Intelligent Design

Peto’s paradox – how intelligent design solves it

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Peto’s paradox – how intelligent design solves it

Marc Tollis (2017): In a multicellular organism, cells must go through a cell cycle that includes growth and division. Every time a human cell divides, it must copy its six billion base pairs of DNA, and it inevitably makes some mistakes. These mistakes are called somatic mutations (cells in the body other than sperm and egg cells). Some somatic mutations may occur in genetic pathways that control cell proliferation, DNA repair, apoptosis, telomere erosion, and growth of new blood vessels, disrupting the normal checks on carcinogenesis. If every cell division carries a certain chance that a cancer-causing somatic mutation could occur, then the risk of developing cancer should be a function of the number of cell divisions in an organism’s lifetime. Therefore, large-bodied and long-lived organisms should face a higher lifetime risk of cancer simply due to the fact that their bodies contain more cells and will undergo more cell divisions over the course of their lifespan. However, a 2015 study that compared cancer incidence from zoo necropsy data for 36 mammals found that a higher risk of cancer does not correlate with increased body mass or lifespan. In fact, the evidence suggested that larger long-lived mammals actually get less cancer. This has profound implications for our understanding of how the cancer problem is solved.

When individuals in populations are exposed to the selective pressure of cancer risk, the population must evolve cancer suppression as an adaptation or else suffer fitness costs and possibly extinction. Discovering the mechanisms underlying these solutions to Peto’s Paradox requires the tools of numerous subfields of biology including genomics, comparative methods, and experiments with cells. For instance, genomic analyses revealed that the African savannah elephant (Loxodonta africana) genome contains 20 copies, or 40 alleles, of the most famous tumor suppressor gene TP53. The human genome contains only one TP53 copy, and two functional TP53 alleles are required for proper checks on cancer progression. When cells become stressed and incur DNA damage, they can either try to repair the DNA or they can undergo apopotosis, or self-destruction. The protein produced by the TP53 gene is necessary to turn on this apoptotic pathway. Humans with one defective TP53 allele have Li Fraumeni syndrome and a ~90% lifetime risk of many cancers, because they cannot properly shut down cells with DNA damage. Meanwhile, experiments revealed that elephant cells exposed to ionizing radiation behave in a manner consistent with what you would expect with all those TP53 copies—they are much more likely to switch on the apoptotic pathway and therefore destroy cells rather than accumulate carcinogenic mutations. 1

Comment: How does the author explain the origin of these protective mechanisms? He claims: “The solution to Peto’s Paradox is quite simple: evolution”. This is an ad-hoc assertion and raises the question: How could complex multicellular organisms have evolved if these cancer protection mechanisms were not implemented before the transition occurred, since, otherwise, these organisms would have gone extinct? This problem becomes even greater if considering, that animals with large body size supposedly evolved independently many times across the history of life, and, therefore, these mechanisms would have had to be recruited multiple times. The paradox is only solved, if we hypothesize that large animals were created independently by God, and right from the beginning equipped with tumor suppressor mechanisms from the get-go.

A. B. Williams (2016): The loss of p53 is a major driver of cancer development mainly because, in the absence of this “guardian of the genome,” cells are no longer adequately protected from mutations and genomic aberrations.  Intriguingly, the evolutionary occurrence of p53 homologs appears to be associated with multicellularity. With the advent of metazoans, genome maintenance became a specialized task with distinct requirements in germ cells and somatic tissues. With the central importance of p53 in controlling genome instability–driven cancer development, it might not be surprising that p53 controls DNA-damage checkpoints and impacts the activity of various DNA-repair systems. 2

B. J. Aubrey (2016): The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. 

TP53:Tumor Suppression and Transcriptional Regulation

Following activation, the TP53 protein functions predominantly as a transcription factor. The TP53 protein forms a homotetramer that binds to specific Tp53 response elements in genomic DNA to direct the transcription of a large number of protein-coding genes. The requirement for TP53 transcriptional activity in tumor suppression has been examined by systematically mutating the transactivation domains of the TP53 protein, rendering it either partially or wholly transcriptionally defective. Importantly, mutations resulting in complete loss of TP53 transcriptional activity ablate its ability to prevent tumor formation, supporting the concept that transcriptional regulation is central to the tumor-suppressor function. TP53-mediated tumor suppression is governed by transcriptional regulation.

TP53-mediated transcriptional regulation varies according to the type of stress stimulus and type of cell, so that appropriate corrective processes can be implemented. For example, minor DNA damage may institute cell-cycle arrest and activate DNA-repair mechanisms, whereas stronger TP53-activating signals induce senescence or apoptosis. Accordingly, the TP53 transcriptional response varies depending on the nature of the activating signal and the type of cell. The number of known or suspected TP53 target genes has increased into the thousands with dramatic differences in transcriptional responses observed among different cell types, different TP53-inducing stress stimuli, and varying time points following TP53 activation. These studies paint an increasingly complex picture of the modes by which TP53 can regulate gene expression. For example, before TP53 activation, a subset of target genes is transcriptionally repressed by the TP53 protein. More recently appreciated functions of the TP53 protein include widespread binding and modulation of enhancer regions throughout the genome and transcriptional activation of noncoding RNAs. Interestingly, the TP53-activated long noncoding RNA, lincRNA-p21, exerts widespread suppression of gene expression. The list of proposed TP53 target genes is vast and they are known to influence diverse cellular processes, including apoptosis, cell-cycle arrest, senescence, DNA-damage repair, metabolism, and global regulation of gene expression, each of which could potentially contribute to its tumor-suppressor function.

The p53 pathway responds to various cellular stress signals (the input) by activating p53 as a transcription factor (increasing its levels and protein modifications) and transcribing a programme of genes (the output) to accomplish a number of functions. Together, these functions prevent errors in the duplication process of a cell that is under stress, and as such the p53 pathway increases the fidelity of cell division and prevents cancers from arising. 3

K. D. Sullivan (2017): The p53 polypeptide contains several functional domains that work coordinately, in a context-dependent fashion, to achieve DNA binding and transactivation. (the increased rate of gene expression) 4

K. Kamagata (2020): Interactions between DNA and DNA-binding proteins play an important role in many essential cellular processes. A key function of the DNA-binding protein p53 is to search for and bind to target sites incorporated in genomic DNA, which triggers transcriptional regulation. How do p53 molecules achieve “rapid” and “accurate” target search in living cells?  The genome encompasses DNA sequences that encode genes, and gene editing is the genetic engineering of a specific DNA sequence, including insertion, deletion, modification, and replacement. The main player in genome editing is a type of protein that can bind to DNA, known as DNA-binding proteins. DNA-binding proteins include enzymes, which can cut DNA or ligate two DNA molecules, and transcription factors, which can activate or deactivate gene expression. These proteins are classified into DNA sequence-specific and nonspecific binders. The transcription factor p53 can induce multiple tumor suppression functions, such as cell cycle arrest, DNA repair, and apoptosis. p53 is presumed to solve the target search problem by utilizing 3D diffusion, 1D diffusion along DNA, and intersegmental transfer between two DNAs in the cell. 5

Comment: This transcription factor p53 actively searches targets in the genome to be expressed. This is a goal-oriented process implemented to activate processes that avoid the origination of cancer. Various players are required that work as a system. It is a team play.  The p53 transcription factor has to be able to perform “rapid” and “accurate” target search, recognize it, and bind to the DNA sequence so it can be expressed, but most important, before it can act like a switch commanding “on”, the gene sequences to be expressed must be there, that is, the actors that are recruited to permit DNA repair, or apoptosis (cell death). It is an all-or-nothing business to convey the function to suppress the development and growth of tumors, and consequently, death. In other words, this is an irreducibly complex system where p53 would be functionless unless the actors to act upon were not there. 

The concepts of machine and factory error monitoring, checking, and repair are all tasks performed with goal-directedness, intent, and purpose. 
1. Repairing things that are broken, malfunctioning, or instantiating complex systems that autonomously prevent things to break are always actions performed by agents with intentions, volition, goal-orientedness, foresight, understanding, and know-how.
2. Man-made machines almost always require direct intelligent intervention by technicians to recognize errors, find which parts of a machine are broken, know how to remove and replace them without breaking surrounding parts of the device, and know how to construct the part that has to be replaced with fidelity, and re-insert and re-connect it where the part was removed. The entire process is complex, demanding know-how, and depends on a high quantity of intelligence in performing all involved actions.
3. Man has not been able to create a fully autonomous, preprogrammed machine or factory, that is able to quality and error monitor all manufacturing processes and the correct performance of all devices involved, and if the products are up to the required quality standard, and, if something drives havoc, repair and re-establish normal function of what was broken or malfunctioning without external intervention.
4. C.H. Loch writes in the science paper: “Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing” (2004): Biological cells are preprogrammed to use quality-management techniques used in manufacturing today. The cell invests in defect prevention at various stages of its replication process, using 100% inspection processes, quality assurance procedures, and foolproofing techniques. An example of the cell inspecting each and every part of a product is DNA proofreading. As the DNA gets replicated, the enzyme DNA polymerase adds new nucleotides to the growing DNA strand, limiting the number of errors by removing incorrectly incorporated nucleotides with a proofreading function. Following is an impressive example:  Unbroken DNA conducts electricity, while an error blocks the current. Some repair enzymes exploit this. One pair of enzymes lock onto different parts of a DNA strand. One of them sends an electron down the strand. If the DNA is unbroken, the electron reaches the other enzyme and causes it to detach. I.e. this process scans the region of DNA between them, and if it’s clean, there is no need for repairs. But if there is a break, the electron doesn’t reach the second enzyme. This enzyme then moves along the strand until it reaches the error, and fixes it. This mechanism of repair seems to be present in all living things, from bacteria to man. Know-how is needed: 

Martin_r:

a. To know that something is broken (DNA damage sensing)

b. To identify where exactly it is broken

c. To know when to repair it (e.g. one has to stop/or put on hold some other ongoing processes, in other words, one needs to know lots of other things, one needs to know the whole system, otherwise one creates more damage…)

d. to know how to repair it (to use the right tools, materials, energy, etc, etc, etc )

e. to make sure that the repair was performed correctly. (this can be observed in DNA repair as well)


5. On top of that: Cells do not even wait until a protein machine fails, but replace it long before it has a chance to break down. Furthermore, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances, as we will describe next.
6. The more sophisticated, advanced, autonomous, complex, and information-driven machines or factories are, the more they carry the hallmark of design. The very concepts of error monitoring, checking, and repair, and replacement in advance to avoid future break-ups are tasks performed with goal-directedness, and purpose. Biological cells are far more advanced than any machine and factory ever devised and invented by man. It is therefore rational and warranted to infer, that biological cells were designed. 

  1. Marc Tollis: Peto’s Paradox: how has evolution solved the problem of cancer prevention? 13 July 2017
  2. A.B. Williams: p53 in the DNA-Damage-Repair Process  2016 May; 6
  3. Brandon J. Aubrey: Tumor-Suppressor Functions of the TP53 Pathway 2016
  4. Kelly D Sullivan: Mechanisms of transcriptional regulation by p53 2017 Nov 10
  5. Kiyoto Kamagata: How p53 Molecules Solve the Target DNA Search Problem: A Review 2020 Feb; 21

One Reply to “Peto’s paradox – how intelligent design solves it

  1. 1
    whistler says:

    Otangelo
    How does the author explain the origin of these protective mechanisms? He claims: “The solution to Peto’s Paradox is quite simple: evolution”.

    🙂 Why he claims that “evolution”(materialist version of miracles manufacturer ) created that second layer of intelligent protection? The answer is pretty simple :because he needs fundings for his next studies and a safe job.

    How could complex multicellular organisms have evolved if these cancer protection mechanisms were not implemented before the transition occurred, since, otherwise, these organisms would have gone extinct?

    Simple, they can’t evolve so they were from the start in genome.

    A. B. Williams (2016): The loss of p53 is a major driver of cancer development mainly because, in the absence of this “guardian of the genome,” cells are no longer adequately protected from mutations and genomic aberrations.

    Strange , darwinists claimed 5 minutes ago that random mutations produce evolution(?=better ,stronger organisms) but the science says that random mutation produce cancer and other thousands of disorders. They see with their own eyes what effects has the randomness on the cell but they believe the opposite because their religion says so.

    This transcription factor p53 actively searches targets in the genome to be expressed. This is a goal-oriented process implemented to activate processes that avoid the origination of cancer. Various players are required that work as a system. It is a team play.

    Forward planning and the killer or “randomness” .

    Cells do not even wait until a protein machine fails, but replace it long before it has a chance to break down.

    🙂 Maybe they have expiration date “labels” that are hidden/coded for scientists but not for the cell.

    PS: I don’t understand why in the world still exist darwinists because all the scientific evidences point against .

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