Replicator first, and metabolism first scenarios

Replicator first, and metabolism first scenarios


http://reasonandscience.heavenforum.org/t1428-replicator-first-and-metabolism-first-scenarios

The replicator first scenario :

There are two approaches to life’s origin, one is the replicator or genetics -first, the other, the metabolism first proposal.



Two different conceptual models for the origin of life, “genetics first” (left) and “metabolism first” (right). In each case, one begins with small organic molecules synthesized abiotically on the Earth or even in parent bodies of meteorites. 
With genetics first, an information carrying molecule arises spontaneously and eventually controls chemical reactions in primitive cells. 

With metabolism first, undirected networks of chemical reactions – autocatalytic cycles – evolve to progressively higher complexity until they develop information-carrying molecules that eventually control the production of catalysts. Adapted from a figure by Trefil et al. (2009), with notional nucleotide from Englehart and Hud (2010).

In metabolism first, one argues that certain structures could form spontaneously, capable of isolating parts of the chemical soup from the environment. These vesicles, if the right chemicals were present, could have become little factories of increasing chemical complexity, eventually growing and splitting in two but still lacking a reliable (or any) genetic code for reproducing the chemical activity within them.

" Could have become little factories ". Really ??!! 

The other approach focuses on the genetic code, in particular, RNA, which might have been synthesized in the environment of the chemical soup, and once synthesized, multiplied and co-opted vesicles to form cells. Neither approach yet tells a convincing story, but both have led to some tantalizing suggestions as to how life could have arisen from complex, energetic chemical systems.

Thanks for the authors admitting the obvious. No, indeed. It's not a convincing story to claim that "certain structures could form spontaneously and become little factories ". 

The synthesis of amino acids is a far cry from the construction of complex, self-replicating molecules that carry enough information to construct proteins from amino acids.

The "RNA World" is essentially a hypothetical stage of life between the first replicating molecule and the highly complicated DNA-protein-based life. The chief problem facing an RNA world is that RNA cannot perform all of the functions of DNA adequately to allow for replication and transcription of proteins.

New findings challenge assumptions about origins of life

http://reasonandscience.heavenforum.org/t1428-replicator-first-and-metabolism-first-scenarios

There is currently no known chemical pathway for an "RNA world" to transform into a "DNA/protein world."

http://phys.org/news/2013-09-assumptions-life.html#jCp

But for the hypothesis to be correct, ancient RNA catalysts would have had to copy multiple sets of RNA blueprints nearly as accurately as do modern-day enzymes. That's a hard sell; scientists calculate that it would take much longer than the age of the universe for randomly generated RNA molecules to evolve sufficiently to achieve the modern level of sophistication. Given Earth's age of 4.5 billion years, living systems run entirely by RNA could not have reproduced and evolved either fast or accurately enough to give rise to the vast biological complexity on Earth today.


The RNA world hypothesis: the worst theory of the early evolution of life

http://www.ncbi.nlm.nih.gov/pubmed/22793875

(i) RNA is too complex a molecule to have arisen prebiotically;
(ii) RNA is inherently unstable;
(iii) catalysis is a relatively rare property of long RNA sequences only; and
(iv) the catalytic repertoire of RNA is too limited.



Can the Origin of the Genetic Code Be Explained by Direct RNA Templating?

http://bio-complexity.org/ojs/index.php/main/article/view/BIO-C.2011.2


In order a molecule to be a self replicator , it has to be a homopolymer, of which the backbone must have the same repetitive units; they must be identical. On the prebiotic world, the generation of a homopolymer was however impossible.

Steven A. Benner, Ph.D. Chemistry, Harvard, prominent origin-of-life researcher and creator of the Foundation for Applied Molecular Evolution, was posted on Huffington Post on December 6, 2013.  In it he said,

"We have failed in any continuous way to provide a recipe that gets from the simple molecules that we know were present on early Earth to RNA."

That lead Leslie Orgel to say :

It would take a miracle if a strand of RNA ever appeared on the primitive Earth.

(Dover, 1999, p. 218).

I would have thought it relevant to point out for biologists in general that not one self-replicating RNA has emerged to date from quadrillions (1024) of artificially synthesized, random RNA sequences


http://scienceandscientist.org/biology/

One of the major assumptions of the RNA world hypothesis is that in the primordial conditions, ribonucleotides spontaneously condense into polymers to form RNA molecules. Once RNA molecules have formed, by its catalytic activity to replicate itself a population of such self-replicating molecules would arise. “It is difficult to believe,” says RNA World research scientist Steven Benner, “that larger pools of random RNA emerged spontaneously without the gentle coaxing of a graduate student desiring a completed dissertation.”[82] In addition, researchers believe that even if RNA could have formed spontaneously, the spontaneous hydrolysis and other destructive conditions operational on the early Earth would have caused it to decompose.[2] Joyce and Orgel recommend that “…myth of a self-replicating RNA molecule that arose de novo from a soup of random polynucleotides. Not only is such a notion unrealistic in light of our current understanding of prebiotic chemistry, but it should strain the credulity of even an optimist’s view of RNA’s catalytic potential.”[83]

Francis Crick confirms that, “At present, the gap from the primal “soup” to the first RNA system capable of natural selection looks forbiddingly wide.”[84] Furthermore, RNA fails to perform all of the functions of DNA sufficiently to support replication and transcription of proteins. Consequently, Leslie Orgel pointed out the inability of the RNA world: “This scenario could have occurred, we noted, if prebiotic RNA had two properties not evident today: A capacity to replicate without the help of proteins and an ability to catalyze every step of protein synthesis.”[75] Orgel further acknowledged that, “The precise events giving rise to the RNA world remain unclear … investigators have proposed many hypotheses, but evidence in favor of each of them is fragmentary at best. The full details of how the RNA world, and life, emerged may not be revealed in the near future.” Consequently the RNA world reverie appears to be dreadfully hopeless.



http://www.ncbi.nlm.nih.gov/pubmed/10868906

IUBMB Life. 2000 Mar;49(3):173-6.
A replicator was not involved in the origin of life.
Shapiro R.
Author information
Abstract

Many scientific theories of the origin of life suggest that life began with the spontaneous formation of a replicator (a self-copying organic polymer) within an unorganized chemical mixture, or "soup." A profound difficulty exists, however, with the idea of RNA, or any other replicator, at the start of life. Existing replicators can serve as templates for the synthesis of additional copies of themselves, but this device cannot be used for the preparation of the very first such molecule, which must arise spontaneously from an unorganized mixture. The formation of an information-bearing homopolymer through undirected chemical synthesis appears very improbable. The difficulties involved in such a synthesis are illustrated by considering the prospects for the assembly of a polypeptide of L-alpha-amino acids, based on the contents of the Murchison meteorite as an example of a mixture of abiotic origin. In that mixture, potential replicator components would be accompanied by a host of interfering substances, which include chain terminators (simple carboxylic acids and amines), branch-formers, D-amino acids, and many classes of substances for which incorporation would disrupt the necessary structural regularity of the replicator. Laboratory experiments dealing with the nonenzymatic synthesis of biopolymers have not addressed the specificity problem. The possibility that formation of the first replicator took place through a very improbable event cannot be excluded, but greater attention should be given to metabolism-first theories, which avoid this difficulty.


http://www.lifesorigin.com/chap10/RNA-self-replication-3.php

Given the extreme difficulties associated with synthesizing an RNA molecule containing 200 or more bases, it is unlikely that even one such molecule ever existed on the primitive earth, and 15 trillion are needed to just get 65 functional ribozymes. Furthermore, ribozymes are not self replicators. The knowledge required for self replication is certainly many orders of magnitude more than the 44 bits required for a marginally functional ribozyme. Finally, the 44 bits calculated above is in a test tube where all competing side reactions are eliminated. If the real primordial soup contains free amino acids, aldehydes, and undesirable isomers of ribose, then the 44 bits will increase by a factor similar to the increase seen for the protein insulin in chapter 5. Taking this last factor into account, the 44 bits is at least one order of magnitude too small.

http://www.the-scientist.com/?articles.view/articleNo/39252/title/RNA-World-2-0/

The odds of suddenly having a self-replicating RNA pop out of a prebiotic soup are vanishingly low," says evolutionary biochemist Niles Lehman of Portland State University in Oregon.

A New Study Questions RNA World

http://www.evolutionnews.org/2012/03/study_questions057501.html

A new study in PLoS One shows that RNA and the proteins involved in protein synthesis must have co-evolved. This flies in the face of RNA-world theories, which presume that RNA formed first and that catalytic function (usually performed by proteins) was completed by catalytic RNA, known as ribozymes.

Researchers at the University of Illinois used phylogenetic modeling methods to evaluate the evolutionary history of the ribosome by correlating RNA structure and the ribosome protein structure. Their studies reveal several things of interest.

One of the assumptions in the RNA first hypothesis is that the active site of the ribosome, the peptidyl transferase center (PTC), which is the key player in protein synthesis, evolved first. However, Harish et al.'s studies reveal that the ribosome subunits actually evolved before the PTC active site and those subunits co-evolved with RNA, or what would eventually be sections of tRNA.

The authors conclude that their study answers some of the difficult questions associated with the RNA First World, while suggesting that there may have been a ribonuceloprotien primordial world:

   Our study therefore provides important clues about the chicken-or-egg dilemma associated with the central dogma of molecular biology by showing that ribosomal history is driven by the gradual structural accretion of protein and RNA structures. Most importantly, results suggest that functionally important and conserved regions of the ribosome were recruited and could be relics of an ancient ribonucleoprotein world.

RNA World
The RNA world or RNA-first hypothesis is arguably one of the stronger origin-of-life scenarios to date. While the field is still rife with inexplicable gaps in the progression from non-life to life, this hypothesis at least recognizes the fundamental need to explain the origin of the nucleotide sequence and subsequent coding for protein construction.

The cell has many types of RNA (messenger RNA, transfer RNA, ribosomal RNA, etc.), indicating that RNA can perform various functions. One particular function, when it was discovered, seemed to affirm notions that RNA may have preceded DNA and, therefore, preceded proteins. This function was the catalytic abilities of RNA. Catalysts, in short, speed a reaction. Proteins that act as catalysts are called enzymes, so catalytic RNA was thus named a ribozyme. Enzymes tend to be highly complex and specific to their particular functions.

The ribozyme seemed to answer the "chicken-or-egg" problem for origin-of-life theorists. Proteins are needed to make nucleic acids (RNA or DNA) and nucleic acids are needed to make proteins. Determining how this closed loop got started would provide answers to this most difficult origin-of-life conundrum.

However, while ribozymes were appealing in theory, they have many limitations that preclude their role as the initiators of early life. For example, RNA can cleave or link other RNA molecules, but this is only under specific laboratory conditions. Furthermore, RNA is limited in its capabilities compared to proteins. Ribozymes perform few functions, but protein synthesis requires multiple proteins, each often performing multiple functions.

This poses problems for how the first protein was produced. As the authors point out:

   Thus far, in vitro peptidyl transferase activity catalyzed by protein-free rRNA derived from extant rRNA or ribozymes is not demonstrated. Perhaps, the primordial cooperative property of the RNP [ribonucleoprotein] complex explains why such attempts have failed.

In other words, the authors believe that the closely tied interaction between the ribosome and RNA cannot be separated.


Top Five Problems with Current Origin-of-Life Theories

http://www.evolutionnews.org/2012/12/top_five_probl067431.html

the first RNA molecules would have to arise by unguided, non-biological chemical processes. But RNA is not known to assemble without the help of a skilled laboratory chemist intelligently guiding the process. New York University chemist Robert Shapiro critiqued the efforts of those who tried to make RNA in the lab, stating: "The flaw is in the logic -- that this experimental control by researchers in a modern laboratory could have been available on the early Earth."13

Second, while RNA has been shown to perform many roles in the cell, there is no evidence that it could perform all the necessary cellular functions currently carried out by proteins.14

Third, the RNA world hypothesis can't explain the origin of genetic information.

RNA world advocates suggest that if the first self-replicating life was based upon RNA, it would have required a molecule between 200 and 300 nucleotides in length.15 However, there are no known chemical or physical laws that dictate the order of those nucleotides.16 To explain the ordering of nucleotides in the first self-replicating RNA molecule, materialists must rely on sheer chance. But the odds of specifying, say, 250 nucleotides in an RNA molecule by chance is about 1 in 10150 -- below the "universal probability bound," a term characterizing events whose occurrence is at least remotely possible within the history of the universe.17 Shapiro puts the problem this way:

The sudden appearance of a large self-copying molecule such as RNA was exceedingly improbable. ... [The probability] is so vanishingly small that its happening even once anywhere in the visible universe would count as a piece of exceptional good luck.


The RNA world hypothesis: the worst theory of the early evolution of life (except for all the others)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673073/

1. Earth Evolution of a Habitable World, Second edition, page 152

The metabolism-first proposal 

Autocatalysis is a process that can lead to complex behavior. Beginning with two chemical substances that tend to react with each other, and supplying enough such reactants to maintain vigorous chemical reactions, progressively more complex molecules can be built up in the soup, including molecules that catalyze certain reactions. The key is a continuous supply of reactants, and a source of energy, that is, the system must be maintained far from equilibrium. Even more significant is that complicated autocatalytic systems, as simulated in computers, have the capacity to increase their level of organization over time. If several sets of autocatalytic cycles are in operation in the same environment, they have the possibility of producing complex chemical species that can couple the sets together and create further organization and complexity. These self-organizing chemical systems increase their network of reaction steps and become more organized so long as energy is available to hold them far from equilibrium. Scientists have argued that perhaps such autocatalytic sets brought organic chemical systems from the simplest starting components – amino acids and nucleic acid bases, for example – to increasing levels of complexity until primitive proteins and other structures were produced. To do this, the chemical system must have been held far from equilibrium, which means isolating the system from the surrounding environment and enabling energy and reactants to be pumped in and products to be removed. This is where vesicles play a role.

In a watery (aqueous) medium, certain simple molecules spontaneously form bilayer membranes that partition off an “inside” from an “outside.” Biological materials such as egg white will do this. Simpler organic molecules called lipids, which need not be produced biologically, will do likewise. So, in the early Earth’s oceans, it may have been that small environments, microns or less in size, were partitioned off spontaneously by simple organic molecules.
Within the interior of a vesicle, the environment was partially isolated from the outside. It then would be possible to create a small system, out of equilibrium, within which complex chemical reactions, perhaps autocatalytic sets, could have occurred. To do so, we must specify two essential ingredients, namely, energy and a pathway for introducing reactants and removing products. The spontaneously formed vesicles would not themselves be a source of energy, except for the heat given off by chemical reactions inside them. This heat, though, represents increase of entropy and is not available to do work inside the vesicle. Likewise, heating from the outside is possible but would merely tend to equalize the inside and outside temperatures – not a promising start for bringing our environment away from equilibrium. One novel suggestion that has been made recently is that certain simple organic molecules, attachable to the vesicle, may have had the capacity for capturing light energy from the Sun and using it to ionize parts of the vesicle membrane. Although speculative, such molecules would transduce energy from the Sun and make it available as chemical energy (via the ions formed from the membrane) inside the vesicle.

What about the transfer of reactants and products? This also appears to be possible through a particular set of complex organic molecules that could have acted as channels, filtering some substances through and excluding others. Some preliminary experiments have suggested the possibility that such an attribute might be developed on the vesicles through molecules available in the organic soup of the early ocean. Although still hypothetical, we have conjectured a vesicle machine that can be charged up, transfer molecules in and out, and serve as an isolated environment for autocatalytic reactions – all of this using molecules plausibly available in the prebiotic environment. The purpose of the machine is simply to make molecules of higher and higher complexity. Whether such molecules eventually would move toward proteins and enzymes is completely unclear. The principle, though, is simple: hold it away from equilibrium and let it get more complex! 3

Lack of evolvability in self-sustaining autocatalytic networks constraints metabolism-first scenarios for the origin of life 2

A basic property of life is its capacity to experience Darwinian evolution.  The replicator concept is at the core of genetics-first theories of the origin of life, which suggest that self-replicating oligonucleotides or their similar ancestors may have been the first “living” systems and may have led to the evolution of an RNA world.  But problems with the nonenzymatic synthesis of biopolymers and the origin of template replication have spurred the alternative metabolism-first scenario, where self-reproducing and evolving proto-metabolic networks are assumed to have predated self-replicating genes.  Recent theoretical work shows that “compositional genomes” (i.e., the counts of different molecular species in an assembly) are able to propagate compositional information and can provide a setup on which natural selection acts.  Accordingly, if we stick to the notion of replicator as an entity that passes on its structure largely intact in successive replications, those macromolecular aggregates could be dubbed “ensemble replicators” (composomes) and quite different from the more familiar genes and memes. In sharp contrast with template-dependent replication dynamics, we demonstrate here that replication of compositional information is so inaccurate that fitter compositional genomes cannot be maintained by selection and, therefore, the system lacks evolvability (i.e., it cannot substantially depart from the asymptotic steady-state solution already built-in in the dynamical equations). We conclude that this fundamental limitation of ensemble replicators cautions against metabolism-first theories of the origin of life, although ancient metabolic systems could have provided a stable habitat within which polymer replicators later evolved.



Evolution Hopes You Don't Know Chemistry: The Problem of Control

Chemical Stability 

Chemical stability is a question of whether the components can even react at all.

By definition, all components in a hypothetical primordial soup would be stable, because if they were not, they would have already reacted. Amino acids are relatively stable in water and do not react to form proteins in water, and nucleotides do not react to form DNA. In order to make amino acids and nucleotides react to form a polymer, they must be chemically activated to react with other chemicals. But this chemical activation must be done in the absence of water because the activated compounds will react with water and break down. How could proteins and DNA be formed in a hypothetical primordial watery soup if the activated compounds required to form them cannot exist in water? This is the problem of Chemical Stability.

Chemical Reactivity

Chemical reactivity deals with how fast the components react in a given reaction.

If life began in a primordial soup by natural chemical reactions, then the laws of chemistry should be able to predict the sequence of these chains. But when amino acids react chemically, they react according to their reactivity, and not in some specified order necessary for life. As the protein or DNA chain is increasing in size through chemical reaction, we should see the most reactive amino acid adding to the chain first, followed by the next most reactive amino acid, and so on.

Let's assume that we begin with the sequence R-T-X, and will add two amino acids "B" and "A" to it. If amino acid "B" is the most reactive amino acid, the sequence would be R-T-X-B-A. However, if "A" is the most reactive amino acid, then the sequence would be R-T-X-A-B. In a random chemical reaction, the sequence of amino acids would be determined by the relative reactivity of the different amino acids. The polymer chain found in natural proteins and DNA has a very precise sequence that does not correlate with the individual components' reaction rates. Since all of the amino acids have relatively similar structures, they all have similar reaction rates; they will all react at about the same rate making the precise sequence by random chemical reactions unthinkably unlikely. This is the problem of Chemical Reactivity.

Chemical Selectivity

Chemical selectivity is a problem of where the components react.

Since the chain has two ends, the amino acids can add to either end of the chain. Even if by some magical process, a single amino acid "B" would react first as desired for the pre-determined life supporting sequence followed by a single amino acid "A," the product would be a mixture of at least four isomers because there are two ends to the chain. If there is an equal chance of amino acid "B" reacting in two different locations, then half will react at one end, half at the other end. The result of adding "B" will form two different products. When the addition of amino acid "A" occurs, it will react at both ends of the chain of both the products already present. As in the previous example, the major products would be R-T-X-B-A and A-R-T-X-B as well as A-B-R-T-X and B-R-T-X-A and others. The result is a mixture of several isomers of which the desired sequence seldom results, and this is the problem with only two amino acids reacting. As the third amino acid is added, it can react at both ends of four products, and so on, insuring randomness, not a precise sequence.

Since proteins may contain hundreds or thousands of amino acids in a sequence, imagine the huge number of undesired isomers that would be present if these large proteins were formed in a random process. Evolutionists might argue that all proteins were formed in this manner, and nature simply selected the ones that worked. However, this is only an ad hoc assumption and it ignores the fact that we do not have billions of "extra" proteins in our body. Furthermore, nature is not intelligent. There is nothing in nature to do the selecting all-the-while splicing together non-functioning (therefore non-selectable) amino acids toward a working whole. Evolutionists say that nature is blind, has no goal, and no purpose, and yet precise selection at each step is necessary. This is the problem of Chemical Selectivity.



Amino acids are relatively stable in water and do not react to form proteins in water, and nucleotides do not react to form DNA. In order to make amino acids and nucleotides react to form a polymer, they must be chemically activated to react with other chemicals. But this chemical activation must be done in the absence of water because the activated compounds will react with water and break down. How could proteins and DNA be formed in a hypothetical primordial watery soup if the activated compounds required to form them cannot exist in water? This is the problem of Chemical Stability.

What is proposed, is a network of chemical reactions that involve small molecules. And these networks need to have some sort of catalysis in order to react into a product. The problem here is that mineral surfaces that have been proposed as catalytic materials have limited catalytic range, means that the products have to migrate to other mineral sites, in order of the pathway to be sustained; that is simply a impossible scenario.

Other proposals, like the reversal citric acid cicle face also sever problems,because the catalysts lack the necessary specificity.

In 2008, Leslie Orgel wrote a article against this proposal :

http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060018

Proposed polymer replication schemes are unlikely to succeed except with reasonably pure input monomers. No solution of the origin-of-life problem will be possible until the gap between the two kinds of chemistry is closed.


http://crev.info/2014/05/origin-of-life-studies-show-signs-of-desperation/

Deep-sixing the deep sea vent hypothesis:  Astrobiology Magazine, ever eager to justify its evidence-free subject, shows a group of happy young researchers out on a cruise.  Within the article about deep-sea vents as possible spots for the origin of life (the “metabolism-first” scenario) is this confession: “it may not have been as easy as previously assumed.”  The theory was appealing, but researchers from the Woods Hole Oceanographic Institute were “surprised by what they found” when they went to test the metabolism-first theory by looking for methanethiol, believed to be a “precursor of life.”  It should be abundant around black smoker vents because of all the available hydrogen.  Contrary to expectations, they found very little.  “Overall, this means that jump-starting proto-metabolic reactions in hydrogen-rich early Earth hydrothermal systems through carbon-sulfur chemistry would likely have been much harder than many had assumed.”  This “disappointing” finding indicates that the chemical is not being produced abiotically, but only with the involvement of living organisms.  In order to turn this work into something “exciting,” they spun the story to focus on the possibility of more life below the seafloor than was previously known.  (This, of course, does not explain where that life came from.)  Maybe, too, the detection of methanethiol on Europa or an exoplanet could be an indicator life is present.  Not deterred by the falsification, they maintained their faith: “The hydrothermal environment is still a perfect place to support early life, and the question of how it all started is still open.”


The Implausibility of Metabolic Cycles on the Prebiotic Earth
Leslie E Orgel†

http://reasonandscience.heavenforum.org/t2110-what-might-be-a-protocells-minimal-genome

Although metabolism-first avoids the infeasibility of forming functional RNA by chance, "replication of compositional information is so inaccurate that fitter compositional genomes cannot be maintained by selection and, therefore, the system lacks evolvability (i.e., it cannot substantially depart from the asymptotic steady-state solution already built-in in the dynamical equations). We conclude that this fundamental limitation of ensemble replicators cautions against metabolism-first theories of the origin of life" [44]. Concerning the chemical cycles required, "These are chemically very difficult reactions ... One needs, therefore, to postulate highly specific catalysts for these reactions. It is likely that such catalysts could be constructed by a skilled synthetic chemist, but questionable that they could be found among naturally occurring minerals or prebiotic organic molecules. The lack of a supporting background in chemistry is even more evident in proposals that metabolic cycles can evolve to 'life-like' complexity. The most serious challenge to proponents of metabolic cycle theories—the problems presented by the lack of specificity of most non-enzymatic catalysts—has, in general, not been appreciated. If it has, it has been ignored. Theories of the origin of life based on metabolic cycles cannot be justified by the inadequacy of competing theories: they must stand on their own"

1) http://www.icr.org/article/evolution-hopes-you-dont-know-chemistry-problem-co/
2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824406/
3. 1. Earth Evolution of a Habitable World, Second edition, page 152

First life: The search for the first replicator

http://www.newscientist.com/article/mg21128251.300-first-life-the-search-for-the-first-replicator.html?full=true#.VUu0OY5VhBc

Life must have begun with a simple molecule that could reproduce itself – and now we think we know how to make one

4 BILLION years before present: the surface of a newly formed planet around a medium-sized star is beginning to cool down. It's a violent place, bombarded by meteorites and riven by volcanic eruptions, with an atmosphere full of toxic gases. But almost as soon as water begins to form pools and oceans on its surface, something extraordinary happens. A molecule, or perhaps a set of molecules, capable of replicating itself arises.

This was the dawn of evolution. Once the first self-replicating entities appeared, natural selection kicked in, favouring any offspring with variations that made them better at replicating themselves. Soon the first simple cells appeared. The rest is prehistory.

Billions of years later, some of the descendants of those first cells evolved into organisms intelligent enough to wonder what their very earliest ancestor was like. What molecule started it all?


As far back as the 1960s, a few of those intelligent organisms began to suspect that the first self-replicating molecules were made of RNA, a close cousin of DNA. This idea has always had a huge problem, though - there was no known way by which RNA molecules could have formed on the primordial Earth. And if RNA molecules couldn't form spontaneously, how could self-replicating RNA molecules arise? Did some other replicator come first? If so, what was it? The answer is finally beginning to emerge.

When biologists first started to ponder how life arose, the question seemed baffling. In all organisms alive today, the hard work is done by proteins. Proteins can twist and fold into a wild diversity of shapes, so they can do just about anything, including acting as enzymes, substances that catalyse a huge range of chemical reactions. However, the information needed to make proteins is stored in DNA molecules. You can't make new proteins without DNA, and you can't make new DNA without proteins. So which came first, proteins or DNA?

The discovery in the 1960s that RNA could fold like a protein, albeit not into such complex structures, suggested an answer. If RNA could catalyse reactions as well as storing information, some RNA molecules might be capable of making more RNA molecules. And if that was the case, RNA replicators would have had no need for proteins. They could do everything themselves.

It was an appealing idea, but at the time it was complete speculation. No one had shown that RNA could catalyse reactions like protein enzymes. It was not until 1982, after decades of searching, that an RNA enzyme was finally discovered. Thomas Cech of the University of Colorado in Boulder found it in Tetrahymena thermophila, a bizarre single-celled animal with seven sexes (Science, vol 231, p 4737).

After that the floodgates opened. People discovered ever more RNA enzymes in living organisms and created new ones in their labs. RNA might be not be as good for storing information as DNA, being less stable, nor as versatile as proteins, but it was turning out to be a molecular jack of all trades. This was a huge boost to the idea that the first life consisted of RNA molecules that catalysed the production of more RNA molecules - "the RNA world", as Harvard chemist Walter Gilbert dubbed it 25 years ago (Nature, vol 319, p 618).

These RNA replicators may even have had sex. The RNA enzyme Cech discovered did not just catalyse any old reaction. It was a short section of RNA that could cut itself out of a longer chain. Reversing the reaction would add RNA to chains, meaning RNA replicators might have been able to swap bits with other RNA molecules. This ability would greatly accelerate evolution, because innovations made by separate lineages of replicators could be brought together in one lineage.

Evolving replicators

For many biologists the clincher came in 2000, when the structure of the protein-making factories in cells was worked out. This work confirmed that nestling at the heart of these factories is an RNA enzyme - and if proteins are made by RNA, surely RNA must have come first.

Still, some issues remained. For one thing, it remained unclear whether RNA really was capable of replicating itself. Nowadays, DNA and RNA need the help of many proteins to copy themselves. If there ever was a self-replicator, it has long since disappeared. So biochemists set out to make one, taking random RNAs and evolving them for many generations to see what they came up with.

By 2001, this process had yielded an RNA enzyme called R18 that could stick 14 nucleotides - the building blocks of RNA and DNA - onto an existing RNA, using another RNA as a template (Science, vol 292, p 1319). Any self-replicating RNA, however, needs to build RNAs that are at least as long as itself - and R18 doesn't come close. It is 189 nucleotides long, but the longest RNA it can make contains just 20.

A big advance came earlier this year, when Philipp Holliger of the MRC Laboratory of Molecular Biology in Cambridge, UK, and colleagues unveiled an RNA enzyme called tC19Z. It reliably copies RNA sequences up to 95 letters long, almost half as long as itself (Science, vol 332, p 209). To do this, tC19Z clamps onto the end of an RNA, attaches the correct nucleotide, then moves forward a step and adds another. "It still blows my mind that you can do something so complex with such a simple molecule," Holliger says.

So biologists are getting tantalisingly close to creating an RNA molecule, or perhaps a set of molecules, capable of replicating itself. That leaves another sticking point: where did the energy to drive this activity come from? There must have been some kind of metabolic process going on - but RNA does not look up to the job of running a full-blown metabolism.

"There's been a nagging issue of whether RNA can do all the chemistry," says Adrian Ferré-D'Amaré of the National Heart, Lung and Blood Institute in Bethesda, Maryland. RNA has only a few chemically active "functional groups", which limit it to catalysing just a few types of chemical reaction.

Functional groups are like tools - the more kinds you have, the more things you can do. Proteins have many more functional groups than RNAs. However, there is a way to make a single tool much more versatile: attach different bits to it, like those screwdrivers that come with interchangeable heads. The chemical equivalents are small helper molecules known as cofactors.

Proteins use cofactors to extend even further the range of reactions they can control. Without cofactors, life as we know it couldn't exist, Ferré-D'Amaré says. And it turns out that RNA enzymes can use cofactors too.

In 2003, Hiroaki Suga, now at the University of Tokyo, Japan, created an RNA enzyme that could oxidise alcohol, with help from a cofactor called NAD+ which is used by many protein enzymes (Nature Structural Biology, vol 10, p 713). Months later, Ronald Breaker of Yale University found that a natural RNA enzyme, called glmS, also uses a cofactor.

Many bacteria use glmS, says Ferré-D'Amaré, so either it is ancient or RNA enzymes that use cofactors evolve easily. Either way, it looks as if RNA molecules would have been capable of carrying out the range of the reactions needed to produce energy.

So the evidence that there was once an RNA world is growing ever more convincing. Only a few dissenters remain. "The naysayers about the RNA world have lost a lot of ground," says Donna Blackmond of the Scripps Research Institute in La Jolla, California. But there is still one huge and obvious problem: where did the RNA come from in the first place?

RNA molecules are strings of nucleotides, which in turn are made of a sugar with a base and a phosphate attached. In living cells, numerous enzymes are involved in producing nucleotides and joining them together, but of course the primordial planet had no such enzymes. There was clay, though. In 1996, biochemist Leslie Orgel showed that when "activated" nucleotides - those with an extra bit tacked on to the phosphate - were added to a kind of volcanic clay, RNA molecules up to 55 nucleotides long formed (Nature, vol 381, p 59). With ordinary nucleotides the formation of large RNA molecules would be energetically unfavourable, but the activated ones provide the energy needed to drive the reaction.

This suggests that if there were plenty of activated nucleotides on the early Earth, large RNA molecules would form spontaneously. What's more, experiments simulating conditions on the early Earth and on asteroids show that sugars, bases and phosphatesMovie Camera would arise naturally too. It's putting the nucleotides together that is the hard bit; there does not seem to be any way to join the components without specialised enzymes. Because of the shapes of the molecules, it is almost impossible for the sugar to join to a base, and even when it does happen, the combined molecule quickly breaks apart.

This apparently insurmountable difficulty led many biologists to suspect to RNA was not the first replicator after all. Many began exploring the possibility that the RNA world was preceded by a TNA world, or a PNA world, or perhaps an ANA world. These are all molecules similar to RNA but whose basic units are thought to have been much more likely to form spontaneously. The big problem with this idea is that if life did begin this way, no evidence of it remains. "You don't see a smoking gun," says Gerald Joyce, also of the Scripps Research Institute.

In the meantime John Sutherland, at the MRC Laboratory of Molecular Biology, has been doggedly trying to solve the nucleotide problem. He realised that researchers might have been going about it the wrong way. "In each nucleotide, you see a sugar, a base and a phosphate group," he says. "So you assume you need to make those building blocks first and then stick them together... and it doesn't work."

Instead he wondered whether simpler molecules might assemble into a nucleotide without ever becoming sugars or bases. In 2009, he proved it was possible. He took half a sugar and half a base, and stuck them together - forming the crucial sugar-base link that everyone had struggled with. Then he bolted on the rest of the sugar and base. Sutherland stuck on the phosphate last, though he found that it needed to be present in the mixture for the earlier reactions to work (Nature, vol 459, p 239).

Goldilocks chemistry

Sutherland was being deliberately messy by including the phosphate from the start, but it gave the best results. That's encouraging: the primordial Earth was a messy place and it may have been ideal for making nucleotides. Sutherland now suspects there is a "Goldilocks chemistry"Movie Camera - not too simple, not too complex - that would produce many key compounds from the same melting pot.

"Sutherland had a real breakthrough," Holliger says. "Everyone else was barking up the wrong tree."

The issue isn't entirely solved yet. RNA has four different nucleotides, and so far Sutherland has only produced two of them. However, he says he is "closing in" on the other two. If he succeeds, it will show that the spontaneous formation of an RNA replicator is not so improbable after all, and that the first replicator was most likely made of RNA.

Many questions remain, of course. Where did the first replicators arise? What was the first life like? How did the transition to DNA and proteins, and the development of the genetic code, occur? We may never know for sure but many promising avenues are being explored. Most biologists think there must have been something like a cell right from the start, to contain the replicator and keep its component parts together. That way, individuals could compete for resources and evolve in different ways.

Jack Szostak of Harvard University has shown that the same clay that produces RNA chains also encourages the formation of membrane-bound sacs rather like cells that enclose cells. He has grown "proto-cells" that can carry RNA and even divide without modern cellular machinery.

Another idea is that life began in alkaline hydrothermal vents on the sea floorMovie Camera. Not only are these vents laced with pores and bubbles, but they also provide the same kind of electrochemical gradient that drives energy production in cells to this day. Conditions may have been ideal for producing long RNA chains.

Holliger has a rather surprising idea: maybe it all happened in ice. At the time life began, the sun was 30 per cent dimmer than today. The planet would have frozen over if the atmosphere hadn't been full of greenhouse gases, and there may well have been ice towards the poles.

Cold RNA lasts longer, and ice has many other benefits. When water laced with RNA and other chemicals is cooled, some of it freezes while the rest becomes a concentrated brine running around the ice crystals. "You get little pockets within the ice," Holliger says. Interestingly, the R18 RNA enzyme works better in ice than at room temperature (Nature Communications, DOI: 10.1038/ncomms1076).

Right now, there's no way to choose between these options. No fossilised vestiges remain of the first replicators as far as we know. But we can try recreating the RNA world to demonstrate how it might have arisen. One day soon, Sutherland says, someone will fill a container with a mix of primordial chemicals, keep it under the right conditions, and watch life emerge. "That experiment will be done."

Creating Life in the Lab, Fazale Rana pg.108:

Metabolism defines the entire set of chemical pathways in the cell. The foremost of these involves the chemical transformation of relatively small molecules, pathways that (1) generate chemical energy through the controlled breakdown of fuel molecules like sugars and fats; and (2) produce (in a stepwise fashion) the building blocks needed to assemble proteins, DNA, RNA, and cell-membrane and cell-wall components. Life’s metabolic pathways often share many molecules. This sharing causes the cell’s metabolic routes to interconnect and form complex webs. An intramural debate exists within the origin-of-life community at this point. One group argues that self-organization started with metabolism (the metabolism-first model), whereas the other insists that life stemmed from self-replicators (the replicator-first model).

Metabolism first.
Metabolism-first proponents maintain that mineral surfaces catalyzed the formation of a diverse collection of small molecules that, with time, evolved to form an interconnected series of chemical reactions. Once in place, these interrelated chemical reactions formed the basis for the cell’s metabolic systems. These chemical networks eventually became encapsulated to form protocells complete with a form of protometabolism. Some metabolism-first scenarios, like the iron-sulfur world, even suggest that minerals (for example, pyrite) became encapsulated along with the protometabolic networks and thereby served as life’s first catalysts. According to the metabolism-first idea, once protometabolic systems were established, they spawned self-replicating molecules.

Replicator first.
The replicator-first enthusiasts propose the emergence of a naked replicator that later became encapsulated along with the precursor molecules needed to sustain its activity. Metabolism subsequently emerged as a means to support the production and turnover of the replicator’s building blocks and ultimately its self-replicating activity. The main focus of the replicator-first research program is to determine the original replicator’s identity. Early on, the replicator-first community debated whether DNA or proteins served as the first replicators. The controversy sparked what origin-of-life researchers call the chicken-and-egg problem.22 This conundrum refers to the complete interdependence that proteins and DNA have on one another when it comes to their synthesis and biochemical roles in the cell. DNA stores within its molecular structure the total information that the cell needs to function. DNA replication produces duplicate copies of this information and transmits it to the next generation as part of the reproductive process. Even though scientists refer to DNA as a self-replicating molecule, its synthesis, and hence its replication, requires a suite of proteins. In other words, proteins replicate DNA. On the other hand, proteins, which play a role in practically every cell function, depend upon DNA for their production because DNA contains the information that the cell’s machinery uses to synthesize proteins. Without DNA, the cell cannot produce proteins.Because of this interdependence, origin-of-life explanations must account for the simultaneous appearance of DNA and proteins. As yet, no one has envisioned a scenario that involves either class of molecule apart from the other.

The RNA World and Its Alternatives
Other origin-of-life researchers find the resolution to this chicken-and-egg problem in RNA. This chainlike molecule shares many structural similarities with DNA. It assumes the role of an intermediary in protein formation by conveying the information stored in DNA to the cell’s proteinmaking systems.Many scientists think that RNA was the premier replicator, predating both DNA and proteins. 23 According to this model, called the RNA-world hypothesis, RNA took on the contemporary biochemical function of both DNA and proteins by operating as a self-replicator that catalyzed its own synthesis. According to the RNA-world hypothesis, numerous RNA molecules with a wide range of catalytic activity emerged through time. RNA-world biochemistry centered exclusively on RNA. Through more time, the RNA world transitioned to an RNA-protein world and finally gave way to contemporary biochemistry with the addition of DNA to the cell’s arsenal. As the RNA world transitioned to the DNA-protein world, RNA’s original function became partitioned between proteins and DNA, with RNA assuming its current intermediary role. The RNA ancestral molecules presumably disappeared without leaving a trace of their primordial existence. The RNA world has its roots in the late 1960s when Francis Crick, Leslie Orgel, and Carl
Woese suggested there must have been a primitive cellular system based on RNA.24 In the mid-1980s the discovery of RNA molecules with enzymatic activity (called ribozymes) propelled the RNAworld hypothesis to prominence.25 Since then, several researchers have produced in the lab a number of ribozymes that engage in a range of potential biological activities.26 For many researchers, this success adds further credibility to the RNA-world explanation. The RNA-world hypothesis may well be the most prominent and promising idea in the origin-oflife arena. Much of the latest research focuses on identifying chemical routes to produce prebiotic
compounds and identifying condensation reactions that have the potential to lead to RNA. Nevertheless, difficulty in making RNA building blocks motivates some origin-of-life researchers to look beyond the RNA-world hypothesis for the first replicator. They are revisiting the possibility that either DNA or proteins filled that role. These revitalized DNA- and protein-world scenarios find support in new studies that demonstrate DNA’s capacity to catalyze (to a limited degree) chemical reactions, and proteins’ ability to self-replicate.27 Other investigators still hold to the RNA-world hypothesis, but incorporate an additional stage in the origin-of-life pathway that precedes the RNA world. Proponents of these pre-RNA-world interpretations search for self-replicating molecules structurally simpler and more stable than RNA. One leading candidate for the first replicator is a class of protein-DNA hybrids called peptidenucleic acids (PNA).28 PNA’s backbone resembles a protein’s, and PNA side groups are the same as those found in DNA and RNA. In principle, PNA may possess the characteristics necessary to selfreplicate.

Hugh Ross & Fazale Rana, Origins of life

Emergence of Self-Replication and Metabolism
Regardless of where prebiotic compounds arose or how they condensed to form more complex biomolecules, all naturalistic origin-of-life scenarios must seek to identify self-organization pathways capable of generating two of life’s key biochemical features: self-replication and metabolism. From a molecular standpoint, self-replication describes the capacity of a complex molecule to guide its own reproduction, typically by serving as a template that directs the assembly of chemical constituents into molecules that are identical to it. Metabolism defines the entire set of chemical pathways in the cell. The foremost of these involves the chemical transformation of relatively small molecules, pathways that (1) generate chemical energy through the controlled breakdown of fuel molecules like sugars and fats; and (2) produce (in a stepwise fashion) the building blocks needed to assemble proteins, DNA, RNA, and cell-membrane and cell-wall components. Life’s metabolic pathways often share many molecules. This sharing causes the cell’s metabolic routes to interconnect and form complex webs. An intramural debate exists within the origin-of-life community at this point. One group argues that self-organization started with metabolism (the metabolism-first model), whereas the other insists that life stemmed from self-replicators (the replicator-first model).

Metabolism first.
Metabolism-first proponents maintain that mineral surfaces catalyzed the formation of a diverse collection of small molecules that, with time, evolved to form an interconnected series of chemical reactions. Once in place, these interrelated chemical reactions formed the basis for the cell’s metabolic systems.21 These chemical networks eventually became encapsulated to form protocells complete with a form of protometabolism. Some metabolism-first scenarios, like the iron-sulfur world, even suggest that minerals (for example, pyrite) became encapsulated along with the protometabolic networks and thereby served as life’s first catalysts. According to the metabolism-first idea, once protometabolic systems were established, they spawned self-replicating molecules.

Replicator first.
The replicator-first enthusiasts propose the emergence of a naked replicator that later became encapsulated along with the precursor molecules needed to sustain its activity. Metabolism subsequently emerged as a means to support the production and turnover of the replicator’s building blocks and ultimately its self-replicating activity. The main focus of the replicator-first research program is to determine the original replicator’s identity. Early on, the replicator-first community debated whether DNA or proteins served as the first replicators. The controversy sparked what origin-of-life researchers call the chicken-and-egg problem.22 This conundrum refers to the complete interdependence that proteins and DNA have on one another when it comes to their synthesis and biochemical roles in the cell. DNA stores within its molecular structure the total information that the cell needs to function. DNA replication produces duplicate copies of this information and transmits it to the next generation as part of the reproductive process. Even though scientists refer to DNA as a self-replicating molecule, its synthesis, and hence its replication, requires a suite of proteins. In other words, proteins replicate DNA. On the other hand, proteins, which play a role in practically every cell function, depend upon DNA for their production because DNA contains the information that the cell’s machinery uses to synthesize proteins. Without DNA, the cell cannot produce proteins. Because of this interdependence, origin-of-life explanations must account for the simultaneous appearance of DNA and proteins.

Metabolite pool
In certain ways, a metabolic pathway is similar to a factory assembly line. Products are assembled from parts by workers who each perform a specific step in the manufacturing process. Enzymes of a cell are like workers on an assembly line; each is only responsible for a particular step in the assembly process.
https://en.wikipedia.org/wiki/Metabolite_pool#:~:text=In%20certain%20ways%2C%20a%20metabolic,step%20in%20the%20assembly%20process.

Irreducible Complexity: The existence of irreducible interdependent structures in biology is an undeniable fact
https://reasonandscience.catsboard.com/t1468-irreducible-complexity-the-existence-of-irreducible-interdependent-structures-in-biology-is-an-undeniable-fact#2133

The whole is more than the sum of the parts. Natural selection would not select for components of a complex system that would be useful only in the completion of that much larger system. Why would natural selection select an intermediate biosynthesis product, which has by its own no use for the organism, unless that product keeps going through all necessary steps, up to the point to be ready to be assembled in a larger system? Never do we see blind, unguided processes leading to complex functional systems with integrated parts contributing to the overarching design goal.
A minimal amount of instructional complex information is required for a gene to produce useful proteins. A minimal size of a protein is necessary for it to be functional. Thus, before a region of DNA contains the requisite information to make useful proteins, natural selection would not select for a positive trait and play no role in guiding its evolution.

The argument of irreducible complexity is obvious and clear. Subparts like a piston in a car engine are only designed, when there is a goal where they will be mounted with specific fitting sizes and correct materials, and have a specific function in the machine as a whole. Individually they have no function. Same in biological systems, which work as factories ( cells ) or machines ( cells host a big number of the most various molecular machines and equal to factory production lines ) For example, in photosynthesis, there is no function for chlorophyll individually, only when inserted in the light-harvesting complex, to catch photons, and direct their excitation energy by Förster resonance energy transfer to the reaction center in Photosystem one and two. Foreplanning is absolutely essential. This is a simple fact, which makes the concept of Irreducible complexity obvious concept. Nonetheless, people argue all the time that it's a debunked argument. Why? That's as if genetic mutations and natural selection had enough probability to generate interdependent individual parts being able to perform new functions while the individual would have no function unless interconnected.