Why the first protocell is harder than you think

[MarkE]

This discussion builds on a recent thread on Damer and Deamer's OoL model [1]. They propose hydrothermal fields in which molecular systems are driven far from equilibrium by cycles of hydration and dehydration, with encapsulation and combinatorial selection in a hydrated phase.

Scenarios involving wetting/drying are not new, nor is this particular model presumed to be correct. However, I think it does highlight key issues that any model will need to address:

1. Chemical SELECTION before chemical EVOLUTION

This is an important distinction. D&D first envisage many different polymers developing independently in parallel. These are then enfolded in membranes during the hydration cycle. Some successfully contribute to membrane structural integrity, and are therefore returned to the laminar structure in the dehydration phase. Thus, they are SELECTED by virtue of being recycled (the others are diffused and lost), but individually they are not replicating, and therefore chemical EVOLUTION is not yet occurring.

Chemical evolution prior to a functioning protocell has been postulated, e.g. a naked molecular replicator, or autocatalytic set/hypercycle of replicators. There are major problems with this, such as the ability to sustainably generate polymers of increasing size and fidelity. Another barrier with this pathway is whatever polymers develop, they are selected for their superior replication in this context, which is essentially unrelated to the integrated functionality required when they are subsequently enclosed in a protocell membrane. It’s like the fastest 100m sprinters being selected...for the debating team.

2. Chemical EVOLUTION

In the course of the chemical selection described above, D&D then imagine the chance coming together and integration of several different polymers to create “minimally viable sets of functional polymers” in the first protocell. Each of these polymers is labelled with a letter as follows [2]:

S - stabilizing factors for membrane integrity
P - pore forming for controlled nutrient and waste transfer
M - metabolism, capable of catalyzing growth
F - controlled by feedback networks
R - self-replication
D - division, e.g. a primitive FtsZ protein that forms a contractile ring for cell division

The transition to “life” as they define it occurs thus: "This system triggers a polymer mechanism D that can duplicate minimally viable sets of these polymers and deliver them by division into daughter cells. If these daughter cells contain fully functional polymer systems and are able to grow and divide again, they form the first lines of living cells."

If the average polymer length is say 50 units, that is 300 units assembled BEFORE replication and Darwinian evolution starts. The chance formation and functional interworking of that many units is a huge hurdle.

Of course, this a speculative and simplistic model, but it gives a fair representation of what must occur, regardless of the specific pathway.

3. PROTEINS are off the menu

“In summary, the above scenario steps beyond serial approaches to the origin of life sometimes characterized as “metabolism first” or “genetics first” by proposing a complex mixture in which both metabolic and genetic functions coemerge within a cycling, lipid-encapsulated polymolecular system (Lazcano, 2010).” [2]

The problem is, long before a ribosome, how is sustained high-fidelity replication of long amino acid chains possible?

The problem is, the proteins vastly greater catalytic function than RNA.

The problem is, what polymer except RNA could satisfy D&D’s model, or any other model which seriously grapples with realistic protocell formation?

3. The OoL field has NOT addressed this (James Tour has a point, despite the shouting)

“[OoL research has] been mainly focused on individual solution chemistry experiments where they want to show polymerization over here, or they want to show metabolism over here, and Dave and I believe that it's time for the field to go from incremental progress to substantial progress. So, these are the four points we've come up with to make substantial progress in the origin of life, and the first one is to employ something called system chemistry, having sufficient complexity so instead of one experiment say about proteins, now you have an experiment about the encapsulation of proteins for example, and informational molecules built from nucleotides in an environment that would say be like an analog of the early Earth, build a complex experiment. Something we're calling sufficient complexity, and all of these experiments have to move the reactions away from equilibrium. And what do we mean by that? Well, in in your high school chemistry experiments, something starts foaming something changes color and then the experiment winds down and stops. Well, life didn't get started that way. Life got started by a continuous run-up of complexity and building upon in a sense nature as a ratchet. So we have to figure out how to build experiments that move will move away from equilibrium…” [3]

4. Show me the money

“You can't sit in a laboratory just using glassware. You have to go to the field. You have to go to hot springs, you have to go to […] Iceland and come check and sit down and see what the natural environment is like, rather than being in the ethereal world of pure reactants and things like that…” [3] @ 6:31

Where are the demonstrations of this? Where is anything like the formation of a minimally viable protocell being addressed wholistically and experimentally shown as D&D call for? And I mean much more than say Jack Szostak's limited focus [4].

Prediction: the naïve hopes of “life in the lab” in the next 5 years, 20 years or 50 years will fade into silence. The OoL gap will be shown to grow into a gulf over time. D&D’s work points to its magnitude.

-------

[1] “Excellent presentation by Bruce Damer and Dave Deamer”
https://groups.google.com/g/talk.origins/c/HMw_ZoXIIOc/m/GhDNtzHcAAAJ

[2] The Hot Spring Hypothesis for an Origin of Life
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133448/#s009title

[3] “A new model for the origin of life: A new model for the origin of life: Coupled phases and combinatorial selection in fluctuating hydrothermal pools.”
https://youtu.be/nk_R55O24t4?feature=shared [4:29]

[4] Protocells and RNA Self-Replication
https://pubmed.ncbi.nlm.nih.gov/30181195/

[erik simpson]

There is solid evidence
https://www.nature.com/articles/s41467-023-42924-w that the LUCA (Last
universal common ancestor) appeared with the first few 100 My (perhaps
as few as ~100 My) after the creation of the moon (4.52 Gya). It took
much longer to get to the first photosynthetic prokaryotes. I'd be
willing to bet $100 that a plausible chemical path to self-replicating
autocatalytic progenators of life will be discovered in the next decade.
Apart from time machines, we'll never know for sure because it
happened so long ago and were eaten shortly thereafter.

[jillery]

Pseudoskeptics like MarkE tend to rely on flexible definitions of
"plausible", in the sense that what they claim is plausible for their
preferred hypothesis, they claim is not at all plausible for opposing
hypothesis, ex. Kalaam Cosmological Argument.

--
To know less than we don't know is the nature of most knowledge

[MarkE]

Wager accepted ;)

The reference you give supports my point, in that it _assumes_ abiogenesis, and instead talks about "early cellular evolution".

My point is, abiogenesis is hugely problematic and progress in the field is actually alarmingly limited, despite widespread perceptions to the contrary:

Statement by D&D: "Dave and I believe that it's time for the field to go from incremental progress to substantial progress."

Decoded version: "Dave and I believe that it's time for the field to go from alarmingly limited progress to actually propose and experimentally demonstrate a pre-biotically plausible holistic scenario for the formation of a viable protocell."

That's what they have proposed, and they have even developed lab equipment to automate the wetting/drying cycles of thermal strings to follow through on their urging of empirical verification. Good on them. But what you will not see is anything of substance after that. In fact, the D&D references I cited were from 2015 and 2018, so the lack of results is already steadily progressing.

[Öö Tiib]

On Tuesday 19 December 2023 at 01:32:13 UTC+2, MarkE wrote:
> This discussion builds on a recent thread on Damer and Deamer's OoL model [1]. They propose hydrothermal fields in which molecular systems are driven far from equilibrium by cycles of hydration and dehydration, with encapsulation and combinatorial selection in a hydrated phase.
>
> Scenarios involving wetting/drying are not new, nor is this particular model presumed to be correct. However, I think it does highlight key issues that any model will need to address:
>
> 1. Chemical SELECTION before chemical EVOLUTION
>
> This is an important distinction. D&D first envisage many different polymers developing independently in parallel. These are then enfolded in membranes during the hydration cycle. Some successfully contribute to membrane structural integrity, and are therefore returned to the laminar structure in the dehydration phase. Thus, they are SELECTED by virtue of being recycled (the others are diffused and lost), but individually they are not replicating, and therefore chemical EVOLUTION is not yet occurring.
>
> Chemical evolution prior to a functioning protocell has been postulated, e.g. a naked molecular replicator, or autocatalytic set/hypercycle of replicators. There are major problems with this, such as the ability to sustainably generate polymers of increasing size and fidelity. Another barrier with this pathway is whatever polymers develop, they are selected for their superior replication in this context, which is essentially unrelated to the integrated functionality required when they are subsequently enclosed in a protocell membrane. It’s like the fastest 100m sprinters being selected...for the debating team.
>
> 2. Chemical EVOLUTION
>
> In the course of the chemical selection described above, D&D then imagine the chance coming together and integration of several different polymers to create “minimally viable sets of functional polymers” in the first protocell. Each of these polymers is labelled with a letter as follows [2]:
>
> S - stabilizing factors for membrane integrity
> P - pore forming for controlled nutrient and waste transfer
> M - metabolism, capable of catalyzing growth
> F - controlled by feedback networks
> R - self-replication
> D - division, e.g. a primitive FtsZ protein that forms a contractile ring for cell division
>
> The transition to “life” as they define it occurs thus: "This system triggers a polymer mechanism D that can duplicate minimally viable sets of these polymers and deliver them by division into daughter cells. If these daughter cells contain fully functional polymer systems and are able to grow and divide again, they form the first lines of living cells."
>
> If the average polymer length is say 50 units, that is 300 units assembled BEFORE replication and Darwinian evolution starts. The chance formation and functional interworking of that many units is a huge hurdle.
>
> Of course, this a speculative and simplistic model, but it gives a fair representation of what must occur, regardless of the specific pathway.
>
> 3. PROTEINS are off the menu
>
> “In summary, the above scenario steps beyond serial approaches to the origin of life sometimes characterized as “metabolism first” or “genetics first” by proposing a complex mixture in which both metabolic and genetic functions coemerge within a cycling, lipid-encapsulated polymolecular system (Lazcano, 2010).” [2]
>
> The problem is, long before a ribosome, how is sustained high-fidelity replication of long amino acid chains possible?
>
> The problem is, the proteins vastly greater catalytic function than RNA.
>
> The problem is, what polymer except RNA could satisfy D&D’s model, or any other model which seriously grapples with realistic protocell formation?
>
> 3. The OoL field has NOT addressed this (James Tour has a point, despite the shouting)
>
> “[OoL research has] been mainly focused on individual solution chemistry experiments where they want to show polymerization over here, or they want to show metabolism over here, and Dave and I believe that it's time for the field to go from incremental progress to substantial progress. So, these are the four points we've come up with to make substantial progress in the origin of life, and the first one is to employ something called system chemistry, having sufficient complexity so instead of one experiment say about proteins, now you have an experiment about the encapsulation of proteins for example, and informational molecules built from nucleotides in an environment that would say be like an analog of the early Earth, build a complex experiment. Something we're calling sufficient complexity, and all of these experiments have to move the reactions away from equilibrium.
>

So what? They will find some interesting polymerisation here, catalysis there
and energy efficient chemical process in third place. So the result is knowledge.
If full path of abiogenesis can be composed of such pieces is of secondary
value.
The naïveté of Intelligent Design is even more astounding. They "search" God in
Big Bang and Origins of Life by expressing doubt about other scientist findings.

>And what do we mean by that? Well, in in your high school chemistry experiments, something starts foaming something changes color and then the experiment winds down and stops. Well, life didn't get started that way. Life got started by a continuous run-up of complexity and building upon in a sense nature as a ratchet. So we have to figure out how to build experiments that move will move away from equilibrium…” [3]
>

No one knows in what way life did start. Gibberish "by a continuous run-up of
complexity and building upon in a sense nature as a ratchet"? Life got started
by bork-bork-bork.

> 4. Show me the money
>
> “You can't sit in a laboratory just using glassware. You have to go to the field. You have to go to hot springs, you have to go to […] Iceland and come check and sit down and see what the natural environment is like, rather than being in the ethereal world of pure reactants and things like that…” [3] @ 6:31
>
> Where are the demonstrations of this? Where is anything like the formation of a minimally viable protocell being addressed wholistically and experimentally shown as D&D call for? And I mean much more than say Jack Szostak's limited focus [4].
>

Intelligent Design search God in events from billions of years ago about
what the evidence is very few and inconclusive. We can not yet tell if whole
universe started with Big Bang or only part of it and we can not tell if life was
originated on Earth or elsewhere. Finding evidences how and to what level
God was involved is clearly out of question about so partially and indirectly
known events.

> Prediction: the naïve hopes of “life in the lab” in the next 5 years, 20 years or 50 years will fade into silence. The OoL gap will be shown to grow into a gulf over time. D&D’s work points to its magnitude.
>

Careful, false prophesy is several times mentioned as characteristic of
wolves in sheep clothes; IIRC both in old and new testament.
Intelligent Design is "studying" things that they clearly can't study, while the
people involved do not look like utterly stupid. Something is weird there. Is it
excuse for not to look where one can actually find? Is it to discredit religion,
to fool believers? Also they fail too noisily, they have none positive fruits.
Caught on copy-pasta like "cdesign proponentists"? So awful and shameful.
God might be is within reach right now and here, but not to them.

[MarkE]

Pier Luigi Luisi (agreeing with me):

The real problem is, I would say, in our mind and intelligence, in the lack of capability to conceive in real chemistry how the passage from nonlife to life arose. The fact that we have several perspectives in competition means that none of them is really convincing. Not at all convincing to me is, for example, the RNA world, a perspective I find full of conceptual flaws, at least in the doc version. This is the theory by which self-replicating RNA (sr-RNA) arose by itself, began to self-reproduce more or less indefinitely until it evolved -- one wonders why -- into ribozymes, capable then to catalyze the synthesis of nucleic acid and proteins.

Nobody in the field has answered the preliminary question, where the sr-RNA came from. And, even if we find one such sr-RNA, there are lots of chemistry constraints: for example, you cannot make self-replication with one single molecule. You need at least a binary complex to start replication, with a concentration to overwhelm the dissociation forces.

Simple calculations show that you need at least 10-12 M of the replicator, our RNA, to start with. This is a lot, in terms of the number of molecules in one liter, or in one microliter. So, you need a metabolism to make RNA, even before you start scheming with the RNA world.

And even granted that, the story of sr-RNA evolving into ribozymes is also a chemical non-sense. Let us suppose, to start with 1 μM solution of the sr-RNA having 50,000 Dalton, replicating nonlinearly (2, 4, 8, 16. . .) in a small 100 l warm pond for, say, 20 generations. You would end up with 1 M solution, and for that you would need 50 tons of nucleotides -- clearly unrealistic. And finally the ribozyme would possibly couple the peptide bond, but so what?

The real problem is to make ordered sequences of amino acids, and of course ordered sequences of nucleic acids -- and on that the prebiotic RNA world is absolutely silent. But this view of the prebiotic RNA world is still the most popular. I think it is a case of social science psychology more than science itself.

(Quoted from the book by Suzan Mazur: The Origin of Life Circus: A How To Make Life Extravaganza. 2014. Kindle Edition.)

[Ernest Major]

On 18/12/2023 23:28, MarkE wrote:
> Prediction: the naïve hopes of “life in the lab” in the next 5 years, 20
> years or 50 years will fade into silence. The OoL gap will be shown to
> grow into a gulf over time. D&D’s work points to its magnitude.

On the one hand, I think that we are more or less in sight of "life in
the lab" (in the form of directed abiogenesis), though I don't expect
that it would shed much if any light on spontaneous abiogenesis.

On the other hand, not every natural process can be replicated in a lab.
You can't create a star in a lab. I find it quite plausible that
spontaneous abiogenesis requires volumes and timescales that are
impracticable in a laboratory setting. The question of interest is
whether there's a form of directed abiogenesis which is closer in
process to spontaneous abiogenesis.

--
alias Ernest Major

[erik simpson]

I think you misunderstand the purpose article (which isn't easy
reading). The purpose of the study is to identify the most highly
conserved bacterial genes that must have been present in the LUCA.
Frosting on the cake is provided by calibration, giving an estimate of
the date for LUCA. Even this date is more recent than that of LUCA's
ancestors, of which we know little. we also know little of what
conditions were present when these stages of evolution took place.

You list several of the attempts to find the chemical steps it took, and
it may turn out that one of these may strike gold and I win the bet (I
will decline payment). The point I'm trying to make is that whatever
happened did it very soon after the earth was sterilized by the
formation of the moon (4.52 Gya). It happened between 100-400 Mya, while
it took ~2 Gy to arrive at bacterial photosynthesis. Eukaryotes took
~1 Gy, modern multicellular life another Gy. Then it got lots easier,
only the last 630 My. Abiogenesis is easier than anything else.

I hope I live to see the (partial) answer. I'm reasonably confident of
the next ten years, hence the conditions of the bet. If it doesn't
happen, let me know by Christmas 2034, and I'll pay up. It probably
won't be worth more than a dime by then.

[MarkE]

On Wednesday, December 20, 2023 at 12:22:13 AM UTC+11, Ernest Major wrote:
> On 18/12/2023 23:28, MarkE wrote:
> > Prediction: the naïve hopes of “life in the lab” in the next 5 years, 20
> > years or 50 years will fade into silence. The OoL gap will be shown to
> > grow into a gulf over time. D&D’s work points to its magnitude.
> On the one hand, I think that we are more or less in sight of "life in
> the lab" (in the form of directed abiogenesis), though I don't expect
> that it would shed much if any light on spontaneous abiogenesis.

Do you mean something like Craig Venter synthesising DNA (by copying the genome of strains of M. mycoides) and inserting it into a cell that has had its DNA removed? This seems to be a demonstration of DNA synthesis (impressive), as well as the need for a complete cell sans DNA to "create life". That's a top-down approach, related to the search for a minimally viable cell, e.g. Venter again: https://www.science.org/content/blog-post/smallest-viable-genome-very-weird

These examples highlight the gulf between any plausible protocell formed before Darwinian evolution starts and a viable self-replicating free-living entity.

> On the other hand, not every natural process can be replicated in a lab.
> You can't create a star in a lab. I find it quite plausible that
> spontaneous abiogenesis requires volumes and timescales that are
> impracticable in a laboratory setting. The question of interest is
> whether there's a form of directed abiogenesis which is closer in
> process to spontaneous abiogenesis.

Fair point to a degree I think. The task is to conceive of a holistic scenario, and selectively experimentally demonstrate key steps. D&D propose going to hydrothermal pools using them as your lab, which amplifies available volume. The millions of years of time nature provides can be approximated in the lab by setting up special by plausible once-in-a-million-years conditions. It's a tricky business though.

If concerted efforts along these lines yield no substantial results, it would give us a measure of the difficulty of the spontaneous formation of life.

It seems to me that the naturalistic formation of life requires a process of exponentially increasing difficulty. You can abiotically create some amino acids and even nucleotides, but putting them together is X times harder, and then integrating even simple polymers into a functional system is a whole other level of difficulty. Miller-Urey was a false dawn. If concentrated, activated, sufficiently pure, homochiral prebiotic amino acids and nucleotides are a Moon landing, then synthesizing meaningful polymers is a manned flight to Mars, and a protocell is a visit to Alpha Centauri.

>
> --
> alias Ernest Major

[MarkE]

:)

You are still assuming abiogenesis and evolution, and then interpreting the data through this lens. Which I get.

Against this mainstream approach, I'm taking the admittedly contentious position of seriously questioning both of these. This questioning says don't assume, instead develop a plausible holistic scenario to go from prebiotic chemistry to a viable self-replicating free-living protocell, and demonstrate the key steps in this experimentally. My claim is we are nowhere near doing this.