Thursday, October 19, 2006

Self-Replicating RNA

In his usually brilliant style David Berlinski disposes of another Darwinian myth with scientific truth. Here is a part of his essay entitled 'On the Origins of Life.' My comments appear in bold print.

"In the grand progression by which life arose from inorganic matter, Miller Time has been concluded. It is now 3.8 billion years ago. The chemical precursors to life have been formed. A limpid pool of nucleotides is somewhere in existence. A new era is about to commence.

The historical task assigned to this era is a double one: forming chains of nucleic acids from nucleotides, and discovering among them those capable of reproducing themselves. Without the first, there is no RNA; and without the second, there is no life.

In living systems, polymerization or chain-formation proceeds by means of the cell’s invaluable enzymes. But in the grim inhospitable pre-biotic, no enzymes were available. And so chemists have assigned their task to various inorganic catalysts. J.P. Ferris and G. Ertem, for instance, have reported that activated nucleotides bond covalently when embedded on the surface of montmorillonite, a kind of clay. This example, combining technical complexity with general inconclusiveness, may stand for many others.

In any event, polymerization having been concluded—by whatever means—the result was (in the words of Gerald Joyce and Leslie Orgel) “a random ensemble of polynucleotide sequences”: long molecules emerging from short ones, like fronds on the surface of a pond. Among these fronds, nature is said to have discovered a self-replicating molecule. But how?"

Berlinski notes the need for a chemical catalyst of nucleotide polymers. He also alludes to the belief that nature generated a self-replicating polymer that initiated a series of reactions culminating in a self-replicating cell.

"Darwinian evolution is plainly unavailing in this exercise or that era, since Darwinian evolution begins with self-replication, and self-replication is precisely what needs to be explained. But if Darwinian evolution is unavailing, so, too, is chemistry. The fronds comprise “a random ensemble of polynucleotide sequences” (emphasis added); but no principle of organic chemistry suggests that aimless encounters among nucleic acids must lead to a chain capable of self-replication."

Berlinski exposes a slight of hand in pointing out that while Darwinian explanations begin with a self-replicating molecule, the self-replicating molecule itself needs explaining.

"If chemistry is unavailing and Darwin indisposed, what is left as a mechanism? The evolutionary biologist’s finest friend: sheer dumb luck.

Was nature lucky? It depends on the payoff and the odds. The payoff is clear: an ancestral form of RNA capable of replication. Without that payoff, there is no life, and obviously, at some point, the payoff paid off. The question is the odds."

So what is the explanation for the self-replicating molecule? Prebiotic conditions that made a self-replicating molecule virtually inevitable? Natural selection? It appears to be nothing short of good fortune; the stuff of OOL legends.

"For the moment, no one knows how precisely to compute those odds, if only because within the laboratory, no one has conducted an experiment leading to a self-replicating ribozyme. But the minimum length or “sequence” that is needed for a contemporary ribozyme to undertake what the distinguished geochemist Gustaf Arrhenius calls “demonstrated ligase activity” is known. It is roughly 100 nucleotides."

This is a key point that is applicable to many OOL experiments. Self-replicating ribozymes are not generated from simulated prebiotic soups. When the need for nucleic acids arises there are ready suppliers in the form of reliable biotechnology companies. The original source of biochemicals is of course a cell.

"Whereupon, just as one might expect, things blow up very quickly. As Arrhenius notes, there are 4100 or roughly 1060 nucleotide sequences that are 100 nucleotides in length. This is an unfathomably large number. It exceeds the number of atoms contained in the universe, as well as the age of the universe in seconds. If the odds in favor of self-replication are 1 in 1060, no betting man would take them, no matter how attractive the payoff, and neither presumably would nature.

“Solace from the tyranny of nucleotide combinatorials,” Arrhenius remarks in discussing this very point, “is sought in the feeling that strict sequence specificity may not be required through all the domains of a functional oligmer, thus making a large number of library items eligible for participation in the construction of the ultimate functional entity.” Allow me to translate: why assume that self-replicating sequences are apt to be rare just because they are long? They might have been quite common.

They might well have been. And yet all experience is against it. Why should self-replicating RNA molecules have been common 3.6 billion years ago when they are impossible to discern under laboratory conditions today? No one, for that matter, has ever seen a ribozyme capable of any form of catalytic action that is not very specific in its sequence and thus unlike even closely related sequences. No one has ever seen a ribozyme able to undertake chemical action without a suite of enzymes in attendance. No one has ever seen anything like it."

In other words why should we believe in a story linked to self-replicating molecules when their generation from conditions resembling a prebiotic starting point is not observed.

"The odds, then, are daunting; and when considered realistically, they are even worse than this already alarming account might suggest. The discovery of a single molecule with the power to initiate replication would hardly be sufficient to establish replication. What template would it replicate against? We need, in other words, at least two, causing the odds of their joint discovery to increase from 1 in 1060 to 1 in 10120. Those two sequences would have been needed in roughly the same place. And at the same time. And organized in such a way as to favor base pairing. And somehow held in place. And buffered against competing reactions. And productive enough so that their duplicates would not at once vanish in the soundless sea."

This is a dose of reality you will not get from OOL propagandists. Note the problematic conditions glossed over by RNA world advocates.

"In contemplating the discovery by chance of two RNA sequences a mere 40 nucleotides in length, Joyce and Orgel concluded that the requisite “library” would require 1048 possible sequences. Given the weight of RNA, they observed gloomily, the relevant sample space would exceed the mass of the earth. And this is the same Leslie Orgel, it will be remembered, who observed that “it was almost certain that there once was an RNA world.”

Initial enthusiam is tempered by sobering assessments.

"To the accumulating agenda of assumptions, then, let us add two more: that without enzymes, nucleotides were somehow formed into chains, and that by means we cannot duplicate in the laboratory, a pre-biotic molecule discovered how to reproduce itself."

Which puts OOLers back to square one and their faith based assumptions.



At 7:27 AM, Blogger Amanda said...

Really interesting-but definitely long-article.

I was wondering what your take is on Hox genes and the theory that hox gene duplication opened the door for mutation and natural selection...the following is an article I read for a class.

It's basically comparing the sequenced hox genes of the coelacanth to tetrapods to show an evolutionary relationship. I don't know if I'm justified in my frustration that they find it necessary to conform their genetic findings to the current phylogenetic tree that regards tetrapods as derived from lobe-finned fishes. What do you think?

At 5:02 PM, Blogger William Bradford said...

Hi Amanda. I'd like to give you a dual response. After reading the paper at the link and others that might be relevant I intend to post on the topic at this blog. That might take a few days. I could also give you some off the cuff remarks about hox genes but would prefer to do that by direct e-mail if that is OK with you. If it is you can contact the moderator of the Yahoo group Intelligently Sequenced (Nathan Munson) and let him know that it would be OK to forward your e-mail address.

At 9:07 AM, Blogger Raevmo said...

"No one has ever seen a ribozyme able to undertake chemical action without a suite of enzymes in attendance. No one has ever seen anything like it."

Actually, some people have:

At 3:47 PM, Blogger William Bradford said...

The sentence prior to the one you quoted is pertinent.

"No one, for that matter, has ever seen a ribozyme capable of any form of catalytic action that is not very specific in its sequence and thus unlike even closely related sequences."

The authors realized this and explained why a ligase rybozyme was used and the design approach required to illustrate a purposeless, unintelligent self-replicating OOL pathway.

"A system based on a ligase ribozyme was used to investigate the ability of catalytic RNA molecules to promote their own synthesis from component oligonucleotides. A self-replicating ribozyme was constructed by using a rational design approach, relying on RNA-catalyzed RNA ligation to bring about a reaction of the form A + B T. An important goal of the design was to have the template and substrates interact with minimal base pairing so that the ligated product could easily dissociate from the template and thus be available to catalyze subsequent ligation reactions. An added consideration was to optimize the construct so that the presence of the template molecule would greatly enhance the rate of ligation of the substrates compared with their ligation in the absence of the template. The R3C RNA ligase ribozyme was chosen for this study because of its simple secondary structure, reasonably fast ligation rate, and ability to function in an intermolecular reaction format."

The authors go on to make this telling point.

"All of the chemical self-replication systems that have been described, including the ribozyme-based system of the present study, are not capable of undergoing Darwinian evolution. These systems usually offer no choice other than to form a particular product molecule. Even in those cases where one template can direct the synthesis of multiple products (13, 31, 35), the products do not "breed true" such that each product species only gives rise to additional copies of itself. Furthermore, product formation typically involves only a single joining reaction. Thus the information content of a particular self-replicating species can be no more than log2(NA·NB), where NA is the number of different A substrates and NB is the number of different B substrates that can be joined and faithfully replicated."


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