Raw materials for life

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The statement that metabolism is not life is not of any logical value because the question is if metabolism under the right circumstances can give rise to life. That is, is there some sort of metabolism that can evolve, and therefore constitute a step on the path to life? The scientists you pick quotes from to argue both sides are wrong, are doing research exactly to answer that question.

No, all you can say is that we have only ever seen cells come from other cells. If you generalize this to be a sort of law without exception(cells only ever come from other cells), then it logically follows there must have been an infinite regression of cell divisions into the past.
But we also know there can’t have been an infinite regression of cell divisions - since if we go back far enough in time, the elements of which cells are made did not even exist, since they were made in stellar nucleosynthesis. So cells must have somehow arose after this.

Since we don’t know how, we’re going to need to find out by doing research. This whole Henry Morris routine you’re playing by picking opinions, quotes, and arguments from different opposing camps in this field to try give the impression that all proposals are wrong(the arguments from camp A disprove camp B, and the arguments of camp B disprove camp A), is a well-worn and misleading creationist trick.

Arch-charlatan Henry Morris wrote an entire book (“That their words may be used against them”) consisting of nothing but such cherry-picked quotes, lifted out of their surrounding and historical context, from opposing camps on a whole host of hotly contested topics in geology and physics, to astronomy and biology.
Taking the quotes at face value one might derive the impression that all of the findings of modern science concerning natural history, from the early history of the universe, to the formation of stars and planets, including Earth, is all wrong. That was of course the purpose for which he went and collected these quotes, being a young Earth creationist his delusional viewpoint basically required adopting the view that all of science is wrong.

Are you trying to say that you believe there is an infinite past of cell divisions?

Of course your statement is wrong, as the evidence from comparative genetics all strongly indicate that cells somehow arose as the natural product of physical and chemical reactions. Evidence for there having been an RNA world, the origin and evolution of the translation system from a time before the existence of the genetic code, the distribution of amino acids in the oldest inferred ancestors of the most widely conserved proteins domains, and so on, all implies cells did at some point arise in the pre-biotic environment.

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48

While I agree that we should be honest about our ignorance and knowledge, I think you are selling OoL researchers short here. We don’t say psychologists and neuroscientists are not experts because they can’t just make a brain in the lab on demand. Origin of life researchers are the experts on the search for a scientific understanding of the origin of life. Just because humanity as a whole still has a long way to go to fully understand how life physically got here doesn’t mean they aren’t experts. I would say they are certainly experts on understanding the problems, possible routes, and what research directions might be fruitful. You can certainly disagree with their conclusions (especially when the may occasionally reach beyond the evidence) if you want but I think it’s another thing to dismiss their life’s work.

We can armchair scientist this all day, but at some point we can’t fault people who do the work for doing it the way that works for them. Generally, scientists will work on things they view as reachable and productive. In fact, given the system of incentives, that’s sort of a requirement.

A basic understanding of how cells might have first form has no relevance for medicine and biotech? :face_with_raised_eyebrow: I’m not sure I buy that people aren’t out there “trying to understand how to build and assemble the component parts of living observable cells”. I know a number of chemical/bio engineers and biophysicists that work that kind of stuff.

I would probably agree (though I’m not an expert in biochemistry) that enzymes are required to drive cellular operations (as we know them certainly), but I would argue they are not required to for primitive precursors to cells. I don’t think anybody envisions the process as going instantaneously from a pre-biotic soup to a cell in one go. You might ask a lot of good questions like, at what point between basic chemicals to the first cells would enzymes need to be available? How could enzymes develop outside the regular cellular mechanisms? To just say “cells need enzymes, enzymes are made by cells, therefore cells could not have formed without intervention” just seems too dismissive of there being multiple ways to accomplish a function.

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49

You wrote:

You were portraying science as entirely retrospective.

There’s the problem. Why do you think that the first steps in abiogenesis must have been cellular?

Indeed. Why cite Tour, then, who never even mentions metabolism AFAIK?

I don’t, as living observable cells are the product of billions of years of evolution and I see no reason to assume that the first steps in abiogenesis were cellular.

But speaking of that, why is the central enzyme in protein synthesis a ribozyme? What’s your hypothesis?

No, that’s ridiculous, as such a cell would have to compete with cells that have enzymes.

No, it doesn’t, and you still haven’t justified your assumption that cells are the starting point instead of acellular replication, catalysis, and/or metabolism.

So why did you write:

If you know that Lane is neither a chemical engineer nor a synthetic chemist?

I don’t see that he has falsified them. I see that he has emphasized the importance of metabolism.

I don’t think you’ve read that many if you think that cellularity is paramount.

Indeed. Lane wrote a great book about it. It’s a good place to start over.

That’s quite a straw man you’ve built. Can you provide evidence to justify your assumption that all of the early events had to occur in the context of a cell?

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I’m fairly confident that most IDcreationists think exactly that, or at least that’s what they claim in public when attacking abiogenesis research. Geremy clearly does.

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Under that scenario, the “soup” seems superfluous.

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Surely, whatever physical conditions were present on those meteorites and others which travel through space were sufficient to drive ribose synthesis without the aid of enzymes or the equipment and reagents available to chemists. This indicates you are baselessly underestimating the ability of natural processes.

No not really, I love studying about self ordering processes aka natural processes, both out of curiosity and because they can be exploited by technology. However quantities and purity matters in biology, just as much as it does in materials science. You have probably heard of quantum dots, the nanoparticles that some TV companies suspend in a thin transparent plastic sheet and place in front of an LED screen to generate sharper colors by acting as monochromatic prisms. The complexity of making such nanoparticles in the lab while daunting, is much simpler than the synthesis of ribose in our cells as you can see in the image below:

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So it shouldn’t surprise you that small quantities of quantum dots spontaneously form during the glass manufacturing process. So why do you think that chemical engineers don’t simply use quantum dots that form spontaneously in glass for TV screens?

The quantities are too small to be useful, so harvesting them from glass is impractical. One would have to manufacture the glass, then physically crush the glass to powders of just the size to search particles that may or may not have formed that are just the right size to trap a given wavelength of light. Also different quantum dot chemistries have different heat tolerances, toxicities and electrical properties, so instead of relying on spontaneous chemical reactions, decades of research were required for chemists to learn how to fabricate quantum dots without using known toxins that wouldn’t melt when exposed to light for prolonged periods of time, etc. Once that fundamental science was done the process was automated using flow chemistry as you can read about below:

https://par.nsf.gov/servlets/purl/10165734

Now when we look at both the quantity of ribose found in meteorites, just like occurred in the the example from inorganic chemistry the quantity of ribose is extremely low, and it is found in a racemic mixture along usually with enantiomers (although the researchers did no study chirality for whatever reason in the study below) as you can see in both Figure 1 and Table 1 in the paper linked below:

https://www.pnas.org/content/116/49/24440/tab-figures-data

When I read the article associated the above link was taken from, I found it noteworthy that the paper specifically speculated that the sugars in the meteorites were the result of a formose like reaction in the meteors parent asteroid stating:

Formose-like reactions are also capable of forming sugars in natural environments (5). The fluid in the parent bodies of carbonaceous chondrites is thought to be alkaline and contains many cations, including Mg2+ (29). Thus, a formose-like reaction would have been possible during aqueous processing in many of the parent asteroids of carbonaceous meteorites.

The Formose reaction is a known process with known capabilities, so if we accept the author’s speculation about how the ribose formed, which seems reasonable, then the small quantities of sugars produced would be in line with what is known to be possible in other aqueous alkaline environments using similar processes. In his paper his first reviewing of OOL research, James Tour used the data collected by Albert Eschenmoser’s experiments that used the Formose reaction to synthesize ribose to explain the self limiting nature of using it to synthesize ribose saying:

This means that time works against life. Over a mere 23 weeks, the desired diastereomer—the racemic ribose-2,4-diphosphates—had been reduced from a 17% yield to a 7% yield. After a year, there would be very little left. In the laboratory, as anywhere else, it is essential to stop a reaction before the desired product degrades

.

So the reason so little ribose is found in nature is because the same processes that create ribose also degrade it, and so there isn’t a scientific reason to believe that sufficient ribose accumulated in the prebiotic environment, due to known processes that make it abiotically which also quickly degrade it. However, in real living cells we can see a functional process that creates ribose in the quantities and the concentrations needed by life, using necessarily complex chemistry, due to the difficulties inherent in its synthesis in observations to date. So I think I have a reasonable degree of confidence in natural self ordering processes, I feel no compulsion to imagine that they can do more or less than they are demonstrably capable of.

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Under a very specific set of conditions. Under different conditions, it behaves completely differently. The products and yields of the formose reaction is strongly dependent on the particular conditions under which it proceeds:

Scientists have barely even begun to scratch the surface of how many of these “classic” chemistries behave under more realistic, cycling, complex natural settings.

Or for the environment to favor certain products over others, by (for example) having intermittent flows selectively wash some products away, and have mineral surfaces retain others, leading to continued accumulation of some products. Products can’t wash away inside a carbonaceous chondrite, and there’s no continuous replenishment of starting chemicals or mineral surfaces.

You are extrapolating conclusions that can’t be supported from billion-year-old meteorites and rather simple one-pot reaction experiments.

No, it’s that the particular microevironment in which the formose reaction occurred in that meteorite had a particular selective profile. Other environments affect the reaction in other ways.

How do you know what’s sufficient? Sufficient for what specifically?

For reasons just explained, and demonstrated in the above experiment, there is no such thing as “the prebiotic environment”. There are many different prebiotic environments, and it matters a lot where and how particular types of chemistry occur.

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Just to buttress this point about the selective behavior of chemical reactions in different environments, there’s this:

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55

Why didn’t you enclose this in quotation marks, since its a quote from my previous comment?

Nice try shifting the goal posts. This was not about the quantity or purity, but whether certain molecules could arise in the first place. You were on about the absence of evidence of RNA emerging in natural environments besides modern cells and labs, and I retorted that was the case for ribose until we found it in meteorites. We have also found amino acids, nucleobases (which is just astounding), and other simple carbohydrates in meteorites, all of which came into existence with no help from enzymes or chemists.

In addition, you complained about “proximity” between the ribonucleotide components not being enough to chemically generate ribonucleotides, hence, the need for a cellular environment studded with enzymes or the reagents and reaction vessels of prebiotic chemists to facilitate the ribonucleotide synthesis. I retorted that despite the absence of the aforementioned conditions obtainable in modern cells and labs, that ribose still arose nonetheless. So not only did the ribose precursors get into close proximity, they also reacted as well to make ribose under whatever conditions were present on those meteorites. The point, which you didn’t seem to grasp, is that some physical conditions drove the relatively complicated synthesis of molecules associated with modern life in prebiotic times without the need for cells or flasks.

If there were conditions that facilitated the synthesis of precursors for molecules like ribose or adenine, then there must have been conditions that allowed ribose and others to accumulate to sufficient amounts and be chemically transformed into the biopolymers we know today (or didn’t know billions of years back). The paper below documents the presence of glycine polymers in meteorites: glycine polymers today only arise through ribosomal synthesis in cells or prebiotic experiments, but we now see them in meteorites indicating polymer synthesis was possible billions of years ago; interestingly, the glycine polymers were complexed with iron, suggesting it may have had something to do with its formation:

https://aip.scitation.org/doi/10.1063/5.0054860

Dude we have meteorites containing ribose (and other sugar) molecules which have literally persisted for billions of years. This tells you these molecules could escape processes that could have degraded them post-synthesis. I don’t see why this couldn’t repeat itself on a prebiotic earth, allowing for the accumulation of these molecules with time.

Approximately 2 billion years ago, there were no “real living” eukaryotic cells, so the only real living cells relevant to OoL are prokaryotic life forms which are relatively simpler to eukaryotes. In addition, modern prokaryotes have been fashioned by the various forces of biological evolution for billions of years, so of more interest would be the ancestors of modern prokaryotes which existed billions of years ago.

Again, there might have been natural processes that retained sufficient amounts of precursor materials on a prebiotic earth, allowing these precursors persist for a much longer time and build up to sufficient amounts. Stop ignoring this possibility.

If ribose formation and glycine polymerization could occur independent of enzyme-based chemistry and the products persist for an extremely long period of time, then I see no reason why similar events couldn’t happen on a prebiotic earth under varied prebiotic conditions.

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On a related note, have you ever considered the difference between replication and self-replication?

Think of something like PCR, where DNA molecules are amplified over multiple rounds of heating and cooling. Here we have replication occurring, facilitated only by base-pairing, catalyzed by a DNA polymerase enzyme.
But the function of this replication is disconnected from the sequence of that which is being replicated, the DNA molecules. That implies you can have something being replicated over and over again, with replication fidelity having little to no impact on the process of replication. It doesn’t matter how many errors the DNA polymerase makes, when replicating the DNA, it’s still being replicated. Thus the function is disconnected from the sequence. The replication is driven by a combination of the catalyst and the cycling temperature.

In a prebiotic context, you could have replication driven by a temperature (and/or wet-dry) cycle in a similar way, with (for example) a mineral surface or dwindling water activity as a product of evaporation or accumulation in a thermal pore acting as a catalyst. Sure, it’s going to be very low fidelity, but it’s replicating nonetheless. And since the catalyst does not depend on the sequence of what is being replicated, the fidelity is actually irrelevant to the mechanism of replication.

So it turns out the low fidelity will enable very quick mutational exploration of the sequence space of the replicated polymers, enabling faster discovery of potentially useful functions that can contribute either to enhanced survival of the replicated polymer, or increased rate of replication. If any such function is discovered, however weak it may be, you have the basis for competition among polymers being replicated. If you have replication and competition, you have evolution.

Higher replication fidelity of sequences that enhance the rate or survival of replicated polymers will outcompete lower replication fidelity, as their “offspring” are less likely to lose the ability to participate in their own replication. In this way it appears possible to bootstrap yourself to high replication fidelity. Sooner or later the exploration of sequence space can discovery sequences that participate in replication, without the process being (at least initially) dependent on it(it merely aids or speeds up the reaction), and therefore no error can prevent replication from occurring. Here a critical aspect is the number of cycles the replicated polymer lasts for, that is, how many “offspring” it can survive to produce before it degrades away.

Thinking that life has to start with a high-fidelity self-replicator is a conceptual mistake. Modeling work has shown that a system can evolve towards the capacity for self-replication, if it starts merely with the function of replication occurring independent of sequence(see below for an example), but being disconnected from the evolving sequence, which can be indirectly evolved towards facilitating it’s own reproduction at the expense of competitors.

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Why didn’t you enclose this in quotation marks, since its a quote from my previous comment?

Simple oversight sorry, my mistake I have fixed it.

Nice try shifting the goal posts. This was not about the quantity or purity, but whether certain molecules could arise in the first place. You were on about the absence of evidence of RNA emerging in natural environments besides modern cells and labs, and I retorted that was the case for ribose until we found it in meteorites.

This is a confusing comment since there still isn’t evidence that RNA can emerge spontaneous in nature without the help of cells, and I mentioned both the quantity and the purity in my very first comment on this thread. In my first comment I said:

Some of the compounds needed to make enzymes, DNA and RNA can be found in trace amounts in comets, and in chemical reactions that attempt to simulate various models of the primordial earth. Is it possible to use the products of such experiments to allow evolution to create enzymes?

Just to be clear I am wondering if quantities of 4.5 parts per billion after hundreds of thousands of years on ice (which should slow down the process of decomposition) is the best that abiotic nature can do, or if anyone has evidence that ribose could actually accumulate on a prebiotic earth to levels where it could form long chains of pure ribose at least. I also said:

Did the researchers need to purchase laboratory chemicals, and then used their advanced knowledge of chemical engineering to purify them beyond what the laboratory had already done?

Here I obviously expressed the idea of purity being a problem as well. So I have not changed any goal posts. Now as far as the spontaneous emerges of RNA this would require that the RNA nucleosides one of which is cytosine which decomposes in just 19 days at 100 C and in 17,000 year when in ice, could have attached to the ribose backbone to make RNA without the actions of intracellular enzymes on synthetic chemists. Just to be clear hear is a detailed explanation of how chemist can attach RNA nucleosides to a ribose to form RNA as characterized by James Tour:

Thomas Carell’s group has accomplished that coupling through the condensation of formamidopyrimidines with ribose providing the natural N-9 nucleosides with high regioselectivity. Starting with 2,4,5,6-tetraaminopyrimidine-sulfate and suspending it in formic acid and sodium formiate, the mixture was heated to 101°C for two hours. The solvent was evaporated under reduced pressure and water was added to dissolve the product. Concentrated ammonium hydroxide was then used to raise the mixture to pH 8. The solution was cooled overnight at 4°C, yielding substantial amounts of formylated tetraminopyrimide as a crystalline solid. This was isolated from the other products. Then, they allowed the formylated product to interact with 15 equivalents of homochiral ribose by grinding the two together thoroughly in the solid state and heating the mixture in an oven at 100°C for eight hours. The team purchased its ribose. I have already shown how hard it is for the world’s best synthetic chemists to make even a gross diastereomeric and racemic mixture of that 5-carbon carbohydrate.2 The solid was then placed in a sealed tube, away from exogenous air (which is tough to do in nature), and treated with concentrated ammonium hydroxide, or basic amino acids, or borax, at 100°C for between one and 14 days. The reaction consumes the ribose starting material; hence a 15-fold excess was used. This resulted in a mixture of products. No bulk separation was attempted. The mixture was subjected to liquid chromatography and mass spectrometry.

This advance by Carell and his team relied on the use of pre-formylated purines and pyrimidines; this made possible their coupling with commercially purchased homochiral ribose. The authors did mention the problems raised by the oxidative instability of aminopyrimidines. There is no reason to suppose that nature could have commanded these exquisite laboratory skills. Often seven major products, and many more minor products, were formed in these reactions, where the combined yield of the anomeric nucleosides could be as high as 60%. When starting with racemic glyceraldehydes and glycoaldehyde, rather than purified homochiral ribose, the yields of the racemic nucleosides dropped to less than 1%, and that 1% contained as many as 16 different isomers. No attempt was made to extract the trace, which was likely less than 0.1%, of targeted nucleosides from the other >99.9% of the gross reaction mixtures.

So the hypothesis that RNA is the result of some self ordering natural process of organic chemistry that doesn’t require the existence of cells and enzymes simply does not have empirical support, which was the point of my first comment, and my last comment and no I haven’t changed a single goal post along the way…

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So what? There wasn’t evidence that Urea could be made outside the context of life until there was. Since cells can’t have existed forever, they must necessarily have arisen somehow. This alone would seem to fundamentally undermine the extrapolation that cells can’t naturally arise which you are seeking to draw from contemporary experiments in abiotic chemistry.

There is evidence there was an RNA world and that life arose from some sort of process of physics and chemistry, which you have consistently ignored, electing instead to just blurt out this vacuous talking point about what has yet to be demonstrated, vaguely implying something you seem to not want to actually have to state so you can avoid having to defend that instead.

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Why would it need to?

Why do you think the only way to get RNA is by the disparate synthesis of the ribose and nucleobase moieties and their subsequent linkage through a glycosidic bond?

And what use is it to blather about the half-life of cytosine if you don’t know it’s rate of production? Why are you bringing up a topic I’ve already asked you to elaborate on before, as if this point of yours has not already been fundamentally called into question?

And please enlighten us here, what do you think happened (instead of what you think didn’t) at the origin of life, and how do you propose to test that experimentally?

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^^^^^This.

Another major conceptual mistake is that early life had to be efficient. It didn’t, because there was no other life to compete with.

Geremy, there’s a very good reason why we’re not going to find RNA emerging spontaneously in nature. It fits nicely into the RNA World hypothesis and relates to competition.

Do you have a hypothesis that explains why the central enzyme in protein synthesis is a ribozyme?

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There is nothing confusing about my comment. Prior to the discovery of ribose and other biorelevant sugars in those meteorites, ribose could only be produced in laboratories using synthetic routes like the formose reaction. Of course, the abiotic synthesis of ribose provided evidence that biorelevant compounds could come into existence without the need for biological systems. Then comes in James Tour with his whining that the experimenters cheated because they used highly purified chemical reagents and state-of-the-art technology to carry out those syntheses. So, James Tour (and you too) would agree that ribose synthesis can happen outside cells but needs the minds of smart chemists to coordinate it. Wham! Meteorites shoot into our atmosphere, bringing with them these sugars that were thought to need intelligence and chemical synthetic principles to create them. The presence of the sugars in the meteorites beautifully demonstrated that only physico-chemical processes could perform complex organic synthesis without the need for the purified starting materials you get in the lab or intelligent minds.

The ribose found in those meteorites were probably synthesized billions of years ago. How exactly that happened is uncertain, but the plausible prebiotic synthetic routes developed in laboratories could explain how that happened (and it seems they formed via some formose-like reaction in space with no test tubes, flasks and highly pure reagents which is just awesome). That is the goal of OoL research.

I wasn’t responding to your arguments about quantity or purity, just the ability of these things to arise in the absence of intelligence. Look at my comments again:

Can you now see why I said you shifted the goal posts?

Who says the meteorites were on ice for hundreds of thousands of years?

Um, ribose formed and got preserved on those studied meteorites, and likely many that hit our planet billions of years ago. If this accumulation could happen on meteors, then it most likely could have happened on a prebiotic earth.

You moved the goal posts in my case. Sorry.

Again, if ribose, glycine polymers, amino acids, nucleobases etcetera could be synthesized in meteorites without enzymes or the minds of chemists, I don’t see why RNA could not have been synthesized via one or more prebiotic synthetic routes.

Do you need me to show you how chemists enact the formose reaction to produce ribose, detailing the steps and complex tools used? It wouldn’t matter though because nature was pretty capable of doing the same without the aid of those pesky chemists or their tools.

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Why do you think the only way to get RNA is by the disparate synthesis of the ribose and nucleobase moieties and their subsequent linkage through a glycosidic bond?

Because I looked into it carefully, and found no evidence that the natural processes readily form nucleobases and ribose in the in the same abiotic environment and cause them to attach to each other. Here is how one paper describes it:

…attempts to synthesize cytidine and uridine under the same reaction conditions demonstrated that glycosidic bond formation for pyrimidine nucleosides does not occur as readily as it does for purines.(199,200) The general rationale for this discrepancy between purine and pyrimidine condensation with sugars has been attributed to the availability of the lone pair of electrons on the purine N-9, which initiates a nucleophilic attack on the aldehydic carbon of ribose. This reaction is less likely to occur with the N-1 of the pyrimidine bases because the tautomerization of uracil, thymine, and cytosine that delocalizes the electron density away from N-1 (Figure 29), creating a kinetic barrier to the glycosidic bond formation.(202) As a result of this kinetic barrier, no efficient direct synthesis of pyrimidine nucleosides by the direct condensation of ribose with uracil or cytosine has been reported to date under plausibly prebiotic conditions.

https://pubs.acs.org/doi/10.1021/acs.chemrev.9b00546

According to the same paper the most plausible prebiotic route to binding the above nucleosides to ribose was accomplished by the Carrel group. It states:

As seen from above, it is difficult to control the regio- and stereoselectivity in the direct nucleosidation reaction between ribose and the purine nucleobase. To overcome these issues, Carell and co-workers showed that N-formamidopyrimidines could be used to generate purine nucleosides with absolute nucleobase regioselectivity (Figure 31).(212)

Now as you no doubt remember this is the same paper that James Tour took the time to describe in great detail. So the most prebiotically plausible scenario is what Tour described in his paper. As you will see I have a healthy skepticism, and verified Tour’s accounting of the difficulty of the above synthesis before I mentioned it to you. Your next statement was:

And what use is it to blather about the half-life of cytosine if you don’t know it’s rate of
production? Why are you bringing up a topic I’ve already asked you to elaborate on before, as if this point of yours has not already been fundamentally called into question?

Okay, in this case I am looking a several papers but a good starting paper is one written by Robert Shapiro some 22 years ago, where he goes into the weeds delineating several reasons why cytosine wouldn’t accumulate in a prebiotic world stating in conclusion:

Rapid incorporation of cytosine into a double-stranded replicator could best be achieved if all components (coding units and backbone) were synthesized under the same set of conditions, and polymer formation took place in the same environment. To avoid cytosine loss, this process should take at most several centuries at 25°C. A change in temperature would not improve matters unless it could be shown that the synthetic processes were retarded less, or enhanced more, than the degradative ones at a different temperature.

Suitable chemistry for such transformations has not been demonstrated, however, and may not exist.

https://www.pnas.org/content/96/8/4396.full

So again I am only saying that the evidence doesn’t exist, you know because it doesn’t exist, if you have evidence to the contrary I’ll read it.

Finally you asked,

And please enlighten us here, what do you think happened (instead of what you think didn’t) at the origin of life, and how do you propose to test that experimentally?

Well obviously if life didn’t spontaneously emerge somehow then it was built, so the real scientific question is how and can we build cells too? To my mind this is the question no matter what one thinks or believes. As I stated earlier those who are confident that unguided chemical reactions made life should at the very least try to build cells using raw materials taken from non living nature at least that way they will know what the constraints on it happening in the way that they imagine would actually be.

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That does not seem to constitute an answer to my question. I asked you why you think the only way to get RNA is by having two different moieties synthesized first and then linked together.

The implication of my question is that there is another way to make RNA that does not involve making both and then linking them together, but an entirely different pathway that begins, essentially, with a molecule already containing what becomes the glycosidic bond, even before ribose and the nucleobases have formed, and then gradually building up the ribose and nucleobase moieties from a different molecule of which the glycosidic bond is already a part.

It’s in the very paper you link, in section 4.2. Alternative (Indirect) Approaches to the Nucleoside/Nucleotide Formation. Look at figure 34.

One proposed alternative path
One proposed alternative path744×573 60.9 KB

I’ve helped you with some green arrow here. Notice how that bond is there right from the beginning.

The point here is not that I am advocating this particular pathway to pre-biotic RNA, but to point out that your conceptions of what has to occur to get RNA is unnecessarily restrictive, and whatever you might think about what challenges apply to correctly linking ribose and some nucleobase clearly does not apply to a scenario such as the one depicted in that figure. There are other possibilities.

Another problem is your argument seems to be that we’ve now fully explored all plausible or possible routes to prebiotic RNA, so in so far as you can quibble about the prebiotic plausibilities of the particular routes of synthesis explored to date, you’ve somehow ruled out any and all plausible routes to prebiotic RNA.

I must repeat here that absence of evidence is only evidence of absence if you have reason to think that you have exhaustively explored a significant fraction of the available chemical space. I have given multiple articles that demonstrate empirically that there is a vast arena of unexplored chemistry that is extremely sensitive to local reaction conditions, that will radically alter the product distributions of even the very chemistries so far explored and discussed here(such as the Formose reaction), implying that there is still so much about the behavior of these reactions we don’t understand and can’t predict simply on the basis of performing a small handful of simplistic one-pot reactions.

I’m looking at the paper and I’m not seeing where we’re told it’s rate of production, so my question still stands. But it’s half-life of 340 years at 25°C does not seem to be particularly restrictive. All that says is that if you get one large lump of it at some instant in time, you’ll have half of it left after 340 years at 25°C. But again I have to ask, what if you’re receiving a continuous feed for 50 000 years? Here the concentration you’ll have during this 50 000 year period will depend on the rate at which it is produced and the temperature, and what sorts of other molecules and minerals are present, and the dynamics of the system. What are the selective profiles of the mineral environment? Water activity? Temperature?

It’s not detected in meteorites, but so what? They’re billions of years old, so if cytosine has a relatively short half-life compared to the other nucleobases, that provides one explanation for why it’s not found in meteorites now billions of years after they first formed. And so what if it isn’t produced in meteorites at all, how do you extract from this the conclusion that it is formed nowhere else? Enlighten me. You seem to be assuming a lot of things you’re not articulating to arrive at your conclusions, but none of the references you bring entail those conclusions.

That’s not obvious to me since the only builders I know of are life, that proposal seems to just lead to the exact same conondrum you’re trying to emphasize with your arguments here. I could make the exact same sort of argument you’ve seem to be advancing:
If there’s no evidence of non-living life-builders, and life-based builders have so far failed to create life, yet life exists, what should that cause us to conclude? Then life must have arose without being built.

It seems to me you’d be forced to make the exact same reply I have been making: Such a conclusion is premature, and all we can really say is that we’ve yet to succeed at creating life, whether by a plausible prebiotic type of process, or by a synthetic pathway.

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Here’s yet another very recent nature-article arguing basically all the same things I’ve said so far:
Asche, S., Cooper, G.J.T., Keenan, G. et al. A robotic prebiotic chemist probes long term reactions of complexifying mixtures. Nat Commun 12, 3547 (2021). A robotic prebiotic chemist probes long term reactions of complexifying mixtures | Nature Communications

Introduction

On the early Earth, prebiotic chemistry underwent a transition to biological chemical systems during a very long period (ca. 100 Myr)1, yet explorations in the laboratory today are traditionally limited to a few hours or, at most, days. Only 3.7% of all experiments reported to Reaxys between 1771 and 2011 were carried out for longer than 2 days2. However, the exploration of unconstrained3 or complex multicomponent systems requires far longer times and a large number of parallel experiments4,5, after which progress is hindered by the analytical complexity of the products; huge numbers of samples containing unknown mixtures6, seen by many as intractable. This is further complicated by the fact that realistic chemical reactions, vital to emulate the types of processes possible on the early Earth at the Origin of Life, did not take place in a clean single environment.

There are many candidate theories and frameworks that aim to explain how living systems can emerge from nonliving substrates7,8,9, but none of these are testable over the long time periods over which life was thought to have emerged on Earth ca. 3.8 B years ago10. For example, it has long been hypothesized that the central carbohydrate metabolism emerged as a geochemical process without enzymes and subsequently evolved via the addition of ever more complex reaction pathways11,12. While component pieces of this idea have been tested, the entire hypothesis cannot be explored using current technology. The same is true of many other hypotheses regarding the origin of cellular membranes and genetic molecules13,14. This exposes an important gap that can be explored. Much current research focuses on prebiotic plausibility, which itself is constrained by our geochemical knowledge15, and a vast amount is simply unknown, namely the space of chemical reactions and starting materials available, as well as the precise reaction conditions and constraints on these conditions. Previous approaches to prebiotic chemistry, which have their origin in synthetic organic chemistry, intentionally try to limit the accessible size of the chemical space in experiments16,17. While this is convenient, as it allows the identification of individual products using standard analytical techniques, experimental conditions need to move away from these single-flask approaches to include controlled environmental factors if we are to explore the chemical space relevant to the emergence of living systems. This can include, for example, the inclusion of mineral surfaces and variable temperature, pH, and redox conditions, some or all of which may be allowed to vary dynamically, driven by, and driving, the chemical reactions in the mixture. Some work has already shown that chemical reactions of simple ‘soups’ in cycles lead to the diversification and differentiation in the product space3,5,18,19, but the number of potential reactions and time needed for all the reactions is vast18,20,21,22.

Currently the field lacks an experimental design framework that would allow researchers to test competing hypotheses23 on long timescales, and the number of candidate experiments is gigantic24,25. This problem is made even bigger when the vastness of search space relevant for the investigation of the emergence of life is considered—such a chemical space cannot be adequately explored using experiments that run for a day or a few hours. Here we show a ‘robotic prebiotic chemist’, an automated closed-loop system that runs unconstrained multicomponent chemistry experiments on mineral surfaces in cycles, with fully automated analytical measurements and a decision-making metric.

It is simply not reasonable to try to conclude that the investigation of plausible prebiotic chemistry is already conclusive. Such a sentiment indicates nothing other than ignorance.

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The point here is not that I am advocating this particular pathway to pre-biotic RNA, but to point out that your conceptions of what has to occur to get RNA is unnecessarily restrictive, and whatever you might think about what challenges apply to correctly linking ribose and some nucleobase clearly does not apply to a scenario such as the one depicted in that figure. There are other possibilities.

I am glad that you aren’t advocating this particular possibility or any of the possibilities in that section of the paper because as the paper I mentioned earlier said:

It must be noted that in all of the above reactions the chirality of the d-glyceraldehyde is assumed ad hoc; however, in a prebiotic context, racemic starting materials are expected to be the norm.

If that was the only unrealistic aspect of that paper that would be bad enough, however this was one of the papers that Tour originally discussed as unrealistic using his knowledge of chemical synthesis, (the acronym “JIT” that you see below represents “Just In Time”) he wrote:

John Sutherland and his coworkers have proposed that pyrimidine ribonuceotides can form short sequences using arabinose amino-oxazoline and anhydronucleoside intermediates, all from simple compounds such as cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate. The use of inorganic phosphate changes the experiment’s basic conditions to a pH-buffered solution, thereby slowing decomposition pathways.41But the work itself shows the intricacies required to generate the desired reactions.

The conditions were cleverly selected:

Although the issue of temporally separated supplies of glycolaldehyde [just-in-time (JIT) scenario 1] and glyceraldehyde [JIT scenario 2] remains a problem, a number of situations could have arisen [prebiotically, what and where?] that would result in the conditions of heating [careful control step 1 at 60°C ] and progressive dehydration [careful control step 2 by lyophilization which is water removal by ice sublimation under reduced pressure of <0.001 atmospheres] followed by cooling [careful control step 3 from 60°C to 23°C], rehydration [careful control step 4 with precise adjustments of pH] and ultraviolet irradiation [careful control step 5 with a selected 254nm light].42

I highlighted the ice sublimation step in bold because this went from being unrealistic to absurd, what natural process would have caused the chemical reaction that was happening at sea level under the pressure of one atmosphere to briefly be relocated to the heterosphere or 100 km above sea level where pressure of 0.001 atmosphreres are available, at a temperature of 60 C (which I can’t explain) only to come back down to sea level to be rehydrated? This why my estimation appears overly restrictive, because I try to actually think about what natural conditions would be necessary to make the conditions of the lab experiments actually happen. So I’m looking for plausible scenarios not just any random scenario an OOL researcher can create in a modern lab.

As far as the half life of cytosine I think the Shapiro’s paper is pretty accurate, you have mentioned chemical reaction that produce lots of cytosine on an ongoing basis for 50,000 years but I can’t find any evidence of such mechanisms. I also think as shown in the paper above one can always speculate that some unrealistic scenario or another made something happen, what is needed is evidence that it could happen.

It’s not detected in meteorites, but so what? They’re billions of years old, so if cytosine has a relatively short half-life compared to the other nucleobases, that provides one explanation for why it’s not found in meteorites now billions of years after they first formed.

I am only trying to keep up with the latest evidence, here is how one paper described it:

Carbonaceous chondritic meteorites are thought to be fragments broken off parent bodies that orbit in the outer Solar System, largely unaltered since their formation. These meteorites contain evidence of reactions with liquid water that was thought to have been lost or completely frozen billions of years ago. Turner et al. examined uranium and thorium isotopes in several carbonaceous chondrites, finding nonequilibrium distributions that imply that uranium ions were transported by fluid flow. Because this signature disappears after several half-lives of the radioactive isotopes, the meteorites must have been exposed to liquid within the past million years. The authors suggest that ice may have melted during the impacts that ejected the meteorites from their parent bodies.

https://science.sciencemag.org/content/371/6525/164

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I totally agree with all of that(and many people have been arguing the exact same things concerning that method of synthesis), yet it is totally irrelevant to the point I was making. So what have you accomplished with your argument? Nothing. The point remains: What you can currently conceive of and what you currently know is no indication of what has to occur, could occur, or must occur for the origin of life.

Again, given that our knowledge of the space of plausible prebiotic chemistry is extremely limited, and we have barely even begun to test the ranges of relevant possible conditions, mindless repetitions of the appeal to “I can’t find any evidence of such mechanisms” indicates next to nothing. It’s like opening the door into a cluttered room full of furniture, boxes and shelves with items, closets and cabinets, and piles of clothes, then taking a quick glance at the scene from the door and confidently declaring “I see no evidence the person who lives here owns a gun” - as if that somehow indicates anything. Buddy, you have barely even begun to look for it.

Yes, and until you’ve thoroughly searched, handwaving that “we haven’t found that evidence yet” can not rationally support the absurd extrapolation that no such process exists. Exactly like you would argue when I point out that there’s no evidence life was or even can be created.

It’s cool to know that carbonaceous chondrites arriving here from the outer solar system come into contact with water-ice, but I don’t see how that affects the point I was making. I must repeat the question: And so what if it[cytosine] isn’t produced in meteorites at all, how do you extract from this the conclusion that it is formed nowhere else? Enlighten me. You seem to be assuming a lot of things you’re not articulating to arrive at your conclusions, but none of the references you bring entail those conclusions.

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