reconcile with the theological underpinnings of most ID advocacy.

Moreover, rejecting the evolutionary explanation for this difference forces ID proponents into an uncomfortable corner. Either they admit that the zebrafish’s regenerative ability arose by chance or necessity through evolution — thereby conceding the central mechanism ID was invented to deny — or they must attribute its absence in humans to an intelligent but inscrutable (and possibly malevolent) will. In doing so, they inadvertently erode the very argument they rely upon to claim evidence for design.

Ultimately, what seems like a modest piece of comparative biology becomes a telling example of how Intelligent Design cannot account for the distribution of biological traits without resorting to ad hoc rationalisations or implicit theological assumptions it otherwise tries to avoid.

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