24 December 2012

New origin of life model fatally requires a nonrandom protein

'The Origin of Membrane Bioenergetics' is a new origin of life model by Nick Lane and William Martin published 21 December [1] in the journal Cell. It is hard to understand for biologists without substantial chemical knowledge. Adding to the complexity of membrane energetics, the article mixes discussion of phylogenetic problems and origin of life problems. For a popular account of the model see ScienceDaily. However, there is one aspect that can be understood by biologists: without protein-coding genes no proteins can be specified. 

The article specifies a number of stages from abiotic chemicals via protocells to free-living cells. Together they form a theory for the origin of life (OOL). The model is an 'energy-first information-later' model. In the first phase there are no proteins and dna. In the last stage proteins and dna are present (dna-protein world). It means that the base sequence of dna specifies the amino acid sequence of proteins. This is also known as the genetic code. The dna-protein world implies dna replication, transcription, translation, ribosomes. In other words, it requires a great number of highly complex proteins.

The authors know that complex enzymes and proteins can not be present in the first stages of the origin of life because life cannot start with the dna-protein world. They claim that in an early stage amino acids, bases, sugars, and lipids can be produced. Although this suggests more, they do not claim that proteins or dna are present in this early stage.
However, a crucial aspect of their model is the presence, at an early stage, of special proteins in membranes ('sodium-proton antiporter'). Without the presence of such a protein the model simply does not work. Now my criticism is:

At any stage before the dna-protein world, the presence of a non-random protein, no matter how simple, is forbidden.

Lane and Martin seem to violate this rule most clearly in this statement:
"Finally, the origins of Na+ pumping required no mechanistically groundbreaking genetic innovations, just a protein, an antiporter that transduced a geochemical gradient (H+) into a biochemical one (Na+)."
If that antiporter protein consists of a few hundred amino acids than its presence before the dna-protein world is forbidden. At other places in their article they suggest that this protein is simple:
"Thus, a simple Na+/H+ antiporter in protocells within vent pores would produce Na+ gradients."
However, even a simple protein is forbidden because it assumes the dna-protein world. There is no small dna-protein world producing small proteins. It's all or nothing. If there exists a dna-protein world, it can produce proteins of any length.

I think they could make the error because they focus on energy problems: 
"But if energy conserved by proteins is needed to make proteins, where did the energy come from that gave rise to the first proteins?" 
Analogously, I would ask: "if information is needed to make proteins, where did the information come from that gave rise to the first proteins?". It is true that energy is required to produce proteins, but information is also required. From a chemical point of view, proteins with random amino acids could be produced [3]. If so, of what use are those proteins? Useful proteins have a specific sequence of amino acids. As far as I know, the specification can only come from DNA or RNA [5]. Furthermore, a large number of identical copies of a specified protein can only be produced in the dna-protein world.

The authors state "At a later protocellular stage, membrane lipids and proteins became genetically encoded". But this implies that a specific functional protein that is not encoded by DNA or RNA exists and later 'became genetically encoded'. Encoding a protein that already exists is impossible because the central dogma of molecular genetics forbids the flow of information from proteins to DNA or RNA [4]. So, if the model depends on the existence of specific non-random proteins before the emergence of the dna-protein world, the model fails.

Similarily Ed Young [2] makes the same error in his Nature news article with the revealing subtitle 'The origin of ion-pumping proteins could explain how life began in, and escaped from, undersea thermal vents.'. Indeed he writes:
"Lane and Martin think that proto-cells escaped this dilemma because they evolved a sodium-proton antiporter — a simple protein that uses the influx of protons to pump sodium ions out of the cell"
The presence of proteins is forbidden in the early stages of every origin of life scenario. Furthermore, Young writes: 'evolved'. Evolving is not possible in a pre-RNA-world or pre-DNA-protein world.
The error is hidden because the article does not strictly separate the different stages and the possibilities and limitations of each stage separately. I am not saying that the ideas in the article are of no value. The publication is important in other respects. But the OOL scenario present in Cell seems fatally flawed by the premature presence of proteins.


  1. Nick Lane and William Martin (2012) The Origin of Membrane Bioenergetics, Cell 151, December 21, 2012 (free access)
  2. Ed Yong (2012) How life emerged from deep-sea rocks, Nature, 20 December 2012 (free access)
  3. According to Pier Luigi Luisi (2006) The emergence of Life: "In fact, we simply do not know how to make long polypeptides by prebiotic means." (p. 64) [added: 28 Dec 2012]
  4. There are no exceptions or violations of the central dogma of molecular genetics known today: information never flows back from proteins to RNA or DNA. Furthermore, proteins do not self-replicate. (added: 28 Dec 2012). The only alternative would be the evolution of the protein from scratch in the DNA-protein world [added 2-1-13]
  5. Recently, a sequence-specific nonribosomal peptide synthesis by an artificial molecular machine is reported in Science 11 Jan 2013: "we report on the design, synthesis, and operation of a rotaxane-based small-molecule machine in which a functionalized macrocycle operates on a thread containing building blocks in a predetermined order to achieve sequence-specific peptide synthesis". So, this is peptide synthesis not based on DNA, nor RNA, nor a ribosome. (Rotaxane is a (very) primitive analog of the ribosome.) This is an interesting mechanism, despite the loss of the sequence information on the strand as it is translated into the product. This system is not heritable information because the information is destructed in the process. Another disadvantage is that peptides are too small to function as an antiporter. [added: 12 Jan 2013]


Acknowledgments: I thank Marleen Roelofs for pointing me to both articles.

Update 25 Dec 2012
I rewrote the following section and included it in the text:

The authors state "At a later protocellular stage, membrane lipids and proteins became genetically encoded". But this implies there is a specific functional protein that is not encoded by DNA or RNA and 'later became genetically encoded'. Encoding a protein that already exists is impossible because the central dogma of molecular genetics forbids the flow of information from proteins to DNA or RNA.

Update 27 Dec 2012
This blog does not attack the natural Origin Of Life! I am merely trying to help the natural selection of fitter Origin-Of-Life theories by elimination of less fitter theories.
31 dec: minor editorial improvement of the intro.

Update 12 Jan 2013
Note 5 added.


  1. If there would be random formation of proteins it might theoretically be possible to obtain by chance one (in number) ionchannel or Na+/H+ antiporter without codification by RNA or DNA. But a protocell needs a lot of these proteins and it is very unlikely to find more than one protein with the same function just by casual arrangement of amino acids.
    So I agree with you that this part of the story remains obscure and that the authors are not very clear about this point. But that life started in the hydrothermal vents by means of protongradients remains a very nice and convincing hypothesis. Their study of acetogens and methanogens supports very well this idea.
    Therefore their hypothesis shows how life could have got started from inanimated matter.

    Maybe there will be some more information in the book Life's Ratchet by Peter M. Hoffmann

  2. Hi Marleen, thanks for your very fast response! I am a little surprised you agree completely with my criticism. I expected a strong defense of the article because you were so excited about it.
    You wrote "the authors are not very clear about this point", indeed I agree. I had a hard time disentangling different stages of their model. Having said that, I still hold it possible they could clarify the matter and improve it. And I think that the publication is creative and innovative and tit contains beautiful insights. I am curious what others have to say...

  3. But then, if you agree with my criticism, you can not claim that "their hypothesis shows how life could have got started from inanimated matter.". The publication tells a lot about the Origin of Membrane Bioenergetics, but not enough about the origin of life to be a succesful theory.

  4. Gert,

    This work shows where the energy comes from, how it could have been conserved and, with the help of mineral catalysts, how it could have been used for chemical reactions of organic molecules. As the authors state, the whole process they describe precedes the origin of replicators.
    What they show is where and how membranes and active ion pumping might have originated. It is a hypothesis, there is no proof whatsoever and they don't claim to prove anything.
    It is shown that protocells might have developed in these vents. All kinds of molecules were able to accumulate in these micropores, so as we discussed under my blog, it is very well possible that macromolecules as proteins and RNA or DNA arose by a slow random association between their respective monomers. So the question is not whether there existed first proteins or RNA/DNA. They might well have been formed at the same time and have formed a promiscuous messy entity of sticky molecules.
    Natural selection then favors the cells that are autonomous, that means that they are able to regulate their osmosis by means of ionchannels and antiporters. Also I think there needs to be information to make these proteins. The authors state that the discussion on how information molecules come into being is beyond the scope of this publication. I think this work should be considered as a step from geochemistry to biology, which is a very important step.

    So the question is: is it possible that randomly developed information carriers as RNA and DNA coexisted with small randomly formed proteins ?

  5. @ Marleen

    “All kinds of molecules were able to accumulate in these micropores, so as we discussed under my blog, it is very well possible that macromolecules as proteins and RNA or DNA arose by a slow random association between their respective monomers.”

    “So the question is: is it possible that randomly developed information carriers as RNA and DNA coexisted with small randomly formed proteins ?”

    Why not : first randomly formed macromolecules as proteins and afterwards randomly developed information carriers as RNA and DNA?

  6. Marleen wrote:
    It is very well possible that macromolecules as proteins and RNA or DNA arose by a slow random association between their respective monomers. So the question is not whether there existed first proteins or RNA/DNA. They might well have been formed at the same time...

    I do not object to the possibility that random rna or dna polymeres could be produced. Whether random proteins could be produced is a matter for chemists to decide. And also both random dna and proteins could be produced at the same time I assume. My point is: the chance production of a functional membrane protein is close to zero. Secondly, if such a protein existed, there is no way to encode it in DNA or RNA because the central dogma of molecular biology states that information is only permitted to go from dna or rna to proteins and not back.

    Nand: the point is that there must be a relation between dna and proteins such that dna encodes proteins (called the genetic code).

  7. Nand, would it be chemically possible that a rna molecule would be sitting in a membrane? and performing the same function as a membrane protein: shuttling molecules in and out?

  8. Gert,

    As we discussed also under my blog, synthesis of protein from DNA requires the presence of tRNA's, mRNA's and ribosomes in modern cells. The classical idea of a RNA-world involves autoreplicating RNA's and ribozymes. Ribozymes might have been able of catalyzing some peptide binding. They have the same properties as ribosomes although they work less efficiently. This means it is quite possible that there is no need for DNA to code for proteins. There might have existed the socalled ribonucleoproteins that were able to synthesize proteins. Moreover there exist RNA viruses that have a cycle that consists exclusively of RNA's. No DNA is needed although for the replication of the ssRNA's, ribosomes of the host cells are needed.
    However, the idea that monomers may accumulate and polymerise where there is formation of small oligomeres and peptides is not a process that goes against the central dogma. Besides, the central dogma is valid for our actual world. Rules may have been different in the primordial world.

    For what concerns your update, I agree with you that the authors make this strange statement. (I was not aware that membrane lipids are genetically coded for.) But considering what I wrote before it is possible to imagine that with a slow but steady increase in complexity of the molecules (RNA, ribozymes, ribosomes, peptides) there might have been the development of tRNA's. These became the carriers of the amino acids and determined the genetic code. So it is very well possible, at a later stage, to have proteins coded for by RNA's alone (without DNA).

    If you don't mind I would like to answer the question you asked Nand with no. Ribonucleic acids are far too hydrophilic to sit in an hyrdrophobic place as the cell membrane.

  9. Marleen, thanks for a number of interesting suggestions!

    1. Ribozymes might have been able catalyzing some peptide binding. I did not know this (or forgot it). Problem: ribozymes themselves need to be long and complex. How specific are they? Are they present in large amounts? Can ribozymes be inherited if the cell splits in two? etc etc

    2. the idea that the central dogma might have been invalid in the past is new to me. Do you know something about this? Evidence? I thought it was a law of nature.

    3. "So it is very well possible, at a later stage, to have proteins coded for by RNA's alone (without DNA)." Of course some time in the origin of life, the origin of encoded information must have happened. But the crucial question is this: does the Lane-Martin model rely on the presence of a membrane protein to generate all the energy necessary for all biochemical synthesis BEFORE the dna-protein world? (or any other way to reproducibly produce specific proteins) (in other words: the the chicken and egg dilemma). Yes or NO? The publication ought to be clear about this. Is it?

    4. If you look 'Figure 1 Possible Stages in Early Bioenergetic Evolution' of the publication: going from A to B all together lipidbilayer + membrane protien + genes + proteins are present! But this is not really helpfull. Too much in one step. We cannot decide whether membrane proteins predate the origin of genes and proteins. So the model is too crude, it contains insufficient detail to decide whether the model could be true.

    5. thanks for your answer about rna in membranes. The purpose of my question was if membrane rna could replace membrane proteins it could solve the problem of the Lane-Martin model. But than again, the membrane RNA would have to be as complex as the protein...

  10. 1. The formation of peptide bonds within the ribosome is still catalyzed by a ribozyme. For this specific action no enzymatic activity of a protein is needed.
    This ribozyme is one of a few RNA's present in the ribosome (ribosomal RNA (rRNA)). These rRNAs are encoded by DNA and are thus inherited.


  11. Gert,

    I guess Lane and Martin didn't want to address the whole discussion on the origin of the code. This problem is not clear at all yet for anyone. So they just skipped it and presume there has been a way to code for the membranal proteins (channels and antiporters). As you stated yourself the article is about the origin of membrane bioenergetics and not about the origin of DNA.

    Following your points:

    1. As we may conclude from the comment by Bastiaan, ribozymes are able to catalyze peptide bonds. The first ribozymes however were not encoded for by DNA but might have been inherited all the same during cell fission and division of the cytoplasm with its content. I have no evidence for these statements because it simply is what I understood of what 'origin of life-scientists' think.

    2. I don't know very much about it, but it seems that small molecules might be able to escape the central dogma. See the following article and watch figure 1. I don't know what small molecule that is, maybe Nand can help us out (it looks like some kind of cholesterol).
    (Rob van der Vlugt brought this article to my attention. Note that it is relatively old, so maybe now there is known more about these molecules)

    3. As I said before, Lane and Martin don't address the issue on codification by DNA or RNA. They presume there has been a moment in the rise of the first cells that DNA or RNA were coding for proteins, but they don't know either when and how.

    4. It might be possible that membrane proteins were synthesized from RNA.

  12. @ Marleen

    I think the small molecule in figure 1 in the article is testosteron:


  13. Marleen, about small molecules and the central dogma: in figure 1 of the article 'Small molecules: the missing link in the central dogma' we see a blue arrow from RNA to Proteins and not back to RNA. And that is exactly the central dogma. So the central dogma is not violated.

  14. Marleen said "4. It might be possible that membrane proteins were synthesized from RNA."
    I have found some evidence for the formation of peptides catalysed by ribozymes (RNA). For example: 'Peptide bond formation by in vitro selected ribozymes'. I don't know if this is enough to produce complete membrane enzymes. Neither do I know whether all this is a realistic possibility under pre-biotic conditions. If anybody knows more, please let me know.

  15. 27 dec: Nederland: het eten van champignons is een morele keuze. Het gaat om witte champignons in die blauwe bakjes. Want het blijkt dat Nederlandse champignons worden geproduceerd onder slechte arbeidsomstandigheden. Dus als je die eet werk je mee aan slavernij. Er is echter ook een Fair Produce keurmerk voor Ned champignons die goede arbeidsomstandigheden garanderen. Keuringsdienst van Waarde)

  16. Has the Orgin Of Life been solved? Perhaps only some minor details have to be filled in? What do OOL researchers themselves think about it? The following overview article might be helpful as a starting point:

    Open Questions on the Origin of Life in: Origins of Life and Evolution of Biospheres, The Journal of the International Astrobiology Society, Oct 2012.

  17. In wikipedia the only critique of the central dogma mentioned is from James Shapiro: "Natural genetic engineering is a reaction against the modern synthesis and the central dogma of molecular biology". But is a vague and confusing sort of critique (wiki): Shapiro does not claim that information can flow from protein to dna, neither does he give an example of this. So the central dogma is still correct.

  18. On ScienceDaily as recently as 27 Dec we read:
    "But as Chaput explains, there's a problem: "The big question is how do you recover that genetic information? You can't reverse transcribe a protein back into DNA. You can't PCR amplify a protein. So we have to do all these molecular biology tricks."


  19. Gert,

    Referring to your review of the Koonin treshold (http://home.planet.nl/~gkorthof/korthof98.htm)I would say that the Koonin treshold doesn't mean very much when you consider that RNA may well have been part of a world in which small peptides and lipides were present. It seems that RNA can interact with amino acids en create peptide bonds.

    Therefore it is quite possible that a RNA-protein world came before the DNA-protein world and that no serious calculations can be made. The primordial world was a mix of different molecules that have a strong influence on each other that can not be quantified. This must be the reason why Koonin placed this calculation in the appendix. The title of this little subchapter is: "...A back-of-the-envelope calculation...".

    The need to invoke a MWO in my opinion equals to the need to invoke the existence of something huge and unknown, a God ??

    I am moderator of a community on Google+ called "Origin of Life". This comunity is also moderated by Yuri Wolf. Do you agree if I post your review of the treshold in this community ?

  20. Marleen, all the best for 2013!
    "I would say that the Koonin treshold doesn't mean very much": that is a very serious statement! (...)
    "A back-of-the-envelope calculations" are famous in science: In the 1930s J.B.S. Haldane had full grasp of the basic quantities and considerations that play a role in kin selection. He famously said: "I would lay down my life for two brothers or eight cousins". This has been worked out in detail by W. D. Hamilton in 1964: the famous Hamilton's rule.
    Also think of Fermat's Last Theorem: This theorem was first conjectured by Pierre de Fermat in 1637, famously in the margin of a copy of Arithmetica where he claimed he had a proof that was too large to fit in the margin.

    "The need to invoke a MWO ..." please don't forget that Koonin published this idea in peer-reviewed journal Biol Direct. 2007: The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life,

    It would be a great honor if you post my Koonin review on the google forum (if you include the original url). Do you have the url of the forum? is it public?

  21. Gert, A happy 2013 also to you.

    Maybe I don't understand well enough the expression "back-of-the-envelope calculations" and you are right that the Koonin treshold is very important. The problem is that it is difficult to imagine a world of pure RNA. So RNA-syntesis may have been influenced by a lot of other factors/molecules.

    The community "Origin of Life" on Google+ is public. You only need to have a Google-account. Once you are in Google+, go here:


    The community is not very active in discussion. I hope your review may wake up some of its members.

  22. Marleen, interessant artikel in Science 11 Jan over een artificial molecular machine die sequence specifieke peptides can produceren op basis van een origineel polymere zonder DNA, RNA, ribosomen: 'Sequence-Specific Peptide Synthesis by an Artificial Small-Molecule Machine'. (note 5)

  23. Gert,

    Dank voor de tip. Ik heb het abstract kunnen lezen en iets meer in ScienceDaily:
    Dit is werkelijk zeer interessant.

    Toevallig ben ik Life's Ratchet van Peter Hoffmann aan het lezen. De schrijver ziet molecular machines als hét punt waar de chaos op atomische schaal orde brengt in het leven. Maar ik dwaal af...

  24. Marleen, bij dit artikel staat een fantastische animatie van het hele proces:
    Rotaxane mimics ribosome to spin out peptides. je ziet dan onmiddellijk waarom de peptide niet lang kan worden: de peptide groeit aan het uiteinde in plaats van aan het begin. Het armpje is gauw te kort en kan het niet meer aan... Maar het blijft mooi!

  25. Dankjewel Gert, Dat maakt het allemaal een stuk duidelijker en mooi is het zeker.
    Het is dus eigenlijk niet echt wat een ribosoom doet, maar wel interessant dat ze op die schaal dit voor elkaar kunnen krijgen.


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