Rosa Rubicondior: Malevolent Design - Why Autism Refutes Intelligent Design

Evolution's well-tinkered machine.

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Autism Research Breakthrough Discovered by Hebrew University Researchers | en.new.huji

Researchers at the Hebrew University of Jerusalem have uncovered a mechanism that leads to autism. If this is the product of intelligent design then the designer is either incompetent or malevolent, but as so often with diseases that arise when systems go wrong, it is exactly what we expect of an evolved process. Their paper has just been published open access in the journal Molecular Psychiatry.

For proponents of Intelligent Design such as Michael Behe and William Dembski, biological systems are supposed to bear the hallmarks of careful engineering — intricate machines whose parts work together with purpose and precision. But the mechanism uncovered in this study looks nothing like the output of a competent engineer. Instead, it reveals a fragile regulatory network in which a single biochemical modification destabilises a key control protein and sends an entire signalling pathway out of balance. The result is a cascade of downstream effects that ultimately alters brain development and behaviour.

What the researchers have uncovered is not a piece of irreducibly complex machinery but a regulatory system that can be knocked off course by a small perturbation. Nitric-oxide signalling modifies the protein TSC2, leading to its degradation and the subsequent overactivation of the mTOR pathway — a pathway that controls cellular growth and protein synthesis throughout the body. In other words, the pathology arises because a normal biological control system fails to maintain the delicate balance on which it depends.

This is precisely the sort of vulnerability we expect from systems produced by evolution. Evolution does not design organisms from scratch with perfect foresight; it works with what already exists, modifying and repurposing pathways that originally evolved for other purposes. The result is a network of interacting components that usually works well enough to keep organisms alive and reproducing, but which inevitably contains points where the system can fail. When those failures occur, the consequences can be severe.

Far from supporting Intelligent Design, discoveries like this highlight the jury-rigged nature of biological systems. They show that life’s complexity arises not from optimal engineering but from the gradual accumulation of workable solutions over evolutionary time — solutions that function most of the time, yet remain vulnerable to the occasional catastrophic malfunction.

Evolutionary “Tinkering” and Biological Complexity. The French evolutionary biologist François Jacob famously described evolution not as an engineer but as a tinkerer. Unlike an engineer who designs a system from scratch with a clear blueprint, evolution works only with what already exists. New functions arise by modifying, reusing, and recombining existing biological parts that originally evolved for different purposes.

Over millions of years this process produces systems that work well enough, but they are rarely elegant or optimally designed. Instead of clean, streamlined architectures, biological pathways often accumulate extra layers of regulation, duplicated components, and overlapping feedback loops. These additions can improve survival in particular circumstances, but they also make the system increasingly complex and vulnerable to disruption.

As a result, biological networks frequently contain single points of failure, delicate regulatory balances, and chemical modifications that can destabilise critical proteins. When one element in such a network is disturbed, the effects can cascade through multiple interacting pathways, sometimes producing serious disease.

This kind of over-complex, error-prone architecture is exactly what we would expect from a long history of evolutionary modification. It is the natural consequence of countless small adjustments made over deep time. By contrast, a competent engineer designing a system from scratch would normally aim to minimise unnecessary complexity and avoid mechanisms that allow minor perturbations to trigger widespread malfunction.

In this sense, the intricate but fragile regulatory networks found throughout biology are not signatures of careful design, but hallmarks of evolution’s long history of improvisation.

The research is outlined in a news item from the Hebrew University of Jerusalem.

Autism Research Breakthrough Discovered by Hebrew University Researchers
For the first time a new study led by Dr. Haitham Amal and his team from the School of Pharmacy in the Faculty of Medicine at the Hebrew University of Jerusalem, discovered a direct connection between levels of nitric oxide (NO) in the brain and autism. The study was published today in the prestigious Advanced Science journal.
Millions of people in the world are diagnosed with autism spectrum disorder every year. In Israel, more than 30,000 children up to the age of 18 have been diagnosed with autism. In the United States, autism is the most common developmental disorder, with one in 44 people under the age of 21 on the spectrum.

The study demonstrated that autism indicators increase as NO increases in the brain, uncovering a new mechanism found in autism. Conversely, in cases where levels of NO in the brains of murine models of autism were lowered in a proactive and controlled manner, autism indicators and behavior decreased accordingly. The Amal Lab members who led this study were Dr. Manish Tripathi, Mr. Shashank Ojha, Ms. Maryam Kartawy, and Ms. Wajeha Hamoudi.

Our research showed – in an extraordinary way – that inhibiting the production of NO, specifically in brain neuron cells in mouse models of autism, causes a decrease in autism-like symptoms. By inhibiting the production of NO on laboratory animals, they became more 'social' and less repetitiveness was observed in their behavior. Additionally, the animals showed interest in new objects and were less anxious. Finally, the decrease in NO levels led to a significant improvement in neuronal indices.

The results on mouse models were correlated with stems cells that were taken from autistic kids as well with blood samples taken from autistic low functioning kids.

Dr. Haitham Amal, senior author.
Institute for Drug Research
School of Pharmacy, Faculty of Medicine
The Hebrew University of Jerusalem
Jerusalem, Israel.

In addition to several mouse models of autism, the study results are based on tests conducted using human stem cells and clinical blood samples from children with low-functioning autism.

This research is a significant breakthrough in autism research with the first direct connection made between an increase in the concentration of NO in the brain and autistic behavior. This discovery can have implications on the relationship of NO with other neurological diseases, such as Alzheimer's, or psychiatric diseases, such as schizophrenia and bipolar disorder. I am hopeful that with our new understanding of the NO mechanism, we can begin to develop therapeutic drugs and help millions of children and adults living with autism around the world.

Dr. Haitham Amal.

Publication:
Ojha, S.K., Kartawy, M., Hamoudi, W. et al.
Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder.
Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03514-6

Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by core behavioral symptoms. We previously showed that nitric oxide (NO) plays a key role in ASD. However, the precise molecular mechanism through which NO acts via its posttranslational modification, S-nitrosylation (SNO), in ASD remains largely unknown. Emerging evidence, including our previous studies, suggests that the mechanistic target of the rapamycin (mTOR) signaling pathway plays a critical role in ASD pathophysiology. Our SNO-proteome systems biology analysis showed the enrichment of the mTOR pathway. In this study, we deciphered a novel mechanism of the cross talk between NO and mTOR pathway using two well-established mouse models as well as clinical samples of children with ASD. To assess changes in the SNO-proteome, we used the SNOTRAP method, revealing increased S-nitrosylation of tuberous sclerosis complex 2 (TSC2) in Shank3^Δ4–22 and Cntnap2^(-/-) mutant mice. We proved that this modification led to the loss of TSC2 protein via ubiquitination, resulting in dysregulated mTOR signaling in both excitatory and inhibitory neurons. Pharmacological inhibition of neuronal nitric oxide synthase (nNOS) successfully prevented TSC2 S-nitrosylation, mTOR overactivation, and altered protein translation in ASD models, highlighting NO’s role in modulating mTOR function. To further validate the role of TSC2 S-nitrosylation in ASD, we generated a cysteine-to-serine mutation (C203S) in TSC2 to prevent its S-nitrosylation. Intracranial injection of the mutant TSC2 (C203S) in Shank3^Δ4–22 mice in the prefrontal cortex prevented ASD-like behaviors, confirming the pathogenic role of NO-mediated TSC2 modification. Critically, analysis of clinical samples from children with ASD, including those with SHANK3 mutations and idiopathic ASD, revealed reduced TSC2 levels and increased mTOR signaling activity, further validating our findings. Collectively, this study uncovers a novel molecular mechanism by which S-nitrosylation disrupts TSC2 function, leading to aberrant mTOR signaling and ASD-like phenotypes. By revealing a unique SNO-TSC2-mTOR axis, our work deciphers the novel nitric oxide-mediated mTOR activation and opens new avenues for targeted therapeutic strategies in ASD, including those carrying SHANK3 mutations.

Ojha, S.K., Kartawy, M., Hamoudi, W. et al.
Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder.
Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03514-6

Copyright: © 2026 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

Once again, the discovery does not reveal the handiwork of an intelligent designer but the workings of a complex biological system that can occasionally go wrong in very specific ways. The researchers have identified a precise biochemical mechanism by which a small molecular modification destabilises an important regulatory protein, allowing a major signalling pathway to run out of control. This sort of cascading failure is exactly what we expect in a deeply interconnected regulatory network where many processes depend on a delicate balance between opposing signals.

It is also another illustration of the point made decades ago by François Jacob: evolution works not like an engineer designing a machine from scratch, but like a tinkerer modifying existing parts. Over hundreds of millions of years, biological systems accumulate layers of regulation, feedback loops, and repurposed components. These systems are remarkably effective most of the time, but their complexity also means that small disturbances can sometimes propagate through the network with unexpected consequences.

Ironically, it is often the study of disease that reveals these underlying compromises most clearly. When a mutation, chemical modification, or environmental influence disrupts one part of a signalling pathway, the resulting pathology exposes the intricate web of interactions that normally keeps the system functioning. Far from being evidence of intelligent design, such vulnerabilities are exactly what we should expect from structures that have evolved through countless incremental modifications rather than through deliberate planning.

So instead of supporting claims that biological systems were intelligently engineered, studies like this reinforce one of the central insights of evolutionary biology: living organisms are the products of a long history of improvisation. They work well enough to survive and reproduce, but their complexity carries an inevitable cost — the occasional catastrophic malfunction when one small part of the system fails.

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