Unintelligent Design - How Creationism's Incompetent Designer Tries To Fix It's Bad Design

New Study Reveals Crucial 'Housekeeping' Genetic Elements and Their Potent Role to Fight Cancer｜THE INSTITUTE OF MEDICAL SCIENCE, THE UNIVERSITY OF TOKYO

The thing about Creationism's putative intelligent [sic] designer is that it isn't just your common or garden variety of jobbing designer; it is allegedly omniscient, omnipotent and perfect, so anything it designs should be perfectly designed to do exactly what it does, nothing more and nothing less. Creationists need to ignore that aspect of its designs when it comes to the problem of all the parasites that live on and in the animals and plants it supposedly created or they need to perform some double-think mental gymnastics and blame something else which, even though their putative intelligent designer is the only entity capable of designing anything living, also designs things.

Creationists also need to ignore the fact that good design is minimally complex and pretend it’s a hallmark of good design. But imagine a manufacturing process that is so badly designed that it needs whole layers of sub-processes to correct the mistakes, and then those sub-processes need more sub-processes to correct their mistakes!

Presumably, a creationist would look at that system with its vast array of monitoring and error corrections as evidence of intelligent design, regardless of the waste and inefficiency built into the system. In reality, of course, any competent process designer would get it right first time, or would scrap a bad design and start over, learning the lessons of earlier failures, so designing the perfect system with minimal complexity and minimal waste should not be beyond the wit of a perfect, omnipotent omniscient designer, should it?

Alas, what we see in nature is nothing like perfectly designed processes; instead, we see muddle, waste and inefficiency with layer upon layer of sub-processes simply to cope with the errors in the processes.

An example of just this situation inside the cells of our allegedly intelligently design bodies was discovered recently by a team of researchers from the Laboratory of Functional Analysis in silico (Nakai-lab) at The Institute of Medical Science, The University of Tokyo, Japan, led by Professor Kenta Nakai, head of the laboratory, and Dr. Martin Loza, Assistant Professor, in collaboration with Dr. Alexis Vandenbon, Associate Professor, from the Institute of Life and Medical Sciences, Kyoto University, Japan. Their work was published, open access, in Nucleic Acids Research on December 12, 2023.

The team found as many as 11,000 gene regulators, all needed for basic 'housekeeping' and error corrections within the cell. These are known as housekeeping cis-regulatory elements (HK-CREs). These elements are vital in maintaining cellular stability beyond conventional gene regulation, influencing diverse cellular functions across healthy cell types. Moreover, a subset of these housekeeping elements, particularly those related to zinc finger genes, was found to have reduced activity in diverse cancers, suggesting their role as potential housekeeping tumor suppressors.

These HK-CREs were believed to be simple on/off switches that regulated the activity of housekeeping genes, but that was far too simple for whatever designed this complex process, of course. The Japanese team found that these switches aren't only important for the enhancement of specific genes but are crucial for the basic functions that keep our cells healthy. In other words, they are needed to clean up and correct the mistakes in the basic cell functions.

Given the significant association between cancer and mutations in epigenetic components, every small insight we gain could be key in the ongoing battle against this disease, which has tragically claimed innumerable lives. Through extensive bioinformatics analyses, we aimed to emphasize HK-CREs profound impact on fundamental cellular processes, including their potential as essential housekeeping tumor suppressors.

Assistant professor Dr. Martin Loza, lead author
The Institute of Medical Science
The University of Tokyo, Japan

To summarise at this point then, the housekeeping genes (HKRs) are needed to clean up the errors and mess of a badly designed process, but then they need more genes (HK-CREs) to regulate their activity!

But it gets worse!

The research team found that HK-CREs were not solely confined to regulating the well-studied housekeeping genes (HKGs), which only constituted less than 20% of the genes associated with these elements. Instead, these elements predominantly resided within core promoter regions of many more genes (around 8,000), indicating a broader regulatory role beyond typical housekeeping gene functions. By employing bioinformatics analyses and levering diverse public datasets, the team validated the robustness of HK-CREs across 50 randomly selected healthy cell types, confirming the location of HK-CREs within the genome. These elements were highly conserved, residing in unmethylated CpG-rich regions, a trait strongly associated with their housekeeping regulatory function.

A reminder at this point: the 'unmethylated' regions of the genome are the genes which have not been switched off by the complex epigenetics system. This system is needed because the cells of multicellular organisms are specialised for particular functions but are replicated by the same process that is used by single-celled organisms that need their entire genome to be replicated each time they divide.

However, in the specialised cells of multicellular organisms, only a few genes are needed for each cell type, so the rest have to be turned off. The evolutionary explanation for this is simply because multicellular organisms evolved from single-celled organisms and simply retained the cell-replicating mechanisms of their ancestors.

The Japanese team also found that failure of this overly complex system is the cause of cancers - something that any omniscient designer should have foreseen!

The team remarked on the intricate cooperative interactions among housekeeping core promoters (HK-CPs), forming complex regulatory networks through promoter–promoter interactions. These observations hint at the significant influence of such interactions not only on HKGs but also on genes specific to various cell types. Turning their attention to cancer cells, researchers discovered a subset of HK-CREs displaying reduced activity in diverse cancer subtypes due to aberrant methylation, particularly those linked to zinc finger genes clustered in sub-telomere regions of chromosome 19. Identifying genes such as ZNF135, ZNF154, ZNF667, and ZNF667-AS1 under the influence of these foundational core promoters, the research suggests their potential as housekeeping tumor suppressor genes.

Genes detected in our study have exhibited decreased activity in multiple cancer cell lines, and survival analysis across various cancer projects have revealed significant increases in survival probability in diverse cancer types like pancreas adenocarcinoma and uveal melanoma.

Assistant professor Dr. Martin Loza.

In essence, the results of this research have uncovered a previously unknown class of HK-CREs critical for cellular stability, extending their influence beyond housekeeping gene regulation.

Our discovery on housekeeping tumor suppressor genes unveils a novel avenue in cancer therapy, harnessing the intrinsic elements within the DNA of every cell. Future approaches to cancer treatment, focusing on these housekeeping tumor suppressor genes, offer a unique solution that could potentially target a broad range of cancers, sidestepping the challenges associated with personalized medicine. Our findings on housekeeping cis-regulatory elements fill a big gap in the current knowledge regarding gene regulatory processes. We anticipate that our findings will enhance the understanding of these processes and serve as a valuable resource for researchers striving to uncover elements inherent in the genome for combating various diseases.

>Assistant professor Dr. Martin Loza.

There is no comfort for creationists to be found in the team's published paper, so they'll probably want to avoid reading it:

Abstract

In this research, we elucidate the presence of around 11,000 housekeeping cis-regulatory elements (HK-CREs) and describe their main characteristics. Besides the trivial promoters of housekeeping genes, most HK-CREs reside in promoter regions and are involved in a broader role beyond housekeeping gene regulation. HK-CREs are conserved regions rich in unmethylated CpG sites. Their distribution highly correlates with that of protein-coding genes, and they interact with many genes over long distances. We observed reduced activity of a subset of HK-CREs in diverse cancer subtypes due to aberrant methylation, particularly those located in chromosome 19 and associated with zinc finger genes. Further analysis of samples from 17 cancer subtypes showed a significantly increased survival probability of patients with higher expression of these genes, suggesting them as housekeeping tumor suppressor genes. Overall, our work unravels the presence of housekeeping CREs indispensable for the maintenance and stability of cells.

Graphic Abstract

Identification of Housekeeping CREs: Genetic switches active in every cell type and their potential role in cancer suppression

Introduction

Characterizing the different components within the complex transcriptional regulatory mechanism has become a long-standing topic of research (1,2). Thanks to the advances in sequencing techniques and experimental protocols, it is possible to investigate different cis-regulatory elements (CREs), e.g. enhancers and promoters, and their differences and similitudes in numerous cell types with unprecedented resolution (3,4). These advances have also made clear that classical discrete definitions of CREs do not necessarily fit the intricate interplay between them. For example, several studies have described CREs that may have both enhancer and promoter functions with similar epigenetic features to either classical marks of enhancers or promoters (2,5). In this way, promoters with enhancer capabilities could drive the activation of neighboring genes through promoter–promoter interactions (5–7). In a recent study, contrary to the classical enhancer–promoter interactions on the regulation of cell type-specific genes, it was demonstrated that housekeeping genes (HKG) are mainly regulated through promoter–promoter interactions (8), delineating the importance of this kind of interplay on the maintenance of cells. These new insights into the regulation of HKG and the intrinsic specificity of the core promoters of HKG to certain gene regulators (9) suggest the existence of ubiquitously active CREs besides the promoters of HKG. However, to our knowledge, the existence of these CREs that are active in all cell types has not been described. In this study, we leveraged the activity by contact (ABC) dataset (10), which provides a list of active CREs and their predicted target genes from 131 cell types and tissues, to investigate ubiquitously active CREs in healthy cell types. We elucidate the existence of such housekeeping CREs (HK-CREs), e.g. CREs active in at least 90% of the healthy cell types and describe their main features. Through several bioinformatic analyses of multiomics data, we show that HK-CREs resided in highly conserved regions that are rich in unmethylated CpG sites, and, similar to HKG (8), they reside in specific loci within the genome as compared with cell type-specific CREs. In conformity with current knowledge on the regulation of HKG (8,9), we show that most of these ubiquitously active CREs localize in core promoter regions and interact with neighboring genes in complex long-distance promoter–promoter interactions. However, contrary to expectations, our analysis revealed that the core promoters of HKG, which are inherently assumed to be active in every cell type, were not the only ubiquitously active CREs; the core promoters of HKG only accounted for around 18% of the total number of HK-CREs. We then compared the biological processes of HKG and the rest of the genes with ubiquitously active core promoters revealing an intrinsic association between these sets of genes, e.g. both groups are enriched in similar or identical housekeeping functions, which suggests their complementarity to ensure the proper functioning and maintenance of cells. Finally, we investigated the HK-CREs in diverse cancer cell lines, discovering a reduction in the activity of a subset of these elements. Interestingly, we found that the most affected HK-CREs in cancer cells reside close to the telomere region of chromosome 19 and are inherently related to zinc finger genes. Moreover, we show that while most of these HK-CREs with reduced activity were cancer-specific, there was a set of core promoters found to be inactive in numerous cancer cell lines, suggesting the existence of housekeeping tumor suppressor genes. We leveraged public data from diverse popular cancer projects and found a decrease in the expression of putative housekeeping tumor suppressor genes (ZNF154, ZNF135, ZNF667, and ZNF667-AS1) due to aberrant methylation of their core promoters in several cancer subtypes. Despite potential cancer-specific regulation of these genes during cancer progression, a joint analysis of more than 5,000 patients from 17 cancer subtypes showed a significant increase in the survival probability of patients with high expression of these genes, confirming, to some degree, the existence of housekeeping tumor suppressor genes in the human genome.

Overall, our work unveils key cis-regulatory elements active in multiple healthy cell types that, if lost, could strongly affect the housekeeping biological processes of cells and possibly culminate in cancer development.

This is yet another example of the ludicrous degree of unnecessary complexity and prolific waste we find in nature and something any omnipotent, omniscient designer should have been capable of avoiding, but we're stuck with it now because evolution can only build on the here and now and has no mechanism for scrapping a bad design and starting again, because evolution is not an intelligent design process.

This is why biological systems have the superficial appearance of design but the lack of intelligence in the process can be found underneath that superficiality. And that is why those who only look at the superficial in nature ("Look at the trees!") believe in intelligent design while those who look at the details (biologists) know that the notion of intelligent design is an ignorant, childish superstition.

It speaks volumes of the intellectual dishonesty and self-deluding nature of creationism that creationists seem to understand this, which is why they can never be induced to look beneath the superficial and find evidence that would change the mind of any anyone interested in discovering the truth.

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