Intelligent Design, the best explanation of Origins

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Chromosome condensation, amazing evidence of design

http://reasonandscience.heavenforum.org/t2086-chromosome-condensation-amazing-evidence-of-design

Imagine trying to stuff about 10,000 miles of spaghetti inside a basketball.  Then, if that was not difficult enough, attempt to find a unique one inch segment of pasta from the middle of this mess, or try to duplicate, untangle and separate individual strings to opposite ends.  This simple analogy illustrates some of the daunting tasks associated with the transcription, repair and replication of the nearly 2 meters of DNA that is packaged into the confines of a tiny eukaryotic nucleus.  The solution to each of these problems lies in the assembly of the eukaryotic genome into chromatin, a structural polymer that not only solves the basic packaging problem, but also provides a dynamic platform that controls all DNA-mediated processes within the nucleus.

Every second, the cells constituting our bodies are replaced through cell division. An adult human consists of about 50,000 billion cells, 1% of which die and are replaced by cell division every day. In order to ensure cell survival and controlled growth of these new cells, the genetic information, stored in DNA molecules, must first be correctly copied and then accurately distributed during cell division. Moreover, to fully ascertain that the new cells will contain the same genetic information as the parental cells, any damage to the DNA, which is organised into several chromosomes, must be repaired.

Quite a bit is known about two of these complexes. One of them, cohesin, keeps the DNA copies together such that they do not separate too early; while the other, condensin, makes the chromosomes more compact, making the separation easier.

During the first stage of mitosis, that of prophase, the duplicated chromosomes are prepared for segregation and the mitotic machinery is assembled. The nucleus of an interphase cell contains tremendous lengths of chromatin fibers. The extended state of interphase chromatin is ideally suited for the processes of transcription and replication but not for segregation into two daughter cells. Before segregating its chromosomes, a cell converts them into much shorter, thicker structures by a remarkable process of chromosome compaction (or chromosome condensation), which occurs during early prophase

Research on chromosome compaction has focused on an abundant multiprotein complex called condensin.

Packing ratio is the length of DNA divided by the length into which it is packaged.

The shortest human chromosome contains 4.6 x 107 bp of DNA (about 10 times the genome size of E. coli). This is equivalent to 14,000 µm of extended DNA, or about 2 meters. In its most condensed state during mitosis, the chromosome is about 2 µm long. This gives a packing ratio of 7000 (14,000/2). That means, it becomes 7000 times shorter !!

To achieve the overall packing ratio, DNA is not packaged directly into final structure of chromatin. Instead, it contains several hierarchies of organization. The first level of packing is achieved by the winding of DNA around a protein core to produce a "bead-like" structure called a nucleosome. This gives a packing ratio of about 6. This structure is invariant in both the euchromatin and heterochromatin of all chromosomes.

The second level of packing is the coiling of beads in a helical structure called the 30 nm fiber that is found in both interphase chromatin and mitotic chromosomes. This structure increases the packing ratio to about 40.

The final packaging occurs when the fiber is organized in loops, scaffolds and domains that give a final packing ratio of about 1000 in interphase chromosomes and about 7,000 in mitotic chromosomes.

Thats a amazing change , from a ratio of 6, to 7.000 !!

Squeezing DNA Into A Small Space

To fit 2 meters of DNA into a tiny nucleus is a monumental engineering feat. DNA is highly compacted yet has to be instantly available to rapidly make proteins in neurons with a momentary change of thought. This regulation is different in each type of cell. . It has been known for some time that the shape of proteins determines their function and the folding is very complex involving four levels of folding . Now it appears that the shape of the chromatin, also, determines function, with new secondary and tertiary structures discovered.

Condensins: universal organizers of chromosomes with diverse functions

Condensins are multisubunit protein complexes that play a fundamental role in the structural and functional organization of chromosomes in the three domains of life. It is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation."

Condensin produces “supercoils” of DNA, one of many steps in packing the delicate DNA strands into a hierarchy of coils that results in a densely-packed chromosome.  “It is not entirely clear how the DNA is held in this supercoiled state,” they say, “but several studies suggest that the V-shaped arms of the condensin complex may loop and clamp the DNA in place.”  This clamping is “rapid and reversible.”  Scientists watching the process in both bacteria and humans are “showing that both vertebrate and bacterial condensins drive DNA compaction in an ATP-dependent fashion with a surprising level of co-operativity that was not fully appreciated.” The condensin molecules work as a team; if not enough condensin is around, nothing happens.     These authors point out also that condensin is just one of many enzymes involved in chromosome formation.  Think about how remarkable it is that during each cell division, the chromosomes are structured so reliably that they can be labeled and numbered under the microscope.  “Our own proteomic analysis,” they claim, “has identified over 350 chromosome-associated proteins, so there is clearly more work to be done.”

How could these nano machines arise by natural means, in a gradual stepwise manner ?   Unless someone can demonstrate a series of small steps to climb mount unprobable (as Richard Dawkins calls the challenge of evolving complex, information-rich, functional biological structures), this is wishful thinking.  The mountain is not a series of small steps, but a sheer cliff with slippery vertical walls.  And why would a mindless molecule even want to go climb uphill against its natural inclinations? The discoveries in biochemistry are making evolution increasingly untenable.  Here we see highly complex molecules, made up of building blocks (amino acids) arranged in precise sequences to build functioning machines.  The complexity is mind-boggling, and it exists all the way down in the very simplest single-celled life forms, with no precursors.  Without these machines, the cell could not divide. Proposing intelligent design is not a argument of ignorance. We know that intelligent minds are capable of projecting complex machines where ideas of problem solutions are required. Intelligent minds are able to store large quantities of information into small spaces, computer chips are a good example.  As conclusion, Intelligent design constitutes the best, most causally adequate, explanation for the information in the cell.

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The irreducible process of phototransduction, 11 cis retinal synthesis, and the visual cycle, essential for vertebrate vision

http://reasonandscience.heavenforum.org/t2061p75-my-articles#5773



http://reasonandscience.heavenforum.org/t1638-origin-of-phototransduction-the-visual-cycle-photoreceptors-and-retina#5753


William Bialek: More Perfect Than We Imagined - March 23, 2013
Excerpt: photoreceptor cells that carpet the retinal tissue of the eye and respond to light, are not just good or great or phabulous at their job. They are not merely exceptionally impressive by the standards of biology, with whatever slop and wiggle room the animate category implies. Photoreceptors operate at the outermost boundary allowed by the laws of physics, which means they are as good as they can be, period. Each one is designed to detect and respond to single photons of light — the smallest possible packages in which light comes wrapped. “Light is quantized, and you can’t count half a photon,” said William Bialek, a professor of physics and integrative genomics at Princeton University. “This is as far as it goes.” … In each instance, biophysicists have calculated, the system couldn’t get faster, more sensitive or more efficient without first relocating to an alternate universe with alternate physical constants. 9

From the book: Evolution of Visual and Non-visual Pigments, page 106
Opsin—the protein that underlies all animal vision., has become a favorite research target, not only of vision scientists but of many researchers interested in the evolution of protein structure, function, and specialization. This level of focus has made the opsins canonical G-protein-coupled receptors (GPCRs) and arguably the most investigated protein group for its evolutionary radiations and diverse functional specializations.  Still, opsin’s early evolution REMAINS PUZZLING, and there are many questions throughout its evolutionary history for which we have partial, but tantalizingly incomplete, answers. Obviously, the invertebrates, with their astonishing diversity and with evolutionary hints of the most ancient animals in their genomes, functions, and even body plans, offer the best hope of answering many of these fundamental questions.

Rhodopsins and Cone opsins have two interdependent agents, namely 11 cis retinal chromophores, and opsins, to which they are attached. By absorbing a photon, 11 cis retinal isomerizes to trans retinal conformation, and that triggers a conformational change in opsins, which trigger the signal transduction cascade, which in the end, provokes the electrical signal, transmitted to the brain for processing.

11-cis-Retinal is a unique molecule with a chemical design that allows optimal interaction with the opsin apoprotein in its binding pocket, and this is essential for the formation of the light-activated conformation of the receptor. 2

There are many things that are functionally important, and must be JUST RIGHT, in order for these molecular mechanisms to work. 

The fact that rhodopsin has been intensely studied, provides a WEALTH of information on a molecular level, which permits to make INFORMED CONCLUSIONS of its origins.

Now OBSERVE how many things must be JUST RIGHT and ESSENTIAL ( following is straightforward from the relevant scientific literature ) :

Rhodopsin Structure and Activation

Rhodopsin consists of an apoprotein opsin and an inverse agonist ( that's like a mechanism which keeps a switch off ), the 11-cis-retinal chromophore, which is covalently bound through a Schiff base linkage to the side chain of Lys296 of opsin protein.

The binding of the chromophore to the opsin is essential to trigger the conformational change. That means, there had to be

- a Schiff base linkage   
- a Lys296 residue where chromophore retinal covalently binds
- the side chain of the residue
- an essential amino acid residue called "counter ion" key factor appears to be the protonation state of the Schiff-base counterion
- a pivotal role of the covalent bond between the retinal chromophore and the lysine residue at position 296 in the activation pathway of  rhodopsin
A key feature of this conformational change is a reorganization of water-mediated hydrogen-bond networks between the retinal-binding pocket and three of the most conserved GPCR sequence motifs. 2

Residues important for stabilizing the tertiary structure

- (e.g. disulphide bridge (S-S),
- amino-terminal (N) glycosylation sites)
- activation/deactivation of photopigments (e.g. carboxyl-terminal (C) phosphorylation sites)
- membrane anchorage (e.g. palmitoylation sites)

For visible light absorption, all opsins contain an essential amino acid residue called "counter ion", in addition to a retinal-binding site, Lys296 (in the bovine rhodopsin numbering system), where chromophore retinal covalently binds through a protonated Schiff base linkage . The proton on the Schiff base is necessary for visible light absorption, but energetically unstable within the opsin molecule. In opsin pigments, a negatively charged amino acid residue, counterion, stabilizes the protonated Schiff base, and is an essential amino acid residue for opsin pigments to absorb visible light.

Various types of opsin-based pigments with absorption maxima in the visible light region possess a “protonated” Schiff base linkage. In the protein moiety, the positive charge on the protonated Schiff base is unstable, and therefore a counterion, a negatively charged amino acid residue is needed to stabilize the positive charge. In vertebrate visual pigment, glutamic acid at position 113 serves as the counterion 11

Furthermore: movement of the cytoplasmic end of the sixth transmembrane helix is essential for pigment activation.

From the above information, it is clear that there is an evidently FINE- TUNED protein-protein interaction, that is, the 11 cis retinal chromophore physical constitution, and the opsin physical constitution, MUST BE JUST RIGHT from the beginning, and be able to interact PRECISELY to trigger the signal transduction chain.

Let's suppose, opsin is able to interact with TRANSDUCIN. So what ?? If the signal transduction pathway is not fully setup, and able to go all the way through - no signal - no vision. So having such a precise protein-protein arrangement will make only sense, if down down there, after many complex molecular interactions, a visual image is generated in the brain. After two amplification steps, the goal is achieved, and a signal is sent to the brain. To get that signal, is a REMARKABLE SIGNAL AMPLIFICATION mechanism:

A single photoactivated rhodopsin catalyzes the activation of 500 transducin molecules. Each transducing can stimulate one cGMP phosphodiesterase molecule and each cGMP phosphodiesterase molecule can break down 1000 molecules of cGMP per second. Therefore, a single activated rhodopsin can cause the hydrolysis of more than 100.000 molecules of cGMP per second.

Following enzymes, molecules, and proteins are ESSENTIAL in the signal transduction pathway:

Rhodopsin  Rhodopsin is an essential G-protein coupled receptor in phototransduction.
Retinal Schiff base cofactor All-trans-retinal is also an essential component of type I, or microbial, opsins such as bacteriorhodopsinchannelrhodopsin, and halorhodopsin.
Transducin  Their function is to mediate the signal transduction from the photoreceptor proteins, the opsins, to the effector proteins, the phosphodiesterases 6
Guanosine diphosphate ( GDP ) Transducin is tightly bound to a small organic molecule called Guanosine diphosphate ( GDP ) 
Guanosine triphosphate GTP when it binds to rhodopsin the GDP dissociates itself from transducin and a molecule called  GTP, which is closely related to, but critically different from, GDP, binds to transducin. 
G-nucleotide exchange factor (GEF)    The exchange of GDP for GTP is done by a G-nucleotide exchange factor (GEF) 7
Cyclic guanosine monophosphate (cGMP) 
phosphodiesterase (PDE)  is necessary to transform cGMP to GMP. This closes the cGMP gated ion channel due to the decreasing amounts of cGMP in the cytoplasm 6  
cGMP-gated channel of rod photoreceptors
Cyclic nucleotide-gated Na+ ion channels

Once the signal goes through,  a system is required to stop the signal that is generated and restore the opsin to its original state. For that task, other essential proteins are needed  to restore the initial state of rhodopsin:

Guanylate cyclase
Rhodopsin kinase
Arrestin

The biosynthesis of 11 Cis retinal, essential in the first step of vertebrate vision, is also REMARKABLE.

There is an INTRIGUING EVOLUTIONARY CONSERVATION  of the key components involved in chromophore production and recycling, these genes also have adapted to the specific requirements of both insect and vertebrate vision. Visual GPCR signaling is unique with respect to its dependence on a diet-derived chromophore (retinal or 2-dehydro-retinal in vertebrates; retinal and 3-hydroxy-retinal in insects). The chromophore is naturally generated by oxidative cleavage of carotenoids (C40) to retinoids.(C20). Then the retinoid cleavage product must be metabolically converted to the respective 11-cis-retinal derivative in either the same carotenoid cleavage reaction or a separate reaction. 3

All animals endowed with the ability to detect light through visual pigments need pathways in which dietary precursors for chromophore, such as carotenoids and retinoids, are first absorbed in the gut, and then transported, metabolized and stored within the body to establish and sustain vision.

Two fundamental processes in chromophore metabolism defied molecular analysis for a long time: the conversion of the parent C40 carotenoid precursor into C20 retinoids and the all-trans to 11-cis isomerization and cleavage involved in continuous chromophore renewal. Following proteins are essential in the pathway to synthesize 11 cis retinals :

retinal pigment epithelial (RPE)  The retinal pigment epithelium (RPE), a single layer of cuboidal cells lying betweenBruch's membrane and the photoreceptors, is an essential component of the visual system.
Lecithin-retinol acyltransferase  Is Essential for Accumulation of All-trans-Retinyl Esters in the Eye and in the Liver 4
Retinyl ester hydrolase
11-cis-retinol dehydrogenases
Isomerohydrolase  It performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. 5
Retinoid-binding proteins
RPE retinal G protein-coupled receptor (RGR)

The absorption of light by rhodopsin results in the isomerization of the 11- cis -retinal chromophore to all- trans forming the enzymatically active intermediate, metarhodopsin II, which commences the visual transduction process.

Continuous vision depends on recycling of the photoproduct all-trans-retinal back to visual chromophore 11-cis-retinal. This process is enabled by the visual (retinoid) cycle, a series of biochemical reactions in photoreceptor, adjacent RPE and Müller cells.

Since the opsins lacking 11-cis-RAL lose light sensitivity, sustained vision requires continuous regeneration of 11-cis-RAL via the process called ‘visual cycle’. Protostomes and vertebrates use essentially different machinery of visual pigment regeneration, and the origin and early evolution of the vertebrate visual cycle is an UNSOLVED MYSTERY.

Restoration of light sensitivity requires chemical reisomerization of trans-retinal via a multistep enzyme pathway, called the visual cycle, in cells of the retinal pigment epithelium (RPE).

When a photon of light is absorbed, 11-cis retinal is transformed to all-trans retinal, and it moves to the exit site of rhodopsin. It will not leave the opsin protein until another fresh chromophore comes to replace it, except for in the ABCR pathway. Whilst still bound to the opsin, all-trans retinal is transformed into all-trans retinol by all-trans Retinol Dehydrogenase. It then proceeds to the cell membrane of the rod, where it is chaperoned to the Retinal Pigment Epithelium (RPE) by Interphotoreceptor Retinoid Binding Protein (IRBP). It then enters the RPE cells, and is transferred to the Cellular Retinol Binding Protein (CRBP) chaperone. 8

The visual cycle fulfills an essential task of maintaining visual function and needs therefore to be adapted to different visual needs such as vision in darkness or lightness. For this, functional aspects come into play: the storage of retinal and the adaption of the reaction speed. Basically vision at low light intensities requires a lower turn-over rate of the visual cycle whereas during light the turn-over rate is much higher. In the transition from darkness to light suddenly, large amount of 11-cis retinal is required. This comes not directly from the visual cycle but from several retinal pools of retinal binding proteins which are connected to each other by the transportation and reaction steps of the visual cycle.

This cycle is present only in vertebrates, as cephalochordates and tunicates do not possess the required enzymes. The isomerization of 11-cis retinal to all-trans retinal in photoreceptors is the first step in vision. For photoreceptors to function in constant light, the all-trans retinal must be converted back to 11-cis retinal via the enzymatic steps of the visual cycle. Within this cycle, all-trans retinal is reduced to all-trans retinol in photoreceptors and transported to the Retinal pigment epithelium (RPE). In the RPE, all-trans retinol is converted to 11-cis retinol, and in the final enzymatic step, 11-cis retinol is oxidized to 11-cis retinal. The first and last steps of the classical visual cycle are reduction and oxidation reactions, respectively, that utilize retinol dehydrogenase (RDH) enzymes.

To make things even more intriguing, there are at least 4 different pathways for regeneration of 11 Cis retinal. Protostomes and vertebrates use essentially different machinery of visual pigment regeneration, and the origin and early evolution of the vertebrate visual cycle is an unsolved mystery. In the vertebrate cycle, following proteins are ESSENTIAL :

Rhodopsin (also known as visual purple) is a light-sensitive receptor protein involved in visual phototransduction.
Photoreceptor cells are specialized type of cell found in the retina that is capable of visual phototransduction.
Retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells
Retinal G-protein-coupled receptor (RGR) is a non-visual opsin expressed in RPE. RGR bound to all-trans-RAL is capable of operating as a photoisomerase that generates 11-cis-RAL in the light-dependent manner
Interphotoreceptor retinoid-binding protein (IRBP), an abundant 140 kDa glycoprotein secreted by photoreceptors . The binding of retinoids by IRBP protects them from oxidation and isomerization.
β-Carotene 15,15′-monooxygenase (BCO) in RPE supplies all-trans-RAL to the visual cycle via central cleavage of β-carotene 
Cellular retinaldehyde-binding protein (CRALBP)  binds 11-cis-ROL and 11-cis-RAL
Retinoid isomerase RPE65 (or isomerohydrolase) in the RPE. RPE65 is involved in the all-trans to 11-cis isomerization.


Retinoids need to be shuttled between different organelles and protected from isomerization, oxidation, and condensation. Thus, key retinoid-binding proteins are critical for maintaining proper retinoid isomeric and oxidation states. Cellular retinaldehyde–binding protein (CRALBP) in the RPE and Müller cells, and extracellular interphotoreceptor retinoid–binding protein (IRBP) are two major carriers involved.  The structure of CRALBP—with its unanticipated isomerase activity—has been elucidated, whereas the structure of IRBP has only been partially characterized. Inactivating mutations in either one of these binding proteins can cause retinal degenerative disease.


Origin of opsins: 

Type I and Type II opsins
Opsins comprise two protein families, called type I and type II opsins, with detailed functional similarities. Both opsin classes are seven-transmembrane (7-TM) proteins that bind to a lightreactive chromophore to mediate a diversity of responses to light. In both families, the chromophore (retinal) binds to the seventh TM domain via a Schiff base linkage to a lysine amino acid.  Two major classes of opsins are defined and differentiated based on primary protein sequence, chromophore chemistry, and signal transduction mechanisms. Several lines of evidence indicate that the two opsin classes evolved separately, illustrating an amazing case of convergent evolution.

Convergent evolution ? Can you believe that ? 

Supposed split of type 1 and type 2 opsins: 
Although parapinopsin ( Any of a group of opsins in the parapineal gland of some fish )  has an amino acid sequence similar to those of vertebrate visual pigments, it has the molecular properties of a bistable pigment, similar toinvertebrate visual pigments (Gq-coupled visual opsin) and Opn3 (encephalopsin)/ TMT-opsin-based pigments. These observations indicate that parapinopsin is one of the key pigments for understanding the molecular evolution of vertebrate visual pigments. Parapinopsin has glutamic acid residues at both positions 113 and 181, similar therefore to vertebrate visual pigments. However, mutational analyses have revealed that Glu181 is the functional counterion residue, as found for invertebrate rhodopsins. Therefore, this suggests that the molecular properties of photoproducts, namely photoregeneration (bistability) and bleaching, may relate to counterion position and that vertebrate visual pigments having bleaching property might have evolved from an ancestral vertebrate bistable pigment similar to parapinopsin.  

This might be not that easy. In order for the transition to work, all the proteins and enzymes, and all metabolic steps of the visual cycle would have to be set up and in place, fully working, otherwise, how could 11 cis retinal be regenerated? and since there are at least 4 different visual cycles, they would have had to emerge independently four times..... and if key retinoid-binding proteins were not there ready to bind retinoid, nothing done.....

Now - THIS is the kind of information that must be studied, considered, and analyzed when talking about origins of vision and phototransduction. 

What is the proposal based on philosophical naturalism to explain the systems described above ? 

The Evolution of Opsins 
T H Oakley and D C Plachetzki, 2012
Opsin genes were very often duplicated and retained during animal evolution. Early opsin gene duplications led to the major opsin groups and more recent duplications mostly led to additional specializations, such as the ability for color vision. As members of highly coordinated protein networks, changes in opsin proteins are sometimes correlated with changes in partnering proteins. The interaction of two evolutionary processes has resulted in the diversity of opsin-based phototransduction pathways observed today that contains a combination of shared and distinct interactions. First, co-option refers to instances where an opsin recruited different intracellular signaling components than its ancestor during evolution. Second, coduplication involved the simultaneous duplication of multiple genes of an ancestral network. Co-option and coduplication are not discrete alternatives; instead, some genes of a network originated by co-duplication, whereas others joined the network by co-option.

Where is the evidence for these claims? So, basically, they claim duplication and co-option did the feat. And furthermore, they go fishing where they should not, using teleological phrasing, like recruited. Recruiting is a conscient direction driven mental process based on intelligence. There is not a shred of evidence for the proposal, nonetheless, it is presented as consumed, proven fact. This is the bitter fruits of methodological naturalism.

1. http://www.sciencedirect.com/science/article/pii/S0042698906003580
2. http://www.nature.com/nature/journal/v471/n7340/abs/nature09795.html
3. https://www.researchgate.net/publication/41621159_The_biochemical_and_structural_basis_for_trans-to-cis_isomerization_of_retinoids_in_the_chemistry_of_vision
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351249/
5. https://www.ncbi.nlm.nih.gov/gene/6121
6. https://www.researchgate.net/publication/267825362_Evolution_of_transducin_alpha_beta_and_gamma_subunit_gene_families
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794341/
8. https://en.wikipedia.org/wiki/Bleach_and_recycle
9. http://darwins-god.blogspot.com/2013/03/william-bialek-more-perfect-than-we.html

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