The RNA world

November 18, 2014 • 6:47 am

by Matthew Cobb

I have just sent off the final version of my book Life’s Greatest Secret: The Story of the Race to Crack the Genetic Code (to appear in 2015 with Profile Books, and Basic Books in the USA). The book is mainly history, covering the period 1943-1961, but the final four chapters bring the story up to date, describing things like the sequencing of the Neanderthal genome, the development of genetic engineering, and epigenetics.

To celebrate, I thought I’d give readers a condensed version of one of the sections dealing with that exotic-sounding entity, the RNA World.


Proteins and DNA, which are so important to life today, have not always existed on our planet. The RNA machinery that exists in every cell of every organism on Earth, and the ability of RNA molecules to act as enzymes, catalysing biochemical reactions without the involvement of proteins, all indicate that another form of life existed before DNA-based life-forms: the RNA world. RNA is a molecule that resembles DNA except it has only one strand, rather than two, and it uses a slightly different set of chemical bases to code information: whereas DNA uses A, C, G and T, RNA uses U in place of T.

Exactly what the first replicating molecules were, and how they made the transition from merely replicating to also interacting with the world, we do not know – they may have been RNA molecules, or perhaps even simpler compounds, such as peptides. They appeared perhaps 4 billion years ago, probably in the microscopic pores of rock around a deep-ocean hydrothermal vent (although Jack Szostak argues they appeared in small vesicles made of fatty acids, and no one actually knows).

Wherever they were found, those early replicating systems would have had to speed up the chemical reactions that define life. If left to their own devices, the kind of reactions that take place in our cells would need billions of years to occur spontaneously; in the presence of RNA they take a fraction of a second.

At some point, perhaps after a period of evolution and competition between various biochemical types of life, the RNA world came into being. There are no direct traces of this world, so our views are based on strong suppositions rather than physical evidence.

This was a very different kind of life to the one we know. In the RNA world, RNA molecules were the basis both for reproduction and for biochemical interaction (that is, they acted as enzymes, speeding up and favouring chemical reactions).

In a world without DNA or proteins, the genetic information contained in an RNA molecule coded simply for that piece of RNA. Reproduction involved the copying of RNA molecules that acted as enzymes to direct chemical reactions. These RNA molecules provided the raw material for natural selection to begin its long work of sifting between variants, eventually leading to the DNA-based life that now covers the planet.

The idea of the RNA world was first been put forward by Oswald Avery’s colleague, Rollin Hotchkiss, at a symposium organised by the New York Academy of Sciences in 1957. Struck by the fact that some viruses use RNA and others use DNA, Hotchkiss suggested that:

[As] a genetic determinant, RNA was replaced during biochemical evolution by the more molecularly and metabolically stable DNA. Cell lines have preserved the RNA entities which, evolutionwise, were primary to DNA and may have allowed them to store their information in DNA and thereby become subservient to it metabolically.

In the late 1960s the idea was taken up by Francis Crick, Leslie Orgel and Carl Woese; Wally Gilbert coined the phrase ‘RNA world’ in 1986.

Although the RNA world no longer exists (but who knows what secrets lurk in the deep ocean?), we all carry its legacy within our cells. When our DNA-based life appeared, evolution did not redesign life from scratch: it used what was to hand, adapting existing RNA biochemical pathways and turning them into something new and strange.

This explains why RNA is not simply a passive messenger between the two apparently fundamental components of life – DNA and proteins. It plays many roles, shuttling genetic information around the cell and shaping how it is expressed, just as it did in the RNA world. As the RNA biochemist Michael Yarus has put it: ‘Without RNA, a cell would be all archive and no action.’

RNA is involved in almost all of the cell’s machinery for getting the genetic information out of DNA and either creating proteins or controlling the activity of genes. In its many forms, RNA performs essential functions within the cell, even if it has lost its role as the embodiment of genetic information, replaced by the semi-inert double helix of DNA. The double helix – iconic, rigid and fixed – contrasts with the many physical forms that RNA can take, enabling it to carry out such a wide range of functions, which would have been such an important feature of the RNA world.

Just as we do not know when the RNA world appeared, so we also do not know when it finally disappeared. All we can do is trace the ancestry of modern, DNA-based organisms back to the Last Universal Common Ancestor (LUCA), a population of single-celled DNA organisms that lived perhaps 3.8 billion years ago. LUCA evolved out of the RNA world, eventually – perhaps rapidly – out-competing and replacing it.

An RNA world model for the successive appearance of RNA, proteins, and DNA during the evolution of life on Earth. Many isolated mixtures of complex organic molecules failed to achieve self-replication, and therefore died out (indicated by the arrows leading to extinction.) The pathway that led to self-replicating RNA has been preserved in its modern descendants. Multiple arrows to the left of self-replicating RNA cover the likely self-replicating systems that preceded RNA. Proteins large enough to self-fold and have useful activities came about only after RNA was available to catalyze peptide ligation or amino acid polymerization, although amino acids and short peptides were present in the mixtures at far left. DNA took over the role of genome more recently, although still >1 billion years ago. LUCA (Last Universal Common Ancestor) already had a DNA genome and carried out biocatalysis using protein enzymes as well as RNP enzymes (such as the ribosome) and ribozymes. Figure and caption taken from Cech (2012)

The replacement of RNA as the repository of genetic information by its more stable cousin, DNA, provided a more reliable way of transmitting information down the generations. This explains why DNA uses thymidine (T) as one of its four informational bases, whereas RNA uses uracil (U) in its place.

The problem is that cytosine (C), one of the two other bases, can easily turn into U, through a simple reaction called deamination. This takes place spontaneously dozens of times a day in each of your cells but is easily corrected by cellular machinery because, in DNA, U is meaningless. However, in RNA such a change would be significant – the cell would not be able to tell the difference between a U that was supposed to be there and needed to be acted upon, and a U that was a spontaneous mutation from C and needed to be corrected.

This does not cause your cells any difficulty, because most RNA is so transient that it does not have time to mutate – in the case of messenger RNA it is copied from DNA immediately before being used. Thymidine is much more stable and does not spontaneously change so easily.

The new DNA life-forms would have had a substantial advantage because they involved proteins in all their cellular activities. Although we do not know when or why protein synthesis developed, it seems unlikely that it occurred instantaneously – there was probably no protein revolution. Initially the interaction of RNA and amino acids (the building blocks of proteins) would have enabled RNA life-forms to gain some additional metabolic property, before eventually the appearance of strings of amino acids – proteins – created the world of protein-based life.

At some point DNA supplanted RNA as the informational molecule, keeping the genetic sequence safe, using RNA to produce rapid translations of that sequence into the patterned production of proteins, as the RNA enzymes were co-opted and turned into bits of cellular machinery such as transfer RNAs and ribosomes. Proteins can carry out an almost infinite range of biological functions, both as structural components and as enzymes. In both respects, they far surpass RNA. The appearance of proteins therefore opened new niches to life, spreading DNA and protein across the planet, creating and continually altering the biosphere.

These new DNA-based life-forms would have out-competed the RNA world organisms in terms of their flexibility and the range of niches that they could occupy. They would also have been able to grow much more quickly: a modern DNA-based cell can replicate itself in about 20 minutes. Experiments suggest that it would have taken days for an RNA-based life-form to reproduce. The RNA world was slow, limited and probably confined to the ocean depths.

The evolutionary and ecological advantages gained through the use of proteins by DNA-based life show that the appearance of translation from a sequence of RNA bases into a sequence of amino acids was a decisive evolutionary step. The evolution of the genetic code was essential for life as we know it. It truly is life’s greatest secret.


Further reading:

If you want to know more, I strongly recommend Michael Yarus’s book Life from an RNA World.

This article by Cech is also excellent, though at a higher level:  Thomas R. Cech (2012) The RNA Worlds in Context Cold Spring Harb Perspect Biol 

98 thoughts on “The RNA world

      1. RNA can even handle one-electron transfers in a Hadean ocean environment (anoxic, FeII solute, 70+degC)!

        It just can’t do metabolism on its own, as it can’t do the thermodynamic engine functions, electron bifurcation, that some metal atoms or their modern enzymes can do. (For driving carbon assimilation, oxygenating photosynthesis and what not.)

    1. Yes, kudos for all science posts in general, and this post in particular!

      Now, unfortunately, I don’t have time to read it. But once the semester ends, both this post and the book go on my “to read” list!

  1. Writing of the highest order. I think that the book (along with PCC’s own book) will be on my must-buy list for 2015.

    And no FFI in sight ….

  2. Very, very cool. And congratulations to Matthew for getting that book out the door.

    When I was getting schooled in Boulder (biochem) mid-80s, Cech’s RNA work showing that not all enzymes were proteins was emerging (and ringing through the halls of the department). I never had the pleasure of taking any of his courses, though I took thermo with his wife Carol. (and that class kicked my butt sideways)

  3. U in DNA is not meaningless. There is a Bacillus subtilis phage whose DNA contains deoxyuridine and no thymidine. The reason cells must get rid of U in DNA formed by oxidative deamination of C is that on replication U will pair with A changing a CG base pair to TA.

    1. U in RNA can pair with G as well as A. Does the same apply to deoxyuridine in DNA of this phage? Presumably this would enhance the spontaneous mutation rate.

  4. So the DNA skyhook was made by a series of cranes? Seems likely. When scientists speculate their “stories” keep firmly on topic.

  5. That’s a nice summary.

    I have one, kind of petty bone to pick:

    “Although we do not know when or why protein synthesis developed, it seems unlikely that it occurred instantaneously – there was probably no protein revolution.”

    But organisms (and molecules) are discrete, not continuous. How can an evolutionary innovation not occur instantly? Am I reading this too literally?

    I understand how a particular innovation might not be instantly expressed across a large population. It takes some amount of time for the more fit organisms to overtake the less fit organisms, but what about the original innovation? I’m obviously not a biologist, but I would probably describe each of the innovations mentioned (RNA, then RNP, then DNA, etc.) as revolutionary.

    1. I had forgotten that we need DNA to get proteins. Is there no way proteins can occur otherwise?

      Look forward to the Coyne/Cobb book tours next summer!

      1. Possibly the other way around. To make stable DNA is fairly energetic.

        And while RNA can do one-electron transfers in Hadean conditions I don’t think anyone has showed DNA production yet.

    2. I think what Matthew means is that we didn’t go from RNA catalysis to full-blown protein synthesis in one generation. There were probably several intervening steps.

      For instance (and let me be clear that I’m speculating here), it seems likely that RNA enzymes might have evolved to exploit the chemical properties of other naturally occurring molecules in the soup, much as hemoglobin exploits the oxygen-binding capacity of iron. So there were probably RNA molecules that gained some advantage by decorating themselves with metal ions, small peptide fragments, or what have you.

      Maybe some RNA species had more than one peptide fragment attached. And maybe in some of those, the peptide fragments started to link up into longer chains. Eventually perhaps a point was reached where the peptides were doing most of the catalytic work, and the RNA served mainly as a template for assembling the peptides. At that point it became feasible for the peptide chain to break away from the RNA backbone and carry out its catalytic function independently, leaving the RNA free to assemble another peptide chain.

      It seems to me that this is the first point at which we can reasonably say that protein synthesis has been invented. But it took a number of incremental steps to get there.

      1. It is pretty much what ribosoome phylogenetics tells us, see my longer comment.

        Note that I think hydrolysis fairly quickly separate peptides from nucleotides. So presumably any dipeptide cofactors would be temporary, and shorter strand “nests” for embedding catalytic metal atoms would be on their own.

  6. Very nice, Matthew. I look forward to reading your book, when it becomes available.

    The transition between the RNA world and the DNA world addressed a significant problem that was inherent in the RNA only world; and that is that, while RNA can form complex two and three dimensional structures and be catalytically active, it is the latter that made it too unstable for prolonged storage of genetic information. DNA is much more stable, but by being so, it is largely catalytically inactive. The point being that one can either be good at catalysis or be stable, but not both at the same time. Thus the reason why the DNA and RNA world ended up winning out.

  7. Thanks for the excerpt! As a geologist I have lectured in several classes on the origin of life, despite being ill-qualified to do so. Your excerpt made explicit and concrete several things that I was aware of only in the abstract (e.g., RNA is less stable than DNA). I will henceforth add these clarifying details to my lectures.

  8. I guess I should add that I would also appreciate any clarifications, if possible on:

    1. The transition from RNA to DNA. Is this simply unknown? Or are there a myriad possibilities that make summary difficult? When I mention this in class, I just say that it happened, hocus pocus.

    2. The transition to the protein-based world. Is this as yet essentially unconstrained?

    I suppose I should go read Yarus’ book as a starting point.

    1. I was going to pose this as an open question, but figured you could be a good starting point — have you heard about or seen any newer work regarding clay substrates as a candidate for life’s origins?

      1. There is a theory called “Ground of Being” in which the authors specifically deny the “Ground” is clay of any form.

        1. (hunting a bit…) Graham Cairns-Smith (1985)

          The general idea, I think, being that silicate materials were/are absolutely everywhere and could provide a sort of template for self-replicating molecules to get their kick-start. I think it may be an attempt to get around problems associated with solution chemistry — dilution & dissolving dynamics that would tend to tear fragile pre-biotic molecules apart (like in irradiated tidepools or deep-sea vents, for example).

        2. ah – only now noticed the magic word in the link you referenced — cool to see James P. Ferris’ group exploring similar ideas too! For some reason, this idea really resonates with me.

      2. As you worked out since, AGC-S’s work focussed on this very point (he was getting on when I saw him lecture in the mid-80s, so surely he’s retired now?).
        I certainly found it fascinating and more than slightly credible, though my natural scepticism keeps me a long way from turning my prayer mat towards Glasgow. It’s certainly a credible element in abiogenesis scenarios, and not inherently incompatible iwth other elements (e.g. Szostack’s spontaneous formation of lipid bi-layers). But that still doesn’t leave me with a really solid feeling that we’ve got a strong grip on what is more likely to have happened than other cases.
        AGC-S certainly shared a university, if not a department, with another generator of powerful abiogenetic ideas, Mike Russell (who goes for a metabolism-first scenario, using flow of hydrothermal fluids through networks of sulphide mineral grains as an environment for doing some damned interesting chemistry ; he acknowledges theoretical underpinnings form Gunther-Wachtersthaler (spelling? – I have to go and look at rocks soon!)

    2. The transition from RNA to DNA. Is this simply unknown?

      Some evidence is available through looking at the “molecular fossils” strewn throughout the various forms of life on this planet. Some virus researchers like to think that DNA was the result of a parasite-host interaction, with the host modifying its genetic material to evade the parasite. Similar situations involving other nucleic modifications (e.g. methylation) are well-known from restriction enzymes which are so useful in biotechnology.


  9. I studied gene expression in bacteria during graduate school, and I isolated “tons” of bacterial ribosomes. To my mind, one of the most profound discoveries during that time (late 90s to early 2000s) was that the peptidyl transferase activity–formation of peptide bonds in the growing protein–of the ribosome was actually catalyzed by a ribozyme (RNA enzyme). This essential life function absolutely relies upon this very ancient catalyst. Thanks for posting this! Some further reading:

  10. What came first: RNA or proteins? If it was proteins and ‘little RNA’ or ‘pre-RNA’ is there any chemical-geological evidence for precursors to RNA?

      1. Szostak’s name reminds me of these. Bearing in mind nominative determinism, does that explain his interest in alternative theories of life origin and early evolution?

      1. Polypeptides may have existed at the time, but had no way of replicating themselves. Almost all proteins involved in life are made by ribosomes translating from nucleic acid genes. This is one reason why the “tornado in a junkyard” improbability calculations for the random assemblage of proteins favoured by creationists are off-target. It is a strawman argument, since the knowledgable biologist does not propose that proteins came about by random assemblage.

  11. For maybe the majority here, 1943-61 is not within your lifetime, but I was around for ~2/3 of it, and while I have dim memories of things that happened in 1953, I have distinct memories of things that happened in 1957, and so I can wonder where I was/what I was doing when somewhere not all that far away, Hotchkiss was giving his talk. The point being, I guess, how relatively recent this all is.

    1. The discovery of RNA enzymes* did not occur until the 1980s, and resulted in a Nobel prize for Thomas Cech and Sidney Altman in 1989.

      * Ribosomes were known to exists before then, and it was known that they consist of both RNA and many proteins. But it wasn’t until the structure was elucidated by X-ray crsytallography around the turn of the century that the catalytic core of the ribosome is a ribozyme, i.e. an RNA enzyme.

      Francis Crick wrote a book on panspermia, Life Itself, published in 1981. Creationists for some reason like to cite this book. But if you actually read the introduction, Crick makes it clear that his motivation for exploring the idea of panspermia was the failure to identify any RNA enzymes. That lack was remedied within a few years of publication.

  12. Matthew,

    You surely know that not all RNA is single-stranded, at least today. RNA viruses have double-stranded RNA. And why are you so certain that the earliest molecules in RNA World were single-stranded as well?

    1. Yes, RNA does double up sometimes, though most of the active RNA in our cells is (I think) of the single-stranded type. I inserted that sentence to explain to readers of the post what RNA was in case they didn’t know. Given we don’t know what the RNA world looked like, then it could indeed have been double-stranded. That seems less likely, though, as the idea of these ribozymes = molecules of RNA that act as enzymes and can copy themselves – is that it is as simple as you can get. A double=stranded RNA molecule would have to unwind itself to start being active as an enzyme, I think.

      1. I assume the first WEIT comment above here is Prof CC and the reply is from Matthew?

        Kinda confoozling when you both share the same ‘identity’…

      2. Maybe both variants evolved eventually.

        I have been looking on RNA viruses. The +ssRNA viruses are diverse so perhaps older, and their more complicated “life cycle” is consistent with parasites (often simple “body plans”, often complex “life cycles”).

        But the dsRNA viruses are also diverse and bring their own partial transcription systems, so could also have arisen by parasite simplification from RNA cells. [ ]

  13. I am not sure if you have seen this yet Jerry, but, horrible as it is, it made me laugh when I remembered Reza Aslan’s statement about men and women being 100% equal in Indonesia. Follow the link and then scroll to the bottom. Here is a taste:

    “Becoming a policewoman in Indonesia, however, is pretty difficult. Female candidates must be between 17 and 22 years old, unmarried, and still be virgins. Yep.”

    1. Yes. And the Indonesian claim (at least in the local papers) is that it is not unequal. Because “there is no requirement on virginity for police officers”.

      But I doubt the male officers go through a deep genital investigation in order to be ‘fit for duty’…

  14. Outside of viruses I was not aware that there were ever any RNA based life forms. I don’t ever remember being taught anything about RNA that didn’t also relate to DNA. I always thought of RNA in terms of a catalyst and not an actual means of storing and replicating a genetic sequence.

    1. Most viruses is RNA viruses, and when parasitic on a cell in its “adult” non-virion stage (as opposed to the virion “spore” stage) perhaps best thought of as a _very_ simplified organism.

      The idea of “molecular organism” has been described, but YMMV.

  15. …science. I read it; I enjoy it; I even understand some of it.

    Thanks for a great post & good luck with the book!

  16. Thanks for this excellent science post, I think I even understood much of it, though I will need to read it again. Thanks for the further reading; I will follow up.
    I had thought RNA was associated with DNA, not that it was the basis for a life form.
    This is why I always read WEIT.
    I will definitely get your book, Mathew, looking forward to it.

  17. As a chemist, I have to say this was very well written and gave me insight as to how chemistry drives evolution. Fascinating.

  18. Just to be a pain, the seventh paragraph has an error in the first sentence: “The idea of the RNA World was first been put forward …”

    Is this a stupid question (tell me if it is), but if RNA evolved into DNA, could it evolve into something else? And given that DNA is more stable, would the new thing be more stable again making evolution slower or less likely?

    Fantastic achievement!

    1. A more stable code platform, DNA, increases copy fidelity, reducing replication errors, increasing probability of survival.

      1. And I think I’ve heard more than once that any precursors or replicators that might evolve or arise naturally would immediately become food for existing organisms. Also that the environmental pressures that spurred the evolution of RNA and DNA were eliminated once the biosphere became self-sustaining (that is, life sustains life in the presence of light, heat and naturally occurring elements), so there is no selection favoring alteration to the code platform itself.

        Is that relevant or even valid?

    2. The current RNA, whether cellular or viral, is slaved to the DNA lineages.

      If you are asking if DNA nucleotides is the only stable metabolic product you can evolve from RNA nucleotides, I think not. Maybe the exact molecule modification could have been different, and the resulting DNA analog having a different stability.

  19. it really makes me more impressed with the world. Thanks for giving me an even deeper sense of wonder. Thanks for explaining it so well.

  20. Can RNA be formed with nucleotides other than A, C, G, and U? If so it seems unlikely that RNA world organisms would be limited to our kind of RNA. If you are looking for autocatalytic properties of RNA it seems like a bad idea to ignore extinct forms of RNA.

    1. Extinct and also intermediate forms, no? Isn’t it part of the theory that cooperation and combination of competing chains could have resulted in a more stable and efficient reproducer? If X+Y=Z and Z outcompetes X and Y, then X and Y are extinct but they also live on in Z.

      Wikipedia tells me about at least four RNA World alternatives or precursors – PNA, TNA, GNA and PAH – so it seems like a lot of work is being done, there’s just no consensus theory yet.

    2. The purines are pretty much given as a metabolic product as soon as you make the 5/6 C sugars from gluconeogenesis. Dunno about the complementary second bases.

      1. … which raise all sorts of interesting possibilities, not least with the SF crowd.
        (IIRC, the scoin of the Dragon* book’s author, Todd McCaffrey has retconned triple-stranded RNA into the biology of Pern, though I suspect that his biology or chemistry wasn’t up to realising just how hard that would make it for inter-domain (in Woese’s sense) parasitic leaps. Or maybe he hoped that his readers would take the retconning with the requisite several kilos of muriate of natron.

  21. Although we do not know when or why protein synthesis developed…

    The usual hypothesis, if one reads the literature on evolution of the ribosome and the genetic code, is that an early RNA enzyme developed which could remove amino acids from a nucleic acid chain. This would improve nucleic acid elongation and replication by clearing up the product of cross-reactions. The removed amino acid was stuck some place else. Only later did the growing chain of amino acids prove to be useful.

    This hypothesis has several advantages. It proposes a series of small steps by which a ribosome could develop and become useful. This is consistent with Darwinian evolution.

    It is consistent with what we know of the history of the ribosome. The ribosome precursor appears to have undergone a duplication, which is clearly discernable in the current ribosomal structure (key word: proto-ribosome). The ribosome consists of both RNA and numerous proteins, but the structure reveals that, at its core, the ribosome is an RNA enzyme.

    1. The deepest putative phylogeny doesn’t support the cleaning function as the original function. It rather looks like it started out producing dipeptide cofactors for ribozymes, from a simple and generic catalytic “nick” on a straight random strand. The tRNAs also preserve generic enzymatic capabilities in Hadean conditions. (See my longish comment for a reference.)

      Wouldn’t hydrolysis separate amino acids fairly quickly?

  22. proteins therefore opened new niches to life, spreading DNA and protein across the planet, creating and continually altering the biosphere

    Well said and a captivating image. The ubiquity of the biosphere is remarkable in that every conceivable niche is exploited by life: if you can imagine an energy source, means of reproduction, type of locomotion, system of mutual benefit or predation, communication, body size, or habitat or climate, there is at least one organism that is able to use it to make their living. And many that other organisms do not naturally exploit are being put to use by one organism (humans) through the use of technology.

    And that all of the above is effected by a finite number of molecules strung together, in single and paired strands, blindly replicating and catalyzing and combining and folding molecules – in the same process whatever creature is the result of the effort.

    I was surprised to learn that there isn’t a consensus as to what preceded RNA, but really glad that remains lots and lots for future human to figure out. I wonder if it matters? If a model were developed that became the consensus on how we got from molecules to replicators to life, would it change how we view present-day processes and biochemistry? Would it fill gaps in our understanding of genetic mechanisms?

    1. I was surprised to learn that there isn’t a consensus as to what preceded RNA

      The primary reason for suggesting that some other polymer preceded RNA was the difficulty of synthesizing RNA from precursors. A significant breakthrough on that came in 2009 with the proposal of a different pathway:
      RNA world easier to make

  23. Thanks – I did not know RNA was that versatile, and could have been the basis of a system without proteins. Which makes me think that the RNA bases may be the thing we would need to find in a comet (or produced when a comet hits Earth) for them to have kickstarted life here.

  24. Fascinating information on the possible origins of life. As a non-biologist, I have to ask, if RNA is a single strand replicator and DNA is a dual strand replicator, are there currently experiments going on that would nudge RNA into becoming DNA?

    I realize that trying to replicate the conditions of early earth is (at least at the present time) speculative at best, but still that seems like a reasonable experimental path.

  25. There is also plentiful additional evidence that RNA preceded DNA.

    For example, DNA is actually manufactured in cells by first making RNA precursors, then modifying them. Since evolution works on what is available to it, this argues that RNA anabolism came first.

    For example, RNA is used in many cell processes; ATP is a common currency of energy in cells. Various protein enzymes include RNA cofactors to help them do their job. These represent possible “molecular fossils” that point to the past.

  26. Huh? The title is in perfectly straight forward English and clearly describes the contents. How will that ever sell? You were supposed to call it something like Craig Venter’s Whiskers: The Quest for the Magic Shotgun and the Code of Life.

    (Well don’t blame me, the host was asking for comments on these articles!)

    1. (To avoid any misunderstandings, I thought Egg & Sperm Race was an excellent title for a book about the history of theories of conception. I highly recommended book to any WEIT readers who haven’t read it yet!)

      1. I suppose that ProfCeilingCobb’s next book could combine the subject with studying how double-stranded DNA organisms might interact with triple-stranded RNA organisms, and lead to “The Three-Legged Egg and Sperm Race
        People who suffered through school sports days may rightly shudder at the messy carnage invoked by such a title.

  27. Around 1900, three geneticists, De Vries, Correns and Tschermak, rediscovered Mendel’s work, validated it and publicized it. Of the three, Tschermak (1871-1962) was still alive in 1961,when decoding the genetic code began. I think it rzther remarkable that a scientist who rediscovered Mendel would live to see the decoding of the genetic code.

  28. Thanks for the excerpt! A fascinating topic that I really knew nothing about; and another reason why evolution is true. I appreciate lucid science writing since science is not my background. It’s technical, but not difficult to understand. And diagrams always help 🙂

    In the book do you go into detail why microscopic pores in rocks around hydrothermal vents are where RNA probably evolved? I assume the vents emit specific minerals.

    1. (I don’t know if ProfCeilingCobb covers the subject in his book, but the head man in such recent work is Mike Russell, if that helps you with your researches. It’s an interesting set of ideas, and Russell’s geological reasoning seems very sound to me. )

  29. I take exception with Matthew’s characterization (or wording) of where the “RNA world” got its start.

    It is very unlikely that the RNA world began in the deep ocean due to the problems of “infinite dilution”. Bimolecular reactions are determined by thermodynamics and also rate equations. The more dilute two reacting molecules, the slower the rate of their combination. Too dilute (like in an ocean) and they never react or more importantly cannot react iteratively to form RNA polymers/replicate by template-directed synthesis.

    Hydrothermal vents/vocanic pits appear to be a reasonable starting niche for the RNA world(lots of metals to stabilize RNA) but heat is not friendly to the ribose sugar backbone. I favor porous rock/shallow pools for RNA’s origins. There remains the problem of making chiral ribose (one handed form) from non-chiral starting materials–technically a violation of parity in chemistry. There are some interesting theories out there though.

    1. I’m not sure I understand, PCR is doing great on heated nucleotides, isn’t it? It has been shown to replicate DNA under hydrothermal vent conditions. [ ]

      And heat is what makes the Hadean ocean (anoxic, FeII solute, 70+ degC) perform glycolysis and potentially gluconeogenesis over say alkaline hydrothermal semi-porous membranes for product separation to make pentose. [“Non‐enzymatic glycolysis and pentose phosphate pathway‐like reactions in a plausible Archean ocean”, Keller et al, Mols Sys Biol 2014; ]

      The reason I don’t think pools are responsible is the small volumes of both the pools themselves and the land at the time life appeared. (Island arcs from subducting oceanic plates.) If the Hadean ocean produced pentose and perhaps also purines (which has a similar Fe enzyme metabolic chain starting with pentose) right at the outer margins of vents delivering the shorter carbon chains, I doubt there was much dilution where strand production happened.

      As I note in my longish comment it isn’t certain that chirality breaking had to happen until competition over ribosome ancestors happened (latest when establishing a genetic code). Evolution produces short generic cross-chiral polymerases in a few generations, and they can therefore be the base for an early non-chiral RNA cell. [“A cross-chiral RNA polymerase ribozyme”, Joyce et al, Nature Sep 2014; ]

      There is still a problem to get to those polymerases in racemic mixtures I guess. But they haven’t tried to shorten them yet, and as I remember it short strands can appear even then.

    2. Dilution is a definite problem in many deep-ocean scenarios for OOL, but no-one sees it as being insuperable. For a start, the Earth at the relevant times was considerably different to today, with around 5 times the heat flow (because the radioactive elements had not decayed so much at that time), and very substantial tides (tens or hundreds of metres) sweeping huge volumes of water onto and off the land surfaces. That’s to say nothing of the irregular boiling off of large proportions of the oceans following major bombardments.
      Dilution is a problem people keep an eye on, but is not considered to be a “dinosaur killer of a problem. There are credible ways around it. And there was also quite a lot of time. Five hundred million years is still a lot of years, even to a geologist. (My oldest fossils are barely twice that age, and most of them barely over half that age!)

  30. I almost forgot:

    Matthew you mentioned that Szostak says RNA appeared in fatty acid vesicles, but the animations from his lab seem to say that RNA appeared before vesicles. The vesicles merely provided a secure place for them to replicate efficiently.
    I’m no expert, but would love some clarification on that.
    Thanks a million.

  31. Super post, fascinating to read. Having finished school before the RNA world hypothesis, I was vaguely aware of it but hadn’t bothered to pursue the details. This was a wonderful summary.

  32. Nice post!

    The RNA/DNA hereditary system and its transition, a split seen in different virus lineages, is interesting.

    Some modern bacteria use chromosome redundancy as a stable and dense phosphate storage, which could have been the original function of evolved DNA metabolism. But its co-option would usher in a split between transcription and translation, making the cell more robust against parasitism.

    Another interesting feature of early metabolism is that the chirality break enabling coding may not have evolved until the code did. While there are many geosystems that can polymerize nucleotides, the most productive being alkaline hydrothermal vent systems doing PCR, they do have a chiral problem. However it isn’t as serious as first believed: ribozymes can do cross-chiral polymerase functions. Evolution produces short generic cross-chiral polymerases in a few generations, and they can therefore be the base for an early non-chiral RNA cell. [“A cross-chiral RNA polymerase ribozyme”, Joyce et al, Nature Sep 2014; ]

    Just as we do not know when the RNA world appeared, so we also do not know when it finally disappeared. All we can do is trace the ancestry of modern, DNA-based organisms back to the Last Universal Common Ancestor (LUCA), a population of single-celled DNA organisms that lived perhaps 3.8 billion years ago.

    While we don’t know how hold the RNA/DNA UCA lineage was, I think the Timetree provides a fair estimate of the DNA LUCA, with a Bacteria/Archaea split @ 4.0 GA bp. Even the deeper 4.3 Ga bp lineage split date could be feasible, as we now know from Jack Hill zircons that the early Earth was cold and wet already @ 4.4 Ga bp. [ ]

    Although we do not know when or why protein synthesis developed, it seems unlikely that it occurred instantaneously – there was probably no protein revolution. Initially the interaction of RNA and amino acids (the building blocks of proteins) would have enabled RNA life-forms to gain some additional metabolic property, before eventually the appearance of strings of amino acids – proteins – created the world of protein-based life.

    If the latest phylogenies of the ribosome is correct, a molecule perhaps not as old as ATP (or pyrophosphates, for that matter) but old enough to be interesting here, this is correct. The ribosome started out as a generic strand with a simple P region nick that catalyzed phosphorylation, then evolved specificity for tRNA strand dipeptide cofactor production by an added A region, then produced short unordered protein “nests” that could embed catalytic metal atoms by evolving an added tunnel. First later it evolved a socket to fit an mRNA coding strand. [“Evolution of the ribosome at atomic resolution”, Petrov et al, PNAS 2014]

    More support for early metabolic function is seen in the fact that rRNA and tRNA sequences have a preserved generic catalytic ability when placed in a Hadean ocean environment (anoxic, FeII solute, 70+ degC), while mRNAs generally have not.

  33. Hey Matthew, beautifully written, thank you for sharing! I was wondering if your book will cover viroids (small circular RNAs)? Diener suggested that they may be relics of the RNA World. Their genomes are small (a few hundred bases), G+C content is high (greater stability), they don’t code for proteins (no need if they predated proteins), and some have catalytic activity (cleavage and ligation, possibly polymerization). Really looking forward to your upcoming book, thanks!

  34. Although we do not know when or why protein synthesis developed, it seems unlikely that it occurred instantaneously – there was probably no protein revolution.

    A few days ago, just before getting the call off to the rig, I came across a vein of interesting “sciencey videos” which I pointed out to ProfCeilingCat as potentially being interesting.
    Since ProfCeilingCobb raises this very interesting topic, I think this is a very appropriate place to introduce them. Since they’re hosted by, and for the purposes of, the SETI Institute. While biogenesis may not be the day to day business of the SETI people, it is certainly a factor in the Drake Equation, at the other end of the Fermi Paradox.
    So, SETI Institute and their weekly colloquia on a variety of topics, constituting brain food from 2007, 2008, … you can figure the rest.
    One that I found particularly interesting (and there is a THICK seam to be mined there!) was on a chemical/ biogenetic concept titled “Life before genetics: autogenesis, information, and the outer solar system”
    This plays directly on the question of the origin of proteins (and I’m at work now, so can’t take time to explain it in any detail), with some side forays into the less suspect tidal pools of panspermia and some chemistry that at least passes my personal “sniff test” : cyanides, sulphurous compounds, and the potential to deliver them to proto-planets in appreciable concentrations.
    There are up-coming collloquia on results from Philae and Rosetta, which I shall indulge myself with when the next bit of engineering needs done. But I have geology to do, so must go!

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