Non-Evolution of Stop Codons

Here is one reason I don’t think life as we know it is the result of ordinary processes.

From Wiki:

https://en.wikipedia.org/wiki/Stop_codon

In the genetic code, a stop codon (or termination codon) is a nucleotide triplet within messenger RNA that signals a termination of translation.[1] Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA (from DNA) correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein. Stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain. While start codons need nearby sequences or initiation factors to start translation, a stop codon alone is sufficient to initiate termination.

Now what happens when there is no stop codon?

A nonstop mutation is a point mutation that occurs within a stop codon. Nonstop mutations cause the continued translation of an mRNA strand into an untranslated region. Most polypeptides resulting from a gene with a nonstop mutation are nonfunctional due to their extreme length.
….
Nonstop mutations have been linked with several congenital diseases including congenital adrenal hyperplasia,[15] variable anterior segment dysgenesis,[16] and mitochondrial neurogastrointestinal encephalomyopathy.

In other words, it would be bad juju if there are no means of reading of DNA and recognizing where one gene ends and the other begins. In fact, without stop codons, it looks like a DNA-RNA-protein-based life on Earth would be dead.

One could postulate a DNA-RNA-protein-based life that had an alternate stopping mechanism that eventually evolved a stop codon. But that just moves the problem elsewhere in as much as a DNA translation system that contains multiple genes needs a gene delimiting mechanism. A stopping mechanism needs proteins to implement it, but without a stopping mechanism to implement proteins, there is no stopping mechanism. We have then a chicken and egg paradox.

One could postulate proteins arose by a method outside of DNA translation and somehow recruited DNAs and RNAs and then defied all probability and somehow figured out how to code the next generation of proteins using DNAs that just happen to be coding the proteins like the ones that miraculously recruited them. At some point, such scenarios are so out of the ordinary they are not distinguishable from miracles.

Some will argue Darwinian evolution in the origin of life. That’s problematic for at least two reasons.

1. even most evolutionists don’t view the origin of life and origin of the protein translation cycle as part of typical evolutionary theory. So in that sense of the word “evolution”, stop codons didn’t evolve.

2. something dead can’t evolve by Darwinian mechanisms, and if this is an origin of life scenario we’re dealing with dead pools of chemicals.

So Darwinian evolution isn’t a solution. Chemistry isn’t a solution. Physical laws aren’t a solution. Probability isn’t a solution. In fact what we know of physical process would work against evolution of stop codons, not for it. Hence stop codons and life that depend on stop codons did not arise out of ordinary physical processes.

249 thoughts on “Non-Evolution of Stop Codons

  1. stcordova,

    The other things you said were most certainly informative, but without transcript termination (nor regulation) of the transcripts, the fate of the cell is not very promising. That would be the case if the entire genome generated one big polycistronic strand.

    Not really. If proteins are terminated by STOP, and you get them for free, all you are doing by over-transcribing is wasting energy and material on unnecessary transcription. Which happens a lot – look at the stuff that shows up in ENCODE. 😉

  2. stcordova,

    The empirical evidence is surely on the side that the proposed evolutionary scenarios would be out of the ordinary because if they were ordinary they would have been observed in the lab.

    Yeah, sure. First, take your non-protein-coding life form …

  3. Allan Miller,

    If proteins are terminated by STOP, and you get them for free, all you are doing by over-transcribing is wasting energy and material on unnecessary transcription.

    That not what I was implying. I was implying one gets the same amount of proteins as there are genes without termination or regulation. That’s not very promising for a cell is it, because some proteins must be more abundant than others.

    Yeah, sure. First, take your non-protein-coding life form …

    So where has termination evolved where none existed before in the lab? If you say it hasn’t been observed, then it affirms my point, the event is exceptional not ordinary.

  4. Regarding your non-homochiral life forms, I will point out a few problems with it from Fishcher’s lock-and-key principle.

    http://www.sciencedirect.com.mutex.gmu.edu/science/article/pii/S0032063396000578

    like the universal adoption of right-handed screws in engineering. It does not matter which hand is adopted so long as only one and is used : the world would run just as efficiently with left-handed screws, provided they were universally adopted ; and D-amino acid/L-sugar “mirror life” would be just as viable as terrestrial L-amino acid/Dsugar life. Fischer (1894) recognized this in his stereochemical “lock and key” hypothesis, which notes that a chiral molecule can “feel” the difference between the two mirror image forms of another chiral molecule, just as a left foot can feel the difference between left and right shoes, and will feel more comfortable in a left shoe. But molecules do not always interact preferentially with other molecues of the same hand, as in the example of feet and shoes ; the preference depends on the situation, e.g. a right hand prefers to shake another right hand (standing facing each other), but prefers to hold a left hand (standing side by side). Chirally discriminating interaction of this kind produces the connection between the t-amino acids and the D-sugars in life (Wolfrom et al., 1949 ; Melcher, 1974). Similarly, whichever hand is selected in ancestral biomolecules will dictate the handedness of the rest of biology through such interactions.

    The importance of homochirality in biological systems is underlined by the fact that the “wrong” hand often has destructive effects, the classic example being the 1960s sedative drug thalidomide, which caused limb deformities in babies born to mothers taking the drug during pregnancy. It was sold as a racemic mixture (equal amounts of L and D), and it seems from a study on mice (Blaschke et al., 1979) that while both hands had sedative properties, only one hand was teratogenic. There is also speculation that a build-up of molecules of the “wrong” hand may play a role in the processes of ageing and carcinogenesis (Ulbricht, 198 1) ; the body contains special enzymes called D-amino acid oxidases to eliminate amino acids of the wrong hand.

    Additionally stable folding happens because of homochirality. Future generations can’t easily build on a racemic system because it won’t be stable, much less alive.

    [Btw, one can supposedly taste the difference in different chiralities for some substances. This underscores the fact the system will work differently with different chrialities.]

    Finally, if one invokes a racemic life-form, one has to then account for how all the lock and key interactions were redone without killing the organism in the process. One will have to retool all the non-homochiral enzymes to homochiral ones. Yikes!

    Non-homochiral life doesn’t necessarily make a hypothetical evolutionary more plausible because it actually creates more problems for an evolutionary scenario than it alleviates.

  5. stcordova,

    That not what I was implying. I was implying one gets the same amount of proteins as there are genes without termination or regulation. That’s not very promising for a cell is it, because some proteins must be more abundant than others.

    You need to separate out termination and regulation. You have been talking hitherto about termination. Come back with those goalposts! If a modern cell has neither termination nor regulation, then yeah, things don’t look good. Nonetheless, in a primitive protein-coding system – say one producing just one protein – what’s it matter if it’s done clumsily, badly-regulated and unterminated, if it’s better than not doing it at all? Hmmm, wonder what process might improve things … ?

    You make the common mistake of assuming that a modern fine-tuned system is the minimum possible. Well, not a mistake; it’s what you want to be the case.

    Me: Yeah, sure. First, take your non-protein-coding life form …

    Sal: So where has termination evolved where none existed before in the lab? If you say it hasn’t been observed, then it affirms my point, the event is exceptional not ordinary.

    The fact that a viable non-terminating modern organism cannot be engineered in the lab (has anyone even tried?) does not mean that the processes involved in evolving termination in the organisms in which it evolved were in any way exceptional. That’s a ridiculous argument. Evolve me a lab-whale, or I say Design.

  6. stcordova,

    I am well aware of stereochemistry in biology. It is, indeed, why life is homochiral. Biopolymers are stereospecific, and they make as well as consume. But note my earlier point about nucleic acids. Random polymerisation of racemic monomers will produce numerous chains of varying composition (note also: with many more different bases than the modern 4). But RNA is magic. It will find complementary sequence and bind to it. There is more complementarity (stronger binding) in a homochiral pairing than a mixture; more in consistent 3′-5′ linkage than a mixture of 2′ and 3′; more where the bases form hydrogen bonds than where they do not. This binding stabilises the pairing, increasing the half-life of the components.

    So from this property alone, stable homochiral double strands of complementary bases will emerge from a messy mixture, and persist longer than unpaired variants. It’s not alive, but it does provide a mechanism for ensuring both homochirality and complementarity. So I don’t invoke a racemic life form. RNA’s own properties pull it away from the razor-edge of an even randomised mix of enantiomers.

    This same affinity of RNA for complementary sequence plays a significant role in regulation too. And, indeed, in translation. RNA (and its close relative, DNA) is both self-stabilising and self-specifying.

    Go on, tell me RNA Life is impossible, or find a chemist who says so! It’s not difficult to do so. But it does have substantial evolutionary merit, and remains my preference, overcoming many of the objections to proteins-first that you are pursuing.

  7. Sheesh. After reading more of the thread, let me quote:

    Why does mRNA need a stop codon? When a ribosome reaches the codon UAG, UAA, or UGA on an mRNA strand then protein synthesis is terminated. A protein known as a release factor binds to the ribosome and adds a water molecule to the end of the amino acid chain. This reaction hydrolyzes the polypeptide chain from the tRNA, allowing the protein to exit the ribosome. Without the stop codon, protein synthesis would simply stop without releasing the completed protein.

    The basic assumption of the OP was that without a stop codon the protein synthesis would simply continue.

  8. To add a few things:

    1. Allan has said pretty much the same thing, but since you don’t seem to have absorbed the point, I’ll reapeat it: The model under discussion seems to be “imagine an organism with all its genes the same sequence but stop codons don’t work – that would be a disaster, no protein would ever terminate! and if more codons were assigned as stop codons because they didn’t have tRNAs that would be even worse, most proteins would stop prematurely!”

    This is a ridiculous model. Like I said before, we don’t know the early history of genetic code evolution, but in a world with fewer amino acids and fewer assigned codons, protein-coding sequences would obviously not have these codons within their open-reading frame. Halting or termination would not be a problem, because the ribosome wouldn’t encounter these unassigned codons when translating genes. As stop codons get reassigned to new amino acids, or degenerate codons get split, the new amino acids could gradually be incorporated into the protein. There is evidence that this has happened multiple times throughout life’s history, after the modern genetic code had already evolved. I mentioned selenocysteine, there’s also pyrrolysine, and evidence that there are plenty more examples where the remaining 3 stop codons have been reassigned to something else. Likewise there are examples where existing codons have been swapped from coding for one amino acid to another. This can happen because even in modern life, some codons are used frequently, and some are quite rare – the rare ones can be changed because changing them causes much less trouble for the cell.

    2. Evolving termination in general is easy, because being a processive polymerase is hard. Both ribosomes and transcriptases are ultimately template-dependent polymerases (they polymerize something, amino acids or nucleotides, respectively, by reading along a template). Staying on the template without falling off is hard – anyone who’s had to optimize reverse transcription or PCR polymerases to get better yield, or tried to evolve a polymerase to read or make unnatural XNAs, or make an RNA polymerase ribozyme has observed this. A polymerase will halt or fall off if it finds part of a template it can’t handle. Even modern transcription polymerases, or the ribosome, will halt or terminate at certain sequences, not because they’re programmed too, but because the template proves too difficult to read through. Evolution has minimized these problems, but not eliminated them. This is what I mean by saying termination is easy – there may be plenty of other challenges in evolving transcription or translation, but termination was baked into the cake from the beginning. Demarcating genes would just be a matter of surrounding sequences that were good templates for transcription or translation with sequences that were not.

    Relatedly, you are over-estimating the costs of stop-codon read through. Loss of a stop codon _can_ cause a problem, and there are cases associated with disease, but many more probably go completely unnoticed, because there’s another stop codon only a few codons down from the original, or the protein doesn’t mind having an extra bunch of amino acids hanging off its tail. Sloppier termination would just mean proteins were more tolerant of sloppy ends – less efficient, but rarely non-functional.

    3. Not familiar enough with the field to say if anyone has evolved a new stop codon in the lab. But here’s a model – take e coli with UGA assigned to a new unnatural amino acid, as has already been done. Put toxic gene downstream of UGA stop; or put disruptive sequence downstream of a protein needed for growth; suppression of the UGA stop codon with the unnatural amino acid will reduce fitness, so evolution will disable UGA suppression, reverting it to its old stop codon function. For a more natural variation, use one of the archaea that use pyrrolysine. Or go with a rarely used non-stop codon, you could probably find an organism that uses one particular codon highly infrequently, in fact, there are organisms which don’t use a particular codon at all, they’re missing the tRNA. Not sure that this would be a particularly valuable experiment to do, and it wouldn’t work all the time- codon reassignment is rare in the history of life, just not non-existent. But yeah, it could be done, it would mostly just recapitulate what genetic evidence shows has happened many times.

  9. Allan and david,

    Your comments are pearls before the Cordovan swine, but I for one appreciate their technical detail and lucidity, and I’m learning from them.

  10. keiths,

    Why thank’ee kindly! Sal does articulate genuine concerns. I really don’t see how ‘proteins-first’ could work. Which is why I bet the farm on RNA world. I’m well aware that there are many biochemists (eg Larry Moran) that think it’s bollocks. The great thing is, if I’m wrong, I’m just some gobshite on the internet. If I’m right … well, I’m still a gobshite, let’s be honest! 🙂

  11. Allan,

    Sal does articulate genuine concerns.

    Yes, some of them are genuine, but Sal’s assessment of their implications is a bit tendentious, to put it mildly.

    The great thing is, if I’m wrong, I’m just some gobshite on the internet. If I’m right … well, I’m still a gobshite, let’s be honest! 🙂

    Yes, but an articulate and knowledgeable gobshite. This gobshite appreciates it.

  12. Discussions of the RNA World can get hopelessly confused given history and terms that no one defines the same way. I’ve had a few brief interactions with Larry in the comments of his blog, and it’s still not clear whether he rejects the entire RNA World hypothesis (that life descends from simpler organisms with RNA genes and RNA catalysts) or just the idea of RNA First (that the first life involved the emergence of self-replicating RNA). He’ll sometimes phrase things as rejecting the former, but its clear that his main arguments involve the latter (and much more generally any “prebiotic soup” model). I have noted to him that his favored metabolism first theorists (Lane/Russel/Martin) all appear to accept the broader RNA World hypothesis; even James Shapiro (the nucleic acids one, not the genomes one), a famous critic of RNA first theories, accepted the existence of an RNA life ancestor in his later publications.

    Obviously my own experiences are anecdotal, but most molecular biologists and biochemists that are familiar with the field accept the broader RNA World hypothesis, largely based on the fact that the ribosome is itself a ribozyme. You will find various people who take exception, of course. Agreement about what happened before the RNA world is much more scattered, and justifiably so – we don’t have much evidence for any model out there.

    As for proteins-first: you do find a few people who hold to this view, but it doesn’t garner much support because, like you say, its hard to see how it could work. The idea that you can trace the ancestry of any modern protein back to a form that preceded nucleic acids entirely would require at some point that that protein ancestor be reverse translated into DNA. That is not only one of the few things that _would_ violate the central dogma, but is highly implausible from a biochemical standpoint to boot. Most proteins first advocates don’t seem to be aware of this problem. Also note the rejection of proteins-first doesn’t exclude non-coded peptide catalysts playing important roles in the RNA World, and even before it (in fact most models for the origins of translation in the RNA world assume this would be the case).

    Metabolism first is much more popular, and I understand the appeal to people who focus on the biochemistry of metabolism in modern organisms. My own view is that folks have come up with some very interesting theories, but haven’t been very good at demonstrating any aspect of these theories experimentally. Still, it would be neat and revolutionize the field if they did; as Leslie Orgel pointed out, the demonstration of a self-sustaining metabolic cycle in the absence of genetically encoded enzymes would be a huge breakthrough.

  13. * correction to above. Robert Shapiro is who I was referring to, not James. I always confuse the two.

  14. david,

    The idea that you can trace the ancestry of any modern protein back to a form that preceded nucleic acids entirely would require at some point that that protein ancestor be reverse translated into DNA. That is not only one of the few things that _would_ violate the central dogma, but is highly implausible from a biochemical standpoint to boot. Most proteins first advocates don’t seem to be aware of this problem.

    From the ones who are aware of the problem, are there any halfway decent proposals for how it might have happened?

  15. I tend to go for ‘RNA first’. It’s perhaps nitpicky semantics, but metabolism seems to me to be something that replicators do to enhance their replication. While carbon compounds will undoubtedly have had an effect on prebiotic chemistry, I think it confusing to term that ‘metabolism’. Non-enzymatic TCA cycles demonstrate that the steps are thermodynamically favourable, but without the involvement of a replicator, I don’t see what this can really achieve. I think it shows how readily the enzymatic version can arise, rather than having prebiotic significance.

    If I was active in research, I would be investigating hybridisation as a possible means of getting the ball rolling (obviously, taking the monomers and short oligonucleotides for granted). The affinity of one nucleic acid strand for its complement is striking. Precursor systems have the problem of transition – how do you get from that system to one in which the bases happen to form complementary pairings when stacked and oriented antiparallel on sugar-phosphate scaffolds? I think that complementarity and homochirality must precede replication, and hybridisation of random short oligonucleotides is potentially a way to achieve that. It’s surprising how many papers one reads that consider RNA as single stranded.

    Nonenzymatic polymerisation of oligonucleotides tends to stop due to cyclisation – the ends tend to form 3′-5′ links, capping extension. This is reminiscent of the bacterial genome in miniature. Perhaps ‘reminiscent’ is the only significance it has, but I have a vague notion of such cyclic chains gradually extending, persisting due to the mutual stabilisation of hybrid strands and the fact that any one breakage is not sufficient to destroy it entirely.

  16. david: even [Robert] Shapiro (the nucleic acids one, not the genomes one), a famous critic of RNA first theories, accepted the existence of an RNA life ancestor in his later publications.

    I think, to be fair to the late Professor Shapiro, he was skeptical of RNA being synthesized by pre-biotic precesses, and skimming through his 1999 book Planetary Dreams, in the chapter entitled The Birth of “RNA World” I note he acknowledges the progress then being made in the search for ribozymes. He seems skeptical only of “RNA first”.

  17. David and Allan Miller,

    Profuse apologies for my delay in responding. This was one of the most informative discussions I’ve been a part of at TSZ. Thank you for your criticisms and corrections and taking time to write such technically informative comments.

    My view is obviously “Intelligent Designer First” scenario. Some of the ID students I minister to are far more knowledgeable in biochemistry than I because they are biology or molecular biology students. I’m just an MS in applied physics with undergraduate degrees in math, engineering, and computer science.

    What I have occasionally put at TSZ is test out refine ideas that I’m considering passing on to them. You have helped identify and rank arguments in terms of relative credibility. You’ve also spared me the embarrassment of saying errant things before them.

    I fundamentally believe the scientific expectation should be that something non-living will remain that way, that there is an inherent tendency if there is replication, that the scientific expectation should be that replication evolve to go simplest route when subject to uncertain environments and events. Hence the natural tendency is toward death state, and if there is life, toward simple life rather than the Rube Goldberg systems of multicellular sexually reproducing creatures like peacocks with extravagant tails.

    Whether there is God or ID behind it is not subject to formal proof. What can be scientifically debated is whether there is justification for the claim that “non-life is expected to remain non-life (especially complex life)”, and how many estimated deviations from that expectation must there be for life to arise and become complex. That can be debated on scientific terms.

    Your responses were informative to help refine my own estimates.

    Many thanks and kind regards. If I don’t have further responses at this time, it is because I take to heart your recommendation to study more in the field.

    At this time I cannot schedule a bio chem course, but I have a very good book from my alma mater on Organic Chemistry by D. Klein. I can at least study that book in the interim.

    I look forward to spending time learning from it. Thank you again!

  18. stcordova: My view is obviously “Intelligent Designer First” scenario.

    Why? It’s possible the universe could be designed but not life. On what basis do you discount that possibility?

  19. OMagain,

    Without using philosophically loaded ideas like “design”, it seems to me the universe is structured such that life is possible, but not probable.

    We obviously know life is possible because we are alive. How probable that something as complex as life (whether made of carbon or whatever) will arise from plausible processes is a scientific question.

    If it is improbable, then one might offer philosophical or scientific conjectures as to why something improbable happened. But that is a separate issue than the basic question of life’s probability arising in this universe.

    On what basis do you discount that possibility?

    Dead things stay dead. What little I know of biology and chemistry and what even biologists and chemists say, “dead things stay dead” is true, or at the very least, it’s a pretty reliable approximation of what we can expect for the description of any chemical system.

  20. keiths, to david:

    From the ones who are aware of the problem, are there any halfway decent proposals for how it might have happened?

    Allan:

    I tend to go for ‘RNA first’…

    Based on what little I know about OOL research, I would also favor ‘RNA first’, but my question was actually about the protein-first advocates. Do they have any half-decent proposals to explain the reverse translation of protein to DNA, which must have happened at some point if they are correct?

  21. Sal,

    Dead things stay dead.

    Except for Jesus, Lazarus, and the revivified corpses that descended upon Jerusalem in Matthew 27, apparently.

  22. Keiths,

    The implicit “dead things stay dead” was a statement for the natural (typical, ordinary, non-miraculous) mode of how things happen in this world. From other things I’ve said, that was obviously what the intended meaning was, and it is a figurative way of saying what the expected outcome is.

    If you want to mince words to make you feel better, that’s up to you, but it doesn’t change the fact “dead thing stay dead” is the norm, not the exception.

  23. Sal,

    The fact that dead things stay dead is a pretty good reason to question the goofy resurrection stories in the Bible.

  24. @keiths
    Proteins-first theories cover a lot of ground. By analogy to RNA first, some proteins first theories hold that proteins similar to the ones we see in modern biology predated DNA, RNA, and genes. To be fair, some of these theories predated our knowledge of the genetic code, or even of DNA (we knew enzymes were proteins for much longer than the rest, so people originally focused on them for origins). There are still a few modern… advocates (see CG Kurland), but to my knowledge they don’t address issues of reverse translation at all, even though these forms of the theory are the ones that most clearly call for it. There are a few newer advocates of an “RNA-proteins” first theory, which holds that coded translation arose simultaneously with RNA, and the two co-evolved from the start. This avoids the need for reversetranslation, since proteins never exist independent of their genes. Ada Yonath and Nick Hud have both written papers on this, I don’t find the ideas terribly convincing though.

    There are also a variety of peptides first theories that hold the catalytic peptides arose early and catalyzed their own replication or a proto-metabolism. These sometimes get lumped with proteins first even though they’re fairly different. Although some forms might assume eventually these peptides became genes, its not necessary for the theory – you could just have coded proteins take over the same enzymatic mechanisms without any sequence information passing from peptides to modern proteins. Stuart Kauffman is the main person for these kinds of theories.

  25. @Allan Miller
    I think the idea for most of these metabolism first theories is that the metabolic cycle itself would be self-reproducing and even capable of evolution. Doron Lancet had some interesting ideas about Darwinian evolution of compositional genomes – i.e. just agglomerations of chemicals that are collectively self-replicating. Its an interesting, not entirely fleshed out idea. Robert Shapiro had a SciAm article years ago (in 2007 I believe) that gives a basic overview of this model. Its appealing, would in principle require a much simpler starting point than RNA, and is entirely unsupported experimentally. Hopefully that will change and we’ll know more about the plausibility in the future.

    As for hybridization with RNA – yes, its an interesting mechanism. Its somewhat analagous to the chiral amplification mechanisms that folks are studying now, though those do not focus on RNA oligomers. Insofar as it still requires some polymerization method to get the oligomers, people are focusing still on finding a robust activation chemistry to get nucleotides to polymerize non-enzymatically. We have a few, but none work great yet. Again, hopefully that will change and a lot of fun experiments will become possible.

    The other problem for RNA first is that even getting to mononucleotides via prebiotic chemistry seems hard, especially if you needed a relatively concentrated pool of them. Obviously John Sutherland’s work and others is aimed at addressing this. But still, I think more than anything else RNA first faces problems with how we got to monomers, not how we got from monomers to polymers.

  26. @ Alan Fox
    Re: Robert Shapiro
    Of course. I didn’t mean to suggest he accepted ancestry from RNA Life reluctantly. I think in his early work he did little to distinguish this from RNA first, but to be fair, most RNA world folks didn’t do a good job with that back then either, and some still don’t. Still, his arguments were almost always directed at the plausibility of the prebiotic routes to RNA. By the end of the 90s, and certainly later with the crystal structure of the ribosome, he, like most folks in biology, found the idea that RNA preceded proteins and DNA pretty convincing. His 2007 SciAm article I mentioned above lays out his views pretty clearly: http://www.scientificamerican.com/article/a-simpler-origin-for-life/

  27. david,

    There are also a variety of peptides first theories that hold the catalytic peptides arose early and catalyzed their own replication or a proto-metabolism. These sometimes get lumped with proteins first even though they’re fairly different. Although some forms might assume eventually these peptides became genes, its not necessary for the theory – you could just have coded proteins take over the same enzymatic mechanisms without any sequence information passing from peptides to modern proteins. Stuart Kauffman is the main person for these kinds of theories.

    So the idea behind these theories, if I’m understanding correctly, is that it’s easier to explain the origin of a nucleic acid coding system if you start from a proto-metabolic ‘springboard’, and that the coding system, once established, can render the proto-metabolic replication obsolete by taking over that function, whether by reverse translation or by the substitution of coded peptides. Is that it?

  28. david: Still, his arguments were almost always directed at the plausibility of the pre-biotic routes to RNA. By the end of the 90s, and certainly later with the crystal structure of the ribosome, he, like most folks in biology, found the idea that RNA preceded proteins and DNA pretty convincing.

    I think RNA world is a good candidate for sidestepping the chicken-and-egg problem of whether enzymic activity or replication came first. RNA can store genetic information and can catalyze biochemical reactions. As you say, Shapiro was sceptical of the ideas then being discussed for the pre-biotic origin of RNA.

    He advocated looking beyond Earth for clues to life’s origin. For instance, say some kind of very simple life (or fossil evidence) were to be found on Mars, it would be a huge boost to the field. If enough evidence were found to say that this Martian organism appeared to be similar to terrestrial organisms, the possibility of biological material travelling through space (on asteroids, maybe) needs considering. If the indication that the Martian life is utterly different to that found on Earth, this suggests, that if life arose independently on two planets of the same star, origin of life must be a common process and the universe is teeming with it.

  29. stcordova: What little I know of biology

    If you have a admitted lack of biological learnings, why pronounce on what can and cannot be at the OOL?

  30. A brief summary of the pros and cons (non-exhaustive)

    PEPTIDES FIRST:

    Cons:

    – Difficult to get peptide bond formation at all without increasing rate of hydrolysis at the same time.
    – No apparent means of repeat specification
    – No apparent means of replication (hence no tuning by selection).
    – No apparent means of transition to the modern system.
    – No apparent means of applying localised energy.
    – Lifetime of single chains limited by hydrolysis

    Pros:
    – Monomer formation is comparatively easy.

    ‘METABOLISM’ FIRST:

    Cons:

    – Diffusion
    – Thermodynamic wells
    – No apparent means of replication (hence no tuning by selection).
    – No apparent means of transition to the modern system.
    – No apparent means of applying localised energy.

    Pros:
    – Provides a potential, if highly speculative, way in to complex monomer formation.

    RNA FIRST:

    Cons:

    – Monomer formation is difficult.
    – Chain extension is limited.
    – Polymer is more fragile

    Pros:
    – Monomer condensation is energetically favourable
    – Double strands give significantly greater stability.
    – Inherent solutions to issues of chirality and base complementarity.
    – The separate processes of replication and transcription to functional ribozymes are (in principle) provided by the same mechanism – multiple copies of both functional molecules and of genomes.
    – No need for transition, other than to the deoxy/methyluridine form for the genetic component.
    – Localised energy freely available if monomers are (energetic intermediates ATP, GTP, NAD, FAD and Coenzyme A are all based upon RNA monomers).

    INTELLIGENCE FIRST:

    Cons:

    – Unclear how intelligence can determine what would work – if there is a complex minimal configuration, how can you know what its composition should be without trial and error (the ‘natural’ process)?
    – Having designed such a cell, how do you implement? You must manoeuvre atoms into place in anticipation of a precise self-sustaining thermodynamic cascade without them reacting on their way to starting position.

    Pros

    – Side-steps the disadvantages noted above by imbuing the designer with whatever capacities are necessary to circumvent them, in a sufficient time period according to one’s reading of the relevant text.

  31. @keiths
    Re: peptides-first
    Yep, that’s the basics. As Allan says, the main appeal is that amino acids are know to form under a variety of prebiotic contexts, whereas mononucleotides are not. The hope then is that these amino acids could polymerize under some context, and the resulting peptides would self-organize some kind of proto-metabolism, and perhaps even accomplish some degree of self-replication. Some point later these systems could develop nucleic acids and genetics, then the peptides would be replaced with genetically encoded proteins.

    To clarify my earlier comments – I don’t think anyone directly proposes a system for reverse-translation. Rather many proposals seem to ignore that this is an implicit requirement if you hold that some modern encoded protein has descended from something that existed before translation.

  32. INTELLIGENCE FIRST:

    One could alternatively claim DNA-RAN-proteins first. 🙂

    One cannot totally dismiss intelligence on scientific grounds. I pointed out Richard Conn Henry considers the possibility of a MIND in the universe based on physics (not religious texts) alone:

    The Quantum Enigma of Consciousness and the Identity of the Designer

    “The ultimate cause of atheism, Newton asserted, is ‘this notion of bodies having, as it were, a complete, absolute and independent reality in themselves.’”

    The 1925 discovery of quantum mechanics solved the problem of the Universe’s nature. Bright physicists were again led to believe the unbelievable — this time, that the Universe is mental.

    According to Sir James Jeans: “the stream of knowledge is heading towards a non-mechanical reality; the Universe begins to look more like a great thought than like a great machine. Mind no longer appears to be an accidental intruder into the realm of matter…we ought rather hail it as the creator and governor of the realm of matter.”
    ….
    The Universe is immaterial — mental and spiritual.

    Richard Conn Henry
    The Mental Universe: Nature Volume 436
    2005

    As an aside, I mentioned blood cells as examples of proteins first and metabolism first. If there are mRNAs floating around (front loaded) in a cell, they can replicate!

    http://www.jpgmonline.com/article.asp?issn=0022-3859;year=1984;volume=30;issue=4;spage=199;epage=206;aulast=Kothari

    “The mammalian red cell is not the sole example of the active survival of the cellular cytoplasmic sac after the nucleus has been voided. The giant unicellular alga, Acetabularia, withstands enucleation, exhibiting thereafter growth and regeneration, the regenerative process producing an essentially normal Acetabularia, although, of course without a nucleus.[13] The cells of Spyrogyra, following nuclear excision, survive for more than 2 months during which time they grow, form new cytoplasm containing; organelles, synthesize proteins, and carry out all their normal physiologic functions.[13] The enucleated egg of the sea urchin Arbacia exhibits repeated cell divisions to the point of forming a blastula that may develop functional cilia.[13] The protein synthesis induced in frog oocytes by pituitary hormones is not abolished by enucleation; indeed, for many hours, the rates of synthesis in nucleate and enucleate oocytes are indistinguishable.[13] Enucleate fragments of cultured human cells survive in vitro for upto 4 days exhibiting movement, pinocytosis, and the incorporation of amino acids to form protein.[8] We can no longer deny the high degree of structural and functional autonomy that the cytoplasm enjoys regardless of the nucleus.”

    My understanding is that if all the nuclear DNA is removed from frog eggs, they can still develop to the blastula stage of several thousand cells.

    But this raises the question, if we have a Protein-RNA system, how are DNAs recruited to be part of the replication cycle?

    Koonin proposes Multi universes or whatever or some biological anthropic principle in order to generate the necessary miraculous POOF:
    http://www.biologydirect.com/content/2/1/15#sec8

    The plausibility of different models for the origin of life on earth directly depends on the adopted cosmological scenario. In an infinite universe (multiverse), emergence of highly complex systems by chance is inevitable. Therefore, under this cosmology, an entity as complex as a coupled translation-replication system should be considered a viable breakthrough stage for the onset of biological evolution.

    But the multi universe is only one hypothesis of physics, Richard Conn Henry’s conception of an intelligence is also a reasonable inference from Quantum Mechanics, for that matter there is the Multiple Universe with an Ultimate Intelligence (Barrow and Tipler).

    I just don’t see a chemical evolutionary scenario as plausible. There is no chemical law that inclines atoms to naturally assemble into complex life. If anything the chemical inclination is to destroy and degrade the raw materials, much less make them persist and build into complex interdependent replicators. Billions of years don’t help the process if the chemical trajectory is toward degraded raw materials.

  33. stcordova: INTELLIGENCE FIRST

    LOL.

    The problem with this, is that there is no agreement over the meaning of “intelligence.”

    In my opinion, homeostatic processes already show sufficient intelligence. And that would seem to make “intelligence first” just an alternate name for “metabolism first.”

  34. Mung: And codemakers first?

    Yet you literally just said:

    Mung: . So asking me to “do some primary research to support a hypothesis to make a positive case” [for ID] is ho hum material. Maybe when I retire.

    So if you want your “codemakers first” idea to progress nobody except you is going to do that. And you’ve already said you are unwilling and unable to do that.

    So the answer to “And codemakers first?” is “there’s no evidence for that”. And it’ll remain that way till you get out of that armchair and do some actual work, you lazy shit.

  35. stcordova: I just don’t see a chemical evolutionary scenario as plausible.

    Remind me again, how old do you think the earth is? And the answer to that is why your opinions on what is plausible are risible.

  36. Mung,

    What about membranes first?

    Like I said: not exhaustive.

    And codemakers first?

    Not really a code. More a physical assembly thing.

  37. stcordova,

    As an aside, I mentioned blood cells as examples of proteins first and metabolism first.

    Yes, and like I said, this is ridiculous and irrelevant. Blood cell proteins are made by DNA which comes from the zygote. The fact that the cells themselves don’t possess DNA is … God, why am I even typing? It’s dumb. All enucleation scenarios take place in the cells of descendants of DNA organisms.

    But this raises the question, if we have a Protein-RNA system, how are DNAs recruited to be part of the replication cycle?

    Take that course! DNA isn’t ‘recruited’; it is a minor variant of RNA. It lacks a 2′ Oxygen, and its Uridine base is methylated. Both of these assist double-strand packing, rendering it a superior genetic material. Deoxynucleotides are made from RNA monomers. Some organisms still use RNA, and they can be copied bidirectionally.

    Koonin proposes Multi universes or whatever or some biological anthropic principle in order to generate the necessary miraculous POOF:

    Yeah, let’s mock all the people who use ‘POOF’ as a mechanism, shall we ? :).

    I just don’t see a chemical evolutionary scenario as plausible.

    I don’t really care. I don’t see parentless multicellular organisms popping into existence in a literal day plausible either, to be honest.

    There is no chemical law that inclines atoms to naturally assemble into complex life.

    There is – the second law of thermodynamics, believe it or no. We live off it. It folds proteins and functional RNAs; it drives complementary hybridisation; it pushes proton gradients and allows them to be tapped and the energy locked in complex carbohydrates, then tapped again to run your car or keep you on the go till supper.

    If anything the chemical inclination is to destroy and degrade the raw materials, much less make them persist and build into complex interdependent replicators. Billions of years don’t help the process if the chemical trajectory is toward degraded raw materials.

    The process is demonstrably self-sustaining. Once the spark is ignited, although individual organisms degrade, they have offspring, and they survive by tapping energy in an entirely ‘natural’, within-physics manner. Nobody is invoking billions of years for the commencement of this process.

  38. Take that course! DNA isn’t ‘recruited’; it is a minor variant of RNA. It lacks a 2′ Oxygen, and its Uridine base is methylated.

    You misread the sense of what I was saying. If there is an RNA-protein replicator, why on chemical ground would it evolve to include DNA as part of the process.

    The eventual death of the enucleated cells shows DNA becoming a part of such a system is guaranteed if such replicators all die, and it is dubious to claim DNA will evolve as a critical part of the system even if the replication line continued.

    If DNA is a life-critical part and it is absent, then the system will die and hence evolve. At best one can only hope for indirect, speculative cooption routes, not the force of scientific expectation.

    The issue is scientific expectation without the necessity of so many qualifiers and exceptional conditions.

    The 2nd law shows heat spontaneously moving from a hot object to a cold object. That is a natural evolution of internal “heat” energy in a system. It doesn’t require a lot of qualification or specialized conditions to work. In contrast the idea that life arises by itself requires a lot of specialized circumstances, and that means it is not consistent with ordinary expectation.

    Replication cycles with so many necessary components to make replication happen will spontaneously happen in the first place, much less add even more steps in its replication recipe, like say multicellularity with sexual reproduction. At the very least, even if formally possible it is not the scientific expectation. It is formally possible two bricks in contact and in thermal equilibrium (same temperature) will spontaneously have one brick hot and the other cold – but it is not the scientific expectation. There is an analogous problem in this discussion.

    The enucleated cells replicate for a while, but they don’t evolve DNAs do they? They just die. Experiment and observation agrees with theory.

  39. stcordova,

    You misread the sense of what I was saying. If there is an RNA-protein replicator, why on chemical ground would it evolve to include DNA as part of the process.

    I answered it anyway – the lack of oxygen allows for tighter packing, and the methyl group on thymine (ie: methyluridine) means that every second base pair is more hydrophobic, again tightening the coil and hence enhancing protection in the double stranded form and making DNA a superior genetic material (side-note: it is an open question whether protein came before or after the transition to DNA as prime storage).

    The eventual death of the enucleated cells shows DNA becoming a part of such a system is guaranteed if such replicators all die, and it is dubious to claim DNA will evolve as a critical part of the system even if the replication line continued.

    Dunno what you mean, to be honest. Enucleated modern cells don’t offer much guidance on primitive replicators in my opinion. Because they aren’t primitive.

    If DNA is a life-critical part and it is absent, then the system will die and hence evolve.

    Sure, if a replicator is essential and it can’t happen, then life can’t happen.

    At best one can only hope for indirect, speculative cooption routes, not the force of scientific expectation.

    Cooption? You are being vague. I propose RNA with (after a period of stabilisation and selection of complementary and homochiral polymers by hybridisation) replication of whole genomes, and ‘mini-replication’ by a very closely related mechanism to produce numerous copies of functional RNAs. At subsequent steps, proteins are formed upon RNA templates, either before or after DNA becomes the primary store. Sure, it’s speculative. One is attempting to uncover the form of a mode of life which is now extinct. ‘Speculative’ and ‘could not possibly have existed’ are two different beasts.

    Care to speculate on how organisms were Created? Head first, bottom-up? Did they come into being with an audible ‘pop’ as they displaced the air? Were they created diploid, as if they had parents? If so, why; if not, why not?

    The issue is scientific expectation without the necessity of so many qualifiers and exceptional conditions.

    There is nothing exceptional being proposed. Atoms and molecules are supposed to have the same properties throughout, though configurations change. The only ‘exceptional’ thing is that it is life, but not as we know it, Jim. But to an RNA replicator, the first DNA-protein replicator was pretty exceptional. We think we’re all that, us DNA-RNA-protein chauvinists.

    The 2nd law shows heat spontaneously moving from a hot object to a cold object.

    Among other things, yes. But a better expression of the law is systems shedding free energy, when such a path is available. That is how proteins fold, how RNA hybridises, how proton gradients equilibrate and drive ATPase. Heat does not have much to do with it. Bloody physicists!

    That is a natural evolution of internal “heat” energy in a system. It doesn’t require a lot of qualification or specialized conditions to work. In contrast the idea that life arises by itself requires a lot of specialized circumstances, and that means it is not consistent with ordinary expectation.

    How many planets have you observed to come to a conclusion as to what is, and what is not, ‘ordinary’?

    The enucleated cells replicate for a while, but they don’t evolve DNAs do they? They just die. Experiment and observation agrees with theory.

    I have never proposed replicator-free persistence of cells, so I don’t know why you are bugging me with this one. I don’t propose cells evolving DNA/RNA. It’s the other way round.

  40. I answered it anyway – the lack of oxygen allows for tighter packing, and the methyl group on thymine (ie: methyluridine) means that every second base pair is more hydrophobic, again tightening the coil and hence enhancing protection in the double stranded form and making DNA a superior genetic material (side-note: it is an open question whether protein came before or after the transition to DNA as prime storage).

    Just because something will function better by having that feature doesn’t mean it’s going to evolve! We have an enucleated cell, it can work better with an nucleus of functioning — doesn’t mean nature is under obligation to work circumstances for that enucleated cell to evolve DNA. Same would be true for any sort of protocell without DNA.

    Just because an architectural change will enable something (a cell, a protocell) to function better or replicate or whatever, doesn’t mean it’s going to happen. The fact enucleated cell lines die should illustrate the point that nature doesn’t have to help something adapt, it could just as well kill it before it can continue evolving an improvement.

    We just can’t declare it will happen in the air without stating something of the scientific theoretical expectation based on first principles of chemistry and probability.

    Saying, “We don’t know”, or “it’s improbable” or “it would be an exceptional event” would be fair characterization given what we know. I can’t seem to even get that from you.

    You seem confident it won’t be an exceptional physical process. How do I define exceptional? Something that doesn’t happen despite all our efforts in the lab and field would begin to be exceptional. Highly implausible conditions to get a feature to pop up is exceptional. Events that are highly improbable are exceptional. If you believe life arose only once in the history of the galaxy, then that is an exceptional event.

  41. It’s an enucleated cell. It has no genetic material, almost by definition. The mRNAs remaining in the cell may let it carry out residual instructions, but they will not replicate on their own. Of course the cells won’t evolve new DNA, they can’t evolve at all! It would be like neutering a whole bunch of rats then saying sexual reproduction can’t evolve since they don’t grow back their testes and ovaries. It’s analogous to your earlier example: “let’s assume everything’s the same but DNA is gone”. No one proposes this as the model for life before DNA.

  42. stcordova,

    Just because something will function better by having that feature doesn’t mean it’s going to evolve!

    Gordon Bennett! No, it is not necessarily true. But this is a pretty weak argument. What makes you think the path from RNA replicators to DNA replicators is blocked? If we agree on superior properties, some very simple modifications (deoxygenation at the 2′ -OH and methylation of uridine) achieve them, and there is bidirectional template-based polymerisation, what’s the problem, other than your apparent need to believe evolution capable of nothing significant?

    We have an enucleated cell […]

    No we don’t. I do not propose an ‘enucleated cell’, nor anything like. I’ve said this a few times now.

    Just because an architectural change will enable something (a cell, a protocell) to function better or replicate or whatever, doesn’t mean it’s going to happen.

    Yeah, whatevs. Check your intellectual curiosity at the door. Any and all proposed evolutionary amendment is denied, because “just because it might be useful doesn’t mean it can happen”. So we can accept nothing other than what we observe in real time – plus Creation?

    We just can’t declare it will happen in the air without stating something of the scientific theoretical expectation based on first principles of chemistry and probability.

    Haha! God said ‘Let Stuff Happen” and lo,stuff happened. Meanwhile, you chide people for being ‘unscientific’. First principles of chemistry and probability have little to do with the selective advantage of 2′ -OH deoxygenation or uridine methylation.

    Saying, “We don’t know”, or “it’s improbable” or “it would be an exceptional event” would be fair characterization given what we know. I can’t seem to even get that from you.

    What use would such admissions be to you? Certainly I don’t know – I have a favoured model, is all. On probability, I don’t know how probable or improbable it was on a prebiotic earth, so why would I say ‘it’s improbable?’. Nor do I know how ‘exceptional’ it is – I don’t know how many reruns of primitive earths would see life forming and how many would not.

    You seem confident it won’t be an exceptional physical process. How do I define exceptional? Something that doesn’t happen despite all our efforts in the lab and field would begin to be exceptional.

    ‘The field’ is stuffed with voracious protein-coders, so I don’t think on this non-sterile earth free biological molecules or poor replicators would stand much of a chance. As to the lab, this is not attracting thousands of researchers, and there are literally millions of possible physicochemical combinations to try, and limited time to reproduce something that had a few million years of ‘real time’. And note that we are essentially, in the early stages, looking for a single molecule. It only takes one replicator with net replacement rate > 1 to ignite the spark. How would you know you’d got one in your flask? Obviously the ideal would be that it came to PCR itself to become the dominant molecule. But that’s pretty naive.

    Highly implausible conditions to get a feature to pop up is exceptional. Events that are highly improbable are exceptional. If you believe life arose only once in the history of the galaxy, then that is an exceptional event.

    I’ve no idea how many times it happened in the galaxy. But say it happens once per 1000 galaxies, and there are 200 billion galaxies. How exceptional is that?

  43. stcordova: Something that doesn’t happen despite all our efforts in the lab and field would begin to be exceptional.

    So Behe’s two mutations is not exceptional? That happens, yet that’s used as an illustration of the impotency of evolution.

  44. stcordova: Koonin proposes Multi universes or whatever or some biological anthropic principle in order to generate the necessary miraculous POOF:

    No, he doesn’t. The suggestion in that paper is actually not “Koonin’s solution to the origin of life”, it is a paper about multiverses and what it does to science in general, using the example of the origin of life, it’s not his views on what is actually required to explain the origin of life.

    You will notice, if you bother to read the paper, how he actually mentions several observations that hints at a gradual and evolutionary beginning to life, not a “miraculous” de novo assembly of fully functioning cells merited by the infinity of an infinite multiverse. Koonin actually also have other papers on the origin of life and the translation system chuck-full of speculation and mysteries, you could go quotemine those too.

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