RNA catalysts and the origin of life

Conversation
101

This is something that I have also been thinking about. Whether there can be a ribozyme (X) capable of replicating itself by using another X as a template strand, which produces the complementary X’ which can be used as a template to make more X. The question I have is, why don’t we see this in biology or among viruses? If it was a stable state that preceded the current state of life where proteins do the job of template directed polymerization of RNA and DNA, then why doesn’t a ribozyme RNA/DNA polymerase exist anymore in some form or another in nature (or maybe it does, I am not aware)?

One could argue that proteins do the job more efficiently such that any old ribozyme was superseded and lost. That could be true, but that also raises the question for why we do still have a couple of very important ribozymes still remaining: Self-splicing introns, spliceosomes that likely evolved from self-splicing introns, RNAse-P that is involved in the maturation of tRNA, various others that can perform (self-) cleavage and/or ligation of RNA, and finally ribosome, which is also composed of proteins but the catalytic PTC site is entirely RNA and a ‘naked’ (protein free) ribosome is capable of peptide bond formation.

One side note: it’s a curious fact that, while prokaryotes only have one RNA polymerase, eukaryotes have multiple types of RNA polymerases that produces distinct classes of RNA. RNA Pol I transcribes rRNA except for 5S RNA, Pol II transcribes mRNA, and Pol III transcribes tRNA, 5S RNA, RNAse-P and spliceosomal RNA. I don’t know why this is he case.

So, ribozymes mostly perform cleavage/ligation on polynucleotides and mediate peptide bond formation, but none perform template directed nucleotide polymerization. If proteins are so much better catalysts such that they replaced these, why didn’t proteins replace the other ribozymes that we still have, such as the ribosome?

My guess (it’s a guess admittedly so I may be wrong) is that a ribozyme transcribing itself wouldn’t work. Let’s suppose there is a ribyzome X, which transcribes another X as a template strand, producing the complement X’ and that is transcribed to make more X. If there is any degree of error, this ribozyme would quickly destroy itself via a run-away feedback loop. One error could make the X ribozyme of the next generation more error prone, and producing more error prone X ribozymes, until any degree of fidelity (or the catalytic function itself) is lost and self-replication grinds to a halt. Why doesn’t this also happen with the protein based replication of RNA and DNA one might ask? After all, you can have the same feedback. Protein polymerases make an error in the coding strand for the polymerase itself, which makes the protein polymerase more error prone, producing more errors later. This doesn’t happen because (as I discussed in a previous comment) the translational system and the genetic code buffers against errors, and proteins themselves often tolerate errors (robustness). Again, take this with a grain of salt, I am open to hear any other suggestions or disagreements.

102

https://doi.org/10.1073/pnas.2313332121

It seems that a ribozyme polymerase has (so far) only been created by in vitro evolution. Haven’t read this paper carefully yet but maybe it answers some of your (our) questions.

1 Like
103

Current state of knowledge and fine detail of stereochemistry is impressive. I was struck by how the hydrogen bonding affinity between nucleotides (U=A, G=C) is so clearly illustrated in the diagrams. Maybe Erwin Chargaff should have shared the Nobel prize.

104

Again, I apologize upfront for the length of my post. The content of my comments must be approved before being displayed, so I might as well make them all at once.

Perhaps you weren’t following along.

The topic of this exchange began on a different thread, where one of the participants talked about how some religious authorities tell their flock what the facts are and how they are to believe those facts – regardless of what the facts really are. Some of the examples given were:

  • “dictate their interpretations”

  • “invent stories to explain away discrepancies”

  • “pass those stories off as facts”

I concurred completely with that assessment but added that this same general (very human) phenomenon takes place in science as well – people are regularly misled by scientific authorities who have their own interpretations, discrepancies, and stories to sell.

That was the genesis of this conversation … at which time I was asked by one of the moderators to make my case, and this thread was born.

Almost immediately, one of the local experts jumped in with a comment that provided a real-time example of exactly what I was talking about. He was first asked to check his comment, but instead, he spent several rounds of conversation trying unsuccessfully to flank the situation, before finally having to acknowledge that his comment was incorrect. Throughout that entire time (and certainly now more than ever) an enormous effort was put forth to not only denigrate me and my statements, but to pretend that this conversation is really about the evolutionary potential of the RNA World (!) – which has nothing whatsoever to do with it.

And of course (as night follows day) if I choose not to reward the continuous attempt to change the subject, then I am labelled as “refusing to engage” and “ignoring rebuttals”.

There is nothing on this thread that is even the slightest bit unexpected.

I did that long ago, and I have repeated it enough times now for any genuinely interested reader to know what the issue is, along with the history of experimental results that confirm it. DNA conveys information by virtue of codons (symbolic tokens of memory) which are established in the system by a coordinated set of constraints. The self-replicating RNA envisioned at the origin of life does not establish this system of constraints. The organizational requirement for this semiotic system was first predicted in 1948 by John Von Neumann using the logic of Alan Turing’s Machine of 1936. Then in 1955 Francis Crick predicted the correct implementation of the system (in the Adapter Hypothesis), which was confirmed via experiment in 1956-58 by Hoagland and Zamecnik. No re-imagining of this claim is necessary.

By the way, Dan, while you continue to question my character, I would like to ask you to recall the very first comment on this thread by a new participant (after it was created). The participant mistook the core issue at hand, but otherwise made a fairly benign analysis of whether or not an RNA could serve both as a folded catalyst as well as an unfolded template.

The participant then followed that analysis with a separate sentence: “I’m not sure, in any case, whether the other commenter meant to address that question in their vacuous claims about “informational capacity””

You can tell by the writer’s own words that this sentence had nothing to do with his prior analysis. Instead, it was tacked on to serve as derogatory positioning statement, completely unsupported by even a single word of rationale. You then defended this comment, suggesting that he was not insulting me as a person who is making vacuous claims, but only that my claims were vacuous — which is as close to being a distinction without a difference as one can get. Frankly, I find that line of reasoning rather ridiculous, however, I would want you to know that I am not saying you are ridiculous, only that your reasoning is ridiculous.

Congratulations to the both of you. I am in my fourth decade as a Director of Research in network media, not a biologist, and I am certain that the Periodic Table of Elements couldn’t care less about any of that.

This is nothing more than the abject denial of measurable physical properties. It is also a complete dismissal of the history of science surrounding the issue. By your standards, you could not know that the computer you are typing on uses a system of symbols.

Does your computer use a system of symbols?

If you say “yes” then you are left to support that “yes” only by knowing upfront that a human intelligence put it together that way (given that you are effectively denying any way to measure the properties of the system and confirm its semiotic nature). But now you are left with the prospect of affirming that a human being can implement semiosis in a physical system, where it is not possible to measure the system’s properties and know that it is semiotic. Yet you still want to turn around and say definitively that the gene system is not semiotic. Based on what exactly? All you have left for evidence is the “I’m a biologist” line that you started your claim with. One truly wonders if you’ve thought this through.

Of course, the alternative to this distortion in reasoning is that scientists other than yourself already know how to measure the properties of the system and have shown it to be semiotic. They are then supported by a significant history of discoveries, coming to the exact same conclusion.

105

What case have you made? I think everyone here has missed it. Now of course we could all just be idiots, but please consider the possibility that you have not been as clear as you suppose.

What is the “coordinated set of constraints” you’re talking about here, and how is it established in the system? Since nobody claims that the self-replicating RNA at the origin of life establishes that system, why are you bringing that up? Beyond that, what point are you trying to make? You appear to be describing the mechanism of protein synthesis. But why?

1 Like
106

Meh. I’ve heard worse from better. Right @Tim? :wink:

OK, now we have it more clearly stated … you are making the PRATT “DNA is Code” argument. You might have lead with that and saved us all a lot of time. DNA is chemistry, and the laws of chemistry are all that apply. Specifically, a Universal Turing Machine (UTM) does not apply.

Sure biological systems are Turing Complete (capable of any computation) - that’s no big deal; a pile of sand can be Turing Complete too. If you really want to make this argument about computation then you need to think bigger; it’s not what molecules are computing, it’s what all life is computing. (I had a good discussion about this with @EricMH some years back.)

2 Likes
107

I was following along. The second comment in that thread doesn’t include anything about statements to the public either. Nor does your first or second comment in either thread. Either by “second” you really meant ‘thirty-third’, which is the post you are apparently referring to, or you are referring to some entirely different “second comment in the thread”, in which case I suggest you link to it.

Apart from that, since you haven’t replied to any of the technical comments I made, including the rebuttals that you asked for which you have ignored while claiming not to ignore rebuttals, or even to my reply to the question you specifically asked, I think corresponding with you is a complete waste of time, so I’ll revert to pointing out your errors and laughing at your misplaced arrogance.

4 Likes
108

That’s at least 7 times he has outright ignored the request to just state explicitly what point he is trying to make.

He keeps insisting that a putative self-replicating ribozyme at the origin of life can’t simultaneously function as a translation system, using non-standard terminology. But refuses to state why he feels compelled to state it over and over again despite everyone here agreeing with the statement.

2 Likes
109

There is some bait-and-switch going on here:

I could agree that DNA is a dynamic system, and that the system as a whole is capable of self-regulation (homeostasis), but an RNA molecules is not a system unto itself. So what? No one claims it is. No one thinks that - at the time of OoL - DNA was present and operating in the cell as it is today. No one thinks that extant life has remained static since it’s origin. Whatever the system that we think life might have originate from, that system changed to a new state and new dynamics.

To my knowledge, there is no statement made by Von Neumann that systems are incapable of changing state.

4 Likes
110

I will note that the first quote is incomplete to the point that it is misleading. A more complete rendition is:

And we still haven’t seen a clear example of scientists going to anything like the same lengths

2 Likes
111

No. There is no symbolism. You can measure all you want (we know you’re only doing rhetoric and won’t), but there’s none.

I know that there are many codes, symbolic and/or abstract, in computing. You obviously don’t understand that the essence of a code is an abstraction. There aren’t any in biology, but plenty in the way we describe it to other people. Big difference. Your arrogance and rhetoric-only approach, bereft of data, blinds you to that.

Why? I plainly see the abstractions for myself. Are you perhaps struggling with this because you’ve offered nothing but a rhetorical approach to biology to date?

You’re obviously confused. Maybe you should start with actual facts, from the primary literature, instead of what people say about them. Given the quotemining you’ve presented, it appears that your only exposure to biology is through IDcreationist rhetoric.

But you’ve never read a single paper from the primary literature, correct?

Where’s the abstraction and/or symbolism in biology?

There’s no evidence for that whatsoever. Their descriptions are, but not the biology.

You’ve shown no evidence that you’ve looked at any biological discoveries. You’re all rhetoric.

Speaking of facts, how many different amino-acid residues are found in functional proteins?

4 Likes
112

This paper by H. H. Pattee (2007) is illuminating. I think it provides much of the missing context that appsandorgs has been unwilling or unable to provide.

ABSTRACT
Biosemiotics distinguishes life from inanimate matter by its dependence on material construction controlled by coded symbolic information. This irreducible primitive distinction between matter and symbol is necessary for open-ended evolvability and the origin of life as we know it. This type of subject/object distinction is reestablished at many levels throughout all of evolution. In physics this becomes the distinction between material laws and symbolic measurements and models; in philosophy this is the distinction between brain and mind. These are all emergent epistemic distinctions, not ontological dualisms. The origin of life requires understanding the origin of this symbolic control and how inanimate molecules become functional messages. I discuss the necessary physical conditions that would allow such evolvable symbolic control of matter to arise.

There is a lot of discussion of symbols and code, and eventually DNA as a code. To my reading Pattee’s interpretation of “DNA as code” does not conflict with DNA as chemistry.

Pattee disagrees. From the top of page 10:

The discovery of enzymatic RNA made it possible to imagine a much simpler translation process in which RNA can function both as a constructing enzyme and as a symbolic description of an enzyme. By description I mean a passive structure that can be copied by template inspection, and by construction I mean a dynamic catalytic process that joins molecules by strong, covalent bonds. The main point is that this double function is only possible by virtue of the two configurations of RNA, the passive one-dimensional sequence memory and the folded three-dimensional active ribozyme.

“Intelligent Design” gets a mention on page 12, and is answered in the three paragraphs following.

4 Likes
113

#Appsandorgs would benefit from a(nother?) careful read of Dr Pattee’s paper.

Not strictly the issue at hand but I’m pleased Pattee agrees with a point made often:

…a random search need not find just one needle in a haystack, but only one of many needles uniformly distributed over the whole haystack. That is, wherever a random search begins in sequence space, it appears likely that a description of a useful molecule will be found nearby.

6 Likes
114

Once again, forgive me for the length of my post. The content of my comments must be approved before they are displayed, so I might as well post them all at once.

Thanks for posting one of Pattee’ s papers. It is a paper I am familiar with, in fact I have perhaps all of Howard Pattee papers in a file cabinet, with a couple hundred others, in my office closet. And his fine Springer book “Laws, Language, and Life” is sitting in my bookshelf, next to Barbieri’s “Code Biology” and “The Organic Codes”, as well as Kupper’s “Information and the Origin of Life” and Rosen’s “Life Itself”, among others.

There wasn’t any missing context. The sequence of codons in DNA specify the sequence of amino acids to be presented for binding to a polypeptide in synthesis. Which codons specify which amino acids is established by the genetic descriptions of the set of molecular constraints. Thus, all the descriptions in that set must be coordinated in order for the system to function. This paper by Pattee is not required as a context to those well-known facts.

Why would it?

“DNA as chemistry” is two chains of polynucleotides (4 types), where hydrogen bonds between the bases hold the two chains together, while alternating covalent sugar-phosphate bonds form a helical backbone in each strand.

“DNA as code” is a sequence of triplet codons, where the spatial arrangement of four different bases distinguishes one referent from another. Following the minimum total potential energy principle, the order of the bases is undetermined by dynamical law, but among those sequences that implement the genetic code, the sequences must be coordinated in order to establish that code.

From a physical standpoint, these two sets of observations are not in conflict (and never have been). But the rate-dependent mathematics of the first description cannot be used to explain or predict the rate-independent coordination in the second. It is that coordination that establishes control with open-ended potential.

First off, there is nothing in that passage that I disagree with. It has clearly made it possible for people to imagine a simpler translation process. But imagining a simpler translation process is not the issue (nor is the RNA World in general). My claim is that the self-replicating ribozyme envisioned at the origin of life does not convey information like DNA. DNA specifies twenty amino acids by virtue of codons (symbolic tokens of memory) which are established in a system by a coordinated set of constraints. This is rate-independent control of a rate-dependent process. Nothing in that passage from Pattee relieves that organizational requirement one iota. In fact, one only needs to look at the part of the quote that you bolded for emphasis – “the main point”.

The main point is that this double function is only possible by virtue of the two configurations of RNA, the passive one-dimensional sequence memory and the folded three-dimensional active ribozyme.

That “passive one-dimensional sequence memory” is a symbol system on one side of a cut, with dynamics on the other side. But when OoL people talk about a self-replicating ribozyme being able to convey information like DNA, they always leave out the part about needing to first establish a rate-independent system of symbols and the appearance of a coordinated set of constraints required to establish that system. It clutters up the pitch.

I know for a fact that Pattee views the Peircean triadic relation (symbol, referent, interpretant) as a fundamental requirement to specify amino acids (like DNA does), even in an RNA World.

Pattee is a scientist’s scientist. He requires propositions to be grounded in physical reality, and he doesn’t pollute his work with ideological drum beating. His brief mention of ID on page 12 is matter-of-fact observation and is the only mention I am aware of in his five decades of publishing. He speaks as much about pizza toppings and boy bands. And none of those “following three paragraphs” alters the topic of organizing rate-independent control in any way whatsoever.

Correct, not the issue at hand. A search through symbol space to find a functional product requires a symbol space. If A requires B for A to exist, then A cannot be the source of B.

Imagine someone saying that in 2024 and being expected to be taken seriously. Over 70 years of biology out the window. Suddenly, the living cell cannot specify itself among alternatives, and even if it could, it couldn’t sense and interact with the world around it. You apparently have a pebble in your shoe about symbolic representation in biology. Here’s a clue; when you touch something hot, the nerves between your fingertips and your brain do not change temperature. “Of course not” you say, “it’s a sensory signal, just chemistry”. But you cannot intercept that signal and use the equations of physical science and derive “hot”. That requires interpretation via constraint, just like a codon.

115

Not in the case of RNA world. There’s no symbolism, just physical templating. Chargaff’s Rule rules.

3 Likes
116

You said that your foundation was in facts. Anything from the primary literature in your cabinet? I’d bet no.

And there’s not a single abstraction involved; therefore the term “code” is being used metaphorically.

You’re trying to rhetorically push the idea that if there’s a code involved, there must have been design.

Your conclusion doesn’t follow from the premises.

Wow. There are not 4 types of POLYnucleotides. I predict that you won’t correct this false claim.

No, it doesn’t. The reason why it doesn’t provides a major clue to how the system evolved. You’re even managing to ignore facts we knew in the 1970s!

There are no such things as “sequences that implement the genetic code,” despite its presence that demonstrates the illiteracy of much of science journalism. The genetic code (a metaphor) is the mapping of codons to amino acids. It is not the genome, it is not coding sequences (again, coding is used metaphorically).

There can be no rational discussion if you can’t get the most fundamental terminology right.

I know for a fact that you have no fundamental understanding of the RNA World hypothesis. It’s your fundamental straw man, brought out again and again.

Say, did you ever encounter any metabolism-first research in your claimed 15 years of study? It’s now Wikipedia-level stuff, backed by plenty of facts, but it never appears in any of your rhetoric regarding OOL. Why?

Then show us the abstractions. I would posit that after 42 publications in the primary literature and >$6M of grants awarded, I’m taken plenty seriously. All of those grant applications were loaded with metaphors, btw.

No, just an understanding of how metaphors are useful in describing biology.

I’ve spent most of my career studying a molecular motor. Turns out that at the single-molecule level, there’s a far better metaphor for its function. Yet we don’t stop using the metaphor “motor.” Can you see why?

Of course not. The question is whether there are any abstractions between them. You can’t point to a single one, so your worthless analogy makes my point again.

But the key to whether there’s any true, nonmetaphorical code is whether there are one or more layers of abstraction in the process. There aren’t, which is key to understanding evolution, instead of ignoring all the facts and pretending that it’s designed simply because scientists write and speak metaphorically.

3 Likes
117

And metabolism has nothing to do with that distinction?

Not very well IMO, given the amount of actual data we have. Except for his haystack metaphor, which is great.

@appsandorgs, check this out:

Furthermore, these sequences are distributed more or less uniformly over the entire sequence space. This means that a random search need not find just one needle in a haystack, but only one of many needles uniformly distributed over the whole haystack.

Do you think Pattee was referring to a real haystack, or was he writing metaphorically?

2 Likes
118

FYI this is true of all of us. This is one of those every-post-must-be-approved threads.

3 Likes
119

And if by “convey information like DNA” means “function as an entire translation system by itself”, nobody claims a putative self-replicating ribozyme would do such a thing, and nobody is claiming DNA does this either because in fact DNA doesn’t actually do that.

How many times do you need to be told? DNA doesn’t translate itself, nobody claims it does. And the same is said for ribozymes. Nobody claims a ribozyme at the origin of life is functioning as an entire translation system.

DNA can’t do it, RNA can’t do it, nobody claims otherwise. Your entire case, the whole “claim” you are making is not something anyone disputes. So why are you claiming it?

5 Likes
120

… then they speak about it’s capacity to function as a template for it’s own replication. After all, that is the informational capacity of relevance at the origin of life: A basis for inheritance that enables sequence-dependent information transfer from ancestor to descendent.

They are NOT talking about it’s potential capacity to self-translate, neither for DNA nor for RNA, because neither DNA nor RNA can self-translate.

The only alternative they could POSSIBLY mean is to contain a coding region that could be translated if all the other components necessary for translation to occur, were present at the origin of life. But nobody claims, thinks, believes, suggests, or infers that such a thing ever occurred. Ever.

He’s talking about replication, not translation. Sequence-memory here refers to RNA’s capacity to function as a template for it’s own replication so the order of bases can be propagated down the generations, with it’s function as a ribozyme being as catalyst for chemical reactions, one of which is possibly to catalyze the templated replication of it’s own sequence.

They can’t leave out something they are not ever suggesting occurred or was the case. You are incredibly and deeply confused.

This is the time to put up or shut up. Produce the paper in which scientists actually claim, or suggest, or propose, or profess belief in, or infers that there was ever a time at which life began with a self-replicating RNA ribozyme able to simultaneously function as a self-replicator while also being able translate itself with no other components of a translation system present or necessary.

4 Likes