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Comment by Calavar | Hacker News Reader

I have always felt that applying the label "origins of life" research on amino acid/nucleic acid synthesis is extremely misleading.

An analogy would be writing an article about the natural abundance of silicon on beaches and calling it "how computers are made."

We have a decent idea of how the first nucleic acids may have been synthesized, and we have a decent framework for how life evolved from protobiont to prokaryote to eukaryote to multicellular organisms. But there is an absolutely staggering gap between the synthesis of individual nucleotides and the synthesis of the first RNA replicase that we know nearly nothing about.

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It's unlikely that RNA replicases ever existed in the absence of short amino acid polymers. The primordial ribosome might be the concept your looking for - an association between short RNA sequences and short amino acid sequences capable of self-replication via various RNA reactions and amino-catalyzed reactions.

This may be the original article discussing this hypothesis:

"The ribosome as a missing link in the evolution of life" (2015) Root-Bernstein & Root-Bernstein, J. Theoretical Biology

https://sci-hub.se/10.1016/j.jtbi.2014.11.025

> "Evolvable entities existing between self-replicating polymers and fully functional cells would presumably have many, though not all, of the functions of a cell, yet be significantly simpler in composition and organization. These entities would be able to self-organize and replicate themselves; store information and replicate that information; translate the information into the components necessary to produce their functional structures; capture metabolic components and energy; and transform these into useful biochemical networks. Norris and his colleagues have called functional forms of organization midway between macromolecules and cells “hyperstructures” (Norris et al., 2007). Such hyperstructures had to be instantiated as evolvable entities, meaning that their components would be subject to variation, replication and natural selection."

If we truly didn't know how computers came about, it's certainly progress to figure out the silicon can come from sand.

How is it not origins of life research to attack every step in the process?

Just a clarifying question but when you use “attack” do you mean from a “critically minded research focused lens” or a “skeptical” one?

It's progress, but the degree of progress is vastly oversold by the media, and sometimes even by academics. Kind of similar to those "amazing new semiconductor" articles that come out every 6 months.

Maybe you mean the regular amazing new battery breakthrough?

Adding to my previous comment:

If a student asked "how did life originate?" a response about about nucleic acid synthesis would be a bit disingenuous, because that covers only very, very tiny fraction of the surface area of the problem. The more honest answer would be that there are so many large gaps in our knowledge that we truly don't know.

To be clear, I'm not trying to cast skepticism on the whole of biology. There are other questions that we have much better answers to, like the evolutionary pathway from single cellular life to multicellular life. Or the evolutionary link between humans and great apes. But abiogenesis is not one of those questions.

> The more honest answer would be that there are so many large gaps in our knowledge that we truly don't know.

Are the gaps really that large? We know that some configurations of nucleotids are enough to create a full metabolism, we know that they arrange at random, and we know how most of them appeared.

Except for the few nucleotides that we don't know how they existed, we do know that if you have enough of them on enough places, some kind of life will appear. So looks like the open question here is how those molecules appeared.

But RNA / DNA isn't sufficient for life, right? How are proteins synthesized from that string of nucleotides without ribosomes? And nucelotides randomly reshuffling certainly doesn't explain how ribosomes would be created.

It's theorized that under the right conditions amino acids will bond to become proteins without needing the mediation of a ribosome. So it's certainly possible that with enough primordial soup you could get proteins. But that doesn't explain how the nucleotide string ends up getting treated as a reusable blueprint for proteins.

That seems like a pretty big gap.

Ribosomes are mostly RNA, and there is good evidence that they evolved from something that was purely RNA. The aminoacid transport and encoding mechanism is also basically composed of RNA, with some evidence that something like them would work without any of the protein parts.

Also, people have created RNA-only self replicating mechanisms that could quite well appear at random, with extremely low odds. Life probably comes from some structure with higher odds that we don't know about, but that's not a huge gap.

I wish I recalled better, but I saw a hypothesis that centered around tRNA rather than the ribosome as the origin of replication. after all, the ribosome simply catalyzes the binding of tRNA to mRNA, and amino acid linkage.

iirc the idea centered around the tRNA "code" having a pattern to it - one shaped by its binding affinity to part of the sequence that codes for the tRNA-aminoacyltransferase enzyme itself. I wish I remembered enough to find the reference.

edit: ah! think I remembered. the hypothesis was that the codon sequence had some sort of binding affinity to the amino acid it codes for. that there's a relationship between them, suggesting a world where codons attracted amino acids to bind to them without an enzyme linking them.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924937/

> If a student asked "how did life originate?" a response about about nucleic acid synthesis would be a bit disingenuous...

As the article title does not say or imply that the answer to this question has been found, let alone that it will be revealed in the article, this is at least beside the point.

In attempting to brush aside gliptic's pertinent question, you have switched to a general (and somewhat subjective) claim that does not seem to hold up in this specific case.

Also, and imo fundamentally, it doesn't define a natural process of system where this reaction is thermodynamiccally favorable.

That, imo, is far more important.

In the context of building computers and defining computation, silicon can be considered an afterthought.

We already had adding machines and the philosophy necessary for digital logic.

It may well be the case with the original system that initiated the process we call life. RNA (and by extension DNA) may have been a complete afterthought.

I'm always disappointed when I see this research outside of a systems context. Like, sure we can show these things happen, but show me a thermodynamic systems, in place,where this can happen.

In you metaphor about sand and beaches, this may be like taking some one to a dune field and saying 'see all this sand. That's where computers come from'.

Is that really a staggering gap? The nucleotides jumble together until they randomly hit a config that leads to a pattern that leads to more of that config. We don’t know what that path is exactly but we can be pretty sure it’s the result of random mumbling through a series of random searches in an organic chemistry space.

Computers don’t arise randomly (without annoying semantic arguments).

> Computers don’t arise randomly (without annoying semantic arguments).

If you believe the human brain's processes are computable, and you believe evolution is a random process, then you believe that computers arise randomly.

Is that what you mean by "annoying semantic arguments"?

Yes. That is an annoying semantic argument. The intended discussion is pretty clearly a purposefully manufactured device made of silicon and how understanding how that instantiates by watching silicon is not at all like watching how nucleotides arrange into rna.

Discussions of what constitutes a computer in this context or whether an nth order effect of a “random” process are just distracting.

Are you saying you are certain that human DNA was not purposefully manufactured?

Human DNA is a lonnnng way down below the timelines and processes we’re talking about buddy.

> Computers don’t arise randomly

You are right. They don't.

> we can be pretty sure it’s the result of random mumbling

If you throw construction materials up 1 quadrillion times, how many times can they randomly fall in the form of a house?

My response is zero. Building a house is not a product of randomness, it's a product of intelligence and will.

Life also can't be a product of randomness. There's some intelligence and will going on in nature's laws to make life happen.

Are you arguing that there was some direct intervention during the origins of life? Like, an intelligent being stuck a probe into a chemical mixture and tipped it towards generating cells?

Or, perhaps you're arguing that the rules of the universe were designed in a way that guaranteed that life would arise?

Something else?

More on line of the second thought, yes.

To me, Universal laws aren't random. If they were, I'd expect them to change from time to time.

These laws are immutable and inexorable. They respect, interact and cooperate perfectly with each other.

How did they come to exist and be that way if not by intelligence and will?

I have no idea how this works or came to exist, but it definitely doesn't look random to me.

They don’t cooperate perfectly; they cooperate somehow. They could be entirely different, and the life would look different - but there’s no reason to think it wouldn’t work.

Wouldn't this also have to assume a single universe. If our universe is just one of many, then randomness can still play an affect. We just happen to live in the universe with these laws. But the universe next door might have gotten a significantly different dice roll. Does that mean life isn't present there? No exactly, but I imagine it would look much different than us.

Our universe is single. The many concept is/was an attempt to make a square fit in a round hole when looking at some perplexing results. To me, Occam’s Razor points to intelligence arguments as simpler rather than the “multi universe” arguments

And what evidence do you base that on? The math shows it is possible for multi-universe. No hard evidence exists it. So couldn't just saying the math that alludes to this is wrong is just as equivalent of this square peg doesn't fit into my round hole?

And the universe also has a bunch of repeated structures, so why wouldn't a universe also be a repeated structure? A heart is a common one found in many different animals. They are each different in their own way, but it is a structure that is repeated. Same with atoms. They all follow the same basic structure, but it is repeated with just various configurations.

There is a physical theory which postulates that life is inevitable and a consequence of the laws of physics:

> The thermodynamic dissipation theory thus assgins an explicit thermodynamic function to life; the dissipative structuring, proliferation, and evolution of molecular pigments and their complexes from common precursor carbon based molecules under the impressed short wavelength solar photon potential to perform the explicit thermodynamic function of dissipating this light into long wavelength infrared light (heat). In a general sense, the origin of life is no different than the origin of other dissipative structuring processes like hurricanes and the water cycle, except that these latter processes deal with structuring involving hydrogen bonding while life deals with structuring involving covalent bonding. The external photon potential supplied continuously by the environment (our Sun), and its dissipation into heat by the assembly of dissipative structures, are, therefore, both integral components necessary for understanding life.

https://encyclopedia.pub/entry/6923

> The formula, based on established physics, indicates that when a group of atoms is driven by an external source of energy (like the sun or chemical fuel) and surrounded by a heat bath (like the ocean or atmosphere), it will often gradually restructure itself in order to dissipate increasingly more energy. This could mean that under certain conditions, matter inexorably acquires the key physical attribute associated with life.

https://www.quantamagazine.org/a-new-thermodynamics-theory-o...

If the origin of life is no different than the origin of hurricanes, could this be taken one step further to say that there might be some self- replicating wind phenomenon on some planet out there? We typically assume that life necessarily means self-replicating molecules, but why limit it to chemical processes?

wind is self replicating on our planet. it consumes energy from the sun and produces more wind.

Whether universal laws are self evident, random or intelligently designed is irrelevant to the discussion at hand though. The laws are there. It is through these laws that life arose. We have a procedural generation algorithm and a seed.

Even if you claim there is a single god that created both of these things, backwards deriving the seed necessary to generate the current state, it still routes through this physical process which is describable with physics and could be extrapolated to other starting conditions or future scenarios that humans can utilize.

It makes no difference.

I think it makes a difference in that we're discussing the origin of life.

Some argue the origin is in the - supposedly random - combination of molecules.

Others think the answer is deeper and relates to more fundamental aspects of nature.

No, you’re arguing for two separate acts of intelligent design. The laws of the universe and the formation of life. But the fact is that the latter is formable by randomness within the former. It is the expected outcome within our universe that stable structure propagate into something that doesn’t look or feel random. Whether you believe the entire universal rule system is intelligently designed is outside the observable scope of things for now so whatever. Sure. God, simulation, just being like it is. Whatever.

how do neural networks learn? is it by intelligence and will?

no, it's by backpropagation. error is propagated and minimized. simple equations lead to emergent complexity.

canyons form as water follows paths of least resistance, and incrementally erode rock. the water doesn't use its intelligence and will to construct a canal, even though the resulting river system looks like a max flow solution.

the intelligence and will emerges from the math. simple systems with enough feedback can become very sophisticated.

Do neural networks come to existence by random combinations of atoms?

We're not discussing how things act intelligently, but rather why, what's the origin of the intelligence in the process.

Some argue there's no intelligence, it's just randomness. Others think this is not a rationally acceptable explanation for what nature is showing us.

https://en.wikipedia.org/wiki/Anthropic_principle

That’s my point. Organic chemistry is not like your construction materials (or silicon computers). The organic chem functionality for nucleotides to begin organizing into repeating patterns exists. We know it does. And while we might not know the exact reactions that it took, they are highly likely to exist, and were arrived upon randomly.

If you arrange your biological soup a large number of times randomly, you will eventually land on a pattern that causes other nucleotides to arrange in a similar or improved pattern around it.

Not too dissimilar from thinking about the creation of specific atoms through various astronomical processes.

Even if you need to believe in god for some reason, it’s not incompatible with god defining the organic chemical reactions that enabled life to form via random interactions of nucleotides until they happened to land on god’s lucky number

And why is it that they can combine?

Because that’s how organic chemistry works.

And do you think randomness is a good explanation for how organic chemistry works? When you see it at work, does it even look random?

it's hard to make a non-trivial ruleset that isn't Turing complete. it's similarly hard to have a bunch of chemistry while precluding life forming.

> If you throw construction materials up 1 quadrillion times, how many times can they randomly fall in the form of a house?

It depends on what you call a house.

It will probably never fall in any given expected shape.

It may very well fall into multiple configurations that someone arriving at the scene after the fact, and without prior knowledge of what you expected when you run the experiment, would call a "house".

Would electricity from the grid run through wires into a power outlet?

Is photosynthesis a requirement for life?

In 20 trillion years, or even infinity, would you consider a rational expectation that electricity will ever flow from the grid through wires into a power outlet, by the work of randomness?

in infinite time, definitely.

It will never form a house. But it doesn't need to, and expecting it to is a misunderstanding of evolutionary processes.

What it needs to form is any kind of a shelter that is better than not a shelter. A 4x8 sheet of plywood that happens to lean against a brick forming a roof is all that is required for a first house.

Life is a product of randomness. There is no intelligence or will going on in nature's laws. Neither of those things are required.

With that line of reasoning, would we conclude that having H2O formed in the planet 4 billion years ago was a form of life better than not a life?

Would we conclude that everything in the Universe is alive?

I think that's a pretty interesting way of seeing things. And (to me, personally) it strengthens my view that there are intelligent processes going on in the Universe.

There is intelligence: solutions can replicate itself, with small variations, and the best variations will be more successful going forward. It’s not complete randomness, it’s an optimizing algorithm.

I was going to disagree with your definition of intelligence. But Wikipedia says "to retain it as knowledge to be applied towards adaptive behaviors within an environment or context", and certainly, in a way, evolutionary processes do indeed retain specific ways to do things that can be applied towards adaptive behaviors. So, yeah! :)

Throwing up materials that randomly fall into the shape of a crude shelter can certainly happen. But without a LOT of evolutionary mechanisms already in place, that crude shelter will just fall apart, and it certainly won't turn itself into something more sophisticated.

What is necessary for life to arise from a random stew of disorganized chemicals is far more than just a good arrangement of a few molecules that exhibit some characteristics of life. Since all life dies as part of the never-ending march toward entropy, you also need to be capable of some form of reproduction and able to carry out reproduction at a faster rate than death. What is the minimum complexity involved in such a thing? I'd argue that it's probably more complicated than any house in existence.

not really, any structure that can absorb energy and replicate could initiate life.

nucleotides spontaneously form, then start to bind to each other in chains. Those chains spontaneously fall apart and reform.

amino acids start to bind to the nucleotide chains and cause them to be more stable. Nucleotide chains bound to the amino acids have a longer life expectancy than those not bound to amino acids. The amino acids start to bind to each other (they naturally do). The RNA binding makes them slightly more energy efficient essentially catalyzing the reaction.

over millions or billions of years, random chaining of nucleotides leads to random chaining of proteins that are slightly more energy efficient. Those forms "outcompete" alternate forms.

Once a particular type of amino acid chain exists, it can influence other amino acid chains to follow the same structure. For example prions are extremely short but binding to normally folded versions of the protein causes the normal version to change patterns.

> over millions or billions of years

one of the interesting constraints is you don't have billions of years. Life appeared on Earth within 100 million years of the planet cooling down enough to have standing water, possibly even less, depending on your reading of the evidence that gets more disputed the farther back you go.

It took 2 billion years for prokaryotes to turn into eukaryotes, and it took another billion for eukaryotes to go multi-cellular, but somehow the initial development of a self-replicating cell with a code took less than a tenth of that.

> There's some intelligence and will going on in nature's laws to make life happen.

And how do you suppose the intelligence you refer to originated? You're not offering a solution, you're merely adding another layer of complexity that still needs an explanation along the same lines.

I'm not trying to explain, just expressing that, to me, randomness also doesn't explain. The fact that I see intelligent processes going on is what makes me conclude that.

Evolution is not randomness. It is running smaller incremental multiple randomlike experiments and only few pass to the next increment where again a lot of variations will be generated and again selected only some few for the next stage ...

So in your example with the house here is how it might be:

Throwing 1 quadrillion times materials will they arrange in a fundation? Of course. Then throw again and will there be some kind of wall or pillar?

Then you now have foundation and pillars. Throw again a huge number of times, will there be materials that might form a wall?

Please also take into consideration that evolution is not only in a vertical progression (from materials to house) but also running horizontally (like creating multiple types of walls of all shapes before going for a roof).

But more importantly evolution will not create a house as long as there is not need for one.

On the other hand, as we are poaching the limits of science: how do you know that given a close to infinite number of arrangements those materials will not arrange into a house?

> Evolution is not randomness.

Darwinian evolution in the narrow sense is duplication of life plus random variation plus filtering (that may also be random, but which at a minimum contains some bias which is, if not consistent over time, at least usually changes very slowly compared to the rate of random of variation.)

Darwinian evolution in the broad sense is the same thing, but without the “of life” part.

But abiogenesis is not Darwinian evolution in the narrow sense, and may or may not significantly involve Darwinian evolution in the broad sense, so arguing about what evolution is or is not in the context of the initial creation of life as opposed to the explosion of diversity of life after its initial creation is, at best, skipping steps.

Assembly theory from Sara Walker et al. takes a principled stab at questions like this using a combinatorial "assembly" framework of small constructions that recombine into larger ones. The model requires only Markov conditions so fits into this description of probabilities of observing certain assemblages.

Intelligence fits into this in interesting ways. One way to consider it is as a guide to the assembly process from less complex from more complex.

> Computers don't arise randomly

As if, contrary to that, humans do/did.

No, it's not as simple as that. The probability of self-replicating RNA arising by random assembly of bases is very low. There was a good Nature article [1] published a couple years back that digs through some of the numerical issues. (And a good, more layperson oriented summary as well [2].) The gist is that a self-replicating RNA sequence would have to be at least 40 nucleotides (and possibly even as long as 100), but the probability of randomly synthesizing a 40-nucleotide long sequence that happens to be self-replicating anywhere in the visible universe over the span of 13 billion years is effectively zero.

To be fair, the probability gets closer to one if you expand your view to include the entire universe and assume that it is many, many orders of magnitude larger than the visible universe. But my take away, at least, is that we are not dealing with a situation where random assembly of RNA is so likely to generate self-replicating sequences that abiogenesis was effectively an inevitability. That was the narrative I was sold in grade school and undergrad, but it appears to be wrong.

There are a good number of free parameters in the journal article that I linked: The fraction of RNA sequences that are self-replicating, the fraction of planets that are habitable for life, the average decay rate of RNA on a habitable planet, etc.

You take can take issue with the empirical estimates for those parameters, but that points to missing pieces in the framework: Was there a chemical process on early earth that stabilized RNA oligomers that no longer exists? Are self-replicating RNA sequences more common than we believe? If so, why haven't we encountered more of them in nature? And so on. In my opinion, these are the truly interesting questions, not whether nucleotides and amino acids can form spontaneously.

[1] https://www.nature.com/articles/s41598-020-58060-0

[2] https://mathscholar.org/2020/05/the-origin-of-life-in-an-inf...

Undiscovered mechanisms of self replicating RNA arising by chance seems very likely though. That’s my point. I agree there’s a lot of good questions to be answered. I think it is likely that we will answer them by staring at nucleotide soup.

>the probability [...] is effectively zero

Is that meaningful? No matter how unlikely our existence is, here we are.

>The probability of self-replicating RNA arising by random assembly of bases is very low.

But it parallelizes extremely well - throughout the entire universe for billions of years.

Or here on Earth over say 100 million years with trillions of little globs of organic chemicals, likely with even simpler replication mechanisms that are not understood currently.

Well, sure, but it wasn’t just Earth - literally everything in observable universe was involved in some complicated processes; it’s just that we came from a particular “branch” of this process and thus assume we’re the most extra special thing in the entire universe.

And then of course there’s https://en.m.wikipedia.org/wiki/Panpsychism.

Back up from that... how are the nucleotides formed? And don't they need energetic polyphosphate groups on them to drive the polymerization? And how does this work in an impure solution with all sorts of variant nucleotides and other cruft?

To my thinking, that means that self replicating systems arose in an even simpler chemical environment and even RNA was a later development.

What this is missing is that it assumes way too little structure. You don't have to generate a self replicating set of RNA. Many RNA strands (maybe most?) will do something, so all you need is to generate a strand of RNA that will eventually produce a self replicating set of RNA which is likely much easier.

> Are self-replicating RNA sequences more common than we believe?

Almost certainly yes.

> If so, why haven't we encountered more of them in nature?

Because they can't compete with modern life. Nearly all of the biomass on earth is in use. A primitive replicator, even if it arose today, would have to compete for resources against all the existing life on earth. It wouldn't stand a chance. This is the reason there is only one universal common ancestor. It's not necessarily that abiogenesis only happened once, it's that only the descendants of one common ancestor survive today. All traces of all other abiogenesis events have been obliterated.

You have to compute the abiogenesis odds for an environment that, by definition, does not yet include life. Here is a rough back-of-the-envelope approximation: the biomass of earth is about 2^52kg. Avogadro's number is 2^76. So there is the potential for the early earth to have 2^120 nucleotide bases and amino acid molecules floating around. If the complexity of a simple replicator is around O(100) bits then the odds of finding one by chance when you are rolling that many dice in parallel approaches 1 in just a few million years. After that, evolution takes over.

First, the majority of the biomass of the earth is water, not organic molecules, and big fraction of what's left is lipids and carbohydrates, not nucleic or amino acids. So a simple multiplication of biomass by Avogadro's number is likely off by at least an order of magnitude.

Second, yes, today's world has an enormous amount of amino acids and nucleic acids, but that is after billions of years of enzyme-catalyzed synthesis inside trillions of living cells. The prevalence of amino acids/nucleic acids prior to abiogenesis would have been orders of magnitude lower in a world where those enzyme pathways didn't exist yet and biologic molecules with catalytic activity were still in the process of being bootstrapped.

Third, does your back of the envelope calculation account for the very short half life of RNA? That is really the biggest issue. If RNA didn't decay, then forget about hundred base sequences; the primordial earth might have been filled with million base sequences.

> the majority of the biomass of the earth is water

The figure I cited is the carbon biomass.

https://www.visualcapitalist.com/all-the-biomass-of-earth-in...

> that is after billions of years of enzyme-catalyzed synthesis inside trillions of living cells

Doesn't matter. What matters is the size of the search space that could be explored by the chemistry, and if even a single replicator exists in that search space. The extent to which that first replicator resembles present-day life is irrelevant. The only reason to refer to that at all is to get some idea of what the information content of a minimal replicator is.

> Third, does your back of the envelope calculation account for the very short half life of RNA?

Again, it doesn't matter. As long as the half-life of the replicator is more than the time it takes it to produce >2 offspring, that's enough to get the ball rolling.

Where do the nucleotides come from?

Dr. Nick Lane is my favorite author on this subject. My reduced summary of a slide he presented titled "what is life" goes:

- free energy powers growth

- growth is thermodynamically favorable

- heredity is growth, doubling by exact copying

- growth combines carbon and energy metabolism

- growth is driven by environmental disequilibria

That doesn't explain away the mystery of the first RNA replicase, but I really like how it explains growth and doubling as a form a growth. That's copy-pasted from a newsletter draft I'm writing. It'll be posted next week on https://0123.substack.com

If you like Nick Lane's writing, I also recommend David Dreamer's Assembling Life. It gets a good deal more technical (chemical?), and has more depth about possible ways that membranes were "invented".

Paul Falkowski's Life's Engines is also quite good.

> We have a decent idea of how the first nucleic acids may have been synthesized,

Really? Nucleotides are already too complex to have been produced in any valid OoL experiment at more than vanishingly small concentrations. Experiments that demonstrate some chemical X can be produced, and then lead to another experiment where X is made available in pure form at high concentration (and then rinse and repeat down the synthesis chain), don't tell us anything interesting at all.

The whole point of the article was discussing how RNA isn't the orgin of life and we need to push our ideas back further.

RNA-Peptide coevolution is the spontaneous immergence of 'replicating' matter. No one molecule in the system has all the requisites for life, but as a whole they do. (I.E.amino acids and nucleobases can transmit information, replicate, move and 'sense' about the world). Pushing this idea of self-replicating orgiins of life back may illuminate the issue. RNA generation doesn't have to be random, it can be selected for like any other evolutionary proceses.

Finally, Listen to what you are saying... The rhetoric was much different 10 years ago.

We have scientifically narrowed the limit of what we can't explain, and this very small gap in our knowledge is what's left. We are making progress in understandng the origins of life.

I think you are grossly exaggerating the state of knowledge in the field. No, there's not a "very small gap" left. There's a lot of smoke and speculation and very little actually known.

There is also a staggering gap between nucleic acids existing, and just random atoms existing. And then an even more staggering gap between atoms existing, and nothing existing.

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