When I was in grad school my default assumption was that ribozymes (catalytic RNA) are far more abundant than we currently know. RNA just very difficult to work with so there’s a selection bias against our ability to measure its behavior in vivo.
Yes, we are RNA organisms that have been incorporated into larger organisms, just as we are prokaryotes that have been incorporated into eukaryotes through endosymbiosis.
https://evolution.berkeley.edu/evolibrary/article/_0_0/endos...
As much as 8% of our DNA was laterally transferred from viruses! In a sense, some infections result in a symbiosis with a host.
Type 4 secretion system: ii- Pilus biogenesis
Even if cellular life has a huge evolutionary advantage we should still find pockets of original life somewhere.
Famous case in point are the Ediacarean fossils in Newfoundland, the first known multicellular organisms. No descendants live today, they are completely extinct. Without these fossils we wouldn't even be aware of this branch of the evolutionary tree.
Why are ribonuclease enzymes so omnipresent?
Is this the only reason why RNA is so difficult to work with, or are there other technical hurdles that are more difficult to overcome?
Are we missing a big piece of the biological puzzle because of this?
Any recent developments in this area?
I haven’t heard of any recent developments — it’s been a decade since I was in grad school and now I build software — but I briefly studied a subcategory of ribozyme called self-splicing group I introns which is where my interest comes from.
[0] https://en.m.wikipedia.org/wiki/Ribonuclease
[1] https://en.m.wikipedia.org/wiki/Group_I_catalytic_intron
Huh... today I learned. I didn't realise we have such "low-level" immune defences, I always just assumed that the simplest defence we had were antibodies.
A primordial soup, without the precision enzymes and constant energy expenditure of this synthetic machinery, will be a grab bag of random glop. In Miller-Urey experiments the concentrations of any particular chemical decline exponentially with the number of atoms in that chemical. I believe ribose has never been seen in any such experiment (and certainly not in any but extremely low concentration), never mind the triphosphorylated nucleotides that provide the energy to drive RNA synthesis.
Also, it is a logical necessity that the transcription of RNA into proteins, including the ribosomes and the transfer RNAs appeared only later than the replication of RNA.
The part of the RNA world hypothesis that seems unlikely because it has very few supporting data is that the original biocatalysts a.k.a. enzymes were RNA molecules unlike anything that exists today.
In my opinion, it is far more likely that the first enzymes were non-ribosomal peptides, somewhat resembling to parts of the proteins that constitute the enzymes of recent life forms.
ATP and other nucleotides must have existed before RNA as a means to perform condensation (i.e. dehydration) reactions and the copolymerization of the nucleotides must have appeared as some undesirable side reaction, which somehow at some point generated some sort of self-replicating RNA, which was in fact the first virus, because its synthesis could not have any beneficial effects for the hosting life form.
Only after the appearance of the transcription of RNA to proteins, the RNA could evolve into a source of components for the hosting life form so that RNA could change from a parasitic entity to an essential part.
Life forms with RNA (and later with DNA) are analog with microprogrammable processors, because the nucleic acid molecules are memories which direct the synthesis of other components, so you can change the components by writing a different information in the memories, without changing the synthesis machinery. This kind of flexibility was certainly necessary for further evolution.
Life forms before RNA are analog to hard-coded processors. Supposing that they were made with non-ribosomal peptides, there must have been a mechanism by which a complete life form was replicated, by a cycle of reactions were some kinds of peptides were assembled by other kinds of peptides.
Non-ribosomal peptides exist even today in all living beings and they are assembled in the correct sequence from amino-acids without depending directly on the information stored in nucleic acids, like the proteins.
Memories, like nucleic acids, are certainly not necessary for designing an ensemble of molecules able of self-replication, exactly like a memory is not necessary for implementing the control automaton of a processor.
Nevertheless, it is likely that the further evolution of such a primordial life form was almost impossible, because all accidental changes in the structure of the component molecules would have resulted in a replication failure.
After the separation of functions between a memory (nucleic acid) and a generic synthesis machine, evolution by changing the memory content became much more likely to be successful.
> the original biocatalysts a.k.a. enzymes were RNA molecules unlike anything that exists today.
Why “unlike anything that exists today”? Catalytically active RNA is still ubiquitous and well preserved across kingdoms (they’re some of the most ancient mechanisms for which we have phylogenetic evidence).
> it is far more likely that the first enzymes were non-ribosomal peptides
Peptides are good catalysts but they lack a high-fidelity copying mechanism so they’re not good raw material for evolution.
Taken together, your hypothesis seems to be based on a disbelief that RNAs lost their catalytic capability (which isn’t actually the case), but conversely you readily accept (without any evidence) that peptides used to have replication capabilities that were lost without a trace.
> Non-ribosomal peptides exist even today in all living beings and they are assembled in the correct sequence from amino-acids without depending directly on the information stored in nucleic acids, like the proteins.
Can you give an example of a catalytically active polypeptide which is assembled without any RNA template? I can’t think of any.
> Memories, like nucleic acids, are certainly not necessary for designing an ensemble of molecules able of self-replication
No, but what’s necessary is some kind of structure that records bits of information in some kind of order, and a mechanism for reading and writing this. Individual oligopeptides are fundamentally insufficient, you need structures capable of larger assemblies, and the information of these assemblies needs to be recorded. RNA elegantly solves both these requirements. DNA solves the storage requirement but is a very bad catalyst. Peptides solve the catalytic part of the requirement but are bad information store (prions can store specific configurations but they don’t seem to generalise).
It’s hard to overstate how important this information storage requirement is for evolution — arguably much more important than even marginally efficient catalysis. To the extent that some (admittedly far-fetched) hypotheses for early life even posit carriers such as clay minerals [1] which have, to a close approximation, zero catalytic capability — simply because they’re such an attractive medium for storing information (in the form of crystal lattice surfaces), high fidelity replication (through deposition of a new layer of minerals), and mutation (through structural modifications of the surface which are carried over through generations).
While the known functions of catalytic RNA are indeed, as you say, ubiquitous, very important and they certainly were already present in the last common ancestor of all present cellular living beings, none of those functions are likely to be so ancient as to have existed in the first life forms.
The nucleotides that compose a RNA molecule do not have chemical properties that are different enough to allow RNA to have a versatility comparable with the peptides/proteins, which can be used to make catalysts for a much wider range of chemical reactions and which can be attached to membranes for some of the most important functions, e.g. for ionic pumps.
While the number of amino-acids must have been much smaller in the beginning, it is likely that about 6 were already in use, i.e. alanine, a hydrophobic (valine), an acid (aspartic), an alcohol (serine) and 2 with unusual forms (glycine and proline) that can determine how the peptide will coil and fold.
The variety of amino-acid properties, even in the minimal set, allows the implementation of much more functions than can be imagined for RNA.
I am not aware of an example of a catalytically active polypeptide which is assembled without any RNA template, but that is not very relevant, because there is no doubt that, after the appearance of the transcription of RNA into proteins, most non-ribosomal peptides must have been replaced by more complex proteins, which were able to perform a more specific and faster catalysis.
I do not agree that "what’s necessary is some kind of structure that records bits of information in some kind of order".
On the contrary, this is what is impossible to have existed and it is the main reason why RNA must have been a later invention, after self-replicating life forms already existed for a long time.
What I say here about RNA, is valid for any other kind of molecular memory, so it is unlikely that any other polymer was used before RNA, as in some hypotheses.
Any other function of RNA besides the self replication of the RNA molecule must have appeared only much later, after a long evolution of RNA.
The reason is that even if any kind of useful RNA molecule, e.g. a catalytic ribozyme, ever appeared earlier, it disappeared without descendents, because it was not replicated.
So, if the RNA replication was the first function, that requires both the presence of ATP and of the other nucleotides and of some macromolecule that will catch the nucleotides and link them into the RNA molecule, using as a template the RNA that is replicated.
Even if we assume that the actual catalyst of the RNA replication was also a RNA molecule, that leaves open the source of the component nucleotides.
There must have already existed a catalytic system that transformed the simple precursors from the environment into ATP and other nucleotides through a long chain of reactions.
There exists no other better hypothesis for the nature of those catalysts than that they were non-ribosomal peptides resembling the active segments of the present-day enzymes that are used for those reactions.
Like I have already said, it is a logical impossibility for any kind of information-recording molecular memory to have existed since the beginning.
The way how the still existing non-ribosomal peptides are assembled in the correct sequence in the present-day organisms is not known well. Also the way how membranes are assembled is not known well. We have much less information about these than about nucleic acid replication and protein synthesis, for which a large number of investigative tools have been developed.
In any case, it is possible to imagine (and I believe that the attempt to design such a system would be a worthy research subject) a self-replicating system without any molecular memory, where some kind of peptides directed the assembling of another kind of peptides, which directed the assembling of another kind of peptides and so on for several steps, until the cycle was closed and the last kind of peptides directed the assembling of the first kind.
Of course, that must not have been just a simple cycle but a network of reactions, to generate all the components of the life form, but the network of reactions must have included all the cycles required to ensure that the complete replication of the life form is done.
In conclusion, you are right about "how important this information storage requirement is for evolution" and I have already written in a previous post that the evolution of the complex living beings of today could not have happened without the invention of a molecular memory.
Nevertheless, it is impossible for any such information storage mechanism to have already existed since the origin of life.