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Monday, March 10, 2014

Bye bye RNA world

I think it's time we started being serious about the limitations of the RNA world as a possible explanation for the origin of life. It's simply not possible to imagine a scenario where the first catalysts are RNA molecules because that requires a primordial soups full of nucleosides and sugar molecules. It requires the spontaneous synthesis of nucleotides and their polymerization.

That ain't happening.

You can salvage the RNA world by postulating that it arose AFTER primitive metabolic pathways were established using peptide catalysts but that's the best you can do. There's a nice article in The Scientist that describes the problem [RNA World 2.0].

Here's a teaser ....
The RNA world, first posited by Francis Crick1 and others in the late 1960s, remains an attractive hypothesis. Many of the chemical hurdles that once challenged the laboratory synthesis of the molecule under presumed primordial conditions are being overcome, and in vitro evolution experiments are yielding RNA molecules that perform numerous functions, including copying themselves or other RNAs. "I don’t think there can be much doubt that RNA was a major central player as both a catalyst and an early replicator," says Nick Lane, a biochemist at the University College London whose research falls under the “metabolism first” label. "So the RNA world is absolutely correct, as far as I’m concerned, in that."

But the notion that RNA, on its own, spontaneously assembled and evolved on early Earth has fallen out of favor. More likely, whatever conditions spawned compounds as complex as nucleotides also generated other organics, perhaps early forms of modern amino acids and fatty acids, the constituent parts of proteins and membranes. "I’m not sure how many people anymore believe in a pure RNA world. I certainly don’t," says Lane. "I think the field has drifted away from that, and there’s now an acknowledgment it had to be ‘dirty.’ "

Changing Ideas About The Origin Of Life
Was the Origin of Life a Lucky Accident?


  1. You can salvage the RNA world by postulating that it arose AFTER primitive metabolic pathways were established using peptide catalysts but that's the best you can do
    The primordial soup idea certainly has its problems, but the idea that peptides came first just isn't consistent with what we see with RNA catalysis. From things like RNase P, we see what appears to be a ribozyme that is being displaced by more efficient protein components. A peptide based start would imply an era of peptides that were replaced with RNA than were again replaced with peptides. It's *possible*, but not very likely. If there was something before RNA it would be more likely some alternative system altogether akin to Wachterhauser's pyrite ideas (not that this doesn't also have issues).

    1. We don't have to think that RNA replaced peptide synthesis. The initial amino acid alphabet was reduced from the extant one, meaning it probably didn't have the full catalytic repertoire of modern proteins. It could be that among the possible chemistries available to this reduced alphabet, was metabolic pathways for RNA synthesis.

      Now the question becomes how to get "reverse translation", so we can start reliably copying of the extant peptides that drive these metabolic pathways?

      There are proposals for that (as in alternatives to actual reverse-translation, that nevertheless explains how the first peptides end up being coded products at the origin of translation), see the GADV-world hypothesis for example. Simply as a matter of probability because of the reduced amino acid alphabet, there's a greater likelyhood that the first random translation products at the origin of translation, have properties similar to the first randomly polymerized peptides that end up driving the metabolism that synthesizes RNA.

      We can probably also count on a certain degree of selectivity and determinism in the outcomes of these pseudo-random reactions that the first peptides catalyze. Even if they are still highly promiscous enzymes, they might still have higher catalytic rates for reaction products that make their own emergence more likely than various side-reactions.

    2. Well, you are pretty much done here.... Tell me a few more of your hypothesis.... I have a hard time sleeping last night, I'm sure your shit can make difference.... ;-)

  2. Was it it ever the case that prebiotic soup->straight to RNA world was the dominant idea of what was meant by RNA world? Or was it always the case that the main RNA world idea was that a precursor stage to the modern DNA-RNA-protein world was an RNA-protein world, and perhaps before that a "pure" RNA world, although I bet no one that ever thought seriously about these matters ever thought there was ever a completely pure anything.

    It remains the case that "RNA-heavy world as a major precursor stage to modern life" remains a strong paradigm that explains a great deal of otherwise peculiar observations about the fundamentals of life's biochemical machinery. Doesn't explain everything, but then nothing ever does.

    Also, the article indicates that Sutherland et al. are doing better than I thought at this RNA stuff...he's going to get a Nobel for sure...

    1. A lot of people have been trying to synthesize bases, nucleosides, and nucleotides in a test tube using inorganic starting material. Why do you think they were trying to do that?

    2. Stop it Nick!!!Just stop it!!! Don't embarrass yourself...!!! Don't you have any dignity left...?

    3. 1. Prebiotic soup -> RNA world was certainly a popular idea starting in the early days of the hypothesis. Walter Gilbert’s 1986 Nature letter where the term “RNA World” was coined mentions this possibility explicitly. I think that if you asked any prebiotic chemist of the time they would have readily agreed that anywhere you might find a pool of nucleotides, it wouldn’t be pure, but have amino acids and other compounds.

      2. Nevertheless, Nick’s view is accurate. The RNA World was presented from the beginning as a precursor to the DNA-RNA-Protein World that explains a number of features of modern biology and demonstrates how life could exist without coded protein synthesis. As far as the origin of life was concerned, the value of the RNA world hypothesis was that it solved the chicken-or-the-egg problem of protein translation, requiring only an explanation for the origin of RNA. That origin could be from the prebiotic soup, but it didn’t have to be: here’s Orgel, from his 1998 article in Trends in Biochemical Sciences: “The central puzzle is now seen to be the origin of the RNA world. Two specific, but intertwined, questions are central to the debate. Was RNA the first genetic material or was it preceded by one or more simpler genetic materials? How much self-organization of reaction sequences is possible in the absence of a genetic material?”

      3. Throughout the 90s and 00s two things happened. First, efforts to find a prebiotic synthesis of RNA reached a dead-end – the components of RNA can be made, but not activated nucleotides, let alone RNA polymers (obviously Sutherland’s new approach has recharged the field). By the mid-00s most everyone agrees (RNA World supporters and skeptics alike) that the spontaneous origin of long RNAs is prebiotically implausible. Second, the evidence for the existence of an RNA World as precursor to modern life grows quite extensive, culminating in the proof that the ribosome itself is a ribozyme. Thus in 00s you get RNA world critics like Shapiro or Morowitz distinguishing “RNA first” theories for the prebiotic origin of RNA that they still criticize from the “RNA world” which they accept as largely supported.

      4. The Scientist article linked to above pretty much conveys that modern understanding, and I don’t think it’s remotely as negative on the RNA World as Larry seems to see it. Everyone quoted in the article basically agreed that the RNA World existed, that origins theories need to explain how you got RNA genomes, and that this involved much more complex mixtures and interactions than a simple soup of activated nucleotides.

      5. I will note, as I have in the past, that although metabolism first ideas are potentially very interesting, the specific model of (self-replicating?) peptide catalysts directing primitive metabolic cycles is something that is not remotely proven by experiment and not all that chemically plausible, so it’s a bit weird to see it touted as some great improvement over prebiotic chemistry making RNA. I would love to see some experiments that prove me wrong but otherwise I’ll just point people to Leslie Orgel’s 2008 paper in PLoS Biology, “The Implausibility of Metabolic Cycles on the Prebiotic Earth,” and leave it at that.

    4. @David,

      I think we agree on everything except that I doubt very much that peptide catalysts were self- replicating.

      The point of my post was to make sure the average person—and average teacher—understands the limitations of RNA world and the current consensus.

      I'm also trying to get everyone to understand why the warm little pond idea (primordial soup) is highly improbable and there are much better ideas out there (metabolism first).

    5. Larry – wow!

      Thank you !!! I remain in your debt! I have been tracing backwards your previous posts on the subject and I am chagrined how naïve and out-of-date my thinking was on this question.

      I am unclear on one question. How does “metabolism-first” resolve the “chirality problem”?

    6. @Larry
      But the whole point is the the RNA world and the primordial soup are entirely orthogonal ideas which are not dependent on each other. Why do you see a connection? The founder of the primordial soup idea, A.I. Oparin, certainly knew nothing about RNA (not to mention Darwin and his "warm little pond"). Later soupists like Miller and Urey certainly weren't into RNA either.

    7. Jonathan badger says,

      But the whole point is the the RNA world and the primordial soup are entirely orthogonal ideas which are not dependent on each other.

      You are correct. That IS the point. I do not want people to think that the origin of life is about the evolution of the first RNA catalysts from a soup of nucleotides that spontaneously polymerize.

    8. @ Jonathan

      Your reply prompted some google-whacking on my part.

      Miller was indeed intrigued with RNA as the first genetic material

      Stanley Miller: "My opinion or working hypothesis is that the first replicated molecule had effectively no asymmetric carbon ... a kind of pre-RNA. RNA has four asymmetric carbons in it. This pre-RNA must have somehow developed into RNA. "

    9. @ Larry

      My naiveté in extremis:

      I had always presumed that the emergence of life indeed began with the first self-replicating RNA ribozyme catalysts from a soup of nucleotides and that protein and DNA were later evolutionary add-ons.

      Cannot the unusual physical properties of ice (including the concentration of solutes and microscopic electric fields) conceivably permit the initial polymerization of nucleotides in a correct orientation? The only trick to getting some self-replicating system is obtaining the original 5` to 3` oligonucleotide to begin with.

      The prerequisite overture of a metabolism-first refinement to such speculation is not too far a stretch.

      OK - I really must be missing something? Where am I going astray? Are we really disagreeing here?

    10. Tom, I think you're missing the crucial step here: Synthesizing all four monomers of RNA in the same environment and then getting them to polymerize. There's a significant experimental and theoretical hurdle to be overcome here. It is certainly concievable that some environment conducive to spontaneous RNA polymerization exists, but the problem is getting all four activated nucleotides synthesized and accumulated into that environment so it can start polymerizing. This is where some kind of peptide and metal catalyzed metabolism comes in to bridge that gap. Peptides can act as catalysts for the synthesis of RNA nucleotides, and can even help with polymerization. The question is if we can find out what such a metabolism looks like, how do the peptides look like? What chemistries to they catalyze? Under what conditions do they form? Still manu unanswered questions here of course. But it's an alternative to the straight-from-abiotic-chemistry-to-selfreplicating-RNA model.

    11. @Larry

      I’m glad we agree about the current consensus, though I’m not sure how broad an area that agreement covers. 2 points – one semantic, one more substantive.

      First, a title like “Bye, bye RNA World” to introduce an article that mainly presents the broad acceptance of the RNA World and advances made in understanding it is not going to clear things up for the average person, even if you ultimately are referring to naïve views of the prebiotic origin of RNA.

      Second, although scientists are now considering much more complex interactions and mixtures in the prebiotic chemistry preceding the origin of the RNA world, that does not mean that metabolism first theories are now broadly accepted consensus science, nor should they be. Unlike work on heterotrophic origins, most metabolism first theories remain at the level of handwaving or toy models, most use implausible assumptions about chemistry, and all have practically no experimental verification. Without some demonstration of a metabolic cycle that can sustain itself and yield increasingly complex biomolecules without enzymes, these theories will justifiably be viewed as speculative. I understand that a number of people, Lane and Russel included, are already exploring the chemistry of simulated alkaline vents, and more power (and grant funding) to them. I think they’ve already made a good case that interesting prebiotic chemistry could have happened at such sites. But until they show otherwise, there’s a lot of reason to doubt that metabolic cycles can spontaneously organize without genetics and evolution.

    12. @ Mikkel Rumraket Rasmussen

      Re: “Tom, I think you're missing the crucial step here: Synthesizing all four monomers of RNA in the same environment and then getting them to polymerize. There's a significant experimental and theoretical hurdle to be overcome here…”

      Hi Mikkel – I think the ability to reply to particular posts in the middle of the string can sometimes impede the ability to communicate. I draw your attention to one of my earlier posts is further down that addresses “life on ice”.

      I believe “the hurdle” you allude to may have been overcome by the efforts of Stanley Miller and those who followed his lead. That said, I have no doubt that my thinking is overly naïve and my expertise less than stellar…

      I understood Eutectic Freezing to concentrate otherwise dilute solutes and as freezing continued to withdraw water from solution, forcing erstwhile hydrolysis reactions to spontaneously convert convert into dehydration synthesis.

      Here is a recent review:

      Meanwhile, the ice surface is a checkerboard of positive and negative charges permitting alignment of pre-existing nucleotides in a correct orientation for polymerization.

      Trinks and Biebricher were able to obtain very large 3`->5` oligonucleotides with eutectic freezing

      Granted, the production of these long oligonucleotides required a long catalytic template.

      Vlassov and his colleagues discovered that enzymes like hairpin worked in reverse under eutectic freezing conditions. Vlassov’s team was able to generate short pseudoprimitive RNA enzymes from even shorter oligonucleotides that assembled themselves into longer polynucleotides by the eutectic reversal of hydrolysis mentioned above.

      That now leaves the vexing problem of how to obtain the original starting material to begin with i.e those nucleotide monomers you mention.

      Here is a great article:

      Prebiotic synthesis of adenine and amino acids under Europa-like conditions.

      I really hesitate to contradict Larry – but I remain very partial to the idea that chirality of life could derive from extra-terrestrial abiogenic synthesis, since amino acids from meteorites persistently present a left-handed bias, whereas their sugars show a predominantly right-handed bias, exactly as found in life.

      Until this blog post – I had always imagined the possibility of a torrent of asteroids and meteorites crashing on the frozen surface of a pre-biotic world under a significantly dimmer sun. Freeze-thawing permitted concentration of these extraterrestrial chirally enriched nucleotides into a concentrated pre-biotic “slushy” along the lines described above.

      The problem of homochirality could possibly be also resolved by differential crystallization of racemic mixtures. I dunno – at this point I am waving my hands while speculating. It doesn’t matter, others more adept than I in the dark arts of Biochemistry have suggested that small enantiomeric excesses can be amplified by asymmetric autocatalysis, all that is required is the initial excess to begin with – ergo my fascination with extra-terrestrial origins of monomers.

      I am grateful to this blog – until now I never realized how naïve my thinking was and how uninformed I was regarding “Metabolism First”.

      I now suspect that some version of “Metabolism First” is probably correct that (in short order) also gave rise to the RNA-world. (cf: my post on Rioboswitches) I still question the need for peptide and metal catalyzed metabolism, if ice can do the trick… Okham’s razor and all that…

      One thing is certain – I definitely need to revisit and rewrite the assignment I made for my students.

      best and grateful regards

      @ Larry - Thank you! I am most grateful!

  3. I'm partial to the idea that primitive cells, or even perhaps the earliest cells, had RNA genomes.

  4. Professor Moran,

    I had never thought I would see this day... but I was wrong.... I have been reading your blog for quite sometime, however, I have been commenting for less than few months...

    Professor Moran and I had some issues in the past...yes
    We had dicusses our issues... I know... I'm a pain.... I know it...

    However, this admission changes everything.. Even for Mr. Altman. The problem with this shit is that once your receive the shit-Noble Prize- THEY will never take it back even if YOU ARE FRICKEN WRONG!!! Would anybody here, at all, wanna hear which
    one of the Noble Prize winners got it wrong and still keeps the shit and the money?

    1. I will quote a statement attributed to Enrico Fermi: a scientist who has never been wrong is a scientist who hasn't accomplished much.

      Even the most important scientists who ever lived have been wrong occasionally, mostly due to the lack of information available at the time.

      1. Isaac Newton was wrong in believing that chemical processes could turn lead into gold; of course, the nuclear nature of matter was unknown at the time. Newton was also wrong to believe that diffraction and interference of light could be explained by a corpuscular theory.

      2. Charles Darwin was wrong about inheritance being an analog process; it is a digital process.

      3. Albert Einstein was wrong about the existence of black holes, despite the fact that his General Theory of Relativity predicted them. He was also wrong about quantum mechanics. God does, indeed, play dice with the universe.

      The individuals who decide on the award of Nobel Prizes are human beings and like all human beings occasionally err. For the overwhelming of such prizes, they are awarded for the most important contributions to scientific knowledge. There have occasional miscarriages. In particular, Lisa Meitner should have shared the Nobel Prize in physics awarded to Otto Hahn, and Chien-Shiung Wu should have shared the Nobel Prize in physics awarded to Lee and Yang. In some cases, individuals have been left out because of the limitation of not more then three for any prize. We had an example of this this very year when Hagen, Guralnik, and Kibble were left out of the award in physics for contributions to the Higgs Boson theory. Sometimes miscarriages occur because a potential awardee has died. The outstanding example is Rosalind Franklin who conceivably could have shared the award in physiology or perhaps received the award in physics or chemistry for her contributions to the discovery of the structure of DNA.

      I expect that there have been awards for contributions that later research found to be wrong or incomplete, although I can't cite any off the top of my head. That's the nature of scientific research. Generally, the Nobel committees are very conservative, sometimes waiting a long time. The Higgs Boson work, for instance, was done 50 years ago and it is only recently that the LHC was available to confirm their work. It is fortunate that the scientists who published the papers in the early 1960s are still alive to be eligible (Peter Higgs is over 80 years old for instance). One wonders if the committee will get around to awarding the prize in physics to Stephen Hawking, who is in very precarious health to say the least and could shuffle off this mortal coil at any moment.

    2. Fermi himself was half wrong in his Nobel awarding work. He was supposed to have created transuranics
      Anders Eg

    3. Wait wait wait since when did black holes stop existing?

    4. Last I heard Hawking made up some stuff about how the event horizon is actually an apparent horizon but didn't publish anything peer-reviewed and has no math whatsoever as back-up.
      Did I totally miss something?

      Black holes have clearly been observed - maybe we changed some perspective on them but how the hell are they nonexistent now?

    5. Re Uncivilized Elki

      It may be that Hawking has become a little off in his declining years. He's 72 years old and has been afflicted with ALS for some 50 years. Although it is generally believed that ALS doesn't have any great affect on cognitive ability, the medical community has no experience with someone living 50 years with the ailment. Thus there is no data relative to the long term affects on cognitive ability. There are some indications of possible onset of senility in the last year or two.

      However, Hawking's contributions to the current theory of black holes that he made 30 or more years ago (e.g. Hawking Radiation), IMHO, merit consideration for a Nobel Prize.

      As for the existence of black holes, Einstein's skepticism of their existence long predated their actual observation, which occurred long after his death. He actually wrote a paper claiming to prove that a black hole would never form.

    6. I think there's a difference between what Hawking is saying now and what Einstein was saying, although I may be wrong. Hawking is talking about the event horizon, while I think Einstein was referring to the nature of the singularity. Very few physicists think the singularity is real as described by Relativity alone. Can you clarify, colnago80?

  5. Oh wow… I am flummoxed! Do I need to modify my assignments?

    I always thought that Stanley Miller had made a good case for a RNA-world/ribozyme emergence of life on ice. - ( a slushy really and not a soup)

    Christof Biebricher managed to coax the generation of up to 700 base-long error-free RNA molecules on ice.

    Granted – Biebricher did cheat by providing the original template to begin with, that and a mix of nucleotides.

    I teach my students that the unusual physical properties of ice (including the concentration of solutes and microscopic electric fields) conceivably permit the initial polymerization of nucleotides in a correct orientation. The trick to getting some self-replicating system is obtaining the original 5` to 3` oligonucle to begin with.

    That is where Alexander Vlassov’s results kick in - oligonucleotides can behave as ligases that generate longer molecues.

    Here is the review I use in class.

    Is this POV still salvageable by avoiding some of the more naive assumptions of a liquid soup?

    1. I'm not enough of a chemist to weigh in on the matter, but Wächterhaüser and Russell's hydrothermal vents did sound like a convincing way to concentrate organic molecules so as to favour their polymerization. I still like the RNA world (or at the very least the RNA-centric world) hypothesis because of parsimony: since both information and enzymatic activity can be carried by RNA molecules of relatively small size (and that our current peptide-based system still heavily depends on RNA at all stages of production), it seems more economical to envision a primitive an all-RNA world to which other components would later be added. (I'm not against the idea, though. Perhaps the RNA world vision is too-deeply ingrained for me to let it go easily). Things like the similarity of self-splicing introns and the structural components of the "modern" spliceosome also strongly hint with an RNA- system first, RNA+protein system second.

      Regarding the metabolism first scenario, I wonder if we're not looking at another Margulis-like fusion between two independent systems: the metabolic world and the RNA world. Both, of course, would need to have been concentrated (somehow) in a restricted space -hence the interest of the hot vents hypothesis.

    2. I found this all very difficult to grasp at first. It appeared to me that “Metabolism First” was just an enhanced version of “primordial soup”.

      Following Larry’s copious and nested posts finally returned me to the same link Larry posted on this very blog post.

      I want to summarize this in my own words so I can share with students in my classroom. I invite correction or suggestions for improvement. I just want to make sure I have it right before presenting in class.

      Stranded high energy electrons in a reducing atmosphere were thought to generate chemical networks that were recursive (generated its own constituents) and self-catalyzing. The earliest reactions could have occurred in the voids of porous rock, surfaces of clays, deep sea vents or in pockets of water within ice.

      The network is feedback-driven and able to “self-prune” any side reactions, resulting in a limited suite of pathways capable of concentrating reagents just as metabolism does. Think of a primitive Citric Acid Cycle running backwards. Meanwhile, these anabolic side-reactions could generate the building blocks for our familiar monomers and eventually polymers.

      That means “Metabolism First” is different than “Primordial Soup”! The original naïve version of Primordial Soup was too random, accidental and dilute. Still, this proto-version of a backwards-running reductive Citric Acid Cycle occurred before the appearance of self-replicating molecules using themselves as a template which made life possible.

      This now casts Riboswitches in a completely new light. Riboswitches could have emerged as part of the abiotic “Metabolism First” scenario.

      The metabolites that bind to riboswitches all regulate transcription of genes involved in the metabolism of that metabolite and these molecules always seem to be involved in nucleic acid metabolism. Perhaps riboswitches are a relic of the RNA-world but before RNA happened, preRNA emerged as player in this stranded electron self-catalyzing and recursive chemical network.

      There still remain some unresolved issues with “Metabolism First”: side products can disrupt the reaction system or simply dilute the reactants, preventing them from accumulating within a pathway. The emergence of “Self-pruning” needs to be addressed.

      I am still unclear on how “Metabolism First” resolves the chirality problem.

    3. I am still unclear on how “Metabolism First” resolves the chirality problem.

      It doesn't strictly need to. There are really two chirality 'problems': sugar and amino acid. One is more fundamental than the other. Catalytic peptides don't have to be homochiral. But they do have to be reasonably tightly specified. At a site that needs (say) L alanine, the D acid is just as much a misfit as glycine. The modern peptide is synthesised in a ribosome and tRNAs are charged by stereospecific enzymes, so modern acid chirality is almost certainly derived from accidental fixation on a particular orientation in an early precursor pathway. It need not be an issue in a racemic prebiotic mixture - if (by a mechanism I have yet to hear elucidated!) peptides-first solves the specificity problem, the chirality issue is solved by that, and early peptides could conceivably have been composed of a mixture. A stereoisomer is just another acid with the 'wrong' side chain - a hydrogen atom. It might have the right side chain round the back, but it's no use there! Side chain specificity gives chiral discrimination for free, assuming the mechanism is positional.

      Sugars is a different matter. You can't have a sensible xNA molecule without homochiral ribose. I think sugar chirality had to be fixed before replication could take place (though I think the binding of complementary sequences could help there, preferentially stabilising homochiral hybrids). Amino acid chirality could wait.

    4. @ Allan,

      Reading your posts above and below, I wonder if you may be presenting a false dichotomy – It is not a question of peptides first and nucleic acids next or the other way around… I think Larry is advocating abiotic metabolism first, followed by increasing complexity directed by RNA catalysis later on albeit with some important role played by peptides, followed by an ever increasing role for peptides as the system becomes even more complicated.

      Larry – I hope I am not putting words into your mouth.

      Allan – I did not understand your answer above on peptide chirality. I read your explanation as still conceding an incorrect entantiomer destroys function leaving us still with the homochirality problem. What am I missing?

      Meanwhile, I wonder if we could be begging the question whether RNA is a prebiotic product or a later evolutionary biotic invention. In all likelihood, something far simpler than nucleoside triphosphates was the starting material for the first catalytic/self-replicating nucleic acids. The problem of ribose becomes a non-problem if in fact ribose did not constitute part of the original proto-nucleotide. Stanley Miller said as much in that 1996 interview above discussed the roles of pre RNA.

      Meanwhile, jack Szostak recently published an interesting paper that a hodgepodge mosaic polymer can exhibit interesting properties that overcome some “hurdles” mentioned earlier.

      Szostak : “We suggest that homogeneous monomers might not have been necessary if populations of heterogeneous nucleic acid molecules could evolve reproducible function. For such evolution to be possible, function would have to be maintained despite the repeated scrambling of backbone chemistry from generation to generation.”

      I have become so distracted by the debate – I lost sight of Larry’s original thesis promoting Jeff Akst’s article:

      Larry: “You can salvage the RNA world by postulating that it arose AFTER primitive metabolic pathways were established using peptide catalysts but that's the best you can do. There's a nice article in The Scientist that describes the problem”

      In summary the article dismisses the likelihood of a naïve-RNA-World for three reasons:
      1 – the instability of ribose
      2 – the inability to recreate purines in abiotic conditions
      3- the inability to polymerize nucleotides without getting a “statistical mess”

      All three objections above are duly slain shibboleths in the discussion above. So where does that leave us?

      I think the salient quote in the article is

      “It’s absurd to think that you might have some kind of an environment where you have just a load of nucleotides or RNA in solution, uncontaminated by anything else,” Nick Lane

      Of course not!!!! That is the ultimate strawman argument!

      “Of course the ultimate goal is we want to have a replicating nucleic acid inside replicating vesicles,” says Szostak


      So what are we debating here?

      Final word to Larry: “The point of my post was to make sure the average person—and average teacher—understands the limitations of RNA world and the current consensus.”

      Thank you! You have had a most positive and beneficial effect on my delivery of this subject in the classroom. I can pay you no higher compliment.

    5. Tom,

      @ Allan,

      Reading your posts above and below, I wonder if you may be presenting a false dichotomy

      Perhaps - there are many subtle variants on the mix one favours for prebiotic chemistry. But it is taken as read by everyone that the monomers for a primitive polymeric catalyst had to come from somewhere. If people want to call that 'metabolism' (meaning that carbon molecules were directly involved in the process) then fine. But we are being invited to shed a tear for RNA hypotheses - that early polymeric catalysts were definitely not RNA, but were instead [mumble mumble sorry didn't quite catch the details of the alternative hypothesis! ;) ]

      Allan – I did not understand your answer above on peptide chirality. I read your explanation as still conceding an incorrect entantiomer destroys function leaving us still with the homochirality problem. What am I missing?

      Chirality is an issue for us 'out here', staring at our test tubes. Molecular weight, polarity, elution rate ... all these 'gross' parameters struggle to distinguish the two versions of asymmetric carbon atoms. But 'down there', at the molecular level, discriminatory mechanisms can grope over the surface of the molecule. If you are looking at the 'L' site for your side chain, all D acids look like Glycine. They have a hydrogen atom there. If we are proposing pre-RNA-templated peptide catalysts, I'd expect to see some kind of specificity. A viable catalyst can't just have any old sequence. Say an important catalyst is L-alanine L-leucine D-arginine L-arginine etc. If a mechanism can glue the 1st 2 together, it must be capable of identifying their side chain. If so, anything with H at that position (eg their stereoisomers) will be excluded. Along with, incidentally, the rest of the 500 or so possible amino acids, beta, gamma, you-name-it. Otherwise, you just have a hopeful mess and no chance of a repeat. The chemistry will be elaborate, but not consistent. If you can achieve positional side chain discrimination, chiral discrimination comes for free. I just don't see any viable proposal on the first.

      To better contend with RNA world, 'metabolism first' needs to do more than just replace hand-wavy speculations about monomer origin with hand-wavy speculations about how prebiotic peptides could be synthesised repeatably without a genome in whose service it is done, and whose template offers specification repeatable in the billions.

  6. Larry,

    This is off-topic but I hoped you would write a post on a recent IDiot post by Ann "Green Screen" Gauger, who breaks her arms hand-waving in an attempt to minimize the human-chimp DNA similarity:

    The 1.3 or 1.2% DNA difference between humans and chimps drives them nuts, so they have to cook the books to push the number down. How can it be done? Well, outright lying helps.

    Here Gauger's primary trick is to talk about indels, duplications and Alu repeats as if they are 100% functional (no Junk DNA!) and moreover, as if every indel, duplication or Alu repeat is 100% different between humans and chimps.

    Example: Green Screen pulls tricks with Alu repeats. Because humans have some Alu repeats that chimps don't, and vice versa, she tells her church audience that Alu repeats are functional-- no such thing as Junk DNA, amirite?-- indeed she insinuates that *ALL* Alu repeats are functional.

    Furthermore, she acts as if each extra duplicate of an Alu ought to add its whole length to the % difference between humans and chimps, although of course, each Alu is nearly a duplicate of others elsewhere.

    Another example: if 6% of the entire genome is different due to duplicated stretches of DNA, "Green Screen" Gauger tells her church audidence that 100% of that 6% is functional (she insinuates it's all coding genes-- like 6% of the genome could be coding!) and that that should add another 6% difference to the 1.2 or 1.3% human-chimp difference, so it really ought to be at least 7.2 or 7.3%.

    In reality, since duplications occur all over, the great majority of that 6% will be Junk DNA; and only a tiny fraction of that 6% will be coding-- perhaps only ~1 to 2% of the 6% will be coding-- so it's more like duplications add just ~0.06% to 0.12% to the chimp-human DNA difference in *CODING* DNA, certainly not another 6% like she tricks her church audience into believing.

    Moreover, that extra 0.06-0.12% is *duplications* by definition, meaning that it's highly homologous if not identical to other human (or chimp) DNA elsewhere, *and* we know that natural processes cause gene duplications, so why do we need to invoke a triune God to explain an observed chemical process?

    She talks about changes to regulatory networks, as if this is some recent, cutting edge results that overturns the paradigm. We've known about that for decades, and most changes to regulatory networks are already included in the 1.2 or 1.3% difference.

  7. Ann "Green Screen" Gauger then pulls the usual Young Earth creationist trick we could get from Ken Ham: if humans are similar to animals, that means we should act like animals!

    In the Bible, Jesus compared Canaanites to pigs and dogs, and compared Jews to snakes and vipers. Those who are not God's people are commonly called "dogs" in the Bible: "The dogs are without..." Of course, creationists didn't have a problem with comparing humans to animals until about 1980. Creationist heroes Louis Agassiz and Cuvier contemptuously compared blacks to animals. In the 1920's, the founder of Flood Geology, George M. Price, followed his prophetess Ellen G. White in saying that blacks and apes were descended from mating between humans (whites) and animals. More recent Christian conservatives are always comparing humans to animals: homosexuals are "beasts", as Jerry Falwell said.

    Even Michael Medved of the Discovery Institute went all weepy over the movie "March of the Penguins" insisting that penguin "monogamy" (for one year) was a vindication of "conservative values." Never mind that amongst penguins there's a lot of same-sex action; that kind of behavior is... just like an animal!, but different-sex action among penguins vindicates the values of the Religious Right.

    And my final observation is this: the creationists always say that human-chimp similarity is no problem for them, because "Common design implies common designer." Of course it doesn't-- different parts of an airplane are designed by different designers-- but if they really believed that, then once in a while they would lie to make the design appear more common than it is. If they really believe "Common design implies common designer", why are they always lying to make the design appear less common than it is?

  8. The RNA world is not without its problems. But the 'peptide-firsters' seem decidely handwavy about some vital biochemical details in their scenario. What I hear is substantially reliant on the ridiculous ease with which peptide monomers can be synthesised, vs the fiendish difficulty of the xNA triphosphates. But then we have an opposing problem: peptide synthesis is energetically unfavourable, xNA polymerisation is not. More damagingly, repeat synthesis of an important peptide catalyst seems improbable. Whereas the complementarity of polymerised xNA provides a strong contender for repeat specification and polymer stabilisation and chemical selection of complementary bases and compelling evolutionary logic. So we have a major problem with both notions - monomer synthesis in one vs polymer synthesis in the other.

    I don't pretend there are no difficulties with RNA first, but they aren't circumvented by just vaguely saying "therefore something else!".

  9. Klinghitler has tweeted the title of Larry's post, in order to portray Larry as conceding defeat on non-supernatural origin of life models:

    "Our sometimes interlocutor biologist Larry Moran is frank about the origin-of-life dilemma: “Bye bye RNA world.”"

  10. Our sometimes interlocutor biologist Larry Moran is frank about the origin-of-life dilemma:

    Sigh. Because everyone else declares it solved!

  11. again... a forgotten item I found burried in my cyber files.

    A great activity for The Molecular Origin of Life: Replication or Metabolism-First?

    ... as taught by high school teachers. A harder version for university alos down-loadable

  12. There is no doubt that other organic molecules were synthesized before nucleotides. But these molecules could not replicate. Life could only establish when RNA was produced. RNA molecules are complex in comparison e.g. to proteins, as they are built from three types of components, not just one. I have however some thoughts on how RNA molecules could be synthesized, not in the ocean, but on land. These thoughts may be found on one of the other Sandwalk "Metabolism first" pages: "Metabolism First and the Origin of Life".