Friday, October 03, 2014

Metabolism first and the origin of life

There are many ideas about the origin of life but the only ones that concern me are the scientific ones. The 21st century debate mostly involves smokers vs. soupers [Changing Ideas About The Origin Of Life].

Soupers are people who believe in some version of the primordial soup. They believe that life originated in a solution of organic molecules and the most primitive way of getting energy was by oxidizing these molecules. For them, the first biochemical pathways were like glycolysis. Most of them think that complex organic molecules were delivered to Earth by asteroids [see NASA Confusion About the Origin of Life].

Smokers, on the other hand, promote an origin of life scenario that relies on the chemistry surrounding hydrothermal vents on the ocean floor. These environments favor reactions that build up organic molecules from inorganic substrates like hydrogen and carbon dioxide. In this case, the most primitive reactions are simple oxidation-reduction reactions and the most primitive pathways are biosynthesis pathways, not catabolism. This view is often referred to as "metabolism first" [Metabolism First and the Origin of Life].

I'm a big fan of metabolism first and especially the versions promoted by Bill Martin and Nick Lane. I think it's the only reasonable model for the origin of life.

A reader alerted me to a paper published last year by all the big names in metabolism first [Sousa et al., 2013]. It's an excellent paper. You should read this paper if you really want to learn about modern thinking on the origin of life problem. The biochemistry is complicated but well worth the effort.

I don't have time to explain it all. Here's a teaser ...
At first sight, the idea that chemiosmosis is a very ancient means of energy transduction might seem counterintuitive. More familiar to many is the old (and popular) doctrine that the most ancient pathway of energy metabolism is a fermentation such as glycolysis [77], an idea that goes back at least to Haldane [2] and hence arose long before anyone had a clue that biological energy can be harnessed in a manner that does not involve substrate-level phosphorylations and ‘high-energy’ bonds [149,150]. In modern life, all biological energy in the form of ATP comes ultimately from chemiosmotic coupling [151], the process of charge separation from the inside of the cell to the outside, and the harnessing of that electrochemical gradient via a coupling factor, an ATPase of the rotor–stator-type. It was not until the 1970s that it became generally apparent that Mitchell [152] was right, his Nobel prize coming in 1978, and it is hard to say when it became clear to microbiologists that all fermentative organisms are derived from chemiosmotic ancestors. We also note that Mitchell's consideration of the problem of the origin of life introduced key concepts of his later chemiosmotic hypothesis, including a definition of life as process, and the idea of vectorial catalysis across a membrane boundary that is inseparable either from the environment or from the organism itself [153].

The maxim that glycolysis is ancient might be an artefact of experience, since it was the first pathway both to be discovered and that we learned in college; in that sense, it really is the oldest. When one suggests that chemiosmotic coupling in methanogens or acetogens might be ancient, many listeners and readers shy away, mainly because the pathways are unfamiliar and often entail dreaded cofactor names.

Sousa, F.L., Thiergart, T., Landan, G., Nelson-Sathi, S., Pereira, I. A., Allen, J.F., Lane, N. and Martin, W.F. (2013) Early bioenergetic evolution. Philosophical Transactions of the Royal Society B: Biological Sciences 368:20130088. [doi: 10.1098/rstb.2013.0088]


  1. Hi Larry, Thank you for this block quote. If you ever decide to write a *metabolism first for biochemical dummies* essay, then I would check that out. Peace, Jim

  2. You should mention that the paper is free.

  3. There's more being published on this alkaline hydrothermal vent idea, recently, Larry. These should be right up your alley too:

    A Bioenergetic Basis for Membrane Divergence in Archaea and Bacteria
    Víctor Sojo, Andrew Pomiankowski, Nick Lane

    Membrane bioenergetics are universal, yet the phospholipid membranes of archaea and bacteria—the deepest branches in the tree of life—are fundamentally different. This deep divergence in membrane chemistry is reflected in other stark differences between the two domains, including ion pumping and DNA replication. We resolve this paradox by considering the energy requirements of the last universal common ancestor (LUCA). We develop a mathematical model based on the premise that LUCA depended on natural proton gradients. Our analysis shows that such gradients can power carbon and energy metabolism, but only in leaky cells with a proton permeability equivalent to fatty acid vesicles. Membranes with lower permeability (equivalent to modern phospholipids) collapse free-energy availability, precluding exploitation of natural gradients. Pumping protons across leaky membranes offers no advantage, even when permeability is decreased 1,000-fold. We hypothesize that a sodium-proton antiporter (SPAP) provided the first step towards modern membranes. SPAP increases the free energy available from natural proton gradients by ~60%, enabling survival in 50-fold lower gradients, thereby facilitating ecological spread and divergence. Critically, SPAP also provides a steadily amplifying advantage to proton pumping as membrane permeability falls, for the first time favoring the evolution of ion-tight phospholipid membranes. The phospholipids of archaea and bacteria incorporate different stereoisomers of glycerol phosphate. We conclude that the enzymes involved took these alternatives by chance in independent populations that had already evolved distinct ion pumps. Our model offers a quantitatively robust explanation for why membrane bioenergetics are universal, yet ion pumps and phospholipid membranes arose later and independently in separate populations. Our findings elucidate the paradox that archaea and bacteria share DNA transcription, ribosomal translation, and ATP synthase, yet differ in equally fundamental traits that depend on the membrane, including DNA replication.

    1. The Drive to Life on Wet and Icy Worlds
      Russell Michael J., Barge Laura M., Bhartia Rohit, Bocanegra Dylan, Bracher Paul J., Branscomb Elbert, Kidd Richard, McGlynn Shawn, Meier David H., Nitschke Wolfgang, Shibuya Takazo, Vance Steve, White Lauren, and Kanik Isik.

      This paper presents a reformulation of the submarine alkaline hydrothermal theory for the emergence of life in response to recent experimental findings. The theory views life, like other self-organizing systems in the Universe, as an inevitable outcome of particular disequilibria. In this case, the disequilibria were two: (1) in redox potential, between hydrogen plus methane with the circuit-completing electron acceptors such as nitrite, nitrate, ferric iron, and carbon dioxide, and (2) in pH gradient between an acidulous external ocean and an alkaline hydrothermal fluid. Both CO2 and CH4 were equally the ultimate sources of organic carbon, and the metal sulfides and oxyhydroxides acted as protoenzymatic catalysts. The realization, now 50 years old, that membrane-spanning gradients, rather than organic intermediates, play a vital role in life's operations calls into question the idea of “prebiotic chemistry.” It informs our own suggestion that experimentation should look to the kind of nanoengines that must have been the precursors to molecular motors—such as pyrophosphate synthetase and the like driven by these gradients—that make life work. It is these putative free energy or disequilibria converters, presumably constructed from minerals comprising the earliest inorganic membranes, that, as obstacles to vectorial ionic flows, present themselves as the candidates for future experiments.

    2. This alkaline hydrothermal vent theory seems to be gaining quite a lot of support recently. It is also interesting to see how the theory can help shed light on some long-standing questions regarding the split between bacteria and archaea.

    3. I've read lots of recent papers but I hadn't seen the massive review that I mentioned in my post.

      What puzzles me is that these ideas have been around for a long time but most scientists are still soupers and most biochemistry teachers still teach the old primordial soup nonsense.

  4. I certainly like the idea that chemiosmotic coupling is more ancient than 'solution biochemistry'. A physical entity of fixed location and reasonably consistent conditions to either side seems more plausible than free-floating reactions, which would rapidly descend into thermodynamic wells, and lose products to diffusion. I'm less convinced of the early involvement of polypeptides (as opposed to the incorporation of amino acids into pre-protein biosynthetic pathways).

  5. Larry said:
    What puzzles me is that these ideas have been around for a long time but most scientists are still soupers and most biochemistry teachers still teach the old primordial soup nonsense.

    I believe there is a certain sluggishness in the scientific 'system'; how long before the Big Bang theory really took hold?

    Maybe my 'position' as an interested but irresponsible layman has made me less reluctant to latch on to new and surprising ideas? Or maybe scientists feel they have to hedge their bets until the new horse has proven itself beyond reasonable doubt? I'v been a stacker for a long time now and have been waiting for news like this.

    I remember reading an essay on how scientific progress is influenced by resistance to new ideas, and how that resistance eventually may help to avoid selling the pelt before the bear has been shot. So I guess that's more or less how it is and probably better than any alternative.

    Not my best, I am forever in a struggle with the English language...

  6. The most interesting thing to me is the centrality of ATP. There doesn't appear to be a strong chemical or energetic reason for that purine, as opposed to another, or a non-purine, to be at the end of ATP, NAD, FAD, CoA etc. But of course it has the special property that, chained polymerically through ribose-phosphate linkages, it can bind a chain of polyuridine running antiparallel, likewise mixed random monomers of those two bases can bind a complementary sequence. This preferentially increases the half-life of these molecules over bases and chain configurations (eg mixed L and D ribose) lacking a complement. So the first nucleic acids worth the name may have actually been formed from hybridisation of short complementary (and probably cyclic) sequences, possibly initially restricted to two bases, and fixing chirality at the outset even before replication was achieved.

    In this scenario, it's the 'informatic' role that fixes adenosine, not the energetic one. When the authors talk of the 'acetyl CoA' pathway, for example, it would not seem to be favoured unless there was a role for that specific purine already in place - ie, in the post-RNA world.

    Of course you need amino acids to make purines, and this may be, as the authors suggest, a 'fossil' of primordial biochemistry. But the polymerisation of those amino acids into catalysts, I think, awaited a means of specification, which the nucleic acids provided, and which their competitive replication allowed to be tuned.

  7. I love this website's animations about the self-assembly of fatty acids and micelles then membranes and protocells. I'd love to hear what you think of this. It certainly seems more smoker than souper to me.

    I know genetic connectivity and population studies are being done at deep sea vents and seeps. I'm truly excited to learn how this information might inform knowledge of LUCA and likely locations of the origin of life. Here's some info about research on cold seeps The NCSU researchers I know (Eggleston and McVeigh) are mostly working on larval movement and the Duke researchers are doing more of the genetic work in these deep sea environments.

  8. Larry,
    We’ve been over this many times…
    How does your view; metabolism first, differ from “the primordial soup sense”…or the pathetic vent worshipers like Rumraket…? I don’t get it…Neither theory has any merit and has nothing to do with real science…What I mean by that is that no experiment has even shown that any of these theories can be considered scientific…Calling them such is like Chris B believing that “the flagellum evolved from a type III secretion complex, common among bacteria. This is based on DNA/protein sequence and functional similarities among type III secretion systems and their corresponding proteins in the flagellum”… This theory may seem pretty good to a moron who either knows nothing about the theme or like many morons here want it to be true… it is pretty clear to most people that an automobile has roots or “has evolved” from a bicycle… however… nobody believes that the more complex parts in an automobile somehow self-improved and excelled in complexity froin m a simple bike…
    Please tell me why you chose to believe this pile of crap…

    1. Quest makes a good point. It would be simpler if we just went back to saying god did it.

    2. Yeah, but then we would just argue about which god. :)

    3. Hey Quest, please tell us the details of your alternative, scientific hypothesis of how, when, and where life originated on Earth.

    4. Quest: "I don’t get it…"

      That much is obvious. You should have just left it at that.

    5. Please tell me why you chose to believe this pile of crap


      Been there. Done that. Time wasted.

    6. nobody believes that the more complex parts in an automobile somehow self-improved and excelled in complexity froin m a simple bike…

      What does this tell you about its relevance to biology?

    7. "I don’t get it"

      Everyone already knows.

    8. Actually Quest, there is a good body of peer reviewed scientific literature showing the similarities between bacterial type II secretion systems and the flagellum. Literature you are completely unaware of. You never even attempt to engage in a scientific and rational manner. You pretend to understand things you know nothing about, and leave comments strewn with ad hominem attacks and declarations that you are right- with zero evidence to support yourself.

      You belittle and ridicule the homology between Type III secretion systems and the flagellum not because of some alternative scientific hypothesis for which you have any evidence, but because the flagellum is a favorite place for you to hide your invisible magical spook.

      That is also why you so predictably jumped on this post. Dr. Moran went clickety-clack across your bridge again by talking about plausible origins of lfe, another favorite gap to put your invisible magical spook. So you had to submit another one of your content-free "refutations" of science.

      Ok, time to stop feeding.

    9. Pest:" This theory may seem pretty good to a moron"

      Why, no, apparently not. After all, Quest doesn't believe it.

    10. Pest: "nobody believes that the more complex parts in an automobile somehow self-improved and excelled in complexity froin m a simple bike…"

      Pest, have you ever noticed that automobiles don't have sex organs? (Hint: truck nuts are not real, they're made of plastic.) Since they don't have sex organs, they can't reproduce, right? Since they don't produce offspring, their offspring can't have mutations, right? Since they don't reproduce, there can't be natural selection, that is, differential reproduction rates for different mutants, right? Since their offspring that don't exist can't have mutations, there are no mutations for biologists to study, right?

      Could it be that perhaps the fact that automobiles can't have offspring with mutations, but organisms do have offspring with mutations, might perhaps explain why biologists think the first did not evolve, but the second did?

    11. Chris B, Dinogene and the rest,

      I personally think it is pretty hilarious that you believe that life originated by some accident which neither of you or anybody else considering himself intelligent can't replicate... I think this is rather embarrassing not to be able to replicate it and still believe that damn luck did what you can't...

      If there was a Nobel Prize for stupidity... you would be the front

    12. Quest, once again you demonstrate how ill-equipped you are for rational discourse.

      "I personally think it is pretty hilarious that you believe that life originated by some accident"

      Nobody but youmade this claim.

      "which neither of you or anybody else considering himself intelligent can't replicate..."

      Whether or not a human being can create new life in the lab has no relevance whatsoever as to the validity of evolution. Where do you get these irrational ideas?

  9. Larry wrote:


    Been there. Done that. Time wasted."
    Actually... this is the first time you responded to my demands for evidence for your beliefs on the theme..I didn't expect anything scientific... because there is no such thing and you know it... and that is why you never did respond... What a pity...

    1. "I didn't expect anything scientific"

      In response to an entry discussing a summary paper about metabolism-first origin of life.
      Fucking classic.
      You just can't make this stuff up.

  10. Not sure if this went through so putting in again Part 1 of 2.
    Many microbes are found in extreme environments, especially Archaea which tend to like toxic conditions. These types of Bacteria and Archaea are the ones that probably were the earliest ones when Earth was toxic. When comets were bringing in toxic organic molecules like formaldehyde, although I am not much of a fan of such "Act of God' theories for how life started here.

    The type of protocells which must have developed on the early Earth must have found a way to utilise the toxic compounds available, just like organisms find ways to survive now. Thus I think that if people are looking for methanogens such as on Mars where the production of methane was sought as evidence of life, they may have it the wrong way around. What is needed is an organism that can somehow utilise toxic conditions and/or a toxic atmosphere, not ones that can produce it! Such organisms that may have existed for the first billion years of toxic Earth, surviving and feeding off what was available! The organisms I suggest may have been involved were anaerobic methanotrophs as there was no oxygen but a lot of methane in the early toxic Earth. Wikipedia describes these (( Anaerobic oxidation of methane occurs in anoxic marine and freshwater sediments. During AOM methane is oxidized with different terminal electron acceptors such as sulfate, nitrate, nitrite and metals. And they produce CO2 which became the next major component of the early atmosphere to be utilised by unicellular organisms. Sadly not much is known about them.

    The pursuit of ET might best be investigated, given our knowledge of life on Earth, in terms of the production of oxygen for an advanced evolutionary atmosphere, or the production of carbon dioxide from methane by methanotrophs for an earlier, toxic one. All that is needed for the production of proteins is apparently a puddle undergoing drying and wetting. However I am a skeptic about the prospects of there being life on any other planet!

    References given by Wikipedia worth following up:
    Ettwig, K. F.; Butler, M. K.; Le Paslier, D.; Pelletier, E.; Mangenot, S.; Kuypers, M. M. M.; Schreiber, F.; Dutilh, B. E.; Zedelius, J.; De Beer, D.; Gloerich, J.; Wessels, H. J. C. T.; Van Alen, T.; Luesken, F.; Wu, M. L.; Van De Pas-Schoonen, K. T.; Op Den Camp, H. J. M.; Janssen-Megens, E. M.; Francoijs, K. J.; Stunnenberg, H.; Weissenbach, J.; Jetten, M. S. M.; Strous, M. (2010). “Nitrite-driven anaerobic methane oxidation by oxygenic bacteria”. Nature 464 (7288): 543–548. doi:10.1038/nature08883.
    Hanson, R. S. and Hanson, T. E. (1996). “Methanotrophic bacteria”. Microbiological reviews 60 (2): 439–471.
    Haroon, M.F., Hu, S., Shi, Y., Imelfort, M., Keller, J., Hugenholtz, P., et al. (2013) Anaerobic oxidation of methane coupled to nitrate reduction in a novel archaeal lineage. Nature 500: 567–570.

  11. Part 2
    Recent research has just changed the ball-game for how life developed on Earth. Forsythe et al. (described in Science Daily as “Finding the origins of life in a drying puddle July 20, 2015; link to 2015 paper below) produced polypeptides in wetting and drying conditions at 65 deg. C., with the likelihood being that proteins evolved on terrestrial Earth and not in the oceans as previously envisaged. This confirmed to me the importance of the role evaporation in life’s evolution. Given that water is the most fundamental molecule to life, the absence of it due to evaporation must play some role.

    Although it is very interesting that a puddle containing the necessary ingredients may have been available for evaporative and hydrating processes to work on, creating polypeptides and later complex proteins in terrestrial zones, that does not per se mean that life itself i.e. the initial protocell, arose terrestrially. Life may still have arisen in the oceans, but this would necessitate the “puddles” being nearby to an ocean, so that coastal inundation could have swept the new proteins into the ocean. There they then would have to have replicated to become abundant enough to reach locations where life formed, e.g. deepsea vents, indicating that RNA may have preceded life. If however the process of polypeptide formation leading to proteins led to life on land, then RNA may have arisen at an early stage after life arose.

    What I do think though is that there is now a conundrum in which it appears proteins may have evolved on land, but life possibly in the sea, so it is the question of getting a to b, and where does RNA then fit in? For example if you have a few complex protein molecules sitting in an evaporating pool, even close to the sea such as on a coast, with the tides washing them into the ocean, how do they multiply to spread to vents without RNA? As much as I admire Nick Lane, I think this new information has thrown something of a spanner into the works.

    I think that there is a further possibility for membranes. Where previously I thought that membranes were water or water-metallic membranes that stretched between rocks eventually forming an enclosure around protein complexes, it seems something else is now possible. Given the desire to prevent evaporation in a drying pond, or alternatively to drown, could the nascent proteins have worked with proteins to form a hydrophobic layer? To me that seems to fall into place so that evolution of proteins was followed by membrane-bound proteins which may have learnt to replicate using RNA, and these then spread to the oceans, where the true protocells began. Fossil bacteria seem to indicate life began in the oceans.


    Forsythe, Jay G. et al. (2015): “Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth”; Angewandte Chemie International Edition (early version online: .

  12. @ccatctc: You seem to like the expression "toxic" a lot, while not defining it so we can understand its use. If it has any: obviously the first populations would thrive in their environment (or life wouldn't survived), so it wasn't 'toxic' for them. Rather, anoxic chemotrophs prefer the same redox conditions that the "smoker" theories are based on. It is a strength of these theories by the way.

    Re the many pot non-reactor soup theory vs a smoker one pot reactor theory, the likelihood is apriori greatest for the latter one. Now there were many impactors that could have partaken in the soup pathway, but there were many vents as well. If impactors and dry/wet cycle on early continents (which we now know were present from 4.4 billion years ago on, see the Jack Hill zircon results) contributed it may have been useful. But it isn't crucial for the "smoker" theories. (Which by the way now have their necessary oceans observed by the JH zircons from before 4.3 billion years, so are much as good time wise.)

    More problematic for the "soup" theories is the recent demonstration by Lane et al that universal chemiosmosis _had_ to evolve near the surface of alkaline hydrothermal vents, only their can the evolutionary pathway proceed. (And it is also only promoted by such an environment.) Now you can possibly have earlier cells establish themselves on a vent, evolve chemiosmosis and then compete all other lineages into extinction. But it seems far fetched. Much easier to believe that chemiosmosis was necessary to free cells from their constrained environment.

  13. The earlier commentary started out intending to be a simple "I don't think so" response. =D But as it swelled, I may as well put in my remaining 2c on the interesting and valuable series of Larry's abiogenesis posts.

    I agree with the distinction between the two soup and vent theories up to a point. But I think the separation is artificially made too severe. Keller et al showed recently that glycolysis (and so gluconeogenesis, by way of product separation) has a non-enzymatic pathway in an anoxic FeII solute Hadean ocean. [ ; and see the accompanying editorial on the gluconeogenesis pathway.] Now that fits more convenient in a vent environment, since the temperature - a 70+/70- degC differential for gluconeogenesis - does, and since it was recently shown in experiments that alkaline vent greigite minerals catalyze the production of the necessary pyruvate substrate from CO2/H2 in the alkaline vent redox environment.

    Keller et al pathway is by the way to my knowledge the first demonstrated non-enzymatic metabolism-like (sufficient lossless, same efficiency as cellular metabolism) pathway before the many-pot one you point to. They make away with the notions of Woese (IIRC), that claimed a chicken-and-egg problem for metabolism vs enzymes. There were 5 such major stumbling blocks a year ago, including how chirality interacted with RNA replication (cross-chirality is actually helpful), but they have now all fallen! [So, a lot of references from here on. In the interest of saving time, I'll produce them if asked to.]

    An environmental glycolysis/gluconeogenesis makes away with Larry's aldolase/separate evolution constraint I think, but his post on those may explain why gluconeogenesis may appear phylogenetically older. Vent and cellular leakage/production variations should have made an enzymatic takeover of the glucose/pentose production a series of fitness promoting events.

    Finally, I don't see today's vent theorists try to explain why substrate level ATP production evolved if chemiosmosis ATP production is both more efficient (~ 20 ATPs vs 2) and evolved first. Yes, they regulate the controlling steps, the irreversible committed steps, of glycolysis. But why there, if not to balance gluconeogenesis ATP demands? You can argue that such balance is useful. But evolution is contingent so it appears as a lucky coincident. Instead I think it could have been enforced by substrate level ATP production evolved as the only - and simpler - game in town at the time.

  14. Net production of ATP by catalysis can only be productive in an environment where there's lot of "high-energy" organic compounds available for degradation ( e.g. glucose). We are used to thinking about animals where such food is readily available and, unfortunately, much of metabolism is taught from this perspective.

    Think about bacteria and algae living in the oceans. This is a more appropriate analogy to the primitive cells that first evolved on Earth. They could not make ATP or its more simple equivalent by substrate level phosphorylation because there's no substrate available. That's why the bottom up approach of metabolim first is so much more reasonable.