Rosa Rubicondior: Unintelligent Design - One Design Blunder Led To Another And Ended Up Causing Cancer

A broken DNA repair tool accelerates aging | News from Goethe University Frankfurt

Researchers from Goethe University, Frankfurt am Main, Germany, have shown how a faulty DNA repair mechanism triggers inflammation and leads to accelerated ageing, developmental abnormalities, and cancer.

Their findings are published in Science.

As I explained in my book, The Unintelligent Designer: Exposing the Intelligent Design Hoax, one of the hallmarks of an evolved system — and one which creationists have been conditioned to mistake for evidence of intelligent design — is complexity. In reality, the opposite is true: intelligently designed objects and processes are typically *minimally

complex, doing exactly what is required and no more.

One reason complexity arises in evolved systems is the need for additional layers of processes to compensate for the suboptimal designs that evolution inevitably produces. An intelligently designed process — especially one devised by a designer endowed with foresight — would require no such compensatory mechanisms. It would function reliably every time and be robust enough to withstand environmental stressors and other causes of malfunction. Nor would a perfectly designed copying process be prone to copying errors.

What we observe in reality, however, is an excessively complex system that still malfunctions — and when it does, it can do so unpredictably and catastrophically, leading to increased suffering and even death. The equivalent, in engineering terms, would be an aircraft manufacturer producing planes that were mostly safe most of the time, yet costly to build because they relied on intricate back-up systems to compensate for other components prone to failure — and which nevertheless suffered unpredictable mid-flight failures when those back-ups failed, causing aircraft to fall from the sky. Such an incompetent aircraft manufacturer would not remain in business for long.

In contrast to evolved systems which are overly complex and still prone to errors, an intelligently designed organism would be minimally complex, maximally efficient, robust enough to withstand environmental stressors and work perfectly every time. As so often, what ID predicts is not what we actually observe. In normal science, the falsification of a hypothesis is regarded as confirmation that the hypothesis was wrong, but in creationism the reverse holds; if the facts fail to confirm the hypothesis the facts must be wrong. The hypothesis must be clung to with grim determination, come what may.

What causes DNA damage?
DNA is a chemically reactive molecule that is constantly under attack. Even in healthy cells, damage occurs continuously and must be repaired to maintain genomic integrity. The main sources of DNA damage fall into several broad categories:

Endogenous (internal) damage Much DNA damage arises unavoidably from normal cellular metabolism:

Reactive oxygen species (ROS) produced during mitochondrial respiration can oxidise DNA bases, leading to mutations such as 8-oxo-guanine.
Spontaneous chemical reactions, including depurination and deamination, cause bases to be lost or altered.
Replication errors occur when DNA polymerases insert incorrect bases or slip on repetitive sequences, creating mismatches or small insertions and deletions.

Environmental and physical damage
External agents add substantially to the burden:

Ultraviolet (UV) radiation from sunlight causes covalent links between adjacent bases (thymine dimers), distorting the DNA helix.
Ionising radiation (X-rays, gamma rays, cosmic radiation) breaks DNA strands directly or via free-radical formation, producing dangerous double-strand breaks.
Thermal stress and background radiation contribute to low-level but continuous damage.

Chemical damage
Numerous chemicals interact directly with DNA:

Environmental mutagens such as tobacco smoke, air pollutants, and industrial chemicals form bulky DNA adducts.
Endogenous toxins, including aldehydes produced during metabolism, also damage DNA.
Certain drugs and chemotherapeutic agents deliberately damage DNA to kill rapidly dividing cells.

Biological sources
Normal biological processes can themselves be hazardous:

Inflammation generates ROS and reactive nitrogen species that damage DNA in surrounding tissues.
Viruses may integrate into the genome or interfere with repair mechanisms.
Mobile genetic elements (transposons) can insert into new locations, disrupting genes.

Why repair is essential
Human cells experience **tens of thousands of DNA lesions per cell per day**. Survival depends on an array of repair pathways — base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair. When these systems fail or become error-prone, the consequences include mutation accumulation, chronic inflammation, accelerated ageing, developmental disorders, and cancer.

How cells repair DNA — and why it matters

Because DNA damage is inevitable, living cells survive only because they possess multiple, overlapping repair systems. These pathways are not optional extras — without them, multicellular life would be impossible.

Base excision repair (BER)

This pathway corrects small, chemically altered bases caused by oxidation, deamination, or spontaneous base loss.

Specialised enzymes recognise damaged bases and remove them.
The resulting gap is filled and sealed using the undamaged strand as a template.
BER operates continuously and fixes thousands of lesions per cell per day.

Nucleotide excision repair (NER)

NER deals with bulky lesions that distort the DNA helix:

Classic examples include UV-induced thymine dimers.
A short stretch of the damaged strand is cut out entirely and resynthesised.
Failure of NER leads to extreme UV sensitivity and greatly elevated cancer risk.

Mismatch repair (MMR)

Mismatch repair corrects copying errors that escape DNA polymerase proofreading:

It identifies mismatched bases and short insertion–deletion loops.
The newly synthesised strand is selectively repaired.
Defects in MMR dramatically increase mutation rates and are strongly associated with cancer.

Double-strand break repair

Breaks affecting both DNA strands are among the most dangerous forms of damage. Cells rely on two main strategies:

Homologous recombination (HR) uses an intact copy of the DNA as a template and is relatively accurate.
Non-homologous end joining (NHEJ) rapidly rejoins broken ends but is error-prone and can introduce mutations.

Why this undermines intelligent design claims

These systems exist precisely because DNA replication, cellular chemistry, and environmental exposure are unreliable. A foresighted designer would not need layer upon layer of error-correction mechanisms to compensate for a fundamentally fragile information system. Instead, we see:

Redundancy piled upon redundancy
Trade-offs between speed and accuracy
Repair pathways that themselves fail, misfire, or introduce new errors

This is exactly what evolutionary theory predicts: a system shaped by incremental modification, constrained by historical baggage, and continually patched rather than optimally designed.

When DNA repair falters, the consequences are predictable — mutation accumulation, chronic inflammation, accelerated ageing, developmental disorders, and cancer — a reality wholly incompatible with the notion of a perfectly designed biological system.

The work of the Goethe University researchers is outlined in this latest news item.

A broken DNA repair tool accelerates aging
Goethe University-led study reveals how mutations in the repair enzyme SPRTN trigger inflammation and premature aging – new insight into Ruijs-Aalfs syndrome
If severe DNA damage is not repaired, the consequences for the health of cells and tissues are dramatic. A study led by researchers at Goethe University Frankfurt, part of the Rhine-Main University Alliance, shows that the failure of a key DNA repair enzyme called SPRTN not only results in genetic damage, but also triggers chronic inflammatory responses that accelerate aging and lead to developmental abnormalities. The findings shed light on the rare hereditary disorder Ruijs-Aalfs syndrome and may open new avenues for therapeutic intervention.

Fatal error: The failure of the repair enzyme SPRTN in these cultured cells leads to fatal errors in cell division, eg by distributing the chromosomes (red) to three daughter cell nuclei instead of two (arrow). Green: Cell division apparatus/cytoskeleton.

© Institute of Biochemistry II, Goethe University Frankfurt.

Although DNA is tightly packed and protected within the cell nucleus, it is constantly threatened by damage from normal metabolic processes or external stressors such as radiation or chemical substances. To counteract this, cells rely on an elaborate network of repair mechanisms. When these systems fail, DNA damage can accumulate, impair cellular function, and contribute to cancer, aging, and degenerative diseases.

One particularly severe form of DNA damage are the so-called DNA–protein crosslinks (DPCs), in which proteins become attached to DNA. DPCs can arise from alcohol consumption, exposure to substances such as formaldehyde or other aldehydes, or from errors made by enzymes involved in DNA replication and repair. Because DPCs can cause serious errors during cell division by stalling DNA replication, DNA–protein crosslinks pose a serious threat to genome integrity.

The enzyme SPRTN removes DPCs by cleaving the DNA-protein crosslinks. SPRTN malfunctions, for example as a result of mutations, may predispose individuals to develop bone deformities and liver cancer in their teenage years. This rare genetic disorder is known as Ruijs-Aalfs syndrome. Its underlying mechanism remains poorly understood, and there are no specific therapies.

Now a research team led by Prof. Ivan Ðikić from the Institute of Biochemistry II at Goethe University demonstrated that the loss of a functional SPRTN enzyme not only leads to the accumulation of damaged DNA in the cell nucleus. Using cell culture experiment and genetically modified mice they found out that, in addition, DNA from the nucleus also leaks into the interior of the cell, the cytoplasm.

SPRTN protects DNA like a helmet by repairing DNA-protein crosslinks.

Artist's impression: Anne-Claire Jacomin, Goethe University Frankfurt

DNA in the cytoplasm is recognized by the cell as a danger signal, as such DNA usually originates from invading viruses or bacteria or from malignant transformation. Cytoplasmic DNA therefore activates defense mechanisms in the cell by initiating the so-called cGAS-STING signaling pathway. Furthermore, the cell releases messenger substances that attract immune cells, leading to chronic inflammation.

The Frankfurt-led research team observed that this chronic inflammatory response is especially pronounced in the mouse embryos and persists in adulthood, particularly in the lung and liver. As a result, the mice died early or showed signs of premature aging similar to those seen in people with Ruijs-Aalfs syndrome. Blocking the relevant immune response alleviates many of the symptoms.

Unrepaired DNA-protein crosslinks have broader systemic consequences. They not only compromise genome stability but also drive chronic inflammation that can significantly influence lifespan.

Dr Ivan Ðikić, corresponding author.
Institute of Biochemistry II
Faculty of Medicine
Goethe University Frankfurt
Frankfurt, Germany.

The physician and molecular biologist sees potential for the development of therapies:

In addition to Ruijs-Aalfs syndrome, there are other rare genetic diseases in which DNA-protein crosslinks play an important role. With our work, we have laid an important foundation for future therapeutic approaches to these diseases as well. By studying the underlying mechanisms of these rare diseases, we discovered a new link between DNA damage, inflammatory responses, and the lifespan of an organism. This also contributes to the understanding of the biology of aging.

Dr Ivan Ðikić.

Partners in the research project included Goethe University and Johannes Gutenberg University Mainz (Institute of Molecular Biology/Professor Petra Beli and Institute of Transfusion Medicine/Professor Daniela Krause) within the Rhine-Main Universities alliance (RMU), the German Consortium for Translational Cancer Research (DKTK), the German Cancer Research Center (DKFZ), EPFL Lausanne, Charité Berlin and the Universities of Cologne and Split (Croatia).

Publication:
Ines Tomaskovic, et al.
DNA-protein crosslinks promote cGAS-STING-driven premature aging and embryonic lethality.
Science (2026) https://doi.org/10.1126/science.adx9445

Structured Abstract

INTRODUCTION
DNA-protein cross-links (DPCs) are highly toxic lesions in which proteins become covalently attached to DNA, blocking essential processes such as replication and transcription. To maintain genome stability, cells rely on specialized repair mechanisms that remove DPCs. The protease SPRTN was the first enzyme identified to resolve these lesions by cleaving the protein component from DNA. Although SPRTN’s function has been well-documented during DNA replication, its role in other phases of the cell cycle remains less understood. Importantly, inherited inactivating mutations in SPRTN cause Ruijs-Aalfs progeria syndrome (RJALS), a rare disorder marked by premature aging and early-onset liver cancer. These observations suggest that unrepaired DPCs have profound effects on health, though the mechanisms linking them to aging and disease remain unclear.

RATIONALE
We hypothesized that persistent DPCs caused by SPRTN inactivation could interfere with mitosis, leading to chromosome mis-segregation, micronucleus formation, and accumulation of mislocalized DNA fragments in the cytoplasm. Such unresolved DPCs may both compromise genome integrity and activate the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) cGAS-STING innate immune pathway through recognition of cytosolic DNA and micronuclei. Given the established role of chronic inflammation in aging, we reasoned that cGAS-STING–mediated inflammatory signaling might contribute to the pathological outcomes of SPRTN deficiency, including progeroid phenotypes.

RESULTS
We found that SPRTN repairs DPCs not only during replication (S phase) but also mitosis (M phase). Inactivation of SPRTN led to the accumulation of DPCs, resulting in chromosome segregation errors and formation of micronuclei containing persistent DPCs and damaged DNA. DNA released into the cytoplasm from these defective nuclei was sensed by the cGAS-STING pathway, triggering inflammatory signaling. Consistently, SPRTN-deficient cells exhibited elevated cytoplasmic DNA and increased expression of interferon-stimulated genes, demonstrating activation of cGAS-STING by DPC-induced DNA leakage.

To explore the physiological consequences of this response, we generated a mouse model carrying a Y118C Sprtn mutation identified in RJALS. These mice accumulated unrepaired DPCs and micronuclei, showed strong innate immune activation, and phenocopied the human disorder. The animals displayed early-onset progeroid traits including reduced body size, craniofacial malformations, eye defects, lipodystrophy, kyphosis, and premature hair graying, some of which manifested during embryogenesis. Genetic or pharmacological inhibition of cGAS-STING from early development ameliorated progeroid features and rescued embryonic lethality. These findings demonstrate that innate immune activation plays a central role in the pathophysiology of unrepaired DPCs.

CONCLUSION
Our study reveals that unrepaired DPCs, including those arising in mitosis, can activate innate immune pathways with harmful consequences for development and aging. SPRTN is essential for repairing both replicative and mitotic DPCs, thereby preventing these lesions from eliciting immune responses. Inhibition of the cGAS-STING pathway rescued mice from lethal developmental defects and premature aging driven by DPC accumulation, uncovering a previously unrecognized link between DNA repair failure and immune-mediated inflammatory disease. These results establish DPCs as a class of DNA damage that promotes chronic inflammation and degenerative aging and suggest that targeting innate immune signaling could represent a therapeutic strategy for disorders caused by defective DPC repair, including RJALS.

DNA-protein cross-links drive cGAS-STING–mediated premature aging. SPRTN depletion causes DNA-protein cross-link (DPC) accumulation, leading to defective mitosis and micronucleus formation. Micronuclei exhibit nuclear envelope assembly defects and rupture, triggering aberrant cGAS-STING activation and inflammatory gene expression. These events induce premature aging, beginning during embryonic development and persisting into adulthood. [Figure created with BioRender.com]

Abstract
DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.

Ines Tomaskovic, et al.
DNA-protein crosslinks promote cGAS-STING-driven premature aging and embryonic lethality.
Science (2026) https://doi.org/10.1126/science.adx9445

© 2026 American Association for the Advancement of Science.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

What this study exposes, once again, is the profound gulf between what we would expect from a genuinely designed system and what we actually observe in biology. Designed systems aim for reliability, simplicity, and predictability. When errors occur, they are rare, bounded, and fail-safe. Biological systems, by contrast, are fragile, convoluted, and riddled with workarounds — layered compensations for processes that are intrinsically unreliable. DNA repair exists not because the system is well designed, but because the system is prone to failure at every level.

Evolution explains this effortlessly. Natural selection can only work with what already exists, modifying and patching rather than redesigning from first principles. The result is a tangled web of interacting mechanisms that usually work well enough to allow reproduction, but which inevitably break down over time, under stress, or through sheer bad luck. Ageing, cancer, inflammation, and developmental disorders are not mysterious flaws in an otherwise perfect system; they are the predictable consequences of an evolved, historically constrained process operating close to its tolerances.

Intelligent Design, by contrast, has nowhere to go. A foresighted designer capable of creating DNA, polymerases, and repair enzymes would not need to build an error-prone information system and then surround it with elaborate damage-control machinery that itself fails. The only way to reconcile the reality of DNA damage, imperfect repair, and the resulting disease with Intelligent Design is to conclude that these outcomes are intentional — that cancer, accelerated ageing, congenital disorders, and premature death are not unfortunate side-effects, but part of the plan.

At that point, Intelligent Design ceases to be a scientific claim and becomes a theological assertion about intent and suffering, usually retreating into theology and Bible literalism for an excuse. Evolution, grounded in evidence and constrained by reality, requires no such moral contortions. It predicts imperfection, vulnerability, and failure — and that is exactly what the biology of DNA damage and repair so clearly reveals.

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