Rosa Rubicondior: Unintelligent Design - If Scientists Can Do It, Why Can't an Intelligent, Omnipotent Designer

Unintelligent Design

If Scientists Can Do It, Why Can't An Intelligent, Omnipotent Designer
If It Wanted To?

Treatment for mitochondrial diseases within reach | University of Gothenburg

If the human body had truly been intelligently designed by an omnibenevolent, omniscient deity, it would operate flawlessly under all conditions, free from the compromises and constraints inherent in evolutionary history.

Were this the case, much of modern medicine would be unnecessary, limited perhaps to the management and repair of traumatic injuries. Parasites, should they exist at all, would be effortlessly repelled by a perfect immune system. Genetic and structural defects, such as hernias, atherosclerosis, autoimmune disorders, blindness, deafness, neurodegenerative diseases, and complications in childbirth would simply not occur.

However, as I showed in my book, The Body of Evidence: How the Human Body Refutes Intelligent Design, the human body is not the product of intelligent design; it has evolved through a process marked by trial and error, adaptation to existing structures, and the utilitarian pressures of survival and reproduction. This explains the vast array of medical conditions that keep healthcare systems busy, often stretched to their limits. It also drives the extensive scientific research dedicated to discovering the causes and developing cures for various illnesses—achievements that an omnipotent and omnibenevolent creator, if one existed, presumably would have provided already.

Recent news highlights this contrast starkly. Scientists may have discovered a groundbreaking cure for a rare mitochondrial disease caused by mutations in the POLG gene, a condition that leads to severe disability or even early death. This advancement prompts a critical question for creationists: If human scientists can find solutions to such devastating genetic problems, why can't—or won't—your purported intelligent designer? And perhaps, more to the point, why was this defect designed in the first place?

What information do you have on the Mitochondrial diseases caused by POLG mutations?

Mitochondrial diseases resulting from mutations in the POLG gene encompass a spectrum of disorders characterized by impaired mitochondrial DNA (mtDNA) replication and maintenance. The POLG gene encodes the catalytic subunit of DNA polymerase gamma, the sole enzyme responsible for mtDNA replication. Mutations in this gene can lead to mtDNA depletion or multiple deletions, disrupting cellular energy production and affecting various organ systems.

Epidemiology

POLG mutations are among the most prevalent single-gene causes of mitochondrial diseases, accounting for approximately 10% of adult cases in certain populations. They are notably the leading cause of mitochondrial epilepsy across all age groups and are implicated in 10–25% of progressive external ophthalmoplegia (PEO) and over 10% of ataxia cases.

Clinical Manifestations

The phenotypic spectrum of POLG-related disorders is broad, with manifestations varying based on the specific mutation and age of onset. Key syndromes include:

Alpers-Huttenlocher Syndrome (AHS): Typically presenting in early childhood, AHS is characterized by progressive encephalopathy, intractable seizures, and liver failure.
Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA): This condition involves myoclonic seizures, muscle weakness, and sensory ataxia.
Ataxia Neuropathy Spectrum (ANS): Patients exhibit symptoms such as ataxia, peripheral neuropathy, and, in some cases, seizures.
Progressive External Ophthalmoplegia (PEO): Characterized by weakness of the eye muscles leading to drooping eyelids (ptosis) and difficulty moving the eyes.

Additional symptoms across POLG-related disorders can include muscle weakness, developmental delays, movement disorders, depression, and anxiety.

Diagnosis

Diagnosing POLG-related mitochondrial diseases involves a combination of clinical evaluation and genetic testing. Molecular genetic testing for POLG mutations is essential to confirm the diagnosis. Supplementary assessments may include brain imaging (MRI or CT scans) to detect characteristic changes and electroencephalograms (EEGs) to evaluate for seizure activity.

Management and Prognosis

Currently, there is no definitive cure for POLG-related disorders. Management focuses on symptomatic treatment and supportive care, including antiepileptic drugs for seizures, physical therapy for muscle weakness, and psychological support for associated mood disorders. The prognosis varies depending on the specific syndrome and severity of manifestations. Early diagnosis and tailored interventions are crucial in optimizing patient outcomes.

Ongoing research aims to better understand the pathophysiology of POLG mutations and develop targeted therapies to improve the quality of life for affected individuals.

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The breakthrough is in identifying a molecule that restores the function of mutated DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients with the POLG mutation.

The discovery was made by a team led by Professors Maria Falkenberg and Claes Gustafsson, at Sahlgrenska Academy at the University of Gothenburg. Their findings are published, open access, in Nature and explained in a University of Gothenburg press release:

Treatment for mitochondrial diseases within reach
A medical breakthrough could result in the first treatment for rare but serious diseases in which genetic defects disrupt cellular energy production. Researchers at the University of Gothenburg have identified a molecule that helps more mitochondria function properly.
Mitochondrial diseases caused by POLG mutations vary in severity. In young children, these diseases can quickly result in brain damage and life-threatening liver problems while others suffer muscle weakness, epilepsy, and organ failure later in childhood. POLG mutations recently received media attention when Prince Frederik of Nassau in Luxembourg died in March 2025 at just 22 years of age.

The POLG gene regulates the production of DNA polymerase gamma, an enzyme that copies mitochondrial DNA. Without it, the mitochondria cannot function normally and, as a result, fail to provide the cell with energy.

A breakthrough

Maria Falkenberg and Claes Gustafsson, professors at Sahlgrenska Academy at the University of Gothenburg, have led the work behind the study now being published in the journal Nature.

We demonstrate that the molecule PZL-A can restore the function of mutated DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients. This improves the ability of the mitochondria to provide the cell with energy.

Professor Maria Falkenberg, co-corresponding author.
Department of Medical Biochemistry and Cell Biology
University of Gothenburg, Gothenburg, Sweden.

This is a breakthrough as for the first time we can demonstrate that a small molecule can help improve the function of defective DNA polymerase. Our results pave the way for a completely new treatment strategy.

Professor Claes M. Gustafsson, co-corresponding author.
University of Gothenburg, Gothenburg, Sweden.

From lab to medication

More than twenty years of basic research led to the discovery of PZL-A. The molecule was identified following the analysis of hundreds of chemical compounds in collaboration with Pretzel Therapeutics, where another one of the lead authors of the study, Simon Giroux, has led the chemical development of the molecule. So far, the molecule has been studied in cells from patients as well as in animal models.

The PZL-A molecule binds between two subunits of POLγ (POLγA and POLγB) and stabilizes the enzyme’s interaction with DNA.

Photo: Sebastian Valenzuela.

Sebastian Valenzuela, a doctoral student at Sahlgrenska Academy, has analyzed the molecule’s structure, including by means of cryo-electron microscopy.

We demonstrate exactly where the molecule binds, between two separate chains of the enzyme. The binding site is extremely specific, which helps us understand how the enzyme works and how we can influence it.

Sebastian Valenzuela, first author.
University of Gothenburg, Gothenburg, Sweden.

Pretzel Therapeutics has just embarked on phase I studies with a refined version of the molecule in order to test its safety on healthy volunteers. Since a lack of mitochondrial DNA is also seen in other mitochondrial, age-related, and neurodegenerative diseases, substances similar to PZL-A may gain broader therapeutic use.

Pretzel Therapeutics is part of the Gothenburg region’s life science cluster, with its Swedish operations conducted at GoCo Health Innovation City and its headquarters located in Waltham, Massachusetts, just outside Boston.

Publication:
Valenzuela, S., Zhu, X., Macao, B. et al.
Small molecules restore mutant mitochondrial DNA polymerase activity. Nature (2025). https://doi.org/10.1038/s41586-025-08856-9

Abstract
Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits¹. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists². Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

Main
Mitochondria are central to health and disease, and dysfunctions in mitochondria are linked to cardiovascular diseases, neurodegeneration, metabolic syndrome and cancer^3,4. Mammalian mtDNA encodes essential protein subunits of the oxidative phosphorylation (OXPHOS) complexes, which are responsible for producing the majority of cellular ATP1. POLG mutations are a leading cause of inherited mitochondrial disorders, and many different disease-causing mutations have been described^2,5 (https://tools.niehs.nih.gov/polg/). These mutations impair POLγ activity and lead to mtDNA depletion and/or deletions in affected patients². Whereas most mutations are rare, a subset of three amino acid substitutions, A467T, W748S and G848S, has been identified in about 70% of affected patients². Disorders caused by POLG mutations encompass a spectrum of overlapping clinical presentations, and the age at which symptoms first appear generally corresponds to the specific clinical features that are observed. Early onset (0–12 years of age) is associated with severe mtDNA depletion and a very short life expectancy, often less than a year. Symptoms include global developmental delay, seizures, hypotonia, muscle weakness and liver dysfunction. In the juvenile or adult-onset form (12–40 years of age), peripheral neuropathy, ataxia, seizures, stroke-like episodes and progressive external ophthalmoplegia are observed. In the late-onset form (after 40 years of age), ptosis and progressive external ophthalmoplegia are predominant, along with peripheral neuropathy, ataxia and muscle weakness. So far, there have been no effective therapeutic strategies available to treat or cure these severe, progressive disorders⁶.

PZL-A stimulates POLγ activity
We set out to identify compounds that could stimulate POLγ activity and mitigate the phenotypes associated with impaired enzyme function. Given the extensive heterogeneity of pathogenic mutations identified in the POLG gene, a therapeutic strategy targeting individual mutations is not feasible. Instead, we hypothesized that a molecule capable of enhancing the activity of wild-type POLγ might also be effective across various POLγ mutations. Therefore, we initially screened compounds against wild-type POLγ and subsequently focused our studies on the disease-associated variants of POLγ.

An initial screen of approximately 270,000 compounds led to the discovery of compound 1 (Fig. 1a). When evaluated in a high-throughput recombinant in vitro DNA synthesis assay (Fig. 1b), compound 1 displayed modest half-maximal activity concentration (AC₅₀, the concentration required to achieve 50% of the maximum effect) for wild-type POLγ and two mutant forms, A467T and G848S. Compound 1 underwent further hit-to-lead optimization, leading to the more potent PZL-A (Fig. 1a). PZL-A exhibited a robust stimulatory effect on common, disease-causing forms of POLγ, including mutations in the exonuclease domain (R232H), the DNA polymerase domain (A467T and G848S), and the intervening linker region (W748S) of POLγA. Across all these mutations, PZL-A exhibited AC₅₀ values in the nanomolar range (20–200 nM) and aided a recovery of enzymatic activity relative to wild-type (Fig. 1c). The stimulatory effect was apparent across a broad range of dNTP concentrations (Extended Data Fig. 1a).

Fig. 1: PZL-A activates mutant POLγ.

a, Chemical structure of compound 1, a high-throughput screening hit, and PZL-A, a more potent compound produced by a medicinal chemistry optimization effort. AC50 values are shown for two POLγ mutants and wild-type. b, Schematic representation of the primer-elongation assay used for hit-to-lead optimization of POLγ activators. A short 20-nucleotide (nt) primer was annealed to circular, single-stranded M13mp18 DNA, providing a preexisting 3′-OH group from which POLγ could initiate DNA synthesis. POLγ activity was followed by monitoring the increase of SYBR Green fluorescence over time as the dye bound to newly formed dsDNA. Drawing by Jennifer Uhler (copyright holder). c, Increasing concentrations of PZL-A activate the indicated mutant POLγ variants in a dose-dependent manner (mean ± s.d.; n = 3 independent experiments). d, Steady-state kinetics of dNMP incorporation (mean ± s.d.; WT: n = 4; mutants: n = 3 independent experiments). Rates were determined by dividing the initial incorporation rates by the concentration of active enzyme–DNA complex (Extended Data Fig. 1b). PZL-A enhances catalytic efficiency in all four mutants. e, Representative plots of differential scanning fluorimetry performed with POLγA mutants (R232H, A467T, W748S and G848S) in complex with POLγB, in the absence or presence of 10 μM PZL-A. Values are presented as normalized fluorescence (F_norm) in arbitrary units (a.u.). The presence of PZL-A induces a shift in melting temperature in all four POLγA mutants and is given as ΔT_m (mean ± s.d.; n = 3 independent experiments). For source data of blots in d, see Supplementary Figs. 1 and 2.

Analysis of kinetic parameters, calculated using the Michaelis–Menten steady-state model, revealed that PZL-A enhances the rate of dNTP incorporation (Fig. 1d, Extended Data Fig. 1b, Table 1). We observed an increase of measured maximum saturated reaction rate (V_max) and the overall reaction rate constant (k_cat), with milder effects on the apparent Michaelis constant (K_{m_app, dNTP}). In addition to its C-terminal DNA polymerase domain, POLγA also contains an N-terminal 3′–5′ exonuclease domain that is crucial for proofreading during mtDNA synthesis^7,8,9. We monitored whether PZL-A could influence exonuclease activity of mutant POLγ variants but observed no negative effects; all mutants were able to perform proofreading in the presence of PZL-A (Extended Data Fig. 1c–f).

We also confirmed that PZL-A interacts directly with the POLγ holoenzyme by monitoring effects on thermal stability. The compound had a stabilizing effect, increasing the unfolding temperature of all the mutant POLγA variants tested¹⁰ (Fig. 1e).

a, Overview of overlaid POLγ(A467T) (blue), POLγ(G848S) (pink) and wild-type POLγ (green) heterotrimeric structures. b, Close-up of A467, A467T and nearby residues. c, Close-up of G848, G848S, DNA and nearby residues. The base pairs in the DNA template strand are numbered according to their proximity to the nucleotide insertion site (n). The introduced serine forms a hydrogen bond (dashed line) with the backbone carbonyl of V845. d, Close-up of the polymerization site while stalled during elongation. The incoming dCTP base pairs with the template strand at the nucleotide insertion site (n). e, Cartoon representation of the cryo-EM structure of PZL-A bound to POLγ(G848S). The binding pocket is highlighted with the cryo-EM density for PZL-A (cyan). PZL-A binds POLγ in a pocket at the interface between POLγA and the proximal POLγB subunit. f, Close-up of PZL-A and its cryo-EM density in the binding pocket. g, The structures of G848S-PZL-A (colours as in e,f) and A467T-PZL-A (grey) superimposed on wild-type POLγ (green). PZL-A forms a hydrogen bond with POLγA (G588, 2.7 Å) and an intramolecular hydrogen bond between the urea and pyrazole groups (2.7–2.8 Å). h, G848S (pink) and G848S-PZL-A (light purple) structures overlaid on the wild-type POLγ (green) structure at the mutation site. The secondary structure is not affected by the mutation or PZL-A. i, Superimposition of the G848S (pink) and G848S-PZL-A (light purple) structures at the binding site of PZL-A. Minor positional changes of nearby residues can be observed upon binding of PZL-A, and the directions of these adjustments are shown with arrows.

Valenzuela, S., Zhu, X., Macao, B. et al.
Small molecules restore mutant mitochondrial DNA polymerase activity. Nature (2025). https://doi.org/10.1038/s41586-025-08856-9

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)

It's hard to explain why an intelligent designer would create a defective gene in the first place; it's even harder to explain why it was unable to produce the cure that this team of scientists appears to have produced, unless, of course, it didn't want to, if its intention was malevolent…

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