Otangelo
Posts: 149
Joined: Oct. 2015
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DNA replication, and its mind boggling nano technology that defies naturalistic explanations
http://reasonandscience.heavenforum.org/t1849-d....aryotes
DNA replication is the most crucial step in cellular division, a process necessary for life, and errors can cause cancer and many other diseases. Genome duplication presents a formidable enzymatic challenge, requiring the high fidelity replication of millions of bases of DNA. It is a incredible system involving a city of proteins, enzymes, and other components that are breathtaking in their complexity and efficiency.
How do you get a living cell capable of self-reproduction from a “protein compound … ready to undergo still more complex changes”? Dawkins has to admit:
“Darwin, in his ‘warm little pond’ paragraph, speculated that the key event in the origin of life might have been the spontaneous arising of a protein, but this turns out to be less promising than most of Darwin’s ideas. … But there is something that proteins are outstandingly bad at, and this Darwin overlooked. They are completely hopeless at replication. They can’t make copies of themselves. This means that the key step in the origin of life cannot have been the spontaneous arising of a protein.” (pp. 419–20)
The process of DNA replication depends on many separate protein catalysts to unwind, stabilize, copy, edit, and rewind the original DNA message. In prokaryotic cells, DNA replication involves more than thirty specialized proteins to perform tasks necessary for building and accurately copying the genetic molecule. These specialized proteins include DNA polymerases, primases, helicases, topoisomerases, DNA-binding proteins, DNA ligases, and editing enzymes. DNA needs these proteins to copy the genetic information contained in DNA. But the proteins that copy the genetic information in DNA are themselves built from that information. This again poses what is, at the very least, a curiosity: the production of proteins requires DNA, but the production of DNA requires proteins.
Proponents of Darwinism are at a loss to tell us how this marvelous system began. Charles Darwin's main contribution, natural selection, does not apply until a system can reproduce all its parts. Getting a reproducible cell in a primordial soup is a giant leap, for which today's evolutionary biologists have no answer, no evidence, and no hope. It amounts to blind faith to believe that undirected, purposeless accidents somehow built the smallest, most complex, most efficient system known to man.
Several decades of experimental work have convinced us that DNA synthesis and replication actually require a plethora of proteins.
Replication of the genetic material is the single central property of living systems. Dawkins provocatively claimed that organisms are but vehicles for replicating and evolving genes, and I believe that this simple concept captures a key aspect of biological evolution. All phenotypic features of organisms—indeed, cells and organisms themselves as complex physical entities—emerge and evolve only inasmuch as they are conducive to genome replication. That is, they enhance the rate of this process, or, at least, do not impede it.
DNA replication is an enormously complex process with many different components that interact to ensure the faithful passing down of genetic components that interact to ensure the faithful passing down of genetic information to the next generation. A large number of parts have to work together to that end. In the absence of one or more of a number of the components, DNA replication is either halted completely or significantly compromised, and the cell either dies or becomes quite sick. Many of the components of the replication machinery form conceptually discrete sub-assemblies with conceptually discrete functions.
Wiki mentions that a key feature of the DNA replication mechanism is that it is designed to replicate relatively large genomes rapidly and with high fidelity. Part of the cellular machinery devoted to DNA replication and DNA-repair. The regulation of DNA replication is a vital cellular process. It is controlled by a series of mechanisms. One point of control is by modulating the accessibility of replication machinery components ( called the replisome ) to the single origin (oriC) region on the DNA. DNA replication should take place only when a cell is about to divide. If DNA replication occurs too frequently, too many copies of the bacterial chromosome will be found in each cell. Alternatively, if DNA replication does not occur frequently enough, a daughter cell will be left without a chromosome. Therefore, cell division in bacterial cells must be coordinated with DNA replication.
In prokaryotes, the DNA is circular. Replication starts at a single origin (ori C) and is bi-directional. The region of replicating DNA associated with the single origin is called a replication bubble and consists of two replication forks moving in opposite direction around the DNA circle. During DNA replication, the two parental strands separate and each acts as a template to direct the enzyme catalysed synthesis of a new complementary daughter strand following the normal base pairing rule. At least 10 different enzymes or proteins participate in the initiation phase of replication. Three basic steps involved in DNA replication are Initiation, elongation and termination, subdivided in eight discrete steps.
http://reasonandscience.heavenforum.org/t1849-d....es#4365
Initiation phase:
Step 1: Initiation begins, when DNA binds around an initiator protein complex DnaA with the goal to pull the two DNA strands apart. That creates a number of problems. First of all, the two strands like to be together - they stick to each other just as if they had tiny magnets up and down their length. In order to pull apart the DNA you have to put energy into the system. In modern cells, a protein called DnaA binds to a specific spot along the DNA, called single origin ( oriC ) and the protein proceeds to open up the double strand. The protein is a monomer, has motifs to bind to unique monomer sites, also they have motifs for protein-protein interaction, thus they can form clusters. They have hydrophobic regions for helical coiling and protein–protein interactions. Binding of the monomers to DnaA-A boxes, in ATP dependent manner (proteins have ATPase activity), leads to cooperative binding of more proteins. This clustering of proteins on DNA makes the DNA to wrap around the proteins, which induces torsional twist and it is this left handed twist that makes DNA to melt at 13-mer region and AT rich region; perhaps the negative super helical topology in this region may further facilitate the melting of the DNA. Opening or unwinding of dsDNA ( double strand DNA ) into single stranded region is an important event in initiation.
Single-strand binding protein (SSB)
http://reasonandscience.heavenforum.org/t1849p1....es#4377
The Hexameric DnaB Helicase
http://reasonandscience.heavenforum.org/t1849p1....es#4367
DnaC, and strategies for helicase recruitment and loading in bacteria
http://reasonandscience.heavenforum.org/t1849p1....es#4371
Unwinding the DNA Double Helix Requires DNA Helicases,Topoisomerases, and Single- Stranded DNA Binding Proteins
http://reasonandscience.heavenforum.org/t1849p1....es#4374
Step 2: During DNA replication, the two strands of the double helix must unwind at each replication fork to expose the single strands to the enzymes responsible for copying them. Three classes of proteins with distinct functions facilitate this unwinding process: DNA helicases, topoisomerases, and single-stranded DNA binding proteins ( SSB's). Helicase ( DnaB ) now comes along. The helicase exposes a region of single-stranded DNA that must be kept open for copying to proceed. Helicase is like a snowplow; it is a molecular machine that plows down the middle of the double helix, pushing apart the two strands. this allows the polymerase and associated proteins to travel along behind it in ease and comfort. DnaB helicase alone has no affinity for ssDNA ( single stranded DNA ) bound by SSB (single- stranded binding protein). Thus, entry of the DnaB helicase complex into the unwound oriC depends on DnaC, a additional protein factor. DnaC helps or facilitates the helicase to be loaded onto ssDNA at the replication fork in ATP dependent manner. The DnaB-DnaC complex forms a topologically open, three-tiered toroid. DnaC remodels DnaB to produce a cleft in the helicase ring suitable for DNA passage. DnaC’s fold is dispensable for DnaB loading and activation. DnaB possesses autoregulatory elements that control helicase loading and unwinding. Using energy derived from ATP hydrolysis, these proteins unwind the DNA double helix in advance of the replication fork, breaking the hydrogen bonds as they go. Helicase recruitment and loading in bacteria is a remarkable process. Following video shows how that works:
https://www.youtube.com/watch?v....LsqMqyE
There is a problem, though, with this setup. If you push apart two DNA strands they generally do not float around separately. If they are close to one another they will rapidly snap back and form a double strand again almost as soon as the helicase passes. Even if the strands are not near each other, a single strand will usually fold up and form hydrogen bonds with itself - in other words, a tangled mess. So it is not enough to push apart the two strands of DNA; there must be a way to keep the strands apart once they have been separated. In modern cells this job is done by single-strand binding proteins, or SBB's. As the helicase separates the strands of DNA, SSB's bind to the single stranded DNA and coats them. . SSB's prevent DNA from reannealing. SSB's associate to form tetramers around which the DNA is wrapped in a manner that significantly compacts the single-stranded DNA. There is another difficulty in being a double helix. The unwinding associated with DNA replication would create an intolerable amount of supercoiling and possibly tangling in the rest of the DNA. It can be illustrated with a simple example. Take two interwined shoe laces and ask a friend to hold them together at each end. Now take a pencil, insert it between the strands near one end, and start pushing it down toward the other end. As you can see, shoestrings behind the pencil become melted, in the jargon of biochemistry. The shoestrings ahead of the pencil become more and more tangled. It becomes harder and harder to push the pencil forward. Helicase and polymerase encounter the same problem with DNA. It does not matter wheter you are talking about interwined strings or interwined DNA strands. The problem of tangling is the result of the topological interconnectness of the two strands. If this problem persisted for very long in a cell, DNA replication would grind to a halt. However, the cell contains several enzymes, called topoisomerases, to take care of the difficulty. The way in which they do so can be illustrated with a enzyme called gyrase. Gyrase binds to DNA, pulls them apart and allows a separate portion of the DNA to pass through the cut. It then reseals the cut and lets go of the DNA. This action decreases the number of twists in DNA. The parental DNA is unwound by DNA helicases and SSB (travels in 5’-3’ direction), the resulting positive super-coiling (torsional stress) is relieved by topoisomerse I and II (DNA gyrase) by inducing transient single stranded breaks.Topoisomerases are amazing enzymes. In this topic, a video shows how they function :
Topoisomerase II enzymes, amazing evidence of design
http://reasonandscience.heavenforum.org/t2111-t....omerase
In modern organisms, helicase, SSB, and gyrase all are required at the replication fork. Mutants in which any of them are missing are not viable - they die.
Question : Had not all three parts , the SSB binding proteins, the topoisomerase, and the helicase and the DnaC loading proteins not have to be there all at once, otherwise, nothing goes ? They might exercise their function but their own, but then they would not replicate DNA or have function in a bigger picture. Its evident that they had to come together to provide a functional whole. What we see here are highly coordinated , goal oriented tasks with specific movements designed to provide a specific outcome. Auto-regulation and control that seems required beside constant energy supply through ATP enhances the difficulty to make the whole mechanism work in the right manner. All this is awe inspiring and evidences the wise guidance and intelligence required to make all this happening in the right way.
Step 3: The enzyme DNA primase (primase, an RNA polymerase) attaches to the DNA and synthesizes a short RNA primer to initiate synthesis of the leading strand of the first replication fork.
Elongation phase :
Step 4: In the elongation fase, DNA polymerase III extends the RNA primer made by primase.
DNA Polymerase
http://reasonandscience.heavenforum.org/t1849p1....es#4375
DNA polymerase possesses separate catalytic sites for polymerization and degradation of nucleic acid strands. All DNA polymerases make DNA in 5’-3’ direction . A ring-shaped sliding clamp protein encircles the DNA double helix and binds to DNA polymerase, thereby allowing the DNA polymerase to slide along the DNA while remaining firmly attached to it. Most enzymes work by colliding with their substrate, catalyzing a reaction and dissociating from the product. If that were the case with DNA polymerase, then it would bind to DNA, add a nucleotide to the new chain that was being made, and then fall off of the chain. Then ,put the next nucleotide onto the growing end, bind it and catalyze the addition. This same cycle would have to repeat itself a very large number of times to complete a new DNA chain. Polymerases however catalyze the addition of a nucleotide but do not fall off the DNA. Rather, they stay bound to it, until the next nucleotide comes in, and then they catalyze its addition to the chain. and they again stay bound. If it were not so, the replication process would be very slow. In the cell, polymerases stay on the DNA until their job is completed, which might be only after millions of nucleotides have been joined. This velocity is only possible because of clamp proteins. These have a ring shape. The ring can be opened up. These clamp proteins are joined to the DNA polymerase in a intricate way, through a clamp loader protein, which has a remarkable shape similar to a human hand. It takes the clamp, like a hand with five fingers would grab it, opens it up becoming like a doughnut shape,where the whole hole in the middle is big enough to accommodate the DNA, and then, when it is on the DNA, it positions it in a precise manner on the DNA polymerase, where it stays bound until it reaches the end of its polymerizing job. Through this ingenious process, the clamp stabilizes the DNA, making it possible to increase the speed of polymerization dramatically. They can be seen here:
The sliding clamp and clamp loader
http://reasonandscience.heavenforum.org/t1849p1....es#4376
Question : How would and could natural , unguided processes have figured out 1. the requirement of high-speed of polymerization ? How could they have figured out the right configuration and process to do so ? how could natural processes have emerged with the right proteins incrementally, with the hand-shaped clamp loader, and the precisely fitting clamp , enabling the fast process ?? Even the most intelligent scientists are still not able to imagine how this process is engineered ? Furthermore, the process requires molecular energy in the form of ATP, and everything must fit together, and be functional. Without the clamp loader protein, the clamp could not be positioned to the polymerase enzyme, and processivity would not rise to the required speed. The whole process must also be regulated and controlled. How could that regulation have been programmed ? Trial and error ?
Several Proteins Are Required for DNA Replication at the Replication Fork
http://reasonandscience.heavenforum.org/t1849p1....es#4398
The various proteins involved in DNA replication are all closely associated in one large complex, called a replisome.
Leading strand synthesis: On the template strand with 3’-5’ orientation, new DNA is made continuously in 5’-3’ direction towards the replication fork. The new strand that is continuously synthesized in 5’-3’ direction is the leading strand.
Lagging strand synthesis: In the lagging strand, the synthesis of DNA also elongates in a 5ʹ to 3ʹ manner, but it does so in the direction away from the replication fork. In the lagging strand, RNA primers must repeatedly initiate the synthesis of short segments of DNA; thus, the synthesis has to be discontinuous.
The Primase (DnaG) enzyme, and the primosome complex
http://reasonandscience.heavenforum.org/t1849p1....es#4379
The length of these fragments in bacteria is typically 1000 to 2000 nucleotides. In eukaryotes, the fragments are shorter—100 to 200 nucleotides. Each fragment contains a short RNA primer at the 5ʹ end, which is made by primase. The remainder of the fragment is a strand of DNA made by DNA polymerase III. The DNA fragments made in this manner are known as Okazaki fragments. To complete the synthesis of Okazaki fragments within the lagging strand, three additional events must occur: removal of the RNA primers, synthesis of DNA in the area where the primers have been removed, and the covalent attachment of adjacent fragments of DNA. In E. coli, the RNA primers are removed by the action of DNA polymerase I. This enzyme has a 5ʹ to 3ʹ exonuclease activity, which means that DNA polymerase I digests away the RNA primers in a 5ʹ to 3ʹ direction, leaving a vacant area. DNA polymerase I then synthesizes DNA to fill in this region. It uses the 3ʹ end of an adjacent Okazaki fragment as a primer. , DNA polymerase I would remove the RNA primer from the first Okazaki fragment and then synthesize DNA in the vacant region by attaching nucleotides to the 3ʹ end of the second Okazaki fragment. After the gap has been completely filled in, a covalent bond is still missing between the last nucleotide added by DNA polymerase I and the adjacent DNA strand that had been previously made by DNA polymerase III. To the left of the origin, the top strand is made continuously, whereas to the right of the origin it is made in Okazaki fragments. By comparison, the synthesis of the bottom strand is just the opposite. To the left of the origin it is made in Okazaki fragments and to the right of the origin the synthesis is continuous. Finally the two ends of the fragment have to be joined together; this is the job of an enzyme called DNA ligase. After the completion of one Okazaki fragment , the equipment has to be released, the clamp has to let go, and a new clamp has to be loaded at the beginning of the next fragment. Clearly the formation and control of the replication fork is an enormously complex process.
Step 5: After DNA synthesis by DNA pol III, DNA polymerase I uses its 5’-3’ exonuclease activity to remove the RNA primer and fills the gaps with new DNA. In the next step, finally DNA ligase joins the ends of the DNA fragments together. As the replisome moves along the DNA in the direction of the replication fork, it must accommodate the fact that DNA is being synthesized in opposite directions along the template on the two stands. Picture above provides a schematic model illustrating how this might be accomplished by folding the lagging strand template into a loop.Creating such a loop allows the DNA polymerase molecules on both the leading and lagging strands to move in the same physical direction, even though the two template strands are oriented with opposite polarity. The replisome faces special challenges as it makes new DNA at rates that can approach 1,000 nucleotides per second. Unlike the machines that make proteins and RNA, which work relatively sluggishly and in a linear fashion, the replisome must simultaneously copy two strands of DNA that are aligned in opposite directions (5ʹ to 3ʹ and 3ʹ to 5ʹ). Replisome chemistry obeys two rules.
Questions: How did they arise with that cabability to " obey two rules " ? Suppose a primitive polymerase were duplicated and somehow started to replicate the second strand in the opposite direction while remaining attached to the first strand - how could that change have been directed , and why should that feat have happened randomly ?
The DNA polymerase holoenzyme alone would not be able to duplicate the long DNA faithfully. Tests have shown that Polymerase III alone gets stuck. Furthermore, Polymerase III is not a simple enzyme. Its rather three enzymes in one. Beside replicating DNA, it can also degrade DNA in two different ways. It does so by three different, discrete regions of the molecule. The exonuclease activity plays a critical role in replication. It allows the enzyme to proofread the new DNA and cut out any mistakes it has made. Although the polymerase reads the sequence of the old DNA to produce a new DNA, it turns out that simple base bairing allows about one mistake per thousand base pairs copied. Proofreading reduces errors to about one mistake in a million base pairs. The question is if wheter a proofreading exonuclease and other DNA repair mechanisms had to be present in the very first cell.
Eigen’s theory revealed the existence of the fundamental limit on the fidelity of replication (the Eigen threshold): If the product of the error (mutation) rate and the information capacity (genome size) is below the Eigen threshold, there will be stable inheritance and hence evolution; however, if it is above the threshold, the mutational meltdown and extinction become inevitable (Eigen, 1971). The Eigen threshold lies somewhere between 1 and 10 mutations per round of replication (Tejero, et al., 2011) regardless of the exact value, staying above the threshold fidelity is required for sustainable replication and so is a prerequisite for the start of biological evolution. Indeed, the very origin of the first organisms presents at least an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all; high-fidelity replication requires additional functionalities that need even more information to be encoded (Penny, 2005). The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^3 and viroids that replicate with the lowest fidelity among the known replicons (about 10^2; Gago, et al., 2009), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual.
DNA damage and repair
http://reasonandscience.heavenforum.org/t2043-d....+repair
http://reasonandscience.heavenforum.org/t1849p3....es#4401
Replication forks may stall frequently and require some form of repair to allow completion of chromosomal duplication. Failure to solve these replicative problems comes at a high price, with the consequences being genome instability, cell death and, in higher organisms, cancer. Replication fork repair and hence reloading of DnaB may be needed away from oriC at any point within the chromosome and at any stage during chromosomal duplication. The potentially catastrophic effects of uncontrolled initiation of chromosomal duplication on genome stability suggests that replication restart must be regulated as tightly as DnaA-directed replication initiation at oriC. This implies reloading of DnaB must occur only on ssDNA at repaired forks or D-loops rather than onto other regions of ssDNA, such as those created by blocks to lagging strand synthesis.Thus an alternative replication initiator protein, PriA helicase, is utilized during replication restart to reload DnaB back onto the chromosome
Question: Could the first cell, with its required complement of genes coded for by DNA, have successfully reproduced for a significant number of generations without a proofreading function ? A further question is how the function of synthesis of the lagging strand could have arisen, and the machinery to do so. That is, the Primosome, and the function of Polymerase I to remove the short peaces of RNA that the cell uses to prime replication, allowing the polymerase III function to fill the gap. These functions all require precise regulation, and coordinated functional machine-like steps. These are all complex, advanced functions and had to be present right from the beginning. How could this complex machinery have emerged in a gradual manner ? the Primosome had to be fully functional, otherwise polymerisation could not have started, since a prime sequence is required.
Step 6: Finally DNA ligase joins the ends of the DNA fragments together.
Termination phase:
Termination of DNA replication
http://reasonandscience.heavenforum.org/t1849p1....es#4399
Step 7: The two replication forks meet ~ 180 degree opposite to ori C, as DNA is circular in prokaryotes. Around this region there are several terminator sites which arrest the movement of forks by binding to the tus gene product, an inhibitor of helicase (Dna B).
Step 8: Once replication is complete, the two double stranded circular DNA molecules (daughter strands) remain interlinked. Topoisomerase II makes double stranded cuts to unlink these molecules.
According to mainstream scientific papers, the following twenty protein and protein complexes are essential for prokaryotic DNA replication. Each one mentioned below. They cannot be reduced. If one is missing, DNA replication cannot occur:
Pre-replication complex Formation of the pre-RC is required for DNA replication to occur
DnaA The crucial component in the initiation process is the DnaA protein
DiaA this novel protein plays an important role in regulating the initiation of chromosomal replication via direct interactions with the DnaA initiator.
DAM methylase It’s gene expression requires full methylation of GATC at its promoter region.
DnaB helicase Helicases are essential enzymes for DNA replication, a fundamental process in all living organisms.
DnaC Loading of the DnaB helicase is the key step in replication initiation. DnaC is essential for replication in vitro and in vivo.
HU-proteins HU protein is required for proper synchrony of replication initiation
SSB Single-stranded binding proteins Single-stranded DNA binding proteins are essential for the sequestration and processing of single-stranded DNA. 6
SSBs from the OB domain family play an essential role in the maintenance of genome stability, functioning in DNA replication, the repair of damaged DNA, the activation of cell cycle checkpoints, and in telomere maintenance. SSB proteins play an essential role in DNA metabolism by protecting single-stranded DNA and by mediating several important protein–protein interactions. 7
Hexameric DNA helicases DNA helicases are essential during DNA replication because they separate double-stranded DNA into single strands allowing each strand to be copied.
DNA polymerase I and III DNA polymerase 3 is essential for the replication of the leading and the lagging strands whereas DNA polymerase 1 is essential for removing of the RNA primers from the fragments and replacing it with the required nucleotides.
DnaG Primases They are essential for the initiation of such phenomena because DNA polymerases are incapable of de novo synthesis and can only elongate existing strands
Topoisomerases are essential in the separation of entangled daughter strands during replication. This function is believed to be performed by topoisomerase II in eukaryotes and by topoisomerase IV in prokaryotes. Failure to separate these strands leads to cell death.
Sliding clamp and clamp loader the clamp loader is a crucial aspect of the DNA replication machinery. Sliding clamps are DNA-tracking platforms that are essential for processive DNA replication in all living organisms
Primase (DnaG) Primases are essential RNA polymerases required for the initiation of DNA replication, lagging strand synthesis and replication restart. They are essential for the initiation of such phenomena because DNA polymerases are incapable of de novo synthesis and can only elongate existing strands.
RTP-Ter complex Ter sequences would not seem to be essential, but they may prevent overreplication by one fork in the event that the other is delayed or halted by an encounter with DNA damage or some other obstacle
Ribonuclease H RNase H1 plays essential roles in generating and clearing RNAs that act as primers of DNA replication.
Replication restart primosome Replication restart primosome is a complex dynamic system that is essential for bacterial survival.
DNA repair:
RecQ helicase In prokaryotes RecQ is necessary for plasmid recombination and DNA repair from UV-light, free radicals, and alkylating agents.
RecJ nuclease the repair machinery must be designed to act on a variety of heterogeneous DNA break sites.
I do not know of any scientific paper that explains in a detailed manner how DNA replication de novo or any of its parts might have emerged in a naturalistic manner, without involving intelligence. The systems responsible for DNA replication are well beyond the explanatory power of unguided natural processes without guiding intelligence involved. Indeed, machinery of the complexity and sophistication of that described above is, is in my view best explained through a intelligent designer.
Precisely BECAUSE WE KNOW that each of the described and mentioned parts is indispensable, it had to arise all at once. We know of intelligence being able to project, plan and make such a motor-like system based on lots of information , and it could not have emerged through evolution ( even less so because evolution depends on dna replication being in place ) we can infer rationally design as the best explanation. Chance is no reasonable option to explain the origin of DNA replication since the individual parts would have no function by their own, and there is no reason why matter aleatory-like would group itself in such highly organized and complex machine-like system.
1) http://www.weizmann.ac.il/plants....ean.pdf
2) http://cshperspectives.cshlp.org/content....16.full
3) https://en.wikipedia.org/wiki....ication
4) http://www.biochem.umd.edu/biochem....ein.htm
5) http://www.nature.com/nsmb....56.html
6) http://www.biomedcentral.com/1471-21....9
7) http://www.ncbi.nlm.nih.gov/pmc....3632105
8 ) Meyer, signature of the cell, page 111
9 ) http://journal.frontiersin.org/article....full#F1
10 ) http://creationsafaris.com/epoi_c0....c08.htm
11) http://creationsafaris.com/ar_srds....rds.htm
12) http://www.ncbi.nlm.nih.gov/books....NBK6360
13) from the book: The Logic of Chance: The Nature and Origin of Biological Evolution By Eugene V. Koonin, page 266
14) https://www-als.lbl.gov/index.p....on.html
15) http://www.nature.com/nature....85.html
16) http://ethos.bl.uk/OrderDe.....604184
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