Rosa Rubicondior: Unintelligent Design - The Design Defect That Can Cause a Cleft Palate

Medical science corrects a design defect.

New study reveals how cleft lip and cleft palate can arise | MIT News | Massachusetts Institute of Technology

In my book, The Body of Evidence: How the Human Body Refutes Intelligent Design, I present numerous examples demonstrating that the human body is not the product of intelligent design, but rather the outcome of an evolutionary process characterised by compromises and suboptimal solutions. Evolution is constrained by what it has to work with and must continually balance competing demands—for instance, short-term reproductive success versus long-term health and well-being, which often contribute little or nothing to the long-term propagation of genes.

The result is an error-prone and overly complex system built upon earlier suboptimal compromises. This complexity gives rise to the many defects and medical problems to which humans are prone—problems that would not exist if the human body were the creation of an intelligent and benevolent designer, such as the deity posited by creationist belief systems. Such a deity would surely have designed a body so robust that there would be little need for a medical profession, save perhaps for treating accidental trauma. The very existence of hospitals and medical science stands as a testament to the failure of the human body's design to approach anything resembling the perfection many creationists claim.

Now, researchers at the Massachusetts Institute of Technology (MIT) have identified yet another example of this flawed complexity: a defect in transfer RNA (tRNA) linked to babies being born with a cleft lip and palate. The defect lies in the DDX1 gene, which is essential for proper tRNA function. Without it, tRNA cannot deliver amino acids to ribosomes to synthesise proteins. In the absence of this crucial process, the cells that form the upper lip and the roof of the mouth cannot fuse correctly during development.

The findings, by a team led by Michaela Bartusel, are published in The American Journal of Human Genetics.

What is the function of the DDX1 gene and what problems does disruption of its function by mutation cause? What is the DDX1 Gene?

DDX1 is a gene that encodes a protein belonging to the DEAD-box family of RNA helicases—enzymes that help unwind RNA molecules. These proteins play a critical role in various processes involving RNA, such as:

Transcription
Splicing
Transport
Translation
tRNA and rRNA processing

The DDX1 protein is especially important in the processing and transport of transfer RNA (tRNA), which is vital for protein synthesis. tRNA molecules carry amino acids to the ribosomes, where proteins are assembled. If tRNA function is disrupted, cells cannot produce the proteins needed for proper development.

When DDX1 Goes Wrong

A mutation in the DDX1 gene can impair its ability to support normal tRNA function. As a result:

The transport of amino acids is disrupted.
Protein synthesis is compromised.
Rapidly developing tissues—such as those forming the face and skull—may not form correctly.

This disruption can lead to craniofacial defects such as cleft lip and cleft palate, where the tissues of the upper lip and the roof of the mouth fail to fuse during embryonic development.

The discovery of DDX1’s role in these congenital anomalies adds to the growing list of biological vulnerabilities that make more sense in the context of evolutionary biology than of intelligent design.

New study reveals how cleft lip and cleft palate can arise
MIT biologists have found that defects in some transfer RNA molecules can lead to the formation of these common conditions.
Cleft lip and cleft palate are among the most common birth defects, occurring in about one in 1,050 births in the United States. These defects, which appear when the tissues that form the lip or the roof of the mouth do not join completely, are believed to be caused by a mix of genetic and environmental factors.

In a new study, MIT biologists have discovered how a genetic variant often found in people with these facial malformations leads to the development of cleft lip and cleft palate.

Their findings suggest that the variant diminishes cells’ supply of transfer RNA, a molecule that is critical for assembling proteins. When this happens, embryonic face cells are unable to fuse to form the lip and roof of the mouth.

Until now, no one had made the connection that we made. This particular gene was known to be part of the complex involved in the splicing of transfer RNA, but it wasn’t clear that it played such a crucial role for this process and for facial development. Without the gene, known as DDX1, certain transfer RNA can no longer bring amino acids to the ribosome to make new proteins. If the cells can’t process these tRNAs properly, then the ribosomes can’t make protein anymore.

Michaela Bartusel, lead author
Department of Biology
Massachusetts Institute of Technology
Cambridge, MA, USA.

Eliezer Calo, an associate professor of biology at MIT, is the senior author of the paper, which appears today in the American Journal of Human Genetics.

Genetic variants

Cleft lip and cleft palate, also known as orofacial clefts, can be caused by genetic mutations, but in many cases, there is no known genetic cause.

The mechanism for the development of these orofacial clefts is unclear, mostly because they are known to be impacted by both genetic and environmental factors. Trying to pinpoint what might be affected has been very challenging in this context.

Associate Professor Eliezer Calo, senior author.
Department of Biology
Massachusetts Institute of Technology
Cambridge, MA, USA.

To discover genetic factors that influence a particular disease, scientists often perform genome-wide association studies (GWAS), which can reveal variants that are found more often in people who have a particular disease than in people who don’t.

For orofacial clefts, some of the genetic variants that have regularly turned up in GWAS appeared to be in a region of DNA that doesn’t code for proteins. In this study, the MIT team set out to figure out how variants in this region might influence the development of facial malformations.

Their studies revealed that these variants are located in an enhancer region called e2p24.2. Enhancers are segments of DNA that interact with protein-coding genes, helping to activate them by binding to transcription factors that turn on gene expression.

The researchers found that this region is in close proximity to three genes, suggesting that it may control the expression of those genes. One of those genes had already been ruled out as contributing to facial malformations, and another had already been shown to have a connection. In this study, the researchers focused on the third gene, which is known as DDX1.

DDX1, it turned out, is necessary for splicing transfer RNA (tRNA) molecules, which play a critical role in protein synthesis. Each transfer RNA molecule transports a specific amino acid to the ribosome — a cell structure that strings amino acids together to form proteins, based on the instructions carried by messenger RNA.

While there are about 400 different tRNAs found in the human genome, only a fraction of those tRNAs require splicing, and those are the tRNAs most affected by the loss of DDX1. These tRNAs transport four different amino acids, and the researchers hypothesize that these four amino acids may be particularly abundant in proteins that embryonic cells that form the face need to develop properly.

When the ribosomes need one of those four amino acids, but none of them are available, the ribosome can stall, and the protein doesn’t get made.

The researchers are now exploring which proteins might be most affected by the loss of those amino acids. They also plan to investigate what happens inside cells when the ribosomes stall, in hopes of identifying a stress signal that could potentially be blocked and help cells survive.

Malfunctioning tRNA

While this is the first study to link tRNA to craniofacial malformations, previous studies have shown that mutations that impair ribosome formation can also lead to similar defects. Studies have also shown that disruptions of tRNA synthesis — caused by mutations in the enzymes that attach amino acids to tRNA, or in proteins involved in an earlier step in tRNA splicing — can lead to neurodevelopmental disorders.

Defects in other components of the tRNA pathway have been shown to be associated with neurodevelopmental disease,” Calo says. “One interesting parallel between these two is that the cells that form the face are coming from the same place as the cells that form the neurons, so it seems that these particular cells are very susceptible to tRNA defects.

Associate Professor Eliezer Calo

The researchers now hope to explore whether environmental factors linked to orofacial birth defects also influence tRNA function. Some of their preliminary work has found that oxidative stress — a buildup of harmful free radicals — can lead to fragmentation of tRNA molecules. Oxidative stress can occur in embryonic cells upon exposure to ethanol, as in fetal alcohol syndrome, or if the mother develops gestational diabetes.

I think it is worth looking for mutations that might be causing this on the genetic side of things, but then also in the future, we would expand this into which environmental factors have the same effects on tRNA function, and then see which precautions might be able to prevent any effects on tRNAs.

Michaela Bartusel

Summary
Orofacial clefts are the most common form of congenital craniofacial malformation worldwide. The etiology of these birth defects is multifactorial, involving genetic and environmental factors. However, in most cases, the underlying causes remain unexplained, precluding a molecular understanding of disease mechanisms. Here, we integrated genome-wide association data, targeted resequencing of case and control cohorts, tissue- and cell-type-specific epigenomic profiling, and genome architecture analyses to molecularly dissect a genomic locus associated with an increased risk of non-syndromic orofacial cleft. We found that common and rare risk variants associated with orofacial cleft intersect with an enhancer (e2p24.2) that is active in human embryonic craniofacial tissue. We mapped e2p24.2 long-range interactions to a topologically associated domain harboring MYCN, DDX1, and CYRIA. We found that M and DDX1, but not CYRIA, are required during craniofacial development in chicken embryos. We investigated the role of DDX1, a key component of the tRNA splicing complex, in cranial neural crest cells (cNCCs). The loss of DDX1 in cNCCs resulted in the accumulation of unspliced tRNA fragments, depletion of mature intron-containing tRNAs, and ribosome stalling at codons decoded by these tRNAs. This was accompanied by defects in both global protein synthesis and cNCC migration. We further showed that the induction of tRNA fragments is sufficient to disrupt craniofacial development. Together, these results uncovered a molecular mechanism in which impaired tRNA splicing affects cNCCs and craniofacial development and positioned MYCN, DDX1, and tRNA processing defects as risk factors in the pathogenesis of orofacial clefts.

Graphical abstract

Bartusel, Michaela; Kim, Skylar X.; Rehimi, Rizwan; Darnell, Alicia M.; Nikolić, Miloš; Heggemann, Julia; Kolovos, Petros; van Ijcken, Wilfred F.J.; Varineau, Jade; Crispatzu, Giuliano; Mangold, Elisabeth; Brugmann, Samantha A.; Vander Heiden, Matthew G.; Laugsch, Magdalena; Ludwig, Kerstin U.; Rada-Iglesias, Alvaro; Calo, Eliezer
A non-syndromic orofacial cleft risk locus links tRNA splicing defects to neural crest cell pathologies The American Journal of Human Genetics (2025), DOI: 10.1016/j.ajhg.2025.03.017.

© 2025 Elsevier.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

The challenge for advocates of intelligent design is to account for such flaws as this in human biology. Within the framework of intelligent design, are defects like this the result of incompetence — a failure to create a robust system resilient to random errors that cause suffering to innocent children? Or are they the consequence of deliberate, malevolent design, intended to inflict suffering arbitrarily? Alternatively, are they better explained by a mindless, utilitarian evolutionary process in which no deity is involved, and thus bears no responsibility?

In other words, is the god of creationism an interventionist but either incompetent or malevolent being, or a detached observer, unwilling or unable to intervene to prevent harm?

Perhaps unsurprisingly, fellows of the Discovery Institute and other intelligent design apologists rarely, if ever, confront these uncomfortable questions - questions to which any genuinely held theory of biological origins should be prepared to offer clear and honest answers.

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