Algorithm discovers how six molecules could evolve into life’s building blocks
chemistryworld.com
chemistryworld.com
Every new form of life tends to fill successively smaller niches. There are more prokaryotes than eucaryotes, more singe celled than multi celled etc. but there is nothing in between the primordial chemical soup and the simplest life forms. I would expect a huge mass of simple RNA based life forms simpler than prokaryotes.
One with no complex lifeforms but sufficient resources to support life seems like the obvious answer.
Also, you can't really ignore the transformative effect that life has had on all environments (underwater and on land) in terms of chemical composition. Less water, less oxygen, etc.
Presumably the evolution of cellular life was synergistic with the evolution of the environments on the planet?
This is the (by far!) most prevalent expert opinion.
Analogy #2: your great-great-...-great grandparents of 10,000 years ago unquestionably existed, but show me any direct evidence they did. You can't. All signal is gone.
From what I can tell, the best science right now is that if you simply put enough neurons in the same place, they'll start questioning the universe.
Why do these building blocks in some circumstances do anything? Why do they make life, or sentience, or even something to reproduce when the building blocks don't need to reproduce at all - nothing new is created or destroyed just the same building blocks being recycled in different configurations. Why would the building blocks go beyond the mere reproducing-life to something that thinks unnecessarily? All an accident that we can appreciate?
From another, thinking is as necessary as anything can be. We observe thinking, therefore it exists. Anthropic principle.
More complex life is more anthropic than simple life and is then an eventuality.
Why are ribonuclease enzymes so omnipresent?
Is this the only reason why RNA is so difficult to work with, or are there other technical hurdles that are more difficult to overcome?
Are we missing a big piece of the biological puzzle because of this?
Any recent developments in this area?
I haven’t heard of any recent developments — it’s been a decade since I was in grad school and now I build software — but I briefly studied a subcategory of ribozyme called self-splicing group I introns which is where my interest comes from.
[0] https://en.m.wikipedia.org/wiki/Ribonuclease
[1] https://en.m.wikipedia.org/wiki/Group_I_catalytic_intron
Huh... today I learned. I didn't realise we have such "low-level" immune defences, I always just assumed that the simplest defence we had were antibodies.
When I was in grad school my default assumption was that ribozymes (catalytic RNA) are far more abundant than we currently know. RNA just very difficult to work with so there’s a selection bias against our ability to measure its behavior in vivo.
Yes, we are RNA organisms that have been incorporated into larger organisms, just as we are prokaryotes that have been incorporated into eukaryotes through endosymbiosis.
https://evolution.berkeley.edu/evolibrary/article/_0_0/endos...
As much as 8% of our DNA was laterally transferred from viruses! In a sense, some infections result in a symbiosis with a host.
Type 4 secretion system: ii- Pilus biogenesis
Even if cellular life has a huge evolutionary advantage we should still find pockets of original life somewhere.
Famous case in point are the Ediacarean fossils in Newfoundland, the first known multicellular organisms. No descendants live today, they are completely extinct. Without these fossils we wouldn't even be aware of this branch of the evolutionary tree.
Also, it is a logical necessity that the transcription of RNA into proteins, including the ribosomes and the transfer RNAs appeared only later than the replication of RNA.
The part of the RNA world hypothesis that seems unlikely because it has very few supporting data is that the original biocatalysts a.k.a. enzymes were RNA molecules unlike anything that exists today.
In my opinion, it is far more likely that the first enzymes were non-ribosomal peptides, somewhat resembling to parts of the proteins that constitute the enzymes of recent life forms.
ATP and other nucleotides must have existed before RNA as a means to perform condensation (i.e. dehydration) reactions and the copolymerization of the nucleotides must have appeared as some undesirable side reaction, which somehow at some point generated some sort of self-replicating RNA, which was in fact the first virus, because its synthesis could not have any beneficial effects for the hosting life form.
Only after the appearance of the transcription of RNA to proteins, the RNA could evolve into a source of components for the hosting life form so that RNA could change from a parasitic entity to an essential part.
Life forms with RNA (and later with DNA) are analog with microprogrammable processors, because the nucleic acid molecules are memories which direct the synthesis of other components, so you can change the components by writing a different information in the memories, without changing the synthesis machinery. This kind of flexibility was certainly necessary for further evolution.
Life forms before RNA are analog to hard-coded processors. Supposing that they were made with non-ribosomal peptides, there must have been a mechanism by which a complete life form was replicated, by a cycle of reactions were some kinds of peptides were assembled by other kinds of peptides.
Non-ribosomal peptides exist even today in all living beings and they are assembled in the correct sequence from amino-acids without depending directly on the information stored in nucleic acids, like the proteins.
Memories, like nucleic acids, are certainly not necessary for designing an ensemble of molecules able of self-replication, exactly like a memory is not necessary for implementing the control automaton of a processor.
Nevertheless, it is likely that the further evolution of such a primordial life form was almost impossible, because all accidental changes in the structure of the component molecules would have resulted in a replication failure.
After the separation of functions between a memory (nucleic acid) and a generic synthesis machine, evolution by changing the memory content became much more likely to be successful.
> the original biocatalysts a.k.a. enzymes were RNA molecules unlike anything that exists today.
Why “unlike anything that exists today”? Catalytically active RNA is still ubiquitous and well preserved across kingdoms (they’re some of the most ancient mechanisms for which we have phylogenetic evidence).
> it is far more likely that the first enzymes were non-ribosomal peptides
Peptides are good catalysts but they lack a high-fidelity copying mechanism so they’re not good raw material for evolution.
Taken together, your hypothesis seems to be based on a disbelief that RNAs lost their catalytic capability (which isn’t actually the case), but conversely you readily accept (without any evidence) that peptides used to have replication capabilities that were lost without a trace.
> Non-ribosomal peptides exist even today in all living beings and they are assembled in the correct sequence from amino-acids without depending directly on the information stored in nucleic acids, like the proteins.
Can you give an example of a catalytically active polypeptide which is assembled without any RNA template? I can’t think of any.
> Memories, like nucleic acids, are certainly not necessary for designing an ensemble of molecules able of self-replication
No, but what’s necessary is some kind of structure that records bits of information in some kind of order, and a mechanism for reading and writing this. Individual oligopeptides are fundamentally insufficient, you need structures capable of larger assemblies, and the information of these assemblies needs to be recorded. RNA elegantly solves both these requirements. DNA solves the storage requirement but is a very bad catalyst. Peptides solve the catalytic part of the requirement but are bad information store (prions can store specific configurations but they don’t seem to generalise).
It’s hard to overstate how important this information storage requirement is for evolution — arguably much more important than even marginally efficient catalysis. To the extent that some (admittedly far-fetched) hypotheses for early life even posit carriers such as clay minerals [1] which have, to a close approximation, zero catalytic capability — simply because they’re such an attractive medium for storing information (in the form of crystal lattice surfaces), high fidelity replication (through deposition of a new layer of minerals), and mutation (through structural modifications of the surface which are carried over through generations).
While the known functions of catalytic RNA are indeed, as you say, ubiquitous, very important and they certainly were already present in the last common ancestor of all present cellular living beings, none of those functions are likely to be so ancient as to have existed in the first life forms.
The nucleotides that compose a RNA molecule do not have chemical properties that are different enough to allow RNA to have a versatility comparable with the peptides/proteins, which can be used to make catalysts for a much wider range of chemical reactions and which can be attached to membranes for some of the most important functions, e.g. for ionic pumps.
While the number of amino-acids must have been much smaller in the beginning, it is likely that about 6 were already in use, i.e. alanine, a hydrophobic (valine), an acid (aspartic), an alcohol (serine) and 2 with unusual forms (glycine and proline) that can determine how the peptide will coil and fold.
The variety of amino-acid properties, even in the minimal set, allows the implementation of much more functions than can be imagined for RNA.
I am not aware of an example of a catalytically active polypeptide which is assembled without any RNA template, but that is not very relevant, because there is no doubt that, after the appearance of the transcription of RNA into proteins, most non-ribosomal peptides must have been replaced by more complex proteins, which were able to perform a more specific and faster catalysis.
I do not agree that "what’s necessary is some kind of structure that records bits of information in some kind of order".
On the contrary, this is what is impossible to have existed and it is the main reason why RNA must have been a later invention, after self-replicating life forms already existed for a long time.
What I say here about RNA, is valid for any other kind of molecular memory, so it is unlikely that any other polymer was used before RNA, as in some hypotheses.
Any other function of RNA besides the self replication of the RNA molecule must have appeared only much later, after a long evolution of RNA.
The reason is that even if any kind of useful RNA molecule, e.g. a catalytic ribozyme, ever appeared earlier, it disappeared without descendents, because it was not replicated.
So, if the RNA replication was the first function, that requires both the presence of ATP and of the other nucleotides and of some macromolecule that will catch the nucleotides and link them into the RNA molecule, using as a template the RNA that is replicated.
Even if we assume that the actual catalyst of the RNA replication was also a RNA molecule, that leaves open the source of the component nucleotides.
There must have already existed a catalytic system that transformed the simple precursors from the environment into ATP and other nucleotides through a long chain of reactions.
There exists no other better hypothesis for the nature of those catalysts than that they were non-ribosomal peptides resembling the active segments of the present-day enzymes that are used for those reactions.
Like I have already said, it is a logical impossibility for any kind of information-recording molecular memory to have existed since the beginning.
The way how the still existing non-ribosomal peptides are assembled in the correct sequence in the present-day organisms is not known well. Also the way how membranes are assembled is not known well. We have much less information about these than about nucleic acid replication and protein synthesis, for which a large number of investigative tools have been developed.
In any case, it is possible to imagine (and I believe that the attempt to design such a system would be a worthy research subject) a self-replicating system without any molecular memory, where some kind of peptides directed the assembling of another kind of peptides, which directed the assembling of another kind of peptides and so on for several steps, until the cycle was closed and the last kind of peptides directed the assembling of the first kind.
Of course, that must not have been just a simple cycle but a network of reactions, to generate all the components of the life form, but the network of reactions must have included all the cycles required to ensure that the complete replication of the life form is done.
In conclusion, you are right about "how important this information storage requirement is for evolution" and I have already written in a previous post that the evolution of the complex living beings of today could not have happened without the invention of a molecular memory.
Nevertheless, it is impossible for any such information storage mechanism to have already existed since the origin of life.
A primordial soup, without the precision enzymes and constant energy expenditure of this synthetic machinery, will be a grab bag of random glop. In Miller-Urey experiments the concentrations of any particular chemical decline exponentially with the number of atoms in that chemical. I believe ribose has never been seen in any such experiment (and certainly not in any but extremely low concentration), never mind the triphosphorylated nucleotides that provide the energy to drive RNA synthesis.
This is an interesting perspective.
Following this line of reasoning, prokaryotes must be close to the simplest unit that can self-replicate and grow to fill the planet. The simpler “proto-life” forms before that built up complex molecules by chance but could never quite achieve a replicative cycle.
Perhaps the closest to a huge mass of simple RNA based life forms that still exist today are viruses.
That aside, people have argued that the viral particle is like a gamete, which is also an incomplete stage of life unable to replicate itself. It would be like calling a sperm a human and saying humans are therefore parasitic and not living. A virus's primary life stage is lived within the environment of the cell which it commandeers, and from where it sends its progeny. The whole commandeered cell is the viral organism, and very much living.
My outlook is that things just exist in some higher dimension but because we perceive things in 3D we wrongfully assume there needs to be a start/end.
Look inside a box of mirrors at the infinitely repeating pattern and ask yourself where it begins/ends?
Curious to hear how other people rationalize the irrational.
It, like every proposed answer to the existential question, is both unverifiable and unrefutable, making pondering it somewhat pointless. Though it is good to know even our proposed higher-dimensional overlords haven’t solved the problem of leaky abstractions!
https://en.wikipedia.org/wiki/Proof_that_%CF%80_is_irrationa...
I think the big question is why we experience the existence of matter.
This is a thought I've often had as well. Like we exist on an X-Y coordinate plane, but there's a Z axis we just can't access. Particles popping into and out of existence? Just moving along the Z axis (our entire existence is on a single scalar value on that axis). GR and the "warping of spacetime"? Well, the bowling ball on a trampoline analogy obviously requires an extra dimension beyond the 2D trampoline surface to warp into. EPR and Bell's Theorem, viz no local hidden variables? Well, there's the non-locality. I'm not a physicist and this is all obviously a vast oversimplification, but it just seems that so many fundamental questions are confounding because they all seem to point to a missing degree of freedom.
Don't come up with weird ass theories and posit them as true or even "possible". Things we don't have good evidence for, at best, can be said to be "an intriguing idea". They are fun to ponder, and help us consider what possibilities could lead to better descriptions of the cosmos, but they don't lead to any actual understanding of what is real
So the best thing for a lot of these questions is to get good at going "I don't know" and instead trying to understand what we do know. We have a bunch of problems to solve about the universe (dark matter / quantum gravity) that may change the nature how we might even ask this kind of question. So I mainly focus on what's the most we can know with reasonable certainty at the moment.
There's a view that the early evolution of "life" involved metabolic cycles that were not yet bounded in cells, but perhaps in increasingly constrained geological boundaries. So for example, early precursors to the Krebs Cycle may have started within oceans, or perhaps some arrangement of pools and geysers or other geological features. So in essence, early life was bounded not in membranes, but within the flows of rock and air and heat of the atmosphere itself.
For more citable references to this stuff, this podcast episode from the Santa Fe Institute touches on it: https://complexity.simplecast.com/episodes/40
On Earth, there was a lot of primordial soup, and there were a lot of chemical reactions. On a span of millions of years, complex data structures (such as RNA) may have occurred constantly somewhere on the planet. Every now and then, a cell randomly formed. Sometimes prokaryotes with RNA formed, like weird things in Conway's game of life. And then maybe once upon a time, a cell with just the right RNA to make it be able to reproduce in the ooze formed.
That or life on Earth is panspermic and we have skipped the pre-prokaryotic evolution altogether
This is tricky. Conway's rules are "simpler" but far more rigid (e.g. tractable/computable). In real life, we deal with not just plain ol' turbulence (Navier–Stokes three-dimensional existence is yet to be proved), but also quantum effects (some of which might also not be computable, such as entropy in a Hamiltonian system).
Want to point out that this is much more than simply "random" constraints (the universe isn't merely a probabilistic machine). These are not (or at least might not be) computable constraints; any comparison with Conway's Game of Life stops right there.
Greg Egan discusses a similar idea with his concept of the "Autoverse"
That’s what life is inside all our cells. Just a bunch of molecules bashing around randomly but because it’s all the right ingredients in there, the right things find each other and fit together and somehow it still works.
Movement at the level of sports won't cause well-mixed cells - their fundamental frequencies are too different.
But actually moving around a lot wouldn't make a difference if the bits in your cells are moving around at hundreds of miles per hour.
Yes, a lot of science has "thought of" at looking intra-cell. In fact, the explanation of "don't shake their cells enough" must be very fringe because I haven't heard it any one time before from any serious scientist or a health book etc. The human body is much more complicated, and the way we understand many of the functions of it, including healthy functions, are based on biochemistry, both intra-cell and throughout the body.
Also "shaking the cells" can't even be that important physically, when you compare the speeds at which the limbs move during running to the base speeds of molecules inside the cell due to basic heat-based brownian motion.
When you see an animation of a cell, it's puzzling how the right molecule shows up in the right place. But in reality, a typical enzyme collides with something to react with 500,000 times per second just from random motion.
I wrote a blog post discussing this in more detail: http://www.righto.com/2011/07/cells-are-very-fast-and-crowde...
A cell is similar (since it is 60% water), but with many other types of molecules as well.
But that is obviously a misconception. Vacuum is not attracting anything, it is the fast moving molecules around it that PUSH themselves into the vacuum if we make a whole in the container.
What makes it hard to visualize is that we don't see the fast-moving molecules ever, which are forcing themselves into the container through the pierced hole by the power of their own (tiny) momentum yet very fast speed. :-)
It is also counter-intuitive that tiny things could have fast speeds, perhaps because we think in terms of a person being able to walk much faster than say an ant.
Found out much later — tag so many amino acids, that it would stumble on ribosome. Genius.
Most chemistry is like that though isn't it? Everything is flying around randomly but the electron density distributions mean some "bonds" have better probability of being broken and made during reactions.
The insides of the simplest cell are far more complicated than any production line.
Thank you.
There are several other publications on this subject by Nick Lane, which can be easily googled, and all of them are good.
They are somewhat incomplete, because there are parts that are not covered, especially about what is known on the metallic catalysts that were required for the emergence of life, but overall, the Nick Lane publications are the best from what I have seen.
There is such a mass: viruses. As such, we know that cellular life has evolved multiple mechanisms to efficiently kill external RNA.
If cellular life can efficiently outcompete non-cellular life for resources (and perhaps for RNA itself), then this outcome is not unreasonable at all.
Counter-example: There are (far) more Homo sapiens on the planet than other primates in total.
You could mix every amino acid, every nucleoside, all known sugars, a bunch of phosphate and any metal salts you'd like in a giant flask, stir for a long time and end up with nothing even close to a self-replicating system at the end of it all.
An origin of life requires an organizational leap that's quite nebulous at this point. Somewhere between building blocks and membranes is the place to be looking for chemical systems that start to show signs of self-propagation.
Also it seems some of the reactions created in this study do “self replicate” in some sense. In the sense that some of the chemical reaction cycles they found self reinforce and create more of the original molecule.
1) There are things too complex to understand without brute computation
2) Complexity is unbounded
3) Our current method of calculation would require all the energy in the known universe to even calculate a human being’s wave function...
Only under the action of such a continuous flux, complex systems may emerge. The simplest example is the appearance of oscillations when you attach a source of energy to various simple arrangement of devices.
For the appearance of life, besides the continuous flux of energy and simple molecules, catalysts were required, which must have been metallic sulfides, mainly of Fe, Co and Ni.
If we would reproduce such a setup now, a large variety of organic compounds would be synthesized. A similar process can be used to obtain synthetic gasoline.
Nevertheless, for the unlikely event of creating a self-replicating system, a very long time will be needed and also the chance of the right combination of metallic sulfide catalysts being located in close proximity and the chance of favorable proportions of the precursors in the flux of gases.
For now, we do not know enough to be able to estimate how likely or unlikely was the appearance of life, but we know that it was possible (I mean we know that this is possible from chemistry, independently of the fact that we know that we exist).
Such an estimation would become possible only after someone will succeed to design a self-replicating system similar with the first life forms.
The first life forms probably not only did not have nucleic acids but also did not use yet phosphate in any way and they were not cellular but they were attached on the surface of minerals. At some point, but probably later than achieving replication, they might have had the form of membranes closing pores of minerals in hydrothermal vents, before the membranes became able to close, forming cells with an interior separated from the exterior. Closed cells could appear only after having a more complex metabolism and various kinds of ionic pumps, while the earlier membranes closing mineral pores could passively exploit the ionic fluxes of the hydrothermal vents.
Nowhere in nature does any cell create a membrane de novo. So far as has been discovered, membranes are always produced by extending an existing membrane. So, arguably, life is that aboriginal membrane extending itself, and picking up helpful molecules on the way.
One thing I'm still unclear about though: Isn't it the case that these RNA-copying molecules are made of proteins? If so, I assume that another necessary ingredient would be the existence of proteins that synthesize new proteins according to what is written in RNA molecules (and also: RNA molecules that describe such synthesizing proteins).
When we talk about the origins of life we need to assume simpler processes. It has lately been discovered that RNA molecules can operate directly as both enzymes and structure. Notably, RNA molecules have been lab-evolved that can transcribe and copy other RNA molecules, given a ready supply of amino acids.
Similarly, in the beginning, we had hot oceans where monoxides, dioxides, and carbon were pressed against volcanic rock, creating chains of fatty acid. When those fatty acids broke off from the rock and floated in the water, their ability to repel water altered the chemistry around them, leading to protocells.
For more details, watch the video I linked. It's not long and it should be accessible for all ages. It's got great animations, too.
> Folding@home (FAH or F@h) is a distributed computing project aimed to help scientists develop new therapeutics to a variety of diseases by the means of simulating protein dynamics. This includes the process of protein folding and the movements of proteins, and is reliant on the simulations run on the volunteers' personal computers.
"AlphaFold: Using AI for scientific discovery" (2020) https://deepmind.com/blog/article/AlphaFold-Using-AI-for-sci...
https://www.kdnuggets.com/2019/07/deepmind-protein-folding-u... :
> At last year’s Critical Assessment of protein Structure Prediction competition (CASP13), researchers from DeepMind made headlines by taking the top position in the free modeling category by a considerable margin, essentially doubling the rate of progress in CASP predictions of recent competitions. This is impressive, and a surprising result in the same vein as if a molecular biology lab with no previous involvement in deep learning were to solidly trounce experienced practitioners at modern machine learning benchmarks.
Citations of "Resource-efficient quantum algorithm for protein folding" (2019) https://scholar.google.com/scholar?cites=1037213034434902738...
Protein folding: https://en.wikipedia.org/wiki/Protein_folding
We've got recently pretty good and reliable estimations of these:
R∗ = the average rate of star formation in our galaxy
Fp = the fraction of those stars that have planets
Ne = the average number of planets that can potentially support life per star that has planets
Fl = the fraction of planets that could support life that actually develop life at some point
?
Computational science: https://en.wikipedia.org/wiki/Computational_science
Computational biology: https://en.wikipedia.org/wiki/Computational_biology
Computational thinking: https://en.wikipedia.org/wiki/Computational_thinking :
> The characteristics that define computational thinking are decomposition, pattern recognition / data representation, generalization/abstraction, and algorithms.
Additional skills useful for STEM fields: system administration / DevOps / DevSecOps, HPC: High Performance Computing (distributed systems, distributed algorithms, performance optimization; rewriting code that is designed to test unknown things with tests and for performance), research a graph of linked resources and reproducibly publish in LaTeX and/or computational notebooks such as Jupyter notebooks, dask-labextension, open source tool development (& sustainable funding) that lasts beyond one grant
But unless I misread, it does not say how many tries were made by the machine to find these 50 biotic ones.
Was it 100 000? 1 million? 1 billion?
The answer to that question gives clue as to the rarity of life as it exists now, in the Universe, and the rarity of chances that it exists, and add food for thought in the debate happening down here about the existence of an intelligence behind that.
https://en.wikipedia.org/wiki/Miller%E2%80%93Urey_experiment details the results for these and other analogue experiments.
The role of phosphate anhydride derivatives (like ATP nowadays) in performing condensation reactions must have been initially fulfilled by sulfur compounds (thioesters & disulfides, probably just pyrite at the earliest time).
The role of phospholipids in membranes must have been fulfilled by some simpler molecules combining hydrophobic with hydrophilic parts, maybe just free fatty acids in the beginning. The first membranes must have been much more permeable than the membranes used by the last common ancestor so either shorter free fatty acids or some simpler ester or ether of shorter fatty acids should have been enough for them.
DNA sequences, which are single molecules, are off the charts compared to the non organic molecules
it is like the game of life. randomly setting pixels generates nothing more complex than fragile gliders, simple cyclers and stable states. the complexity originally in the random distribution quickly devolves to ash
we only get stable enormous complexity with human designs, such as the game of life in the game of life
why should the chemical world be any different?