Most mutations are negative dead-ends, not unlikely DNA now where most pregnancies spontaneously abort due to errors. But life has many, many chances — especially at the molecular scale. So what’s the actual problem?
Similarly, if you have a soup of 10-15 nucleotide sequences, what are the odds actually that they’d link into larger segments?
Let’s suppose that density is a million times lower than blood, so you have one picogram per gram of water. There are 10^24 grams of water on Earth’s surface and 10 base pairs weighs 10^-20 grams, giving us approximately 10^32 segments of that length.
Feel free to play with my numbers, but I’m supposed to believe that with ~10^30 pieces, we can’t have ten of them form the right sequence?
A combinatorial explosion. To have mutations you need to have replication first. If a smallest viable self-replicator is, say, 100 nucleotides long, and there's not many other such replicators of the same length, the improbability of its spontaneous formation (~4^-100) dwarfs any amount of material available on Earth.
The researchers have found QT45 replicator. But it replicates other RNA strands, that is it needs another replicator nearby to replicate itself, which brings the probability down to 4^-90 range.
Life didn't have to start on Earth. It could have started on any one of an unbounded number of worlds. It's only in retrospect that this world seems special.
What's the probability of spontaneous formation across an infinite universe?
In an infinite universe even events with probability 0 can happen[1], but it's hard to find this explanation satisfactory. Any hypothesis that raises probability of abiogenesis to make it likely to happen at least in the observable universe looks more satisfactory than "but it could have happened anyway in an infinite universe despite being totally improbable."
If you mean panspermia specifically in respect to earth it's a lot more bounded in space and time to the parts that were close enough to interact with earth, but if not then yes there is probably anything that can be represented by atoms out there somewhere or other.
The simple combinatorial explosion criticism feels reductive to me. It's exceedingly unlikely that a single "self-replicating RNA molecule" formed independently by chance and then propagated.
Let's say that you have some RNA soup with some ribozymes some of which weakly encourage some reaction involving other RNA molecules. The occurrence of a cycle of reinforcing reactions might be sufficient to build a crude evolutionary ratchet.
In fact the "cycle of reactions" perspective feels a bit more robust to me since it allows for the proto-replication process to take place over a longer period of time and over larger areas.
Yeah, it's more probable a priory, but it still can be false. For example, such reaction chains might not lead to a sufficiently probable increase in complexity.
I doubt a replicator came out of thin air. It seems more likely, at least to me, that we started with constructors, that created primitive sequences.
Imagine you have molecules that can form spontaneously, like gliders in Conway's Game of Life. You may have several different molecules that are capable of helping to create one another -- an autocatalytic set.
Eventually this could result in more complex chains, and eventually a self replicating molecule can arise.
Imagine slamming a bunch of gliders together to make a machine that replicates more gliders. It's possible! Not likely, but there are so many variables that can influence the environment substantially. It's not like there was a giant homogeneous soup. Parts from over here and over there would form differently and when they meet, amazing things can happen.
In the Game of Life, this spontaneous event is extremely unlikely, astronomically unlikely.
Unlike Game of Life, the real world has a few advantages that improve performance. For one, it's less fragile. Bonds are much stronger and collisions don't cause everything to break. Another advantage is that bonds are attractive: molecules can rotate and turn to snap together strongly. Gliders just explode violently. And finally, the real world is very dense. We're talking trillions of molecules mixing around millions of times per second per microdroplet. Compound that with a few hundred million years... it certainly doesn't feel as surprising as you might expect.
If there were a highly advanced alien race watching earth over a long period of time, it might be interesting, but not unexpected, that suddenly an Eiffel tower springs forth from the surface of the planet, erected by intelligent organisms.
I also don't understand. Adding billions of years to your numbers probably makes it an even better point.
"Life's first molecule." Take your favorite quantum field theory and consider how it draws a line between a molecule and not a molecule. Consider how it draws a line between life or not. That'd be cool. Consider that it doesn't give a shit who did what first.
Your numbers are fine - but RNA is fragile; making one copy of something really rare will not be able to do anything as it will not last long enough to meaningfully contribute.
Interestingly we now are thinking about ways to use mutations in other ways, youve spent a lot of energy making these polymers, so it would be a shame to waste that right? We think that they can be used to assemble larger functional pieces as mutations are mostly deterministic meaning you'll get the same kinds of errors - so why not put them to use!
Early on that may have been a feature though, isn't it?
What strikes me as the most interesting thing about life is that almost immediately (on geological time scales) after Earth had developed an environment where life in theory could exist it came to be. That suggests strongly that the mechanism to do so was relatively simple. Then again, the Earth was a vast laboratory and it only has to happen once.
Fragility may indeed have been a feature as separating 2 RNA strands when they get even quite long (69 nt -> melting temp ~100 C) is almost impossible on the Early Earth and perhaps you just have to fragment long RNA to be able to reuse it. What we havent figured out yet is how to do that recyling - the 2,3cyclic phosphate that RNA terminates with when hydrolyzing is very stable!
Yes it is remarkable how seemingly quickly life started however most productive chemical reactions occurr on the order of hours and days so a couple of million years is still a long time to explore chemical space!
It seems obvious that if replication of elementary particles appears that everything else will be an emerging property given enough time. And if you look at atoms and math there're definite parallels that once atoms can interconnect stronger than everything else (considering the 3d world) and something like Penrose's tiles where you get repeating interconnecting structures that more higher level structures would be possible. And with energy connected to the particles momentum and Heisenberg's uncertainty principle you get fluctuations in the structures that allow for both new structures and enforcing of the construction rules. You also have clear levels between forces that work on different levels that create boundaries to the structures. 3 spacial dimensions give additional directions of interactions between structures. And voila, given conditions, there's a place for emerging properties. Whether it was RNA who knows. It does seem that the search becomes way murkier toward going into the actual mechanism but the ingredients seem to be in place
The hardest part of the transition from prebiotic chemistry (assembling the building blocks) to an 'RNA World' is doing so in a way that can support RNA copying. As others have shown the chance of finding one replicator is low - so you need supporting RNA copying chemistry at a pretty substantial level to help that happen.
This is where the hard part of the field is currently: finding chemistry that can support accurate RNA copying that is also both sufficiently high yielding and also compatible with these reactions being inside protocells (fatty acids for example). An RNA genome only really has value when it can be selfish and keep any innovations it makes to itself inside a protocell!
I work in Origins Research - if you have questions please ask and ill try to answer with the current opinions of the field!
Does the current SOTA believe that it's most likely that life originated on Earth? I know there are some theories that at least one of the critical building blocks was delivered via asteroid or other extra-terrestrial process.
But that doesn't answer the origin of life. Even if it came from outer space, it must have an origin somewhere. Currently, the science is focusing on the possibility that life originated here because the problem does not become easier to solve by considering another planet's environment.
Most people think that is the case yes but we have n=1 data points right? We are mostly in the business of learning the physical processes that create life like phenomena and not perfectly recreating how life arose on this planet - which seems unsolvable to any degree of satisfaction!
PS most asteroids that hit earth hit with such an angle and speed that pretty much nothing survives! When you read articles about finding building blocks of life on steroids it doesn't matter as they wont survive impact with a planet - its mostly just interesting that the chemistry is general enough to work in space and on earth!
For a long time, since I learned about how evolution works at the gene level, I’ve been bedazzled by sharks. Here is a configuration of genes which has reached such a sweet spot in the eyes of evolution that it has cruised mostly uncharged (modulo the shrinking due to change in oxygen composition) for hundreds of millions of years. Then I learned about the code of RNA (credit to Deutsch I think in his treatment of evolution in Fabric or maybe it was Beginning, I don’t recall) and my mind was blown! The actual knowledge encoded in the RNA sequence—†not the physical stuff; but the precise coded sequence—required for replication is actually quite ubiquitous across species and unchanged on timescales vastly larger than I had previously fathomed, mountains look like sand castles and sharks are brand new in the eyes of the code of RNA. This is only an analogy; but it felt like how Unix works: RNA is like the tiny kernel which has spread everywhere due to being tiny and good enough to solve the problem and therefore difficult to replace. Anyways, this is only a day dream since I’m not really in the weeds; but I wonder if you can correct any of my misconceptions. Like: RNA is like code for DNA replication, is it sort of like low-level machinery for life? Has the precise RNA code survived a really long time and it’s sort of like an old operating system which just keeps humming in the background? And it is older than sharks right? Any other cool stuff to recommend pursuing for someone like me who really loves evolution; but is just a layperson?
†one note about my em dashes: I am a real person who thinks evolution AND em dashes are cool and for a total aside: it’s such a bummer people think I’m a bot just because I like tinkering w/ f* punctuation marks.
> actual knowledge encoded in the RNA sequence—†not the physical stuff; but the precise coded sequence—required for replication is actually quite ubiquitous across species and unchanged on timescales
There is a chance that before 'LUCA' there were many dead ends and we ended up on the lucky branch by definition, and we don't actually know much about what happened before then so there is some possibility that what you are seeing there is the single largest example of 'survivorship bias'.
We have started to call the first life FUCA (First universal common ancestor)! There must have been much evolution before LUCA as we know that it had a complex metabolism and a sophisticated DNA genome - far more advanced than and RNA based life could probably achieve!
Yes, untold generations in between those two. What I'm wondering though: if we had a nice sample of 'FUCA' in a petri dish, would we even recognize it as life?
Yes, I often think about that scenario. It's interesting to think about it in a sort of like alternate history sort of way like 'what if Wang computer survived' or 'Xerox had commericalized Parc instead of giving the keys to the kingdom Apple'
It may just be that the life that ended up thriving on Earth isn't objectively the best for the environment but it just happens to be what won out by being at the right place at the right time and the better chemistry or body plan was at the wrong place at the wrong time and got hit by a meteor or some massive gas burst from the interior of the earth that wiped them out.
In that context it's neat to think about alternate biochemical systems that could be available to us provided that we can figure them out and that would have tremendous economic potential.
Yeah this is an interesting way to think about. In modern biology DNA still acts as long term data storage with RNA acting as a mostly transient species that while essential is slightly more disposable. However, we think that RNA probably satisfied both roles at the origin of life which simplifies many problems including the need for simultaneous synthesis of RNA and DNA building blocks, the segregated polymerization of RNA and DNA and any cross talk between them.
We have a lot of conserved RNA sequences because it has done a good enough job since LUCA (Last Universal Common Ancestor - 4.2 billion years ago!) and its been trapped epistatically ever since! Things like the ribosome (an RNA based machine that makes all our proteins) for example is very conserved across all domains of life from us to sharks and trees and bacteria!
I would recommend reading the primary literature and asking AI to help you fill in context that authors leave out!
Is there a reason why the alternative idea of closed autocatalytic sets from Stuart Kauffman doesn't get nearly as much attention or discussion as the RNA origin hypothesis?
Ever since I first learned about it, it seems to me a much more likely origin of life hypothesis, as it doesn't require something to catalyze itself, which causes inevitable problems with mutation causing loss of catalytic efficiency.
Also, it is not incompatible with RNA being one of the early building blocks. It just doesn't require RNA to be where everything started.
I don't think you can say this with certainty. It is assumed that life and evolution go hand-in-hand from the beginning but it is not proven to be the case.
It could be proven if there was a record found of something that predated the currently known fossilized bits from really long ago that would give a hint about how life at that stage was put together. This is highly unlikely to happen.
No, that isn't true. Life could have started out as something that accidentally happened and that did not require evolution, and then evolution itself could be the first mutation.
Evolution is actually the accumulation of errors that happen to have a beneficial effect. But that does not say anything about how it all began, that's just what we are seeing now. So there are two options: evolution was there from the beginning and is a requirement for the kind of life that came into being or it was an upgrade that came a little later.
“ Holliger’s team looked for catalytic activity in small RNAs (between 20 and 40 nucleotides in length), allowing for small changes in length in each cycle of mutation. They found a 45-nucleotide molecule that they christened QT45 (“quite tiny”) that could seize another RNA strand and copy it. “In principle it can copy any sequence,” Holliger said.”
Autocatalysis is essentially the goal of an RNA world right - we want an RNA that can make more RNA using RNA - autocatalysis. The problem with vague autocatalytic sets is they are very hard to find and if not also coupled to information storage their utility is limited. An innovation in a catalytic set is lost when conditions change - which coded information (RNA) does not suffer from!
To me the Closure of Constraints theory sounds the most promising, which is based partly from Kauffman. Life is very complex and interconnected. So any "this was first" theory has issues explaining complexity. Was it replication (RNA?) or cell walls or metabolism? Closure of constraints gives a path forward where everything evolves together and nothing complicated has to be first (except "closure"). What was first? All of the key functions were equally "first", but in simpler forms and provided by the environment not the organism. So we don't need a complicated self replicating molecule, replication is provided by the environment, not the closure being replicated. Slowly over time, more and more functionality shifts from environment to the closure.
suddenly, the speculative possibility of intelligent design becomes more plausible as we enter the realm of nanotechnology ourselves. Who knows how, what, or where life had started, but we might be the second version.
this kind of speculation only moves the needle forward, the main question remains: even if life on earth is part of an intelligent design experiment, how does life in this intelligent entity world began in a first place?
I think the biggest unresolved question isn't whether RNA can replicate itself, but how you get from occasional replication to a self-sustaining system
> There’s scarcely any corner of Earth in which life hasn’t gained a foothold[..]
About that, not that long ago I was entertaining the idea of what environments can be completely devoid of life. I was thinking about examples like a volcano Cauldron, a nuclear reactor or the insides of a particle accelerator.
When I read about self-replicating RNA I always think about the equivalent in the protein world, the prions. One can make many parallelisms with these scary proteins, responsible of the Creutzfeldt-Jakob disease.
Of course, the are too many limitations for evolving into some more complex, but they can self-replicate and they can infect other organisms. If we could give them an oceanic soup of PrPC and enough time, who knows?
Prion "replication" seems rather different from self-replicating RNA.
Isn't the building block that a prion requires to create a copy of itself essentially a chemically almost-identical protein that is just folded differently?
How about an alternative analogy of the prion folding pattern spreading through chemically-similar molecules like a meme through a population of similarly conditioned brains?
Yes, I agree and that is why I mentioned that there are limitations. It really depends how one interprets "replication" and that the ingredients needed to self-propagate are to be considered valid building blocks for the beginning of life or not. As far as I know, RNA would use nucleotides and prions similar already existing complex proteins. It seems that the RNA hypothesis is more plausible. However, I just found out that there's some that actually believe that life started with prions and not RNA since proteins are more stable. Although
I like your analogy memes and prions need an already existing condition and then twist them into something else. If we are allowed to enter the philosophical domain, it's like the devil's work twisting the mind of the righteous or the Sith turning the force-sensitive beings :-)
The big problem I have with the RNA world idea, and its experimental implementation, is that it runs in a soup that doesn't seem plausible.
RNA gets made from pure, energy-rich molecules that themselves are quite complex. This soup of pure monomers isn't something that just arises naturally in the absence of life. Prebiotic chemistry produces a random soup of a wide variety of chemical species, with the abundance of each declining exponentially in its size and complexity.
You see this issue all the time in origin of life claims. For example, that recent result of "all the bases of RNA and DNA were found on this asteroid by the Japanese" tended to slide over the fact that they were there at extremely low levels, mixed with huge numbers of other non-biological organic molecules.
Trying to replicate RNA in a mix of random crap will just give you polymers of crap.
OoL needs an idea that will work in a soup of junk, not in massive artificial pure soup on a lab bench.
53 comments
[ 0.24 ms ] story [ 29.5 ms ] threadMost mutations are negative dead-ends, not unlikely DNA now where most pregnancies spontaneously abort due to errors. But life has many, many chances — especially at the molecular scale. So what’s the actual problem?
Similarly, if you have a soup of 10-15 nucleotide sequences, what are the odds actually that they’d link into larger segments?
Let’s suppose that density is a million times lower than blood, so you have one picogram per gram of water. There are 10^24 grams of water on Earth’s surface and 10 base pairs weighs 10^-20 grams, giving us approximately 10^32 segments of that length.
Feel free to play with my numbers, but I’m supposed to believe that with ~10^30 pieces, we can’t have ten of them form the right sequence?
A combinatorial explosion. To have mutations you need to have replication first. If a smallest viable self-replicator is, say, 100 nucleotides long, and there's not many other such replicators of the same length, the improbability of its spontaneous formation (~4^-100) dwarfs any amount of material available on Earth.
The researchers have found QT45 replicator. But it replicates other RNA strands, that is it needs another replicator nearby to replicate itself, which brings the probability down to 4^-90 range.
What's the probability of spontaneous formation across an infinite universe?
[1]https://en.wikipedia.org/wiki/Almost_surely
Let's say that you have some RNA soup with some ribozymes some of which weakly encourage some reaction involving other RNA molecules. The occurrence of a cycle of reinforcing reactions might be sufficient to build a crude evolutionary ratchet.
In fact the "cycle of reactions" perspective feels a bit more robust to me since it allows for the proto-replication process to take place over a longer period of time and over larger areas.
Imagine you have molecules that can form spontaneously, like gliders in Conway's Game of Life. You may have several different molecules that are capable of helping to create one another -- an autocatalytic set.
Eventually this could result in more complex chains, and eventually a self replicating molecule can arise.
Imagine slamming a bunch of gliders together to make a machine that replicates more gliders. It's possible! Not likely, but there are so many variables that can influence the environment substantially. It's not like there was a giant homogeneous soup. Parts from over here and over there would form differently and when they meet, amazing things can happen.
In the Game of Life, this spontaneous event is extremely unlikely, astronomically unlikely.
Unlike Game of Life, the real world has a few advantages that improve performance. For one, it's less fragile. Bonds are much stronger and collisions don't cause everything to break. Another advantage is that bonds are attractive: molecules can rotate and turn to snap together strongly. Gliders just explode violently. And finally, the real world is very dense. We're talking trillions of molecules mixing around millions of times per second per microdroplet. Compound that with a few hundred million years... it certainly doesn't feel as surprising as you might expect.
If there were a highly advanced alien race watching earth over a long period of time, it might be interesting, but not unexpected, that suddenly an Eiffel tower springs forth from the surface of the planet, erected by intelligent organisms.
Because we have segments of 10-15 length that stably form and a large body of that combinatorical space is excluded by that.
We’re only looking for replicators over those stable segments.
Using your raw numbers, 400M years for abiogenesis, you get something like 10^46 attempts.
So the question is does having stable 10-15 length segments reduce the difficulty of assembly from completely random assembly, by ~10^15.
"Life's first molecule." Take your favorite quantum field theory and consider how it draws a line between a molecule and not a molecule. Consider how it draws a line between life or not. That'd be cool. Consider that it doesn't give a shit who did what first.
"given any word, there's no such thing"
Interestingly we now are thinking about ways to use mutations in other ways, youve spent a lot of energy making these polymers, so it would be a shame to waste that right? We think that they can be used to assemble larger functional pieces as mutations are mostly deterministic meaning you'll get the same kinds of errors - so why not put them to use!
Early on that may have been a feature though, isn't it?
What strikes me as the most interesting thing about life is that almost immediately (on geological time scales) after Earth had developed an environment where life in theory could exist it came to be. That suggests strongly that the mechanism to do so was relatively simple. Then again, the Earth was a vast laboratory and it only has to happen once.
aside: you have the most interesting job!
Yes it is remarkable how seemingly quickly life started however most productive chemical reactions occurr on the order of hours and days so a couple of million years is still a long time to explore chemical space!
This is where the hard part of the field is currently: finding chemistry that can support accurate RNA copying that is also both sufficiently high yielding and also compatible with these reactions being inside protocells (fatty acids for example). An RNA genome only really has value when it can be selfish and keep any innovations it makes to itself inside a protocell!
I work in Origins Research - if you have questions please ask and ill try to answer with the current opinions of the field!
PS most asteroids that hit earth hit with such an angle and speed that pretty much nothing survives! When you read articles about finding building blocks of life on steroids it doesn't matter as they wont survive impact with a planet - its mostly just interesting that the chemistry is general enough to work in space and on earth!
†one note about my em dashes: I am a real person who thinks evolution AND em dashes are cool and for a total aside: it’s such a bummer people think I’m a bot just because I like tinkering w/ f* punctuation marks.
Good source that develops on this?
https://en.wikipedia.org/wiki/Ribosomal_RNA#Sequence_conserv...
It may just be that the life that ended up thriving on Earth isn't objectively the best for the environment but it just happens to be what won out by being at the right place at the right time and the better chemistry or body plan was at the wrong place at the wrong time and got hit by a meteor or some massive gas burst from the interior of the earth that wiped them out.
In that context it's neat to think about alternate biochemical systems that could be available to us provided that we can figure them out and that would have tremendous economic potential.
We have a lot of conserved RNA sequences because it has done a good enough job since LUCA (Last Universal Common Ancestor - 4.2 billion years ago!) and its been trapped epistatically ever since! Things like the ribosome (an RNA based machine that makes all our proteins) for example is very conserved across all domains of life from us to sharks and trees and bacteria!
I would recommend reading the primary literature and asking AI to help you fill in context that authors leave out!
Evolutionary theory: https://www.nature.com/articles/227520a0
Origins research: https://www.nature.com/articles/35053176 https://www.science.org/doi/abs/10.1126/sciadv.aax3419
Ever since I first learned about it, it seems to me a much more likely origin of life hypothesis, as it doesn't require something to catalyze itself, which causes inevitable problems with mutation causing loss of catalytic efficiency.
Also, it is not incompatible with RNA being one of the early building blocks. It just doesn't require RNA to be where everything started.
I don't think you can say this with certainty. It is assumed that life and evolution go hand-in-hand from the beginning but it is not proven to be the case.
Evolution is actually the accumulation of errors that happen to have a beneficial effect. But that does not say anything about how it all began, that's just what we are seeing now. So there are two options: evolution was there from the beginning and is a requirement for the kind of life that came into being or it was an upgrade that came a little later.
About that, not that long ago I was entertaining the idea of what environments can be completely devoid of life. I was thinking about examples like a volcano Cauldron, a nuclear reactor or the insides of a particle accelerator.
Of course, the are too many limitations for evolving into some more complex, but they can self-replicate and they can infect other organisms. If we could give them an oceanic soup of PrPC and enough time, who knows?
Isn't the building block that a prion requires to create a copy of itself essentially a chemically almost-identical protein that is just folded differently?
How about an alternative analogy of the prion folding pattern spreading through chemically-similar molecules like a meme through a population of similarly conditioned brains?
https://www.youtube.com/watch?v=K0K-pMPFzGY
I like your analogy memes and prions need an already existing condition and then twist them into something else. If we are allowed to enter the philosophical domain, it's like the devil's work twisting the mind of the righteous or the Sith turning the force-sensitive beings :-)
Sorry, I went off the rails.
RNA gets made from pure, energy-rich molecules that themselves are quite complex. This soup of pure monomers isn't something that just arises naturally in the absence of life. Prebiotic chemistry produces a random soup of a wide variety of chemical species, with the abundance of each declining exponentially in its size and complexity.
You see this issue all the time in origin of life claims. For example, that recent result of "all the bases of RNA and DNA were found on this asteroid by the Japanese" tended to slide over the fact that they were there at extremely low levels, mixed with huge numbers of other non-biological organic molecules.
Trying to replicate RNA in a mix of random crap will just give you polymers of crap.
OoL needs an idea that will work in a soup of junk, not in massive artificial pure soup on a lab bench.