Responding to "The RNA-World Paradox" by Finding Truth @Ahmed_AbdelSattar

We have had a previous conversation here about the “LUCA’s paradox”, but here is another video by @Ahmed_AbdelSattar

It starts off by explaining the bear minimum of for the motivation behind the RNA world proposal. In modern organisms (excluding viruses obviously), DNA carries the function for preserving and transmitting hereditary information, while proteins carry the function of (mainly but not limited to) catalysis. But since RNA is a “simpler” version of DNA and since it can perform both functions of DNA and protein, perhaps prior to DNA and proteins, life relied on RNA instead. There isn’t anything particularly wrong about this initial description (although I wouldn’t say that RNA is simpler than DNA), but the reasoning for an RNA phase of life goes far beyond this.

Firstly, as I pointed out in a recent post, the way polypeptides (incl. proteins) are synthesized by polymerizing amino acids is entirely RNA based. The transnational system uses mRNA and tRNA, both are RNA obviously. But even the ribosome is RNA. Although the ribosome is also composed of protein, the part that is actually responsible for the peptide synthetic chemistry is RNA based. And it turns out that a “naked” RNA ribosome (having no proteins) is still capable of peptide synthesis. So the fact that (1) you don’t need protein to make polypeptides, all you need is RNA; and (2) the fact that even modern organisms rely on a ribozyme to synthesize proteins, is strong evidence for the RNA world hypothesis, and for the ribosome (and the translation system in general) being a remnant of that early phase of life.

Secondly, RNA isn’t exactly “simpler” than DNA…well…it’s a muddled description at best. Thymine in DNA is a methylated version of uracil RNA, which makes DNA less susceptible to certain types of mutations. On the other hand, RNA has a 2’hydroxyl group but is absent in DNA. In this respect would make DNA chemically simpler. The presence of this chemical group makes RNA more prone to hydrolysis, but it makes RNA also more reactive and thus capable of catalysis unlike DNA. But RNA being an antecedent is evident in the way the DNA is synthesized. DNA polymerization is performed by the aptly named DNA polymerase, but it is only capable of adding new DNA nucleotides at the 3’OH end of an already existing strand. It can only perform elongation, but it can’t add the first free nucleotide onto the template strand. That’s why DNA polymerase needs primers. In the lab doing PCR we use DNA primers that are pre-made before they bind onto the template strand, but organisms make primers of RNA that are directly synthesized onto the DNA template strand. And the evidence gets even stronger when looking at how life makes the DNA monomers, which occurs at the tail ends of the biosynthetic pathways for RNA nucleotides, wherein rNTPs are reduced (removing the 2’OH group) into dNTPs. In other words, you need to polymerise RNA before you can polymerise DNA; and you need to make RNA nucleotides before you can make DNA nucleotides. These facts give more credence to the RNA world hypothesis

But things get even interesting still if we look at the biosynthetic pathways for RNA nucleotides, specifically purines, and note the intermediates as well as the other metabolites that are derived from these.

(click on images for sources, which are also on life’s origins)

Note the purine RNA nucleotides GTP and ATP in this pathway, these are the monomers used to be polymerized into RNA strands and also used as precursors to DNA nucleotides as mentioned before. They start of from the metabolite abbreviated by PRPP, but note that GTP and ATP aren’t the only products. These include other biochemicals known as cofactors (specifically coenzymes), which some enzymes (about half actually) require to function. These often function to transfer chemical groups or electrons. Also, to make many of these coenzymes we require the precursors in our diet as vitamins.

THF and other folates (vitamin B9) directly produced from GTP are involved in transferring C1 groups. Also from GTP, riboflavin (vitamin B2) is the precursor to electron carriers such as FAD, which is part of electron transport chains. Some coenzymes made from ATP include Coenzyme A (vitamin B5), NAD+/NADH (vitamin B3), SAM (non essential in diet) and histidine (an essential amino acid). While histidine is an amino acid, it’s biochemical synthesis is uniquely different and the properties of it’s side chain is very much like a cofactor. It’s important in catalysis, and it is often part of the catalytic triad of proteins. Coenzyme A (CoA) and SAM transfer acyl and methyl groups respectively, while NAD+/NADH is an electron carrier. Not to mention that ATP itself is also a cofactor that transfers phosphoryl groups, and functions as the quintessential energy carrier of all life. One final quirk of biosynthesis to note here that these cofactors often exhibit the beginnings of polymerization (containing multiple monomers). Not just that, some of these are also made from amino acids as well as nucleotides, some of these bonds are the same as those in aminoacyl-tRNAs. CoA is also derived from cystein and SAM from methionine. RNA-peptide world anyone?

The cofactors ATP, CoA, and NADH especially, play important roles in core metabolism. In fact, while about half of all enzymes require cofactors, all the enzymes involved in key steps of core metabolism have cofactors. Thus cofactors they may have played the role of catalysts prior to proteins and were only later enfolded into complex proteins while retaining their biochemical roles. Interestingly, several of the most ancient protein motifs function to bind to (moieties: common parts) of these and other cofactors. Furthermore, simple polypeptides are capable to perform these functions to some extent. All of this gives strong support for ribo-nucleotide derived/based cofactors as molecular fossils of the RNA world and also of the early evolution of proteins.

Let’s move on with the rest of the video, trying to be more concise. Last time Ahmed neatly numbered his paradoxes he had with LUCA, but here these aren’t numbered. So I will just note the problems I have seen during the video. Correction: I was writing down each point he brought up a before I got to the end of the video where he numbered them, still I think I covered them here.

He mentioned a hypothesis that says that if RNA can act as catalysts, ribozymes, then perhaps you could have ribozymes that can function as RNA polymerase, and thus catalyse their own replication. So maybe life starting with self-replicating ribozymes. However, this is part of what is called the “Strong” version of the RNA world hypothesis that emerged from an unorganized set of organics (primordial soup). but I don’t buy that. I am more in favor of the metabolism first hypothesis that a self-organized organic synthetic network that extended out from geochemistry (reflecting core metabolism) provided the preconditions from which the RNA world later emerged. But in any case, Ahmed goes on to say that unfortunately, when the synthesized strands are long enough, the self-replication by ribozymes will not work properly. He highlights the following sections from this paper.

Arguably the greatest limitation of the RNA world hypothesis is the lack of an RNA replicase ribozyme, which has been coined the holy grail in the ribozyme community (Szostak et al. 2001; McGinness and Joyce 2003). […] This polymerase can extend an RNA primer-template (PT) complex by up to 14 nt in a template-directed manner after 24 h of incubation. Nonetheless, the ability of the Round-18 ribozyme to polymerize more than one RNA helical turn is limited; more typically the Round-18 polymerase adds only a few nucleotides to a given PT complex. This poor polymerization ability has been attributed to weak and highly variable PT recognition (Lawrence and Bartel 2003)…

However, this is from the introduction where it talking about the work that came before producing this Round-18 ribozyme. This paper reports the isolation of a new ribozyme called B6.61 that exhibits superior extension and fidelity compared to Round-18. This can be seen just from the abstract. I don’t know why Ahmed would skip that and highlight just the part of the introduction and not show the actual work that was done by this study.

Next, Ahmed entertains the possibility that RNA was replicated by an enzyme that itself was RNA based. I guess he meant a protein enzyme, which itself is encoded onto an RNA strand. Basically a RdRp gene in a RNA genome. I say this because he later mentions that some RNA viruses encode an RdRp that is translated into the enzyme by the ribosome of the host and that replicates the genome of the virus. Ahmed suddenly that we shouldn’t rely on proteins in the RNA world, but let’s assume that it exists, that an RNA gene exists that encodes for this protein. But for that you need a ribosome to translate the RNA, the problem is that the ribosome is complex and the ribosome is also composed of protein. And again, Ahmed insists that we are in the RNA world, it should not have proteins in them and we shouldn’t solve the problems with proteins. However, as I mentioned before, the catalytic functions of the ribosome in translation are RNA based and it can still perform that function without the proteins. Plus, I also talked about a paper on a seperate thread where scientists demonstrated a simpler system of RNA directed peptide synthesis just by single RNA nucleotide monomers and short oligmers that is the precursor to ribosomes. That quasi-translation system with RNA monomers, RNA oligomers and peptides, as well as the association of amino acids and RNA in cofactor biosynthesis (also mentioned before), would indicate that there wasn’t just RNA in the RNA world. RNA and polypeptides already had an interrelationship leading to proteins encoded by RNA genomes by the point the ribosome existed.

Next he says that another problem is that proteins are pretty complex in their manufacuring. In addition to ribosomes for translating the proteins, they also require enzymes to help them to fold into proteins. This isn’t the case at all. Not every proteins needs chaperons to be folded. They fold themselves into a shape that minimizes the hydrophobic side chains contacting water maximizing the entropy of the system. Yes, entropy can order stuff. Good video by the way:

Also, there are proteins that are intrinsically disordered. They don’t have a stable fold, yet they function too. Lastly, this paper and this paper elegantly shows that during the evolution of the ribosome the RNA chaperoned the evolution of protein folding, which remains recorded by the ribosomal proteins and their interactions with it’s RNA core of the ribosome.

Then Ahmed says let’s assume that we have the ribosome and RNA polymerase. The problem with this is that you need a bigger and bigger RNA genome coding for all those enzymes and proteins. The funny thing is that in this paper and this paper, scientists showed that the ribosome ITSELF is a remnant of an RNA genome that encoded…among other things…the ribosomal proteins and polymerases. So, since we have already assumed the ribosome, you have already assumed the genome that you required to solve this problem.

Next, he goes outside the RNA world a bit points out that all this RNA and protein cannot sit in a vacuum. It needs metabolism and cannot simply float in water, it needs to be enclosed so that there are boundaries for the system. He says that we need to convert food into energy, but that’s not how life started. He is probably thinking in terms of humans who must eat, but there are life forms that are autotrophs and make their own “food”. I have already mentioned the metabolism first hypothesis. According to that, the energy and the “food” is provided by a redox reaction between hydrogen and carbon dioxide, which produces organic precursors of biochemistry and also releases energy that can drive metabolism. This has been aptly described as a free lunch you are paid to eat. About the need for boundaries, that is provided by alkaline hydrothermal vents (no membranes with proteins required) which also provides the geochemical environment to drive the redox chemistry that I just mentioned.

About his complaints of genome size for an RNA organism, it’s basically the Eigen Error threshold, which has been discussed by Koonin with the start of the Darwin-Eigen cycle. I don’t want to go into full detail here (getting tired) so here is the link to his paper, and also reccomend his book the logic of chance.

At the end he eludes to the possibility of a pre-RNA world (which I also mentioned here) and he also incoherently rambles a bit about the possibility of separate organisms holding little fragments of genetic material doing different jobs. I don’t know what he is referring to…is he referring to the progenotes that existed prior to the Darwinian Threshold according to Woese? But he doesn’t go any further into this so, yeah, we leave it at that.


For the same reason that Keith Davies and Jon Sarfati would quote “the mystery of the missing remnants” but not quote “… is also solved”.


Hi Nesslig,
Thank you for taking time to comment.
I was travelling with little access, and actually paused the course for a week.
Will respond to you within the coming 2-3 days.

Just a couple general, and mostly rhetorical, questions: Do you have a firm and detailed understanding of the scientific issues and literature that @Nesslig20 discusses? If not, why do you consider yourself qualified to teach a course on this subject?


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