Dr. Alexandra Nusawardhana, the lead author of the study and who earned her doctorate in biomedical sciences this year from Penn State College of Medicine, conducts research to understand genomic instability and cancer treatment response.
Credit: Jason Plotkin / Penn State. Creative Commons
A characteristic of evolved biological systems, and one that distinguishes them from systems designed from first principles, is that they are often unnecessarily complex, vulnerable to failure and dependent on layers of patchwork compensation. This is what we should expect from systems produced by utilitarian, suboptimal compromises built from whatever was available at the time.
With no plan, no foresight and no predetermined objective, natural selection can only favour whatever leaves more descendants in a particular environment. The result is not an ideal solution, but merely a workable one — one that is better than what preceded it, even if it remains a very long way from perfection. An intelligent designer, such as the one proposed by advocates of intelligent design, would be under no such historical constraints and could, in principle, rebuild a system from scratch to arrive at the optimal solution.
To illustrate this, this post and the next will look at two recent papers that incidentally demonstrate how many human health problems arise from these over-complex, error-prone systems — systems that would not exist if the human body were the pinnacle of created perfection that creationists imagine it to be. Unless, of course, the designer intended us to suffer when its systems failed.
The first concerns a paper published in February 2026 in Nature Communications by researchers at Penn State College of Medicine. It shows how one component of the DNA repair machinery — a system needed because DNA replication and maintenance are themselves vulnerable to error and damage — can itself go wrong and produce a pattern of genomic instability resembling that seen when the BRCA1 and BRCA2 tumour-suppressor pathway is defective.
The culprit is EXO1, a gene that encodes an exonuclease involved in DNA processing and repair. In normal cells, EXO1 helps trim and process damaged or mismatched DNA so that repair can proceed. But when EXO1 is overexpressed, as the researchers found in a significant proportion of several cancers, including about 20–30% of breast and ovarian cancers as well as melanoma, testicular, cervical and hepatobiliary cancers, too much of this normally useful protein becomes destructive. Instead of helping to preserve genome integrity, excessive EXO1 activity can degrade newly synthesised DNA during replication stress, expanding single-stranded DNA gaps and degrading reversed replication forks.
The result is a BRCA-like pattern of genomic instability even in cells whose BRCA pathway is still functional. In other words, the cell behaves in some important respects like a BRCA-mutant tumour cell, not because BRCA1 or BRCA2 is mutated, but because too much EXO1 has overwhelmed the normal protective system. This matters clinically because such tumours may respond to some of the same treatments used against BRCA-mutant cancers, including drugs that target DNA repair vulnerabilities.
So, we have a DNA replication and maintenance system that needs elaborate repair machinery because the genome is constantly vulnerable to damage; then we have the catastrophic consequences when that repair machinery itself goes rogue. Compare that with the simpler, more robust system we might expect from an intelligent designer endowed with foresight and unconstrained by evolutionary history. Complexity is not the hallmark of intelligent design that creationists claim it to be. In biology, it is very often the accumulated consequence of failure-prone, suboptimal compromises produced by evolutionary tinkering without a predetermined objective.
DNA Repair^ The Cell’s Patchwork Maintenance Crew. DNA is often described as the cell’s information store, but it is not an invulnerable molecule. Every time a cell divides, its DNA must be copied, and that copying process is vulnerable to errors, chemical damage, oxidative stress, radiation and interference from other cellular processes. Without repair systems, cells would quickly accumulate mutations and broken chromosomes.The paper in Nature Communications was accompanied by a news release from Penn State by Christine Yu:
Cells therefore rely on several overlapping DNA repair mechanisms. These include systems for correcting copying errors, removing damaged bases, repairing broken strands and rescuing stalled DNA replication. These mechanisms are not the product of foresighted engineering from a clean drawing board, but a collection of inherited biochemical processes that have been modified, duplicated and repurposed during evolution.
One especially vulnerable moment comes during DNA replication. The copying machinery can stall when it meets damaged DNA or runs short of the raw materials needed to continue. This can leave exposed single-stranded DNA gaps or cause the replication fork — the point where DNA is being copied — to reverse temporarily. These structures must be protected and repaired, otherwise they can collapse into dangerous double-strand breaks.
The BRCA1 and BRCA2 genes are best known because harmful mutations in them increase the risk of breast, ovarian and some other cancers. Their normal role, however, is protective: they help cells repair serious DNA damage and protect vulnerable structures that arise during replication stress. When this protection fails, the genome becomes unstable.
EXO1 is another part of the cell’s DNA maintenance machinery. It encodes an exonuclease — a molecular trimming tool — that can remove sections of DNA during repair. At the right level, and in the right context, this is useful. But too much EXO1 can become destructive. Instead of helping to preserve the genome, it can enlarge single-stranded gaps and degrade newly made DNA at reversed replication forks.
The result is a striking example of biological compromise. A repair system that exists because DNA is vulnerable to damage can itself become a source of damage when one of its components is overproduced. In cancer cells, this can produce a BRCA-like pattern of genomic instability even when the BRCA genes themselves are not mutated.
Clinically, that may matter because tumours with excessive EXO1 activity could respond to some of the same treatments used against BRCA-mutant cancers. Biologically, it illustrates a wider point: living systems are not simple, fail-safe machines. They are layered, historically constrained systems in which yesterday’s useful repair mechanism can become today’s pathological weakness.
DNA repair protein gene gone rogue may unlock new cancer treatments
Overproduction of a DNA repair protein creates DNA damage that mimics BRCA mutations — and may respond to the same targeted treatment
When it comes to cancer, tumor suppressor genes are usually thought of as the “good guys.” These genes make proteins that protect and repair DNA in cells. If they stop functioning or there’s not enough, cancer risk goes up. But there can be too much of a good thing: When cells overexpress the gene EXO1 — meaning that they make more of the protein than they should — it can degrade the DNA it’s supposed to repair. This causes damage that can disrupt the genome, which is a hallmark of cancer, according to a team of researchers from Penn State College of Medicine.
In a study published in Nature Communications, the researchers found that the EXO1 gene is overexpressed in 20% to 30% of breast and ovarian cancers as well as in melanoma, testicular, cervical and hepatobiliary cancers, which develop in the liver, gall bladder and bile duct. Tumor cells with high levels of EXO1 protein exhibit characteristics similar to cells with a BRCA mutation, a genetic code change known for its link to hereditary breast and ovarian cancers. That means that these tumor cells behave like BRCA-mutant cells — including their response to the chemotherapies and other drugs — even when there is no BRCA mutation present, a finding the researchers said hasn’t previously been established.
EXO1 doesn’t predict cancer risk, but it could potentially serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapy treatments, leading to more personalized therapies. The same drugs that are reserved for treating BRCA-mutant tumors and that have fewer side effects could potentially be used to treat EXO1 overexpressing tumors, which don’t have BRCA mutations. It would expand the applicability of those drugs.
Professor George-Lucian Moldovan, senior author
Department of Molecular and Precision Medicine
The Pennsylvania State University College of Medicine
Hershey, PA, USA.
For this study, the research team analyzed The Cancer Genome Atlas, a cancer genomic program of the National Cancer Institute, for EXO1 alterations in tumor samples. They found that EXO1 was overproduced in several tumors, including those in the breast, skin, liver and cervix, which aligns with previous studies in the field. Specifically, high levels of EXO1 were linked to basal-like breast cancers, an aggressive subtype of breast cancer.
The research team conducted laboratory studies with commercially available human cancer cells. The researchers overexpressed the EXO1 gene in the cells to see how an overabundance affected the cell’s DNA. They also overexpressed a biochemically disabled version of the EXO1 gene, meaning the proteins it produced were present but not interacting with other cells, to confirm that any DNA damage observed was specifically caused by protein activity and not just the presence of the protein.
In normal cells, the EXO1 protein acts like a pair of molecular scissors, trimming and repairing damaged DNA. When there’s too much EXO1 in cells, the researchers found that it started cutting things that it shouldn’t. They observed that EXO1 destabilizes newly synthesized DNA in two primary ways — by expanding single-stranded DNA gaps and degrading reversed replication forks. Both processes chew up DNA and leads to localized loss of DNA sequences, Moldovan explained.
Regardless of which pathway, EXO1 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double strand breaks, which we ultimately think is what makes the tumor more sensitive to chemotherapy and increases cell death.
Dr. Alexandra Nusawardhana, first author.
Department of Molecular and Precision Medicine
The Pennsylvania State University College of Medicine
Hershey, PA, USA.
Normally, BRCA genes produce proteins that protect these genomic structures; when there’s a mutation in the BRCA genes, cells can’t protect its DNA during replication, which can eventually lead to cancer development. However, in this study, high levels of EXO1 protein bypassed BRCA’s defenses, even in cells where BRCA is fully functional and there is no mutation. The researchers found that EXO1 worked in concert with another protein called MRE11 to expand gaps in DNA and create dangerous breaks.
Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells [But unlike BRCA mutations, EXO1 overexpression isn’t inherited and it’s not known if it causes cancer].
Professor George-Lucian Moldovan
Because of the similar behavior, the researchers wanted to know if tumor cells that overexpressed EXO1 would also respond to cancer treatments the same way that BRCA-mutant tumors, too. They tested how EXO1 overexpressing tumors responded to olaparib, an existing medication used to treat BRCA-mutant cancers by targeting the cellular repair system. They found that the tumors were hypersensitive to the drug, responding like the BRCA-mutant cancers. The finding suggests that tumors that overexpress EXO1, but don’t have a BRCA mutation, might also benefit from the same kind of cellular repair-targeted therapy. The researchers also found that EXO1-overexpressing tumors responded to cisplatin, a widely used chemotherapy drug, suggesting that lower doses of cisplatin could potentially achieve the same tumor shrinkage with less side effects.
Since EXO1 overexpression is more common across tumors than the BRCA mutation, its presence in cancer cells could potentially be a useful biomarker to identify more personalized treatment options, according to Moldovan.We shouldn’t treat cancers based on what tissue they come from but based on the landscape of the genetic mutations present in the tumors. That would result in high efficiency treatment. That’s the future of cancer treatment.
Professor George-Lucian Moldovan
The research team plans to continue this line of research with the goal of eventually conducting clinical trials with cancer patients with tumors that exhibit EXO1 overexpression.
Claudia Nicolae, assistant professor of molecular and precision medicine at Penn State College of Medicine, also contributed to the paper.
Publication:
The significance of this is that it is not merely a matter of something occasionally going wrong in an otherwise perfect system. The problem arises from the way the system is constructed. DNA replication is vulnerable to error and damage, so cells need elaborate repair mechanisms. Those repair mechanisms must themselves be regulated, because too little repair leaves the genome unstable, while too much activity from the wrong component, in the wrong place, at the wrong time, can make the damage worse. That is not the clean, robust simplicity we might expect from intelligent design; it is the layered fragility of an evolved system held together by compensating mechanisms.
Creationists will no doubt have their usual escape routes ready. One is to retreat into “mystery” and claim that their god must have had some inscrutable reason for designing a system in which the very machinery intended to repair DNA can become a cause of genomic instability and cancer. But that is not an explanation. It is an admission that the evidence does not fit the claim of intelligent design, followed by an attempt to protect the claim from falsification. Once “mystery” is allowed to explain away any failure, no possible observation could ever count against the belief.
Another familiar refuge is “The Fall”, the theological device by which creationists try to blame all biological defects, diseases and cruelties on a mythical ancestral act of disobedience, resulting in a creative force over which the supposedly supreme creator god has no control. But invoking The Fall explains nothing about the biochemical details. It does not explain why DNA replication should be vulnerable in this particular way, why repair requires such intricate and failure-prone machinery, why EXO1 overexpression should mimic aspects of BRCA failure, or why tumours should exploit the same weaknesses that normal cells depend on for survival. It simply moves the discussion from biology to mythology.
Science, by contrast, does not need to invent a supernatural excuse for every awkward fact. It follows the evidence into the cell, identifies the mechanisms, tests them and explains how they operate. What it finds, again and again, is not the signature of perfect engineering but the unmistakable marks of evolutionary tinkering: workable compromises, improvised safeguards, overlapping systems and vulnerabilities inherited from earlier solutions. The genome is maintained not by flawless design, but by a precarious balance of processes that can preserve life when they work and cause disease when they fail.
That is exactly what evolution predicts. It is not what intelligent design leads us to expect.
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