22nd Jul, 2022
University of California, San Diego
Discussion
Started 16th Feb, 2022
Discussion on the RNA World Hypothesis and the Origin of Life
Kindly discuss your ideas and viewpoints on the origin of life and the RNA world hypothesis.
What are the contradictory views on why researchers are still unsure about the origin of life through RNA or such analogous molecular intermediate pre-cursors preceding its existence?
"The general notion of an “RNA World” is that, in the early development of life on the Earth, genetic continuity was assured by the replication of RNA and genetically encoded proteins were not involved as catalysts. There is now strong evidence indicating that an RNA World did indeed exist before DNA- and protein-based life. However, arguments regarding whether life on Earth began with RNA are more tenuous. It might be imagined that all of the components of RNA were available in some prebiotic pool and that these components assembled into replicating, evolving polynucleotides without the prior existence of any evolved macromolecules. A thorough consideration of this “RNA-first” view of the origin of life must reconcile concerns regarding the intractable mixtures that are obtained in experiments designed to simulate the chemistry of the primitive Earth. Perhaps these concerns will eventually be resolved, and recent experimental findings provide some reason for optimism. However, the problem of the origin of the RNA World is far from being solved, and it is fruitful to consider the alternative possibility that RNA was preceded by some other replicating, evolving molecule, just as DNA and proteins were preceded by RNA." - Robertson and Joyce
[This is as per the explanation by Michael P Robertson and Gerald F Joyce in the article: "The origins of the RNA world." published in the Cold Spring Harb. Perspect. Biol. 4, a003608 (2012).]
The scientific community must resolve this contradicting conjecture through rational discussion and debate backed by strong experimental evidence on what must be the pre-cursor molecule to the Origin of Life if it is not RNA!
Most recent answer
My biggest concern is whether the RNA components would be stable enough for them to survive long enough to be concentrated to a level that would allow them to polymerize into a photo-RNA molecule. Even that would happen, the polymer itself would likely have a fairly short life-time in the waters of the primitive Earth.
All replies (8)
Very exciting topic,
We have published few articles on the issue of origin of life and the role of self-replicationg RNA. However, no interest was shown:
Liposomes: from the origin of life to nanotherapy
MR Mozafari
Cellular and Molecular Biology Letters 10 (Suppl.) 2005
You may also find this nostalgic Abstract, related to your question, interesting:
Importance of nucleic acid–lipid interactions in functioning of the initial cell.
G Kahveci, MR Mozafari, F Rouhvand, G Altay, RI Zhdanov
12th National Congress of Biochemistry, Istanbul, p. C-338. 1994.
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See also:
Formation of the initial cell membranes under primordial Earth conditions.
- January 2004
- Cellular & Molecular Biology Letters 9(S2):97-99
Dear Mrutyunjaya,
I am not really in a position to assess the likelihood of an RNA World scenario for the origin of life on Earth. However, I would like to point out that from an astrobiological standpoint, I think that we should keep an open mind on the huge variety and broad range of potential (evolutionary) pathways leading to life. Moreover, a lot also depends on the precise definition of "life" and from which stage or time onwards we classify certain phenomena as "life". If life exists outside of Earth, it may look very different to what we have become accustomed to on our "pale blue dot". Once we have confirmed at least a second, independent instance of a living system in the universe, we may also see clearer on how probable a RNA World scenario may have been for the case of Earth (even if we may never be able to reconstruct and verify the exact pathway...).
Thanks & all the best,
Julius
2 Recommendations
18th Feb, 2022
I do not deny the issue of RNA world, however is relevance comes with the understanding about how it becomes part of the cell. Because the life stars with the cell.
One of the issues that is holding the concept of an RNA world back from being more scientifically useful - irrespective of whether there ever was such a thing - is that we don't use the idea in the scientific way it was intended. Just like any other prebiotic scenario, it is not (nor has it ever been) a scientific hypothesis. In fact, scenarios are usually not intended as such. Scenario authors from all niches (including RNA world) have pointed out that scenarios themselves are untestable. However, they guide thinking and allow to conceive of hypotheses that are testable. If we go through the old literature we find very explicit passages to support this fact.
For the specific authors advanced in the question, G.F. Joyce and L.E. Orgel, we have a passage from 1999 in "prospects for understanding the origins of the RNA world". (The RNA World 2nd ed. 49-77).
"The presumed RNA World should be viewed as a milestone, a plateau in the early history of life on earth. So too, the concept of an RNA World has been a milestone in the scientific study of life's origins. Although this concept does not explain how life originated, it has helped to guide scientific thinking and has served to focus experimental efforts."
You can find this point of view expressed in foundational work for all niches related to the popular scenarios today. But you can also find it for scenarios most people in origins have never heard of. E.g. the idea that celllular life started with terpenoids found in G. Ourisson and Y. Nakatomi's "the terpenoid theory of the origin of cellular life: the evolution of terpenoids to cholesterol. (1994) Chem & Biol. 1 11-23".
"The hypothesis provides an attractive way of ordering the terpenoids: like all evolutionary theories, it cannot be tested directly. The ideas summarized here do, however, suggest a multitude of experiments having some bearing on the fundamental and fascinating question: how did the first cells appear? We hope to carry out some of them."
A related line of thought - but highly influential - is the exposition by Harold J. Morowitz from 1992 in his book "Beginnings of Cellular Life: Metabolism Recapitulates Biogenesis". If we go to the conclusion, we find this explicit clarification on the distinction between a genuine scientific theory and a scenario:
"at this stage of the thought process, it is important to focus on the hypothesis that intermediary metabolism recapitulates prebiotic chemical evolution. This hypothesis is not a strictly vulnerable theory in the Popperian sense, but it does provide us with a valuable heuristic method for using modern knowledge of biochemistry to search for events that have left their trace. If the intermediary metabolism of autotrophs does not recapitulate biogenesis, then the discontinuities will have to be explained."
More than 2 decades back, many authors made a clear distinction regarding this nuance. Scenarios are here to help: they guide thinking and design experiments. They only guide thinking in a scientifically meaningful direction as long as we can easily abondon scenarios and enthusiastically continue replacing them with new, more informed scenarios. A situation where a scenario gets entrenched and where researchers treat it as a scientific hypothesis is - by construction - hard to escape.
In fact, this is exactly the situation that many researchers have described around the 80s, when criticism mounted against the prebiotic broth scenario. The passage from Wächtershäuser's 1988 "Theory of a Surface Metabolism" is telling:
"The prebiotic broth theory has received devastating criticism for being logically paradoxical (11, 135), incompatible with thermodynamics (11, 144, 160), chemically and geochemically implausible (134, 136, 144), discontinuous with biology and biochemistry (160), and experimentally refuted (135, 160). The reason for the tenacity with which it is retained as accepted dogma has been forcefully and clearly stated by Scherer (126): "If this rejection is substantiated, there will remain no scientifically valid model of the selforganization of the first living cells on earth."
Clearly, the broth scenario had overstayed its welcome. One reason for this is that its 'claims' (which for a scenario can only be speculations) were too much in contradiction with claims from fields of science that do not suffer the same restrictions when it comes to testing and refuting their theories. One example of a very controversial idea that can be found in Haldane's formulation of a broth scenario, is the purported necessity of a long, highly functional protein randomly emerging from a soup, as an extremely rare event: we expect this to be prohibitively unlikely and hence a far from parsimonious explanation.
Quite a few of the critiques voiced against the prebiotic broth scenario are equally valid critiques of some scenarios we have today, including RNA world.
The RNA world is an old and multifaceted concept. There are contrasting formulations that make different claims (to be interpreted as speculations) about history. As with the prebiotic broth scenario (and any scenario), it has raised genuine scientific objections. These have remained largely unadressed, in spite of its long dominance.
It is instructive to bear in mind that scenarios don't come from nowhere. They're fairly detailed speculations about purported historical events. To make them, each author makes assumptions. Some of these concern speculations that later became testable, e.g. about chemistry and physics. You will find different scenario authors make different assumptions and different arguments (and flaws therein). There's an inevitable bias here with respect to the fields an author is trained in. Some of the foundational assumptions in popular scenarios like RNA world are at least 50 years old, but some unchallenged assumptions date back to a literature that is more than a century old. A time before IUPAC, modern quantum mechanics, genetics, and so forth.
That has been enough time to forget that scenarios like RNA world are by construction not testable hypotheses and that they were not intended as such. Scenarios are here to guide thinking, to inspire experiments. The best thing a scenario can do for us, is generate insights that spur us to change the way we think and thereby necessitate replacing our old scenarios with new ones, and repeat the cycle. The science coming out of the community today is a lot more conducive to doing that than previously.
The same cannot be said for the rather myopic RNA-centric framing of a question in the cited passage, which attempts to elevate RNA world to more than a scenario. Rather than forcing ourselves to think about the rather narrow and outdated proposal by Joyce and Robertson, ("consider the alternative possibility that RNA was preceded by some other replicating, evolving molecule"), it is more productive to critically revisit all the things that have been assumed and argued when the concept of an RNA world was conceived and how which of these premises are considered valid or plausible today, and which ones back then. Is there a formulation of RNA world for abiogenesis that is logically sufficient? And if so is it logically necessary that abiogenesis proceeded this way?
It is also instructive to check how much of the logic was sound. e.g. the rhetorical tricks employed in RNA world introduce all sorts of hidden assumptionsm.
As an example of the latter: some still justify an RNA world by the party trick 'chicken-and-egg' question 'protein or RNA, which came first?', only to conclude with 'RNA, it encodes proteins' and hastily conclude with an even stronger 'RNA-first' for abiogenesis. 'chicken-and-egg' fallacies are nothing new in origins. In fact, they were already identified as such long ago. E.g. in chapter 8 of "Seven Clues to the Origin of Life (1985)" by Cairns-Smith, there's an illustrated passage detailing that these types of paradoxes in origins frame the question in a manner that prevent us from considering scaffolds.
"
The fact is that even the so-called simple organisms such as E. coli are very complex enterprises with all sorts of things going on together. There is plenty of scope for accidental discoveries of effective new combinations of subsystems. It seems inevitable that every so often an older way of doing things will be displaced by a newer way that depends on a new set of subsystems. It is then that seemingly paradoxical collaborations may come about.
To see how, consider this very simplified model - an arch of stones: This might seem to be a paradoxical structure if you had been told that it arose from a succession of small modifications, that it had been built one stone at a time.
scaffolds that starts like this:
This might seem to be a paradoxical structure if you had been told that it arose from a succession of small modifications, that it had been built one stone at a time. How can you build any kind of arch gradually? The answer is with a supporting scaffolding. In this case you might have used a scaffolding of stones. First you would build a wall, one stone at a time:
Then you would remove stones to leave the 'paradoxical' structure.
"
It should be noted that in 2022, even in RNA-world, very few scholars remain that find RNA-first a convincing idea. As a scenario, however, it is not useless: it is instructive to consider what the underlying ideas are that at some point in time made such a highly specific idea compelling to so many of us.
A fixed motif in scenario papers is to start explicitly and implicitly assuming a few things about what chemistry can and cannot do and some properties of abiogenesis. These sort of assumptions used to be spelled out routinely, also outside scenario papers. Let me give two examples.
The original 1953 paper for the "Frank Model" "on spontaneous asymmetric synthesis", has the passages
".. the defining property of a living entity the ability to reproduce its own kind ...
confining attention to chemical molecules, the complexity of any having this essential property of life is likely to be great enough to make it highly improbable that it has a centre of symmetry."
(*I should point out that Frank makes an important error here: the capacity for molecular reproduction is not a molecular property but a property of a reaction network. If we add an additional thermodynamic criterion this property is autocatalysis and we can then check this claim from the IUPAC definition: https://goldbook.iupac.org/terms/view/C00876. It turns out there are trivial ways to make small networks that have this property https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c74d67469df42226f44295/original/emergent-autocat-animation.gif.)
The point to retain here is that Frank considers it to be generally accepted that one can assume this property to be prohibitively rare in chemistry. This belief was wideheld, and we can e.g. read in "the units of selection" (1970) by Lewontin a summary on scientific views on abiogenesis
"The present view ... Since there was no autocatalysis, there was no reproduction or heredity and so no possibility of natural selection."
The coacervates in Oparins scenario were notably invoked to adress this issue.
When it comes to assumptions in scenarios, this systematically involved conjecturing that chemistry 'in the wild' intrinsically and deterministically becomes a 'mess', undergoing no meaningful complexification, and for which no reproduction and evolution can reasonably be expected. From there, it appears that no process of abiogenesis should conceivably occur naturally, and thereafter some specific sequence of exceptional events is proposed as plausible, because it appears to be the sole contender.
Let us make more explicit why this is not an innocent procedure:
We still find our understanding of 'basic chemistry' to be plagued with limitations and long-lived misinterpretations (e.g. 2 days ago we learned that methyl substitution destabilizes radicals instead of the textbook knowledge that it stabilizes them ).
Moving beyond the basics, we by and large lack a lot of formal theory, experiment, or even a simple reference frame for the things that happen then. Joyce and Robertson honor the tradition of purporting from the outset that 'chemistry in the wild' becomes an intractable mess. The issue is that we don't know at all if that's the case. We cannot assume this from the outset, we need to extensively study it. We require extensive experiments and theory and a reference frame for all the phenomenology associatied with complex systems (e.g. multiple components, compartments, multiple forms of nonequilibrium driving, length scales, time scales).
In making the routine assumption of 'messy, intractable chemistry that can neither complexify nor multiply', we have decided in advance that, once we finally understand 'chemistry in the wild' with its 'so-called intractible mixtures', it cannot have any bearing on abiogenesis. Let alone explain it.
That is a disproportionately bold conjecture about fundamental science, and a very consequential one: all historical scenarios - RNA world being one out of many - have been justified by formulating conjectures of this sort (many authors also insist on other properties, e.g. chemistry being deterministic). Clearly, it should be the first priority of everyone in the field to test this conjecture, by extensively and rigorously studying complex chemical systems as an end in itself. If the conjecture is correct, it provides an important validation for historical scenario approaches. If the conjecture turn out wrong, we are in a much better position to conceive of more scientifically informed scenarios, but potentially the approach will change entirely.
In presenting it as such, I am making it appear as if it could be an open question whether the chemical conjectures underpinning our scenarios in origins may be true or not. In fact, we have learned quite a few things in the meantime. And some clumsy mistakes were made elsewhere.
- Determinism:
When it comes to chemistry being deterministic (a key tennet of e.g. Sutherlands scenario and Wächtershäusers surface metabolism): upon critical evaluation of what is known of basic chemistry this idea becomes unacceptable, especially when considering the chemical processes on the surface of a planet, as opposed to a quick reaction in pyrex.
1) insofar as it is reproducible, modern chemistry owes much of it to big strides of standardization in glassware, methodology, synthesis protocols (e.g. usage of stirring bars).
2) lab chemistry exhibits many forms of contingency. This is particularly the case when it comes to phase behavior, e.g. habit modification, polymorphism. Aspirin purportedly has 8 reported polymorphs, phenobarbitone 13.
3) glassware is cleaned between reactions, thereby making successive reactions in the same glassware independent. In nature, this property of independence is absent. In fact, effort to make an evolutionary classification of minerals are rooted in the opposite: that certain minerals start to form conditional on the presence of certain others. (https://pubs.geoscienceworld.org/msa/ammin/article/104/6/810/570840/An-evolutionary-system-of-mineralogy-Proposal-for)
- Autocatalysis:
A first issue to get out of the way is the misconception that autocatalysis is prohibitively rare. A prominent PI in origins (RNA world, not a chemist) told me that chemists throughout history have found exactly one example. Claims about the contents of a literature one cannot realistically have read in a lifetime is a common error we can find in the origins literature. Below are some reviews.
Article Mechanisms of Autocatalysis
I should stress that these reviews discuss examples from a few niches in chemistry. These reviews do at least allow to have 100s of counterexamples to dubious claims about no autocatalysis in chemistry, but it's only a small fraction. Virtually all branches of chemistry have regular reports of autocatalysis, but very few focus on autocatalysis in its own right. And hence most branches do not review their reported examples.
By critically examining the IUPAC definitions, one can show that autocatalysis is dramatially more widespread than long thought. In part, this is because the definition applies to a wealth of situations where the term is not routinely employed. By examinging the requirements of autocatalysis as an emergent network property, one can demonstrate that this property emerges particularly readily in a heterogeneous / multicompartment context. With the disclaimer that I'm an author I refer to the following:
- Messy chemistry:
Refreshing counterexamples are afforded by the literature on systems chemistry and dynamic combinatorial libraries.
In the context of origins, a recent work that is greatly aiding in fixing our misconceptions is : https://www.nature.com/articles/s41557-022-00956-7
Where a reaction of purported immense complexity is found to exhibit highly reproducible and ordered behavior as function of environmental inputs. How chemistry exactly works on this level is still poorly understood. I think I do, but it'll have to await peer review. But we cannot in good scientific conscience take for granted anymore that chemistry becomes messy and intractable. When we do the experiments, we see something very different.
in conclusion, I want to come back to the final point of the question
"The scientific community must resolve this contradicting conjecture through rational discussion and debate backed by strong experimental evidence on what must be the pre-cursor molecule to the Origin of Life if it is not RNA!"
No. The sientific community should strive to do what it can justify scientifically. Those that find it fruitful to relegate the RNA world - which is not a hypothesis - are justified in doing so. Notably because it is is founded on scientifically refuted premises and logical errors.
Those that find ways to make it fruitful to keep it are justified in doing so: it's a scenario, one can draw inspiration from it. Perhaps a thoroughly altered version can be developed that fixes previous issues.
Above all else, RNA is an amazing molecule that has been used for fundamental research that concerns everyone in origins, and will continue to do so irrespective of how serious the RNA world scenario is still taken.
What the origins of life community needs, first and foremost, however, is concern itself with more important matters.
Complex chemistry needs to be studied thoroughly on an experimental and theoretical level.
New scenarios are needed. And these scenarios should no longer require chemistry to have properties it doesn't have, and vice versa. These scenarios should also explicitly be appraciated for what they are, an for what they're not. They're here to help, to guide thinking, inspire experiments, produce testable predictions, update our beliefs. They are not scientific hypotheses in and of themselves.
2 Recommendations
My biggest concern is whether the RNA components would be stable enough for them to survive long enough to be concentrated to a level that would allow them to polymerize into a photo-RNA molecule. Even that would happen, the polymer itself would likely have a fairly short life-time in the waters of the primitive Earth.
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