Scientists have discovered that a protein responsible for regulating DNA repair can itself become a source of genomic instability, contributing to cancers and neurodegenerative diseases. The finding provides another example of the fragile and failure-prone complexity that characterises biological systems shaped by evolutionary tinkering rather than the work of a competent designer.
The research, reported in an open access paper published in the journal Nucleic Acids Research, was carried out by a team led by Professor Muralidhar L. Hegde, PhD, professor of neurosurgery at the Houston Methodist Research Institute's Center for Neuroregeneration and Department of Neurosurgery. The team describe how a key regulatory protein, TDP43, which controls the genes involved in DNA repair, can itself become a major cause of genomic instability.
When the regulation of TDP43 fails, the consequences can include cancers, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). The difficulty is that this protein can either be absent or overproduced, and both conditions cause the DNA repair genes it regulates to become overactive, resulting in a destabilised genome. This sort of delicate regulatory balance is exactly what evolutionary biologists expect from systems assembled gradually through natural selection, where new control mechanisms are added to existing processes rather than engineered from scratch.
This presents an awkward problem for creationists who claim that biological complexity is evidence of intelligent design. For those with the intellectual integrity to confront the implications, the findings present a difficult choice. Either accept that evolution provides a coherent explanation for such biological paradoxes, or accept that what is claimed to be evidence of intelligent design instead suggests a designer who is incompetent, malevolent, or possibly both—certainly nothing like the allegedly omnibenevolent god of the Bible and Qur'an.
There are also a couple of additional problems here for ID creationists. First, well-designed DNA should not require an additional layer of complexity in the form of a suite of repair genes, followed by yet another regulatory system to control them. Secondly, a well-designed repair mechanism should not itself require such delicate regulation, and the regulatory system should certainly not fail—let alone fail catastrophically. Within the ID creationist paradigm, this is difficult to reconcile with the idea of a competent and benevolent designer.
Evolutionary “Tinkering” and Regulatory Networks.In 1977 the French molecular biologist François Jacob famously described evolution not as an engineer but as a tinkerer. Unlike an engineer, who designs systems from scratch with a clear plan, evolution works by modifying what already exists. New biological functions emerge by altering, duplicating, and repurposing existing components rather than by creating entirely new ones.
Over long periods of evolutionary time this process produces layered regulatory networks. Genes acquire additional control mechanisms, proteins evolve new regulatory roles, and signalling pathways become interlinked with others that originally served different functions. The result is a complex web of interacting controls rather than a simple, streamlined design.
These networks often involve:
- Regulatory proteins that switch genes on or off
- Feedback loops that adjust activity levels
- Multiple control points that fine-tune cellular processes
- Redundant or overlapping pathways that evolved from duplicated genes
While such complexity allows cells to adapt and respond to changing conditions, it also creates points of vulnerability. Because these systems depend on precise balances, small changes in gene expression or protein levels can disrupt the entire network.
This is why many diseases arise not from missing genes but from misregulation of otherwise normal biological components. Proteins that are essential for life can become harmful if they are produced in the wrong amounts or controlled incorrectly. The regulatory protein TDP-43 is one such example: when its levels fall outside the narrow range required for normal function, the mechanisms controlling DNA repair become destabilised.
Such delicate balances are exactly what evolutionary theory predicts from systems assembled gradually through modification of earlier components. They are much less what one would expect from a system designed from the ground up by an all-knowing engineer.
The Houston Methodist Research Institute team provide a short explanation of their findings in a press release, which summarises the biological mechanism they uncovered:
New research discovers dementia-linked protein’s role in DNA mistakes
New Houston Methodist research has revealed that a protein associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis (ALS) also plays a role in regulating DNA mismatch repair, a process essential for replicating genetic information and cell health. The finding could change how scientists understand both cancer and neurodegeneration.
The study, published in Nucleic Acids Research, finds that the protein,‘TDP43’regulates genes that fix DNA mistakes. When this protein is lost or overproduced, these repair genes become overactive, damaging neurons and destabilizing the genome, which could lead to cancer.
Graphical representation of the study's abstract
DNA repair is one of the most fundamental processes in biology. What we found is that TDP43 is not just another RNA-binding protein involved in splicing, but a critical regulator of mismatch repair machinery. That has major implications for diseases like ALS and frontotemporal dementia (FTD) where this protein goes awry.
Professor Muralidhar L. Hegde, Ph.D., senior author
Division of DNA Repair Research
Center for Neuroregeneration
Department of Neurosurgery
Houston Methodist Research Institute
Houston, TX, USA.
The team also found an association between the protein and cancer. Their analysis of large cancer datasets revealed that high levels correlate with increased mutation rates.This tells us that the biology of this protein is broader than just ALS or FTD. In cancers, this protein appears to be upregulated and linked to increased mutation load. That puts it at the intersection of two of the most important disease categories of our time: neurodegeneration and cancer.
Professor Muralidhar L. Hegde.
Researchers said the discovery opens doors for new treatments. By reducing overactive DNA repair in lab models, they partially reversed damage caused by TDP43 problems. Hegde said that Controlling DNA mismatch repair may offer a therapeutic strategy.
Other collaborators in the study were Vincent Provasek, Suganya Rangaswamy, Manohar Kodavati, Joy Mitra, Vikas Malojirao, Velmarini Vasquez, Gavin Britz and Sankar Mitra from Houston Methodist; Albino Bacolla and John Tainer from MD Anderson Cancer Center; Issa Yusuf and Zuoshang Xu from University of Massachusetts; Guo-Min Li from UT Southwestern Medical Centerand Ralph Garruto from Binghamton University.
Publication:
What this study reveals is a system that works only because a delicate regulatory balance is maintained. The protein TDP-43 must exist within a narrow range: too little and DNA repair mechanisms fail; too much and those same mechanisms become dangerously overactive, destabilising the genome. This sort of fragile equilibrium is precisely what evolutionary biologists expect from systems assembled gradually through modification of earlier biological components, where new regulatory layers are added to control existing processes.
It is much harder to reconcile with the notion that biological systems were designed from scratch by a perfectly competent and benevolent intelligence. An engineer designing a repair system would presumably build one that simply corrected damage reliably without requiring multiple levels of regulation that can themselves malfunction. Yet biological systems repeatedly show exactly the opposite pattern: intricate regulatory networks that function only when numerous interacting components remain in precise balance.
Far from being evidence of intelligent design, discoveries like this highlight the historical nature of biological complexity. Evolution works not by planning and designing optimal systems, but by modifying what already exists, producing workable solutions that often carry the marks of their evolutionary history. The regulatory networks that control DNA repair are another example of this process — ingenious in their functionality, but also vulnerable, imperfect and prone to failure.
For creationists who claim that biological complexity points to intelligent design, findings such as these present an increasingly difficult problem. The more we learn about the inner workings of cells, the more clearly we see the fingerprints of evolutionary tinkering rather than the hallmarks of deliberate engineering.
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